Whole Brain Radiotherapy Research Articles

QOL-11. LATE MORBIDITY AND MORTALITY IN SURVIVORS OF CHILDHOOD EPENDYMOMA: A REPORT FROM THE CHILDHOOD CANCER SURVIVOR STUDY (CCSS)

Abstract BACKGROUND Between the 1970s and 1990s, therapy for childhood ependymoma evolved to include chemotherapy and focal rather than whole-brain radiation. The impact of these changes on health outcomes is unknown. METHODS 404 five-year survivors of ependymoma (52.5% male, median 6 [range 0-20] years old at diagnosis, 22 [5-49] years from diagnosis) were evaluated for cumulative incidence of late mortality, subsequent neoplasms, and chronic health conditions (CHC). Outcomes were analyzed by diagnosis decade and brain radiation and chemotherapy exposures. Fine-Gray’s test compared cumulative incidence curves. Relative Risks (RRs) with 95% CIs estimated outcomes using multivariable piecewise exponential models. RESULTS Throughout the three decades whole brain radiation exposure decreased (32.7% to 2.3%) while focal brain radiation increased (16.4% to 59.2%), and chemotherapy use increased (23.6% to 47.9%). Fifteen-year all-cause late mortality (incidence, 95% CI) estimates were similar across treatment eras: 1970s (9.3%, 3.4-18.8%), 1980s (14.7%, 9.4-21.2%), 1990s (10.3%, 6.7-14.9%), (p=0.9). Mortality was higher with whole brain radiation (22.5%, 11.2-36.5%) compared to focal radiation (11.4%, 7.5-16.1%) or no brain radiation (3.5%, 0.9-9.1%), (p <0.001). Mortality was also higher with chemotherapy (14.4%, 9.6-20.0%) compared to no chemotherapy (6.8%, 3.8-11.0%) (p=0.004). Differences in mortality were due to recurrence/progression of the primary cancer and health-related causes. Compared to no brain radiation, there were increased risks (RR, 95% CI) of any grade 3-4 CHCs for focal (2.6, 1.3-5.4) and whole brain radiation (3.5, 1.5-8.1) and >1 Grade 3-4 CHCs for whole brain radiation (6.5, 1.3-31.6). There were no differences in CHCs or subsequent neoplasms by chemotherapy exposure. CONCLUSIONS Despite the treatment changes over the 1970s to 1990s, late morbidity and mortality in pediatric ependymoma remained unchanged. Whole and focal brain radiation were associated with increased risk of grade 3-4 CHCs compared to no radiation. Future therapies for childhood ependymoma should target reductions in late morbidity and mortality.

RADT-10. LITHIUM TREATMENT PROTECTS MICROGLIA AND NEWLY GENERATED NEURONAL POPULATIONS IN A MOUSE MODEL OF CRANIAL RADIOTHERAPY

Abstract BACKGROUND Radiotherapy remains a cornerstone of the treatment of high-grade brain tumors. However, while lifesaving, it results in long-term complications in 50-96 % of the treated individuals, where cognitive deficits are particularly debilitating. Currently, no treatments or preventive strategies are available to avert these deficits. Lithium (Li), long used to treat bipolar affective disorder, has been shown to reduce radiation-induced cognitive deficits in rodent models by preventing apoptosis of the neuronal stem and progenitor cells in the hippocampus and stimulating their proliferation. This work aimed to further elucidate the mechanisms behind the protective and pro-regenerative actions of Li in the irradiated young brain. METHODS Postnatal day (PD) 21, C57BL6/J mice were injected intraperitoneally with Li chloride (4 mmol/kg) and kept on a Li carbonate-containing diet for 4 weeks. Control animals were injected with saline and administered an equivalent control diet. On PD 25, the animals were administered a single-dose whole-brain radiation of 8 Gy and were subsequently sacrificed at different time points, spanning from 2 weeks to 1 year. At sacrifice, the hippocampi were harvested for single-cell RNA sequencing using a novel, 2-step protocol to harvest viable cells of all types, including neurons. RESULTS The results showed that radiation triggered the expression of senescence-related genes in the hippocampal microglia (e.g., Cdkn1a, Ccl12), which Li has prevented through the activation of the Bcl2 family of genes. Moreover, they corroborate the protective effect of Li on newly generated hippocampal neurons, which undergo remodeling over time, leading to the emergence of new subpopulations. CONCLUSIONS This work represents another advancement towards understanding the action of Li in the irradiated brain and confirms its potential to become the first pharmacological treatment for radiation-induced complications.

GCT-16. LONG-TERM OUTCOMES AND COMPLICATION MANAGEMENT IN CNS GERM CELL TUMORS: INSIGHTS FROM A PHASE II HISTOPATHOLOGY-STRATIFIED TREATMENT TRIAL

Abstract BACKGROUND This detailed examination merges outcomes from a Phase II clinical trial targeting central nervous system (CNS) germ cell tumors (GCTs) conducted between 1995 and 2003. It evaluates the impact of histopathologically driven treatment modalities on survival, recurrence, and post-treatment life and social outcomes, aiming to delineate the long-term effects of such stratified treatment approaches. METHODS The cohort comprised 228 patients, stratified into three groups based on histology: germinoma (n=161), intermediate prognosis (n=38), and poor prognosis (n=28), each receiving customized chemotherapy and radiation treatments. With a median follow-up duration of 222 months, this longitudinal study scrutinized survival rates, recurrence patterns, and a spectrum of socio-economic and health-related outcomes. RESULTS For the germinoma group, the 10- and 20-year event-free survival (EFS) rates stood impressively at 82% and 73%, respectively, with overall survival (OS) rates reaching 97% and 92%. The intermediate prognosis group witnessed 10- and 20-year EFS rates of 76% and 66%, and OS rates of 87% and 70%. The poor prognosis group recorded EFS rates of 49% at both intervals, with OS diminishing to 61% and 53%. Notably, germinomas localized in the basal ganglia exhibited high relapse rates absent initial whole-brain radiation, yet were effectively managed upon subsequent interventions. The comprehensive follow-up illuminated striking disparities in socio-economic achievements: higher educational attainments, more stable employment, and improved health outcomes were predominantly observed among patients without recurrence. Non-recurrent germinoma patients, in particular, showcased enhanced educational and employment status, vividly illustrating the profound impact of disease progression and treatment on life quality. CONCLUSIONS The findings highlight the critical importance of customized initial treatments for improving survival and life quality in CNS GCT patients, stressing the need for detailed long-term follow-up to address relapses and complications effectively. The study advocates for personalized care that balances treatment intensity to optimize long-term outcomes, enhancing post-treatment care.

Neuroprotective effects of saxagliptin against radiation-induced cognitive impairment: Insights on Akt/CREB/SIRT1/BDNF signaling pathway

Radiation-induced cognitive impairment has recently fueled scientific interest with an increasing prevalence of cancer patients requiring whole brain irradiation (WBI) in their treatment algorithm. Saxagliptin (SAXA), a dipeptidyl peptidase-IV (DPP-IV) inhibitor, has exhibited competent neuroprotective effects against varied neurodegenerative disorders. Hence, this study aimed at examining the efficacy of SAXA in alleviating WBI-induced cognitive deficits. Male Sprague Dawley rats were distributed into control group, WBI group exposed to 20 Gy ϒ-radiation, SAXA group treated for three weeks with SAXA (10 mg/kg. orally, once daily), and WBI/SAXA group exposed to 20 Gy ϒ-radiation then treated with SAXA (10 mg/kg. orally, once daily). SAXA effectively reversed memory deterioration and motor dysfunction induced by 20 Gy WBI during behavioural tests and preserved normal histological architecture of the hippocampal tissues of irradiated rats. Mechanistically, SAXA inhibited WBI-induced hippocampal oxidative stress via decreasing lipid peroxidation while restoring catalase antioxidant activity. Moreover, SAXA abrogated radiation-induced hippocampal neuronal apoptosis through downregulating proapoptotic Bcl-2 Associated X-protein (Bax) and upregulating antiapoptotic B-cell lymphoma 2 (Bcl-2) expressions and eventually diminishing expression of cleaved caspase 3. Furthermore, SAXA boosted hippocampal neurogenesis by upregulating brain-derived neurotrophic factor (BDNF) expression. These valuable neuroprotective capabilities of SAXA were linked to activating protein kinase B (Akt), and cAMP-response element-binding protein (CREB) along with elevating the expression of sirtuin 1 (SIRT-1). SAXA successfully mitigated cognitive dysfunction triggered by WBI, attenuated oxidative injury, and neuronal apoptosis, and enhanced neurogenesis through switching on Akt/CREB/BDNF/SIRT-1 signaling axes. Such fruitful neurorestorative effects of SAXA provide an innovative therapeutic strategy for improving the cognitive capacity of cancer patients exposed to radiotherapy.

Efficacy and safety of EGFR-TKIs for non-small cell lung cancer: A meta-analysis of randomized controlled clinical trials.

We conducted this meta-analysis based on updated literature and research to compare the efficacy and safety of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) as treatments for patients with non-small cell lung cancer (NSCLC). A literature search was conducted using PubMed, Embase, Medline and Web of Science databases to perform a systematic literature search based on random control trials. In these articles, EGFR-TKIs were compared with placebos, chemotherapy, or whole-brain irradiation as treatments for NSCLC. In this research, a meta-analysis of the literature was performed to produce a combined risk ratio (RR) with a 95% confidence interval (CI) for progression-free survival (PFS), overall survival (OS), and adverse events. The data were synthesized with Review Manager 5.3 software, which was used to manage the process. There were 15 random control trials included in the study, involving 4249 patients in total. There was evidence that EGFR-TKIs can significantly prolong OS (RR: 0.87, 95% CI: 0.75-1) and PFS (RR: 0.75, 95% CI: 0.66-0.86) in NSCLC patients. There was an increase in the incidence of adverse events after treatment with EGFR-TKI, including diarrhea (RR: 0.18, 95% CI: 0.10-0.26), infection (RR: 0.09, 95% CI: 0.02-0.16), and rash (RR: 0.37, 95% CI: 0.22-0.51). It has been shown that EGFR-TKIs prolong OS and PFS in patients with NSCLC. NSCLC patients may benefit from EGFR-TKIs as an important treatment option in order to prolong their survival.

A Phase II Trial of Bevacizumab in Patients with Recurrent/Progressive Solid Tumor Brain Metastases That Have Progressed Following Whole-Brain Radiation Therapy.

Patients with solid tumor brain metastases that progress after whole-brain radiation have limited options. This prospective trial investigated the efficacy, safety, and tolerability of bevacizumab as salvage therapy in this population. Eligible patients received bevacizumab 10 mg/kg intravenously every 2 weeks until progression. The primary endpoint was radiologic response using Response Assessment in Neuro-Oncology (RANO) criteria. The secondary endpoints were progression-free survival (PFS), overall survival (OS), duration of response, and safety. Quality of life (QOL) was studied using the Functional Assessment of Cancer Therapy-Brain (FACT-Br) scale. Twenty-seven patients were enrolled, with twenty-four having evaluable data for response. The majority of histologies (n = 21, 78%) were breast cancer. The remaining histologies were non-small-cell lung cancer (n = 4, 15%), neuroendocrine cancer (n = 1, 3%), and papillary fallopian serous adenocarcinoma (n = 1, 3%). Eighteen patients had radiologic response, with two patients demonstrating partial response (8.33%) and sixteen patients demonstrating stable disease (66.7%). The median duration of response was 203 days. PFS at 6 months was 46%, median PFS was 5.3 m, and median OS was 9.5 m. Treatment was well tolerated, with six patients experiencing grade 3 lymphopenia and hypertension. There was one grade 3 thromboembolism. QOL was not negatively impacted. Bevacizumab is a safe and feasible salvage treatment with durable response and favorable overall survival for patients with progressive brain metastases after whole-brain radiation.

A phase II study of plerixafor combined with whole brain radiation therapy (WBRT) for patients with newly diagnosed glioblastoma.

2075 Background: Plerixafor inhibits the binding of stromal cell-derived factor 1 (SDF-1a / CXCL12) to its receptor on CD11b+ monocytes, inhibiting vasculogenesis and tumor recurrence in preclinical models. An early phase trial demonstrated that Plerixafor administration decreased cerebral blood volume (CBV) within the irradiated field of glioblastoma patients, and that the majority of recurrences occurred outside of the irradiated field (Thomas R. et al, Clin Cancer Res). This follow up study investigates the efficacy of Plerixafor in combination with WBRT, with the hypothesis that widening the radiation therapy (RT) field with WBRT may reduce out-of-field tumor recurrence and improve survival. Methods: This was a Phase II, open-label, non-randomized, single-arm trial.Adults between 18-75 years old with newly diagnosed high grade glioma as defined by WHO 2016 criteria and KPS ≥ 60 were eligible for enrollment. Patients underwent maximal safe resection followed by 6 weeks of concurrent radiation therapy and temozolomide (TMZ). Of note, modifications to the conventional treatment paradigm included completing 30 Gy of standard intensity-modulated RT followed by 30 Gy of WBRT, as well as completing a 4-week continuous infusion of Plerixafor dosed at 400 µg/kg/day. Patients then started adjuvant TMZ after completing Plerixafor. Primary endpoint was 6-month progression free survival (PFS6) after chemoradiation. Secondary endpoints included median overall survival (mOS), adverse events (AEs), MRI-based patterns of recurrence, and neurocognitive outcomes measured by the Trail Making Test, Controlled Oral Word Association Test, and the Hopkins Verbal Learning Test. Additionally, maximum arterial spin labeling-cerebral blood flow (ASL-CBF) values of primary lesions were compared over various time points during the study. Results: 14 of 17 enrolled patients completed the Plerixafor infusion, and all 17 patients completed WBRT. Median age was 57 years. 15 patients (88.2%) were IDH wildtype and 13 patients (76.5%) were pMGMT unmethylated. 13 patients (76.5%) underwent gross total resection, 2 (11.8%) underwent subtotal resection, and 2 (11.8%) underwent biopsy only. The PFS6 was 91.7%. The mOS was 15.11 months. 3 patients discontinued Plerixafor early due to rash (n=1), rising creatinine (n=1), or worsening confusion and agitation (n=1). Common Gr2 treatment-related AEs included alopecia (n=4), nausea (n=4), and vomiting (n=2). 1 patient had Gr3 alopecia. There were no Grade 4/5 AEs. 80% of patients scored worse on their neurocognitive assessments at 6 months compared to screening. ASL-CBF values of primary lesions appeared relatively stable throughout the study. Conclusions: The combination of Plerixafor and WBRT did not improve mOS compared to the original study using focused RT only. There was an overall decline in neurocognitive performance over the course of the study. Clinical trial information: NCT03746080 .

Stereotactic radiosurgery in patients with small cell lung cancer and 1-10 brain metastases: A multi-institutional, phase II, prospective clinical trial.

2020 Background: Stereotactic radiosurgery (SRS) as opposed to whole brain radiation (WBRT) represents the standard of care for patients with a limited number of brain metastases. Brain metastases from small cell lung cancer (SCLC), however, represent an exception to this dogma, given that prior trials evaluating SRS in lieu of WBRT excluded patients with SCLC due to the historical role of prophylactic cranial irradiation (PCI) and concerns relating to neurologic decline and death when WBRT is omitted from upfront management. We conducted a prospective, multi-center, phase II trial of SRS in patients with SCLC and 1-10 brain metastases to determine how rates of neurologic death compared to historical controls managed with WBRT. Methods: Following approval from the Dana-Farber/Harvard Cancer Center IRB, we opened a single-arm, multi-center, phase II trial to investigate SRS in patients with SCLC and 1-10 brain metastases naïve to prior brain-directed radiation including PCI (NCT03391362). Prior resection of a brain metastasis was permitted. Patients with leptomeningeal disease were excluded. Metastases <2cm in maximal size were generally managed with SRS to 20 Gy; larger tumors, or those near sensitive structures, were dose reduced to 16-19 Gy or managed with fractioned SRS (SRT) to 30 Gy in 5 fractions. Gross totally resected brain metastases received SRT to 25 Gy in 5 fractions. We sought to determine, as the primary endpoint, whether or not use of SRS in lieu of WBRT would lead to meaningfully higher rates of neurologic death (HR 1.61, corresponding to a 1-year event rate of 26.7% relative to a historical 1-year rate of 17.5% in patients previously managed with WBRT at our center), with 90% power and a one-sided alpha error of 5%. Neurologic death was defined as marked, progressive, radiographic brain progression accompanied by corresponding neurologic symptomatology without systemic disease progression / systemic symptoms of a life-threatening nature and was assessed by a panel of 2-3 neuro-radiation oncologists. Results: Between 3/2018 – 4/2023, 100 patients were enrolled across 4 centers. The median age was 68 years (IQR 63 – 74 years). The median number of brain metastases was 2 (IQR 1 – 3); 16 (16%) of patients underwent prior neurosurgical resection. On study, 66 (66%) patients were treated with SRS alone while 32 (32%) were treated with SRT to at least 1 site; 2 patients died of systemic disease progression before study treatment. The median overall survival was 10.3 months. In total, 19 neurologic deaths were observed, relative to 62 systemic deaths. The neurologic death rate at 1 year was 11.0% (95% CI 4.8% – 17.2%). Conclusions: Our prospective, multi-institutional study demonstrated modest rates of neurologic death when SRS as opposed to WBRT is used in patients with SCLC and 1-10 brain metastases and represents the largest prospective experience to date. Clinical trial information: NCT03391362 .

Prognostic factors for patients with sarcoma with brain metastases.

e23542 Background: Sarcomas arise in mesenchymal tissue occurring anywhere in the body with a propensity to metastasize often to the lung, liver, and bones. The brain is a rare site of metastasis with increasing incidences found in those relapsing after prolonged disease control with treatment. Brain metastases development has been associated with dismal prognoses, and more data is necessary to assess factors for improved outcomes of patients. Methods: The retrospective cohort includes 81 patients diagnosed with sarcomas metastasizing to the brain treated at five sarcoma centers between 1/1998 and 12/2021. Demographic data, characteristics and presentation of brain metastases, and treatment modalities for malignancy were identified and analyzed. Results: In total, there were 45 men and 36 women with the mean age of diagnosis being 43 years. Upon presentation, 89% of patients were symptomatic with the most common presenting symptom being focal neurological deficits (37.9%) and headaches (22.1%). At the time of analysis, 58 patients (71.6%) had died of metastatic sarcoma, 16 patients (19.8%) were alive with disease, and 3 patients (3.7%) were alive without evidence of disease. The most frequent histologies were leiomyosarcoma (12.3%) and undifferentiated pleomorphic sarcoma (12.3%). In 70.4% of patients, the tumor also had metastasized to the lung. Median time from sarcoma diagnosis to brain metastases was 1.9 years (range: 0-34.6 yrs). Median time from diagnosis of brain metastases until death was 6 months (range: 0.5-330 mo). Treatment modalities of brain metastasis varied widely with 18 patients (22.2%) undergoing whole brain radiation therapy (WBRT), 11 (13.6%) undergoing systemic chemotherapy and WBRT, and 10 (12.3%) undergoing combined surgery, systemic chemotherapy, and stereotactic radiosurgery. In multivariate analysis, the variables identified as statistically significant for predicting improved survival outcomes included surgery (HR 0.30) and chemotherapy (HR 0.24), but not radiation therapy. In patients undergoing surgery or chemotherapy, the median survival time after brain metastasis diagnosis was markedly improved, with 13.9 months and 12 months respectively versus the overall patient median of 6 months. In patients undergoing radiation therapy, there was significantly improved survival with stereotactic radiosurgery (SRS, mOS 11.6mo) as opposed to whole brain radiation therapy (WBRT, mOS 8.3mo) probably due to decreased mean number of brain metastases found in those necessitating SRS (3.2) compared to WBRT (5.7). Conclusions: Together, our findings identify that patients with metastatic sarcoma to the brain have poor prognoses, often have concurrent metastasis, and have median survival of only 6 months. However, there were significantly improved outcomes with interventions such as surgery, chemotherapy, or SRS, suggesting that aggressive treatments are warranted despite the overall poor prognosis.

Outcomes of R-MPV followed by ara-c in primary central nervous system lymphoma: A single-center retrospective analysis.

e19046 Background: Primary central nervous system lymphoma (PCNSL) lymphoma is a rare non-Hodgkin’s Lymphoma. Currently, there is no uniform consensus in the optimal management of PCNSL. In patients that can tolerate systemic therapy, induction therapy is typically done with a high-dose methotrexate-based regimen, due to evidence of better penetration of the blood brain barrier. One such regimens is high dose methotrexate combined with rituximab, procarbazine, and vincristine (R-MPV). Options for consolidation therapy include high-dose systemic therapy with stem cell rescue (ASCT), whole brain radio therapy (WBRT) and high-dose cytarabine (ara-c) with or without etoposide (EA). At our institution we utilize an R-MPV induction approach with some form of ara-c consolidation without etoposide. We aimed to execute a retrospective cohort study to analyze outcomes of this approach. Methods: All the patients diagnosed with PCNSL who received an induction regimen of R-MPV from 10/01/2020 to 06/01/2023 were included. Data was then gathered by chart review of the electronic medical record. Treatment outcomes were evaluated based on imaging with brain MRIs and PET scans. Central findings such as complete response (CR) rate, progression free survival (PFS) and overall survival (OS) were ascertained. Results: 10 charts were reviewed. 9 out of the 10 patients had a histological presentation consistent with diffuse large B-cell lymphoma; 1 patient had a diagnosis of B-cell lymphoma. In terms of demographics, the patients ages ranged from 54 to 83 years, with a median of 74 years. Complete response was achieved in 5 out of the 10 patients (CR rate of 50%), and no relapse was noted in any of these patients. 2 out of the 10 patients progressed on treatment, with 1 dying from progression of the disease. The median follow-up for patients who were still alive was 24 months. 2-year PFS was 80%, and 2-year OS was 90%. Median PFS and OS were not reached. Mean PFS and OS were 28 months and 30.5 months respectively. Conclusions: Based on our study results, the CR rate we observed for R-MPV appears consistent with existing literature on this regimen and other methotrexate-based induction regimens. Our results for R-MPV with ara-c consolidation provides similar outcomes to existing studies on treatment with different methotrexate-based induction and consolidation with ASCT, particularly the 80% PFS we observed. This percent PFS also appears similar to studies of consolidation with ara-c and EA, and superior to PFS with WBRT. Overall, these results are reassuring as in a specific set of older patients who might not be candidates for ASCT, our specific nonmyeloablative approach could be worthwhile. However, our study does have the limitation of being a single center retrospective perspective. [Table: see text]

Predictors of time to brain metastasis and survival in patients diagnosed with breast cancer.

e13122 Background: Patients with breast cancer (BC) who develop brain metastases (BM) have poor survival outcomes. We aimed to identify significant predictors of time to develop BM and survival after diagnosis. Methods: Patient records were retrospectively reviewed from the Cleveland Clinic database between 2010-2020. Patients with a BC and a BM diagnosis were included for analysis. One way ANOVA was used to compare mean time to BM across subgroups (mean ± SE), and Kaplan-Meier method was used to compute median overall survival (mOS) after BM diagnosis (95% CI). Results: N=109 patients were included in the analysis with a mean age of 52 ± 13 years, mean time to developing BM of 42 ± 35 months, and mOS after BM of 12.00 months (8.99-15.01). The patients’ characteristics were as follows: female (98.2%), white (83.5%), married (56%), privately insured (43.1%), had a Karnofsky Performance Status (KPS) >80 (61.7%), and 21% had stage IV at initial diagnosis. In terms of BC characteristics, 80.4% of cases were ductal, 63.7% were Grade III, 52.3% were HR+, and 31.5% were HER2+, and 32.4% were triple negative. Most patients had extracranial metastases (ECM) at the time of BM diagnosis (67.8%), had at least 2 sites of BM (71.6%), parenchymal only BM (75%), and 10-30 mm BM (44.2%). 15.8% of patients underwent craniotomy and 86.2% received at least one form of radiotherapy (RT) for BM. The HR+/HER2- group had the longest time to BM compared to the shortest in the triple negative group (61.29 ± 6.95 vs 28.59 months ± 4.80, p<0.001). Patients receiving hormonal therapy had longer time to BM compared to those who didn’t (50.83 ± 5.04 vs 35.98 ± 4.67 months, p=0.034). Patients with Stage I disease had the longest time to develop BM (68.50 ± 13.66 months, p=0.009), while grade III status had the shortest time to BM (34.46 ± 3.46 months, p=0.002). Uninsured patients had the shortest time to BM (22.92 ± 4.09 months, p=0.003). After BM diagnosis, the HR+/HER2+ group achieved the best mOS at 35.00 months (14.20-55.80, p=0.040). Patients receiving Gamma Knife Radiosurgery (GKRS) achieved longer mOS than the other RT modalities at 30.00 months (11.46-48.51) vs 20.00 (1.26-38.74) in GKRS + Whole Brain RT (WBRT), 9.00 (3.43-14.57) in the WBRT, and 2.00 (1.12-2.88) in no RT group (p=0.022). Patients with a KPS of <80 had a shorter mOS compared to those with a KPS of >80 [5.00 (2.02-7.98) vs 17.00 (9.41-24.6), p=0.002]. Patients receiving hormonal therapy had longer mOS compared to those who did not [17.00 (6.58-27.43) vs 9.00 (3.72-14.28), p=0.016]. Patients with stage I disease had longer mOS compared to those with stage II-IV disease [41.00 (22.70-59.30) vs 10.00 (6.60-13.40), p=0.025]. Conclusions: This study identifies significant clinical predictors for BM development and survival in patients with BC including Hormone receptor status, treatment modalities, stage, and KPS. These findings emphasize the need for early BM screening in high-risk patients to improve survival.

Results from METIS (EF-25), an international, multicenter phase III randomized study evaluating the efficacy and safety of tumor treating fields (TTFields) therapy in NSCLC patients with brain metastases.

2008 Background: For non-small cell lung cancer (NSCLC) with brain metastases (BM) stereotactic radiosurgery (SRS) is the current preferred therapy. Due to frequent intracranial failures, there is a high unmet need for salvage therapies. Whole brain radiotherapy (WBRT) reduces intracranial failure but used less frequently due to cognitive consequences. Tumor Treating Fields (TTFields) are electric fields that disrupt cancer cell division and have shown improved survival and safety in patients with glioblastoma and metastatic NSCLC. Phase 3 METIS trial [NCT02831959] aimed to evaluate the efficacy and safety of TTFields therapy in NSCLC patients with BM treated with SRS, specifically in terms of lengthening time to intracranial progression without cognitive decline. Methods: Mutation negative (M-) NSCLC patients with 1–10 BM were randomized 1:1 to receive stereotactic radiosurgery (SRS) followed by Tumor Treating Fields (TTFields; 150 kHz) therapy with best supportive care (BSC) or SRS followed by BSC. Patients with Karnofsky Performance Status (KPS) ≥70, newly diagnosed with one inoperable or 2–10 supra-/infratentorial brain metastases suitable for SRS and receiving optimal extracranial disease therapy were included. Exclusions were prior WBRT and single operable or recurrent brain metastases. Primary endpoint was time to first intracranial progression (RANO-BM) based on cumulative risk. Patients were followed every two months until second intracranial progression. Cognition and patient quality of life (QoL) were evaluated. Results: Between July 2016 and September 2022, 298 patients were randomized. Baseline characteristics were balanced: median age was 63.5 (range 37-84) years, 37.6% females, majority of patients had a KPS ≥ 80, median time from initial NSCLC diagnosis was 1.8 months (range: 0.2-55.7), 77% had adenocarcinoma. Median treatment duration of TTFields was 16 weeks, with a median usage time of 67%. Primary endpoint, time to intracranial progression from SRS, was significantly prolonged with SRS followed by TTFields therapy with BSC vs. TTFields plus BSC arm (median of 21.9 vs. 11.3 months); HR=0.67 [0.48-0.93], p=0.02. TTFields-related AEs were mainly dermatological, and Grade ≤2. TTFields therapy also improved deterioration-free survival of global health status, physical functioning, and fatigue according to QoL, and did not negatively impact cognition. Conclusions: METIS study met its primary endpoint, demonstrating that TTFields therapy following SRS in mutation negative NSCLC patients with BM, significantly prolongs time to intracranial progression and could postpone WBRT, without QoL and cognition decline. Clinical trial information: NCT02831959 .

Descriptive analysis of brain metastases (BM) of solid neoplasms in an academic hospital from a low- and middle-income country (LMIC) with a Hispanic population.

e14015 Background: Multidisciplinary management of BM of solid cancers integrates different combinations of treatment modalities. The scarcity of SRS centers has prevented widespread adoption of this therapy for appropriately selected patients. Methods: One-hundred eighteen (51.7% female, 48.3% male, median age 59 years) BM patients from a National Health Institute from Mexico (INCMNSZ) were included and analyzed. Results: The most common primary tumors were lung and breast cancers (25 cases each, representing 21% of the whole cohort), kidney cancer (14%), male germ cell tumors (10%), metastatic carcinoma of unknown primary (CUP) (5%), upper- and lower- gastrointestinal cancers (5%), thyroid differentiated cancers (5%), followed by melanoma, prostate, ovarian, hepatobiliary cancers and sarcoma (3% each of them) and urothelial carcinoma (2%) being the least common. No biopsy was reported for only one case. The most common histomolecular tumors were adenocarcinoma of the lung (17 cases), renal cell carcinoma (17), triple negative (TN) breast cancer (BC) (9), HER-2+ BC (7), Nonseminomatous germ cell tumor (7), CUP (6), ER+/HER-2+ BC (5), Germ cell tumor with choriocarcinoma (5), small-cell lung cancer (SCLC) (5), melanoma (5), prostate adenocarcinoma (5), thyroid differentiated cancer not otherwise specified (NOS) (5). Rectal adenocarcinoma, high-grade serous ovarian cancer, ER+/PR+ BC, sarcomas and NSCLC (3 cases, each) and urothelial carcinoma (2). Rare tumor subtypes, with one case, each included hepatocellular carcinoma, PR+/HER2+ BC, follicular thyroid cancer, esophageal, gastric and colonic adenocarcinomas, neuroendocrine prostate, neuroendocrine gallbladder, endometrial, large cell neuroendocrine lung carcinomas and cholangiocarcinoma. A solitary BM was present in 44 patients (37.3%), 2-3 BM in 30 (25.4%) and >3 BM in 44 patients (37.3%). 18 patients (15.2%) were not symptomatic at the time of diagnosis. 79 patients were treated with Whole-Brain Radiotherapy (WBRT), ten with a combination of surgery and adjuvant WBRT, seven with surgical resection without radiotherapy, only five included SRS as part of their treatment and seventeen received only supportive care. There was no difference in overall survival (OS) between treatment modalities excluding supportive care (p=0.05). Conclusions: Our experience from a LMIC with Hispanic population highlights that more than 50% of BM metastasize from solid tumors different from lung and breast cancers. Even though SRS has been included in recent guidelines from ASCO and ESMO, WBRT is the option most commonly included in multimodality treatments.

Orelabrutinib, rituximab, temozolomide and high-dose methotrexate (RMOT) in newly diagnosed primary central nervous system lymphoma (PCNSL): A retrospective analysis on efficacy and safety.

e19041 Background: PCNSL is a rare, aggressive malignant tumor and has a poor prognosis. HD-MTX-based regimen is the first-line treatment of PCNSL. Orelabrutinib is a novel, potent, highly selective BTK inhibitor with a high CSF concentration. Recent evidence has shown the efficacy and safety of orelabrutinib in PCNSL. Therefore, we conducted a retrospective study of clinical outcomes in newly diagnosed PCNSL patients (pts) treated with RMOT regimen in routine clinical care. Methods: This retrospective cohort included the pts (aged 18-80 years) with newly diagnosed PCNSL who received 6 cycles of RMOT regimen (rituximab 375 mg/m2 iv day 1; MTX 3.5 g/m2 iv day 1; temozolomide 150 mg/m2 po day 1 to day 5; orelabrutinib 150 mg qd po; 4 weeks per cycle) as the first-line induction therapy between Nov. 2021 and Aug. 2023. All the pts were proposed to receive orelabrutinib monotherapy as maintenance after RMOT therapy. We recommend to receive autologous stem cell transplantation (ASCT) or whole brain radiation therapy (WBRT) as consolidation after RMOT therapy. Efficacy was assessed by MRI/PET per the International PCNSL Collaborative Group (IPCG) criteria. The primary endpoint was overall response rate (ORR); secondary endpoints were CR rate, progression-free survival (PFS), overall survival (OS), and safety. Results: Ten pts (6 males) with PCNSL were included, with a median age of 61 years (range, 45-77). All pts had a histologically confirmed diffuse large B-cell lymphoma. 4 pts (40%) underwent WBRT after induction therapy. As of the cut-off date (December 31, 2023), the median follow-up time was 9.7 (range, 4.8-25.7) month. All pts were evaluated for the treatment response. An interim evaluation after 4 cycles was available for 10 pts, showing complete remission (CR) rate of 80% (8/10), partial response (PR) rate of 20% (2/10), giving an ORR of 100.0% (10/10, Table). At data cutoff, the best ORR was 100.0% (10/10), with all pts achieved CR. Of 10 responders, 9 had an ongoing response, and 1 died of covid-19 infection. Median PFS/OS was not reached (NR) (95% CI NR-NR). The most common AEs were anemia, other include white blood cell or platelet count decreased. Reported AEs were generally manageable and resolved soon after supportive treatment. Only 1 (10%) pts experienced ≥grade 3 AEs—acute kidney injury. No treatment-related death occurred. Conclusions: This retrospective data suggested that RMOT had an encouraging anti-tumor activity in newly diagnosed PCNSL pts, with a toleratable safety profile. This orelabrutinib-containing regimens may provide a potential treatment strategy for pts with PCNSL. [Table: see text]

Brain metastases in patients with pleural mesothelioma receiving dual checkpoint blockade compared to single-agent checkpoint blockade or chemotherapy.

e20093 Background: Immunotherapy (IO) has emerged as a treatment option in pleural mesothelioma (PM). Historically, brain metastases (BM) in PM were rare, thus brain imaging is not routine practice or included in guidelines. We characterize the incidence of BMs by type of treatment received. Methods: In this retrospective analysis,adult patients with PM treated at the Hospital of the University of Pennsylvania between 1/1/2015- 8/31/2023 were included. Patient demographic data, treatment, brain imaging and clinical history were extracted from the electronic medical record.A two-tailed Z score with alpha 0.05 was used to determine a difference in proportion of patients with BM by treatment group. Results: 290 patients were included in the study. 154 (53.1%) were treated with chemotherapy (CT), 94 (32.4%) were treated with pembrolizumab (pembro), 39 (13.4%) were treated with ipilimumab + nivolumab (ipi/nivo), and 3 (1.0%) were treated with another IO. A higher proportion of patients treated with ipi/nivo developed BM compared to those treated with pembro alone (4/39, 10.3% vs 2/94, 2.1%; Z score p= 0.038). None of the 154 patients treated with CT developed BM. All BMs were detected due to symptoms. Of the six patients that developed BM, the median age was 72.5 (range 47-80), 83% were male, 67% identified as Caucasian, and there was an even distribution of histology with 33% each of epithelioid, biphasic, and sarcomatoid. All patients received IO most recently or were currently on it when BM developed. Median time to BM from start of immunotherapy was 144.5 days (range 2-913 days). On imaging, all 6 patients had edema surrounding the brain metastases and 4 also showed hemorrhage. Survival after development of BM was poor (Table1). Four patients (67%) underwent surgery for the BM, while all patients received brain radiation. Two patients received whole brain radiation therapy (WBRT), while four patients received stereotactic radiosurgery (SRS) to a median of four brain metastases (range 1-7). Three patients developed subsequent intracranial progression (out-of-field) including one with rapid intracranial progression 20 days post-radiation. Conclusions: In this large retrospective study of patients with PM treated with systemic therapy, BM was most prevalent in those patients receiving ipi/nivo compared to pembro alone and not seen in those receiving chemotherapy. The presence of edema suggests a possible immune infiltrate while on IO (correlative studies in progress). Brain imaging should be considered prior to starting IO in patients with PM. [Table: see text]

Real world outcomes of patients with small cell lung cancer (SCLC) presenting with brain metastasis at diagnosis in a single institution health system.

e20136 Background: Extensive-stage small cell lung cancer (ES-SCLC) is an aggressive lung cancer subtype with high propensity for brain metastases (mets). Despite this, there is no consensus on the treatment of brain mets especially in the setting of frontline chemoimmunotherapy and advanced radiation techniques like Gamma Knife radiosurgery (GKRS). Methods: In this single-institution retrospective study, we queried the Yale Tumor registry for all patients diagnosed with ES-SCLC in 1/2016-4/2023. Patients with brain mets at the time of presentation were identified and underwent manual chart review for abstraction of clinical information specifically pertaining to brain mets and treatment modalities. Survival outcomes including median progression free survival (mPFS), median central nervous system-progression free survival (mcPFS) and median overall survival (mOS) measured in months were also captured. Results: 423 ES-SCLC patients were identified. Of those, 92 (22%) had brain mets at initial presentation and were reviewed. 44 (48%) of patients with brain mets were treated with frontline chemotherapy (platinum doublet) while 42 (46%) were treated with chemoimmunotherapy (platinum doublet with atezolizumab or durvalumab). Patients treated with upfront chemotherapy had mPFS 6.4 (95% CI -1.2, 14.1), mcPFS 7.7 (95% CI -1.2, 17.1), and mOS 9.3 (95% CI -13.7, 36.4), compared to patients treated with chemoimmunotherapy, who had mPFS 4.9 (p=0.23; 95% CI -3.5, 15.4), mcPFS 6.7 (p=0.99; 95% CI 3.3, 20.8), and mOS 7.7 (p=0.89; 95% CI -11.4, 33.9). 63 (68%) of patients underwent upfront brain radiation. 44 (48%) had whole brain radiation (WBRT) while 19 (30%) underwent GKRS. Of the patients undergoing GKRS, 8 (42%) were symptomatic. 7 patients (37%) presented with 1 brain met, and 12 (63%) patients presented with 2-5 brain mets. For patients treated with GKRS, mPFS 6.8 (95% CI 2.3, 10.4), mcPFS 7.2 (95% CI 2.9, 12.6), and mOS 11.1 (95% CI -13.0, 40.9). For patients undergoing WBRT, mPFS 6.5 (p = 1.0; 95% CI -4.5, 20.2), mcPFS 6.5 (p = 0.96; 95% CI -3.9, 21.6), and mOS 8.6 (p = 0.21; 95% CI -17.7, 39.9). Conclusions: GKRS is a viable option for SCLC patients presenting with brain metastases, especially in those with a low number of mets. Further studies are required to determine the optimal ES-SCLC candidates for upfront GKRS. [Table: see text]

Impact of gadopiclenol on decision making in patients with brain metastases: A post-hoc study.

e14003 Background: Gadopiclenol (Elucirem, Guerbet, France) is a new high relaxivity macrocyclic gadolinium-based contrast agent (GBCA), recently approved by the FDA and EMA at the dose of 0.05 mmol/kg. The aim of this post-hoc analysis was to evaluate the impact of contrast-enhanced MRI with gadopiclenol at 0.1 mmol/kg on decision making and radiotherapy (RT) treatment planning of brain metastases (BM). Methods: This is a post-hoc analysis of data from a phase IIb study where patients underwent two separate MRI examinations, one with gadopiclenol at 0.025, 0.05, 0.1 or 0.2 mmol/kg and one with gadobenate dimeglumine at 0.1 mmol/kg. MR images of patients who received both GBCAs at 0.1 mmol/kg, with ≥1 BM detected in either of the scans, were subjected to a blinded reader analysis and contouring by two radiation oncology experts. For each patient, treatment plans (stereotactic radiosurgery [SRS] or whole-brain radiotherapy [WBRT]) were determined for both MRIs, with the gross target volume (GTV) indicating the contrast-enhancing aspects of the tumor. Mean GTVs and normal tissue volumes receiving 12 Gy (V12), as well as the Dice similarity coefficient (DSC) were obtained for the paired contours. The Spearman´s rank (ρ) correlation was additionally calculated. Furthermore, three experts blindly evaluated the contrast enhancement of each lesion for contouring purposes and subjectively qualified them as “better”, in detriment of the counterpart, or “equal”. Results: In total, images from 13 adult patients were analyzed. MRI with gadopiclenol depicted additional BM as compared with gadobenate dimeglumine in 7 patients (54%). The treatment plan was changed in 2 patients (15%), from no treatment to SRS and from SRS to WBRT. Gadopiclenol depicted additional BM in these 2 patients (from 0 and 10 BM with gadobenate dimeglumine to 1 and 15 BM with gadopiclenol). The mean GTVs and V12 were comparable between gadopiclenol and gadobenate dimeglumine (p=0.694, p=1.974). The mean DSC was 0.70 (SD: 0.14, ρ0.82). From a total of 36 answers, contrast enhancement was qualified as better with gadopiclenol in 21 (58.3%) evaluations, better with gadobenate dimeglumine in 8 (22.2%) evaluations, while no difference was observed in 7 (19.4%) evaluations. Conclusions: Gadopiclenol at 0.1 mmol/kg improved BM detection and contrast enhancement with potential impact on RT treatment decisions.

The TAC-GReD trial: The combination of talazoparib and carboplatin in DNA damage repair deficient recurrent high-grade glioma.

2047 Background: Recurrent high-grade glioma (rHGG) has a dismal prognosis with limited treatment options. Given that a high proportion of these gliomas harbor deficiencies in the DNA damage repair (DDRd) pathway, this genomic occurrence may confer synergistic lethality and sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors. Therefore, we hypothesize that DDRd rHGG may be sensitive to the combination of a PARP inhibitor, talazoparib, and carboplatin. Methods: This is a prospective phase II, single-arm open-label biomarker stratified single-institution trial conducted in Hong Kong (NCT04740190). Tumor tissue was sent for comprehensive next-generation sequencing (C-NGS) to screen for genomic aberrations associated with the DDRd pathway. Patients with rHGG (WHO grade III-IV) and at least one pathogenic mutation in the DDR pathway were deemed eligible. Patients were initially treated with whole-brain radiotherapy (2 Gy/1 Fr) on C1D1. Starting at dose level 0, talazoparib (0.75mg on Days 1-4) and carboplatin (AUC 1.5 on Day 1), were administered weekly for a total of 18 cycles, followed by maintenance talazoparib. The primary endpoint was the 6-month progression-free survival (PFS-6). Results: 61 patients were screened and 33 patients with DDRd rHGG were enrolled, 23 males, 10 females, and a median age of 55 years (range: 29-70 years). 73% (n=24) had a baseline ECOG PS of 0-1. Among the recruited patients, 12% (n=4) were classified as WHO grade III, while the remaining 88% (n=29) were WHO grade IV. Dose level escalation was achieved in 27% (n=9) of the cohort. The 6-PFS was 29% (95% CI 16.2-51.9%) and the median PFS was 3.5 months (95% CI: 2.4-6.3 months). The OS at 3 and 12 months were 90.4% (95% CI 80.7-100%) and 30% (95% CI 17-53%), respectively. The most common grade 3-4 toxicities were neutropenia (21.2%, n=7), thrombocytopenia (18.2%, n=6) and anemia (9.1%, n=3). One patient developed a grade 4 thromboembolic event. Dose level reduction was implemented in 54% (n=18) of patients and treatment was terminated in 6.1% (n=2) due to toxicity. Conclusions: Talazoparib and carboplatin in a DDRd-enriched rHGG is feasible and tolerable. Additional analysis including correlation of biomarkers with long-term outcomes is underway. Clinical trial information: NCT04740190 .

Clinical features and outcomes of patients with breast cancer with leptomeningeal carcinomatosis.

e13162 Background: Leptomeningeal carcinomatosis (LMC) is a rare, but deadly complication in breast cancer, with prior studies showing median overall survival (OS) of 15 weeks. There is a paucity of data on histologic and receptor subtype-specific survival, and there is no standard of care currently for treatment of LMC in breast cancer. We reviewed the outcomes of a contemporary cohort of breast cancer patients (pts) with LMC. Methods: This is a single-institution retrospective analysis of 38 female breast cancer pts diagnosed with LMC between 2016-2023, based on radiographic features and/or positive cerebrospinal fluid (CSF) cytology or CSF circulating tumor cells (CTCs). Patients consented to share information with a research biorepository, and we conducted a chart review of their clinical features and OS with LMC. Results: 25 pts (65.8%) had invasive ductal carcinoma (IDC), 7 pts (18.4%) had invasive lobular carcinoma (ILC), 4 (10.5%) had metaplastic carcinoma, and 2 (5.3%) had mixed IDC/ILC. 22 pts (57.9%) had triple-negative breast cancer (TNBC), 12 (31.6%) had estrogen receptor positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-), and 4 (10.5%) had HER2+ disease. Median age at LMC diagnosis was 50 years. Median time between Stage IV and LMC diagnosis was 11 months. Pts received a median of 2 lines of systemic therapy for metastatic disease prior to LMC diagnosis. 11 pts (28.9%) had parenchymal brain metastasis prior to LMC diagnosis. 32 pts (84.2%) had signs of LMC on Magnetic Resonance Imaging of the brain and/or spine at diagnosis. 25 pts underwent CSF cytology and 13 pts underwent CSF CTC evaluation at LMC diagnosis; 14/25 pts (56%) had positive CSF cytology and 10/13 pts (76.9%) had detectable CSF CTCs. 21 pts (55.3%) underwent whole-brain radiotherapy, and 2 pts (5.3%) received proton craniospinal irradiation. 21 pts (55.3%) received IT therapy. 27 pts (71.1%) received at least 1 line of systemic therapy post-LMC diagnosis. Median OS between LMC diagnosis and death or last oncology follow up for the entire cohort was 5 months (range 0-57 months, 95% CI 3.0-8.0). There was a significant difference in median OS with LMC by receptor subtype: TNBC 3.5 months, ER+/HER2- 8 months, and HER2+ 23 months (p=0.0047). Two HER2+ pts survived ≥ 3 years post-LMC diagnosis with anti-HER2 antibody-drug conjugates and tyrosine kinase inhibitors +/- stereotactic radiosurgery (SRS) to parenchymal brain metastases. Amongst 9 pts with ER+/HER2-low disease, longer survival with LMC (≥ 16 months) was observed with trastuzumab deruxtecan, IT topotecan +/- IT trastuzumab, and SRS to parenchymal brain metastases. Conclusions: This study highlights heterogeneity in outcomes amongst breast cancer pts with LMC by receptor subtype, as well as improvement in outcomes for selected pts treated with novel therapeutics and a multidisciplinary approach. Larger prospective studies are needed to inform treatment paradigms for LMC.

Comprehensive Analysis of Blood Test Results Predicting Prognosis in Patients Undergoing Whole-brain Radiotherapy for Brain Metastases.

Blood tests, such as those included in the validated LabBM score (laboratory parameters in patients with brain metastases) predict survival after treatment of brain metastases. The model incorporates five test results [serum lactate dehydrogenase (LDH), C-reactive protein (CRP), albumin, platelets and hemoglobin]. However, many other abnormalities, albeit less well-studied, may be present in patients with metastatic cancer. Therefore, this study aimed to examine a broader range of blood tests. This retrospective analysis included 132 patients managed with primary whole-brain radiotherapy. Additional tests, such as liver enzymes, lymphopenia, hyponatremia, and others, were also conducted. Extracranial disease extent was also analyzed. According to forward conditional Cox regression analyses, blood tests (albumin, hemoglobin, lymphopenia, hyponatremia) in conjunction with the number of organs affected by extracranial metastases (at least two, such as liver and bones) provided the best prognostic model. Based on these parameters, at least four prognostic strata can be assigned (median survival between 4.6 and <1 months, p=0.0001). This initial pilot study in a limited number of patients suggests that numerous blood test results may contribute to further refinement of existing prognostic models, and provides justification for additional large-scale studies.