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Leptomeningeal (LM) disease occurs in 9% to 10% of EGFR mutated non-small cell lung cancer (NSCLC) cases. The natural history and optimal systemic treatment strategies for this disease are not well-characterized, particularly in the era of osimertinib.We identified 54 patients with EGFR mutated NSCLC and LM disease diagnosed between January 3, 2000 to March 31, 2020 and treated at an academic oncology practice in Seattle, Washington. We abstracted demographic, tumor, treatment, and outcome data from the electronic medical record. Univariate Cox models were run to evaluate the association between post-LM disease systemic therapy and overall survival. Differences in LM disease natural history and healthcare utilization between groups were assessed using Student's t test or a chi-squared test.Patients that received osimertinib prior to LM disease had a longer median time to LM disease diagnosis and trended toward better performance status than those that did not. Patients that received any post-LM disease systemic therapy had a lower risk of death relative to those that did not (HR 0.17, P.001), with a suggestion that osimertinib-containing regimens result in longer median overall survival. Emergency department, hospital and hospice utilization were not associated with receipt of post-LM disease systemic therapy.Prior exposure to osimertinib appears to favorably influence the natural history of LM disease. Any systemic therapy after LM disease diagnosis is associated with longer survival and does not increase healthcare utilization. Additional research is needed to assess whether an osimertinib-containing regimen confers a survival benefit after LM disease diagnosis among patients who received prior osimertinib.

AbstractAs a result of treatment and diagnosis, adults with primary or metastatic brain tumors experience comorbidities that impacts their health and well-being. The Children’s Oncology Group has guideline recommendations for childhood survivors of brain tumors; however, guidelines for monitoring long-term sequela among adult brain tumor survivors are lacking. The purpose of this review is to present the screening recommendations for the long-term complications after brain tumor treatment from a multidisciplinary panel of healthcare professionals. Chronic complications identified include cognitive dysfunction, vasculopathy, endocrinopathy, ophthalmic, ototoxicity, physical disability, sleep disturbance, mood disorder, unemployment, financial toxicity, and secondary malignancy. We invited specialists across disciplines to perform a literature search and provide expert recommendations for surveillance for long-term complications for adult brain tumor survivors. The Brain Tumor Center Survivorship Committee recommends routine screening using laboratory testing, subjective assessment of symptoms, and objective evaluations to appropriately monitor the complications of brain tumor treatments. Effective monitoring and treatment should involve collaboration with primary care providers and may require referral to other specialties and support services to provide patient-centered care during neuro-oncology survivorship. Further research is necessary to document the incidence and prevalence of medical complications as well as evaluate the efficacy of screening and neuro-oncology survivorship programs.

Relapsed or refractory primary CNS lymphoma (rrPCNSL) is a rare and challenging malignancy for which better evidence is needed to guide management. We present a retrospective cohort of 66 consecutive patients with rrPCNSL treated at the University of Washington between 2000 and 2020. Immunosuppressed and secondary CNS lymphoma patients were excluded. During a median follow-up of 40.5 months from initial diagnosis, median OS for relapsed disease was 14.1 (0.2–88.5) months and median PFS was 11.0 (0.2–73.9) months. At diagnosis (r2 = 0.85, p

Gestational trophoblastic diseases and neoplasias (GTDs and GTNs) comprise a spectrum of diseases arising from abnormally proliferating placental/trophoblastic tissue following an antecedent molar or non-molar pregnancy. These can spread to the brain hematogenously in about 10% of patients, mostly in high-risk disease. The optimal management of patients with brain metastases from GTN is unclear, with multiple systemic regimens under use and an uncertain role for radiotherapy.Here, we review the epidemiology, workup, and treatment of GTN with central nervous system (CNS) involvement. Literature searches in PubMed and Google Scholar were conducted using combinations of keywords such as 'gestational trophoblastic disease,' 'gestational trophoblastic neoplasia,' 'choriocarcinoma,' and 'brain metastases.'Systemic therapy is the frontline treatment for GTN with brain metastases, and radiotherapy should only be considered in the context of a clinical trial or for resistant/recurrent disease. Surgery has a limited role in palliating symptoms or relieving intracranial pressure/bleeding. Given the highly specialized care these patients require, treatment at a high-volume referral center with multidisciplinary collaboration likely leads to better outcomes. Randomized trials should be conducted to determine the best systemic therapy option for GTN.

Adult-onset medulloblastoma is a rare tumor for which limited data exists. Current treatment is based on data from childhood medulloblastoma. We present a retrospective cohort of 130 consecutive patients age ≥ 18 years and treated at the University of Washington (N = 61), University of Florida (N = 50), and Stanford University (N = 19), from 2000-2021. Median duration of follow-up was 57.3 months. Patients were 57.7% male (75/130), with median age at diagnosis of 29 years. 5 and 10-year overall survival were 78.9% and 67.6% and no recurrence was seen beyond 10 years. 31/130 (23.8%) patients had Chang M1 or greater disease and molecular typing was available for 41/130 patients. There was no improvement in progression-free survival (PFS) or overall survival (OS) either in patients who received proton therapy or those who received concurrent vincristine. There was a trend favoring longer OS in patients receiving radiotherapy within 6 weeks of surgery. A trend towards shorter OS in patients receiving a higher craniospinal radiation dose ( > 30Gy) likely reflected accurate clinical risk stratification. There was no improvement in OS or PFS for adjuvant chemotherapy overall, but patients receiving ≥ 5 cycles had improved PFS (HR 2.10, 95% CI = 1.19 - 3.90, p = 0.038) and a trend to improved OS (HR 2.07, 95%CI = 0.81-5.25, p = 0.125). After first progression, median OS was 20.7 months and both 5 and 10-year survival were 24.8%. We conclude that surveillance past 10 years may be unnecessary and that 1 in 4 patients achieve long-term survival after first relapse. Within the confines of a retrospective study, these data suggest equivalence between proton and photon radiotherapy, no benefit to concurrent vincristine, and that at least 5 cycles of adjuvant chemotherapy are required to delay progression.

Background: The development of oral chemotherapies (OC) have transformed cancer care for millions of patients. Most patients with brain tumors have temozolomide (TMZ) delivered to their home. While this has improved the patient experience, it presents significant challenges to safety of prescription, administration, and side effect monitoring. While there are guidelines for documentation, there is not a best practices system for managing OC. This project identified areas of latent errors and implemented a standardized process for OC management. Methods: After review of the literature, we developed a process map for our institution’s practice and performed hazard analysis. We then evaluated the process at 3 other neuro-oncology practices. Based on these evaluations, changes were implemented at several stages (Table 1). Objective binary measures that could be recorded for every TMZ prescription were collected by chart review of the 6 months prior to process change. These measures were monitored every 2 weeks after process change implementation using run charts. A baseline process mean was calculated for each measure from the 6 months before program implementation. Successful change implementation was defined as 7 consecutive 2-week averages that were continually on one side of the process mean. Results: At the time of this abstract submission, we had successfully reduced refills for OC and increased documentation of dose calculation and dose ordered. There is improvement in independent dose calculation by 2 providers and dedicated chemotherapy teaching visits; however, these have not yet reached criteria for process change. Additionally, oral chemotherapy order sets were created in the electronic medical records system and an on-site specialty pharmacy was added as another safety measure in OC management. Conclusions: This project used published studies and multi-institutional process mapping and hazard analysis to implement a standardized ordering of TMZ for patients with brain tumors. This process can be implemented for OC management in other oncology practices.

Intracranial stereotactic radiosurgery (SRS) is an effective and convenient treatment for many brain conditions. Data regarding safety come mostly from retrospective single institutional studies and a small number of prospective studies. Variations in target delineation, treatment delivery, imaging follow-up protocols and dose prescription limit the interpretation of this data. There has been much clinical focus on radiation necrosis (RN) in particular, as it is being increasingly recognized on follow-up imaging. Symptomatic RN may be treated with medical therapy (such as corticosteroids and bevacizumab) with surgical resection being reserved for refractory patients. Nevertheless, RN remains a challenging condition to manage, and therefore upfront patient selection for SRS remains critical to provide complication-free control. Mitigation strategies need to be considered in situations where the baseline risk of RN is expected to be high-such as large target volume or re-irradiation. These may involve reduction in the prescribed dose or hypofractionated stereotactic radiation therapy (HSRT). Recently published guidelines and international meta-analysis report the benefit of HSRT in larger lesions, without compromising control rates. However, careful attention to planning parameters and SRS techniques still need to be adhered, even with HSRT. In cases where the risk is deemed to be high despite mitigation, a combination approach of surgery with or without post-operative radiation should be considered.

Late and long-term sequelae of treatment for patients with brain tumors can greatly affect their quality of life, daily functioning, and even mortality. Though some late effects are permanent, many can be mitigated or addressed with interventions. Thus, it is important to follow patients long term to monitor for treatable late effects and recognize other unexpected toxicities from radiation therapy. This chapter outlines possible late effects and treatments after brain irradiation.

Relapsed or refractory primary CNS lymphoma (rrPCNSL) is a rare and challenging malignancy for which better evidence is needed to guide management.We present a retrospective cohort of 66 consecutive patients with rrPCNSL treated at the University of Washington between 2000 and 2020. Immunosuppressed and secondary CNS lymphoma patients were excluded.During a median follow-up of 40.5 months from initial diagnosis, median OS for relapsed disease was 14.1 (0.2-88.5) months and median PFS was 11.0 (0.2-73.9) months. At diagnosis (rPFS may be a useful surrogate endpoint which predicts OS in PCNSL. Consolidation with ASCT was associated with improved PFS in rrPCNSL.

Opinion statement At this time, there are no FDA-approved immune therapies for glioblastoma (GBM) despite many unique therapies currently in clinical trials. GBM is a highly immunosuppressive tumor and there are limitations to a safe immune response in the central nervous system. To date, there have been several failures of phase 3 immune therapy clinical trials in GBM. These trials have targeted single components of an antitumor immune response. Learning from these failures, the future of immunotherapy for GBM appears most hopeful for combination of immune therapies to overcome the profound immunosuppression of this disease. Understanding biomarkers for appropriate patient selection as well as tumor progression are necessary for implementation of immunotherapy for GBM

TPS2069 Background: High-grade gliomas (WHO grade III-IV) patients experience marked morbidity and mortality. While the standard of care for newly diagnosed high-grade glioma patients is surgery followed by concurrent chemotherapy and radiation therapy (RT), the outcomes remain poor. BMX-001 (MnTnBuOE-2-PyP5+) is a metalloporphyrin with differential action in response to radiation therapy and chemotherapy-induced oxidative stress. As shown in preclinical evaluations, BMX-001, when used with radiation, can protect normal, healthy tissues and augment cell kill in malignant cancer cells, notably, human glioblastoma xenografts. We evaluated the safety of BMX-001 in combination with concurrent RT and temozolomide (TMZ) in a phase 1 study of newly diagnosed high-grade glioma patients and we found that BMX-001 is safe and well-tolerated in this population. The maximum tolerated dose of BMX-001 during concurrent RT and TMZ was determined to be 28 mg delivered subcutaneously (SC) followed by 16 biweekly SC doses at 14 mg (Peters et al., Neuro-Oncology 2018). Methods: For this multi-site, open-label, phase 2 study (NCT02655601), we will randomize approximately 160 patients 1:1 to concurrent RT and TMZ with BMX-001 versus concurrent RT and TMZ alone. Key eligibility criteria include newly diagnosed histologically confirmed high-grade glioma (WHO III-IV), 18 ≥ years, and Karnofsky performance status ≥ 70%. The primary endpoint is overall survival. Secondary endpoints are objective cognitive performance, bone marrow protection, safety and tolerability, progression-free survival, overall tumor response rate, and plasma pharmacokinetics. Exploratory endpoints are patient-reported outcomes of health-related quality of life (as assessed by Functional Assessment of Cancer Therapy–Brain, Functional Assessment of Cancer Therapy-Cognition, and Functional Assessment of Chronic Illness Therapy-Fatigue), qualitative hair loss, and white matter integrity (as measured by MRI diffusion tensor/susceptibility imaging). Since November 2018, this phase 2 study has enrolled 147 of 160 high-grade glioma patients at nine sites in US. Clinical trial information: NCT02655601.

Relapsed or refractory primary CNS non-Hodgkin’s lymphoma (rrPCNSL) is a rare and challenging malignancy for which better evidence is needed to guide management. We present a retrospective cohort of 70 consecutive patients with rrPCNSL treated at the University of Washington between 2000-2020. HIV positive and secondary CNS lymphoma patients were excluded. During a median follow-up of 19.8 months, median overall survival (OS) was 18.30 months and median progression-free survival (PFS) was 12.67 months. At all stages of disease (diagnosis, first relapse, multiple relapses), PFS was an excellent predictor of OS. There was a small effect of age < 70 on PFS after initial diagnosis (PFS1), but no effect on PFS after first (PFS2) or subsequent (PFS3+) relapses. There was no effect of age < 60 on PFS1, PFS2, or PFS3+. Patients reinduced with high-dose methotrexate-based (HD-MTX) regimens had an overall response rate (ORR) of 86.7% and median PFS 17.2 months. For patients who responded to reinduction therapy, those consolidated with autologous stem cell transplant (ASCT) had median PFS of 30.3 months (n=11) compared with 12.1 months for other consolidation strategies (n=9), and 9.0 months for no consolidation (n=20). Although patients receiving ASCT were younger, KPS, sex, and the median number of recurrences were similar between consolidation groups. We conclude that PFS is a useful endpoint for rrPCNSL which predicts OS and is not associated with age. Using PFS as an endpoint, we did not detect a benefit to any consolidation strategy other than ASCT.

BACKGROUND LC is a late and often fatal manifestation of advanced EGFR mutated NSCLC with up to 9% of patients developing LC. Given the higher incidence of LC in EGFR mutated tumors, we hypothesized it may have unique imaging and clinical characteristics. METHODS We identified 23 patients with EGFR mutated NSCLC and LC treated at a large academic institution between 2016 and 2019. Clinical and treatment characteristics were obtained from the electronic medical record. Radiographic subtype of LC and presence of ventriculomegaly were determined by independent review of available brain and spine MRI imaging. RESULTS Among 23 eligible patients, mean age was 57 years, 96% had advanced NSCLC at diagnosis and 61% had EGFR exon 19 deletion. Median time from NSCLC diagnosis to LC development was 23 months (95% CI:13–33), with only 17% of patients presenting with LC in the absence of parenchymal brain metastases. Of the 91% of patients with radiographic evidence of LC, equal numbers had nodular or linear LC (22% each) and 39% had a mixed presentation. Additionally, 30% of patients had evidence of spinal LC. Ventriculomegaly was present in 52% of patients, with 48% developing clinical symptoms of hydrocephalus and 13% receiving shunt placement. Median overall survival (OS) from time of LC diagnosis was 3.9 months (95% CI:2.7–10.0), which is lower than in prior published studies. Patients with nodular LC and absence of ventriculomegaly fared better with a median OS of 6.5 months and 5.7 months respectively. CONCLUSIONS OS is poor in patients with LC associated with EGFR mutated NSCLC, although appears better in patients with nodular LC. The high incidence of hydrocephalus emphasizes the need for its early recognition and treatment. Further studies are needed to identify promising treatment strategies and to determine factors associated with improved OS in this population.

TPS2577 Background: Patients diagnosed with malignant high-grade gliomas (WHO grade III-IV) experience significant morbidity and mortality associated with these cancers. While the mainstay of therapy for patients with newly diagnosed high-grade glioma is surgery followed by concurrent chemotherapy and radiation therapy (RT), the outcomes remain very poor. BMX-001 (MnTnBuOE-2-PyP5+) is a metalloporphyrin with differential action in response to radiation therapy and chemotherapy-induced oxidative stress. Early preclinical studies demonstrated BMX-001’s ability to act as a radioprotectant to healthy tissue such as a central nervous white matter and as a radiosensitizer to cancer cells, in particular, human glioblastoma xenografts. We evaluated the safety of BMX-001 in combination with concurrent RT and temozolomide (TMZ) in a phase I study of newly diagnosed high-grade glioma patients, and we found that BMX-001 is safe and well-tolerated in this population. The maximum tolerated dose of BMX-001 during concurrent RT and TMZ was determined to be 28 mg delivered subcutaneously (SC) followed by 16 biweekly SC doses at 14 mg (Peters et al., Neuro-Oncology 2018). Methods: For this multi-site, open-label, phase II study (NCT02655601), we will randomize approximately 160 patients 1:1 to concurrent RT and TMZ with BMX-001 versus concurrent RT and TMZ alone. Key eligibility criteria include newly diagnosed histologically confirmed high-grade glioma (WHO III-IV), 18 ≥ years, and Karnofsky performance status ≥ 70%. The primary endpoint is overall survival. Secondary endpoints include cognitive performance as assessed by standardized cognitive testing, bone marrow protection, safety and tolerability, progression-free survival, overall tumor response rate, and plasma pharmacokinetics. Exploratory endpoints are health-related quality of life (as assessed by Functional Assessment of Cancer Therapy–Brain, Functional Assessment of Cancer Therapy-Cognition, and Functional Assessment of Chronic Illness Therapy-Fatigue), qualitative hair loss, and white matter integrity (as measured by MRI diffusion tensor/susceptibility imaging). Since November 2018, this phase II study has enrolled 64 of 160 high-grade glioma patients at six sites with future sites planned to be implemented. Clinical trial information: NCT02655601 .

e14540 Background: Glioblastoma (GBM) is the most common primary central nervous system (CNS) malignancy. In recent years, molecular and histological analyses have identified GBM with primitive neuronal component (GBM-PNC) as a distinct entity with poor regional control and worse overall prognosis. GBM-PNCs are more prone to CNS dissemination and leptomeningeal (LM) metastasis, occurring in up to 40% of patients. Given the concern for distal CNS spread, we hypothesized that craniospinal irradiation (CSI) may be an effective treatment option for GBM-PNC. Methods: We performed a retrospective chart review of patients diagnosed with GBM-PNC treated at a large academic center with institutional review board approval. Clinical, histologic and treatment characteristics, as well as disease outcomes were obtained from the electronic medical record. Results: Ten patients diagnosed with GBM-PNC were identified in the period of 2005-2019. Median follow-up was 17 months. Overall, 80% of patients were men, median age was 49 years (range 20-64) and ECOG 0-1. Fifty percent of patients received CSI as opposed to involved field radiation therapy (IFRT). Four of five patients receiving CSI were treated with proton therapy. All patients, but one received concurrent Temozolomide. Both IFRT and CSI were tolerated well with minimal grade 3-4 toxicities. Patients treated with CSI were more likely to experience transient grade 3-4 lymphopenia (60% vs 0%). Eighty percent of patients experienced a recurrence after treatment with median progression free survival (PFS) of 13 months (range 8-26). PFS did not differ between patients receiving IFRT and CSI (14 vs 12.5 months, p = 0.9). Median overall survival (OS) was 30 months for patients who received IFRT, and median OS was not reached in the CSI group. Of the patients who received CSI as part of their treatment, all recurrences were within the high dose radiation area. On the contrary, 75% of patients who received IFRT experienced multiple recurrences at new intracranial sites and later in the leptomeninges or the spine, requiring multiple treatment courses. Conclusions: This hypothesis generating study demonstrates that CSI may prevent distant intracranial metastasis and LM disease progression. CSI delivered with proton therapy was well tolerated with minimal additional toxicity. A larger study is needed to guide the optimal treatment of patients diagnosed with glioblastoma with primitive neuronal component.

The occurrence of amyotrophic lateral sclerosis (ALS) and neuromyelitis optica (NMO) in a single patient is exceedingly rare. We report a case of a 54-year-old woman of East Asian descent with a prior diagnosis of ALS who developed an episode of unexplained hiccups and nausea and vomiting consistent with area postrema syndrome 3 months prior to the onset of acute transverse myelitis. Magnetic resonance imaging revealed abnormal T2 hyperintensity and gadolinium enhancement at the cervicomedullary junction with extension to C3. Imaging was also notable for nonenhancing central cord T2 hyperintensity from T6 to T8 suggesting previous demyelination. The patient's cerebrospinal fluid analysis was mildly inflammatory. She was found to have a positive NMO/aquaporin-4 immunoglobulin G titer (cell-based assay) greater than 1:100 000, consistent with a diagnosis of NMO. The unusual coexistence of ALS and NMO prompts consideration of potential common pathological neuroinflammatory processes.

Malignant brain tumors such as glioblastoma (GBM) and brain metastasis have poor prognosis despite conventional therapies. Successful use of vaccines and checkpoint inhibitors in systemic malignancy has increased the hope that immune therapies could improve survival in patients with brain tumors. Manipulating the immune system to fight malignancy has a long history of both modest breakthroughs and pitfalls that should be considered when applying the current immunotherapy approaches to patients with brain tumors. Therapeutic vaccine trials for GBM date back to the mid 1900s and have taken many forms; from irradiated tumor lysate to cell transfer therapies and peptide vaccines. These therapies were generally well tolerated without significant autoimmune toxicity, however also did not demonstrate significant clinical benefit. In contrast, the newer checkpoint inhibitors have demonstrated durable benefit in some metastatic malignancies, accompanied by significant autoimmune toxicity. While this toxicity was not unexpected, it exceeded what was predicted from pre-clinical studies and in many ways was similar to the prior trials of immunostimulants. This review will discuss the history of these studies and demonstrate that the future use of immune therapy for brain tumors will likely need a personalized approach that balances autoimmune toxicity with the opportunity for significant survival benefit.

258 Background: Oral chemotherapies (OC) have transformed cancer care for millions of patients. While this has improved the patient experience, it presents significant challenges to safety of prescription, administration and side effect monitoring. While there are guidelines for documentation, there is not a best practices system for managing OC. This project identified areas of latent errors and implemented a standardized process for OC management. Methods: After review of the literature, we developed a process map for OC prescriptions at our institution. We then compared processes at three other neuro oncology clinics. We completed a hazard analysis and implemented several changes (see table). We identified binary measures in the medical record for every OC prescription that related to the process changes. Chart review of the 6 months prior to process change was used to create a baseline process mean for each variable. These same variables were monitored every 2 weeks after process change implementation using run charts. Successful process shift was defined as 7 consecutive 2-week averages that were continually on one side of the baseline process mean. Results: 5 months after process change was implemented, we had successfully reduced refills for OC and increased documentation of dose and dose calculation. There is a trend towards improvement in independently verified dose calculation and dedicated chemotherapy teaching visits, however these have not yet reached criteria for process change. Conclusions: This project used published studies, multi-institutional process mapping and hazard analysis to develop and implement a standardize process for OC. This process can be implemented for OC management in other oncology practices. [Table: see text]

Opinion statement Management of non-small cell lung cancer (NSCLC) with brain metastasis (BrM) has been revolutionized by identification of molecular subsets that have targetable oncogenes. Historically, survival for NSCLC with symptomatic BrM was weeks to months. Now, many patients are surviving years with limited data to guide treatment decisions. Tumors with activating mutations in epidermal growth factor receptor (EGFRact+) have a higher incidence of BrM, but a longer overall survival. The high response rate of both systemic and BrM EGFRact+ NSCLC to tyrosine kinase inhibitors (TKIs) has led to the rapid incorporation of new therapies but is outpacing evidence-based decisions for BrM in NSCLC. While whole brain radiation therapy (WBRT) was the foundation of management of BrM, extended survival raises concerns for the subacute and late effects radiotherapy. We favor the use of TKIs and delaying the use of WBRT when able. At inevitable disease progression, we consider alternative dosing schedules to increase CNS penetration (such as pulse dosing of erlotinib) or advance to next generation TKI if available. We utilize local control options of surgery or stereotactic radiosurgery (SRS) for symptomatic accessible lesions based on size and edema. At progression despite available TKIs, we use pemetrexed-based platinum doublet chemotherapy or immunotherapy if the tumor has high expression of PDL-1. We reserve the use of WBRT for patients with more than 10 BrM and progression despite TKI and conventional chemotherapy, if performance status is appropriate.