Prognostic value of cerebrospinal fluid tumor cell count in leptomeningeal disease from solid tumors.

PURPOSE: Treatment decisions for leptomeningeal disease (LMD) rely on patient risk stratification, since clinicians lack objective prognostic tools. The introduction of rare cell capture technology for identification of cerebrospinal fluid tumor cells (CSF-TCs), such as CNSide assay, improved the sensitivity of LMD diagnosis, but prognostic value is unknown. This study assesses the prognostic value of CSF-TC density in patients with LMD from solid tumors. METHODS: We conducted a retrospective cohort study of patients with newly diagnosed or previously treated LMD from a single institution who had CNSide assay testing for CSF-TCs from 2020 to 2023. Univariable and multivariable survival analyses were conducted with Cox proportional-hazards modeling. Maximally-selected rank statistics were used to determine an optimal cutpoint for CSF-TC density and survival. RESULTS: Of 31 patients, 29 had CSF-TCs detected on CNSide. Median (interquartile range [IQR]) CSF-TC density was 67.8 (4.7-639) TCs/mL. CSF cytology was positive in 16 of 29 patients with positive CNSide (CNSide diagnostic sensitivity = 93.5%, negative predictive value = 85.7%). Median (IQR) survival from time of CSF-TC detection was 176 (89-481) days. On univariable and multivariable analysis, CSF-TC density was significantly associated with survival. An optimal cutpoint for dichotomizing survival by CSF-TC density was 19.34 TCs/mL. The time-dependent sensitivity and specificity for survival using this stratification were 76% and 67% at 6 months and 65% and 67% at 1 year, respectively. CONCLUSIONS: CSF-TC density may carry prognostic value in patients with LMD from solid tumors. Integrating CSF-TC density into LMD patient risk-stratification may help guide treatment decisions.

Craniospinal irradiation for CNS leukemia: rates of response and durability of CNS control.

PURPOSE: Management of CNS involvement in leukemia may include craniospinal irradiation (CSI), though data on CSI efficacy are limited. METHODS: We retrospectively reviewed leukemia patients who underwent CSI at our institution between 2009 and 2021 for CNS involvement. CNS local recurrence (CNS-LR), any recurrence, progression-free survival (PFS), CNS PFS, and overall survival (OS) were estimated. RESULTS: Of thirty-nine eligible patients treated with CSI, most were male (59%) and treated as young adults (median 31 years). The median dose was 18 Gy to the brain and 12 Gy to the spine. Twenty-five (64%) patients received CSI immediately prior to allogeneic hematopoietic cell transplant, of which 21 (84%) underwent total body irradiation conditioning (median 12 Gy). Among 15 patients with CSF-positive disease immediately prior to CSI, all 14 assessed patients had pathologic clearance of blasts (CNS-response rate 100%) at a median of 23 days from CSI start. With a median follow-up of 48 months among survivors, 2-year PFS and OS were 32% (95% CI 18-48%) and 43% (95% CI 27-58%), respectively. Only 5 CNS relapses were noted (2-year CNS-LR 14% (95% CI 5-28%)), which occurred either concurrently or after a systemic relapse. Only systemic relapse after CSI was associated with higher risk of CNS-LR on univariate analysis. No grade 3 or higher acute toxicity was seen during CSI. CONCLUSION: CSI is a well-tolerated and effective treatment option for patients with CNS leukemia. Control of systemic disease after CSI may be important for CNS local control. CNS recurrence may reflect reseeding from the systemic space.

An overview of the therapeutic strategies for neoplastic meningitis due to breast cancer: when and why?

INTRODUCTION: Neoplastic meningitis (NM), also known as leptomeningeal carcinomatosis, is characterized by the infiltration of tumor cells into the meninges, and poses a significant therapeutic challenge owing to its aggressive nature and limited treatment options. Breast cancer is a common cause of NM among solid tumors, further highlighting the urgent need to explore effective therapeutic strategies. This review aims to provide insights into the evolving landscape of NM therapy in breast cancer by collating existing research, evaluating current treatments, and identifying potential emerging therapeutic options. AREAS COVERED: This review explores the clinical features, therapeutic strategies, recent advances, and challenges of managing NM in patients with breast cancer. Its management includes multimodal strategies, including systemic and intrathecal chemotherapy, radiation therapy, and supportive care. This review also emphasizes targeted drug options and optimal drug concentrations, and discusses emerging therapies. Additionally, it highlights the variability in treatment outcomes and the potential of combination regimens to effectively manage NM in breast cancer. EXPERT OPINION: Challenges in treating NM include debates over clinical trial end points and the management of adverse effects. Drug resistance and low response rates are significant hurdles, particularly inHER2-negative breast cancer. The development of more precise and cost-effective medications with improved selectivity is crucial. Additionally, global efforts are needed for infrastructure development and cancer control considering the diverse nature of the disease.

Central Nervous System Lymphoma.

Central nervous system lymphoma (CNSL) is a rare and aggressive malignancy that primarily affects the brain, spinal cord, and meninges. This article provides a comprehensive overview of the current understanding of CNSL encompassing its epidemiology, pathophysiology, clinical presentation, diagnosis, treatment modalities, and prognosis. Although the main focus is on primary CNS lymphoma (PCNSL), ocular lymphoma, primary leptomeningeal lymphoma, and secondary CNS lymphoma are also discussed. The pathobiology of CNSL involves the infiltration of malignant lymphocytes within the CNS parenchyma or leptomeninges. Various risk factors and immunological mechanisms contribute to its development, including immunodeficiency states, chronic inflammation, and genomic alterations. Accurate diagnosis is crucial for appropriate management, given the heterogeneous clinical presentation. The neuroimaging, systemic imaging, and other modalities for diagnosis and evaluation for extent of disease involvement will be discussed. Additionally, the importance of histopathological examination, cerebrospinal fluid (CSF) analysis, and molecular testing in confirming the diagnosis and guiding treatment decisions are highlighted. The treatment landscape for CNSL has evolved significantly. Therapeutic approaches encompass a multimodal strategy combining high-dose methotrexate-based chemotherapy, consolidation with whole-brain radiation therapy, and high-dose chemotherapy with stem cell rescue. Recent advancements in targeted therapies and immunomodulatory agents offer promising avenues for future treatment options. We review the clinical outcomes and prognostic factors influencing the survival of CNSL patients, including age, performance status, disease stage, and genetic abnormalities.

Emergent radiotherapy for spinal cord compression/impingement-a narrative review.

BACKGROUND AND OBJECTIVE: Malignant epidural spinal cord compression (MESCC), often presenting with back pain and motor/sensory deficits, is associated with poor survival, particularly when there is loss of ambulation. The purpose of this review is to evaluate the literature and discuss appropriate workup and management of MESCC, specifically in the emergent setting. METHODS: A PubMed search was conducted on "spinal cord compression" and "radiation therapy." Articles were analyzed for the purpose of this narrative review. KEY CONTENT AND FINDINGS: If MESCC is suspected, neurologic examination and complete spine imaging are recommended. Emergent treatment is indicated if there is radiographic evidence of high-grade compression and/or clinically significant motor deficits. Treatment involves a combination of medical management, surgical decompression, radiation therapy (RT), and rehabilitation. For motor deficits, emergent initiation of high dose steroids is recommended. Circumferential surgical decompression ± stabilization followed by RT provides superior clinical outcomes than RT alone. For patients whom surgery is not reasonable, RT alone may provide significant treatment response which depends on radioresponsiveness of the pathology. Systemic therapy, if indicated, is typically reserved till after primary treatment of MESCC, but patients with chemoresponsive tumors may receive primary chemotherapy. The selected RT schedule should be personalized to each patient and commonly is 30 Gy in 10 fractions (fx), 20 Gy in 5 fx, or 8 Gy in 1 fx. MESCC recurrence may be treated with additional RT, if within the spinal cord tolerance, or surgery. Stereotactic body radiation therapy (SBRT) has been used for high grade MESCC in patients with relatively intact neurologic function at a few centers with a very robust infrastructure to support rapid initiation of treatment within a short period of time, but is generally not feasible for most clinical practices. SBRT may be advantageous for low grade MESCC, recurrence, or in the post-operative setting. Detection of MESCC prior to development of high-grade compression or deterioration of neurologic function may allow patients to benefit more from advanced therapies and improve prognosis. CONCLUSIONS: MESCC is a devastating condition; optimal treatment should be personalized to each patient and approached collaboratively by a multidisciplinary team.

Emergent radiotherapy for brain and leptomeningeal metastases: a narrative review.

BACKGROUND AND OBJECTIVE: As novel systemic therapies allow patients to live longer with cancer, the risk of developing central nervous system (CNS) metastases increases and providers will more frequently encounter emergent presentation of brain metastases (BM) and leptomeningeal metastases (LM). Management of these metastases requires appropriate work-up and well-coordinated multidisciplinary care. We set out to perform a review of emergent radiotherapy (RT) for CNS metastases, specifically focusing on BM and LM. METHODS: We review the appropriate pathways for workup and initial management of BM and LM, while reviewing the literature supporting emergent treatment of these entities with surgery, systemic anti-cancer therapy, and RT. To inform this narrative review, literature searches in PubMed and Google Scholar were conducted, with preference given to articles employing modern RT techniques, when applicable. Due to the paucity of high-quality evidence for management of BM and LM in the emergent setting, discussion was supplemented by the authors' expert commentary. KEY CONTENT AND FINDINGS: This work highlights the importance of surgical evaluation, particularly for patients presenting with significant mass effect, hemorrhagic metastases, or increased intracranial pressure. We review the rare situations where emergent initiation of systemic anti-cancer therapy is indicated. When defining the role of RT, we review factors guiding selection of appropriate modality, treatment volume, and dose-fractionation. Generally, 2D- or 3D-conformal treatment techniques prescribed as 30 Gy in 10 fractions or 20 Gy in 5 fractions, should be employed in the emergent setting. CONCLUSIONS: Patients with BM and LM present from a diverse array of clinical situations, requiring well-coordinated multidisciplinary management, and there is a paucity of high-quality evidence guiding such management decisions. This narrative review aims to more thoroughly prepare providers for the challenging situation of emergent management of BM and LM.

Management of Brain Metastases from Human Epidermal Growth Factor Receptor 2 Positive (HER2+) Breast Cancer.

In the past 5 years, the treatment options available to patients with HER2+ breast cancer brain metastasis (BCBM) have expanded. The longer survival of patients with HER2+ BCBM renders understanding the toxicities of local therapies even more important to consider. After reviewing the available literature for HER2 targeted systemic therapies as well as local therapies, we present a simplified algorithm for when to prioritize systemic therapies over local therapies in patients with HER2+ BCBM.

Intracranial Solitary Fibrous Tumor/Hemangiopericytoma Treated with Microsurgical Resection: Retrospective Cohort Analysis of a Single-Center Experience.

Objective: To provide benchmarks for further studies of solitary fibrous tumor/hemangiopericytoma (SFT/HPC) of the central nervous system (CNS), we investigated the association of baseline demographic, clinico-pathologic, and treatment factors with outcomes in those treated at our center. Methods: We conducted a retrospective, cohort analysis of patients treated for SFT/HPC at the University of Washington 1990-2020. Kaplan-Meier and univariable Cox analyses assessed relationships between baseline variables and local or global CNS recurrence, extraneural recurrence, progression-free survival (PFS) and overall survival (OS). Results: Among 34 eligible patients, median duration of follow-up was 79 months (range 13-318 months). Local and global CNS recurrence occurred at a median of 81 m (95% CI 48-151) and 81 m (95% CI 47-112), respectively. Extraneural metastases occurred at a median 248 m (95% CI 180-Not Reached) and only in grade 3 tumors. Median PFS and OS were 76 months (95% CI: 47-109 months) and 210 months (95% CI 131-306 months), respectively. Univariable Cox analyses showed that age at diagnosis was associated with local (p = 0.01) and global CNS relapse (p = 0.01), and PFS (p = 0.03). Gross total resection was associated with decreased local or global CNS relapse (p = 0.02) and improved PFS (p = 0.03); peri-operative radiation was associated with decreased local CNS relapse (p = 0.02). Conclusion: Following microsurgical resection of SFT/HPC, CNS relapse is common and associated with age, extent of resection, and adjuvant radiation. Extraneural relapse occurs in some patients. Delayed time-to-initial relapse justifies prolonged surveillance, but optimal approaches have not been defined.

The optimal management of brain metastases from gestational trophoblastic neoplasia.

INTRODUCTION: 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. AREAS COVERED: 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.' EXPERT OPINION: 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.

Novel Therapeutic Approaches in Neoplastic Meningitis.

Central nervous system (CNS) metastasis from systemic cancers can involve the brain parenchyma, leptomeninges, or the dura. Neoplastic meningitis (NM), also known by different terms, including leptomeningeal carcinomatosis and carcinomatous meningitis, occurs due to solid tumors and hematologic malignancies and is associated with a poor prognosis. The current management paradigm entails a multimodal approach focused on palliation with surgery, radiation, and chemotherapy, which may be administered systemically or directly into the cerebrospinal fluid (CSF). This review focuses on novel therapeutic approaches, including targeted and immunotherapeutic agents under investigation, that have shown promise in NM arising from solid tumors.

Radiation Necrosis from Stereotactic Radiosurgery-How Do We Mitigate?

OPINION STATEMENT: 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.

Advances in Management of Brain and Leptomeningeal Metastases.

PURPOSE OF REVIEW: The management of brain and leptomeningeal metastases has changed significantly over the past decade. RECENT FINDINGS: Historically, radiation therapy had been the mainstay of treatment. Several strategies to limit toxicities with radiation have been developed in the recent years. Increasingly systemic therapy options are being considered an important therapeutic option for CNS metastases. Numerous novel small molecule inhibitors and immunotherapy agents have intracranial activity to varying degrees, in addition to good extracranial disease control. Overall, the prognosis of select patients with CNS metastases has improved over the past several years with advent of new therapeutic strategies. Systemic therapy options with CNS benefit should be considered in select patients with small and asymptomatic CNS metastases. Further areas of research focus on molecular alterations predisposing to CNS metastases, identification of small molecule inhibitors with CNS activity, and the combination of radiation therapy and immunotherapy.

Stereotactic radiosurgery in the treatment of adults with metastatic brain tumors.

Brain metastasis is the most common type of intracranial tumor affecting a significant proportion of advanced cancer patients. In recent years, stereotactic radiosurgery (SRS) has become commonly utilized. It has contributed significantly to decreased toxicity, prolonged quality of life and general improvement in outcomes of patients with brain metastases. Frequent imaging and advanced treatment techniques have allowed for the treatment of more patients with large and numerous metastases extending their overall survival. The addition of targeted therapy and immunotherapy to SRS has introduced novel treatment paradigms and has further improved our ability to effectively treat brain lesions. In this review, we examined in detail the available evidence for the use of SRS alone or in combination with surgery and systemic therapies. Given our developing understanding of the importance of primary tumor histology, the use of different treatment strategies for different metastasis is evolving. Combining SRS with immunotherapy and targeted therapy in breast cancer, lung cancer and melanoma as well as the use of preoperative SRS have shown significant promise in recent years and are investigated in multiple ongoing prospective trials. Further research is needed to guide the optimal sequence of therapies and to identify specific patient subgroups that may benefit the most from aggressive, combined treatment approaches.

Central Nervous System Metastasis in Patients With Urothelial Carcinoma: Institutional Experience and a Comprehensive Review of the Literature.

INTRODUCTION: Central nervous system (CNS) metastasis in patients with urothelial carcinoma (UC) is uncommon and poorly understood. We aimed to explore the clinical behavior and outcomes of this unique patient population. MATERIALS AND METHODS: We performed a retrospective analysis of patients with UC and CNS metastasis, treated in our institution (2006-2018), along with an exploratory patient-point meta-analysis of a similar patient population derived from a comprehensive literature review. Data regarding diagnosis, management, and outcomes were extracted. Overall survival, time to CNS metastasis (TTCM), and residual survival (RS) from CNS involvement to death were calculated (Kaplan-Meier method). Cox regression was used for testing key clinicopathologic associations. RESULTS: We identified 20 "institutional" and 154 "literature" patients with adequate data granularity for analysis. Median TTCM was 17.7 (institutional cohort) and 10 (literature cohort) months. Most patients who developed CNS metastases had previous non-CNS metastasis (15/20 [75%] and 103/154 [67%], respectively). CNS lesions without previous history of metastasis were identified in 5/20 (25%) and 33/154 (21%) cases and those patients had a shorter TTCM. CNS lesions in the absence of known UC history were also documented in 18/154 (12%) literature cases. Multifocal CNS disease was associated with shorter RS in both cohorts in univariate, but not multivariate, analysis. CONCLUSION: We observed a variability in disease presentation and course, with a subset of patients showing an early predilection for CNS insult, potentially reflecting a diverse underlying biology. Genomic profiling studies, elucidating the molecular landscape, and driving future treatments should be considered in this setting.

The Judicious Use of Stereotactic Radiosurgery and Hypofractionated Stereotactic Radiotherapy in the Management of Large Brain Metastases.

Brain metastases are the most common intracranial malignant tumor in adults and are a cause of significant morbidity and mortality for cancer patients. Large brain metastases, defined as tumors with a maximum dimension >2 cm, present a unique clinical challenge for the delivery of stereotactic radiosurgery (SRS) as patients often present with neurologic symptoms that require expeditious treatment that must also be balanced against the potential consequences of surgery and radiation therapy-namely, leptomeningeal disease (LMD) and radionecrosis (RN). Hypofractionated stereotactic radiotherapy (HSRT) and pre-operative SRS have emerged as novel treatment techniques to help improve local control rates and reduce rates of RN and LMD for this patient population commonly managed with post-operative SRS. Recent literature suggests that pre-operative SRS can potentially half the risk of LMD compared to post-operative SRS and that HSRT can improve risk of RN to less than 10% while improving local control when meeting the appropriate goals for biologically effective dose (BED) and dose-volume constraints. We recommend a 3- or 5-fraction regimen in lieu of SRS delivering 15 Gy or less for large metastases or resection cavities. We provide a table comparing the BED of commonly used SRS and HSRT regimens, and provide an algorithm to help guide the management of these challenging clinical scenarios.

Impact of EGFR mutation and ALK rearrangement on the outcomes of non-small cell lung cancer patients with brain metastasis.

BACKGROUND: The impact of activating alterations in non-small cell lung cancer (NSCLC) (epidermal growth factor receptor [EGFR] mutation/anaplastic lymphoma kinase [ALK] translocation) in prognosticating patients with brain metastasis (BM) is not well defined. This study was sought to identify this impact in NSCLC patients with BM accounting for the known validated variables. METHODS: Among 1078 NSCLC-BM patients diagnosed/treated between January 1, 2000 and December 31, 2015, three hundred and forty-eight with known EGFR/ALK status were analyzed. Overall survival (OS) and intracranial progression-free survival (PFS) were measured from the time of BM. RESULTS: Ninety-one patients had either ALK (n = 23) alterations or EGFR (n = 68) mutation and 257 were wild type (WT; negative actionable mutations/alterations). Median age of EGFR/ALK+ NSCLC BM patients was 60 years (range 29.8-82.6 y) and ~50% (n = 44) had Karnofsky performance status (KPS) score >80. Median number of BM was 2 (1 to ≥99). The median OS for the ALK/EGFR+ NSCLC BM was 19.9 versus 10.1 months for the WT (P = 0.028). The number of BM in the EGFR/ALK+ group did not impact OS (BM = 1 with 21.1 months vs 2-3 with 19.1 months and >3 with 23.7 months, P = 0.74), whereas fewer BM in the WT cohort had significantly better OS (BM = 1 with 13.8 mo, 2-3 with 11.0 mo and >3 with 8.1 mo; P = 0.006) with the adjustment of age, KPS, symptoms from BM and synchronicity. CONCLUSIONS: Number of BM does not impact outcomes in the EGFR/ALK+ NSCLC patients, implying that targeted therapy along with surgery and/or radiation may improve OS irrespective of the number of BM. Number of BM, extracranial metastasis (ECM), and KPS independently affected OS/PFS in WT NSCLC BM, which was consistent with the known literature.

Neurologic complications of melanoma.

Neurologic complications are common in patients with melanoma and are often associated with a poor prognosis. In an era with new, effective treatments, patients are living longer, and this has resulted in an increase in complications of both the disease and the therapy. A multidisciplinary approach to neurologic complications in patients with melanoma, with involvement from medical oncology, neuro-oncology, radiation oncology, and often neurosurgery, is necessary. In this review, neurologic complications of melanoma, including clinical implications and treatment strategies, are described.