Iatrogenic immunodeficiency-associated lymphoproliferative disorders of the central nervous system: a treatment paradox.

Background: Primary central nervous system lymphomas (PCNSLs) have historically had dismal survival rates until the advent of high-dose methotrexate (HD-MTX) based chemotherapy regimens. With increasing prevalence of autoimmune disease and development of new immunosuppressants, a genetically distinct entity known as iatrogenic immunodeficiency-associated lymphoproliferative disorder (LPD) has emerged. Many of these cases arise following methotrexate use, challenging feasibility of standard HD-MTX regimens. The aim of this study was to further characterize this disorder and determine the optimal management strategy. Methods: We describe a case of a 76-year-old female with iatrogenic immunodeficiency-associated PCNSL successfully treated with surgical resection followed by an antiviral and rituximab based regimen. We then performed a systematic literature review and identified 58 cases of non-transplant iatrogenic immunodeficiency-associated LPD involving the CNS. We used a linear probability statistical model to determine correlations with outcome. Results: Natalizumab was associated with EBV negative tumors (P = .023), and EBV positive tumors were associated with improved outcomes (P = .016). Surgical resection was associated with improved outcomes (P = .032), although limited by potential confounding effect. Antiviral treatment (P = .095), rituximab (P = .111), and stem cell transplant (SCT) (P = .198) showed a trend toward improved outcomes. The remaining treatments including methotrexate showed no improvement. Conclusion: We propose that surgical resection, rituximab, and antiviral treatment may be considered as an alternative to standard HD-MTX based regimens when managing iatrogenic immunodeficiency-associated LPD of the CNS. Further study through prospective cohort studies or randomized clinical trials is warranted.

Association of Autologous Tumor Lysate-Loaded Dendritic Cell Vaccination With Extension of Survival Among Patients With Newly Diagnosed and Recurrent Glioblastoma: A Phase 3 Prospective Externally Controlled Cohort Trial.

Importance: Glioblastoma is the most lethal primary brain cancer. Clinical outcomes for glioblastoma remain poor, and new treatments are needed. Objective: To investigate whether adding autologous tumor lysate-loaded dendritic cell vaccine (DCVax-L) to standard of care (SOC) extends survival among patients with glioblastoma. Design, Setting, and Participants: This phase 3, prospective, externally controlled nonrandomized trial compared overall survival (OS) in patients with newly diagnosed glioblastoma (nGBM) and recurrent glioblastoma (rGBM) treated with DCVax-L plus SOC vs contemporaneous matched external control patients treated with SOC. This international, multicenter trial was conducted at 94 sites in 4 countries from August 2007 to November 2015. Data analysis was conducted from October 2020 to September 2021. Interventions: The active treatment was DCVax-L plus SOC temozolomide. The nGBM external control patients received SOC temozolomide and placebo; the rGBM external controls received approved rGBM therapies. Main Outcomes and Measures: The primary and secondary end points compared overall survival (OS) in nGBM and rGBM, respectively, with contemporaneous matched external control populations from the control groups of other formal randomized clinical trials. Results: A total of 331 patients were enrolled in the trial, with 232 randomized to the DCVax-L group and 99 to the placebo group. Median OS (mOS) for the 232 patients with nGBM receiving DCVax-L was 19.3 (95% CI, 17.5-21.3) months from randomization (22.4 months from surgery) vs 16.5 (95% CI, 16.0-17.5) months from randomization in control patients (HR = 0.80; 98% CI, 0.00-0.94; P = .002). Survival at 48 months from randomization was 15.7% vs 9.9%, and at 60 months, it was 13.0% vs 5.7%. For 64 patients with rGBM receiving DCVax-L, mOS was 13.2 (95% CI, 9.7-16.8) months from relapse vs 7.8 (95% CI, 7.2-8.2) months among control patients (HR, 0.58; 98% CI, 0.00-0.76; P < .001). Survival at 24 and 30 months after recurrence was 20.7% vs 9.6% and 11.1% vs 5.1%, respectively. Survival was improved in patients with nGBM with methylated MGMT receiving DCVax-L compared with external control patients (HR, 0.74; 98% CI, 0.55-1.00; P = .03). Conclusions and Relevance: In this study, adding DCVax-L to SOC resulted in clinically meaningful and statistically significant extension of survival for patients with both nGBM and rGBM compared with contemporaneous, matched external controls who received SOC alone. Trial Registration: ClinicalTrials.gov Identifier: NCT00045968.

A Single-Center Experience of Dopamine Antagonist ONC201 for Recurrent Histone H3 Lysine 27-to-Methionine (H3K27M)-Mutant Glioblastoma in Adults.

This study aimed to report a single-center experience of three adult subjects receiving ONC201 as part of the ONC018-expanded access clinical trial (NCT03134131). ONC201 is an oral investigational antagonist against the D2 dopamine receptor that has shown encouraging results for malignant gliomas harboring the histone H3 lysine 27-to-methionine (H3K27M) mutation in the H3 histone complex. Responses have been reported in pediatric subjects with such tumors. An expanded access clinical trial (ONC018) was available to eligible patients allowing them access to this agent pending FDA review. Our site enrolled three subjects in the ONC018 trial. We present the demographic, clinical, and molecular characteristics of our enrolled subjects. We report the tolerability, adverse events, and outcome measures including survival, Karnofsky Performance Status (KPS), and quality-of-life measured by the MD Anderson symptom inventory instrument (MDASI). Three subjects were registered at our site onto ONC018 with the age range of 18-44 years, two of three were female, residing in Norway, India, and the United States. Tumor locations were brainstem, corpus callosum, and thalamus. Pathology includes glioblastoma (3/3), methylguanine-DNA methyltransferase (MGMT) methylated (2/3), isocitrate dehydrogenase 1 (IDH1) mutant (0/3), epidermal growth factor receptor (EGFR) amplification (0/3), and α thalassemia/mental retardation syndrome X­linked (ATRX) (3/3). Median change from baseline KPS ≤20% decrease; MDASI of 2/3 experienced decrease from baseline (median 6%), consistent with improved quality of life. No clinically significant laboratory abnormalities were found. All adverse events were grades I-II. We found that the study drug was quite tolerable. No serious adverse events nor radiographic responses were seen. Analyses of the larger study cohort and additional randomized controlled trials are necessary to provide insight into the safety and efficacy.

The Emergence of Virtual Tumor Boards in Neuro-Oncology: Opportunities and Challenges.

Background Virtual tumor board (VTB) platforms are an important aspect of cancer management. They enable easier access to a multidisciplinary team of experts. To deliver high-quality cancer care, it is necessary to coordinate numerous therapies and providers, share technical knowledge, and maintain open lines of communication among all professionals involved. The VTB is an essential tool in the diagnosis and treatment of brain cancer. For patients with glioma and brain metastases, multidisciplinary tumor board guidelines should guide diagnosis and therapy throughout the course of the illness. VTBs are an emerging resource across various cancer care networks in the United States. Methodology We performed a systematic search of all VTBs incorporating a platform designed for this specific role. We reviewed the records of the Genomet VTB, the Medical University of South Carolina (MUSC) VTB, and Xcures VTB. Summary data examined included the year of launch, demographics, characteristics of cases, average response time, advantages, and how they handle protected health information. Results Overall, 30% of VTBs examined were launched in 2017. All had a Health Insurance Portability and Accountability Act-compliant online environment. On a review of Xcures records, the median age of the female patients was 57 years and the median age of the male patients was 55 years. The data showed that 44% (4.4 out of every 10 patients) with a confirmed treatment chose the VTB integrated option. Overall, 76% of patients in the Xcures registry had primary central nervous system tumors, with at least 556 patients in the tumor registry which included 46% glioblastoma cases (96% primary, 4% secondary). In the MUSC VTB project, 112 thoracic tumor cases and nine neuro-oncology cases were reviewed. The tumor board met weekly, and the average response time was within 24 hours of case review and presentation. The Genomet VTB de-identifies all patient information; this is a virtual platform primarily focused on neuro-oncology cases. Cases involved a median of five specialists most commonly neuro-oncologists, neurosurgeons, radiation oncologists, molecular pathologists, and neuroradiologists. The case review revealed an age range of six months to 84 years (mean age = 44.5 years), with 69.6% males and 30.4% females, 43.5% glioblastomas, 8.7% adenocarcinomas, and 8.7% infratentorial tumors. The average response time observed in all cases was ≤24 hours. Conclusions VTBs allow for quicker expert analysis of cases. This has resulted in an accelerated number of cases reviewed with a shortened communication time. More studies are needed to gain additional insights into user engagement metrics.

Negative Impact of COVID-19 Upon Primary Brain Tumor Care.

Meningiomas are the most common primary central nervous system tumors, as they can account for up to one-third of all primary brain tumors. Most meningiomas are benign, although up to one-fourth of such tumors are classified as atypical or malignant. Atypical and malignant meningiomas are associated with an increased risk of local recurrence and decreased overall survival. Our patient is a 57-year-old male with a history of recurrent malignant meningioma, with metastasis to the liver. He underwent multiple surgical interventions, radiation treatments, and systemic therapies for a malignant meningioma, ultimately requiring transfer to hospice care. Not only did a positive novel coronavirus (COVID-19) infection delay his ability to receive radiation therapy, the infection in itself may have had an impact on the course of care for this patient. Treatment targeting the patient's COVID-19 infection may have suppressed the immune system, and as a result, caused the progression of metastatic disease. Palliative care was needed in the setting of losing all functional goals for quality of life due to malignant neoplasm.

Correlation of Tumor Treating Fields Dosimetry to Survival Outcomes in Newly Diagnosed Glioblastoma: A Large-Scale Numerical Simulation-Based Analysis of Data from the Phase 3 EF-14 Randomized Trial.

INTRODUCTION: Tumor Treating Fields (TTFields) are approved for glioblastoma based on improved overall survival (OS) and progression-free survival (PFS) in the phase 3 EF-14 trial of newly diagnosed glioblastoma. To test the hypothesis that increasing TTFields dose at the tumor site improves patient outcomes, we performed a simulation-based study investigating the association between TTFields dose and survival (OS and PFS) in patients treated with TTFields in EF-14. METHODS AND MATERIALS: EF-14 patient cases (N = 340) were included. Realistic head models were derived from T1-contrast images captured at baseline. The transducer array layout on each patient was obtained from EF-14 records; average compliance (fraction of time patient was on active treatment) and average electrical current delivered to the patient were derived from log files of the TTFields devices used by patients. TTFields intensity distributions and power densities were calculated using the finite element method. Local minimum dose density (LMiDD) was defined as the product of TTFields intensity, tissue-specific conductivities, and patient compliance. The average LMiDD within a tumor bed comprising the gross tumor volume and the 3-mm-wide peritumoral boundary zone was calculated. RESULTS: The median OS and PFS were significantly longer when the average LMiDD in the tumor bed was ≥0.77 mW/cm3: OS was 25.2 versus 20.4 months (P = .003, hazard ratio [HR] = 0.611) and PFS was 8.5 versus 6.7 months (P = .02, HR = 0.699). The median OS and PFS were longer when the average TTFields intensity was >1.06 V/cm: OS was 24.3 versus 21.6 months (P = .03, HR = 0.705) and PFS was 8.1 versus 7.9 months (P = .03, HR = 0.721). CONCLUSIONS: In this study we present the first reported analysis demonstrating patient-level dose responses to TTFields. We provide a rigorous definition for TTFields dose and set a conceptual framework for future work on TTFields dosimetry and treatment planning.

Correction to: First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma.

Following publication of the original article [1], the authors reported an error in the spelling of one of the author names. In this Correction the incorrect and correct author names are indicated and the author name has been updated in the original publication. The authors also reported an error in the Methods section of the original article. In this Correction the incorrect and correct versions of the affected sentence are indicated. The original article has not been updated with regards to the error in the Methods section.

First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma.

BACKGROUND: Standard therapy for glioblastoma includes surgery, radiotherapy, and temozolomide. This Phase 3 trial evaluates the addition of an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax®-L) to standard therapy for newly diagnosed glioblastoma. METHODS: After surgery and chemoradiotherapy, patients were randomized (2:1) to receive temozolomide plus DCVax-L (n = 232) or temozolomide and placebo (n = 99). Following recurrence, all patients were allowed to receive DCVax-L, without unblinding. The primary endpoint was progression free survival (PFS); the secondary endpoint was overall survival (OS). RESULTS: For the intent-to-treat (ITT) population (n = 331), median OS (mOS) was 23.1 months from surgery. Because of the cross-over trial design, nearly 90% of the ITT population received DCVax-L. For patients with methylated MGMT (n = 131), mOS was 34.7 months from surgery, with a 3-year survival of 46.4%. As of this analysis, 223 patients are ≥ 30 months past their surgery date; 67 of these (30.0%) have lived ≥ 30 months and have a Kaplan-Meier (KM)-derived mOS of 46.5 months. 182 patients are ≥ 36 months past surgery; 44 of these (24.2%) have lived ≥ 36 months and have a KM-derived mOS of 88.2 months. A population of extended survivors (n = 100) with mOS of 40.5 months, not explained by known prognostic factors, will be analyzed further. Only 2.1% of ITT patients (n = 7) had a grade 3 or 4 adverse event that was deemed at least possibly related to the vaccine. Overall adverse events with DCVax were comparable to standard therapy alone. CONCLUSIONS: Addition of DCVax-L to standard therapy is feasible and safe in glioblastoma patients, and may extend survival. Trial registration Funded by Northwest Biotherapeutics; Clinicaltrials.gov number: NCT00045968; https://clinicaltrials.gov/ct2/show/NCT00045968?term=NCT00045968&rank=1 ; initially registered 19 September 2002.

Novel approaches to treating leptomeningeal metastases.

Leptomeningeal metastasis is a devastating complication of the central nervous system in patients with late-stage solid or hematological cancers. Leptomeningeal metastasis results from the multifocal seeding of the leptomeninges by malignant cancer cells. Although central nervous system metastasis usually presents in patients with widely disseminated and progressive late-stage cancer, malignant cells may spread to the cerebrospinal fluid during earlier disease stages in particularly aggressive cancers. Treatment of leptomeningeal metastasis is largely palliative but will often provide stabilization and protection from further neurological deterioration and improve quality of life. There is a need to raise awareness of the impact of leptomeningeal metastases on cancer patients and its known and putative biological basis. Novel diagnostic approaches include identification of biomarkers that may stratify the risk for developing leptomeningeal metastasis. Current therapies can be used more effectively while waiting for advanced treatments to be developed.

Randomized double-blind placebo-controlled trial of bevacizumab therapy for radiation necrosis of the central nervous system.

PURPOSE: To conduct a controlled trial of bevacizumab for the treatment of symptomatic radiation necrosis of the brain. METHODS AND MATERIALS: A total of 14 patients were entered into a placebo-controlled randomized double-blind study of bevacizumab for the treatment of central nervous system radiation necrosis. All patients were required to have radiographic or biopsy proof of central nervous system radiation necrosis and progressive neurologic symptoms or signs. Eligible patients had undergone irradiation for head-and-neck carcinoma, meningioma, or low- to mid-grade glioma. Patients were randomized to receive intravenous saline or bevacizumab at 3-week intervals. The magnetic resonance imaging findings 3 weeks after the second treatment and clinical signs and symptoms defined the response or progression. RESULTS: The volumes of necrosis estimated on T(2)-weighted fluid-attenuated inversion recovery and T(1)-weighted gadolinium-enhanced magnetic resonance imaging scans demonstrated that although no patient receiving placebo responded (0 of 7), all bevacizumab-treated patients did so (5 of 5 randomized and 7 of 7 crossover) with decreases in T(2)-weighted fluid-attenuated inversion recovery and T(1)-weighted gadolinium-enhanced volumes and a decrease in endothelial transfer constant. All bevacizumab-treated patients-and none of the placebo-treated patients-showed improvement in neurologic symptoms or signs. At a median of 10 months after the last dose of bevacizumab in patients receiving all four study doses, only 2 patients had experienced a recurrence of magnetic resonance imaging changes consistent with progressive radiation necrosis; one patient received a single additional dose of bevacizumab and the other patient received two doses. CONCLUSION: The Class I evidence of bevacizumab efficacy from the present study in the treatment of central nervous system radiation necrosis justifies consideration of this treatment option for people with radiation necrosis secondary to the treatment of head-and-neck cancer and brain cancer.

Neoplastic meningitis resulting from hematological malignancies: pharmacokinetic considerations and maximizing outcome.

Neoplastic meningitis, also known as leptomeningeal metastases, is a complication of various types of cancer that occurs when tumor cells enter the cerebrospinal fluid (CSF), travel along CSF pathways and grow. Treatment options include drug delivery directly into the CNS or systemic administration for targeted action in the CNS. CNS drug delivery is limited by the blood-brain barrier and the blood-CSF barrier. It may be possible to partially overcome this by using high-dose systemic therapy; however, this is done at the possible expense of increased systemic toxicity. Intra-CSF drug delivery bypasses the blood-brain barrier and allows direct access of the chemotherapeutic agent to the CSF. Because neoplastic meningitis occurs in an increasingly large percentage of all cancer patients, it is imperative to optimize drug delivery to the CSF and meninges. Both the pharmacokinetic profile of the chemotherapeutic agent and the site of administration influence therapeutic efficacy. Achieving prolonged therapeutic cytotoxic drug concentrations and even distribution in the CSF will improve efficacy. In this article we summarize data on the efficacy, safety and outcome of high-dose systemic and intra-CSF treatments.

Breast cancer surface receptors predict risk for developing brain metastasis and subsequent prognosis.

Determining the status of breast cancer surface receptors (estrogen receptor, progesterone receptor, HER2/neu) has become routine in the care of patients with this disease and has proven to be helpful in guiding treatment. For this reason, breast cancer has become a model for molecularly guided therapy in solid tumors. Emerging data support that these receptors are associated with risk for developing brain metastases. Additionally, once brain metastases have occurred these receptors may also correlate with prognosis.

Seizures and epilepsy in cancer: etiologies, evaluation, and management.

Seizure and epilepsy are common neurologic issues in cancer patients. Etiologies include structural abnormalities of the brain (eg, brain metastasis), cerebrovascular disease, reversible posterior leukoencephalopathy syndrome (RPLS), and radiation toxicity. Seizures associated with these etiologies often have focal features. Metabolic causes include hypoglycemia, electrolyte abnormalities, tumor lysis syndrome, thrombotic thrombocytopenic purpura (TTP), and medications used in cancer. A careful clinical evaluation can suggest the seizure etiology and guide subsequent work-up. Nonconvulsive status epilepticus should be suspected with persistent decreased level of consciousness following a seizure. Certain etiologies, such as RPLS and TTP, must be treated aggressively to minimize permanent neurologic injury. Routine prophylaxis with antiepileptic drugs (AEDs) is not recommended in patients with primary brain tumors or brain metastasis who have never had a seizure. Where indicated, the selection of AEDs should take into consideration side effects and interactions with chemotherapy. For this reason, non-enzyme-inducing AEDs are preferable in the cancer setting.