Management of Complications in Neuro-oncology Patients.

OBJECTIVE: The purpose of this article is to familiarize the reader with the spectrum of neurologic and medical complications relevant to the care of patients with neurologic cancer while highlighting best practices to prevent morbidity and mortality. Topics include tumor-related epilepsy, vasogenic edema, complications of corticosteroid use, disruption of the hypothalamic-pituitary axis, venous thromboembolism, and opportunistic infection. LATEST DEVELOPMENTS: In 2021, a joint guideline from the Society for Neuro-Oncology and the European Association of Neuro-Oncology reaffirmed recommendations first established in 2000 that patients with newly diagnosed brain tumors should not be prescribed an antiseizure medication prophylactically. For those with tumor-related epilepsy, monotherapy with a non-enzyme-inducing anticonvulsant is the preferred initial treatment, and levetiracetam remains the preferred first choice. Surveys of physician practice continue to demonstrate excessive use of glucocorticoids in the management of patients with both primary and metastatic central nervous system malignancy. This is particularly concerning among patients who require checkpoint inhibitors as the efficacy of these agents is blunted by concomitant glucocorticoid use, resulting in a reduction in overall survival. Finally, direct oral anticoagulants have been shown to be safe in patients with brain tumors and are now favored as first-line treatment among those who require treatment for venous thromboembolism. ESSENTIAL POINTS: Medical care for patients impacted by primary and secondary central nervous system malignancy is complex and requires a committed team-based approach that routinely calls upon the expertise of physicians across multiple fields. Neurologists have an important role to play and should be familiar with the spectrum of complications impacting these patients as well as the latest recommendations for management.

Inaugural Results of the Individualized Screening Trial of Innovative Glioblastoma Therapy: A Phase II Platform Trial for Newly Diagnosed Glioblastoma Using Bayesian Adaptive Randomization.

PURPOSE: The Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) is a phase II platform trial that uses response adaptive randomization and genomic profiling to efficiently identify novel therapies for phase III testing. Three initial experimental arms (abemaciclib [a cyclin-dependent kinase [CDK]4/6 inhibitor], neratinib [an epidermal growth factor receptor [EGFR]/human epidermal growth factor receptor 2 inhibitor], and CC-115 [a deoxyribonucleic acid-dependent protein kinase/mammalian target of rapamycin inhibitor]) were simultaneously evaluated against a common control arm. We report the results for each arm and examine the feasibility and conduct of the adaptive platform design. PATIENTS AND METHODS: Patients with newly diagnosed O6-methylguanine-DNA methyltransferase-unmethylated glioblastoma were eligible if they had tumor genotyping to identify prespecified biomarker subpopulations of dominant glioblastoma signaling pathways (EGFR, phosphatidylinositol 3-kinase, and CDK). Initial random assignment was 1:1:1:1 between control (radiation therapy and temozolomide) and the experimental arms. Subsequent Bayesian adaptive randomization was incorporated on the basis of biomarker-specific progression-free survival (PFS) data. The primary end point was overall survival (OS), and one-sided P values are reported. The trial is registered with ClinicalTrials.gov (identifier: NCT02977780). RESULTS: Two hundred thirty-seven patients were treated (71 control; 73 abemaciclib; 81 neratinib; 12 CC-115) in years 2017-2021. Abemaciclib and neratinib were well tolerated, but CC-115 was associated with ≥ grade 3 treatment-related toxicity in 58% of patients. PFS was significantly longer with abemaciclib (hazard ratio [HR], 0.72; 95% CI, 0.49 to 1.06; one-sided P = .046) and neratinib (HR, 0.72; 95% CI, 0.50 to 1.02; one-sided P = .033) relative to the control arm but there was no PFS benefit with CC-115 (one-sided P = .523). None of the experimental therapies demonstrated a significant OS benefit (P > .05). CONCLUSION: The INSIGhT design enabled efficient simultaneous testing of three experimental agents using a shared control arm and adaptive randomization. Two investigational arms had superior PFS compared with the control arm, but none demonstrated an OS benefit. The INSIGhT design may promote improved and more efficient therapeutic discovery in glioblastoma. New arms have been added to the trial.

Alliance A071401: Phase II Trial of Focal Adhesion Kinase Inhibition in Meningiomas With Somatic NF2 Mutations.

PURPOSE: Patients with progressive or recurrent meningiomas have limited systemic therapy options. Focal adhesion kinase (FAK) inhibition has a synthetic lethal relationship with NF2 loss. Given the predominance of NF2 mutations in meningiomas, we evaluated the efficacy of GSK2256098, a FAK inhibitor, as part of the first genomically driven phase II study in recurrent or progressive grade 1-3 meningiomas. PATIENTS AND METHODS: Eligible patients whose tumors screened positively for NF2 mutations were treated with GSK2256098, 750 mg orally twice daily, until progressive disease. Efficacy was evaluated using two coprimary end points: progression-free survival at 6 months (PFS6) and response rate by Macdonald criteria, where PFS6 was evaluated separately within grade-based subgroups: grade 1 versus 2/3 meningiomas. Per study design, the FAK inhibitor would be considered promising in this patient population if either end point met the corresponding decision criteria for efficacy. RESULTS: Of 322 patients screened for all mutation cohorts of the study, 36 eligible and evaluable patients with NF2 mutations were enrolled and treated: 12 grade 1 and 24 grade 2/3 patients. Across all grades, one patient had a partial response and 24 had stable disease as their best response to treatment. In grade 1 patients, the observed PFS6 rate was 83% (10/12 patients; 95% CI, 52 to 98). In grade 2/3 patients, the observed PFS6 rate was 33% (8/24 patients; 95% CI, 16 to 55). The study met the PFS6 efficacy end point both for the grade 1 and the grade 2/3 cohorts. Treatment was well tolerated; seven patients had a maximum grade 3 adverse event that was at least possibly related to treatment with no grade 4 or 5 events. CONCLUSION: GSK2256098 was well tolerated and resulted in an improved PFS6 rate in patients with recurrent or progressive NF2-mutated meningiomas, compared with historical controls. The criteria for promising activity were met, and FAK inhibition warrants further evaluation for this patient population.

Chronic convection-enhanced delivery of topotecan for patients with recurrent glioblastoma: a first-in-patient, single-centre, single-arm, phase 1b trial.

BACKGROUND: Topotecan is cytotoxic to glioma cells but is clinically ineffective because of drug delivery limitations. Systemic delivery is limited by toxicity and insufficient brain penetrance, and, to date, convection-enhanced delivery (CED) has been restricted to a single treatment of restricted duration. To address this problem, we engineered a subcutaneously implanted catheter-pump system capable of repeated, chronic (prolonged, pulsatile) CED of topotecan into the brain and tested its safety and biological effects in patients with recurrent glioblastoma. METHODS: We did a single-centre, open-label, single-arm, phase 1b clinical trial at Columbia University Irving Medical Center (New York, NY, USA). Eligible patients were at least 18 years of age with solitary, histologically confirmed recurrent glioblastoma showing radiographic progression after surgery, radiotherapy, and chemotherapy, and a Karnofsky Performance Status of at least 70. Five patients had catheters stereotactically implanted into the glioma-infiltrated peritumoural brain and connected to subcutaneously implanted pumps that infused 146 µM topotecan 200 µL/h for 48 h, followed by a 5-7-day washout period before the next infusion, with four total infusions. After the fourth infusion, the pump was removed and the tumour was resected. The primary endpoint of the study was safety of the treatment regimen as defined by presence of serious adverse events. Analyses were done in all treated patients. The trial is closed, and is registered with ClinicalTrials.gov, NCT03154996. FINDINGS: Between Jan 22, 2018, and July 8, 2019, chronic CED of topotecan was successfully completed safely in all five patients, and was well tolerated without substantial complications. The only grade 3 adverse event related to treatment was intraoperative supplemental motor area syndrome (one [20%] of five patients in the treatment group), and there were no grade 4 adverse events. Other serious adverse events were related to surgical resection and not the study treatment. Median follow-up was 12 months (IQR 10-17) from pump explant. Post-treatment tissue analysis showed that topotecan significantly reduced proliferating tumour cells in all five patients. INTERPRETATION: In this small patient cohort, we showed that chronic CED of topotecan is a potentially safe and active therapy for recurrent glioblastoma. Our analysis provided a unique tissue-based assessment of treatment response without the need for large patient numbers. This novel delivery of topotecan overcomes limitations in delivery and treatment response assessment for patients with glioblastoma and could be applicable for other anti-glioma drugs or other CNS diseases. Further studies are warranted to determine the effect of this drug delivery approach on clinical outcomes. FUNDING: US National Institutes of Health, The William Rhodes and Louise Tilzer Rhodes Center for Glioblastoma, the Michael Weiner Glioblastoma Research Into Treatment Fund, the Gary and Yael Fegel Foundation, and The Khatib Foundation.

Practical guidance for telemedicine use in neuro-oncology.

While the COVID-19 pandemic has catalyzed the expansion of telemedicine into nearly every specialty of medicine, few articles have summarized current practices and recommendations for integrating virtual care in the practice of neuro-oncology. This article identifies current telemedicine practice, provides practical guidance for conducting telemedicine visits, and generates recommendations for integrating virtual care into neuro-oncology practice. Practical aspects of telemedicine are summarized including when to use and not use telemedicine, how to conduct a virtual visit, who to include in the virtual encounter, unique aspects of telehealth in neuro-oncology, and emerging innovations.

Diagnosis of Leptomeningeal Metastasis in Women With Breast Cancer Through Identification of Tumor Cells in Cerebrospinal Fluid Using the CNSide™ Assay.

INTRODUCTION: Diagnosis of LM is limited by low sensitivity of cerebrospinal fluid (CSF) cytopathology. Detecting tumor cells in CSF (CSF-TCs) might be more sensitive. We evaluated if CNSide (CNSide), a novel assay for tumor cell detection in CSF, can detect CSF-TCs better than conventional CSF cytology. METHODS: We enrolled adults with metastatic breast cancer and clinical suspicion for LM to undergo lumbar puncture (LP) for CSF cytopathology and CNSide. CNSide captured CSF-TCs using a primary 10-antibody mixture, streptavidin-coated microfluidic channel, and biotinylated secondary antibodies. CSF-TCs were assessed for estrogen receptor (ER) expression by fluorescent antibody and HER2 amplification by fluorescent in situ hybridization (FISH). CSF cell-free DNA (cfDNA) was extracted for next-generation sequencing (NGS). Leptomeningeal disease was defined as positive CSF cytology and/or unequivocal MRI findings. We calculated sensitivity and specificity of CSF cytology and CNSide for the diagnosis of LM. RESULTS: Ten patients, median age 51 years (range, 37-64), underwent diagnostic LP with CSF evaluation by cytology and CNSide. CNSide had sensitivity of 100% (95% Confidence Interval [CI], 40%-100%) and specificity of 83% (95% CI, 36%-100%) for LM. Among these patients, concordance of ER and HER2 status between CSF-TCs and metastatic biopsy were 60% and 75%, respectively. NGS of CSF cfDNA identified somatic mutations in three patients, including one with PIK3CA p.H1047L in blood and CSF. CONCLUSIONS: CNSide may be a viable platform to detect CSF-TCs, with potential use as a diagnostic tool for LM in patients with metastatic breast cancer. Additional, larger studies are warranted.

Causes of Death and End-of-Life Care in Patients With Intracranial High-Grade Gliomas: A Retrospective Observational Study.

BACKGROUND AND OBJECTIVES: To understand patterns of care and circumstances surrounding end of life in patients with intracranial gliomas. METHODS: We retrospectively analyzed end-of-life circumstances in patients with intracranial high-grade gliomas at Columbia University Irving Medical Center who died from January 2014 to February 2019, including cause of death, location of death, and implementation of comfort measures and resuscitative efforts. RESULTS: There were 152 patients (95 men, 57 women; median age at death 61.5 years, range 24-87 years) who died from January 2014 to February 2019 with adequate data surrounding end-of-life circumstances. Clinical tumor progression (n = 117, 77.0%) was the most common cause of death, with all patients transitioned to comfort measures. Other causes included, but were not limited to, infection (19, 12.5%); intratumoral hemorrhage (5, 3.3%); seizures (8, 5.3%); cerebral edema (4, 2.6%); pulmonary embolism (4, 2.6%); autonomic failure (2, 1.3%); and hemorrhagic shock (2, 1.3%). Multiple mortal events were identified in 10 (8.5%). Seventy-three patients (48.0%) died at home with hospice. Other locations were inpatient hospice (40, 26.3%); acute care hospital (34, 22.4%), including 27 (17.8%) with and 7 (4.6%) without comfort measures; skilled nursing facility (4, 3.3%), including 3 (2.0%) with and 1 (0.7%) without comfort measures; or religious facility (1, 0.7%) with comfort measures. Acute cardiac or pulmonary resuscitation was performed in 20 patients (13.2%). DISCUSSION: Clinical tumor progression was the most common (77.0%) cause of death, followed by infection (12.5%). Hospice or comfort measures were ultimately implemented in 94.7% of patients, although resuscitation was performed in 13.2%. Improved understanding of circumstances surrounding death, frequency of use of hospice services, and frequency of resuscitative efforts in patients with gliomas may allow physicians to more accurately discuss end-of-life expectations with patients and caregivers, facilitating informed care planning.

Patterns of seizure prophylaxis after oncologic neurosurgery.

BACKGROUND: Evidence supporting routine postoperative antiepileptic drug (AED) prophylaxis following oncologic neurosurgery is limited, and actual practice patterns are largely unknown beyond survey data. OBJECTIVE: To describe patterns and predictors of postoperative AED prophylaxis following intracranial tumor surgery. METHODS: The MarketScan Database was used to analyze pharmacy claims data and clinical characteristics in a national sample over a 5-year period. RESULTS: Among 5895 patients in the cohort, levetiracetam was the most widely used AED for prophylaxis (78.5%) followed by phenytoin (20.5%). Prophylaxis was common but highly variable for patients who underwent open resection of supratentorial intraparenchymal tumors (62.5%, reference) or meningiomas (61.9%). In multivariate analysis, biopsies were less likely to receive prophylaxis (44.8%, OR 0.47, 95% CI 0.33-0.67), and there was near consensus against prophylaxis for infratentorial (9.7%, OR 0.07, CI 0.05-0.09) and transsphenoidal procedures (0.4%, OR 0.003, CI 0.001-0.010). Primary malignancies (52.1%, reference) and secondary metastases (42.2%) were more likely to receive prophylaxis than benign tumors (23.0%, OR 0.63, CI 0.48-0.83), as were patients discharged with home services and patients in the Northeast. There was a large spike in duration of AED use at approximately 30 days. CONCLUSIONS: Use of seizure prophylaxis following intracranial biopsies and supratentorial resections is highly variable, consistent with a lack of guidelines or consensus. Current practice patterns do not support a clear standard of care and may be driven in part by geographic variation, availability of post-discharge services, and electronic prescribing defaults rather than evidence. Given uncertainty regarding effectiveness, indications, and appropriate duration of AED prophylaxis, well-powered trials are needed.

Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT): A Bayesian Adaptive Platform Trial to Develop Precision Medicines for Patients With Glioblastoma.

PURPOSE: Adequately prioritizing the numerous therapies and biomarkers available in late-stage testing for patients with glioblastoma (GBM) requires an efficient clinical testing platform. We developed and implemented INSIGhT (Individualized Screening Trial of Innovative Glioblastoma Therapy) as a novel adaptive platform trial (APT) to develop precision medicine approaches in GBM. METHODS: INSIGhT compares experimental arms with a common control of standard concurrent temozolomide and radiation therapy followed by adjuvant temozolomide. The primary end point is overall survival. Patients with newly diagnosed unmethylated GBM who are IDH R132H mutation negative and with genomic data available for biomarker grouping are eligible. At the initiation of INSIGhT, three experimental arms (neratinib, abemaciclib, and CC-115), each with a proposed genomic biomarker, are tested simultaneously. Initial randomization is equal across arms. As the trial progresses, randomization probabilities adapt on the basis of accumulating results using Bayesian estimation of the biomarker-specific probability of treatment impact on progression-free survival. Treatment arms may drop because of low probability of treatment impact on overall survival, and new arms may be added. Detailed information on the statistical model and randomization algorithm is provided to stimulate discussion on trial design choices more generally and provide an example for other investigators developing APTs. CONCLUSION: INSIGhT (NCT02977780) is an ongoing novel biomarker-based, Bayesian APT for patients with newly diagnosed unmethylated GBM. Our goal is to dramatically shorten trial execution timelines while increasing scientific power of results and biomarker discovery using adaptive randomization. We anticipate that trial execution efficiency will also be improved by using the APT format, which allows for the collaborative addition of new experimental arms while retaining the overall trial structure.

Headaches in Patients with Pituitary Tumors: a Clinical Conundrum.

PURPOSE OF REVIEW: Pituitary tumors account for approximately 17% of all intracranial neoplasms, with the majority being pituitary adenomas. Often, these are found incidentally during a workup for headache; however, the relationship between symptom and pathology remains unclear. The purpose of this article is to review the most recent literature on the epidemiology, pathophysiology, and management of headaches in patients with pituitary tumors. RECENT FINDINGS: The current literature is limited, with few prospective trials focusing on this question. With the exception of pituitary apoplexy, the relationship between headaches and pituitary masses remains unclear. Intervention does not always improve headache and can lead to development of new headache syndromes. Further research is needed to better elucidate the relationship between pituitary tumors and headaches. Headache alone is rarely an indication for surgical management of a pituitary adenoma.

Effectiveness of perioperative antiepileptic drug prophylaxis for early and late seizures following oncologic neurosurgery: a meta-analysis.

OBJECTIVE: The purpose of this meta-analysis was to evaluate the impact of perioperative antiepileptic drug (AED) prophylaxis on short- and long-term seizure incidence among patients undergoing brain tumor surgery. It is the first meta-analysis to focus exclusively on perioperative AED prophylaxis among patients undergoing brain tumor surgery. METHODS: The authors searched PubMed/MEDLINE, Embase, Cochrane Central Register of Controlled Trials, clinicaltrials.gov, and the System for Information on Gray Literature in Europe for records related to perioperative AED prophylaxis for patients with brain tumors. Risk of bias in the included studies was assessed using the Cochrane risk of bias tool. Incidence rates for early seizures (within the first postoperative week) and total seizures were estimated based on data from randomized controlled trials. A Mantel-Haenszel random-effects model was used to analyze pooled relative risk (RR) of early seizures (within the first postoperative week) and total seizures associated with perioperative AED prophylaxis versus control. RESULTS: Four RCTs involving 352 patients met the criteria of inclusion. The results demonstrated that perioperative AED prophylaxis for patients undergoing brain tumor surgery provides a statistically significant reduction in risk of early postoperative seizures compared with control (RR = 0.352, 95% confidence interval 0.130-0.949, p = 0.039). AED prophylaxis had no statistically significant effect on the total (combined short- and long-term) incidence of seizures. CONCLUSIONS: This meta-analysis demonstrates for the first time that perioperative AED prophylaxis for brain tumor surgery provides a statistically significant reduction in early postoperative seizure risk.

Fractionated stereotactic radiation therapy for brain metastases: a systematic review with tumour control probability modelling.

OBJECTIVE: Fractionated stereotactic radiotherapy (FSRT) is a relatively new option for the treatment of brain metastases. We performed a quantitative systematic review to determine if local control (LC) following is affected by FSRT dosing regimen. METHODS: We reviewed articles describing LC following FSRT for brain metastases. LC data from each study were extracted from actuarial survival curves and aggregated to form a single data set. LC curves were generated using the Kaplan-Meier method. Log-rank testing and Cox proportional hazards modelling were utilized to test for associations between the biologically effective dose (BED) and LC. Tumour control probability modelling was performed to illustrate the relationship between the BED and the likelihood of LC after FSRT. RESULTS: 10 studies (720 metastases) met inclusion criteria. Prescription doses ranged from 18 to 42 Gy, delivered in 3-12 fractions (BED range: 29-100 Gy10). 1- and 2-year actuarial LC rates were 80% and 69%, respectively. Increasing BED was associated with improved LC (HR = 0.77 per increase of 10 Gy10, p = 0.009). Tumour control probability models demonstrated that the BEDs of 40, 50 and 60 Gy10 yield predicted 1-year LC rates of 73%, 78% and 84%, respectively. The BEDs of 40, 50 and 60 Gy10 yield 2-year LC rates of 62%, 69% and 81%, respectively. CONCLUSION: FSRT provides high rates of LC for patients with brain metastases. We found evidence for a dose-response relationship that should be explored in prospective trials. Advances in knowledge: This review identified a dose-response relationship for LC in patients treated with FSRT for brain metastases.

Autologous stem cell transplant in recurrent or refractory primary or secondary central nervous system lymphoma using thiotepa, busulfan and cyclophosphamide.

The prognosis for patients with central nervous system (CNS) involvement by recurrent or refractory diffuse large B-cell lymphoma is poor, with overall survival (OS) of 4-10 months. High-dose chemotherapy (HDC) and autologous stem cell transplant (ASCT) is a potential treatment alternative. We reviewed patients with recurrent primary (PCNSL) or secondary (SCNSL) CNS lymphoma referred for consolidation HDC-ASCT utilizing thiotepa, busulfan and cyclophosphamide (TBC). Among the 17 patients included, all had achieved a complete remission after salvage induction chemotherapy, which incorporated methotrexate in 82% of patients. Two patients failed stem-cell harvesting and 15 (88%) underwent transplant. The estimated 3-year progression-free survival (PFS) and OS were both 93% (95% confidence interval 61-99%). Median PFS and OS were not reached. There was no transplant-related mortality. These results confirm the benefit of TBC followed by ASCT in select patients with recurrent PCNSL and suggest a potential role for the regimen in those with SCNSL. Further investigation is warranted.

Retrospective analysis of the effects of steroid therapy and antidiabetic medication on survival in diabetic glioblastoma patients.

AIMS: Type 2 diabetes mellitus (DM2) affects 10% of the population, but little is known about how DM2 and antidiabetic medication impact glioblastoma (GBM) patients. PATIENTS & METHODS: We retrospectively reviewed GBM patients with DM2 seen at a single institution from 1998 to 2010. RESULTS: Of 988 GBMs, 124 (12.6%) were affected by DM2. Thirty-four developed DM2 after steroid use and 89 had pre-existing DM2. Median overall survival among diabetic GBMs was 10 months compared with 13 months among nondiabetics. Only 15% of diabetic patients achieved sustained steroid taper. Sixty-seven (54%) were managed with a single antidiabetic medication and, within this monotherapy group, Karnofsky Performance Score, resection status, steroid dependency and metformin use were the most important predictors of survival on multivariate analysis. CONCLUSION: The prevalence of DM2 among GBMs is similar to that of the general population. A more aggressive approach to steroid tapering and the choice of antidiabetic drug may improve survival within this patient population.

Outcomes of the oldest patients with primary CNS lymphoma treated at Memorial Sloan-Kettering Cancer Center.

Up to 20% of all primary CNS lymphoma (PCNLS) patients are aged 80 years or older, yet data are limited on how best to treat this rapidly growing population. Despite demographic pressures and the proven efficacy of methotrexate (MTX)-based regimens, automatic de-escalation of care based on age is standard practice outside of tertiary care centers. We performed a retrospective review of all PCNSL patients aged 80 years or older treated at Memorial Sloan-Kettering Cancer Center from 1993 to 2011. Demographic and clinical variables were evaluated as predictors of survival by multivariate analysis. Twenty-three of 24 patients were treated with chemotherapy (92% with high-dose MTX, typically in combination with vincristine and procarbazine). One patient received ocular radiation alone for disease limited to the eyes. Response to treatment was noted in 62.5% of patients; 9 (37.5%) had refractory disease. Median overall survival was 7.9 months (95% confidence interval [CI]: 5.8-53), and median progression-free survival was 6.5 months (95% CI: 4.4-29.5). Two-year survival rate was 33%; 3-year survival rate was 17%. Three patients lived more than 4 years postdiagnosis. Most patients tolerated therapy well, and despite low baseline creatinine clearance, no significant renal toxicity was noted. Response status and deep brain involvement were identified as the most important predictors of survival. Multidrug regimens containing high-dose MTX are feasible and efficacious among the oldest patients, particularly those who achieve a complete response by their fifth treatment cycle. Aggressive therapy should be offered to select patients irrespective of advanced age.