Evaluating the Base Excision Repair Inhibitor TRC102 and Temozolomide for patients with Recurrent Glioblastoma in the Phase 2 Adult Brain Tumor Consortium Trial BERT.

PURPOSE: Patients with glioblastoma (GBM) have a dismal prognosis. While DNA alkylating agent temozolomide (TMZ) is mainstay of chemotherapy, therapeutic resistance develops rapidly in patients. Base excision repair inhibitor TRC102 (methoxyamine) reverses TMZ resistance in preclinical glioma models. We sought to investigate efficacy and safety of oral TRC102+TMZ for recurrent GBM (rGBM). PATIENTS AND METHODS: A pre-registered (NCT02395692), non-randomized, multicenter, phase 2 clinical trial (BERT) was planned and conducted through the Adult Brain Tumor Consortium (ABTC-1402). Arm 1 included bevacizumab-naïve GBM patients at first recurrence, with primary endpoint of response rates. If sufficient activity was identified, a second arm was planned in bevacizumab-refractory patients. Secondary endpoints were overall survival (OS), progression-free survival (PFS), PFS at six months (PFS-6), and toxicity. RESULTS: Arm 1 enrolled 19 patients with median of two treatment cycles. Objective responses were not observed, hence, arm 2 did not open. Median OS was 11.1 months (95%CI 8.2-17.9). Median PFS was 1.9 months (95%CI 1.8-3.7). PFS-6 was 10.5% (95%CI 1.3-33.1%). Most toxicities were Grade 1-2, with two Grade 3 lymphopenias and one Grade 4 thrombocytopenia. Two patients with PFS ≥17 months and OS >32 months were deemed 'extended survivors'. RNA sequencing of tumor tissue, obtained at diagnosis, demonstrated significantly enriched signatures of DNA damage response (DDR), chromosomal instability (CIN70, CIN25), and cellular proliferation (PCNA25) in 'extended survivors'. CONCLUSIONS: These findings confirm safety and feasibility of TRC102+TMZ for rGBM patients. They also warrant further evaluation of combination therapy in biomarker-enriched trials enrolling GBM patients with baseline hyperactivated DDR pathways.

Endoglin inhibitor TRC105 with or without bevacizumab for bevacizumab-refractory glioblastoma (ENDOT): a multicenter phase II trial.

BACKGROUND: Glioblastoma (GBM), the most lethal primary brain tumor, has limited treatment options upon recurrence after chemoradiation and bevacizumab. TRC105 (carotuximab), a chimeric anti-endoglin (CD105) antibody, inhibits angiogenesis and potentiates activity of VEGF inhibitor bevacizumab in preclinical models. This study sought to assess safety, pharmacokinetics, and efficacy of TRC105 for bevacizumab-refractory GBM. METHODS: We conducted a pre-registered (NCT01564914), multicenter, open-label phase II clinical trial (ENDOT). We administered 10 mg/kg TRC105 monotherapy (first cohort) in adults with GBM and radiographic progression following radiation, temozolomide and bevacizumab therapy. Primary outcome was median time-to-progression (TTP), amended after first cohort's enrollment to median overall survival (mOS). Secondary outcomes were objective response rate, safety and tolerability, and progression-free survival (PFS). RESULTS: 6 patients were enrolled in TRC105 monotherapy cohort. Median TTP and PFS of 5 evaluable patients receiving monotherapy was 1.4 months, in whom plasma VEGF-A levels were elevated post-therapy. Lack of response led to protocol amendment, and second cohort's addition of bevacizumab+TRC105 with primary endpoint of mOS. 16 patients were enrolled in bevacizumab+TRC105 cohort. mOS of 15 evaluable patients was 5.7 (95%CI: 4.2-9.8) months. All 22 patients had measurable disease at baseline. Median PFS of 14 evaluable patients receiving bevacizumab+TRC105 was 1.8 months (95%CI 1.2-2.1). Serum TRC105 was measurable above target concentration of 25 ug/mL in all evaluable patients. Study medications were well-tolerated in both cohorts. Combined administration did not potentiate known toxicities of either medication, with cerebral hemorrhage not observed. CONCLUSIONS: Single-agent TRC105 lacks activity in bevacizumab-refractory GBM, possibly secondary to upregulated VEGF-A expression. Meaningful mOS in bevacizumab+TRC105 cohort warrants further trials to investigate efficacy of combination therapy.

Glioblastoma is an aggressive and lethal brain tumor, with patients typically expected to survive for 14 to 16 months after diagnosis. Nearly all patients experience tumor recurrence once conventional treatment strategies fail, after which a drug called bevacizumab is used. However, subsequent treatment options are extremely limited. We performed a clinical trial in which we investigated how safe and effective a new drug called TRC105 (carotuximab) is in patients who no longer respond to chemotherapy, radiotherapy or bevacizumab. We tested TRC105 both with and without bevacizumab, since TRC105 might enhance the activity of bevacizumab. We found that patients survived for an average of 5.7 months when given TRC105 and bevacizumab in combination. These findings suggest that further clinical trials are needed to confirm whether or not this combination therapy is a useful approach in patients with glioblastoma recurrence.

Association of metabolic syndrome with glioblastoma: a retrospective cohort study and review.

BACKGROUND: Metabolic syndrome is identified as a risk factor for the development of several systemic cancers, but its frequency among patients with glioblastoma and its association with clinical outcomes have yet to be determined. The aim of this study was to investigate metabolic syndrome as a risk factor for and affecting survival in glioblastoma patients. METHODS: A retrospective cohort study, consisting of patients with diagnoses at a single institution between 2007 and 2013, was conducted. Clinical records were reviewed, and clinical and laboratory data pertaining to 5 metabolic criteria were extrapolated. Overall survival was determined by time from initial surgical diagnosis to date of death or last follow-up. RESULTS: The frequency of metabolic syndrome among patients diagnosed with glioblastoma was slightly greater than the frequency of metabolic syndrome among the general population. Within a subset of patients (n = 91) receiving the full schedule of concurrent radiation and temozolomide and adjuvant temozolomide, median overall survival was significantly shorter for patients with metabolic syndrome compared with those without. In addition, the presence of all 5 elements of the metabolic syndrome resulted in significantly decreased median survival in these patients. CONCLUSIONS: We identified the metabolic syndrome at a slightly higher frequency in patients with diagnosed glioblastoma compared with the general population. In addition, metabolic syndrome with each of its individual components is associated with an overall worse prognosis in patients receiving the standard schedule of radiation and temozolomide after adjustment for age.

Immune checkpoint-mediated myositis and myasthenia gravis: A case report and review of evaluation and management.

BACKGROUND: We present a case of myositis and possible overlapping neuromuscular junction disorder following treatment with nivolumab for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). METHODS: We report a 75-year-old man with recurrent stage IVA, T1N2cM0 oral cavity HNSCC treated with weight-dosed nivolumab who presented three weeks later with severe fatigue, generalized weakness, and bilateral ptosis. Evaluation demonstrated elevated creatine kinase and myopathic motor units on electromyography, supporting a diagnosis of an underlying muscle disease. Elevated serum acetylcholine receptor binding antibodies raised the possibility of concurrent myasthenia gravis. RESULTS: He received corticosteroids and plasmapheresis without improvement in muscle weakness. His course was complicated by bacteremia, cardiac arrest, and concerns for recurrent malignancy. Following a two-month hospital stay, he was made comfort care and died. CONCLUSIONS: With increasing usage of checkpoint inhibitors in HNSCC, clinicians must be aware of and vigilant for associated rare but serious adverse events.

Comparative Brain and Central Nervous System Tumor Incidence and Survival between the United States and Taiwan Based on Population-Based Registry.

PURPOSE: Reasons for worldwide variability in the burden of primary malignant brain and central nervous system (CNS) tumors remain unclear. This study compares the incidence and survival of malignant brain and CNS tumors by selected histologic types between the United States (US) and Taiwan. METHODS: Data from 2002 to 2010 were selected from two population-based cancer registries for primary malignant brain and CNS tumors: the Central Brain Tumor Registry of the United States and the Taiwan Cancer Registry. Two registries had similar process of collecting patients with malignant brain tumor, and the quality of two registries was comparative. The age-adjusted incidence rate (IR), IR ratio, and survival by histological types, age, and gender were used to study regional differences. RESULTS: The overall age-adjusted IRs were 5.91 per 100,000 in the US and 2.68 per 100,000 in Taiwan. The most common histologic type for both countries was glioblastoma (GBM) with a 12.9% higher proportion in the US than in Taiwan. GBM had the lowest survival rate of any histology in both countries (US 1-year survival rate = 37.5%; Taiwan 1-year survival rate = 50.3%). The second largest group was astrocytoma, excluding GBM and anaplastic astrocytoma, with the distribution being slightly higher in Taiwan than in the US. CONCLUSION: Our findings revealed differences by histological type and grade of primary malignant brain and CNS tumors between two sites.

International Differences in Treatment and Clinical Outcomes for High Grade Glioma.

BACKGROUND: High grade gliomas are the most common type of malignant brain tumor, and despite their rarity, cause significant morbidity and mortality. This study aimed to compare the treatment patterns of high grade glioma to examine survival patterns in patients who receive specific treatments between cohorts in Ohio and Taiwan. METHOD: Patients aged 18 years and older at age of diagnosis with World Health Organization (WHO) grade III or IV astrocytoma from 2007-2012 were selected from the Ohio Brain Tumor Study and the Taiwan Cancer Registry. The treatment information was derived from medical chart reviews in Ohio and National Health Insurance Research Data in Taiwan. Treatment examined included surgical procedure (brain biopsy and/or resection), radiotherapy (radiation and/or radiosurgery), and alkylating chemotherapy. Kaplan-Meier and parametric survival models were used to examine the effect of treatment on survival, adjusted for age, sex, and comorbidities. RESULTS: 294 patients in Ohio and 1,097 patients in Taiwan met the inclusion criteria. 70.3% patients in Ohio and 51.4% in Taiwan received surgical resection, followed by concurrent chemoradiation. Patients who received this treatment had the highest survival rate, with a 1-year survival rate of 72.8% in Ohio and 73.4% in Taiwan. Patients who did not receive surgical resection, followed by concurrent chemoradiation had an increased risk of death (hazard ratio of 5.03 [95% confidence interval (CI): 3.61-7.02] in Ohio and 1.49 [95% CI: 1.31-1.71] in Taiwan) after adjustment for age, sex, and comorbidities. CONCLUSION: Surgical resection followed by concurrent chemoradiation was associated with higher survival rate of patients with high grade glioma in both Ohio and Taiwan; however, one-third of patients in Ohio and half in Taiwan did not receive this treatment.

Extra-CNS metastasis from glioblastoma: a rare clinical entity.

Extra-CNS metastasis from glioblastoma (ECMGBM) is an emerging but little known clinical entity. We review pre-clinical and translational publications assessing the ability of GBM to spread locally and outside the CNS. Reported cases demonstrating ECMGBM are reviewed providing a summary of presentations for the entity. Special attention is placed on transmission of GBM through organ transplantation. Finally, predictions are made as to the future significance of ECMGBM, especially in the context of better outcomes in CNS GBM.

Histologically Proven Radiation-Induced Brainstem Glioma 93 Months After External Beam Radiotherapy for Pituitary Macroadenoma: Radiation Treatment Dose and Volume Correlation.

Patient is a 29-year-old with a history of recurrent growth hormone-secreting pituitary macroadenoma diagnosed 12 years prior to presentation. Eight years prior to current presentation, the patient underwent re-resection and received 50.4 Gy external beam radiotherapy (EBRT) in 28 fractions of 1.8 Gy each. Serial postradiation MRIs demonstrated regression in pituitary tumor size. Patient presented with new headaches 7.5 years after completing EBRT. Brain MRI demonstrated new FLAIR hyperintensity and contrast enhancement within the pons and medulla, corresponding to the 36 Gy isodose line of each radiation dose fraction. Differential diagnosis included radiation necrosis and radiation-induced glioma (RIG). The patient's neurologic exam worsened over the following 4 months. MRI showed progressive increase in mass effect, extent of FLAIR hyperintensity, and contrast enhancement in the brainstem. Stereotactic-assisted biopsy showed infiltrating astrocytoma with moderate atypia. A PubMed search showed this is the first case of histologically verified brainstem RIG correlated with 3-dimensional conformational radiation therapy dose and volume planning following EBRT for a pituitary adenoma. The rare occurrence of brainstem RIG after radiation therapy for pituitary tumor supports the need for long-term imaging monitoring of such patients.

Chemotherapy and immunotherapy of brain tumors: what the epileptologist must know.

I present an overview of therapy for the most common brain tumors encountered in clinical practice if adult patients. Current therapy paradigms and evolving therapies are reviewed. The introduction of non-enzyme-inducing antiepileptic drugs (NEIADs) has simplified the approach to combined medical treatment of epilepsy and brain tumors, but the major interactions between enzyme-inducing antiepileptic drugs (EIAEDs) are included, to serve as guidance in selecting these medications if they are required.

Neurologic complications of radiation.

PURPOSE OF REVIEW: Radiation administered to treat CNS neoplasms or systemic cancers adjacent to the CNS can result in a variety of acute, subacute, and delayed clinical syndromes of the brain and spinal cord. Less commonly, the brachial or lumbosacral plexus or the cranial nerves are damaged by radiation therapy (RT). Cranial blood vessels can also be affected by brain RT, especially when it is administered during childhood and results in delayed vessel structural changes. These disorders are important because their presentation can mimic tumor recurrence. Knowledge of the classic clinical signs, imaging features, and time interval from RT will assist the practitioner in establishing the diagnosis and recommending treatment when appropriate. RECENT FINDINGS: The acute and subacute syndromes are temporary. An important subacute syndrome following focal external beam RT in combination with chemotherapy to treat newly diagnosed glioblastoma, termed pseudoprogression, has recently been characterized. In addition, recent clinical experience indicates that the delayed RT-induced CNS syndromes, once considered irreversible, can be treated effectively in some patients. SUMMARY: Recent and ongoing research is lending new insights into the mechanisms of RT-related CNS injury and will hopefully lead to more effective methods for the prevention and treatment of this undesired, but typically unavoidable, complication of RT.

Erlotinib therapy for central nervous system hemangioblastomatosis associated with von Hippel-Lindau disease: a case report.

There is a need for effective systemic therapy for central nervous system (CNS) hemangioblastomas (HBs). We report a case of erlotinib therapy for CNS HBs in a patient with von Hippel-Lindau disease, in whom the HBs were associated with diffuse leptomeningeal seeding. We provide the first report of paired serum and cerebrospinal fluid (CSF) levels of erlotinib while on standard dosing. The patient exhibited neurologic and imaging signs of recurrent CNS HBs and progressive leptomeningeal metastasis following surgery, radiation, and stereotactic radiosurgery. The patient was treated with erlotinib 150 mg daily. The patient achieved a minor response to erlotinib therapy, including clinical improvement, reduction in size of two enhancing brain lesions (one of which, however, proved at autopsy to be radiation necrosis) and stabilization of leptomeningeal enhancement. In addition, the CSF white count improved. The duration of response was 9 months. The median plasma and CSF levels of erlotinib while on treatment were 1146.06 and 247.83 ng/ml, respectively (CSF 21.6% of plasma). Erlotinib may have antitumor activity in CNS HBs.

Cerebrovascular complications in patients with cancer.

Stroke in the cancer patient is often caused by disorders of coagulation that are induced by the cancer, by cancer metastatic to the central nervous system, or by coagulation disorders or vascular injury due to cancer therapy. Nonbacterial thrombotic endocarditis in association with diffuse thrombosis of cerebral vessels is often the cause of cerebral infarction. Venous occlusion is most common in leukemic patients, but can also result from growth of solid tumor in the adjacent skull or dura. Chemotherapy administration is associated with a small risk of cerebral arterial or venous thrombosis. Radiation that is administered to the neck can result in delayed carotid atherosclerosis. Tumor embolization to the brain is a rare cause of stroke. Fungal septic cerebral emboli occur most commonly in leukemic patients who have undergone bone marrow transplantation. Hemorrhages occur in the brain parenchyma or the subdural and subarachnoid spaces and are most commonly caused by acute disseminated intravascular coagulation or metastatic tumor. Hemolysis from chemotherapy administration is a rare cause of brain hemorrhage. Careful clinical assessment, neuroimaging studies, measurement of coagulation function, and echocardiography are the most useful modalities to identify the cause of stroke.

Prolonged survival after multifocal brain radiation necrosis associated with whole brain radiation for brain metastases: case report.

Radiation necrosis of the brain is a well documented adverse effect of radiation therapy. The authors report an unusual case of relapsing multifocal radiation necrosis following whole brain radiation therapy (WBRT) for brain metastases from a systemic germ cell tumor. Anticoagulation with warfarin may have had therapeutic benefit. The patient is alive without a neurological deficit 10 years after the diagnosis of radiation necrosis.

Management of stroke in cancer.

Cerebrovascular disorders, including brain infarction, brain hemorrhage, and cerebral venous thrombosis, can occur as an early sign of cancer, but typically occur late in the clinical course. These disorders are due to a variety of pathogenic mechanisms, including coagulation disorders associated with the cancer, invasion or compression of vessels from tumor in or adjacent to the brain, and the adverse effects of cancer therapy. The appropriate therapy for these cerebrovascular disorders is empiric in most instances, because as yet there are no prospective treatment trials for them. A review of the existing literature reveals that improvement in patient quality of life and prevention of further cerebrovascular events can be obtained in some clinical situations.

The influence of caregiver mastery on depressive symptoms.

PURPOSE: The purpose of this study was to explore how the relationship between care recipients' problem behaviors and caregivers' depressive symptoms varies as a function of caregiver mastery, controlling for the effects of caregiver age, gender, and relationship to the care recipient in caregivers of people with primary malignant brain tumor (PMBT). DESIGN: A cross-sectional design was used to gather data via telephone interviews from 95 caregivers of people with primary malignant brain tumor, recruited from 2003 to 2004 from a brain tumor treatment center, two national support groups, and a statewide cancer registry. METHODS: Measures for the study included the Neuropsychiatric Inventory-Questionnaire, Caregiver Mastery, and the Center for Epidemiologic Studies-Depression. A stepwise regression procedure was used to evaluate potential moderating and mediating relationships. FINDINGS: Data did not indicate that caregiver mastery was a moderating variable. The analysis showed caregiver mastery as a partial mediator, with both a direct effect of care recipients' problem behaviors on caregivers' depressive symptoms and an indirect effect through caregiver mastery. Concerning the indirect effect, care recipients' problem behaviors were related to lower levels of caregiver mastery, which in turn were related to more depressive symptoms in caregivers. CONCLUSIONS: Findings showed a link between care recipients' problem behaviors and caregivers' depressive symptoms, a relationship that has not been well established in oncology. This association indicates one mechanism through which problem behaviors in the care recipient might lead to caregiver depressive symptoms.