The immune system plays a significant role in cancer prevention and outcome. In high grade astrocytomas (HGA), severe lymphopenia is associated with shortened survival due to tumor progression. This ...study was performed to quantify serial changes in lymphocyte subsets in HGA following standard radiation (RT) and temozolomide (TMZ). Adults (KPS >60, HIV negative) with newly diagnosed HGA scheduled to receive concurrent RT and TMZ and adjuvant TMZ were eligible. Blood was collected before beginning concurrent RT/TMZ and at weeks 6, 10, 18, and 26, and 3 months after completing adjuvant TMZ. Lymphocyte subsets were analyzed by flow cytometry. Twenty patients (70% glioblastoma, median age 53, 50% male, 80% Caucasian) who enrolled from January 2014 to August 2014 were followed until April 2016. Baseline dexamethasone dose was 0.5 mg/day and 15% had absolute lymphocyte counts (ALC) <1000 cells/mm
3
before starting RT/TMZ. However, 75% developed lymphopenia with ALC <1000 cells/mm
3
after completion of RT/TMZ. NK cells, B cells and all T lymphocytes subsets dropped significantly after concurrent RT/TMZ and remained depressed for the 48 weeks of observation. The CD4+/CD8+ ratio was not affected significantly during follow-up. Severe lymphopenia involving all subsets occurred early in treatment and remained present for nearly 1 year. To our knowledge, this is the first report of serial trends in lymphocyte subsets following standard RT and TMZ for HGA.
Abstract
BACKGROUND
Cancer stem-like cells are a major cause of resistance to therapy in patients with glioblastoma (GBM) as well as other cancers. Tumor cells are maintained in a stem-like ...proliferative state in large part through the Notch signaling pathway. The function of this pathway in turn depends on gamma secretase activity. Inhibition of this enzyme therefore inhibits the Notch pathway and tumor growth as measured by a reduction in the formation of brain tumor neurospheres in murine models. RO4929097 is an oral gamma secretase inhibitor.
OBJECTIVE
To estimate the 6-mo progression-free survival rate (PFS6) in patients with progressive GBM and to inhibit by 50% the generation of neurospheres in fresh tissue resected from patients treated with RO4929097.
METHODS
In this phase II and pharmacodynamic study, patients with recurrent GBM received RO4929097 in a study of 2 groups. Group A patients had unresectable disease and received drug in a standard phase II design. Group B patients had resectable disease and received drug before and after surgical resection. Endpoints included PFS6 and the inhibition of neurosphere formation in the resected tumor samples.
RESULTS
A total of 47 patients received treatment, 7 of whom had tumor resection. The PFS6 was 4%, and the inhibition of neurosphere formation occurred in 1 of 7 patient samples.
CONCLUSION
RO4929097 was inactive in recurrent GBM patients and demonstrated minimal inhibition of neurosphere formation in fresh tissue samples.
Graphical Abstract
Graphical Abstract
Patients with glioblastoma (GBM) frequently deteriorate clinically and radiographically after chemoradiation and may require repeat surgical intervention. We attempted to correlate pathologic ...findings with preoperative clinical characteristics and survival in patients undergoing reoperation for GBM.
Patients eligible for this retrospective analysis had pathologically confirmed GBM diagnosed between 2005 and 2010, received standard radiation and temozolomide, and underwent repeat resection within 18 months of diagnosis.
Thirty-eight patients were identified. Median age was 56 years (range, 30 to 80 y), 55% were male, and 66% had baseline performance status ≥90%. Median survival was 16.3 months (95% confidence interval CI, 13.3-19.8) from initial surgery. At reoperation, 21% of patients had no pathologically evident tumor. Median time from initial diagnosis to second surgery was similar in patients with and without evident tumor (8.5 vs. 8.8 mo, respectively). Patients without evident tumor tended to have a worse performance status. Median overall survival from second surgery was 7 months (95% CI, 4.2-10.1) and 9.1 months (95% CI, 2.1-25.3) for patients with and without evident tumor, respectively. Multivariate proportional hazards analysis showed a hazard ratio for death of 0.61 (95% CI, 0.25-1.49) for patients without evident tumor after adjusting for Karnofsky performance status and second surgical procedure.
GBM patients with and without disease recurrence have similar clinical characteristics at the time of second surgical resection. Pathologic outcomes were not correlated with specific clinical or radiologic characteristics, including the time from diagnosis to reoperation. There was a trend toward improved overall survival among patients without evident tumor at reoperation.
Abstract Purpose: Patients with glioblastoma (GBM) have a dismal prognosis. Although the DNA alkylating agent temozolomide (TMZ) is the mainstay of chemotherapy, therapeutic resistance rapidly ...develops in patients. Base excision repair inhibitor TRC102 (methoxyamine) reverses TMZ resistance in preclinical glioma models. We aimed to investigate the efficacy and safety of oral TRC102+TMZ in recurrent GBM (rGBM). Patients and Methods: A preregistered (NCT02395692), nonrandomized, multicenter, phase 2 clinical trial (BERT) was planned and conducted through the Adult Brain Tumor Consortium (ABTC-1402). Arm 1 included patients with bevacizumab-naïve GBM at the first recurrence, with the primary endpoint of response rates. If sufficient activity was identified, a second arm was planned for the bevacizumab-refractory patients. The secondary endpoints were overall survival (OS), progression-free survival (PFS), PFS at 6 months (PFS6), and toxicity. Results: Arm 1 enrolled 19 patients with a median of two treatment cycles. Objective responses were not observed; hence, arm 2 did not open. The median OS was 11.1 months 95% confidence interval (CI), 8.2–17.9. The median PFS was 1.9 months (95% CI, 1.8–3.7). The PFS6 was 10.5% (95% CI, 1.3%–33.1%). Most toxicities were grades 1 and 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 the safety and feasibility of TRC102+TMZ in patients with rGBM. They also warrant further evaluation of combination therapy in biomarker-enriched trials enrolling GBM patients with baseline hyperactivated DDR pathways.
Venous thromboembolism occurs commonly throughout the clinical course of patients with brain tumors. A number of hemostatic and clinical factors contribute to this hypercoagulable state. Concern over ...the possibility of intracranial bleeding has limited the use of anticoagulation in this population. However, mechanical approaches such as vena cava filters have high complication and treatment failure rates in patients with intracranial malignancies. In addition, the available data suggest that anticoagulation can be used safely and effectively in most of these patients. Patients with thrombocytopenia, recent neurosurgery, and tumor types prone to bleeding require special consideration. When intracranial hemorrhage does occur, it is often due to overanticoagulation, requiring prompt anticoagulation reversal and neurosurgical consultation.
Vorinostat, a histone deacetylase (HDAC) inhibitor, has shown radiosensitizing properties in preclinical studies. This open-label, single-arm trial evaluated the maximum tolerated dose (MTD; phase I) ...and efficacy (phase II) of vorinostat combined with standard chemoradiation in newly diagnosed glioblastoma.
Patients received oral vorinostat (300 or 400 mg/day) on days 1-5 weekly during temozolomide chemoradiation. Following a 4- to 6-week rest, patients received up to 12 cycles of standard adjuvant temozolomide and vorinostat (400 mg/day) on days 1-7 and 15-21 of each 28-day cycle. Association between vorinostat response signatures and progression-free survival (PFS) and overall survival (OS) was assessed based on RNA sequencing of baseline tumor tissue.
Phase I and phase II enrolled 15 and 107 patients, respectively. The combination therapy MTD was vorinostat 300 mg/day and temozolomide 75 mg/m2/day. Dose-limiting toxicities were grade 4 neutropenia and thrombocytopenia and grade 3 aspartate aminotransferase elevation, hyperglycemia, fatigue, and wound dehiscence. The primary efficacy endpoint in the phase II cohort, OS rate at 15 months, was 55.1% (median OS 16.1 mo), and consequently, the study did not meet its efficacy objective. Most common treatment-related grade 3/4 toxicities in the phase II component were lymphopenia (32.7%), thrombocytopenia (28.0%), and neutropenia (21.5%). RNA expression profiling of baseline tumors (N = 76) demonstrated that vorinostat resistance (sig-79) and sensitivity (sig-139) signatures had a reverse and positive association with OS/PFS, respectively.
Vorinostat combined with standard chemoradiation had acceptable tolerability in newly diagnosed glioblastoma. Although the primary efficacy endpoint was not met, vorinostat sensitivity and resistance signatures could facilitate patient selection in future trials.
BackgroundThe benefit of immune checkpoint inhibitors (ICIs) in patients with leptomeningeal metastases (LMM) is unknown.MethodsWe undertook a phase II trial of pembrolizumab in patients with LMM ...from solid tumors. Eligible patients had radiologic/cytologic LMM and Eastern Cooperative Oncology Group performance status 0–1. Pembrolizumab was administered intravenously at 200 mg q3W until disease progression/unacceptable toxicity. The primary endpoint was central nervous system (CNS) response after four cycles, defined radiologically/cytologically/clinically. Serial cerebrospinal fluid (CSF) was assessed for tumor-derived DNA (t-DNA) aneuploidy and cytokines.ResultsThirteen of a planned 16 patients were treated between April 2017 and December 2019. The study closed early for poor accrual. Median age was 57 years (range: 22–79). Sixty-two percent of patients had tumors not traditionally ICI-responsive (hormone-receptor (HR)-positive breast carcinoma=39%; high-grade glioma=23%), while 38% had ICI-responsive tumors (non-small cell lung cancer (NSCLC)=23%, head and neck carcinoma=8%, cutaneous squamous carcinoma (CSC)=8%). CNS response was observed in 38% of patients at 12 weeks (95% CI 13.9% to 68.4%) by pre-defined criteria and LM-RANO, and 2 achieved durable complete responses (CSC=1, overall survival (OS) 3+ years; NSCLC=1, OS 9 months). Median CNS progression-free survival and OS was 2.9 months (95% CI 1.3 to NR) and 4.9 months (95% CI 3.7 to NR), respectively. Grade 3+ treatment-related adverse events occurred in 15% of patients. Sensitivity for LMM detection by t-DNA and cytopathology was 84.6% (95% CI 54.6% to 98.1%) and 53.9% (95% CI 25.1% to 80.8%), respectively. Pre-therapy and on-therapy CSF cytokine analysis demonstrated complete responders clustered together.ConclusionsPembrolizumab conferred a 38% CNS response rate in patients with LMM, a tolerable safety profile, and deep responses in selected patients with ICI-responsive tumors. CSF t-DNA may be sensitive for LMM detection, and immunologic subsets of CNS response warrant further study.Trial registration numberNCT03091478
The 2‐year survival rate of patients with glioblastoma accrued to research studies increased from 10% to nearly 40% from 2000 to 2010. These improvements began with the demonstration of a survival ...benefit when daily temozolomide was administered with 6 weeks of standard radiation and for 6 months thereafter. This treatment regimen is often associated with significant lymphopenia, thrombocytopenia, and progressive blood–brain barrier dysfunction that can result in clinical and radiologic deterioration without true tumor progression (“pseudoprogression”). With new evidence that combining this cytotoxic agent with radiation improves survival in this malignancy, many investigators have modified the regimen to further improve patient outcomes. These largely uncontrolled studies highlight controversies regarding the optimal therapy of this disease. This review focuses on the following selected controversies: (a) What is the appropriate temozolomide dose, schedule, and duration in the postradiation period? (b) How should other U.S. Food and Drug Administration–approved therapies (such as carmustine wafers and bevacizumab) be incorporated into this treatment regimen? (c) Should the results in glioblastoma be extrapolated to patients aged >70 and to patients with lower grade gliomas? and (d) How should novel therapeutic approaches be added to radiation and temozolomide in clinical trials for patients with newly diagnosed glioblastoma?
摘要
据研究报告，胶质母细胞瘤患者2年生存率从2000年的10%上升到2010年的近40%。这些进步源于以下研究证据：即每日替莫唑胺联合6周标准放疗继以替莫唑胺单药治疗6个月可改善患者生存。该治疗方案通常会引发淋巴细胞减少、血小板减少和进行性血脑屏障损害，进而导致临床和影像学恶化而非真正的肿瘤进展（“假性进展”）。凭借该细胞毒性药物联合放疗改善肿瘤生存的新证据，许多研究者已改良了该方案，以进一步改善患者转归。这些研究多为非对照研究，凸显了围绕该病最佳治疗的争论。本综述侧重以下争论点：①放疗后如何确定恰当的替莫唑胺剂量、方案以及疗程？②经美国FDA批准的其他疗法（例如卡莫司汀植入膜剂和贝伐单抗）应如何与以上治疗方案相整合？③胶质母细胞瘤的结果是否应推及>70岁的患者和低级别神经胶质瘤患者？④临床试验中新诊断的胶质母细胞瘤患者应如何在放疗和替莫唑胺治疗的基础上加用新型治疗手段？
Controversies in the adjuvant therapy of newly diagnosed high‐grade gliomas are analyzed and discussed.
Reports of cytomegalovirus (CMV) detection in high-grade gliomas (HGG)/glioblastoma have been conflicting. We undertook a comprehensive approach to determine the presence or absence of CMV in tissue, ...plasma, and serum of HGG patients.
In a retrospective arm, 25 fresh frozen tissues from glioblastoma patients were tested for CMV by real-time PCR. Tissue microarrays from 70 HGG patients were tested by IHC and 20 formalin-fixed paraffin-embedded (FFPE) glioblastoma tissues by IHC and chromogenic
hybridization (CISH), targeting CMV-encoded IE1/2 and pp65. In a prospective arm, 18 patients with newly diagnosed HGG provided tissue and blood samples.
All retrospectively collected tissues were negative for CMV by all methods. In the prospective cohort, 18 patients with newly diagnosed HGG provided blood samples at the time of diagnosis and during follow-up. Of 38 plasma specimens, CMV DNA was detected in 3 of 18 samples at baseline and 1 of 20 follow-up samples. Serum CMV IgG was positive in 8 of 15 (53%) of patients. Among the FFPE samples tested in the prospective arm, all were negative for CMV by IHC, CISH, and PCR.
Utilizing 6 highly sensitive assays with three orthogonal technologies on multiple specimens and specimen types, no evidence for CMV in glioblastoma tissues was found. Our findings call for multicenter blinded analyses of samples collected from different geographical areas with agreed upon study designs and determination of causality or lack thereof of CMV in HGG/glioblastoma for future guidance on the necessary antiviral and/or CMV-based therapies.
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