RESUMO
The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of the following adult CNS cancers: glioma (WHO grade 1, WHO grade 2-3 oligodendroglioma [1p19q codeleted, IDH-mutant], WHO grade 2-4 IDH-mutant astrocytoma, WHO grade 4 glioblastoma), intracranial and spinal ependymomas, medulloblastoma, limited and extensive brain metastases, leptomeningeal metastases, non-AIDS-related primary CNS lymphomas, metastatic spine tumors, meningiomas, and primary spinal cord tumors. The information contained in the algorithms and principles of management sections in the NCCN Guidelines for CNS Cancers are designed to help clinicians navigate through the complex management of patients with CNS tumors. Several important principles guide surgical management and treatment with radiotherapy and systemic therapy for adults with brain tumors. The NCCN CNS Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel's most recent recommendations regarding molecular profiling of gliomas.
Assuntos
Neoplasias Encefálicas , Neoplasias do Sistema Nervoso Central , Adulto , Humanos , Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/terapia , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Sistema Nervoso Central , MutaçãoRESUMO
Ibrutinib is a first-in-class inhibitor of Bruton tyrosine kinase (BTK) and has shown single-agent activity in recurrent/refractory central nervous system (CNS) lymphoma. Clinical responses are often transient or incomplete, suggesting a need for a combination therapy approach. We conducted a phase 1b clinical trial to explore the sequential combination of ibrutinib (560 or 840 mg daily dosing) with high-dose methotrexate (HD-MTX) and rituximab in patients with CNS lymphoma (CNSL). HD-MTX was given at 3.5 g/m2 every 2 weeks for a total of 8 doses (4 cycles; 1 cycle = 28 days). Ibrutinib was held on days of HD-MTX infusion and resumed 5 days after HD-MTX infusion or after HD-MTX clearance. Single-agent daily ibrutinib was administered continuously after completion of induction therapy until disease progression, intolerable toxicity, or death. We also explored next-generation sequencing of circulating tumor DNA (ctDNA) in cerebrospinal fluid (CSF) before and during treatment. The combination of ibrutinib, HD-MTX, and rituximab was tolerated with an acceptable safety profile (no grade 5 events, 3 grade 4 events). No dose-limiting toxicity was observed. Eleven of 15 patients proceeded to maintenance ibrutinib after completing 4 cycles of the ibrutinib/HD-MTX/rituximab combination. Clinical responses occurred in 12 of 15 patients (80%). Sustained tumor responses were associated with clearance of ctDNA from the CSF. This trial was registered at www.clinicaltrials.gov as #NCT02315326.
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Antineoplásicos/uso terapêutico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Linfoma/tratamento farmacológico , Metotrexato/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Rituximab/uso terapêutico , Adenina/análogos & derivados , Adulto , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Idoso , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/patologia , DNA Tumoral Circulante/genética , Feminino , Humanos , Linfoma/genética , Linfoma/patologia , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Piperidinas , Inibidores de Proteínas Quinases/efeitos adversos , Pirazóis/efeitos adversos , Pirazóis/farmacocinética , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Rituximab/efeitos adversos , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: /Objectives: Pancreatic adenocarcinoma (PDAC) metastatic to the leptomeninges is a rare and lethal event. Leptomeningeal disease (LMD) research is limited in PDAC, and insights into clinical descriptors, possible disease predictors, and treatment strategies is necessitated. METHODS: Memorial Sloan Kettering databases were queried with Institutional Review Board approval to identify patients with LMD and PDAC treated between January 2000 and June 2020. Medical record review was used to abstract clinical, genomic, pathologic, and radiographic data. Overall survival was calculated from date of PDAC diagnosis to date of death. Previously published literature on LMD from PDAC was reviewed. RESULTS: Four patients with LMD from PDAC were identified, two males and two females. Age at diagnosis ranged from 57 to 68 years. All four patients had predominant lung metastasis and a relatively low burden of intra-abdominal disease. Somatic testing indicated alterations typical of PDAC and no PDAC defining pathogenic germline mutations were identified. An extended clinical course prior to LMD diagnosis was observed in all patients, ranging from 16 to 148 months. Upon diagnosis of LMD, three patients elected for supportive care and one patient received a limited course of craniospinal radiation. The median survival following diagnosis of LMD was 1.6 months (range 0.5-2.8 months). CONCLUSIONS: LMD from PDAC is a rare occurrence that may be more frequent in patients with lung metastasis and/or a more indolent clinical course. Following diagnosis of LMD, prognosis is poor, and survival is short. New treatment strategies for this manifestation of PDAC are needed.
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Carcinoma Ductal Pancreático/secundário , Neoplasias Meníngeas/secundário , Neoplasias Pancreáticas/patologia , Idoso , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/terapia , Terapia Combinada , Bases de Dados Factuais , Evolução Fatal , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Masculino , Neoplasias Meníngeas/diagnóstico , Neoplasias Meníngeas/terapia , Pessoa de Meia-Idade , Neoplasias Pancreáticas/terapia , Prognóstico , Estudos RetrospectivosRESUMO
Primary central nervous system lymphomas (PCNSLs) are rare cancers of the central nervous system (CNS) and are predominantly diffuse large B-cell lymphomas of the activated B-cell (ABC) subtype. They typically present in the sixth and seventh decade of life, with the highest incidence among patients aged >75 years. Although many different regimens have demonstrated efficacy in newly diagnosed and relapsed or refractory PCNSL, there have been few randomized prospective trials, and most recommendations and treatment decisions are based on single-arm phase II trials or even retrospective studies. High-dose methotrexate (HD-MTX; 3-8 g/m2) is the backbone of preferred standard induction regimens. Various effective regimens with different toxicity profiles can be considered that combine other chemotherapies and/or rituximab with HD-MTX, but there is currently no consensus for a single preferred regimen. There is controversy about the role of various consolidation therapies for patients who respond to HD-MTX-based induction therapy. For patients with relapsed or refractory PCNSL who previously experienced response to HD-MTX, repeat treatment with HD-MTX-based therapy can be considered depending on the timing of recurrence. Other more novel and less toxic regimens have been developed that show efficacy in recurrent disease, including ibrutinib, or lenalidomide ± rituximab. There is uniform agreement to delay or avoid whole-brain radiation therapy due to concerns for significant neurotoxicity if a reasonable systemic treatment option exists. This article aims to provide a clinically practical approach to PCNSL, including special considerations for older patients and those with impaired renal function. The benefits and risks of HD-MTX or high-dose chemotherapy with autologous stem cell transplantation versus other, better tolerated strategies are also discussed. In all settings, the preferred treatment is always enrollment in a clinical trial if one is available.
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Neoplasias Encefálicas , Neoplasias do Sistema Nervoso Central , Transplante de Células-Tronco Hematopoéticas , Linfoma não Hodgkin , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Sistema Nervoso Central , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/terapia , Irradiação Craniana , Humanos , Linfoma não Hodgkin/tratamento farmacológico , Metotrexato/uso terapêutico , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/terapia , Estudos Prospectivos , Estudos Retrospectivos , Transplante AutólogoRESUMO
The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of adult CNS cancers ranging from noninvasive and surgically curable pilocytic astrocytomas to metastatic brain disease. The involvement of an interdisciplinary team, including neurosurgeons, radiation therapists, oncologists, neurologists, and neuroradiologists, is a key factor in the appropriate management of CNS cancers. Integrated histopathologic and molecular characterization of brain tumors such as gliomas should be standard practice. This article describes NCCN Guidelines recommendations for WHO grade I, II, III, and IV gliomas. Treatment of brain metastases, the most common intracranial tumors in adults, is also described.
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Astrocitoma , Neoplasias Encefálicas , Neoplasias do Sistema Nervoso Central , Glioma , Adulto , Astrocitoma/diagnóstico , Astrocitoma/terapia , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/terapia , Sistema Nervoso Central , Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/terapia , Glioma/diagnóstico , Glioma/terapia , Humanos , Guias de Prática Clínica como AssuntoRESUMO
PURPOSE: It can be challenging to differentiate pseudoprogression from progression. We assessed the ability of dynamic contrast enhanced T1 MRI (DCE-MRI) perfusion to identify pseudoprogression in melanoma brain metastases. METHODS: Patients with melanoma brain metastases who underwent immunotherapy and DCE-MRI were identified. Enhancing lesions ≥ 5mm in diameter on DCE-MRI and that were new or increased in size between a week from beginning the treatment, and a month after completing the treatment were included in the analysis. The 90th percentiles of rVp and rKtrans and the presence or absence of hemorrhage were recorded. Histopathology served as the reference standard for pseudoprogression. If not available, pseudoprogression was defined as neurological and radiographic stability or improvement without any new treatment for ≥ 2 months. RESULTS: Forty-four patients were identified; 64% received ipilimumab monotherapy for a median duration of 9 weeks (range, 1-138). Sixty-four lesions in 44 patients were included in the study. Of these, nine lesions in eight patients were determined to be pseudoprogression and seven lesions were previously irradiated. Forty-four progression lesions and eight pseudoprogression lesions were hemorrhagic. Median lesion volume for pseudoprogression and progression were not significantly different, at 2.3 cm3 and 3.2 cm3, respectively (p = 0.82). The rVp90 was smaller in pseudoprogression versus progression, at 2.2 and 5.3, respectively (p = 0.02), and remained significant after false discovery rate adjustment (p = 0.04). CONCLUSIONS: Pseudoprogression exhibited significantly lower rVp90 on DCE-MRI compared with progression. This knowledge can be useful for managing growing lesions in patients with melanoma brain metastases who are receiving immunotherapy.
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Neoplasias Encefálicas/patologia , Imunoterapia/métodos , Imageamento por Ressonância Magnética/métodos , Melanoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/terapia , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Melanoma/terapia , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Meningiomas represent a full spectrum of tumors that are the most common type of brain tumor in adults. Although most are benign, recent research has shown that the recurrence rate is high, especially for WHO grades 2 and 3, and overall survival is poor for these grades. Treatment is evolving, and recently sunitinib and bevacizumab have shown promise compared with historical treatments. However, more research is needed to identify better treatments for meningiomas. Treatment of brain metastases is another evolving field. Studies suggest that stereotactic radiosurgery is preferable to whole-brain radiation therapy and that immune checkpoint inhibitors and therapies targeted to the T790M mutation and ALK can improve outcomes in patients with non-small cell lung cancer and brain metastases.
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Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/terapia , Neoplasias do Sistema Nervoso Central/etiologia , Terapia Combinada/métodos , Gerenciamento Clínico , Humanos , Gradação de Tumores , Estadiamento de Neoplasias , Guias de Prática Clínica como Assunto , Resultado do TratamentoRESUMO
PURPOSE: An increased incidence in hematologic toxicity has been reported with the addition of bevacizumab to lomustine for patients with recurrent or progressive high grade gliomas (HGG). Data regarding incidence of toxicity with combination bevacizumab and carmustine is limited. The purpose of this study is to compare toxicity of single agent carmustine and carmustine plus bevacizumab for patients with HGGs. METHODS: This single center retrospective study at Memorial Sloan Kettering Cancer Center included pathologically confirmed HGG with age ≥ 18 years who received carmustine between January 2003 and May 2017. RESULTS: Sixty-five patients with HGGs collectively received 110 doses of BCNU during the specified time period. Sixteen patients received single agent BCNU (30 doses); 49 patients received combination bevacizumab with BCNU (80 doses). There was no significant difference in incidence or grade of toxicity between single agent and combination therapy with respect to hepatotoxicity, leukopenia, lymphopenia, neutropenia, anemia, and thrombocytopenia. Rates of grade 3 and 4 neutropenia (20% vs 13.8%, p = 0.55) and thrombocytopenia (23.3% vs 23.8%, p = 1) did not differ between single agent BCNU versus combination therapy. When stratified based on dose ( < 150 mg/m2, 150 mg/m2, > 150 mg/m2), there was no statistically significant difference between the two groups with respect to grade 3 and 4 neutropenia or thrombocytopenia. CONCLUSIONS: This is the first study to report the toxicity of carmustine with or without bevacizumab for the treatment of recurrent and refractory HGG. The addition of bevacizumab to carmustine did not increase incidence or grade of hematologic toxicity when compared to single agent carmustine.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Encefálicas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Glioma/tratamento farmacológico , Doenças Hematológicas/induzido quimicamente , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Bevacizumab/administração & dosagem , Neoplasias Encefálicas/patologia , Carmustina/administração & dosagem , Feminino , Seguimentos , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia/patologia , Estudos Retrospectivos , Adulto JovemRESUMO
PURPOSE: Perifosine (PRF) is an oral alkylphospholipid with antineoplastic effects and reasonable tolerability. It inhibits signaling through the PI3/AKT axis and other cascades of biologic importance in glioblastoma, and has promising pre-clinical activity in vitro and in vivo. Therefore, we conducted a phase II open-label single-arm clinical trial of perifosine for patients with recurrent glioblastoma (GBM). METHODS: We planned to accrue up to 30 adults with recurrent GBM with a minimum Karnofsky Performance Status of 50 following radiotherapy but without other restrictions on the number or types of prior therapy. Concurrent p450 stimulating hepatic enzyme inducing anticonvulsants were prohibited. Patients were treated with a loading dose of 600 mg PRF (in 4 divided doses on day 1) followed by 100 mg daily until either disease progression or intolerable toxicity. The primary endpoint was the 6-month progression free survival (PFS6) rate, with at least 20% considered promising. Accrual was continuous but if 0 of the first 12 patients with GBM reached PFS6, then further accrual would terminate for futility. Patients with other high grade gliomas were accrued concurrently to an exploratory cohort. RESULTS: Treatment was generally well tolerated; gastrointestinal toxicities were the most common side effects, although none resulted in treatment discontinuation. However, there was limited to no efficacy in GBM (n = 16): the PFS6 rate was 0%, median PFS was 1.58 months [95% CI (1.08, 1.84)], median overall survival was 3.68 months [95% CI (2.50, 7.79)], with no radiographic responses. There was a confirmed partial response in one patient with anaplastic astrocytoma (n = 14). CONCLUSIONS: PRF is tolerable but ineffective as monotherapy for GBM. Preclinical data suggests synergistic effects of PRF in combination with other approaches, and further study is ongoing.
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Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Fosforilcolina/análogos & derivados , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Adulto , Idoso , Neoplasias Encefálicas/patologia , Feminino , Seguimentos , Glioblastoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Fosforilcolina/uso terapêutico , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida , Adulto JovemRESUMO
High-dose methotrexate-based chemotherapy is the mainstay of treatment of primary central nervous system lymphoma (PCNSL), but relapses remain frequent. High-dose chemotherapy (HDC) with autologous stem-cell transplant (ASCT) may provide an alternative to address chemoresistance and overcome the blood-brain barrier. In this single-center phase-2 study, newly diagnosed PCNSL patients received 5 to 7 cycles of chemotherapy with rituximab, methotrexate (3.5 g/m(2)), procarbazine, and vincristine (R-MPV). Those with a complete or partial response proceeded with consolidation HDC with thiotepa, cyclophosphamide, and busulfan, followed by ASCT and no radiotherapy. Primary end point was 1-year progression-free survival (PFS), N = 32. Median age was 57, and median Karnofsky performance status 80. Following R-MPV, objective response rate was 97%, and 26 (81%) patients proceeded with HDC-ASCT. Among all patients, median PFS and overall survival (OS) were not reached (median follow-up: 45 months). Two-year PFS was 79% (95% confidence interval [CI], 58-90), with no events observed beyond 2 years. Two-year OS was 81% (95% CI, 63-91). In transplanted patients, 2-year PFS and OS were 81%. There were 3 treatment-related deaths. Prospective neuropsychological evaluations suggested relatively stable cognitive functions posttransplant. In conclusion, this treatment was associated with excellent disease control and survival, an acceptable toxicity profile, and no evidence of neurotoxicity thus far. This trial was registered at www.clinicaltrials.gov as NCT00596154.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Nervoso Central/terapia , Transplante de Células-Tronco Hematopoéticas , Linfoma não Hodgkin/terapia , Adolescente , Adulto , Idoso , Anticorpos Monoclonais Murinos/administração & dosagem , Bussulfano/administração & dosagem , Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/mortalidade , Terapia Combinada , Ciclofosfamida/administração & dosagem , Citarabina/administração & dosagem , Feminino , Seguimentos , Humanos , Linfoma não Hodgkin/diagnóstico , Linfoma não Hodgkin/mortalidade , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Procarbazina/administração & dosagem , Prognóstico , Rituximab , Taxa de Sobrevida , Tiotepa/administração & dosagem , Transplante Autólogo , Vincristina/administração & dosagem , Adulto JovemRESUMO
For many years, the diagnosis and classification of gliomas have been based on histology. Although studies including large populations of patients demonstrated the prognostic value of histologic phenotype, variability in outcomes within histologic groups limited the utility of this system. Nonetheless, histology was the only proven and widely accessible tool available at the time, thus it was used for clinical trial entry criteria, and therefore determined the recommended treatment options. Research to identify molecular changes that underlie glioma progression has led to the discovery of molecular features that have greater diagnostic and prognostic value than histology. Analyses of these molecular markers across populations from randomized clinical trials have shown that some of these markers are also predictive of response to specific types of treatment, which has prompted significant changes to the recommended treatment options for grade III (anaplastic) gliomas.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/análise , Neoplasias do Sistema Nervoso Central/diagnóstico , Glioma/diagnóstico , Sistema Nervoso/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/normas , Neoplasias do Sistema Nervoso Central/classificação , Neoplasias do Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/terapia , Terapia Combinada/métodos , Terapia Combinada/normas , Glioma/classificação , Glioma/patologia , Glioma/terapia , Humanos , Terapia Neoadjuvante/métodos , Terapia Neoadjuvante/normas , Gradação de Tumores , Prognóstico , Radioterapia/métodos , Radioterapia/normasRESUMO
Antiangiogenic therapies for malignant gliomas often result in transient response, and recurrent disease is characterized by adoption of invasive and hypoxic phenotype. The notch signaling pathway is activated in gliomas, and augments cell migration and hypoxic response. Here we report a clinical study of the combination of bevacizumab and RO4929097, an inhibitor of the notch signaling cascade. A phase I clinical trial was conducted through the Adult Brain Tumor Consortium in subjects with recurrent malignant glioma. Primary objectives were to assess safety and to define the maximum tolerated dose of RO4929097 in combination with bevacizumab. Secondary objectives were to determine overall survival, progression free survival, radiographic response, pharmacokinetic evaluation, and tissue biomarker analysis. Thirteen subjects were enrolled. Of the three subjects treated with the highest dose of RO4929097, one grade 3 toxicity and one grade 2 toxicity were observed. Definitive maximum tolerated dose of RO4929097 in combination with bevacizumab was not identified due to manufacturer's decision to halt drug production. 2 of 12 evaluable subjects demonstrated radiographic response; one subject experienced CR and the second PR. The median overall survival was 10.9 months with a median progression-free survival of 3.7 months. Two subjects remained free of disease progression at 6 months from treatment initiation. PK evaluation did not identify clinically significant drug-drug interactions. All analyzed tissue specimens revealed activation of notch signaling. Combination of RO4929097 and bevacizumab was well-tolerated. Given the compelling scientific rationale, additional studies of antiangiogenic and notch signaling inhibitors should be considered.
Assuntos
Antineoplásicos/uso terapêutico , Benzazepinas/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Adulto , Neoplasias Encefálicas/mortalidade , Feminino , Glioma/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de TempoRESUMO
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Central Nervous System (CNS) Cancers provide interdisciplinary recommendations for managing adult CNS cancers. Primary and metastatic brain tumors are a heterogeneous group of neoplasms with varied outcomes and management strategies. These NCCN Guidelines Insights summarize the NCCN CNS Cancers Panel's discussion and highlight notable changes in the 2015 update. This article outlines the data and provides insight into panel decisions regarding adjuvant radiation and chemotherapy treatment options for high-risk newly diagnosed low-grade gliomas and glioblastomas. Additionally, it describes the panel's assessment of new data and the ongoing debate regarding the use of alternating electric field therapy for high-grade gliomas.
Assuntos
Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/radioterapia , Guias de Prática Clínica como Assunto , Adulto , Neoplasias do Sistema Nervoso Central/patologia , Humanos , Metástase NeoplásicaRESUMO
Pseudoprogression may present as transient new or increasing enhancing lesions that mimic recurrent tumors in treated glioblastoma. The purpose of this study was to examine the utility of dynamic contrast enhanced T1 magnetic resonance imaging (DCE MRI) in differentiating between pseudoprogression and tumor progression and devise a cut-off value sensitive for pseudoprogression. We retrospectively examined 37 patients with glioblastoma treated with radiation and temozolomide after surgical resection that then developed new or increasing enhancing lesion(s) indeterminate for pseudoprogression versus progression. Volumetric plasma volume (Vp) and time-dependent leakage constant (Ktrans) maps were measured for the enhancing lesion and the mean and ninetieth percentile histogram values recorded. Lesion outcome was determined by clinical follow up with pseudoprogression defined as stable disease not requiring new treatment. Statistical analysis was performed with Wilcoxon rank-sum tests. Patients with pseudoprogression (n = 13) had Vp (mean) = 2.4 and Vp (90 %tile) = 3.2; and Ktrans (mean) = 3.5 and Ktrans (90 %tile) = 4.2. Patients with tumor progression (n = 24) had Vp (mean) = 5.3 and Vp (90 %tile) = 6.6; and Ktrans (mean) = 7.4 and Ktrans (90 %tile) = 9.1. Compared with tumor progression, pseudoprogression demonstrated lower Vp perfusion values (p = 0.0002) with a Vp (mean) cutoff <3.7 yielding 85% sensitivity and 79% specificity for pseudoprogression. Ktrans (mean) of >3.6 had a 69% sensitivity and 79% specificity for disease progression. DCE MRI shows lower plasma volume and time dependent leakage constant values in pseudoprogression than in tumor progression. A cut-off value with high sensitivity for pseudoprogression can be applied to aid in interpretation of DCE MRI.
Assuntos
Neoplasias Encefálicas/patologia , Meios de Contraste/metabolismo , Glioblastoma/patologia , Imageamento por Ressonância Magnética , Recidiva Local de Neoplasia/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Alcaloides , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Dacarbazina/análogos & derivados , Dacarbazina/uso terapêutico , Imagem de Difusão por Ressonância Magnética , Progressão da Doença , Feminino , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/radioterapia , Curva ROC , Estudos Retrospectivos , Temozolomida , Fatores de Tempo , Resultado do TratamentoRESUMO
Leptomeningeal disease (LMD) is a devastating complication of melanoma with a dismal prognosis. We present the case of a young man with stage IV BRAF V600E mutant melanoma with lung, lymph node, and brain metastases initially treated with ipilimumab and nivolumab, who subsequently developed LMD. Upon change to BRAF/MEK targeted therapy with nivolumab, a durable complete response was achieved and remains ongoing, off treatment, 7 years from diagnosis. Management of symptomatic LMD remains a critical unmet clinical challenge, with limited clinical trial data. This exceptional case is instructive, as the first published case of the use of the triplet, and the first durable response with therapy discontinuation, in melanoma LMD. The triple-drug regimen may be considered a viable option in fit patients. This case highlights the potential for long-term disease control and the critical and urgent need to develop clinical trials inclusive of patients with LMD to define the best treatment strategies.
RESUMO
BACKGROUND: Ibrutinib is a first-in-class inhibitor of Bruton tyrosine kinase (BTK). We previously reported the safety and short-term antitumor activity of ibrutinib in 20 patients with relapsed or refractory (r/r) primary (PCNSL) or secondary CNS lymphoma (SCNSL). PATIENTS AND METHODS: We enrolled 26 additional patients with r/r PCNSL/SCNSL into the dose-expansion cohort of the trial into a combined cohort of 46 patients (31 PCNSLs, 15 SCNSLs). Patients received ibrutinib at 560mg or 840mg daily in the dose-escalation and 840mg daily in the expansion cohort. Median follow up was 49.9 and 62.1 months for patients with PCNSL and SCNSL, respectively. We sequenced DNA from available tumor biopsies and cerebrospinal fluid (CSF) collected before and during ibrutinib therapy. RESULTS: Tumor responses were observed in 23/31 (74%) PCNSLs and 9/15 (60%) SCNSLs, including 12 complete responses in PCNSL and 7 in SCNSL. Median progression-free survival (PFS) for PCNSL was 4.5 months (95%CI: 2.8-9.2) with 1y-PFS at 23.7% (95%CI: 12.4%-45.1%). Median duration of response (DOR) in the 23 PCNSL responders was 5.5 months. Median PFS in SCNSL was 5.3 months (95%CI: 1.3-14.5) with a median DOR 8.7 months for the 9 responders. Exploratory biomarker analysis suggests that mutations in TBL1XR1 may be associated with a long-term response to ibrutinib in PCNSL (p=0.0075). Clearance of circulating tumor DNA from CSF was associated with complete and long-term ibrutinib response. CONCLUSIONS: Our study confirms single-agent activity of ibrutinib in r/r CNS lymphoma and identifies molecular determinants of response based on long-term follow up. CLINICAL TRIAL INFORMATION: NCT02315326.
RESUMO
Central Nervous System (CNS) Lymphomas are aggressive brain tumors with limited treatment options. Targeting the phosphoinositide 3-kinase (PI3K) pathway yields promising responses across B-cell malignancies, but its therapeutic potential in CNS lymphomas remains unexplored. We present pre-clinical and clinical data on the pan-PI3K inhibitor Buparlisib in CNS lymphomas. In a primary CNS lymphoma-patient-derived cell line, we define the EC50. Four patients with recurrent CNS lymphoma were enrolled in a prospective trial. We evaluated Buparlisib plasma and cerebrospinal fluid pharmacokinetics, clinical outcomes, and adverse events. Treatment was well tolerated. Common toxicities include hyperglycemia, thrombocytopenia, and lymphopenia. The presence of Buparlisib in plasma and CSF was confirmed 2h post-treatment with a median CSF concentration below the EC50 defined in the cell line All four patients were evaluated for response and the median time to progression was 39 days. Buparlisib monotherapy did not lead to meaningful responses and the trial was prematurely stopped.Clinical Trial Registration: NCT02301364.
Assuntos
Linfoma não Hodgkin , Fosfatidilinositol 3-Quinases , Humanos , Estudos Prospectivos , Recidiva Local de Neoplasia/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Aminopiridinas/efeitos adversos , Doença Crônica , Sistema Nervoso CentralRESUMO
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.
Assuntos
Neoplasias Meníngeas , Meningioma , Humanos , Proteína-Tirosina Quinases de Adesão Focal/genética , Proteína-Tirosina Quinases de Adesão Focal/uso terapêutico , Neoplasias Meníngeas/tratamento farmacológico , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/patologia , Meningioma/tratamento farmacológico , Meningioma/genética , Mutação , Recidiva Local de Neoplasia/tratamento farmacológicoRESUMO
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.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/patologia , Distribuição Aleatória , Teorema de Bayes , Neoplasias Encefálicas/terapia , Receptores ErbB/genética , BiomarcadoresRESUMO
Immune-mediated anti-tumoral responses, elicited by oncolytic viruses and augmented with checkpoint inhibition, may be an effective treatment approach for glioblastoma. Here in this multicenter phase 1/2 study we evaluated the combination of intratumoral delivery of oncolytic virus DNX-2401 followed by intravenous anti-PD-1 antibody pembrolizumab in recurrent glioblastoma, first in a dose-escalation and then in a dose-expansion phase, in 49 patients. The primary endpoints were overall safety and objective response rate. The primary safety endpoint was met, whereas the primary efficacy endpoint was not met. There were no dose-limiting toxicities, and full dose combined treatment was well tolerated. The objective response rate was 10.4% (90% confidence interval (CI) 4.2-20.7%), which was not statistically greater than the prespecified control rate of 5%. The secondary endpoint of overall survival at 12 months was 52.7% (95% CI 40.1-69.2%), which was statistically greater than the prespecified control rate of 20%. Median overall survival was 12.5 months (10.7-13.5 months). Objective responses led to longer survival (hazard ratio 0.20, 95% CI 0.05-0.87). A total of 56.2% (95% CI 41.1-70.5%) of patients had a clinical benefit defined as stable disease or better. Three patients completed treatment with durable responses and remain alive at 45, 48 and 60 months. Exploratory mutational, gene-expression and immunophenotypic analyses revealed that the balance between immune cell infiltration and expression of checkpoint inhibitors may potentially inform on response to treatment and mechanisms of resistance. Overall, the combination of intratumoral DNX-2401 followed by pembrolizumab was safe with notable survival benefit in select patients (ClinicalTrials.gov registration: NCT02798406).