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1.
J Neurooncol ; 161(1): 33-43, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-36581779

RESUMEN

PURPOSE: Gliomagenesis and resistance of glioblastoma (GBM) are believed to be mediated by glioma stem cells (GSC). Evidence suggests that SHH signaling promotes GSC proliferation and self-renewal. METHODS: ABTC-0904 was a two-arm, multicenter phase 0/II study of GDC-0449, an oral inhibitor of Smoothened (SMO) in patients undergoing resection for recurrent GBM. All patients (Arms I and II) had surgery and received drug post-operatively. Only patients in Arm I received drug prior to surgery. The primary objective was to determine 6-month progression free survival (PFS-6). Secondary endpoints include median PFS (mPFS) and overall survival (mOS), response rate, and toxicity. Correlative studies included bioanalysis of GDC-0449, and inhibition of SHH signaling, GSC proliferation and self-renewal. RESULTS: Forty-one patients were enrolled. Pharmacokinetics of GDC-0449 in plasma demonstrated levels within expected therapeutic range in 75% of patients. The proportion of tumorcells producing CD133+ neurospheres, neurosphere proliferation, self-renewal, and expression of the SHh downstream signaling was significantly decreased in Arm I following GDC-0449 treatment (p < 0.005; p < 0.001 respectively) compared to Arm II (no drug pre-op). Treatment was well tolerated. There were no objective responders in either arm. Overall PFS-6 was 2.4% (95% CI 0.9-11.1%). Median PFS was 2.3 months (95% CI 1.9-2.6) and mOS was 7.8 months (95% CI 5.4-10.1). CONCLUSIONS: GDC-0449 was well tolerated, reached tumor, and inhibited CD133+ neurosphere formation, but had little clinical efficacy as a single agent in rGBM. This suggests growth and maintenance of rGBM is not solely dependent on the SHH pathway thus targeting SMO may require combined approaches.


Asunto(s)
Antineoplásicos , Neoplasias Encefálicas , Glioblastoma , Glioma , Humanos , Glioblastoma/patología , Proteínas Hedgehog/metabolismo , Recurrencia Local de Neoplasia/patología , Glioma/patología , Antineoplásicos/metabolismo , Células Madre Neoplásicas/patología , Neoplasias Encefálicas/patología
2.
Oncologist ; 25(9): 747-e1273, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32520407

RESUMEN

LESSONS LEARNED: The findings from this study using monotherapy with pemetrexed in a pretreated patient population are, overall, encouraging. Unlike high-dose methotrexate, which requires several days of inpatient hospitalization, pemetrexed is relatively easy to administer in the outpatient setting and remains a viable treatment option in this patient population. The maximum tolerated dose of pemetrexed administered (900 mg/m2 every 2 weeks) was generally well tolerated and showed activity in patients with relapsed or refractory CNSL. BACKGROUND: There is currently no standard salvage treatment for patients with relapsed/refractory central nervous system (CNS) lymphoma (CNSL). We report the results of a phase I study of pemetrexed, an antifolate drug with broader activity than methotrexate (MTX). We provide the safety, tolerability, and maximum tolerated dose (MTD) of pemetrexed in patients with recurrent CNSL. METHODS: Through October 2015, 17 patients with relapsed/refractory CNSL received pemetrexed every 2 weeks with the first cohort receiving 600 mg/m2 and dose escalation in increments of 300 mg/m2 to a maximum of 1,200 mg/m2 . Three patients were to enroll at each dose level with expansion to six patients in the event of dose-limiting toxicity. Patients with both primary CNS lymphoma (PCNSL) and secondary CNS lymphoma (SCNSL) could be enrolled. RESULTS: Seventeen patients were evaluable with a median age of 63.7 years. Main adverse events included fatigue (82.4%), anemia (82.4%), and neutropenia (70.6%). The MTD was established at 900 mg/m2 . Dose-limiting toxicities were recorded in one patient in the 600 mg/m2 cohort and in two patients in the 1,200 mg/m2 cohort. Fourteen patients were evaluable for response assessment; 21.4% achieved a complete response, 35.7% had a partial response, 14.3% had stable disease, and 28.6% had progressive disease. The median progression-free survival was 4.2 months. The median overall survival was 44.5 months. In the original study protocol, the plan was to add an expansion cohort of six patients at MTD level. However, the first phase of the study was characterized by slow recruitment. Therefore, after achieving the primary objective of the study and establishing the MTD, the investigators decided to amend the protocol and to close the study. CONCLUSION: Pemetrexed administered at 900 mg/m2 every 2 weeks exhibits single-agent activity in patients with recurrent CNSL; it is well tolerated, and side effects are manageable.


Asunto(s)
Linfoma no Hodgkin , Linfoma , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Sistema Nervioso Central , Humanos , Linfoma/tratamiento farmacológico , Linfoma no Hodgkin/tratamiento farmacológico , Dosis Máxima Tolerada , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Pemetrexed/uso terapéutico
3.
Oncologist ; 24(1): 76-85, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30266893

RESUMEN

BACKGROUND: Discussions regarding palliative care and end-of-life care issues are frequently delayed past the time of usefulness, resulting in unwanted medical care. We sought to develop a patient-reported outcome (PRO) instrument that allows patients to voice their symptom burdens and facilitate timing of discussions. SUBJECTS, MATERIALS, AND METHODS: A seven-item PRO instrument (Cota Patient Assessed Symptom Score-7 item [CPASS-7]) covering physical performance status, pain, burden, and depression was administered (September 2015 through October 2016) with correlation to overall survival, correcting for time to complete survey since diagnosis. RESULTS: A total of 1,191 patients completed CPASS-7 at a median of 560 days following the diagnosis of advanced cancer. Of these patients, 49% were concerned that they could not do the things they wanted; 35% reported decreased performance status. Financial toxicity was reported by 39% of patients, with family burdens noted in 25%. Although depression was reported by 15%, 43% reported lack of pleasure. Pain was reported by 33%. The median CPASS-7 total symptom burden score was 16 (possible 0-112). With a median follow-up of 15 months from initial survey, 46% had died. Patients with symptom burden scores <29 and ≥29 had a 6-month overall survival rate of 87% and 67%, respectively, and 12-month survival rates of 72% and 50%. A one-point score increase resulted in a 1.8% increase in expected hazard. CONCLUSION: Patients with advanced cancer with higher levels of symptom burden, as self-reported on the CPASS-7, had inferior survival. The PRO facilitates identification of patients appropriate for reassessment of treatment goals and potentially palliative and end-of-life care in response to symptom burden concerns. IMPLICATIONS FOR PRACTICE: A seven-item patient-reported outcome (PRO) instrument was administered to 1,191 patients with advanced cancers. Patients self-reporting higher levels of physical and psychological symptom burden had inferior overall survival rates. High individual item symptom PRO responses should serve as a useful trigger to initiate supportive interventions, but when scores indicate global problems, discussions regarding end-of-life care might be appropriate.


Asunto(s)
Costos de la Atención en Salud/tendencias , Neoplasias/economía , Neoplasias/mortalidad , Cuidados Paliativos/métodos , Medición de Resultados Informados por el Paciente , Calidad de Vida/psicología , Anciano , Femenino , Humanos , Masculino , Cuidado Terminal
4.
J Neurooncol ; 135(3): 581-591, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-28975467

RESUMEN

While salvage re-irradiation is often used for recurrent high-grade glioma (HGG), there have been few comparisons between various re-radiation dose/fractionation schedules or with bevacizumab alone. We analyzed patients with recurrent HGG who received re-irradiation at Dana-Farber Cancer Institute and Brigham and Women's Hospital from 2010 to 2014 (n = 67), as well as those who received bevacizumab alone (n = 177). Cox proportional hazards modeling was used to examine factors associated with overall survival (OS). Propensity score modeling was used to compare survival after re-irradiation vs. bevacizumab alone. Median time from initial diagnosis to re-irradiation was 31.4 months. The most common re-irradiation dose/fractionations used were 6 Gy × 5 (36%), 3.5 Gy × 10 (21%), 2.67 Gy × 15 (15%), and 18-20 Gy × 1 (15%). No early or late toxicities >grade 2 were observed. Median PFS and OS after re-irradiation were 4.8 and 10.7 months, respectively. Number of progressions prior to re-irradiation (adjusted hazard ratio [AHR] 1.6; 95% CI, 1.1-2.3; p = .007), and recurrence in a new brain location (vs. local-only; AHR 7.4; 95% CI, 2.4-23.1; p < .001) were associated with OS; dose/fractionation was not. Compared with bevacizumab alone, re-irradiated patients had a non-significant increase in OS (HR 0.80; 95% CI, 0.53-1.23; P = .31). Among patients with a local-only recurrence, there was a trend towards longer median OS after re-irradiation compared to bevacizumab alone (12.4 vs. 8.0 months; p = .12). Survival after re-irradiation for recurrent HGG appears independent of dose/fractionation and compares favorably with bevacizumab alone.


Asunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Bevacizumab/uso terapéutico , Neoplasias Encefálicas/terapia , Glioma/terapia , Reirradiación , Terapia Recuperativa , Adolescente , Adulto , Neoplasias Encefálicas/patología , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Glioma/patología , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Recurrencia Local de Neoplasia , Puntaje de Propensión , Modelos de Riesgos Proporcionales , Factores de Tiempo , Resultado del Tratamiento , Adulto Joven
5.
CA Cancer J Clin ; 60(3): 166-93, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-20445000

RESUMEN

Malignant gliomas are the most common and deadly brain tumors. Nevertheless, survival for patients with glioblastoma, the most aggressive glioma, although individually variable, has improved from an average of 10 months to 14 months after diagnosis in the last 5 years due to improvements in the standard of care. Radiotherapy has been of key importance to the treatment of these lesions for decades, and the ability to focus the beam and tailor it to the irregular contours of brain tumors and minimize the dose to nearby critical structures with intensity-modulated or image-guided techniques has improved greatly. Temozolomide, an alkylating agent with simple oral administration and a favorable toxicity profile, is used in conjunction with and after radiotherapy. Newer surgical techniques, such as fluorescence-guided resection and neuroendoscopic approaches, have become important in the management of malignant gliomas. Furthermore, new discoveries are being made in basic and translational research, which are likely to improve this situation further in the next 10 years. These include agents that block 1 or more of the disordered tumor proliferation signaling pathways, and that overcome resistance to already existing treatments. Targeted therapies such as antiangiogenic therapy with antivascular endothelial growth factor antibodies (bevacizumab) are finding their way into clinical practice. Large-scale research efforts are ongoing to provide a comprehensive understanding of all the genetic alterations and gene expression changes underlying glioma formation. These have already refined the classification of glioblastoma into 4 distinct molecular entities that may lead to different treatment regimens. The role of cancer stem-like cells is another area of active investigation. There is definite hope that by 2020, new cocktails of drugs will be available to target the key molecular pathways involved in gliomas and reduce their mortality and morbidity, a positive development for patients, their families, and medical professionals alike.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Inhibidores de la Angiogénesis/uso terapéutico , Apoptosis , Biomarcadores de Tumor , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Factor de Crecimiento Epidérmico/efectos de los fármacos , Glioblastoma/genética , Glioblastoma/patología , Humanos , Biología Molecular , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Transducción de Señal , Insuficiencia del Tratamiento , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores
6.
Stroke ; 47(8): 2075-82, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-27387994

RESUMEN

BACKGROUND AND PURPOSE: Patients with atrial fibrillation and previous ischemic stroke (IS)/transient ischemic attack (TIA) are at high risk of recurrent cerebrovascular events despite anticoagulation. In this prespecified subgroup analysis, we compared warfarin with edoxaban in patients with versus without previous IS/TIA. METHODS: ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) was a double-blind trial of 21 105 patients with atrial fibrillation randomized to warfarin (international normalized ratio, 2.0-3.0; median time-in-therapeutic range, 68.4%) versus once-daily edoxaban (higher-dose edoxaban regimen [HDER], 60/30 mg; lower-dose edoxaban regimen, 30/15 mg) with 2.8-year median follow-up. Primary end points included all stroke/systemic embolic events (efficacy) and major bleeding (safety). Because only HDER is approved, we focused on the comparison of HDER versus warfarin. RESULTS: Of 5973 (28.3%) patients with previous IS/TIA, 67% had CHADS2 (congestive heart failure, hypertension, age, diabetes, prior stroke/transient ischemic attack) >3 and 36% were ≥75 years. Compared with 15 132 without previous IS/TIA, patients with previous IS/TIA were at higher risk of both thromboembolism and bleeding (stroke/systemic embolic events 2.83% versus 1.42% per year; P<0.001; major bleeding 3.03% versus 2.64% per year; P<0.001; intracranial hemorrhage, 0.70% versus 0.40% per year; P<0.001). Among patients with previous IS/TIA, annualized intracranial hemorrhage rates were lower with HDER than with warfarin (0.62% versus 1.09%; absolute risk difference, 47 [8-85] per 10 000 patient-years; hazard ratio, 0.57; 95% confidence interval, 0.36-0.92; P=0.02). No treatment subgroup interactions were found for primary efficacy (P=0.86) or for intracranial hemorrhage (P=0.28). CONCLUSIONS: Patients with atrial fibrillation with previous IS/TIA are at high risk of recurrent thromboembolism and bleeding. HDER is at least as effective and is safer than warfarin, regardless of the presence or the absence of previous IS or TIA. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00781391.


Asunto(s)
Anticoagulantes/uso terapéutico , Fibrilación Atrial/prevención & control , Isquemia Encefálica/prevención & control , Piridinas/uso terapéutico , Accidente Cerebrovascular/prevención & control , Tiazoles/uso terapéutico , Warfarina/uso terapéutico , Anciano , Fibrilación Atrial/tratamiento farmacológico , Isquemia Encefálica/tratamiento farmacológico , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recurrencia , Prevención Secundaria , Accidente Cerebrovascular/tratamiento farmacológico , Resultado del Tratamiento
7.
Br J Haematol ; 172(5): 709-15, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26686858

RESUMEN

Bing-Neel syndrome (BNS) is a rare complication seen in patients with Waldenström macroglobulinaemia (WM), in which lymphoplasmacytic lymphoma cells colonize the central nervous system. In this retrospective multi-centre study, we present the clinicopathological features, imaging findings, therapy, response and outcomes of 34 patients with BNS. The median time from WM diagnosis to BNS diagnosis was 3 years, 15% of patients were diagnosed with BNS at the time of WM diagnosis, and 22% of patients developed BNS when responding to active treatment for WM. Patients with BNS presented with variable clinical features including limb motor deficits, change in mental status and cranial nerve palsies. The diagnosis was made using a combination of cerebrospinal fluid cytology, flow cytometry and detection of the MYD88 L265 mutation, and magnetic resonance imaging. The estimated 3-year overall survival rate was 59%. Of the survivors, 40% have evidence of pathological and/or radiological persistence of disease. Age older than 65 years, platelet count lower than 100 × 10(9) /l, and treatment for WM prior to BNS diagnosis were associated with worse outcome. Exposure to rituximab for treatment of BNS was associated with a better outcome. Multi-institutional collaboration is warranted to improve treatment and outcomes in patients with BNS.


Asunto(s)
Neoplasias del Sistema Nervioso Central/diagnóstico , Macroglobulinemia de Waldenström/diagnóstico , Adulto , Anciano , Antineoplásicos/uso terapéutico , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Progresión de la Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Síndrome , Resultado del Tratamiento , Macroglobulinemia de Waldenström/tratamiento farmacológico
8.
Cancer ; 121(24): 4376-81, 2015 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-26308667

RESUMEN

BACKGROUND: The prognosis for patients with atypical and malignant meningioma is guarded; whether the extent of resection is associated with survival-based outcomes in this population remains poorly defined. This study investigated the association between gross total resection (GTR) and all-cause mortality in patients with atypical and malignant meningioma. METHODS: The Surveillance, Epidemiology, and End Results program was used to identify 575 and 64 patients betweens the ages of 18 and 70 years who were diagnosed with atypical and malignant meningioma, respectively, between 2004 and 2009. Multivariate Cox proportional hazards regression was used to assess the adjusted impact of GTR versus subtotal resection on all-cause mortality. RESULTS: Baseline patient characteristics were similar for patients who did undergo GTR and patients who did not undergo GTR. The 5-year overall survival rates were 91.3% (95% confidence interval [CI], 86.2%-94.5%) and 78.2% (95% CI, 70.0%-84.3%) for patients with atypical meningioma who did and did not undergo GTR, respectively, and 64.5% (95% CI, 45.9%-78.1%) and 41.1% (95% CI, 17.9%-63.1%) for patients with malignant meningioma who did and did not undergo GTR, respectively. After adjustments for available, pertinent confounding variables, GTR was associated with lower all-cause mortality in patients with atypical (hazard ratio, 0.39; 95% CI, 0.23-0.67; P < .001) and malignant meningioma (hazard ratio, 0.35; 95% CI, 0.15-0.81; P = .01). CONCLUSIONS: The extent of resection is a powerful predictor of outcome for patients with atypical and malignant meningioma. These data highlight the hazard associated with the presence of gross tumor bulk after surgery and suggest a value for more extensive resections that should be balanced against the additional potential morbidity.


Asunto(s)
Neoplasias Meníngeas/cirugía , Meningioma/cirugía , Adolescente , Adulto , Factores de Edad , Anciano , Estudios de Cohortes , Procedimientos Quirúrgicos de Citorreducción , Femenino , Humanos , Masculino , Neoplasias Meníngeas/mortalidad , Meningioma/mortalidad , Persona de Mediana Edad , Neoplasia Residual , Procedimientos Neuroquirúrgicos , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Programa de VERF , Tasa de Supervivencia , Carga Tumoral , Adulto Joven
9.
J Neurooncol ; 121(3): 557-63, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25411098

RESUMEN

Tumor cell infiltration is a major mechanism of treatment escape in glioblastoma. Src is an intracellular tyrosine kinase that mediates tumor cell motility and invasiveness. We evaluated the efficacy and safety of bosutinib, a tyrosine kinase inhibitor that potently inhibits Src and Abl, in patients with recurrent glioblastoma. In this two-arm study, patients with histologically confirmed recurrent glioblastoma and ≤2 relapses, not previously treated with anti-vascular endothelial growth factor (VEGF) therapy, were administered oral bosutinib 400 mg daily. Arm A planned for 6 patients who were candidates for surgical resection to be given bosutinib for 7-9 days prior to resection. Arm B was a two-stage design phase 2 trial targeting 30 patients. The primary endpoint was progression-free survival at 6 months (PFS6) in Arm B. After 9 patients enrolled onto stage 1 of Arm B, 9 (100 %) patients progressed within 6 months. Therefore, the study met the pre-specified criteria for early closure and both Arms were closed. In Arm B, Median PFS was 7.71 weeks and median OS was 50 weeks. Best objective response was stable disease in one patient (11.1 %). Seven patients (77.8 %) had treatment-related AEs of any grade and 2 (22.2 %) were grade ≥3. Arm A was closed after 2 patients enrolled. Src activation was evident in all archival tumor samples. Bosutinib monotherapy does not appear to be effective in recurrent glioblastoma. However, Src remains a potential target based on its upregulation in tumor samples and role in glioma invasion.


Asunto(s)
Compuestos de Anilina/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Glioblastoma/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Nitrilos/uso terapéutico , Quinolinas/uso terapéutico , Familia-src Quinasas/antagonistas & inhibidores , Adulto , Neoplasias Encefálicas/mortalidad , Supervivencia sin Enfermedad , Femenino , Glioblastoma/mortalidad , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Familia-src Quinasas/metabolismo
10.
J Neurooncol ; 121(3): 627-34, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25503302

RESUMEN

Targeting specific molecular alterations in glioblastoma (GBM) might more effectively kill tumor cells and increase survival. Vandetanib inhibits epidermal growth factor receptor and vascular endothelial growth factor receptor 2. Sirolimus inhibits mammalian target of rapamycin (mTOR), a member the phosphoinositide 3-Kinase signaling pathway. We sought to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of vandetanib combined with sirolimus. Twenty-two patients (14 men; 8 women) with recurrent GBM enrolled. Median age and KPS were 52.5 years and 90 %, respectively. Patients were naive to anti-VEGF and anti-EGF therapy and mTOR inhibitors, and not on CYP3A4-inducing drugs. Vandetanib and sirolimus were orally administered on a continuous daily dosing schedule in escalating dose cohorts. Ten patients enrolled in the dose escalation phase. Twelve more enrolled at the MTD to explore progression-free survival at 6 months (PFS6) in a single arm, single stage phase II-type design. In total, 19 patients received at least one dose at the MTD, and 15 completed at least 1 cycle at MTD. MTD was 200 mg vandetanib plus 2 mg sirolimus. The DLT was elevated AST/SGOT. The most common toxicities were lymphopenia, fatigue, rash, and hypophosphatemia. For 19 patients who received at least one dose at the MTD, including seven from the phase I group, two had a partial response [10.5 %; 95 % CI (1, 33 %)] and PFS6 was 15.8 % [95 % CI (3.9, 34.9 %)]. Vandetanib and sirolimus can be safely co-administered on a continuous, daily dosing schedule.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Glioblastoma/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Anciano , Estudios de Cohortes , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Piperidinas/administración & dosificación , Piperidinas/efectos adversos , Quinazolinas/administración & dosificación , Quinazolinas/efectos adversos , Sirolimus/administración & dosificación , Sirolimus/efectos adversos
11.
J Neurooncol ; 124(1): 137-46, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-26033544

RESUMEN

Despite a high symptom burden, little is known about the incidence or predictors of hospitalization among glioblastoma patients, including risks during chemoradiation (CRT). We studied 196 consecutive newly diagnosed glioblastoma patients treated at our institution from 2006-2010. Toxicity data were reviewed during and after the CRT phase, defined as the period between diagnosis and 6 weeks after radiotherapy completion. Logistic regression and proportional hazards modeling identified predictors of hospitalization and overall survival (OS). Median age was 59 years (range, 23-90) and 83 % had Karnofsky performance status (KPS) score ≥ 70. Twenty-six percent of patients underwent gross total resection, 77 % received ≥ 59.4 Gy of radiotherapy, and 89 % received concurrent temozolomide. Median OS was 15.6 months (IQR, 8.5-26.8 months). Forty-three percent of patients were hospitalized during the CRT phase; OS was 10.7 vs. 17.8 months for patients who were vs. were not hospitalized, respectively (P < .001). Nearly half of the hospitalizations were due to generalized weakness (17 % of hospitalizations), seizures (16 %), or venous thromboembolism (13 %). On multivariate analysis, age (odds ratio [OR], 1.03; 95 % CI, 1.002-1.060; P = .034) and KPS (OR, 0.95; 95 % CI, 0.93-0.97; P < .001) were associated with risk of hospitalization. Hospitalization during the CRT phase was associated with decreased OS (adjusted hazard ratio, 1.47; 95 % CI, 1.01-2.13; P = .043), after adjustment for known prognostic factors. Hospitalization during the CRT phase is common among glioblastoma patients in the temozolomide era and is associated with shorter overall survival.


Asunto(s)
Neoplasias Encefálicas/complicaciones , Neoplasias Encefálicas/terapia , Quimioradioterapia , Glioblastoma/complicaciones , Glioblastoma/terapia , Hospitalización/estadística & datos numéricos , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Factores de Riesgo , Adulto Joven
12.
J Neurooncol ; 121(2): 297-302, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25338318

RESUMEN

Bevacizumab is FDA-approved for patients with recurrent GBM. However, the median duration of response is only 4 months. Potential mechanisms of resistance include upregulated FGF signaling and increased PDGF-mediated pericyte coverage. Nintedanib is an oral, small-molecule tyrosine kinase inhibitor of PDGFR α/ß, FGFR 1-3, and VEGFR 1-3 that may overcome resistance to anti-VEGF therapy. This was a two-stage phase II trial in adults with first or second recurrence of GBM, stratified by prior bevacizumab therapy (ClinicalTrials.gov number NCT01380782; 1199.94). The primary endpoint was PFS6 in the bevacizumab-naive arm (Arm A) and PFS3 in the post-bevacizumab arm (Arm B). Up to 10 anaplastic glioma (AG) patients were accrued to each arm in exploratory cohorts. Twenty-two patients enrolled in Arm A and 14 in Arm B. Arm A included 12 GBMs (55 %), 13 patients with one prior regimen (59 %), and median age 54 years (range 28-75). Arm B included 10 GBMs (71 %), one patient with one prior regimen (7 %), and median age 52 years (range 32-70). Median KPS overall was 90 (range 60-100). There were no responses. In Arm A (GBM only), PFS6 was 0 %, median PFS 28 days (95 % CI 27-83), and median OS 6.9 months (3.7-8.1). In Arm B (GBM only), PFS3 was 0 %, median PFS 28 days (22-28), and median OS 2.6 months (1.0-6.9). Among AG patients in each arm, PFS6 was 0 %. Treatment was well tolerated. In conclusion, nintedanib is not active against recurrent high-grade glioma, regardless of prior bevacizumab therapy.


Asunto(s)
Antineoplásicos/uso terapéutico , Glioma/tratamiento farmacológico , Indoles/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Anciano , Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/efectos adversos , Bevacizumab , Estudios de Cohortes , Femenino , Glioma/patología , Humanos , Indoles/efectos adversos , Estimación de Kaplan-Meier , Estado de Ejecución de Karnofsky , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Recurrencia Local de Neoplasia/patología , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Resultado del Tratamiento
13.
J Neurooncol ; 119(1): 149-58, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24805151

RESUMEN

While patients with recurrent glioblastoma receiving anti-angiogenic therapy demonstrate significant response rates, the benefit on patient survival is less clear. We assessed whether histogram analysis of diffusion weighted MRI can stratify for progression-free and overall survival. Baseline and 3-6 week post-treatment MRI exams of 91 patients with recurrent glioblastoma treated with bevacizumab were retrospectively evaluated. Histograms of apparent diffusion coefficient (ADC) within the volume of contrast enhancing and nonenhancing T2/FLAIR lesions were analyzed using curve-fit analysis. Overall survival (OS) and progression-free survival (PFS) were assessed using ADC parameters in a Cox proportional hazards model adjusted for clinical variables. Baseline ADC(L)/ADC(M) within nonenhancing T2/FLAIR volume (> or ≤0.64) can stratify OS (HR = 2.24, p = 0.002) and PFS (HR = 1.90, p = 0.005). %ADC(H) within enhancing T1+C volume (> or ≤25 %) can also stratify OS (HR = 0.59, p = 0.034) and PFS (HR = 0.56, p = 0.01). Stratification of patient survival can be improved by merging these two ADC parameters into a single combined ADC factor (HR = 0.17, p < 0.0001). The median OS ratio of patient groups stratified by this combined factor was 2.03, larger than median OS ratio when stratifying by either %ADC(H) within T1+C volume alone (1.3) or ADC(L)/ADC(M) within T2/FLAIR alone (1.86). ADC histogram analysis within both enhancing and nonenhancing components of tumor can be used to stratify for PFS and OS in patients with recurrent glioblastoma.


Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Neoplasias Encefálicas/patología , Glioblastoma/patología , Recurrencia Local de Neoplasia/patología , Adulto , Anciano , Anciano de 80 o más Años , Bevacizumab , Neoplasias Encefálicas/tratamiento farmacológico , Imagen de Difusión por Resonancia Magnética , Progresión de la Enfermedad , Femenino , Glioblastoma/tratamiento farmacológico , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Pronóstico , Estudios Retrospectivos , Carga Tumoral , Adulto Joven
14.
Cancer ; 119(19): 3479-88, 2013 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-23821555

RESUMEN

BACKGROUND: Despite a high radiographic response rate in patients with recurrent glioblastoma following bevacizumab therapy, survival benefit has been relatively modest. We assess whether tumor volume measurements based on baseline and early posttreatment MRI can stratify patients in terms of progression-free survival (PFS) and overall survival (OS). METHODS: Baseline (-4 +/- 4 days) and posttreatment (30 +/- 6 days) MRI exams of 91 patients with recurrent glioblastoma treated with bevacizumab were retrospectively evaluated for volume of enhancing tumor as well as volume of the T2/FLAIR hyperintensity. Overall survival (OS) and progression-free survival (PFS) were assessed using volume parameters in a Cox regression model adjusted for significant clinical parameters. RESULTS: In univariable analysis, residual tumor volume, percentage change in tumor volume, steroid change from baseline to posttreatment scan, and number of recurrences were associated with both OS and PFS. With dichotomization by sample median of 52% change of enhancing volume can stratify OS (52 weeks vs. 31 weeks, P = .013) and PFS (21 weeks vs. 12 weeks, P = .009). Residual enhancing volume, dichotomized by sample median of 7.8 cm(3) , can also stratify for OS (64 weeks vs. 28 weeks, P < .001) and PFS (21 weeks vs. 12 weeks, P = .036). CONCLUSIONS: Volumetric percentage change and absolute early posttreatment volume of enhancing tumor can stratify survival for patients with recurrent glioblastoma receiving bevacizumab therapy.


Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Adulto , Anciano , Anciano de 80 o más Años , Inhibidores de la Angiogénesis/efectos adversos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Bevacizumab , Neoplasias Encefálicas/diagnóstico , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Glioblastoma/diagnóstico , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/diagnóstico , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del Tratamiento , Adulto Joven
15.
Expert Opin Emerg Drugs ; 18(2): 137-53, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23668489

RESUMEN

INTRODUCTION: Primary and metastatic brain tumors remain a major challenge. The most common primary adult malignant brain tumor, glioblastoma (GBM), confers a dismal prognosis as does the development of CNS metastases for most systemic malignancies. Anti-angiogenic therapy has been a major clinical research focus in neuro-oncology over the past 5 years. AREAS COVERED: Culmination of this work includes US FDA accelerated approval of bevacizumab for recurrent GBM and the completion of two placebo-controlled Phase III studies of bevacizumab for newly diagnosed GBM. A multitude of anti-angiogenics are in evaluation for neuro-oncology patients but none has thus far surpassed the therapeutic benefit of bevacizumab. EXPERT OPINION: These agents demonstrate adequate safety and the majority of GBM patients derive benefit. Furthermore, their anti-permeability effect can substantially decrease tumor-associated edema leading to stable or improved neurologic function and quality of life. In particular, anti-angiogenics significantly prolong progression-free survival - a noteworthy achievement in the context of infiltrative and destructive brain tumors like GBM; however, in a manner analogous to other cancers, their impact on overall survival for GBM patients is modest at best. Despite substantial clinical research efforts, many fundamental questions regarding anti-angiogenic agents in brain tumor patients remain unanswered.


Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Bevacizumab , Glioblastoma/tratamiento farmacológico , Humanos
16.
J Neurooncol ; 115(2): 267-76, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23974656

RESUMEN

Although bevacizumab represented an important advance in treatment of recurrent high-grade gliomas (HGG), responses occur in fewer than half of patients. There are no validated biomarkers for anti-angiogenic therapy that are available for routine clinical use. We assessed the prognostic values of imaging and molecular markers in this patient population. MRI scans from 191 patients with recurrent HGG obtained prior to initiating bevacizumab were reviewed for areas of enhancement, necrosis, T2/FLAIR abnormality, and ADC values. Serial MRI scans following the initiation of bevacizumab were evaluated for response and progression. Non-radiographic markers including EGFR and MGMT status were also assessed with respect to response and patient survival. 65 of 191 patients (34 %) showed complete or partial response at the time of their best response MRI and demonstrated longer progression free survival (PFS) and overall survival (OS) compared to the group without response (PFS: 6.9 vs 3.5 months, OS: 10.9 vs 6.1 months). Minimum ADC values within enhancing and non-enhancing regions were lower in responders compared to those of non-responders (1,099 vs 984 × 10(-6) mm(2)/s, p = 0.006). Smaller enhancing area was associated with longer OS (HR = 1.99, p = 0.017). The ratio of T2/FLAIR to enhancing area was prognostic of OS for only the Grade III HGG subgroup (HR = 0.14, p = 0.004). Area of enhancing tumor at baseline can stratify survival in patients with recurrent HGG treated with bevacizumab. The extent of edema relative to enhancing area may have a prognostic role specific to Grade III HGG.


Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Metilación de ADN , Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Receptores ErbB/genética , Glioma/mortalidad , Recurrencia Local de Neoplasia/mortalidad , Proteínas Supresoras de Tumor/genética , Bevacizumab , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidad , ADN de Neoplasias/genética , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Glioma/tratamiento farmacológico , Glioma/genética , Humanos , Hibridación Fluorescente in Situ , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Reacción en Cadena de la Polimerasa , Pronóstico , Regiones Promotoras Genéticas/genética , Estudios Retrospectivos , Tasa de Supervivencia
17.
J Neurooncol ; 115(1): 71-7, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23828279

RESUMEN

There is currently no standard therapy for recurrent or chemotherapy-refractory central nervous system lymphoma (CNSL). Pemetrexed has been reported to have activity in patients with primary CNSL (PCNSL). The use of pemetrexed in secondary CNS lymphoma (SCNSL) has not previously been reported. Here we retrospectively review the outcomes and toxicities of standard and modified doses of pemetrexed as salvage therapy in 18 PCNSL and 12 SCNSL patients. The overall response rate for PCNSL patients was 64.7 %, all of whom achieved a complete response (CR). The median progression-free survival (PFS) was 5.8 months. For the SCNSL patients, RR was 58.3 % with 2 CR (16.7 %); the median PFS was 2.5 months. Grade ≥3 adverse events included leukopenia in 5 patients (16.7 %), neutropenia in 1 patient (3.3 %), and fatigue in 3 patients (10.0 %). 3 patients died while on treatment, 2 due to infections and 1 due to pulmonary embolism. Our results indicate that pemetrexed has activity as salvage therapy in recurrent PCNSL, even with modified dosing, but outcomes trend towards less favorable in SCNSL.


Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Glutamatos/uso terapéutico , Guanina/análogos & derivados , Linfoma de Células B/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Terapia Recuperativa , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias del Sistema Nervioso Central/patología , Femenino , Estudios de Seguimiento , Guanina/uso terapéutico , Humanos , Linfoma de Células B/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Pemetrexed , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia
18.
J Neurooncol ; 109(1): 187-93, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22544653

RESUMEN

Atypical and anaplastic (WHO Grades II and III) meningiomas are aggressive tumors, and patients often progress despite surgery and radiation. There is no known effective chemotherapeutic option for these patients. Meningiomas have a high expression of vascular endothelial growth factor receptor (VEGFR). We sought to retrospectively study the activity of bevacizumab, which is an anti-angiogenic agent targeting the VEGF pathway in these tumors. This is a retrospective review of WHO Grade II and III meningiomas treated at four institutions, selecting only those patients who received bevacizumab. We analyzed radiographic response according to standard RANO criteria, progression-free survival (PFS) and overall survival from the initiation of bevacizumab therapy using Kaplan-Meier statistics. We identified 15 patients across four institutions who carried a diagnosis of atypical or anaplastic meningioma and were treated with bevacizumab. Best radiographic response was stable disease. MR perfusion studies showed decreased tumor blood volume in one patient. Three patients developed non-fatal intratumoral hemorrhage. Median PFS was 26 weeks (95 % CI, 10-29 weeks). Six month PFS rate was 43.8 % (95 % CI, 15.7-69.1 %). Bevacizumab was well-tolerated in our patients, and may be considered in patients who have exhausted radiation and surgical options. Prospective studies are required to define the safety and efficacy of bevacizumab in atypical and anaplastic meningiomas.


Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Neoplasias Meníngeas/tratamiento farmacológico , Meningioma/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Bevacizumab , Femenino , Estudios de Seguimiento , Humanos , Imagen por Resonancia Magnética , Masculino , Neoplasias Meníngeas/mortalidad , Neoplasias Meníngeas/patología , Meningioma/clasificación , Meningioma/mortalidad , Meningioma/patología , Persona de Mediana Edad , Clasificación del Tumor , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia
19.
J Neurooncol ; 106(1): 121-5, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21706358

RESUMEN

Venous thromboembolic events (VTE) are common in glioma patients and are typically treated with anticoagulant medications. The anti-angiogenic agent bevacizumab (BVZ) increases the risks of both VTE and hemorrhagic complications. Little is known about the hemorrhagic risk of anticoagulation in glioma patients receiving BVZ. We reviewed medical records from 282 BVZ-treated patients at our center and identified 64 who received concurrent anticoagulant therapy. The risk and severity of hemorrhagic complications were assessed. Fisher's exact test was used to compare the risk of hemorrhage between subjects who received and did not receive anticoagulants. Forty-seven patients (73%) had glioblastoma, 15 (23%) anaplastic glioma, and 2 (3%) other tumors. Thirteen (20%) and 51 (80%) patients received warfarin and low-molecular-weight heparin, respectively. The indication for anticoagulation was deep venous thrombosis in 37 patients (58%), pulmonary embolism in 22 (34%), and both in 5 (8%). Thirteen patients (20%) experienced hemorrhage, of which four hemorrhages (6%) were serious (grade ≥ 3): one patient had grade 5 intracerebral hemorrhage (ICH), one grade 4 ICH, one grade 3 epistaxis, and one grade 3 gastrointestinal hemorrhage. ICH was seen in seven patients (11%), of which five (8%) were grade 1. Among 218 patients who did not receive anticoagulants, there were two (1%) serious hemorrhages (both grade 4 ICH). Both the serious hemorrhage rate and overall ICH rate were higher in patients who received anticoagulants (P = 0.03 and 0.02, respectively). Anticoagulant use during BVZ therapy may increase the risk of hemorrhage in glioma patients, although it is generally well tolerated.


Asunto(s)
Inhibidores de la Angiogénesis/efectos adversos , Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticoagulantes/uso terapéutico , Neoplasias Encefálicas/complicaciones , Hemorragia Cerebral/complicaciones , Glioma/complicaciones , Adulto , Anciano , Anciano de 80 o más Años , Bevacizumab , Neoplasias Encefálicas/tratamiento farmacológico , Hemorragia Cerebral/tratamiento farmacológico , Terapia Combinada , Femenino , Glioma/tratamiento farmacológico , Hemorragia/complicaciones , Humanos , Masculino , Persona de Mediana Edad , Recuento de Plaquetas , Embolia Pulmonar/tratamiento farmacológico , Estudios Retrospectivos , Riesgo
20.
J Neurooncol ; 106(2): 409-15, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21938530

RESUMEN

We prospectively evaluated the efficacy and safety of imatinib plus hydroxyurea in patients with progressive/recurrent meningioma. A total of 21 patients with progressive/recurrent meningioma were enrolled in this dual center, single-arm, phase II trial. All patients received 500 mg of hydroxyurea twice a day. Imatinib was administered at 400 mg/day for patients not on CYP3A enzyme inducing anti-epileptic drugs (EIAEDs) and at 500 mg twice a day for patients on EIAEDs. The primary endpoint was progression-free survival at 6 months (PFS-6) and secondary endpoints were safety, radiographic response rate, and overall survival (OS). Best radiographic response was stable disease and was observed in 14 patients (67%). PFS-6 for all patients, those with grade I tumors (n = 8) and those with grade II or III tumors (n = 13) was 61.9, 87.5 and 46.2%, respectively. Patients with grade II or III tumors had poorer PFS and OS than those with grade I tumors, (P = 0.025 and P = 0.018) respectively. The only grade 3 or greater adverse event occurring in ≥ 10% of patients was anemia (10%). Imatinib plus hydroxyurea is well tolerated among patients with meningioma but has modest anti-tumor activity for this indication.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Meníngeas/tratamiento farmacológico , Meningioma/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Benzamidas , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Humanos , Hidroxiurea/administración & dosificación , Mesilato de Imatinib , Estimación de Kaplan-Meier , Masculino , Neoplasias Meníngeas/mortalidad , Neoplasias Meníngeas/patología , Meningioma/mortalidad , Meningioma/patología , Persona de Mediana Edad , Clasificación del Tumor , Recurrencia Local de Neoplasia/patología , Piperazinas/administración & dosificación , Pirimidinas/administración & dosificación
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