RESUMEN
After stimulation, dendritic cells (DCs) mature and migrate to draining lymph nodes to induce immune responses. As such, autologous DCs generated ex vivo have been pulsed with tumour antigens and injected back into patients as immunotherapy. While DC vaccines have shown limited promise in the treatment of patients with advanced cancers including glioblastoma, the factors dictating DC vaccine efficacy remain poorly understood. Here we show that pre-conditioning the vaccine site with a potent recall antigen such as tetanus/diphtheria (Td) toxoid can significantly improve the lymph node homing and efficacy of tumour-antigen-specific DCs. To assess the effect of vaccine site pre-conditioning in humans, we randomized patients with glioblastoma to pre-conditioning with either mature DCs or Td unilaterally before bilateral vaccination with DCs pulsed with Cytomegalovirus phosphoprotein 65 (pp65) RNA. We and other laboratories have shown that pp65 is expressed in more than 90% of glioblastoma specimens but not in surrounding normal brain, providing an unparalleled opportunity to subvert this viral protein as a tumour-specific target. Patients given Td had enhanced DC migration bilaterally and significantly improved survival. In mice, Td pre-conditioning also enhanced bilateral DC migration and suppressed tumour growth in a manner dependent on the chemokine CCL3. Our clinical studies and corroborating investigations in mice suggest that pre-conditioning with a potent recall antigen may represent a viable strategy to improve anti-tumour immunotherapy.
Asunto(s)
Vacunas contra el Cáncer/inmunología , Quimiocina CCL3/inmunología , Células Dendríticas/efectos de los fármacos , Glioblastoma/inmunología , Glioblastoma/terapia , Toxoide Tetánico/administración & dosificación , Toxoide Tetánico/farmacología , Animales , Antígenos de Neoplasias/inmunología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Vacunas contra el Cáncer/administración & dosificación , Vacunas contra el Cáncer/uso terapéutico , Movimiento Celular/efectos de los fármacos , Células Dendríticas/citología , Células Dendríticas/inmunología , Femenino , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Humanos , Inmunoterapia/métodos , Ganglios Linfáticos/citología , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/inmunología , Ratones , Ratones Endogámicos C57BL , Fosfoproteínas/química , Fosfoproteínas/genética , Fosfoproteínas/inmunología , Especificidad por Sustrato , Tasa de Supervivencia , Toxoide Tetánico/uso terapéutico , Resultado del Tratamiento , Proteínas de la Matriz Viral/química , Proteínas de la Matriz Viral/genética , Proteínas de la Matriz Viral/inmunologíaRESUMEN
Although optic pathway gliomas are the most common brain tumors associated with neurofibromatosis type 1 (NF1), extra-optic gliomas occur and may behave more aggressively with outcomes that differ by age. A retrospective case-control study was designed to describe the clinical course of adult NF1 patients with progressive extra-optic pilocytic astrocytomas (PAs) and compare to a pediatric cohort. Data for patients treated at the Johns Hopkins Comprehensive Neurofibromatosis Center from 2003 to 2013 were reviewed to identify cases (adults, age >18) and controls (pediatric, age <18) with clinically or radiographically progressive extra-optic PAs. Demographic, clinical, histologic, and radiographic data were collected. Three adult NF1 cases and four pediatric NF1 controls were identified. Mean age was 32.3 ± 9.5 years, 66% male (cases); 12.8 ± 4.2 years, 100% male (controls). Symptomatic progression occurred in two-of-three adults (67%) while the majority of pediatric patients presented with isolated radiographic progression (n = 3, 75%). Onset tended to be more rapid in adults (4 ± 1 vs. 14 ± 8.3 months, P = 0.10). Subtotal resection was the treatment for all pediatric patients. Radiotherapy (n = 2), chemotherapy (n = 2), and targeted, biologic agents (n = 2) were administered in adults. Although all pediatric patients are living, outcomes were universally poor in adults with progression to death in all (median survival 17.1 months, range 6.6-30.3). In conclusion, despite grade I histology, all three adult NF1 patients with progressive extra-optic PAs suffered an aggressive clinical course which was not seen in pediatric patients. Clinicians should be aware of this clinico-histologic discrepancy when counseling and managing adult NF1 patients with progressive extra-optic PAs. © 2016 Wiley Periodicals, Inc.
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Astrocitoma/diagnóstico , Astrocitoma/etiología , Neurofibromatosis 1/complicaciones , Adulto , Astrocitoma/mortalidad , Astrocitoma/terapia , Biopsia , Encéfalo/patología , Estudios de Casos y Controles , Terapia Combinada , Diagnóstico por Imagen , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Clasificación del Tumor , Neurofibromatosis 1/diagnóstico , Fenotipo , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: In malignant glioma (MG) patients undergoing radiation therapy (RT) with concomitant temozolomide, chemoradiation-induced nausea and vomiting (cRINV) degrades quality of life (QoL) and reduces treatment adherence, which thereby potentially compromises cancer control. METHODS: We conducted a 6-week phase II single-arm trial of PAL, a second-generation 5-HT3RA antiemetic, for cRINV prevention in MG patients receiving radiation therapy (RT; 54-60 Gy) and concomitant daily temozolomide (TMZ; 75 mg/m(2)/dX42d). Each week before radiation, patients received single-dose palonosetron (PAL) 0.25 mg IV (total = 6 doses). With safety/tolerability as the primary endpoint, the study was designed to differentiate between toxicity rates of 25 % (unacceptable) and 10 % (acceptable) toxicity rates. Secondary endpoints included the percentage of patients achieving cRINV complete response (CR: no emesis or rescue antiemetic) and QoL. Patients reported adverse effects in Common Toxicity Criteria for Adverse Events diaries; recorded vomiting, nausea, and rescue medication use in diaries (which were used to assess cRINV-CR); and reported QoL 4 days/week using the Modified Functional Living Index-Emesis (M-FLIE) and Osoba nausea and vomiting/retching modules. RESULTS: We enrolled 38 patients (mean age 59 years, 55 % female, 95 % white, 68 % used oral corticosteroids, 76 % reported low alcohol use). Four patients (10.5 %) experienced unacceptable treatment-related toxicity, defined as any grade 3, 4, or 5 non-hematologic toxicity. M-FLIE and Osoba scores showed no evidence of treatment impact on QoL. Overall, cRINV-CR rates for 6 weeks ranged from 67-79 %. CONCLUSION: Single-dose weekly PAL is a safe and tolerable antiemetic for cRINV prevention in MG patients receiving standard RT and concomitant TMZ.
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Antineoplásicos/uso terapéutico , Quimioradioterapia/métodos , Dacarbazina/análogos & derivados , Glioma/tratamiento farmacológico , Glioma/radioterapia , Isoquinolinas/uso terapéutico , Calidad de Vida/psicología , Quinuclidinas/uso terapéutico , Administración Intravenosa , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Dacarbazina/efectos adversos , Dacarbazina/farmacología , Dacarbazina/uso terapéutico , Femenino , Glioma/patología , Humanos , Isoquinolinas/efectos adversos , Isoquinolinas/farmacología , Masculino , Persona de Mediana Edad , Palonosetrón , Quinuclidinas/efectos adversos , Quinuclidinas/farmacología , Encuestas y Cuestionarios , TemozolomidaRESUMEN
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), is a rare yet highly aggressive malignancy with a poor prognosis. Currently, there are no SCCOHT treatment guidelines. After surgery, many patients with SCCOHT receive adjuvant cisplatin and etoposide (CE), based on its efficacy in small cell lung cancer (SCLC). Nonetheless, CE-refractory SCCOHT is still common. Novel therapies (ie, histone deacetylase [HDAC] inhibitors) are being studied as they may target abnormal chromatin remodeling known to be associated with SCCOHT. We present the case of a 21-year-old female with Stage IC SCCOHT status after unilateral oophorectomy. Despite adjuvant CE, the patient developed disease progression. This is the first case report of a patient with CE-refractory SCCOHT treated with second-line topotecan (a topoisomerase-1 inhibitor) and romidepsin (an HDAC inhibitor). Although our patient's SCCOHT further progressed and lead to her death, her story highlights the importance of discovering better therapeutic targets for the treatment of SCCOHT.
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Carcinoma de Células Pequeñas/patología , Carcinoma de Células Pequeñas/terapia , Depsipéptidos/uso terapéutico , Neoplasias Ováricas/patología , Neoplasias Ováricas/terapia , Topotecan/uso terapéutico , Antibióticos Antineoplásicos/uso terapéutico , Progresión de la Enfermedad , Resultado Fatal , Femenino , Humanos , Ovariectomía , Inhibidores de Topoisomerasa I/uso terapéutico , Adulto JovenRESUMEN
Kikuchi-Fujimoto disease (KFD), also known as histiocytic necrotizing lymphadenitis (HNL), is a rare, self-limiting disease most commonly reported in young Asian women worldwide. We present the case of a 27-year-old African American male who had three weeks of high-grade fevers, night sweats, a 10-pound weight loss, and tender unilateral posterior cervical lymphadenopathy. A complete workup of infectious, rheumatologic, and neoplastic diseases was pursued. Lymph node biopsies revealed histiocyte proliferation with areas of necrosis. These findings were diagnostic of KFD. While KFD has been reported most commonly in young Asian women, in the US, this disease must be considered in both males and females and in diverse ethnicities.
Asunto(s)
Histiocitos/patología , Linfadenitis Necrotizante Histiocítica , Ibuprofeno/administración & dosificación , Ganglios Linfáticos , Linfadenopatía/diagnóstico , Adulto , Negro o Afroamericano , Antiinflamatorios no Esteroideos/administración & dosificación , Biopsia/métodos , Diagnóstico Diferencial , Linfadenitis Necrotizante Histiocítica/diagnóstico , Linfadenitis Necrotizante Histiocítica/patología , Linfadenitis Necrotizante Histiocítica/fisiopatología , Linfadenitis Necrotizante Histiocítica/terapia , Humanos , Ganglios Linfáticos/diagnóstico por imagen , Ganglios Linfáticos/patología , Masculino , Cuello , NecrosisRESUMEN
LESSONS LEARNED: Trials focusing on unresectable multifocal glioblastoma are needed because of the extremely poor prognosis and challenges in receiving standard therapy, such as concurrent radiation and chemotherapy.Developing a strategy to chemically debulk tumors before radiation and/or surgery is warranted. BACKGROUND: Extent of resection remains a key prognostic factor in glioblastoma (GBM), with gross total resection providing a better prognosis than biopsy or subtotal resection. We conducted a phase II trial of upfront therapy with bevacizumab (BV), irinotecan (CPT-11), and temozolomide (TMZ) prior to chemoradiation in patients with unresectable, subtotally resected, and/or multifocal GBM. METHODS: Patients received up to 4 cycles of TMZ at 200 mg/m(2) per day on days 1-5 (standard dosing) and BV at 10 mg/kg every 2 weeks on a 28-day cycle. CPT-11 was given every 2 weeks on a 28-day cycle at 125 mg/m(2) or 340 mg/m(2) depending on antiepileptic drugs. Magnetic resonance imaging of the brain was done every 4 weeks, and treatment continued as long as there was no tumor progression or unmanageable toxicity. The primary endpoint was tumor response rate, with a goal of 26% or greater. RESULTS: Forty-one patients were enrolled from December 2009 to November 2010. Radiographic responses were as follows: 9 patients (22.0%) had partial response, 25 (61.0%) had stable disease, and 2 (4.9%) had progression; 5 patients were not assessed. Cumulative response rate was 22%. Median overall survival was 12 months (95% confidence interval: 7.2-13.5 months). CONCLUSION: Upfront treatment with BV, TMZ, and CPT-11 is tolerable and can lead to radiographic response in unresectable and/or subtotally resected GBM.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Glioblastoma/tratamiento farmacológico , Bevacizumab/administración & dosificación , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/cirugía , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Dacarbazina/administración & dosificación , Dacarbazina/análogos & derivados , Esquema de Medicación , Femenino , Glioblastoma/mortalidad , Glioblastoma/radioterapia , Glioblastoma/cirugía , Humanos , Irinotecán , Masculino , Persona de Mediana Edad , Temozolomida , Resultado del TratamientoRESUMEN
Identification of targetable oncogenic mutations in non-small cell lung cancer (NSCLC) has been a major advance in cancer treatment. Laboratory techniques to assess human epidermal growth factor receptor 2 (HER2) positivity in NSCLC include immunohistochemistry (IHC) for protein overexpression, fluorescent in situ hybridization (FISH) for gene amplification, and next generation sequencing (NGS) for HER2 gene mutations. These tests have a controversial prognostic and predictive value, with an emerging association between HER2 gene mutations and treatment response to HER2 targeted therapy. We present a case of a woman with metastatic lung adenocarcinoma with HER2 positivity assessed by IHC and FISH, as well as a high gene copy number noted on NGS. She was observed to have significant disease progression following standard first-line platinum doublet chemotherapy. She was started on dual HER2 blockade in the second-line setting, which yielded a great response in the liver with stable disease elsewhere. To our knowledge, this is the first report describing successful use of dual HER2 blockade in metastatic HER2 positive NSCLC. We also review common laboratory techniques for determining HER2 positivity in NSCLC and their clinical applications.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Receptor ErbB-2/antagonistas & inhibidores , Anciano , Carcinoma de Pulmón de Células no Pequeñas/secundario , Neoplasias Cerebelosas/tratamiento farmacológico , Neoplasias Cerebelosas/secundario , Variaciones en el Número de Copia de ADN , Femenino , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/secundario , Neoplasias Pulmonares/patología , Mutación , Receptor ErbB-2/genéticaRESUMEN
Lymphodepletion augments adoptive cell transfer during antitumor immunotherapy, producing dramatic clinical responses in patients with malignant melanoma. We report that the lymphopenia induced by the chemotherapeutic agent temozolomide (TMZ) enhances vaccine-driven immune responses and significantly reduces malignant growth in an established model of murine tumorigenesis. Unexpectedly, despite the improved antitumor efficacy engendered by TMZ-induced lymphopenia, there was a treatment related increase in the frequency of immunosuppressive regulatory T cells (T(Regs); P = .0006). Monoclonal antibody (mAb)-mediated inhibition of the high-affinity IL-2 receptor α (IL-2Rα/CD25) during immunotherapy in normal mice depleted T(Regs) (73% reduction; P = .0154) but also abolished vaccine-induced immune responses. However, during lymphodepletion, IL-2Rα blockade decreased T(Regs) (93% reduction; P = .0001) without impairing effector T-cell responses, to augment therapeutic antitumor efficacy (66% reduction in tumor growth; P = .0024). Of clinical relevance, we also demonstrate that anti-IL-2Rα mAb administration during recovery from lymphodepletive TMZ in patients with glioblastoma reduced T(Reg) frequency (48% reduction; P = .0061) while permitting vaccine-stimulated antitumor effector cell expansion. To our knowledge, this is the first report of systemic antibody-mediated T(Reg) depletion during lymphopenia and the consequent synergistic enhancement of vaccine-driven cellular responses, as well as the first demonstration that anti-IL-2Rα mAbs function differentially in nonlymphopenic versus lymphopenic contexts.
Asunto(s)
Anticuerpos Monoclonales/farmacología , Subunidad alfa del Receptor de Interleucina-2/antagonistas & inhibidores , Depleción Linfocítica/métodos , Linfopenia/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Adulto , Animales , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Alquilantes/uso terapéutico , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/terapia , Vacunas contra el Cáncer/uso terapéutico , Células Cultivadas , Terapia Combinada , Dacarbazina/análogos & derivados , Dacarbazina/uso terapéutico , Daclizumab , Evaluación Preclínica de Medicamentos , Glioblastoma/inmunología , Glioblastoma/terapia , Humanos , Inmunoglobulina G/farmacología , Inmunoglobulina G/uso terapéutico , Inmunoterapia/métodos , Subunidad alfa del Receptor de Interleucina-2/inmunología , Linfopenia/patología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Persona de Mediana Edad , Especificidad por Sustrato/efectos de los fármacos , Especificidad por Sustrato/inmunología , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/inmunología , Temozolomida , Adulto JovenRESUMEN
Temozolomide, an alkylating agent, has shown promise in treating primary central nervous system lymphoma (PCNSL). The enzyme O(6)-methylguanine-DNA methyltransferase (MGMT) repairs alkylating damage, such as that induced by temozolomide. We hypothesized that MGMT immunohistochemistry would predict resistance to temozolomide in PCNSL. A retrospective study of newly-diagnosed and recurrent PCNSL patients treated at our institution was conducted to study the predictive value of MGMT immunohistochemistry for response to temozolomide. 20 patients who were treated with temozolomide as a single agent were identified during the study time period. 6/20 patients demonstrated a response, corresponding to an objective response rate of 30 % (95 % CI 8-52). Five patients with low MGMT level (<30 %) showed a response to temozolomide. Only one of 10 patients (10 %) with high MGMT level (≥30 %) exhibited a response to temozolomide. Small sample numbers precluded formal statistical comparisons. Two patients with complete response remain alive without progressive disease 6.7 and 7.2 years after temozolomide initiation. Immunohistochemistry can be performed on small biopsies to selectively assess MGMT status in tumor versus surrounding inflammation. MGMT analysis by immunohistochemistry may predict response to temozolomide in PCNSL and should be prospectively investigated.
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Antineoplásicos Alquilantes/efectos adversos , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/metabolismo , Dacarbazina/análogos & derivados , Linfoma/metabolismo , O(6)-Metilguanina-ADN Metiltransferasa/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Dacarbazina/efectos adversos , Resistencia a Antineoplásicos , Femenino , Humanos , Estudios Longitudinales , Linfoma/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , TemozolomidaRESUMEN
Leptomeningeal metastasis (LM), also known as leptomeningeal carcinomatosis (LC), is a devastating complication of metastatic cancer that occurs when neoplastic cells invade the meningeal space. Diagnosis of LM remains challenging given the heterogeneous signs and symptoms at presentation and requires thorough neurological examination, cerebrospinal fluid (CSF) analysis, and MRI of the brain and spine with gadolinium. Detecting neoplastic cells in the CSF is the gold standard for diagnosing leptomeningeal metastases; however, it has low sensitivity and may require multiple CSF samples. New emerging technologies, such as liquid biopsy of CSF, have increased sensitivity and specificity for detecting circulating tumor cells in CSF. The management of LM in patients with NSCLC requires an individualized multidisciplinary approach. Treatment options include surgery for ventricular shunt placement, radiation therapy to bulky or symptomatic disease sites, systemic or intrathecal chemotherapy, molecularly targeted agents, and, more recently, immunotherapy. Targeting actionable mutations in LM from NSCLC, such as EGFR tyrosine kinase inhibitors or anaplastic lymphoma kinase gene rearrangement inhibitors, has shown encouraging results in terms of disease control and survival. Although there are limited data regarding the use of immunotherapy in LM, immunotherapy has produced promising results in several case reports. In this review, we focused on the epidemiology, pathophysiology, clinical presentation, diagnosis, and current treatment strategies, with a special emphasis on novel agents, including targeted therapies and immunotherapy of LM in patients with NSCLC.
Asunto(s)
Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Carcinomatosis Meníngea , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Carcinomatosis Meníngea/terapia , Carcinomatosis Meníngea/tratamiento farmacológico , Antineoplásicos/uso terapéutico , PronósticoRESUMEN
BACKGROUND: The authors performed a phase 2 trial of combined protracted daily temozolomide and biweekly bevacizumab for patients with recurrent glioblastoma who had previously received radiation therapy and temozolomide. METHODS: There was no limit on the number of previous disease progressions or previous regimens allowed. Thirty-two adult patients were enrolled. Patients received temozolomide 50 mg/m(2) daily and bevacizumab 10 mg/kg intravenously every 14 days. Patients underwent physical examination and brain magnetic resonance imaging every 8 weeks. RESULTS: The authors observed a 6-month progression-free survival (PFS) rate of 18.8% (95% confidence interval [CI], 7.6%-33.7%) and a median PFS of 15.8 weeks. The median overall survival (OS) was 37 weeks, the 6-month OS rate was 62.5% (95% CI, 43.5%-76.7%), and the 12-month OS rate was 31.3% (95% CI, 16.4%-47.3%). Nine patients (28%) had a radiographic response, and 7 patients (22%) had disease progression within the first 8 weeks of treatment. Patterns of progression were available for 21 patients. The authors observed that 52% of patients (n = 11) progressed locally, 38% (n = 8) progressed with a diffuse pattern, and 10% (n = 2) progressed at a distant site. Two patients discontinued therapy secondary to toxicity (prolonged thrombocytopenia and grade 4 pancreatitis). One patient experienced grade 5 pneumonia. CONCLUSIONS: The current study demonstrated that a regimen of combined daily temozolomide and biweekly bevacizumab had some activity and was well tolerated. However, the results obtained in this study were inferior to those observed in studies of bevacizumab monotherapy and of combined irinotecan and bevacizumab therapy. The current patient population was more heterogeneous and was pretreated more heavily than patients in previous studies.
Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias Encefálicas/tratamiento farmacológico , Dacarbazina/análogos & derivados , Glioblastoma/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Bevacizumab , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/radioterapia , Terapia Combinada , Dacarbazina/administración & dosificación , Esquema de Medicación , Femenino , Glioblastoma/mortalidad , Glioblastoma/patología , Glioblastoma/radioterapia , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Análisis de Supervivencia , Temozolomida , Resultado del TratamientoRESUMEN
BACKGROUND: We evaluated the efficacy of imatinib plus hydroxyurea in patients with progressive/recurrent low-grade glioma. METHODS: A total of 64 patients with recurrent/progressive low-grade glioma were enrolled in this single-center study that stratified patients into astrocytoma and oligodendroglioma cohorts. All patients received 500 mg of hydroxyurea twice a day. Imatinib was administered at 400 mg per day for patients not on enzyme-inducing antiepileptic drugs (EIAEDs) and at 500 mg twice a day if on EIAEDs. The primary endpoint was progression-free survival at 12 months (PFS-12) and secondary endpoints were safety, median progression-free survival, and radiographic response rate. RESULTS: Thirty-two patients were enrolled into each cohort. Eleven patients (17%) had before radiotherapy and 24 (38%) had received before chemotherapy. The median PFS and PFS-12 were 11 months and 39%, respectively. Outcome did not differ between the histologic cohorts. No patient achieved a radiographic response. The most common grade 3 or greater adverse events were neutropenia (11%), thrombocytopenia (3%), and diarrhea (3%). CONCLUSIONS: Imatinib plus hydroxyurea was well tolerated among recurrent/progressive LGG patients but this regimen demonstrated negligible antitumor activity.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Astrocitoma/tratamiento farmacológico , Neoplasias Encefálicas/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Oligodendroglioma/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Alquilantes/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Astrocitoma/mortalidad , Benzamidas , Neoplasias Encefálicas/mortalidad , Estudios de Cohortes , Dacarbazina/análogos & derivados , Dacarbazina/uso terapéutico , Diarrea/inducido químicamente , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Humanos , Hidroxiurea/administración & dosificación , Hidroxiurea/efectos adversos , Mesilato de Imatinib , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/mortalidad , Neutropenia/inducido químicamente , Oligodendroglioma/mortalidad , Piperazinas/administración & dosificación , Piperazinas/efectos adversos , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Temozolomida , Trombocitopenia/inducido químicamente , Resultado del TratamientoRESUMEN
Despite contemporary surgery, image-guided radiotherapy, and chemotherapy, glioblastoma multiforme (GBM) persists or relapses in nearly all patients, and tumors almost always recur locally. Management of recurrent GBM is variable, but approaches include best supportive care, reoperation, reirradiation, and/or systemic therapy. Promising novel therapies include antiangiogenic agents and stereotactic radiosurgery, which have cytotoxic effects on tumor microvasculature. Emerging data suggest the safety and efficacy of bevacizumab and radiosurgery either alone or in combination. This report presents the case of a man with locally recurrent GBM treated with stereotactic radiosurgery and concurrent bevacizumab, and reviews the preclinical and clinical data supporting this approach.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Recurrencia Local de Neoplasia/terapia , Radiocirugia , Bevacizumab , Encéfalo/patología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/cirugía , Terapia Combinada , Glioblastoma/tratamiento farmacológico , Glioblastoma/cirugía , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/cirugía , Resultado del TratamientoRESUMEN
Although outcome following bevacizumab among recurrent grade IV malignant glioma patients is documented as poor by several analyses, outcome for recurrent grade III patients following bevacizumab therapy has not been specifically evaluated. We performed a pooled analysis of 96 recurrent grade III malignant glioma patients enrolled on three consecutive phase II bevacizumab salvage trials to evaluate overall outcome following bevacizumab trial discontinuation. Outcome on the three bevacizumab trials, which included similar eligibility, treatment and assessment criteria, was comparable. Forty-nine patients who progressed on bevacizumab trial therapy and remained alive for at least 30 days elected to receive additional therapy. These patients achieved a median PFS-6 and OS of 30.6% (95% CI: 18.4, 43.6) and 10.3 months (95% CI: 5.2, 11.7), respectively. Among patients who continued bevacizumab therapy (n = 23) after study progression, PFS-6 and median OS were 39.1% (95% CI: 19.9, 58.0) and 9.2 months (95% CI: 5.2, 13.6), respectively, compared to 23.1% (95% CI: 9.4, 40.3; P = 0.51) and 10.3 months (95% CI: 2.5, 14.4; P = 0.91) for patients who initiated non-bevacizumab containing therapy (n = 26). Outcome after discontinuation of bevacizumab therapy for recurrent grade III malignant glioma patients is associated with improved outcome compared to historical data for recurrent grade IV malignant glioma patients. Salvage therapies following bevacizumab failure have modest activity for grade III malignant glioma patients that is independent of further bevacizumab continuation.
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Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Glioma/tratamiento farmacológico , Terapia Recuperativa , Adulto , Anciano , Bevacizumab , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Femenino , Estudios de Seguimiento , Glioma/mortalidad , Glioma/patología , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Tasa de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
We evaluated the efficacy of carboplatin, irinotecan, and bevacizumab among bevacizumab-naïve, recurrent glioblastoma (GBM) patients in a phase 2, open-label, single arm trial. Forty eligible patients received carboplatin (area under the plasma curve [AUC] 4 mg/ml-min) on day one, while bevacizumab (10 mg/kg) and irinotecan (340 mg/m(2) for patients on CYP3A-enzyme-inducing anti-epileptics [EIAEDs] and 125 mg/m(2) for patients not on EIAEDs) were administered on days 1 and 14 of every 28-day cycle. Patients were evaluated after each of the first two cycles and then after every other cycle. Treatment continued until progressive disease, unacceptable toxicity, non-compliance, or voluntary withdrawal. The primary endpoint was progression-free survival at 6 months (PFS-6) and secondary endpoints included safety and median overall survival (OS). All patients had progression after standard therapy. The median age was 51 years. Sixteen patients (40%) had a KPS of 90-100, while 27 (68%) were at first progression. The median time from original diagnosis was 11.4 months. The PFS-6 rate was 46.5% (95% CI: 30.4, 61.0%) and the median OS was 8.3 months [95% confidence interval (CI): 5.9, and 10.7 months]. Grade 4 events were primarily hematologic and included neutropenia and thrombocytopenia in 20 and 10%, respectively. The most common grade 3 events were neutropenia, thrombocytopenia, fatigue, and infection in 25, 20, 13, and 10%, respectively. Eleven patients (28%) discontinued study therapy due to toxicity and 17 patients (43%) required dose modification. One patient died due to treatment-related intestinal perforation. The addition of carboplatin and irinotecan to bevacizumab significantly increases toxicity but does not improve anti-tumor activity to that achieved historically with single-agent bevacizumab among bevacizumab-naïve, recurrent GBM patients. (ClinicalTrials.gov number NCT00953121).
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Glioblastoma/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Bevacizumab , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Carboplatino/administración & dosificación , Femenino , Estudios de Seguimiento , Glioblastoma/mortalidad , Glioblastoma/patología , Humanos , Irinotecán , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
To determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of dasatinib, an inhibitor of the Src family kinase proteins, with erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, among recurrent malignant glioma patients. Once daily dasatinib was escalated in successive cohorts while erlotinib was administered daily at established doses based on concurrent CYP3A-inducing anticonvulsant (EIAEDS) use. Dasatinib pharmacokinetic analyzes were performed. Forty-seven patients enrolled including 37 (79 %) with grade IV and 10 (21 %) with grade III malignant glioma. Thirty patients (64 %) were at ≥second recurrence, while 27 (57 %) had received prior bevacizumab. The dasatinib MTD was 180 mg when combined with either 150 mg of erlotinib for patients not on EIAEDs, or 450 mg of erlotinib for patients on EIAEDs. The most common DLTs were diarrhea and fatigue, while most adverse events were grade 2. Pharmacokinetic data suggests that dasatinib exposure increased with increased dasatinib dose and concurrent erlotinib administration, while concurrent EIAED use diminished dasatinib exposure. No radiographic responses were observed, and only one patient (2 %) remained progression-free at 6 months. We demonstrate that dasatinib plus erlotinib can be safely co-administered on a continuous, daily dosing schedule with erlotinib, and established the recommended dose level of this combination.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Glioma/tratamiento farmacológico , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/prevención & control , Adulto , Anciano , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/mortalidad , Dasatinib , Clorhidrato de Erlotinib , Femenino , Glioma/mortalidad , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Recurrencia Local de Neoplasia/mortalidad , Pronóstico , Pirimidinas/administración & dosificación , Quinazolinas/administración & dosificación , Tiazoles/administración & dosificación , Distribución Tisular , Adulto JovenRESUMEN
Intracranial meningiomas are often indolent tumors which typically grow over years to decades. Nonetheless, meningiomas that progress after maximum safe resection and radiation therapy pose a significant therapeutic challenge and effective therapies have yet to be identified. Preclinical studies implicate angiogenesis in the pathophysiology of more aggressive meningiomas, suggesting that anti-angiogenic therapies may be of utility in this setting. We performed a retrospective review of fourteen patients with recurrent meningioma treated at Duke University Medical Center with bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor, administered either alone or in combination with chemotherapy. Most patients were heavily pre-treated. Progression-free survival at 6 months was 86 % and was comparable regardless of meningioma grade and whether bevacizumab was administered as monotherapy or in combination with chemotherapy. Most toxicities were mild however single patients developed CNS hemorrhage (grade 1) and intestinal perforation (grade 4), respectively. Bevacizumab can be administered safely to patients with meningioma and appears to be associated with encouraging anti-tumor effect when administered as either a single agent or in combination with chemotherapy. Phase II trials investigating bevacizumab in patients with progressive/recurrent meningioma are warranted.
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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 , Bevacizumab , Femenino , Estudios de Seguimiento , Humanos , Imagen por Resonancia Magnética , Masculino , Neoplasias Meníngeas/mortalidad , Neoplasias Meníngeas/patología , Meningioma/mortalidad , Meningioma/patología , Persona de Mediana Edad , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Adulto JovenRESUMEN
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.
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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 & dosificaciónRESUMEN
BACKGROUND: There were nearly 700,000 patients in the United States in 2010 living with brain tumor diagnoses. The incidence of seizures in this population is as high as 70% and is historically difficult to control. Approximately 30-40% of brain tumors patients who present with status epilepticus (SE) will not respond to typical therapy consisting of benzodiazepines and phenytoin (PHT), resulting in patients with refractory status epilepticus (RSE). RSE is usually treated with anesthetic doses of propofol or midazolam infusions. This therapy can have significant risk, particularly in patients with cancer. METHODS: A retrospective chart review was performed on 23 patients with primary or metastatic brain tumors whose SE was treated with intravenous PHT, levetiracetam (LEV), and oral pregabalin (PGB). RESULTS: In all the patients under study, PHT or LEV was used as first-line therapy. PGB was typically used as third-line treatment. The median daily dose of PGB was 375 mg (usually divided BID or TID), and the median daily dose of LEV 3000 mg (usually divided BID). Cessation of SE was seen in 16/23 (70%) after administration of PHT, LEV, and PGB. SE was aborted, on average, 24 h after addition of the third antiepileptic drug. Only one patient in the responder group required intubation. Mortality rate was zero in the responder group. No adverse reactions to this medication regimen were observed. CONCLUSION: Our study suggests that the administration of PHT, LEV, and PGB in brain tumor patients with RSE is safe and highly effective.
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Anticonvulsivantes/administración & dosificación , Neoplasias Encefálicas/complicaciones , Estado Epiléptico/tratamiento farmacológico , Estado Epiléptico/etiología , Enfermedad Aguda , Anciano , Neoplasias Encefálicas/mortalidad , Quimioterapia Combinada , Femenino , Humanos , Levetiracetam , Masculino , Persona de Mediana Edad , Fenitoína/administración & dosificación , Piracetam/administración & dosificación , Piracetam/análogos & derivados , Pregabalina , Estudios Retrospectivos , Estado Epiléptico/mortalidad , Resultado del Tratamiento , Ácido gamma-Aminobutírico/administración & dosificación , Ácido gamma-Aminobutírico/análogos & derivadosRESUMEN
Patients with smoldering multiple myeloma (SMM) are observed until progression, but early treatment may improve outcomes. We conducted a phase II trial of elotuzumab, lenalidomide, and dexamethasone (EloLenDex) in patients with high-risk SMM and performed single-cell RNA and T cell receptor (TCR) sequencing on 149 bone marrow (BM) and peripheral blood (PB) samples from patients and healthy donors (HDs). We find that early treatment with EloLenDex is safe and effective and provide a comprehensive characterization of alterations in immune cell composition and TCR repertoire diversity in patients. We show that the similarity of a patient's immune cell composition to that of HDs may have prognostic relevance at diagnosis and after treatment and that the abundance of granzyme K (GZMK)+ CD8+ effector memory T (TEM) cells may be associated with treatment response. Last, we uncover similarities between immune alterations observed in the BM and PB, suggesting that PB-based immune profiling may have diagnostic and prognostic utility.