RESUMO
Therapeutic outcomes for patients with brain metastases need to improve. A critical review of trials specifically addressing brain metastases shows key issues that could prevent acceptance of results by regulatory agencies, including enrolment of heterogeneous groups of patients and varying definitions of clinical endpoints. Considerations specific to disease, modality, and treatment are not consistently addressed. Additionally, the schedule of CNS imaging and consequences of detection of new or progressive brain metastases in trials mainly exploring the extra-CNS activity of systemic drugs are highly variable. The Response Assessment in Neuro-Oncology (RANO) working group is an independent, international, collaborative effort to improve the design of trials in patients with brain tumours. In this two-part series, we review the state of clinical trials of brain metastases and suggest a consensus recommendation for the development of criteria for future clinical trials.
Assuntos
Neoplasias Encefálicas/secundário , Ensaios Clínicos como Assunto , Neoplasias Encefálicas/terapia , Intervalo Livre de Doença , Humanos , Imageamento por Ressonância MagnéticaRESUMO
PURPOSE: Gamma knife radiosurgery (RS) may be an alternative to open surgery for mesial temporal lobe epilepsy (MTLE), but morbidities and the anticonvulsant mechanisms of RS are unclear. Examination of visual field defects (VFDs) after RS may provide evidence of the extent of a postoperative fixed lesion. VFDs occur in 52-100% of patients following open surgery for MTLE. METHODS: This multicenter prospective trial of RS enrolled patients with unilateral hippocampal sclerosis and concordant video-electroencephalography (EEG) findings. Patients were randomized to low (20 Gy) or high (24 Gy) doses delivered to the amygdala, hippocampal head, and parahippocampal gyrus. Postoperative perimetry were obtained at 24 months after RS. Visual field defect ratios (VFDRs) were calculated to quantify the degree of VFDs. Results were contrasted with age, RS dose and 50% isodose volume, peak volume of radiation-induced change at the surgical target, quality of life measurements, and seizure remission. KEY FINDINGS: No patients reported visual changes and no patients had abnormal bedside visual field examinations. Fifteen (62.5%) of 24 patients had postoperative VFDs, all homonymous superior quadrantanopsias. None of the VFDs were consistent with injury to the optic nerve or chiasm. Clinical diagnosis of VFDs correlated significantly with VFDRs (p = 0.0005). Patients with seizure remission had smaller (more severe) VFDRs (p = 0.04). No other variables had significant correlations. SIGNIFICANCE: VFDs appeared after RS in proportions similar to historical comparisons from open surgery for MTLE. The nature of VFDs was consistent with lesions of the optic radiations. The findings support the hypothesis that the mechanism of RS involves some degree of tissue damage and is not confined entirely to functional changes in neuromodulation.
Assuntos
Transtornos da Percepção/etiologia , Complicações Pós-Operatórias/etiologia , Radiocirurgia/efeitos adversos , Campos Visuais/fisiologia , Relação Dose-Resposta à Radiação , Eletroencefalografia , Epilepsia do Lobo Temporal/complicações , Epilepsia do Lobo Temporal/cirurgia , Seguimentos , Hipocampo/patologia , Humanos , Imageamento por Ressonância Magnética , Esclerose/complicações , Esclerose/patologia , Estatísticas não Paramétricas , Gravação em Vídeo , Testes de Campo VisualRESUMO
Aberrant methylation of CpG islands and genomic deletion are two predominant mechanisms of gene inactivation in tumorigenesis, but the extent to which they interact is largely unknown. The lack of an integrated approach to study these mechanisms has limited the understanding of tumor genomes and cancer genes. Restriction landmark genomic scanning (RLGS; ref. 1) is useful for global analysis of aberrant methylation of CpG islands, but has not been amenable to alignment with deletion maps because the identity of most RLGS fragments is unknown. Here, we determined the nucleotide sequence and exact chromosomal position of RLGS fragments throughout the genome using the whole chromosome of origin of the fragments and in silico restriction digestion of the human genome sequence. To study the interaction of these gene-inactivation mechanisms in primary brain tumors, we integrated RLGS-based methylation analysis with high-resolution deletion maps from microarray-based comparative genomic hybridization (array CGH; ref. 3). Certain subsets of gene-associated CpG islands were preferentially affected by convergent methylation and deletion, including genes that exhibit tumor-suppressor activity, such as CISH1 (encoding SOCS1; ref. 4), as well as genes such as COE3 that have been missed by traditional non-integrated approaches. Our results show that most aberrant methylation events are focal and independent of deletions, and the rare convergence of these mechanisms can pinpoint biallelic gene inactivation without the use of positional cloning.
Assuntos
Alelos , Inativação Gênica , Neoplasias/genética , Northern Blotting , Ilhas de CpG , Metilação de DNA , Regulação para Baixo , Deleção de Genes , Técnicas Genéticas , Genoma Humano , Humanos , Repetições de Microssatélites/genética , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sulfitos/farmacologia , Regulação para CimaRESUMO
Advances in the management of gliomas, including the approval of agents such as temozolomide and bevacizumab, have created an evolving therapeutic landscape in glioma treatment, thus affecting our ability to reliably use historical controls to comparatively assess the activity of new therapies. Furthermore, the increasing availability of novel, targeted agents--which are competing for a small patient population, in view of the low incidence of primary brain tumours--draws attention to the need to improve the efficiency of phase 2 clinical testing in neuro-oncology to expeditiously transition the most promising of these drugs or combinations to potentially practice-changing phase 3 trials. In this report from the Response Assessment in Neurooncology (RANO) group, we review phase 2 trial designs that can address these challenges and capitalise on scientific and clinical advances in brain tumour treatment in neuro-oncology to accelerate and optimise the selection of drugs deserving further testing in phase 3 trials. Although there is still a small role for single-arm and non-comparative phase 2 designs, emphasis is placed on the potential role that comparative randomised phase 2 designs--such as screening designs, selection designs, discontinuation designs, and adaptive designs, including seamless phase 2/3 designs--can have. The rational incorporation of these designs, as determined by the specific clinical setting and the trial's endpoints or goals, has the potential to substantially advance new drug development in neuro-oncology.
Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Ensaios Clínicos Fase II como Assunto/métodos , Glioma/tratamento farmacológico , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de PesquisaRESUMO
Cilengitide is a cyclic pentapeptide that is a specific inhibitor of the αvß3 and αvß5 integrins. Preclinical studies demonstrate antiangiogenic activity and anti-invasive activity in a number of glioma models. This study was designed to evaluate the efficacy and tumor delivery of cilengitide in patients with recurrent glioblastoma. Patients with recurrent glioblastoma who require a surgical resection for optimal clinical care received 3 intravenous doses of cilengitide at either 500 or 2000 mg (day -8, -4, -1) prior to undergoing tumor resection with corresponding blood samples for plasma to tumor comparisons. After recovery from surgery, patients were treated with cilengitide (2000 mg i.v. twice weekly, maximum of 2 years of treatment). The study accrued 30 patients with recurrent glioblastoma, 26 were evaluable for efficacy. The 6-month progression free survival rate was 12%. Cilengitide was detected in all tumor specimens with higher levels in the group receiving 2000 mg dosing while corresponding plasma concentrations were low, often below the lower limit of detection. These results confirm drug delivery and possibly retention in tumor. This study provides evidence that with established dosing, cilengitide is adequately delivered to the tumor, although as a single agent, efficacy in recurrent glioblastoma is modest. However, these results demonstrating drug delivery to tumor do support continued investigation of this agent as preliminary results from recent studies combining cilengitide with cytotoxic therapies are promising.
Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Venenos de Serpentes/uso terapêutico , Adulto , Idoso , Neoplasias Encefálicas/cirurgia , Terapia Combinada , Intervalo Livre de Doença , Determinação de Ponto Final , Feminino , Glioblastoma/cirurgia , Humanos , Imunoterapia , Integrinas/fisiologia , Avaliação de Estado de Karnofsky , Masculino , Pessoa de Meia-Idade , Recidiva , Venenos de Serpentes/efeitos adversos , Venenos de Serpentes/farmacocinéticaRESUMO
The purpose of this study is to evaluate the roles of resection extent and adjuvant radiation in the treatment of craniopharyngiomas. We reviewed the records of 122 patients ages 11-52 years who received primary treatment for craniopharyngioma between 1980 and 2009 at the University of California, San Francisco (UCSF). Primary endpoints were progression free survival (PFS) and overall survival (OS). Secondary endpoints were development of panhypopituitarism, diabetes insipidus (DI), and visual field defects. Of 122 patients, 30 (24%) were treated with gross total resection (GTR) without radiation therapy (RT), 3 (3%) with GTR + RT, 41 (33.6%) with subtotal resection (STR) without RT, and 48 (39.3%) with STR + RT. Median age at diagnosis was 30 years, with 46 patients 18 years or younger. Median follow-up for all patients was 56.4 months (interquartile range 18.9-144.2 months) and 47 months (interquartile range 12.3-121.8 months) for the 60 patients without progression. Fifty six patients progressed, 10 have died, 6 without progression. Median PFS was 61.1 months for all patients. PFS rate at 2 years was 61.5% (95% CI: 52.1-70.9). OS rate at 10 years was 91.1% (95% CI 84.3-97.9). There was no significant difference in PFS and OS between patients treated with GTR vs. STR + XRT (PFS; p = 0.544, OS; p = 0.735), but STR alone resulted in significantly shortened PFS compared to STR + RT or GTR (p < 0.001 for both). STR was associated with significantly shortened OS compared to STR + RT (p = 0.050) and trended to shorter OS compared to GTR (p = 0.066). GTR was associated with significantly greater risk of developing DI (56.3 vs. 13.3% with STR + XRT, p < 0.001) and panhypopituitarism (54.8 vs. 26.7% with STR + XRT, p = 0.014). In conclusion, for patients with craniopharyngioma, STR + RT may provide superior clinical outcome, achieving better disease control than STR and limiting side effects associated with aggressive surgical resection.
Assuntos
Craniofaringioma/radioterapia , Craniofaringioma/cirurgia , Neoplasias Hipofisárias/radioterapia , Neoplasias Hipofisárias/cirurgia , Adolescente , Adulto , Criança , Terapia Combinada , Craniofaringioma/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Neoplasias Hipofisárias/mortalidade , Radioterapia Adjuvante/métodos , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: To assess outcomes of language, verbal memory, cognitive efficiency and mental flexibility, mood, and quality of life (QOL) in a prospective, multicenter pilot study of Gamma Knife radiosurgery (RS) for mesial temporal lobe epilepsy (MTLE). METHODS: RS, randomized to 20 Gy or 24 Gy comprising 5.5-7.5 ml at the 50% isodose volume, was performed on mesial temporal structures of patients with unilateral MTLE. Neuropsychological evaluations were performed at preoperative baseline, and mean change scores were described at 12 and 24 months postoperatively. QOL data were also available at 36 months. KEY FINDINGS: Thirty patients were treated and 26 were available for the final 24-month neuropsychological evaluation. Language (Boston Naming Test), verbal memory (California Verbal Learning Test and Logical Memory subtest of the Wechsler Memory Scale-Revised), cognitive efficiency and mental flexibility (Trail Making Test), and mood (Beck Depression Inventory) did not differ from baseline. QOL scores improved at 24 and 36 months, with those patients attaining seizure remission by month 24s accounting for the majority of the improvement. SIGNIFICANCE: The serial changes in cognitive outcomes, mood, and QOL are unremarkable following RS for MTLE. RS may provide an alternative to open surgery, especially in those patients at risk of cognitive impairment or who desire a noninvasive alternative to open surgery.
Assuntos
Transtornos Cognitivos/diagnóstico , Epilepsia do Lobo Temporal/cirurgia , Complicações Pós-Operatórias/diagnóstico , Radiocirurgia/métodos , Adulto , Transtornos Cognitivos/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Projetos Piloto , Complicações Pós-Operatórias/epidemiologia , Estudos Prospectivos , Lobo Temporal/cirurgia , Resultado do TratamentoRESUMO
The purpose of this study is to identify the needs of brain tumor patients and their caregivers to provide improved health services to these populations. Two different questionnaires were designed for patients and caregivers. Both questionnaires contained questions pertaining to three realms: disease symptoms/treatment, health care provider, daily living/finances. The caregivers' questionnaires contained an additional domain on emotional needs. Each question was evaluated for the degree of importance and satisfaction. Exploratory analyses determined whether baseline characteristics affect responder importance or satisfaction. Also, areas of high agreement/disagreement in satisfaction between the participating patient-caregiver pairs were identified. Questions for which >50% of the patients and caregivers thought were "very important" but >30% were dissatisfied include: understanding the cause of brain tumors, dealing with patients' lower energy, identifying healthful foods and activities for patients, telephone access to health care providers, information on medical insurance coverage, and support from their employer. In the emotional realm, caregivers identified 9 out of 10 items as important but need further improvement. Areas of high disagreement in satisfaction between participating patient-caregiver pairs include: getting help with household chores (P value = 0.006) and finding time for personal needs (P value < 0.001). This study provides insights into areas to improve services for brain tumor patients and their caregivers. The caregivers' highest amount of burden is placed on their emotional needs, emphasizing the importance of providing appropriate medical and psychosocial support for caregivers to cope with emotional difficulties they face during the patients' treatment process.
Assuntos
Neoplasias Encefálicas/psicologia , Cuidadores/psicologia , Necessidades e Demandas de Serviços de Saúde/estatística & dados numéricos , Qualidade de Vida/psicologia , Atividades Cotidianas , Adaptação Psicológica , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/enfermagem , Emoções , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Satisfação do Paciente , Estatísticas não Paramétricas , Inquéritos e Questionários , Adulto JovemRESUMO
OBJECTIVE: The safety, efficacy, and morbidity of radiosurgery (RS) must be established before it can be offered as an alternative to open surgery for unilateral mesial temporal lobe epilepsy. We report the 3-year outcomes of a multicenter, prospective pilot study of RS. METHODS: RS was randomized to 20 or 24Gy targeting the amygdala, hippocampus, and parahippocampal gyrus. Seizure diaries evaluated the final seizure remission between months 24 and 36. Verbal memory was evaluated at baseline and 24m with the Wechsler Memory Scale-Revised (WMS-R) and California Verbal Learning Test (CVLT). Patients were classified as having "significant improvement," "no change," and "significant impairment" based on relative change indices. RESULTS: Thirteen high-dose and 17 low-dose patients were treated. Both groups showed significant reductions in seizures by 1 year after treatment. At the 36-month follow-up evaluation, 67% of patients were free of seizures for the prior 12 months (high dose: 10/13, 76.9%; low dose: 10/17, 58.8%). Use of steroids, headaches, and visual field defects did not differ by dose or seizure remission. The prevalence of verbal memory impairment was 15% (4/26 patients); none declined on more than one measure. The prevalence of significant verbal memory improvements was 12% (3/26). INTERPRETATION: RS for unilateral mesial temporal lobe epilepsy offers seizure remission rates comparable with those reported previously for open surgery. There were no major safety concerns with high-dose RS compared with low-dose RS. Additional research is required to determine whether RS may be a treatment option for some patients with mesial temporal lobe epilepsy.
Assuntos
Epilepsia do Lobo Temporal/fisiopatologia , Epilepsia do Lobo Temporal/cirurgia , Memória/fisiologia , Radiocirurgia/métodos , Aprendizagem Verbal/fisiologia , Adulto , Relação Dose-Resposta à Radiação , Feminino , Cefaleia/etiologia , Humanos , Masculino , Testes Neuropsicológicos , Projetos Piloto , Estudos Prospectivos , Radiocirurgia/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Campos VisuaisRESUMO
To report long-term results for children with low-grade hypothalamic/chiasmatic gliomas treated on a phase II chemotherapy protocol. Between 1984 and 1992, 33 children with hypothalamic/chiasmatic LGGs received TPDCV chemotherapy on a phase II prospective trial. Median age was 3.0 years (range 0.3-16.2). Twelve patients (36%) underwent STRs, 14 (42%) biopsy only, and seven (21%) no surgery. Twenty patients (61%) had pathologic JPAs, nine (27%) grade II gliomas, and four (12%) no surgical sampling. Median f/u for surviving patients was 15.2 years (range 5.3-20.7); 20 of the 23 surviving patients had 14 or more years of follow-up. Fifteen-year PFS and OS were 23.4 and 71.2%, respectively. Twenty-five patients progressed, of whom 13 are NED, two are AWD, and 10 have died. All children who died were diagnosed and first treated at age three or younger. Age at diagnosis was significantly associated with relapse and survival (P = 0.004 for PFS and P = 0.037 for OS). No PFS or OS benefit was seen with STR versus biopsy/no sampling (P = 0.58 for PFS, P = 0.59 for OS). For patients with JPAs and WHO grade II tumors, the 15-year PFS was 18.8 and 22.2% (P = 0.95) and 15-year OS was 73.7 and 55.6% (P = 0.17), respectively. Upfront TPDCV for children with hypothalamic/chiasmatic LGGs resulted in 15-year OS of 71.2% and 15-year PFS of 23.4%. No survival benefit is demonstrated for greater extent of resection. Age is a significant prognostic factor for progression and survival.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Glioma/tratamento farmacológico , Neoplasias Hipotalâmicas/tratamento farmacológico , Adolescente , Fatores Etários , Criança , Pré-Escolar , Progressão da Doença , Intervalo Livre de Doença , Feminino , Glioma/mortalidade , Humanos , Neoplasias Hipotalâmicas/mortalidade , Lactente , Lomustina/uso terapêutico , Estudos Longitudinais , Masculino , Mitolactol/uso terapêutico , Valor Preditivo dos Testes , Procarbazina/uso terapêutico , Estudos Retrospectivos , Terapia de Salvação/métodos , Tioguanina/uso terapêutico , Resultado do Tratamento , Vincristina/uso terapêuticoRESUMO
Recent evidence suggests the Akt-mTOR pathway may play a role in development of low-grade gliomas (LGG). We sought to evaluate whether activation of this pathway correlates with survival in LGG by examining expression patterns of proteins within this pathway. Forty-five LGG tumor specimens from newly diagnosed patients were analyzed for methylation of the putative 5'-promoter region of PTEN using methylation-specific PCR as well as phosphorylation of S6 and PRAS40 and expression of PTEN protein using immunohistochemistry. Relationships between molecular markers and overall survival (OS) were assessed using Kaplan-Meier methods and exact log-rank test. Correlation between molecular markers was determined using the Mann-Whitney U and Spearman Rank Correlation tests. Eight of the 26 patients with methylated PTEN died, as compared to 1 of 19 without methylation. There was a trend towards statistical significance, with PTEN methylated patients having decreased survival (P = 0.128). Eight of 29 patients that expressed phospho-S6 died, whereas all 9 patients lacking p-S6 expression were alive at last follow-up. There was an inverse relationship between expression of phospho-S6 and survival (P = 0.029). There was a trend towards decreased survival in patients expressing phospho-PRAS40 (P = 0.077). Analyses of relationships between molecular markers demonstrated a statistically significant positive correlation between expression of p-S6(235) and p-PRAS40 (P = 0.04); expression of p-S6(240) correlated positively with PTEN methylation (P = 0.04) and negatively with PTEN expression (P = 0.03). Survival of LGG patients correlates with phosphorylation of S6 protein. This relationship supports the use of selective mTOR inhibitors in the treatment of low grade glioma.
Assuntos
Neoplasias Encefálicas/mortalidade , Glioma/mortalidade , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , PTEN Fosfo-Hidrolase/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/fisiologia , Adulto , Neoplasias Encefálicas/tratamento farmacológico , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioma/tratamento farmacológico , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Fosforilação/efeitos dos fármacos , Valor Preditivo dos Testes , Estudos Retrospectivos , Serina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estatísticas não Paramétricas , Sulfitos/farmacologia , Sulfitos/uso terapêutico , Serina-Treonina Quinases TOR , Adulto JovemRESUMO
There are no established treatments for recurrent meningioma when surgical and radiation options are exhausted. The epidermal growth factor receptor (EGFR) is often over-expressed in meningiomas and may promote tumor growth. In open label, single arm phase II studies of the EGFR inhibitors gefitinib (NABTC 00-01) and erlotinib (NABTC 01-03) for recurrent malignant gliomas, we included exploratory subsets of recurrent meningioma patients. We have pooled the data and report the results here. Patients with recurrent histologically confirmed meningiomas with no more than 2 previous chemotherapy regimens were treated with gefitinib 500 mg/day or erlotinib 150 mg/day until tumor progression or unacceptable toxicity. Twenty-five eligible patients were enrolled with median age 57 years (range 29-81) and median Karnofsky performance status (KPS) score 90 (range 60-100). Sixteen patients (64%) received gefitinib and 9 (36%) erlotinib. Eight patients (32%) had benign tumors, 9 (36%) atypical, and 8 (32%) malignant. For benign tumors, the 6-month progression-free survival (PFS6) was 25%, 12-month PFS (PFS12) 13%, 6-month overall survival (OS6) 63%, and 12-month OS (OS12) 50%. For atypical and malignant tumors, PFS6 was 29%, PFS12 18%, OS6 71%, and OS12 65%. The PFS and OS were not significantly different by histology. There were no objective imaging responses, but 8 patients (32%) maintained stable disease. Although treatment was well-tolerated, neither gefitinib nor erlotinib appear to have significant activity against recurrent meningioma. The role of EGFR inhibitors in meningiomas is unclear. Evaluation of multi-targeted inhibitors and EGFR inhibitors in combination with other targeted molecular agents may be warranted.
Assuntos
Neoplasias Meníngeas/tratamento farmacológico , Meningioma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Relação Dose-Resposta a Droga , Cloridrato de Erlotinib , Feminino , Seguimentos , Gefitinibe , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Receptor tyrosine kinases such as epidermal growth factor receptors (EGFRs) and their downstream signaling pathways such as the Ras-Raf-mitogen-activated protein kinase (MAPK) pathway play important roles in glioblastoma (GBM). This study investigated the safety, pharmacokinetics, and efficacy of sorafenib (Ras/Raf/MAPK inhibitor) in combination with erlotinib (EGFR inhibitor) for treatment of recurrent GBMs. METHODS: Patients with recurrent GBM were eligible. A novel sequential accrual trial design was used, where patients were sequentially accrued into separate treatment arms in phase I and phase II investigations to optimize recruitment efficiency. In phase I, a standard 3 + 3 format was used to identify dose-limiting toxicities (DLTs), determine maximum tolerated dose (MTD), and investigate pharmacokinetics. Phase II followed a 2-stage design with the primary endpoint being 6-month progression-free survival (PFS6). RESULTS: Sixteen patients were recruited for phase I, and the MTD was determined to be sorafenib 200 mg twice daily and erlotinib 100 mg once daily. DLTs include Grade 3 hypertension, Grade 3 elevated liver transaminases, and Grade 4 elevated lipase. While erlotinib did not affect sorafenib levels, sorafenib reduced erlotinib levels. In phase II, 3 of 19 stage 1 participants were progression free at 6 months. This did not meet the predetermined efficacy endpoint, and the trial was terminated. CONCLUSION: This study identified the MTD and DLTs for sorafenib and erlotinib combination therapy for recurrent GBMs; however, efficacy data did not meet the primary endpoint. This study also demonstrates the feasibility of a novel sequential accrual clinical trial design that optimizes patient recruitment for multiarm studies, which is particularly effective for multicenter clinical trials.
RESUMO
The purpose of this study was to describe the quality of life (QOL) of low-grade glioma (LGG) patients at baseline prior to chemotherapy and through 12 cycles of temozolomide (TMZ) chemotherapy. Patients with histologically confirmed LGG with only prior surgery were given TMZ for 12 cycles. QOL assessments by the Functional Assessment of Cancer Therapy-Brain (FACT-Br) were obtained at baseline prior to chemotherapy and at 2-month intervals while receiving TMZ. Patients with LGG at baseline prior to chemotherapy had higher reported social well-being scores (mean difference = 5.0; p < 0.01) but had lower reported emotional well-being scores (mean difference = 2.2; p < 0.01) compared to a normal population. Compared to patients with left hemisphere tumors, patients with right hemisphere tumors reported higher physical well-being scores (p = 0.01): 44% could not drive, 26% did not feel independent, and 26% were afraid of having a seizure. Difficulty with work was noted in 24%. Mean change scores at each chemotherapy cycle compared to baseline for all QOL subscales showed either no significant change or were significantly positive (p < 0.01). Patients with LGG on TMZ at baseline prior to chemotherapy reported QOL comparable to a normal population with the exception of social and emotional well-being, and those with right hemisphere tumors reported higher physical well-being scores compared to those with left hemisphere tumors. While remaining on therapy, LGG patients were able to maintain their QOL in all realms. LGG patients' QOL may be further improved by addressing their emotional well-being and their loss of independence in terms of driving or working.
Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Astrocitoma/tratamento farmacológico , Neoplasias Encefálicas/tratamento farmacológico , Dacarbazina/análogos & derivados , Oligodendroglioma/tratamento farmacológico , Avaliação de Resultados em Cuidados de Saúde , Qualidade de Vida , Adulto , Idoso , Astrocitoma/patologia , Astrocitoma/psicologia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/psicologia , Dacarbazina/uso terapêutico , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Oligodendroglioma/patologia , Oligodendroglioma/psicologia , Prognóstico , Estudos Prospectivos , Perfil de Impacto da Doença , Temozolomida , Resultado do Tratamento , Adulto JovemRESUMO
Distinguishing between low-grade oligodendrogliomas (ODs) and astrocytomas (AC) is of interest for defining prognosis and stratifying patients to specific treatment regimens. The purpose of this study was to determine if the apparent diffusion coefficient (ADC) and fractional anisotropy (FA) from diffusion imaging can help to differentiate between newly diagnosed grade II OD and AC subtypes and to evaluate the ADC and FA values for the mixed population of oligoastrocytomas (OA). Fifty-three patients with newly diagnosed grade II gliomas were studied using a 1.5T whole body scanner (23 ODs, 16 ACs, and 14 OAs). The imaging protocol included post-gadolinium T1-weighted images, T2-weighted images, and either three and/or six directional diffusion imaging sequence with b = 1000 s/mm(2). Diffusion-weighted images were analyzed using in-house software to calculate maps of ADC and for six directional acquisitions, FA. The intensity values were normalized by values from normal appearing white matter (NAWM) to generate maps of normalized apparent diffusion coefficient (nADC) and normalized fractional anisotropy (nFA). The hyperintense region in the T2 weighted image was defined as the T2All region. A Mann-Whitney rank-sum test was performed on the 25th, median, and 75th nADC and nFA among the three subtypes. Logistic regression was performed to determine how well the nADC and nFA predict subtype. Lesions diagnosed as being OD had significantly lower nADC and significantly higher nFA, compared to AC. The nADC and nFA values individually classified the data with an accuracy of 87%. Combining the two did not enhance the classification. The patients with OA had nADC and nFA values between those of OD and AC. This suggests that ADC and FA may be helpful in directing tissue sampling to the most appropriate regions for taking biopsies in order to make a definitive diagnosis.
Assuntos
Imagem de Difusão por Ressonância Magnética , Glioma/diagnóstico , Adulto , Idoso , Anisotropia , Feminino , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Patients with brain tumors including intracranial meningiomas are at increased risk for developing deep vein thrombosis (DVTs) and suffering thromboembolic events (VTEs). Many surgeons are concerned that early use of low dose enoxaparin may increase the risk of intracranial hemorrhage which outweighs the benefit of DVT/VTE reduction. We aimed to address concerns around the use of enoxaparin after meningioma resection in the development of postoperative intracranial hemorrhages and DVT/VTEs. This is a retrospective review of 86 patients with intracranial meningiomas who underwent craniectomy and surgical resection of the mass, treated by one attending surgeon at UCSF Medical Center between 2000 and 2005. Within 48 h after surgery patients treated 2003-2005 routinely received enoxaparin therapy unless there was documented intracranial hemorrhage, lumbar subarachnoid drain, enoxaparin hypersensitivity, or thrombocytopenia (n = 24). These were compared to a cohort treated 2000-2002 who did not receive the drug (n = 62). Exclusion criteria were prior VTEs or coagulopathies. The groups were similar in tumor and surgical characteristics. Enoxaparin therapy did not increase the incidence of intracranial hemorrhage following surgical meningioma resection and the incidence of DVTs/VTEs was 0% (n = 0) versus 4.8% (n = 3) in the non-enoxaparin group. Results did not reach statistical significance. In this retrospective study, postoperative administration of enoxaparin following meningioma resection does not increase the risk of intracranial hematoma though enoxaparin administration may slightly decrease the incidence of post-surgical thromboembolic events. Due to study design and power, we were not able to demonstrate DVT/VTE reduction with statistical significance.
Assuntos
Anticoagulantes/uso terapêutico , Enoxaparina/uso terapêutico , Neoplasias Meníngeas/complicações , Meningioma/complicações , Complicações Pós-Operatórias/prevenção & controle , Trombose/prevenção & controle , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Adjuvante , Feminino , Humanos , Incidência , Hemorragias Intracranianas/epidemiologia , Masculino , Neoplasias Meníngeas/cirurgia , Meningioma/cirurgia , Pessoa de Meia-Idade , Procedimentos Neurocirúrgicos , Estudos Retrospectivos , Trombose/etiologiaRESUMO
Seizures are common in patients with gliomas, and phenytoin (PHT) is frequently used to control tumor-related seizures. PHT, however, has many undesirable side effects (SEs) and drug interactions with glioma chemotherapy. Levetiracetam (LEV) is a newer antiepileptic drug (AED) with fewer SEs and essentially no drug interactions. We performed a pilot study testing the safety and feasibility of switching patients from PHT to LEV monotherapy for postoperative control of glioma-related seizures. Over a 13-month period, 29 patients were randomized in a 2:1 ratio to initiate LEV therapy within 24 h of surgery or to continue PHT therapy. 6 month follow-up data were available for 15 patients taking LEV and for 8 patients taking PHT. In the LEV group, 13 patients (87%) were seizure-free. In the PHT group, 6 patients (75%) were seizure-free. Reported SEs at 6 months was as follows (%LEV/%PHT group): dizziness (0/14), difficulty with coordination (0/29), depression (7/14) lack of energy or strength (20/43), insomnia (40/43), mood instability (7/0). The pilot data presented here suggest that it is safe to switch patients from PHT to LEV monotherapy following craniotomy for supratentorial glioma. A large-scale, double-blinded, randomized control trial of LEV versus PHT is required to determine seizure control equivalence and better assess differences in SEs.
Assuntos
Anticonvulsivantes/uso terapêutico , Neoplasias Encefálicas/complicações , Glioma/complicações , Fenitoína/uso terapêutico , Piracetam/análogos & derivados , Convulsões/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/cirurgia , Craniotomia/efeitos adversos , Feminino , Glioma/cirurgia , Humanos , Levetiracetam , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Piracetam/uso terapêutico , Convulsões/etiologiaRESUMO
Glioblastoma Multiforme (GBM) are heterogeneous lesions, both in terms of their appearance on anatomic images and their response to therapy. The goal of this study was to evaluate the prognostic value of parameters derived from physiological and metabolic images of these lesions. Fifty-six patients with GBM were scanned immediately before surgical resection using conventional anatomical MR imaging and, where possible, perfusion-weighted imaging, diffusion-weighted imaging, and proton MR spectroscopic imaging. The median survival time was 517 days, with 15 patients censored. Absolute anatomic lesion volumes were not associated with survival but patients for whom the combined volume of contrast enhancement and necrosis was a large percentage of the T2 hyperintense lesion had relatively poor survival. Other volumetric parameters linked with less favorable survival were the volume of the region with elevated choline to N-acetylaspartate index (CNI) and the volume within the T2 lesion that had apparent diffusion coefficient (ADC) less than 1.5 times that in white matter. Intensity parameters associated with survival were the maximum and the sum of levels of lactate and of lipid within the CNI lesion, as well as the magnitude of the 10th percentile of the normalized ADC within the contrast-enhancing lesion. Patients whose imaging parameters indicating that lesions with a relatively large percentage with breakdown of the blood brain barrier or necrosis, large regions with abnormal metabolism or areas with restricted diffusion have relatively poor survival. These parameters may provide useful information for predicting outcome and for the stratification of patients into high or low risk groups for clinical trials.
Assuntos
Glioblastoma/metabolismo , Glioblastoma/patologia , Imageamento por Ressonância Magnética , Adulto , Idoso , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Mapeamento Encefálico , Neoplasias Encefálicas , Colina/metabolismo , Creatina/metabolismo , Diagnóstico Diferencial , Imagem de Difusão por Ressonância Magnética , Feminino , Glioblastoma/diagnóstico por imagem , Glioblastoma/mortalidade , Humanos , Aumento da Imagem , Processamento de Imagem Assistida por Computador , Estimativa de Kaplan-Meier , Ácido Láctico/metabolismo , Lipídeos/análise , Espectroscopia de Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Prótons , Cintilografia , Estudos RetrospectivosRESUMO
The blood-brain barrier is a substantial obstacle for delivering anticancer agents to brain tumors, and new strategies for bypassing it are greatly needed for brain-tumor therapy. Intranasal delivery provides a practical, noninvasive method for delivering therapeutic agents to the brain and could provide an alternative to intravenous injection and convection-enhanced delivery. We treated rats bearing intracerebral human tumor xenografts intranasally with GRN163, an oligonucleotide N3'-->P5'thio-phosphoramidate telomerase inhibitor. 3'-Fuorescein isothiocyanate (FITC)-labeled GRN163 was administered intranasally every 2 min as 6 microl drops into alternating sides of the nasal cavity over 22 min. FITC-labeled GRN163 was present in tumor cells at all time points studied, and accumulation of GRN163 peaked at 4 h after delivery. Moreover, GRN163 delivered intranasally, daily for 12 days, significantly prolonged the median survival from 35 days in the control group to 75.5 days in the GRN163-treated group. Thus, intranasal delivery of GRN163 readily bypassed the blood-brain barrier, exhibited favorable tumor uptake, and inhibited tumor growth, leading to a prolonged lifespan for treated rats compared to controls. This delivery approach appears to kill tumor cells selectively, and no toxic effects were noted in normal brain tissue. These data support further development of intranasal delivery of tumor-specific therapeutic agents for brain tumor patients.
Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Inibidores Enzimáticos/administração & dosagem , Glioma/tratamento farmacológico , Oligonucleotídeos/administração & dosagem , Telomerase/antagonistas & inibidores , Administração Intranasal , Animais , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Humanos , Masculino , Ratos , Ratos Nus , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The North American Brain Tumor Consortium (NABTC) uses 6-month progression-free survival (6moPFS) as the efficacy end point of therapy trials for adult patients with recurrent high-grade gliomas. In this study, we investigated whether progression status at 6 months predicts survival from that time, implying the potential for prolonged survival if progression could be delayed. We also evaluated earlier time points to determine whether the time of progression assessment alters the strength of the prediction. Data were from 596 patient enrollments (159 with grade III gliomas and 437 with grade IV tumors) in NABTC phase II protocols between February 1998 and December 2002. Outcome was assessed statistically using Kaplan-Meier curves and Cox proportional hazards models. Median survivals were 39 and 30 weeks for patients with grade III and grade IV tumors, respectively. Twenty-eight percent of patients with grade III and 16% of patients with grade IV tumors had progression-free survival of >26 weeks. Progression status at 9, 18, and 26 weeks predicted survival from those times for patients with grade III or grade IV tumors (p < 0.001 and hazard ratios < 0.5 in all cases). Including KPS, age, number of prior chemotherapies, and response in a multivariate model did not substantively change the results. Progression status at 6 months is a strong predictor of survival, and 6moPFS is a valid end point for trials of therapy for recurrent malignant glioma. Earlier assessments of progression status also predicted survival and may be incorporated in the design of future clinical trials.