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Bevacizumab (BEV, Avastin(®)) produces durable objective radiological responses of 20-26 %, median response durations of 16-18 weeks, and median overall survival (mOS) of 31-40 weeks. While the use of BEV is well-established, the lack of dose-response studies in glioblastoma (GBM) patients raises the question whether current dosing practice is optimal. As a result of differing approaches to BEV dosing that ranged from the FDA approved package insert dose of 10 mg/kg every 2 weeks to 7.5 mg/kg every 3-4 weeks, among physicians within Northern California Kaiser Permanente hospitals over 4+ years, we did an IRB-approved retrospective analysis of patients seen in Northern California Kaiser Permanente facilities and treated with BEV. Between September 1, 2008 and August 31, 2013, 181 patients received BEV for tumor progression/recurrence starting 2.6 weeks after completion of chemoradiation. The integrated BEV administered dose-week (AUCBEV) for all patients had a median AUCBEV of 3.6 mg·wk/kg). Maximum likelihood analysis found patients over 65 years did worse than younger patients (p = 0.004), women lived longer (p = 0.002), and patients treated below the AUCBEV did better than those treated above the median AUCBEV (p = 0.003). mOS for BEV starting 1 month after chemoradiation was 45 versus 68 weeks (p = 0.012) and BEV starting 3 months after chemoradiation was 40 versus 74 weeks (p = 0.0085). Dosing BEV at half the standard dose for progressive/recurrent GBM was at least equivalent to or, maybe better than standard dosing. Unexplained was the observation that females had longer OS with BEV than males.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias Encefálicas/mortalidade , Glioblastoma/mortalidade , Recidiva Local de Neoplasia/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Progressão da Doença , Feminino , Seguimentos , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Terapia de Salvação , Taxa de Sobrevida , Adulto JovemRESUMO
Bruton tyrosine kinase (BTK) links the B-cell antigen receptor (BCR) and Toll-like receptors with NF-κB. The role of BTK in primary central nervous system (CNS) lymphoma (PCNSL) is unknown. We performed a phase I clinical trial with ibrutinib, the first-in-class BTK inhibitor, for patients with relapsed or refractory CNS lymphoma. Clinical responses to ibrutinib occurred in 10 of 13 (77%) patients with PCNSL, including five complete responses. The only PCNSL with complete ibrutinib resistance harbored a mutation within the coiled-coil domain of CARD11, a known ibrutinib resistance mechanism. Incomplete tumor responses were associated with mutations in the B-cell antigen receptor-associated protein CD79B. CD79B-mutant PCNSLs showed enrichment of mammalian target of rapamycin (mTOR)-related gene sets and increased staining with PI3K/mTOR activation markers. Inhibition of the PI3K isoforms p110α/p110δ or mTOR synergized with ibrutinib to induce cell death in CD79B-mutant PCNSL cells.Significance: Ibrutinib has substantial activity in patients with relapsed or refractory B-cell lymphoma of the CNS. Response rates in PCNSL were considerably higher than reported for diffuse large B-cell lymphoma outside the CNS, suggesting a divergent molecular pathogenesis. Combined inhibition of BTK and PI3K/mTOR may augment the ibrutinib response in CD79B-mutant human PCNSLs. Cancer Discov; 7(9); 1018-29. ©2017 AACR.See related commentary by Lakshmanan and Byrd, p. 940This article is highlighted in the In This Issue feature, p. 920.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Linfoma de Células B/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adenina/análogos & derivados , Adulto , Tirosina Quinase da Agamaglobulinemia , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Proteínas Adaptadoras de Sinalização CARD/genética , Neoplasias do Sistema Nervoso Central/sangue , Neoplasias do Sistema Nervoso Central/líquido cefalorraquidiano , Neoplasias do Sistema Nervoso Central/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Guanilato Ciclase/genética , Humanos , Linfoma de Células B/sangue , Linfoma de Células B/líquido cefalorraquidiano , Linfoma de Células B/metabolismo , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Mutação , Piperidinas , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirazóis/efeitos adversos , Pirazóis/farmacocinética , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Resultado do Tratamento , Adulto JovemRESUMO
Brain metastases have traditionally been treated with a surgical or radiotherapeutic approach. Chemotherapy is used occasionally as salvage therapy. The blood-brain barrier excludes most chemotherapeutic agents, rendering many systemic options ineffective within the CNS. Intrathecal chemotherapies do not penetrate into brain tissue or bulky parenchymal tumors, so are ineffective in treatment of brain metastases. However, some patients with brain metastases benefit from chemotherapy, and temozolomide or targeted therapies like gefitinib have demonstrated activity. A better understanding of the biological behavior of brain metastases may lead to development of effective treatments for this common complication of systemic cancer. The review discusses the biology of brain metastases and provides an update on current chemotherapeutic strategies.
Assuntos
Antineoplásicos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Barreira Hematoencefálica/metabolismo , Neoplasias Encefálicas/metabolismo , Terapia Combinada , HumanosRESUMO
PURPOSE: This open-label, prospective, multicenter single-arm phase II study combined bevacizumab (BV) with radiation therapy (RT) and temozolomide (TMZ) for the treatment of newly diagnosed glioblastoma (GBM). The objectives were to determine the efficacy of this treatment combination and the associated toxicity. PATIENTS AND METHODS: Seventy patients with newly diagnosed GBM were enrolled between August 2006 and November 2008. Patients received standard RT starting within 3 to 6 weeks after surgery with concurrent administration of daily TMZ and biweekly BV. After completion of RT, patients resumed TMZ for 5 days every 4 weeks and continued biweekly BV. MGMT promoter methylation was assessed on patient tumor tissue. A University of California, Los Angeles/Kaiser Permanente Los Angeles (KPLA) control cohort of newly diagnosed patients treated with first-line RT and TMZ who had mostly received BV at recurrence was derived for comparison. RESULTS: The overall survival (OS) and progression-free survival (PFS) were 19.6 and 13.6 months, respectively, compared to 21.1 and 7.6 months in the University of California, Los Angeles/KPLA control cohort, and 14.6 and 6.9 months in the European Organisation for Research and Treatment of Cancer-National Cancer Institute of Canada cohort. Correlation of MGMT promoter methylation and improved OS and PFS was retained in the study group. Comparative subset analysis showed that poor prognosis patients (recursive partitioning analysis class V/VI) may derive an early benefit from the use of first-line BV. Toxicity attributable to RT/TMZ was similar, and additional toxicities were consistent with those reported in other BV trials. CONCLUSION: Patients treated with BV and TMZ during and after RT showed improved PFS without improved OS compared to the University of California, Los Angeles/KPLA control group. Additional studies are warranted to determine if BV administered first-line improves survival compared to BV at recurrence.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/efeitos adversos , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab , Neoplasias Encefálicas/irrigação sanguínea , Terapia Combinada , Dacarbazina/administração & dosagem , Dacarbazina/efeitos adversos , Dacarbazina/análogos & derivados , Feminino , Glioblastoma/irrigação sanguínea , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , TemozolomidaRESUMO
Glioblastoma is one of the most common primary brain tumors and one of the most difficult to treat. In population-based studies only 30% of patients will survive 1 year and in the most efficacious surgery, irradiation, and chemotherapy clinical trials approximately 20% will live 2 years. Bevacizumab is a recombinant, antivascular epidermal growth factor receptor (VEGF) monoclonal antibody with 6 VEGF-binding residues that binds to VEGF, preventing VEGF from binding to its target, VEGFR-1 and VEGFR-2, on endothelial cells. Through its binding to VEGF ligands bevacizumab reduces tumor angiogenesis and vasogenic brain edema; the consequences are that bevacizumab reduces the rate of glioblastoma tumor growth and its associated tumoral edema, thereby improving quality of life and survival for patients suffering from cerebral glioblastoma. In this review, we will summarize the studies that led to the use of bevacizumab in glioblastoma and the potential side-effects and complications that can be associated with its use and, finally, new opportunities for drug combinations with bevacizumab.
RESUMO
Central nervous system (CNS) metastases from breast cancer carry a poor prognosis. Systemic chemotherapy is often ineffective due to the impermeability of the blood-brain barrier (BBB) and inherent chemoresistance of CNS metastases. There are limited data supporting the use of capecitabine in this setting. Medical records of seven patients with brain metastases from breast cancer who received capecitabine treatment at Memorial Sloan-Kettering Cancer Center from 1994-2006 were reviewed. Treatment outcomes were analyzed retrospectively in those patients. Median time from breast cancer diagnosis to the development of CNS metastasis was 48 (18-165) months. Four patients had brain metastases alone, two patients had both leptomeningeal and brain metastases and one patient had leptomeningeal metastasis alone. Five out of seven patients had failed other treatment modalities before capecitabine. Three patients showed complete response (CR) and three patients had stable disease (SD) after capecitabine. The patient with leptomeningeal disease improved clinically, but refused repeat cerebrospinal fluid (CSF) studies. Median overall and progression-free survival from initiation of capecitabine was 13 and 8 months, respectively, for all patients. Capecitabine may achieve a CR and provide long-term control in patients with both leptomeningeal and parenchymal CNS metastases from breast cancer.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Carcinoma/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Desoxicitidina/análogos & derivados , Fluoruracila/análogos & derivados , Neoplasias Meníngeas/tratamento farmacológico , Adulto , Neoplasias da Mama/patologia , Capecitabina , Carcinoma/secundário , Neoplasias do Sistema Nervoso Central/secundário , Desoxicitidina/uso terapêutico , Intervalo Livre de Doença , Feminino , Fluoruracila/uso terapêutico , Humanos , Neoplasias Meníngeas/secundário , Pessoa de Meia-Idade , Pró-Fármacos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Therapeutic options for refractory or recurrent primary central nervous system lymphoma (PCNSL) are limited. The blood-brain barrier makes many agents used in systemic lymphomas ineffective in CNS lymphomas. The objective of this study was to determine whether intravenous radioimmunotherapy using anti-CD20 antibody can be delivered to PCNSL. METHODS: This was a single-institution prospective study. Indium-111 ibritumomab tiuxetan was used for imaging and dosimetry. Yttrium-90 ibritumomab tiuxetan at doses of 0.3 to 0.4 mCi/kg were subsequently given for the treatment of recurrent or refractory PCNSL. 111In data were used to estimate radiation doses to lesions delivered by 90Y ibritumomab tiuxetan therapy. RESULTS: Six patients (4 men, 2 women) with a median age of 60 years and median Karnofsky performance status of 70 received both indium-111 and yttrium-90 ibritumomab tiuxetan. The median absorbed dose delivered to the CNS lymphoma was 701 cGy compared with 70 cGy to normal brain. The median progression-free and overall survival times were 6.8 weeks and 14.3 weeks, respectively. CONCLUSIONS: The results from this study suggest that it may be feasible to deliver radiolabeled monoclonal anti-CD20 antibodies as a component of therapy for PCNSL.