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1.
Curr Neurol Neurosci Rep ; 20(7): 26, 2020 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-32506161

RESUMO

PURPOSE OF REVIEW: The management of brain and leptomeningeal metastases has changed significantly over the past decade. RECENT FINDINGS: Historically, radiation therapy had been the mainstay of treatment. Several strategies to limit toxicities with radiation have been developed in the recent years. Increasingly systemic therapy options are being considered an important therapeutic option for CNS metastases. Numerous novel small molecule inhibitors and immunotherapy agents have intracranial activity to varying degrees, in addition to good extracranial disease control. Overall, the prognosis of select patients with CNS metastases has improved over the past several years with advent of new therapeutic strategies. Systemic therapy options with CNS benefit should be considered in select patients with small and asymptomatic CNS metastases. Further areas of research focus on molecular alterations predisposing to CNS metastases, identification of small molecule inhibitors with CNS activity, and the combination of radiation therapy and immunotherapy.


Assuntos
Neoplasias Encefálicas , Neoplasias do Sistema Nervoso Central , Encéfalo , Neoplasias Encefálicas/terapia , Humanos , Imunoterapia , Prognóstico
2.
Curr Opin Neurol ; 31(6): 740-746, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30379704

RESUMO

PURPOSE OF REVIEW: Meningiomas, the most common primary brain tumor, have historically been managed with surgery and radiation. Traditional chemotherapy has not been effective. Fortunately, recent advances in genetic sequencing have led to an improved understanding of the molecular drivers in meningioma. This article aims to discuss the diagnostic and therapeutic implications of recently discovered genetic alterations in meningiomas. RECENT FINDINGS: Many of the recently discovered genetic alterations correlate with distinct clinical phenotypes. SMO, AKT and PIK3CA mutations are enriched in the anterior skull base. KLF4 mutations are specific for secretory histology, and BAP1 alterations are common in progressive rhabdoid meningiomas. Alterations in TERT, DMD and BAP1 correlate with poor clinical outcomes. Importantly, the discovery of clinically actionable alterations in a number of genes, including SMO, AKT1 and PIK3CA, has opened up novel potential avenues for therapeutic management of meningiomas. Overexpression of PD-L1 in higher grade meningiomas also provides preclinical support for the investigation of checkpoint blockade. SUMMARY: The discovery of genetic alterations has improved our understanding of the natural history and classification of meningiomas. Clinical trials with several novel agents targeting driver mutations are currently accruing patients and they can lead to better treatment strategies.


Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Meningioma/tratamento farmacológico , Meningioma/genética , Proteínas de Neoplasias/genética , Animais , Humanos , Fator 4 Semelhante a Kruppel , Proteínas de Neoplasias/efeitos dos fármacos
4.
Curr Neurol Neurosci Rep ; 18(10): 70, 2018 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-30121715

RESUMO

PURPOSE OF THE REVIEW: Brain metastasis is a common complication of advanced malignancies, especially, lung cancer, breast cancer, renal cell carcinoma, and melanoma. Traditionally surgery, when indicated, and radiation therapy, either as whole-brain radiation therapy or stereotactic radiosurgery, constituted the major treatment options for brain metastases. Until recently, most of the systemic chemotherapy agents had limited activity for brain metastases. However, with the advent of small molecule tyrosine kinase inhibitors and immunotherapy agents, there has been renewed interest in using these agents in the management of brain metastases. RECENT FINDINGS: Immune checkpoint inhibitors have revolutionized the treatment of metastatic melanoma, lung cancer, kidney cancer, and bladder cancer among others. They modulate the immune system to recognize tumor antigens as "non-self" antigens and mount an immune response against them. Initial studies of using immune checkpoint inhibitors in brain metastases have shown promising activity, and several clinical trials are currently underway. Studies are also assessing the combination of radiation therapy and immunotherapy in brain metastases. The results of these ongoing clinical trials have the potential to change the therapeutic paradigm in patients with brain metastases.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Imunoterapia/métodos , Irradiação Craniana , Humanos , Melanoma , Radiocirurgia/métodos
5.
Oncology (Williston Park) ; 31(9): 659-67, 2017 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-29071693

RESUMO

Until recently, therapeutic strategies for melanoma brain metastases focused on local treatments: surgery, whole-brain radiation therapy, and stereotactic radiosurgery. Historically, systemic therapy had limited utility. Immunotherapeutic drugs, such as anti-cytotoxic T-lymphocyte-associated antigen 4 and anti-programmed death 1 agents, and agents targeting the BRAF-MEK pathway have revolutionized the systemic treatment of melanoma brain metastases. Recent clinical trials of these agents have shown activity against melanoma brain metastases, and they are increasingly being used in clinical practice. In this article, we provide an overview of the currently available systemic agents, including immunotherapeutic agents and targeted tyrosine kinase inhibitors. We also provide a practical management algorithm to guide the practicing oncologist in the use of both of these new therapies and the more traditional local treatments.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Imunossupressores/uso terapêutico , Melanoma/complicações , Melanoma/tratamento farmacológico , Metástase Neoplásica/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
6.
Oncology (Williston Park) ; 31(8): 602-6, 2017 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-28812301

RESUMO

Melanoma is the third most common cause of brain metastases, after lung and breast cancer. The management of melanoma brain metastases can be broadly divided into symptom control and therapeutic strategies. Supportive treatments include corticosteroids to reduce peritumoral edema, antiepileptics for seizure control, and medications to preserve cognitive function. Until recently, therapeutic strategies consisted primarily of local treatments, including surgery, whole-brain radiation therapy (WBRT), and stereotactic radiosurgery (SRS). Surgery, WBRT, and SRS-alone and in various combinations-still play an important role in treatment, especially in patients with few and/or smaller brain lesions. Much work has been done recently to try to determine the optimal settings for these therapies, the most effective ways to combine them, and ideal radiation dose and fractions.


Assuntos
Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/terapia , Melanoma/secundário , Neoplasias Encefálicas/diagnóstico , Irradiação Craniana , Humanos , Prognóstico , Radiocirurgia
7.
Curr Neurol Neurosci Rep ; 17(4): 37, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28326470

RESUMO

PURPOSE OF REVIEW: Brain metastases are the most common intracranial tumors in adults. Historically, the median survival after the diagnosis of brain metastases has been dismal and medical therapies had a limited role in the management of these patients. RECENT FINDINGS: The advent of targeted therapy has ushered in an era of increased hope for patients with brain metastases. The most common malignancies that result in brain metastases-melanoma, lung cancer, and breast cancer, often have actionable mutations, which make them good candidates for targeted systemic therapy. These brain metastases have been shown to have relevant and sometimes divergent genetic alterations, and there has been a resurgence of interest in targeted drug delivery to the brain by using standard or pulsatile dosing to achieve adequate concentration in the brain. An increased understanding of oncogenic alterations, a surge in targeted drug development with good blood barrier penetration, and inclusion of patients with active brain metastases on clinical trials have led to improved outcomes for patients with brain metastases.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Terapia de Alvo Molecular , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundário , Ensaios Clínicos como Assunto , Sistemas de Liberação de Medicamentos , Humanos , Mutação
8.
Int J Mol Sci ; 17(9)2016 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-27649142

RESUMO

The discovery of various driver pathways and targeted small molecule agents/antibodies have revolutionized the management of metastatic breast cancer. Currently, the major targets of clinical utility in breast cancer include the human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF) receptor, mechanistic target of rapamycin (mTOR) pathway, and the cyclin-dependent kinase 4/6 (CDK-4/6) pathway. Brain metastasis, however, remains a thorn in the flesh, leading to morbidity, neuro-cognitive decline, and interruptions in the management of systemic disease. Approximately 20%-30% of patients with metastatic breast cancer develop brain metastases. Surgery, whole brain radiation therapy, and stereotactic radiosurgery are the traditional treatment options for patients with brain metastases. The therapeutic paradigm is changing due to better understanding of the blood brain barrier and the advent of tyrosine kinase inhibitors and monoclonal antibodies. Several of these agents are in clinical practice and several others are in early stage clinical trials. In this article, we will review the common targetable pathways in the management of breast cancer patients with brain metastases, and the current state of the clinical development of drugs against these pathways.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Neoplasias da Mama/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Barreira Hematoencefálica/efeitos dos fármacos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/imunologia , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Ensaios Clínicos como Assunto , Feminino , Humanos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Análise de Sobrevida , Resultado do Tratamento
9.
Cancer Treat Res ; 163: 103-15, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25468228

RESUMO

Glioblastoma is the most common adult malignant primary brain tumor. Despite the advances in therapeutic options, survival of patients with glioblastoma remains dismal at 15-18 months. Current standard of care for newly diagnosed glioblastoma is maximal possible safe resection consistent with the preservation of neurologic function followed by concurrent temozolomide with radiation and adjuvant. Treatment options at recurrence include surgical resection with or without the placement of carmustine wafers, re-irradiation and chemotherapeutics such as nitrosoureas (lomustine, carmustine) or bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor (VEGF).


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Carmustina/uso terapêutico , Humanos , Terapia de Alvo Molecular , Recidiva Local de Neoplasia/tratamento farmacológico
10.
Expert Rev Neurother ; 24(1): 77-103, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38145503

RESUMO

INTRODUCTION: Neoplastic meningitis (NM), also known as leptomeningeal carcinomatosis, is characterized by the infiltration of tumor cells into the meninges, and poses a significant therapeutic challenge owing to its aggressive nature and limited treatment options. Breast cancer is a common cause of NM among solid tumors, further highlighting the urgent need to explore effective therapeutic strategies. This review aims to provide insights into the evolving landscape of NM therapy in breast cancer by collating existing research, evaluating current treatments, and identifying potential emerging therapeutic options. AREAS COVERED: This review explores the clinical features, therapeutic strategies, recent advances, and challenges of managing NM in patients with breast cancer. Its management includes multimodal strategies, including systemic and intrathecal chemotherapy, radiation therapy, and supportive care. This review also emphasizes targeted drug options and optimal drug concentrations, and discusses emerging therapies. Additionally, it highlights the variability in treatment outcomes and the potential of combination regimens to effectively manage NM in breast cancer. EXPERT OPINION: Challenges in treating NM include debates over clinical trial end points and the management of adverse effects. Drug resistance and low response rates are significant hurdles, particularly inHER2-negative breast cancer. The development of more precise and cost-effective medications with improved selectivity is crucial. Additionally, global efforts are needed for infrastructure development and cancer control considering the diverse nature of the disease.


Assuntos
Neoplasias da Mama , Carcinomatose Meníngea , Meningite , Humanos , Feminino , Carcinomatose Meníngea/complicações , Carcinomatose Meníngea/tratamento farmacológico , Neoplasias da Mama/complicações , Neoplasias da Mama/terapia , Neoplasias da Mama/patologia , Resultado do Tratamento , Terapia Combinada , Meningite/etiologia , Meningite/terapia
11.
Cancers (Basel) ; 15(1)2022 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-36612116

RESUMO

Central nervous system (CNS) metastasis from systemic cancers can involve the brain parenchyma, leptomeninges, or the dura. Neoplastic meningitis (NM), also known by different terms, including leptomeningeal carcinomatosis and carcinomatous meningitis, occurs due to solid tumors and hematologic malignancies and is associated with a poor prognosis. The current management paradigm entails a multimodal approach focused on palliation with surgery, radiation, and chemotherapy, which may be administered systemically or directly into the cerebrospinal fluid (CSF). This review focuses on novel therapeutic approaches, including targeted and immunotherapeutic agents under investigation, that have shown promise in NM arising from solid tumors.

12.
Front Oncol ; 9: 99, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30886831

RESUMO

The discovery and clinical application of agents targeting pivotal molecular pathways in malignancies such as lung, breast, renal cell carcinoma, and melanoma have led to impressive improvements in clinical outcomes. Mutations in epidermal growth factor receptor (EGFR), and rearrangements of anaplastic lymphoma kinase (ALK) are targetable in lung cancer, while BRAF mutations have been successfully targeted in metastatic melanoma. Targeting estrogen receptors, cyclin dependent kinases, and HER2 (Human Epidermal Receptor) have resulted in improvement in survival in breast cancer. Major strides have been made in the management of metastatic renal cell carcinoma by targeting the vascular endothelial growth factor (VEGF) pathway. However, intracranial metastases remain a major hurdle in the setting of targeted therapies. Traditional treatment options for brain metastases include surgery, whole brain radiation therapy (WBRT), and stereotactic radiosurgery (SRS). Surgery is effective in symptomatic patients with dominant lesions or solitary intracranial metastases, however, recovery time can be prolonged, often requiring an interruption in systemic treatment. WBRT and SRS provide symptomatic relief and local control but data on improving overall survival is limited. Most targeted therapies which provide extracranial control have limited penetration through the blood brain barrier. Given the limited therapeutic options and increasing prevalence of brain metastases, finding new strategies for the management of intracranial metastatic disease is critical. Genomic analysis of brain metastases has led to a better understanding of variations in the driver mutations compared to the primary malignancy. Furthermore, newer generations of targeted agents have shown promising intracranial activity. In this review, we will discuss the major molecular alterations in brain metastases from melanoma, lung, breast, and renal cell carcinoma. We will provide an in-depth review of the completed and ongoing clinical trials of drugs targeting the molecular pathways enriched in brain metastases.

13.
Handb Clin Neurol ; 149: 137-153, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29307351

RESUMO

Central nervous system metastases cause grave morbidity in patients with advanced malignancies. Lung cancer, breast cancer, and melanoma are the three most common causes of brain metastases. Although the exact incidence of brain metastases is unclear, there appears to be an increasing incidence which has been attributed to longer survival, better control of systemic disease, and better imaging modalities. Until recently surgical resection of solitary or symptomatic brain metastases, and radiation therapy (either whole-brain radiation therapy or stereotactic radiation) were the mainstay of treatment for patients with brain metastases. The majority of traditional chemotherapies have shown limited activity in the central nervous system, which has been attributed to the blood-brain barrier and the molecular structure of the used agents. The discovery of driver mutations and drugs targeting these mutations has changed the treatment landscape. Several of these targeted small-molecule tyrosine kinase inhibitors do cross the blood-brain barrier and/or have shown activity in the central nervous system. Another major advance in the care of brain metastases has been the advent of new immunotherapeutic agents, for which initial studies have shown intracranial activity. In this chapter, we will review the unique challenges in the treatment of brain metastases. The pertinent clinical studies of chemotherapy in brain metastases will be discussed. The currently reported clinical trials and evidence for use of targeted therapies and immunotherapeutic agents will be emphasized.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/terapia , Imunoterapia/métodos , Radiocirurgia/métodos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/secundário , Humanos , Neoplasias/patologia
14.
Curr Treat Options Neurol ; 20(11): 48, 2018 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-30259236

RESUMO

PURPOSE OF REVIEW: Brain metastases are frequent complication of lung cancer and are associated with poor prognosis. Patients with brain metastases secondary to lung cancer have traditionally been managed with surgery and radiation with limited role for systemic chemotherapy. In the past decade, however, this paradigm has shifted largely due to the advent of targeted therapies and immunotherapies, both of which have demonstrated efficacy in the treatment of brain metastases and extracranial disease. RECENT FINDINGS: While patients with brain metastases secondary to lung cancer have historically been excluded from trials, recent data suggest efficacy of novel targeted therapies and immunotherapies in these patients. In fact, there are multiple ongoing trials to further evaluate these therapies in this patient profile. Targeted therapies and immunotherapies have the potential to improve outcomes in patients with brain metastases secondary to lung cancer.

15.
Am Soc Clin Oncol Educ Book ; 38: 78-86, 2018 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-30231395

RESUMO

As we consider best practices and approaches to targeted therapy in the clinic and in terms of trial design, breast cancer can serve as a useful model for other disease types, because estrogen receptor-positive and HER2-positive breast cancer have been known entities for several decades. In this review, we provide a history of the development of anti-estrogen therapy and anti-HER2-directed therapy and we discuss our growing understanding of resistance to targeted therapy as seen through this lens. We highlight some of the recent breakthroughs that have enhanced our understanding of resistance to endocrine and anti-HER2 therapy, and we discuss some of the ongoing research in the field.


Assuntos
Biomarcadores Tumorais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Terapia de Alvo Molecular , Medicina de Precisão , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Terapia Combinada , Feminino , Humanos , Metástase Neoplásica , Estadiamento de Neoplasias , Medicina de Precisão/métodos , Receptor ErbB-2/antagonistas & inibidores , Pesquisa
16.
Drug Des Devel Ther ; 11: 1175-1182, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28442891

RESUMO

Several tyrosine kinase inhibitors targeting the vascular endothelial growth factor receptors and molecules inhibiting the mammalian target of rapamycin are being used for management of metastatic renal cell carcinoma (mRCC); however, there is still a potential for improvement. Immune checkpoint inhibitors like nivolumab and other PD-1/PD-L1 inhibitors provide an alternative approach for patients with mRCC. In this article, the authors review the safety profile and outcomes of phase 1, 2, and 3 clinical trials of nivolumab in mRCC.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Desenho de Fármacos , Neoplasias Renais/tratamento farmacológico , Animais , Anticorpos Monoclonais/química , Antineoplásicos/síntese química , Antineoplásicos/química , Carcinoma de Células Renais/imunologia , Ensaios Clínicos como Assunto , Humanos , Neoplasias Renais/imunologia , Nivolumabe
17.
Chin Clin Oncol ; 4(2): 18, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26112804

RESUMO

Brain metastases (BM) are the most serious neurological complication of cancer that results in significant morbidity and mortality in these patients. The most common primary malignancies that lead to BM include lung, breast and melanoma. Until recently the outcomes of patients with BM has been dismal. The current therapeutic options include surgery, whole brain radiation therapy (WBRT), stereotactic radiation (SRS), systemic therapy and symptom management only. Prognostic scores, a useful tool for BM patients, as an estimation of a patient's prognosis can guide tailored treatment for these patients. It is appropriate to recommend more aggressive approaches in patients with good performance status and limited disease and focus on symptom control and palliative measures when the disease is more advanced, or comorbidity preclude aggressive therapy. Due to vastly different outcomes, prognostic scores are important to stratify patients in clinical trials. A number of prognostic scoring systems for BM patients have been proposed that include Recursive Partitioning Analysis (RPA), the Score Index For Radiosurgery (SIR), the Basic Score for Brain Metastases (BSBM), the Rotterdam system (ROTTERDAM), the Golden Grading System (GGS), 2 Rades classification (RADES), the Graded Prognostic Assessment (GPA) and the disease specific Graded Prognostic Assessment (ds-GPA). In this article, we will review the important prognostic scoring systems and their utility in clinical decision making and trial design.


Assuntos
Neoplasias Encefálicas/secundário , Ensaios Clínicos como Assunto/métodos , Técnicas de Apoio para a Decisão , Indicadores Básicos de Saúde , Projetos de Pesquisa , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/terapia , Humanos , Seleção de Pacientes , Valor Preditivo dos Testes , Prognóstico , Medição de Risco , Fatores de Risco
19.
Transl Lung Cancer Res ; 3(4): 262-4, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25806309

RESUMO

We report a case of granular cell tumor (GCT) of the lung with coexistent invasive adenocarcinoma. GCTs are rare tumors and often benign and amenable to local bronchoscopic excision. However, occasionally they are more aggressive and locally infiltrative requiring definitive surgical resection. Our patient had a central and infiltrative GCT, in addition a very small (6 mm) peripheral nodule in the same lobe as the GCT, which after careful examination of the surgical specimen during grossing was found to be an invasive adenocarcinoma. There are a few reports in the literature of GCTs with coexistent bronchogenic cancer. Our case highlights the importance of careful evaluation and exploration of the surgical specimens during grossing of patients with GCTs. In GCT patients presenting with additional pulmonary nodules, a more definitive surgical approach should be considered.

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