RESUMEN
With improved systemic treatment and prolonged survival even with metastatic disease, diagnosing, treating, and monitoring brain metastases has become a central topic in the care of patients with melanoma. Patients with brain metastases from melanoma are typically excluded from pivotal clinical trials. When allowed, inclusion and exclusion criteria are rather selective and do not reflect the larger population of melanoma patients with brain metastases who frequently present with neurological symptoms and signs and require steroid medications. Moreover, the lack of consensus on reporting symptomatic brain involvement complicates the interpretation and implications of trial results for the overall population of patients with melanoma and brain metastasis. Here, we review the evidence regarding brain metastasis from melanoma and discuss the challenges of longitudinal neurological clinical assessments, including tools to capture cognition and quality of life. Finally, we propose the adoption of standardized tools to interpret neurological deficits in patients with melanoma and brain metastases and to assess the neurological status in the context of clinical trials.
Asunto(s)
Neoplasias Encefálicas , Melanoma , Calidad de Vida , Humanos , Melanoma/secundario , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/terapia , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/terapiaRESUMEN
These joint European Association of Neuro-Oncology (EANO)European Society for Medical Oncology (ESMO) recommendations for the diagnosis and treatment of leptomeningeal metastasis (LM) from solid tumours provide an update of the first joint EANOESMO guideline1 and complement the EANOESMO guideline on brain metastasis from solid tumours.2 LM is defined as the spread of tumour cells within the leptomeninges and the subarachnoid space. The present recommendations address LM from extra-central nervous system (CNS) solid tumours, but do not address LM from primary brain tumours, lymphoma or leukaemia. The recommendations cover diagnosis, treatment and follow-up, but do not cover the differential diagnosis, treatment-related adverse events (AEs) or supportive or palliative care in detail. The authors propose diagnostic criteria and assign levels of certainty to the diagnosis of LM in order to provide guidance regarding when to treat versus when to intensify diagnostic efforts and which patients to include in clinical trials. The authors also provide a pragmatic treatment algorithm based on LM subtypes. Supporting evidence for this guideline focuses on LM-specific data with reference to the EANOESMO guideline on brain metastasis from solid tumours2 when LM-specific data are not available. Given the low level of evidence available, recommendations are often based on expert opinion and consensus rather than on evidence from informative clinical trials. Still, these EANOESMO multidisciplinary recommendations serve as a valuable source of information for physicians and other health care providers, as well as for patients and relatives.
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Humanos , Neoplasias Meníngeas/prevención & control , Espectroscopía de Resonancia Magnética , Líquido Cefalorraquídeo , Citotoxinas/uso terapéutico , Inmunoterapia , Neoplasias Meníngeas/diagnóstico por imagenRESUMEN
BACKGROUND: Glioblastomas (GBMs) induce a peritumoural vasogenic oedema impairing functional status and quality of life. Steroids reduce brain tumour-related oedema but are associated with numerous side-effects. It was reported in a retrospective series that angiotensin receptor blockers might be associated with reduced peritumoural oedema. The ASTER study is a randomised, placebo-controlled trial to assess whether or not the addition of Losartan to standard of care (SOC) can reduce steroid requirement during radiotherapy (RT) in patients with newly diagnosed GBM. PATIENTS AND METHODS: Patients with a histologically confirmed GBM after biopsy or partial surgical resection were randomised between Losartan or placebo in addition to SOC with RT and temozolomide (TMZ). The primary objective was to investigate the steroid dosage required to control brain oedema on the last day of RT in each arm. The secondary outcomes were steroids dosage 1 month after the end of RT, assessment of cerebral oedema on magnetic resonance imaging, tolerance and survival. RESULTS: Seventy-five patients were randomly assigned to receive Losartan (37 patients) or placebo (38 patients). No difference in the steroid dosage required to control brain oedema on the last day of RT, or one month after completion of RT, was seen between both arms. The incidence of adverse events was similar in both arms. Median overall survival was similar in both arms. CONCLUSIONS: Losartan, although well tolerated, does not reduce the steroid requirement in newly diagnosed GBM patients treated with concomitant RT and TMZ. Trial registration number NCT01805453 with ClinicalTrials.gov.
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Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Neoplasias Encefálicas/terapia , Quimioradioterapia/mortalidad , Edema/prevención & control , Glioblastoma/terapia , Losartán/uso terapéutico , Prednisona/administración & dosificación , Anciano , Antiinflamatorios/administración & dosificación , Neoplasias Encefálicas/patología , Método Doble Ciego , Quimioterapia Combinada , Edema/epidemiología , Femenino , Estudios de Seguimiento , Francia/epidemiología , Glioblastoma/patología , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Tasa de SupervivenciaRESUMEN
Challenges in obtaining tissue specimens from patients with brain tumours limit the diagnosis and molecular characterisation and impair the development of better therapeutic approaches. The analysis of cell-free tumour DNA in plasma (considered a liquid biopsy) has facilitated the characterisation of extra-cranial tumours. However, cell-free tumour DNA in plasma is limited in quantity and may not reliably capture the landscape of genomic alterations of brain tumours. Here, we review recent work assessing the relevance of cell-free tumour DNA from cerebrospinal fluid in the characterisation of brain cancer. We focus on the advances in the use of the cerebrospinal fluid as a source of cell-free tumour DNA to facilitate diagnosis, reveal actionable genomic alterations, monitor responses to therapy, and capture tumour heterogeneity in patients with primary brain tumours and brain and leptomeningeal metastases. Profiling cerebrospinal fluid cell-free tumour DNA provides the opportunity to precisely acquire and monitor genomic information in real time and guide precision therapies.
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Biomarcadores de Tumor/genética , Neoplasias Encefálicas/patología , Neoplasias del Sistema Nervioso Central/secundario , ADN Tumoral Circulante/genética , ADN de Neoplasias/genética , Biopsia Líquida/métodos , Biomarcadores de Tumor/líquido cefalorraquídeo , Neoplasias Encefálicas/líquido cefalorraquídeo , Neoplasias Encefálicas/genética , Neoplasias del Sistema Nervioso Central/líquido cefalorraquídeo , Neoplasias del Sistema Nervioso Central/genética , ADN Tumoral Circulante/líquido cefalorraquídeo , ADN de Neoplasias/líquido cefalorraquídeo , Humanos , Estadificación de NeoplasiasRESUMEN
BACKGROUND: High-field intraoperative MRI (IoMRI) is a useful tool to improve the extent of glioma resection (EOR). OBJECTIVE: To compare the interest of 1.5T IoMRI in glioma surgery between enhancing and non-enhancing tumors, based on volumetric analysis. METHODS: A prospective single-center study included consecutive adult patients undergoing glioma surgery with IoMRI. Volumetric evaluation was based on FLAIR hypersignal after gadolinium injection in non-enhancing tumors and T1 hypersignal after gadolinium injection in enhancing tumors. Endpoints comprised: residual tumor volume (RTV), EOR, workflow and clinical outcome on Karnofsky performance score (KPS). RESULTS: Fifty-three surgeries were performed from July 2014 to January 2016. Thirty-four patients underwent one IoMRI, and 19 two IoMRIs. In non-enhancing tumors, intraoperative RTV on 1st IoMRI T2/FLAIR was higher than in enhancing tumors on T1 sequences (7.25cm3 vs. 0.74cm3, respectively; P=0.008), whereas the RTV on 2nd IoMRIs and final RTV were no longer significantly different. After IoMRI, 72% of patients underwent additional resection. In non-enhancing tumors, EOR increased from 77.3% on 1st IoMRI to 97.4% on last MRI (P<0.001). Taking all tumors together, final RTV values were: median=0cm3, mean=3.9cm3. Mean final EOR was 94%. In 25% of patients, KPS was reduced during early postoperative course; at 3 and 6 months postoperatively, median KPS was 90. CONCLUSION: Intraoperative MRI guidance significantly enhanced the extent of glioma resection, especially for non- or minimally enhancing tumors, while preserving patient autonomy.
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Neoplasias Encefálicas/cirugía , Glioma/cirugía , Imagen por Resonancia Magnética , Neoplasia Residual/cirugía , Adulto , Anciano , Neoplasias Encefálicas/patología , Femenino , Gadolinio , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Targeted therapies (TT) and immune checkpoint inhibitors (ICI) are currently modifying the landscape of metastatic cancer management and are increasingly used over the course of many cancers treatment. They allow long-term survival with controlled extra-cerebral disease, contributing to the increasing incidence of brain metastases (BMs). Radiation therapy remains the cornerstone of BMs treatment (either whole brain irradiation or stereotactic radiosurgery), and investigating the safety profile of radiation therapy combined with TT or ICI is of high interest. Discontinuing an efficient systemic therapy, when BMs irradiation is considered, might allow systemic disease progression and, on the other hand, the mechanisms of action of these two therapeutic modalities might lead to unexpected toxicities and/or greater efficacy, when combined. PATIENTS AND METHODS: We carried out a systematic literature review focusing on the safety profile and the efficacy of BMs radiation therapy combined with targeted agents or ICI, emphasizing on the role (if any) of the sequence of combination scheme (drug given before, during, and/or after radiation therapy). RESULTS: Whereas no relevant toxicity has been noticed with most of these drugs, the concomitant use of some other drugs with brain irradiation requires caution. CONCLUSION: Most of available studies appear to advocate for TT or ICI combination with radiation therapy, without altering the clinical safety profiles, allowing the maintenance of systemic treatments when stereotactic radiation therapy is considered. Cognitive functions, health-related quality of life and radiation necrosis risk remain to be assessed. The results of prospective studies are awaited in order to complete and validate the above discussed retrospective data.
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Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/terapia , Inmunoterapia/métodos , Anticuerpos Monoclonales/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/radioterapia , Terapia Combinada , Irradiación Craneana , Humanos , Terapia Molecular Dirigida , RadiocirugiaRESUMEN
BACKGROUND: The aim of our study was to report the usefulness of intraoperative MRI guidance in the resection of brain lesions adjacent to eloquent areas. PATIENTS AND METHODS: A single center prospective series of gliomas amenable to optimized resection with intraoperative MRI between September 2014 and December 2015. RESULTS: The study included 56 patients. The median duration of the first intraoperative MRI was 38min, interquartile range (IQR 30-46). Fourteen patients (40%) underwent a second intraoperative MRI, which had a median duration of 26min (IQR, 18-30). The median total operative time was 265min (IQR, 242-337). After the first intraoperative MRI, the median residual glioma volume of the 35 gliomas adjacent to eloquent areas was 7.04cm3 (IQR, 2.22-13.8), which did not significantly differ from the other gliomas (P=0.07). After the second intraoperative MRI, the median residual glioma volume was 3.86cm3 (IQR, 0.82-6.99), which did not significantly differ from the other patients (P=0.700). On the postoperative MRI, the median extent of the glioma resections adjacent to eloquent areas was 99.78% (IQR, 88.9-100), which was not significantly different from the rest of the population (P=0.290). At 6 months after surgery, the median Karnofsky Performance Score was 90, and 2.8% of the patients presented a permanent new neurological deficit. CONCLUSION: Our results suggest that intraoperative MRI is an effective and safe technique to improve the extent of brain lesion resections close to eloquent areas.
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Neoplasias Encefálicas/cirugía , Encéfalo/cirugía , Glioma/cirugía , Imagen por Resonancia Magnética , Monitoreo Intraoperatorio , Adolescente , Adulto , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/fisiopatología , Femenino , Glioma/diagnóstico por imagen , Glioma/fisiopatología , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Monitoreo Intraoperatorio/métodos , Neuronavegación/métodos , Estudios ProspectivosRESUMEN
Leptomeningeal metastasis is a fatal manifestation seen in advanced cancer patients. Its incidence is increasing, reaching 3.8% in molecularly unselected non-small cell lung cancer patients and up to 5% and 9% in ALK-rearranged and EGFR-mutant lung cancer patients, respectively. The prognosis remains poor despite systemic treatment, intrathecal chemotherapy, radiation therapy and personalized treatments in molecularly selected patients. However, new therapies with improved cerebral-spinal fluid penetration have been developed for subgroups of molecular selected patients indicating they could be promising therapeutic options for managing leptomeningeal disease. Systemic chemotherapy, which may be combined with intrathecal chemotherapy, remains standard treatment for lung cancer patients with leptomeningeal disease and a good-risk profile. We summarize evidence reported in the literature for managing this complication in lung cancer patients. Based on this, we have selected potential therapeutic strategies that could be used in daily clinical practice.
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Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Carcinomatosis Meníngea/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Carcinomatosis Meníngea/secundario , Medicina de Precisión/métodosRESUMEN
INTRODUCTION: Radionecrosis (RN) represents the main complication of stereotactic radiotherapy (SRT) for brain metastases. It may be observed in up to 34% of cases at 24 months after treatment and associated with significant morbidity in 10-17%. AREAS COVERED: Our aim is to discuss the results of original studies on RN related to SRT for brain metastases. Expert commentary: Although the development of RN is unpredictable, larger volume of the lesion, prior whole brain irradiation, and higher dose of radiation represent the major risk factors. RN appears on MRI as contrast-enhancing necrotic lesions, surrounded by edema, occurring at least 3 months after SRT, localized within fields of irradiation. No firm criteria are established. Surgery can provide symptomatic relief but is associated with a risk of complications. Corticosteroids are considered the standard of care treatment, despite limited efficacy and many adverse effects. Bevacizumab represents another interesting option that needs to be validated.
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Neoplasias Encefálicas , Radiocirugia , Encéfalo , Humanos , Necrosis , Traumatismos por RadiaciónRESUMEN
INTRODUCTION: Meningioma comprise 20-30% of all primary brain tumors. Notwithstanding surgery and radiotherapy, a subset of patients will manifest recurrent meningioma. Systemic therapy is recommended only when further surgery and radiotherapy are not possible. No prospective study with a high level of evidence is available to inform as to recommendations regarding systemic therapy. AREAS COVERED: We aim to summarize systemic therapies for recurrent meningioma. Expert commentary: Hydroxurea, temozolomide, irinotecan, the combination of cyclophosphamide/adriamycine/vincristine, interferon-alpha, somatostatin analogs, mifepristone, megestrol acetate, imatinib, erlotinib and gefitinib are considered as having limited efficacy. Potential activity of VEGF (vascular endothelial growth factor) inhibitors such as sunitinib, valatinib, and bevacizumab is suggested in small non-controlled studies and requires validation in randomized trials. The identification of new prognostic markers such as TERT promoter mutations and potential new therapeutic targets, such as KLF4, AKT1, TRAF7, and SMO mutations hopefully facilitate this endeavor.
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Meningioma/tratamiento farmacológico , Factor A de Crecimiento Endotelial Vascular , Gefitinib , Humanos , Factor 4 Similar a Kruppel , Neoplasias Meníngeas , Estudios Prospectivos , QuinazolinasRESUMEN
The therapeutic management of brain metastases depends upon their diagnosis and characteristics. It is therefore imperative that imaging provides accurate diagnosis, identification, size and localization information of intracranial lesions in patients with presumed cerebral metastatic disease. MRI exhibits superior sensitivity to CT for small lesions identification and to evaluate their precise anatomical location. The CT-scan will be made only in case of MRI's contraindication or if MRI cannot be obtained in an acceptable delay for the management of the patient. In clinical practice, the radiologic metastasis evaluation is based on visual image analyses. Thus, a particular attention is paid to the imaging protocol with the aim to optimize the diagnosis of small lesions and to evaluate their evolution. The MRI protocol must include: 1) non-contrast T1, 2) diffusion, 3) T2* or susceptibility-weighted imaging, 4) dynamic susceptibility contrast perfusion, 5) FLAIR with contrast injection, 6) T1 with contrast injection preferentially using the 3D spin echo images. The role of the nuclear medicine imaging is still limited in the diagnosis of brain metastasis. The Tc-sestamibi brain imaging or PET with amino acid tracers can differentiate local brain metastasis recurrence from radionecrosis but still to be evaluated.
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Neoplasias Encefálicas/secundario , Diagnóstico por Imagen/métodos , Neuroimagen/métodos , Neoplasias Encefálicas/diagnóstico , Radioisótopos de Carbono , Carcinoma/epidemiología , Carcinoma/secundario , Protocolos Clínicos , Medios de Contraste/efectos adversos , Gadolinio/efectos adversos , Humanos , Enfermedades Renales/inducido químicamente , Imagen por Resonancia Magnética , Melanoma/epidemiología , Melanoma/secundario , Metionina , Tomografía de Emisión de Positrones , Radiofármacos , Tecnecio Tc 99m Sestamibi , Tomografía Computarizada por Rayos XRESUMEN
Brain metastases management has evolved over the last fifteen years and may use varying strategies, including more or less aggressive treatments, sometimes combined, leading to an improvement in patient's survival and quality of life. The therapeutic decision is subject to a multidisciplinary analysis, taking into account established prognostic factors including patient's general condition, extracerebral disease status and clinical and radiological presentation of lesions. In this article, we propose a management strategy based on the state of current knowledge and available therapeutic resources.
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Neoplasias Encefálicas/secundario , Manejo de la Enfermedad , Grupo de Atención al Paciente , Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/terapia , Neoplasias de la Mama/patología , Carcinoma/secundario , Carcinoma/terapia , Terapia Combinada , Irradiación Craneana , Femenino , Humanos , Inmunoterapia , Comunicación Interdisciplinaria , Estado de Ejecución de Karnofsky , Neoplasias Pulmonares/patología , Masculino , Medicina , Terapia Molecular Dirigida , Procedimientos Neuroquirúrgicos , Cuidados Paliativos , Selección de PacienteRESUMEN
Melanomas have a high rate of brain metastases. Both the functional prognosis and the overall survival are poor in these patients. Until now, surgery and radiotherapy represented the two main modalities of treatment. Nevertheless, due to the improvement in the management of the extracerebral melanoma, the systemic treatment may be an option in patients with brain metastases. Immunotherapy with anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) - ipilimumab - or BRAF (serine/threonine-protein kinase B-raf) inhibitors - vemurafenib, dabrafenib - has shown efficacy in the management of brain metastases in a- or pauci-symptomatic patients. Studies are ongoing with anti-PD1 (programmed cell death 1) and combinations of targeted therapies associating anti-RAF (raf proto-oncogene, serine/threonine kinase) and anti-MEK (mitogen-activated protein kinase kinase).
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Neoplasias Encefálicas/secundario , Melanoma/secundario , Abatacept , Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Antígeno CTLA-4/antagonistas & inhibidores , Ensayos Clínicos Fase II como Asunto , Dacarbazina/uso terapéutico , Humanos , Imidazoles/uso terapéutico , Inmunoconjugados/uso terapéutico , Inmunoterapia , Indoles/uso terapéutico , Interleucina-2/uso terapéutico , Ipilimumab , Melanoma/tratamiento farmacológico , Melanoma/genética , Melanoma/terapia , Terapia Molecular Dirigida , Proteínas de Neoplasias/antagonistas & inhibidores , Oximas/uso terapéutico , Mutación Puntual , Inhibidores de Proteínas Quinasas , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Sulfonamidas/uso terapéutico , VemurafenibRESUMEN
Brain metastases impact on the survival of the patients, but on their quality of life as well. The objective of the management of these patients is then double. Currently, due to medical advances, survivals tend to improve, especially for some tumor subtypes. During the course of the disease, different neurological signs and symptoms can be observed according to the location, the number and the volume of the metastase(s). Patients and caregivers are especially worried about the loss of autonomy and cognitive impairments. A permanent dialogue, during the course of the disease, is mandatory, in order to adapt the management to the objectives determined by the patients and the medical team. These objectives may vary according to the objective response rates of the disease to anticancer therapies, according to the impact of the disease and its management in daily living. Anticancer therapies and supportive care must be appreciated according to their impact on the survival, on the preservation of the functional independence and the quality of life of the patient, on their abilities to preserve the neurological status and delay the apparition of new neurological signs and symptoms, and their adverse events. Supportive care, cognition and quality of life should be regularly evaluated and adapted according to the objectives of the management of brain metastases patients. Different approaches are described in this paper.