RESUMO
BACKGROUND: The treatment of patients with brain-spread renal cell carcinoma (RCC) is an unmet clinical need, although more recent therapeutic strategies have significantly improved RCC patients' life expectancy. Our multicenter, retrospective, observational study investigated a real-world cohort of patients with brain metastases (BM) from RCC (BMRCC). PATIENTS AND METHODS: A total of 226 patients with histological diagnosis of RCC and radiological evidence of BM from 22 Italian institutions were enrolled. Univariate and multivariate models were performed to investigate the impact of clinicopathological features and multimodal treatments on both overall survival (OS) from the BM diagnosis and intracranial progression-free survival (iPFS). RESULTS: The median OS from the BM diagnosis was 18.8 months (interquartile range: 6.2-43 months). Multivariate analysis confirmed the following as positive independent prognostic factors: a Karnofsky Performance Status >70% [hazard ratio (HR) = 0.49, 95% confidence interval (CI) 0.26-0.92, P = 0.0026] and a single BM (HR = 0.51, 95% CI 0.31-0.86, P = 0. 0310); in contrast, the following were confirmed as worse prognosis factors: progressive extracranial disease (HR = 1.66, 95% CI 1.003-2.74, P = 0.00181) and only one line of systemic therapy after the BM occurrence (HR = 2.98, 95% CI 1.62-5.49, P = 0.029). Subgroup analyses showed no difference in iPFS according to the type of the first systemic treatment [immunotherapy (IT) or targeted therapy (TT)] carried out after the BM diagnosis (HR = 1.033, 95% CI 0.565-1.889, P = 0.16), and revealed that external radiation therapy (eRT) significantly prolonged iPFS when combined with IT (10.7 months, 95% CI 4.9-48 months, P = 0.0321) and not when combined with TT (9.01 months, 95% CI 2.7-21.2 months, P = 0.59). CONCLUSIONS: Our results suggest a potential additive effect in terms of iPFS for eRT combined with IT and encourage a more intensive multimodal therapeutic strategy in a multidisciplinary context to improve the survival of BMRCC patients.
Assuntos
Neoplasias Encefálicas , Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/terapia , Neoplasias Renais/terapia , Neoplasias Renais/patologia , Estudos Retrospectivos , Prognóstico , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/secundárioRESUMO
INTRODUCTION: Upfront criteria to foresee immune checkpoint inhibitors (ICIs) efficacy are far from being identified. Thus, we integrated blood descriptors of pro-inflammatory/immunosuppressive or effective anti-tumor response to non-invasively define predictive immune profiles in ICI-treated advanced non-small cell lung cancer (NSCLC). METHODS: Peripheral blood (PB) was prospectively collected at baseline from 109 consecutive NSCLC patients undergoing ICIs as first or more line treatment. Soluble PD-L1 (sPD-L1) (immunoassay), CD8+PD-1+ and NK (FACS) cells were assessed and interlaced to generate an Immune effector Score (IeffS). Lung Immune Prognostic Index (LIPI) was computed by LDH levels and derived Neutrophil-to-Lymphocyte Ratio (dNLR). All these parameters were correlated with survival outcome and treatment response. RESULTS: High sPD-L1 and low CD8+PD-1+ and NK number had negative impact on PFS (P < 0.001), OS (P < 0.01) and ICI-response (P < 0.05). Thus, sPD-L1high, CD8+PD-1+low and NKlow were considered as risk factors encompassing IeffS, whose prognostic power outperformed that of individual features and slightly exceeded that of LIPI. Accordingly, the absence of these risk factors portrayed a favorable IeffS characterizing patients with significantly (P < 0.001) prolonged PFS (median NR vs 2.3 months) and OS (median NR vs 4.1) and greater benefit from ICIs (P < 0.01). We then combined each risk parameter composing IeffS and LIPI (LDHhigh, dNLRhigh), thus defining three distinct prognostic classes. A remarkable impact of IeffS-LIPI integration was documented on survival outcome (PFS, HR = 4.61; 95%CI = 2.32-9.18; P < 0.001; OS, HR=4.03; 95%CI=1.91-8.67; P < 0.001) and ICI-response (AUC=0.90, 95%CI=0.81-0.97, P < 0.001). CONCLUSION: Composite risk models based on blood parameters featuring the tumor-host interaction might provide accurate prognostic scores able to predict ICI benefit in NSCLC patients.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Antígeno B7-H1 , Linfócitos T CD8-Positivos , Carcinoma Pulmonar de Células não Pequenas/terapia , Humanos , Imunoterapia , Células Matadoras Naturais , Neoplasias Pulmonares/terapia , Prognóstico , Receptor de Morte Celular Programada 1RESUMO
BACKGROUD: Synergistic combinations between BRAF and MEK inhibitors, such as dabrafenib plus trametinib, vemurafenib plus cobimetinib or encorafenib plus binimetinib, represent the current standard of care in metastatic or locally advanced BRAF V600 mutated malignant melanomas (MM). However, no studies explored the direct head-to-head comparison between the three different combinations. In this paper, we performed a network meta-analysis to evaluate their efficacy in terms of overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and safety profile. METHOD: We performed a systematic review of the literature about published first line trials of BRAF and MEK inhibitors doublets in advanced mutated malignant melanoma. We compared then the results with an adjusted indirect analysis of randomized-controlled trials. Our primary survival outcome was OS. Secondary endpoints were PFS, ORR, G3-4 toxicities described in at least 5% of patients in experimental arms. RESULTS: We identified three phase-3 trials: coBRIM (vemurafenib and cobimetinib), COMBI-v (dabrafenib and trametinib) and Columbus study (encorafenib and binimetinib) for a total of 1230 included patients. The control arm was vemurafenib in all studies. The indirect comparison revealed no statistically differences for OS, PFS and ORR across trials, while safety profile differed between the three couples of agents. CONCLUSION: This indirect adjusted meta-analysis suggests a similar efficacy and a slightly different safety profile, related to specific molecular properties of the three different BRAF and MEK inhibitors currently approved in the management of advanced MM.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Melanoma/tratamento farmacológico , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Humanos , Melanoma/genética , Melanoma/patologia , Mutação , Metanálise em Rede , Proteínas Proto-Oncogênicas B-raf/genética , Resultado do TratamentoRESUMO
Background: Prognostic scores have been developed to estimate the risk of recurrence and the probability of survival after nephrectomy for renal cell carcinoma (RCC). The use of these tools, despite being helpful to plan a customized schedule of follow-up, to the patient's tailored counselling and to select individuals who could potentially benefit from adjuvant treatment, currently is not routine, due to their relative complexity and to the lack of histological data (i.e. necrosis). Patients and methods: We developed a simple score called GRade, Age, Nodes and Tumor (GRANT) based on four easily obtained parameters: Fuhrman grade, age, pathological nodal status and pathological tumor size. Patients with 0 or 1 factor are classified as favorable risk, whereas patients with two or more risk factors as unfavorable risk. The large population of RCC patients from the ASSURE adjuvant trial was used as independent dataset for this external validation, to investigate the prognostic value of the new score in terms of disease-free survival and overall survival and to evaluate its possible application as predictive tool. Statistical analyses were carried out by the Department of Biostatistics & Computational Biology, Dana-Farber Cancer Institute (Boston, USA) for the ASSURE trial patients' population. Results: The performance of the new model is similar to that of the already validated score systems, but its strength, compared with the others already available, is the ease and clarity of its calculation, with great speed of use during the clinical practice. Limitations are the use of the Fuhrman nuclear grade, not valid for rare histologies, and the TNM classification modifications over time. Conclusion: The GRANT score demonstrated its potential usefulness for clinical practice. ClinicalTrials.gov Identifier for the ASSURE trial: NCT00326898.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/mortalidade , Neoplasias Renais/mortalidade , Recidiva Local de Neoplasia/mortalidade , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Feminino , Seguimentos , Indicadores Básicos de Saúde , Humanos , Indóis/administração & dosagem , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Niacinamida/administração & dosagem , Niacinamida/análogos & derivados , Compostos de Fenilureia/administração & dosagem , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Pirróis/administração & dosagem , Fatores de Risco , Sorafenibe , Sunitinibe , Taxa de SobrevidaRESUMO
UNLABELLED: ESSENTIALS: We performed a pooled analysis of 926 patients with cancer-associated incidental pulmonary embolism (IPE). Vitamin K antagonists (VKA) are associated with a higher risk of major hemorrhage. Recurrence risk is comparable after subsegmental and more proximally localized IPE. Our results support low molecular weight heparins over VKA and similar management of subsegmental IPE. BACKGROUND: Incidental pulmonary embolism (IPE) is defined as pulmonary embolism (PE) diagnosed on computed tomography scanning not performed for suspected PE. IPE has been estimated to occur in 3.1% of all cancer patients and is a growing challenge for clinicians and patients. Nevertheless, knowledge about the treatment and prognosis of cancer-associated IPE is scarce. We aimed to provide the best available evidence on IPE management. METHODS: Incidence rates of symptomatic recurrent venous thromboembolism (VTE), major hemorrhage, and mortality during 6-month follow-up were pooled using individual patient data from studies identified by a systematic literature search. Subgroup analyses based on cancer stage, thrombus localization, and management were performed. RESULTS: In 926 cancer patients with IPE from 11 cohorts, weighted pooled 6-month risks of recurrent VTE, major hemorrhage and mortality were 5.8% (95% confidence interval [CI] 3.7-8.3%), 4.7% (95% CI 3.0-6.8%), and 37% (95% CI 28-47%). VTE recurrence risk was comparable under low molecular weight heparins (LMWH) and vitamin K antagonists (VKAs) (6.2% vs. 6.4%; hazard ratio [HR] 0.9; 95% CI 0.3-3.1), while 12% in untreated patients (HR 2.6; 95% CI 0.91-7.3). Risk of major hemorrhage was higher under VKAs than under LMWH (13% vs. 3.9%; HR 3.9; 95% CI 1.6-10). VTE recurrence risk was comparable in patients with an subsegmental IPE and those with a more proximally localized IPE (HR 1.1; 95% CI 0.50-2.4). CONCLUSION: These results support the current recommendation to anticoagulate cancer-associated IPE with LMWH and argue against different management of subsegmental IPE.
Assuntos
Hemorragia/complicações , Neoplasias/complicações , Embolia Pulmonar/complicações , Tromboembolia Venosa/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/uso terapêutico , Estudos de Coortes , Interpretação Estatística de Dados , Feminino , Seguimentos , Hemorragia/diagnóstico , Hemorragia/prevenção & controle , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Embolia Pulmonar/diagnóstico , Recidiva , Sistema de Registros , Fatores de Risco , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Tromboembolia Venosa/diagnóstico , Vitamina K/antagonistas & inibidores , Adulto JovemRESUMO
Malignant pleural mesothelioma (MPM) is a rare and aggressive tumor with generally disappointing results in terms of survival, however, there are occasional long-term survivors probably due to the biologic characteristics of the disease. Standard uptake value (SUV) of [(18)F] Fluorodeoxyglucose (FDG) evaluated by photon emission tomography (PET) is now widely accepted as an indicator of biologic behavior in several malignancies. The aim of this study was to verify whether SUV(max) and SUV(mean) are inversely associated with the prognosis of patients with MPM and whether there was a correlation between grading/disease stage and SUV value. Patients with histologically proven MPM underwent integrated PET and computed tomography (CT) scanning. Patients fasted and received 5.18 MBq of FDG per kilogram of body weight. Based on the maximum Chi-Square method, a SUV(max) of 4.21 (range: 2.30-14.74) and a SUV(mean) of 2.78 (range: 1.80-7.00) were used to classify patients as having a good or poor prognosis, respectively. From January 2004 to March 2010, 27 patients were analyzed: median age was 65 years (range: 54-77) and histologic MPM subtypes were epithelioid (23 patients) and biphasic (4 patients). At a median follow-up of 23 months (range: 1-52), there was no difference in median survival for either high or low SUV(max) [26 months (range: 11-not reached) vs.19 months (range: 12-not reached); p=0.811] or for high or low SUV(mean) [26 months (range: 8-not reached) vs.19 months (range: 11-not reached); p=0.831]. High SUV(max) (p=0.018) was statistically correlated with high-stage disease. There was only a trend towards statistical significance between high-grade disease and high SUV(mean) (p=0.083); no such trend was found between advanced stages and SUV(max) (p=0.268). We observed a significant correlation only between high SUV(max) and high-grade disease. No other relationships between SUV(max) and SUV(mean) with biologic and clinical parameters were found. This is probably due to the patient characteristics and to the non-routine use of 18F-FDG PET/CT to stage rare tumors such as MPM.