RESUMO
BACKGROUND: Approximately 20% of patients with non-small-cell lung cancer (NSCLC) receive a diagnosis of stage III disease. There is no current consensus regarding the most appropriate treatment for these patients. METHODS: In this open-label, phase 2 trial, we randomly assigned patients with resectable stage IIIA or IIIB NSCLC to receive neoadjuvant nivolumab plus platinum-based chemotherapy (experimental group) or chemotherapy alone (control group), followed by surgery. Patients in the experimental group who had R0 resections received adjuvant treatment with nivolumab for 6 months. The primary end point was a pathological complete response (0% viable tumor in resected lung and lymph nodes). Secondary end points included progression-free survival and overall survival at 24 months and safety. RESULTS: A total of 86 patients underwent randomization; 57 were assigned to the experimental group and 29 were assigned to the control group. A pathological complete response occurred in 37% of the patients in the experimental group and in 7% in the control group (relative risk, 5.34; 95% confidence interval [CI], 1.34 to 21.23; P = 0.02). Surgery was performed in 93% of the patients in the experimental group and in 69% in the control group (relative risk, 1.35; 95% CI, 1.05 to 1.74). Kaplan-Meier estimates of progression-free survival at 24 months were 67.2% in the experimental group and 40.9% in the control group (hazard ratio for disease progression, disease recurrence, or death, 0.47; 95% CI, 0.25 to 0.88). Kaplan-Meier estimates of overall survival at 24 months were 85.0% in the experimental group and 63.6% in the control group (hazard ratio for death, 0.43; 95% CI, 0.19 to 0.98). Grade 3 or 4 adverse events occurred in 11 patients in the experimental group (19%; some patients had events of both grades) and 3 patients in the control group (10%). CONCLUSIONS: In patients with resectable stage IIIA or IIIB NSCLC, perioperative treatment with nivolumab plus chemotherapy resulted in a higher percentage of patients with a pathological complete response and longer survival than chemotherapy alone. (Funded by Bristol Myers Squibb and others; NADIM II ClinicalTrials.gov number, NCT03838159; EudraCT number, 2018-004515-45.).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Nivolumabe , Compostos de Platina , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/cirurgia , Recidiva Local de Neoplasia/tratamento farmacológico , Estadiamento de Neoplasias , Nivolumabe/administração & dosagem , Nivolumabe/efeitos adversos , Nivolumabe/uso terapêutico , Compostos de Platina/administração & dosagem , Compostos de Platina/efeitos adversos , Compostos de Platina/uso terapêutico , Análise de Sobrevida , Terapia CombinadaRESUMO
CONTEXT: The use of scrotal ultrasonography (SUS) has increased the detection rate of indeterminate testicular masses. Defining radiological characteristics that identify malignancy may reduce the number of men undergoing unnecessary radical orchidectomy. OBJECTIVE: To define which SUS or scrotal magnetic resonance imaging (MRI) characteristics can predict benign or malignant disease in pre- or post-pubertal males with indeterminate testicular masses. EVIDENCE ACQUISITION: This systematic review was conducted in accordance with Cochrane Collaboration guidance. Medline, Embase, Cochrane controlled trials and systematic reviews databases were searched from (1970 to 26 March 2021). Benign and malignant masses were classified using the reported reference test: i.e., histopathology, or 12 months progression-free radiological surveillance. Risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 tool (QUADAS-2). EVIDENCE SYNTHESIS: A total of 32 studies were identified, including 1692 masses of which 28 studies and 1550 masses reported SUS features, four studies and 142 masses reported MRI features. Meta-analysis of different SUS (B-mode) values in post-pubertal men demonstrated that a size of ≤0.5 cm had a significantly lower odds ratio (OR) of malignancy compared to masses of >0.5 cm (P < 0.001). Comparison of masses of 0.6-1.0 cm and masses of >1.5 cm also demonstrated a significantly lower OR of malignancy (P = 0.04). There was no significant difference between masses of 0.6-1.0 and 1.1-1.5 cm. SUS in post-pubertal men also had a statistically significantly lower OR of malignancy for heterogenous masses vs homogenous masses (P = 0.04), hyperechogenic vs hypoechogenic masses (P < 0.01), normal vs increased enhancement (P < 0.01), and peripheral vs central vascularity (P < 0.01), respectively. There were limited data on pre-pubertal SUS, pre-pubertal MRI and post-pubertal MRI. CONCLUSIONS: This meta-analysis identifies radiological characteristics that have a lower OR of malignancy and may be of value in the management of the indeterminate testis mass.
Assuntos
Orquiectomia , Neoplasias Testiculares , Masculino , Humanos , Radiografia , Neoplasias Testiculares/patologia , Escroto , Imageamento por Ressonância Magnética/métodosRESUMO
BACKGROUND: There are scarce data of the costs of non-small cell lung cancer (NSCLC) recurrence in Spain. The objective of this study is to assess the economic burden of disease recurrence, for both locoregional and/or metastatic relapses, after appropriate early-stage NSCLC treatment in Spain. MATERIALS AND METHODS: A two-round consensus panel of Spanish oncologists and hospital pharmacists was conducted to collect information on patient's flow, treatments, use of healthcare resources and sick leaves in patients with relapsed NSCLC. A decision-tree model was developed to calculate the economic burden of disease recurrence after appropriate early-stage NSCLC. Both direct and indirect costs were considered. Direct costs included drug acquisition and healthcare resources costs. Indirect costs were estimated using the human-capital approach. Unit costs were obtained from national databases (euros of 2022). A multi-way sensitivity analysis was performed to provide a range to the mean values. RESULTS: Among a cohort of 100 patients with relapsed NSCLC, 45 patients would have locoregional relapse (36.3 would eventually progress to metastasis and 8.7 would be considered in remission) and 55 patients would have metastatic relapse. Over time, 91.3 patients would experience a metastatic relapse (55 as first relapse and 36.6 after previous locoregional relapse). The overall cost incurred by the 100-patients cohort is 10,095,846 (9,336,782 direct costs, 795,064 indirect costs). The average cost of a locoregional relapse is 25,194 (19,658 direct costs, 5536 indirect costs), while the average cost a patient with metastasis who receives up to 4 lines of treatment is 127,167 (117,328 direct, 9839 indirect). CONCLUSIONS: To our knowledge, this is the first study that specifically quantifies the cost of relapse in NSCLC in Spain. Our findings shown that the overall cost of a relapse after appropriate treatment of early-stage NSCLC patients is substantial, and it increases considerably in the metastatic relapse setting, mainly due to the high cost and long duration of first-line treatments.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Espanha , Custos de Cuidados de Saúde , Estresse Financeiro , Efeitos Psicossociais da Doença , Recidiva Local de NeoplasiaRESUMO
Identifying the druggable target is crucial for patients with nonsquamous advanced non-small cell lung cancer (NSCLC). This article adds to the spectrum of ROS1 fusion cases described in NSCLC. We describe a novel SLC12A2-ROS1 rearrangement that has not been previously reported in other cancers: a fusion that has clinical and radiological sensitivity to crizotinib. Fluorescence in situ hybridization detected the SLC12A2-ROS1 fusion and it was confirmed through hybrid capture-based next-generation sequencing (NGS); however, the fusion could not be detected by amplicon-based assay. The success of implementing NGS into routine clinical practice depends on the accuracy of testing. The test's methodological features should then be considered because they significantly affect the results. Given this patient's response to crizotinib, identifying patients with undescribed ROS1 fusions has important therapeutic implications. KEY POINTS: This is the first known description of an SLC12A2-ROS1 fusion. Considering the patient's clinical features and tumor response observed after crizotinib therapy, the authors confirm that this new rearrangement has relevant clinical impact for patients with non-small cell lung cancer. The success of implementing next-generation sequencing (NGS) into routine clinical practice depends on the accuracy of the testing. Different assays and NGS platforms can achieve differing results. Each assay's limitations need to be considered to ensure the quality of precision medicine in clinical practice.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Crizotinibe/farmacologia , Crizotinibe/uso terapêutico , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hibridização in Situ Fluorescente , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Proteínas de Fusão Oncogênica/genética , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Membro 2 da Família 12 de Carreador de SolutoRESUMO
Lung cancer continues to be the leading cause of cancer mortality and a serious health problem despite the numerous advances made in the last decade and the rapid advance of research in this field. In recent years, there has been a decrease in mortality from lung cancer coinciding with the approval times of targeted therapy. To date, targeted therapy has been used in the context of advanced disease in clinical practice, with great benefits in survival and quality of life. The next step will be to incorporate targeted therapy into the treatment of earlier stages of non-small-cell lung cancer, and there is already a randomized trial showing a disease-free survival benefit. However, there are many questions that need to be resolved first. In the present review, the authors discuss the findings of published reports and ongoing clinical trials assessing the role of targeted therapies in nonmetastatic disease.
Lay abstract Despite major therapeutic advances over the last decade, lung cancer continues to present the highest mortality rate of all cancers. Precision and personalized therapy directed at specific alterations in the genetic material of the tumor as well as immunotherapy has significantly improved survival in metastatic non-small-cell lung cancer. The next step will be to incorporate precision medicine into the treatment of earlier stages of non-small-cell lung cancer. The recent publication of the results of the ADAURA phase III trial showing a significant improvement in disease-free survival in patients with resected EGFR-mutated non-small-cell lung cancer who received an adjuvant EGFR-directed tyrosine kinase inhibitor called osimertinib has opened the doors to the incorporation of this novel agent into routine clinical practice. However, there are many questions that need to be resolved first. In the present review, the authors discuss the findings of published reports and ongoing clinical trials assessing the role of precision medicine in nonmetastatic disease.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Terapia de Alvo Molecular , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Terapia Combinada , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Mutação , Estadiamento de NeoplasiasRESUMO
Three cardinal manifestations of neoplasia, namely inflammation, immune dysfunction, and coagulopathy are also seen in patients with severe SARS-CoV-2 infection, providing a biological rationale for testing selected anticancer drugs for their ability to control the symptoms and/or modify the course of COVID-19.
Assuntos
Antineoplásicos/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Reposicionamento de Medicamentos/métodos , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Corticosteroides/uso terapêutico , Anticoagulantes/uso terapêutico , Antineoplásicos/farmacologia , COVID-19 , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/virologia , Humanos , Fatores Imunológicos/uso terapêutico , Inflamação/tratamento farmacológico , Interleucina-6/antagonistas & inibidores , Pandemias , Pneumonia Viral/fisiopatologia , Pneumonia Viral/virologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , SARS-CoV-2 , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Tratamento Farmacológico da COVID-19RESUMO
DUSP6/MKP3 is a dual-specific phosphatase that regulates extracellular regulated kinase ERK1/2 and ERK5 activity, with an increasingly recognized role as tumor suppressor. In silico studies from Gene expression Omnibus (GEO) and Cancer Genome atlas (TCGA) databases reveal poor prognosis in those Non-small cell lung cancer (NSCLC) patients with low expression levels of DUSP6. In agreement with these data, here we show that DUSP6 plays a major role in the regulation of cell migration, motility and tumor growth. We have found upregulation in the expression of several genes involved in epithelial to mesenchymal transition (EMT) in NSCLC-DUSP6 depleted cells. Data obtained in RNA-seq studies carried out in DUSP6 depleted cells identified EGFR, TGF-ß and WNT signaling pathways and several genes such as VAV3, RUNXR2, LEF1, FGFR2 whose expression is upregulated in these cells and therefore affecting cellular functions such as integrin mediated cell adhesion, focal adhesion and motility. Furthermore, EGF signaling pathway is activated via ERK5 and not ERK1/2 and TGF-ß via SMAD2/3 in DUSP6 depleted cells. In summary DUSP6 is a tumor suppressor in NSCLC and re-establishment of its expression may be a potential strategy to revert poor outcome in NSCLC patients.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/genética , Fosfatase 6 de Especificidade Dupla/genética , Genes Supressores de Tumor , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Citoesqueleto de Actina/metabolismo , Adenocarcinoma de Pulmão/enzimologia , Adenocarcinoma de Pulmão/patologia , Junções Aderentes/metabolismo , Animais , Carcinogênese/genética , Carcinogênese/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Adesão Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Forma Celular/genética , Progressão da Doença , Fosfatase 6 de Especificidade Dupla/metabolismo , Adesões Focais/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/patologia , Sistema de Sinalização das MAP Quinases , Camundongos Nus , Fator de Crescimento Transformador beta/metabolismoRESUMO
AIMS: To study programmed death ligand 1 (PD-L1) expression, tumour-infiltrating T lymphocytes (TILs) and the molecular context in patients with early-stage squamous cell lung carcinomas (SCCs). METHODS AND RESULTS: The study included samples from 40 patients (discovery cohort) and 29 patients (validation cohort) diagnosed with early-stage SCC. PD-L1 immunohistochemistry (IHC) was performed with three commercially available clones (E1L3N, SP263 and SP142). CD8+ TILs were scored with a digital algorithm. All tumours were analysed with targeted next-generation sequencing (NGS). Additionally, TP53 mutations were investigated with direct sequencing. In both cohorts, we observed a significant association between CD8+ TILs density and high PD-L1 IHC expression in tumour cells (TCs). Furthermore, high SP142 PD-L1 expression in immune cells (ICs) was also associated significantly with CD8+ TILs density. Therefore, CD8+ TILs density discriminated between patients with high versus low PD-L1 IHC expression with excellent sensitivity and specificity. Interestingly, the highest percentages of PD-L1-positive TCs with the three antibodies were found in samples with cyclin-dependent kinase 6 (CDK6) amplification, with high amplification of proto-oncogene C-Myc (CMYC) or with cyclin D1-PI3 kinase subunit alpha (CCND1-PIK3CA) co-amplification. High SP142 PD-L1 IHC expression in ICs showed a non-significant correlation with TP53 mutations. Conversely, most cases with fibroblast growth factor receptor 1 (FGFR1) amplification were negative for all PD-L1 clones. CONCLUSIONS: Our preliminary results support the use of digital CD8+ TILs scoring and targeted NGS alongside PD-L1 expression. The approach presented herein could help define patients with SCCs candidates to immune checkpoints inhibitors.
Assuntos
Biomarcadores Tumorais/análise , Carcinoma de Células Escamosas , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Interpretação de Imagem Assistida por Computador/métodos , Neoplasias Pulmonares , Adulto , Idoso , Antígeno B7-H1/análise , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Proto-Oncogene MasRESUMO
BACKGROUND: Data are scarce regarding real-world health care resource use (HCRU) for non-small cell lung cancer (NSCLC). An understanding of current clinical practices and HCRU is needed to provide a benchmark for rapidly evolving NSCLC management recommendations and therapeutic options. The objective of this study was to describe real-world HCRU for patients with advanced NSCLC. METHODS: This multinational, retrospective chart review study was conducted at academic and community oncology sites in Italy, Spain, Germany, Australia, Japan, South Korea, Taiwan, and Brazil. Deidentified data were drawn from medical records of 1440 adults (≥18 years old) who initiated systemic therapy (2011 to mid-2013) for a new, confirmed diagnosis of advanced or metastatic (stage IIIB or IV) NSCLC. We summarized HCRU associated with first and subsequent lines of systemic therapy for advanced/metastatic NSCLC. RESULTS: The proportion of patients who were hospitalized at least once varied by country from 24% in Italy to 81% in Japan during first-line therapy and from 22% in Italy to 84% in Japan during second-line therapy; overall hospitalization frequency was 2.5-11.1 per 100 patient-weeks, depending on country. Emergency visit frequency also varied among countries (overall from 0.3-5.9 per 100 patient-weeks), increasing consistently from first- through third-line therapy in each country. The outpatient setting was the most common setting of resource use. Most patients in the study had multiple outpatient visits in association with each line of therapy (overall from 21.1 to 59.0 outpatient visits per 100 patient-weeks, depending on country). The use of health care resources showed no regular pattern associated with results of tests for activating mutations of the epidermal growth factor receptor (EGFR) gene or anaplastic lymphoma kinase (ALK) gene rearrangements. CONCLUSIONS: HCRU varied across countries. These findings suggest differing approaches to the clinical management of advanced NSCLC among the eight countries. Comparative findings and an understanding of country-specific clinical practices can help to identify areas of need and guide future resource allocation for patients with advanced NSCLC. Further studies evaluating the costs associated with resource use are warranted.
Assuntos
Assistência Ambulatorial/estatística & dados numéricos , Carcinoma Pulmonar de Células não Pequenas/terapia , Serviços Médicos de Emergência/estatística & dados numéricos , Hospitalização/estatística & dados numéricos , Neoplasias Pulmonares/terapia , Idoso , Austrália , Brasil , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Alemanha , Pesquisa sobre Serviços de Saúde , Humanos , Itália , Japão , Tempo de Internação/estatística & dados numéricos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , República da Coreia , Estudos Retrospectivos , Espanha , TaiwanRESUMO
BACKGROUND: There are no data from prospective studies focused exclusively on patients with advanced lung and thymic carcinoids. We aimed to assess the efficacy and safety of long-acting pasireotide and everolimus, administered alone or in combination, in patients with advanced carcinoids of the lung or thymus. METHODS: LUNA was a prospective, multicentre, randomised, open-label, phase 2 trial of adult patients (aged >18 years) with advanced (unresectable or metastatic), well differentiated carcinoid tumours of the lung or thymus, with radiological progression within 12 months before randomisation, and a WHO performance status of 0-2. At each centre, the investigator or their designee registered each patient using an interactive voice recognition system into one of the three treatment groups. The randomisation allocation sequence was generated by an external company; patients were randomly assigned (1:1:1) to receive treatment with long-acting pasireotide (60 mg intramuscularly every 28 days), everolimus (10 mg orally once daily), or both in combination, for the core 12-month treatment period. Patients were stratified by carcinoid type (typical vs atypical) and line of study treatment (first line vs others). The primary endpoint was the proportion of patients progression-free at month 9, defined as the proportion of patients with overall lesion assessment at month 9 showing a complete response, partial response, or stable disease according to local Response Evaluation Criteria in Solid Tumors, version 1.1, assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment. The trial is registered with ClinicalTrials.gov, number NCT01563354. The extension phase of the study is ongoing. FINDINGS: Between Aug 16, 2013, and Sept 30, 2014, 124 patients were enrolled from 36 centres in nine countries: 41 were allocated to the long-acting pasireotide group, 42 to the everolimus group, and 41 to the combination group. At month 9, the proportion of patients with an overall lesion assessment of complete response, partial response, or stable disease was 16 of 41 patients (39·0%, 95% CI 24·2-55·5) in the long-acting pasireotide group, 14 of 42 patients (33·3%, 19·6-49·5) in the everolimus group, and 24 of 41 patients (58·5%, 42·1-73·7) in the combination group. The most common grade 1-2 adverse events with a suspected association with long-acting pasireotide monotherapy were diarrhoea (15 [37%] of 41), hyperglycaemia (17 [41%]), and weight loss (8 [20%]); those with a suspected association with everolimus monotherapy were stomatitis (26 [62%] of 42) and diarrhoea (16 [38%]); and those suspected to be associated with combination treatment were hyperglycaemia (27 [66%] of 41]), diarrhoea (19 [46%]), and asthenia (8 [20%]). The most common grade 3-4 adverse events with a suspected association with long-acting pasireotide monotherapy were γ-glutamyltransferase increased (four [10%] of 41 patients), diarrhoea (three [7%]), and hyperglycaemia (three [7%]); those for everolimus were hyperglycaemia (seven [17%] of 42 patients), stomatitis (four [10%]), and diarrhoea (three [7%]); those for combination treatment were hyperglycaemia (nine [22%] of 41 patients) and diarrhoea (four [10%]). 11 patients died during the core 12-month treatment phase or up to 56 days after the last study treatment exposure date: two (5%) of 41 in the long-acting pasireotide group, six (14%) of 42 in the everolimus group, and three (7%) of 41 in the combination group. No deaths were suspected to be related to long-acting pasireotide treatment. One death in the everolimus group (acute kidney injury associated with diarrhoea), and two deaths in the combination group (diarrhoea and urinary sepsis in one patient, and acute renal failure and respiratory failure in one patient) were suspected to be related to everolimus treatment. In the latter patient, acute renal failure was not suspected to be related to everolimus treatment, but respiratory failure was suspected to be related. INTERPRETATION: The study met the primary endpoint in all three treatment groups. Safety profiles were consistent with the known safety profiles of these agents. Further studies are needed to confirm the antitumour efficacy of the combination of a somatostatin analogue with everolimus in lung and thymic carcinoids. FUNDING: Novartis Pharma AG.
Assuntos
Tumor Carcinoide/tratamento farmacológico , Everolimo/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Segurança do Paciente , Somatostatina/análogos & derivados , Neoplasias do Timo/tratamento farmacológico , Administração Oral , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Tumor Carcinoide/mortalidade , Tumor Carcinoide/patologia , Preparações de Ação Retardada/administração & dosagem , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Everolimo/efeitos adversos , Feminino , Humanos , Injeções Intramusculares , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Somatostatina/administração & dosagem , Somatostatina/efeitos adversos , Análise de Sobrevida , Neoplasias do Timo/mortalidade , Neoplasias do Timo/patologia , Resultado do TratamentoRESUMO
AIM: Providing epidemiological data and treatment of anemia in lung cancer patients undergoing first-line chemotherapy. METHODS: Epidemiological, observational, retrospective and multicenter study carried out at 30 sites throughout Spain. RESULTS: The prevalence of anemia (hemoglobin [Hb] level <12 g/dl) was 18.3% and the incidence 80.7%. Mean Hb levels were 13.4 g/dl (95% Cl: 13.2-13.6) and 11.5 g/dl (95% Cl: 11.3-11.7) at starting and at the end of chemotherapy, respectively. Of the 294 patients with anemia, 174 (59.2%) were treated. Erythropoiesis-stimulating agents were given to 90.2% patients, alone in 31.6% and combined iron in 39.7%, transfusion in 9.2% and iron and transfusion in 9.8%. CONCLUSION: These results suggest an appropriate and rational use of erythropoiesis-stimulating agents in the treatment of chemotherapy-associated anemia in lung cancer patients. [corrected].
Assuntos
Anemia/epidemiologia , Anemia/terapia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Hematínicos/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia/induzido quimicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/administração & dosagem , Transfusão de Sangue , Hidrocarbonetos Aromáticos com Pontes/administração & dosagem , Carboplatina/administração & dosagem , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Etoposídeo/administração & dosagem , Feminino , Hemoglobinas/metabolismo , Humanos , Incidência , Ferro/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Observacionais como Assunto , Prevalência , Estudos Retrospectivos , Espanha/epidemiologia , Taxoides/administração & dosagem , Vimblastina/administração & dosagem , Vimblastina/análogos & derivados , Vinorelbina , Adulto Jovem , GencitabinaRESUMO
The incidence and mortality of lung cancer in women are rising, with both increasing by 124% between 2003 and 2019. The main risk factor for lung cancer is tobacco use, but indoor radon gas exposure is one of the leading causes in nonsmokers. The most recent evidence demonstrates that multiple factors can make women more susceptible to harm from these risk factors or carcinogens. For this consensus statement, the Association for Lung Cancer Research in Women (ICAPEM) invited a group of lung cancer experts to perform a detailed gender-based analysis of lung cancer. Clinically, female patients have different lung cancer profiles, and most actionable driver alterations are more prevalent in women, particularly in never-smokers. Additionally, the impact of certain therapies seems to be different. In the future, it will be necessary to carry out specific studies to improve the understanding of the role of certain biomarkers and gender in the prognosis and evolution of lung cancer.
Assuntos
Poluição do Ar em Ambientes Fechados , Neoplasias Pulmonares , Radônio , Masculino , Humanos , Feminino , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/terapia , Radônio/efeitos adversos , Poluição do Ar em Ambientes Fechados/efeitos adversos , Fatores de Risco , IncidênciaRESUMO
The use of anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs), such as lorlatinib, for the treatment of patients with ALK gene rearrangement (or ALK-positive) non-small cell lung cancer (NSCLC) has been shown to improve the overall survival and quality of life of these patients. However, lorlatinib is not exempt from potential adverse events. Adequate monitoring and management of these adverse events are critical for increasing patient adherence to lorlatinib, thereby maximizing the benefits of treatment and minimizing the risks associated with treatment discontinuation. Considering that the adverse events of lorlatinib can affect different organs and systems, the participation of a multidisciplinary team, including cardiologists, neurologists, internal medicine specialists, and oncology pharmacists, is needed. This article presents specific and pragmatic strategies for identifying and treating the most relevant adverse events associated with lorlatinib in patients with advanced ALK-positive NSCLC based on the clinical experience of a multidisciplinary panel of experts.
RESUMO
Glioblastoma (GB) is a devastating tumor of the central nervous system characterized by a poor prognosis. One of the best-established predictive biomarker in IDH-wildtype GB is O6-methylguanine-DNA methyltransferase (MGMT) methylation (mMGMT), which is associated with improved treatment response and survival. However, current efforts to monitor GB patients through mMGMT detection have proven unsuccessful. Small extracellular vesicles (sEVs) hold potential as a key element that could revolutionize clinical practice by offering new possibilities for liquid biopsy. This study aimed to determine the utility of sEV-based liquid biopsy as a predictive biomarker and disease monitoring tool in patients with IDH-wildtype GB. Our findings show consistent results with tissue-based analysis, achieving a remarkable sensitivity of 85.7% for detecting mMGMT in liquid biopsy, the highest reported to date. Moreover, we suggested that liquid biopsy assessment of sEV-DNA could be a powerful tool for monitoring disease progression in IDH-wildtype GB patients. This study highlights the critical significance of overcoming molecular underdetection, which can lead to missed treatment opportunities and misdiagnoses, possibly resulting in ineffective therapies. The outcomes of our research significantly contribute to the field of sEV-DNA-based liquid biopsy, providing valuable insights into tumor tissue heterogeneity and establishing it as a promising tool for detecting GB biomarkers. These results have substantial implications for advancing predictive and therapeutic approaches in the context of GB and warrant further exploration and validation in clinical settings.
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Biomarcadores Tumorais , Neoplasias Encefálicas , Metilação de DNA , Metilases de Modificação do DNA , Enzimas Reparadoras do DNA , Vesículas Extracelulares , Glioblastoma , Proteínas Supressoras de Tumor , Humanos , Glioblastoma/genética , Glioblastoma/patologia , Glioblastoma/diagnóstico , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/genética , Biópsia Líquida/métodos , Metilases de Modificação do DNA/genética , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/genética , Enzimas Reparadoras do DNA/metabolismo , Masculino , Feminino , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Pessoa de Meia-Idade , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/diagnóstico , Idoso , Adulto , PrognósticoRESUMO
PURPOSE: Transcriptomic subtyping holds promise for personalized therapy in extensive-stage small cell lung cancer (ES-SCLC). In this study, we aimed to assess intratumoral transcriptomic subtype diversity and to identify biomarkers of long-term chemoimmunotherapy benefit in human ES-SCLC. EXPERIMENTAL DESIGN: We analyzed tumor samples from 58 patients with ES-SCLC enrolled in two multicenter single-arm phase IIIb studies evaluating frontline chemoimmunotherapy in Spain: n = 32 from the IMfirst trial and n = 26 from the CANTABRICO trial. We used the GeoMx Digital Spatial Profiler system to perform multi-region transcriptomic analysis. For subtype classification, we performed hierarchical clustering using the relative expression of ASCL1 (SCLC-A), NEUROD1 (SCLC-N), POU2F3 (SCLC-P), and YAP1 (SCLC-Y). RESULTS: Subtype distribution was found to be similar between bothcohorts, except for SCLC-P, which was not identified in the CANTABRICO_DSP cohort. A total of 44% of the patients in both cohorts had tumors with multiple coexisting transcriptional subtypes. Transcriptional subtypes or subtype heterogeneity was not associated with outcomes. Most potential targets did not show subtype-specific expression. Consistently in both cohorts, tumors from patients with long-term benefit (time to progression ≥12 months) contained an IFNγ-dominated mRNA profile, including enhanced capacity for antigen presentation. Hypoxia and glycolytic pathways were associated with resistance to chemoimmunotherapy. CONCLUSIONS: This work suggests that intratumoral heterogeneity, inconsistent association with outcome, and unclear subtype-specific target expression might be significant challenges for subtype-based precision oncology in SCLC. Preexisting IFNγ-driven immunity and mitochondrial metabolism seem to be correlates of long-term efficacy in this study, although the absence of a chemotherapy control arm precludes concluding that these are predictive features specific for immunotherapy.
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Biomarcadores Tumorais , Perfilação da Expressão Gênica , Imunoterapia , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Transcriptoma , Humanos , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/patologia , Carcinoma de Pequenas Células do Pulmão/terapia , Biomarcadores Tumorais/genética , Masculino , Feminino , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Idoso , Imunoterapia/métodos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Resultado do Tratamento , Regulação Neoplásica da Expressão Gênica , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , PrognósticoRESUMO
INTRODUCTION: Recent advances in the treatment of locally advanced NSCLC have led to changes in the standard of care for this disease. For the selection of the best approach strategy for each patient, it is necessary the homogenization of diagnostic and therapeutic interventions, as well as the promotion of the evaluation of patients by a multidisciplinary oncology team. OBJECTIVE: Development of an expert consensus document with suggestions for the approach and treatment of locally advanced NSCLC leaded by Spanish Lung Cancer Group GECP. METHODS: Between March and July 2023, a panel of 28 experts was formed. Using a mixed technique (Delphi/nominal group) under the guidance of a coordinating group, consensus was reached in 4 phases: 1. Literature review and definition of discussion topics 2. First round of voting 3. Communicating the results and second round of voting 4. Definition of conclusions in nominal group meeting. Responses were consolidated using medians and interquartile ranges. The threshold for agreement was defined as 85% of the votes. RESULTS: New and controversial situations regarding the diagnosis and management of locally advanced NSCLC were analyzed and reconciled based on evidence and clinical experience. Discussion issues included: molecular diagnosis and biomarkers, radiologic and surgical diagnosis, mediastinal staging, role of the multidisciplinary thoracic committee, neoadjuvant treatment indications, evaluation of response to neoadjuvant treatment, postoperative evaluation, and follow-up. CONCLUSIONS: Consensus clinical suggestions were generated on the most relevant scenarios such as diagnosis, staging and treatment of locally advanced lung cancer, which will serve to support decision-making in daily practice.
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Carcinoma Pulmonar de Células não Pequenas , Consenso , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patologia , Espanha , Equipe de Assistência ao Paciente , Técnica Delphi , Estadiamento de NeoplasiasRESUMO
BACKGROUND: Immunotherapy-based treatments have demonstrated high efficacy in patients with advanced and locally advanced non-small-cell lung cancer (NSCLC). BRAF mutations affect a small but significant fraction of NSCLC. The efficacy of these therapies in this subgroup of patients is unknown. MATERIALS AND METHODS: Plasma and tissue samples from 116 resectable stage IIIA/B NSCLC patients, included in NADIM and NADIM II clinical trials (NADIM cohort), and from a prospective academic cohort with 84 stage IV NSCLC patients (BLI-O cohort), were analyzed by next-generation sequencing. RESULTS: The p.G464E, p.G466R, p.G466V, p.G469V, p.L597Q, p.T599I, p.V600E (n = 2) BRAF mutations, were identified in four (3.45 %) samples from the NADIM cohort, all of which were cases treated with neoadjuvant chemoimmunotherapy (CH-IO), and four (4.76 %) samples from the BLI-O cohort, corresponding to cases treated with first-line immunotherapy (n = 2) or CH-IO (n = 2). All these patients were alive and had no evidence of disease at data cut-off. Conversely, patients with BRAF wild-type (wt) tumors in the BLI-O cohort had a median progression-free survival (PFS) of 5.49 months and a median overall survival (OS) of 12.00 months (P-LogRank = 0.013 and 0.046, respectively). Likewise, PFS and OS probabilities at 36 months were 60.5 % and 76.1 % for patients with BRAF-wt tumors in the NADIM cohort. The pathological complete response (pCR) rate after neoadjuvant CH-IO in patients with BRAF-positive tumors (n = 4) was 100 %, whereas the pCR rate in the BRAF-wt population was 44.3 % (RR: 2.26; 95 % CI: 1.78-2.85; P < 0.001). CONCLUSION: BRAF mutations may be a good prognostic factor for advanced and locally advanced NSCLC patients undergoing immunotherapy-based treatments.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Mutação , Proteínas Proto-Oncogênicas B-raf , Humanos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/terapia , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Estadiamento de Neoplasias , Prognóstico , Adulto , Estudos Prospectivos , Imunoterapia/métodos , Biomarcadores Tumorais/genética , Idoso de 80 Anos ou mais , Metástase NeoplásicaRESUMO
Introduction: RET inhibitors with impressive overall response rates are now available for patients with NSCLC, yet the identification of RET fusions remains a difficult challenge. Most guidelines encourage the upfront use of next-generation sequencing (NGS), or alternatively, fluorescence in situ hybridization (FISH) or reverse transcriptase-polymerase chain reaction (RT-PCR) when NGS is not possible or available. Taken together, the suboptimal performance of single-analyte assays to detect RET fusions, although consistent with the notion of encouraging universal NGS, is currently widening some of the clinical practice gaps in the implementation of predictive biomarkers in patients with advanced NSCLC. Methods: This situation prompted us to evaluate several RET assays in a large multicenter cohort of RET fusion-positive NSCLC (n = 38) to obtain real-world data. In addition to RNA-based NGS (the criterion standard method), all positive specimens underwent break-apart RET FISH with two different assays and were also tested by an RT-PCR assay. Results: The most common RET partners were KIF5B (78.9%), followed by CCDC6 (15.8%). The two RET NGS-positive but FISH-negative samples contained a KIF5B(15)-RET(12) fusion. The three RET fusions not identified with RT-PCR were AKAP13(35)-RET(12), KIF5B(24)-RET(9) and KIF5B(24)-RET(11). All three false-negative RT-PCR cases were FISH-positive, exhibited a typical break-apart pattern, and contained a very high number of positive tumor cells with both FISH assays. Signet ring cells, psammoma bodies, and pleomorphic features were frequently observed (in 34.2%, 39.5%, and 39.5% of tumors, respectively). Conclusions: In-depth knowledge of the advantages and disadvantages of the different RET testing methodologies could help clinical and molecular tumor boards implement and maintain sensible algorithms for the rapid and effective detection of RET fusions in patients with NSCLC. The likelihood of RET false-negative results with both FISH and RT-PCR reinforces the need for upfront NGS in patients with NSCLC.
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The clinical and functional significance of RNA-interference machinery in lung cancer is poorly understood. Besides, microRNAs (miRNA) have the potential to serve both as biomarkers and therapeutic agents, by personalizing diagnosis and therapy. In this study, we investigated whether the expression levels of DICER1 and DROSHA, components of the RNA-interference machinery, can predict survival, and whether the miRNA expression profiles can differentiate histologic subtypes in non-small cell lung cancer (NSCLC). Levels of DICER1, DROSHA and five different miRNAs were measured in NSCLC specimens (N = 115) by qRT-PCR assay and correlated with clinical outcomes. Low expression of DROSHA was associated with an increased median survival (154.2 versus 39.8 months, P = 0.016). Also, high DROSHA expression was associated with decreased median survival in the following subgroups: adenocarcinoma (P = 0.011), grade III tumors (P = 0.038) and low-stage patients (P = 0.014). In multivariate analyses, we found two independent predictors of reduced disease-specific survival: high DROSHA expression [hazards ratio = 2.24; P = 0.04] and advanced tumor stage (hazards ratio = 1.29, P = 0.02). In general, the overall tumor miRNA expression was downregulated in our cohort compared with normal tissues. Expression levels of hsa-let-7a (P = 0.005) and miR-16 (P = 0.003) miRNA were significantly higher in squamous cell carcinoma than in adenocarcinoma samples. This study supports the value of the expression profiling of the components of the miRNA-processing machinery in the prognosis of NSCLC patients, especially DROSHA expression levels. In addition, differential expression of miRNAs, such as hsa-let-7a and miR-16 may be helpful tools in the histologic subclassification of NSCLC.
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Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , RNA Helicases DEAD-box/biossíntese , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , MicroRNAs/biossíntese , Ribonuclease III/biossíntese , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , RNA Helicases DEAD-box/genética , Regulação para Baixo , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/patologia , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Prognóstico , Ribonuclease III/genéticaRESUMO
BACKGROUND: Erlotinib has been shown to improve progression-free survival compared with chemotherapy when given as first-line treatment for Asian patients with non-small-cell lung cancer (NSCLC) with activating EGFR mutations. We aimed to assess the safety and efficacy of erlotinib compared with standard chemotherapy for first-line treatment of European patients with advanced EGFR-mutation positive NSCLC. METHODS: We undertook the open-label, randomised phase 3 EURTAC trial at 42 hospitals in France, Italy, and Spain. Eligible participants were adults (> 18 years) with NSCLC and EGFR mutations (exon 19 deletion or L858R mutation in exon 21) with no history of chemotherapy for metastatic disease (neoadjuvant or adjuvant chemotherapy ending ≥ 6 months before study entry was allowed). We randomly allocated participants (1:1) according to a computer-generated allocation schedule to receive oral erlotinib 150 mg per day or 3 week cycles of standard intravenous chemotherapy of cisplatin 75 mg/m(2) on day 1 plus docetaxel (75 mg/m(2) on day 1) or gemcitabine (1250 mg/m(2) on days 1 and 8). Carboplatin (AUC 6 with docetaxel 75 mg/m(2) or AUC 5 with gemcitabine 1000 mg/m(2)) was allowed in patients unable to have cisplatin. Patients were stratified by EGFR mutation type and Eastern Cooperative Oncology Group performance status (0 vs 1 vs 2). The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. We assessed safety in all patients who received study drug (≥ 1 dose). This study is registered with ClinicalTrials.gov, number NCT00446225. FINDINGS: Between Feb 15, 2007, and Jan 4, 2011, 174 patients with EGFR mutations were enrolled. One patient received treatment before randomisation and was thus withdrawn from the study; of the remaining patients, 86 were randomly assigned to receive erlotinib and 87 to receive standard chemotherapy. The preplanned interim analysis showed that the study met its primary endpoint; enrolment was halted, and full evaluation of the results was recommended. At data cutoff (Jan 26, 2011), median PFS was 9·7 months (95% CI 8·4-12·3) in the erlotinib group, compared with 5·2 months (4·5-5·8) in the standard chemotherapy group (hazard ratio 0·37, 95% CI 0·25-0·54; p < 0·0001). Main grade 3 or 4 toxicities were rash (11 [13%] of 84 patients given erlotinib vs none of 82 patients in the chemotherapy group), neutropenia (none vs 18 [22%]), anaemia (one [1%] vs three [4%]), and increased amino-transferase concentrations (two [2%] vs 0). Five (6%) patients on erlotinib had treatment-related severe adverse events compared with 16 patients (20%) on chemotherapy. One patient in the erlotinib group and two in the standard chemotherapy group died from treatment-related causes. INTERPRETATION: Our findings strengthen the rationale for routine baseline tissue-based assessment of EGFR mutations in patients with NSCLC and for treatment of mutation-positive patients with EGFR tyrosine-kinase inhibitors. FUNDING: Spanish Lung Cancer Group, Roche Farma, Hoffmann-La Roche, and Red Temática de Investigacion Cooperativa en Cancer.