RESUMO
BACKGROUND: In the phase III CheckMate 227 study, first-line nivolumab + ipilimumab significantly prolonged progression-free survival (co-primary end-point) versus chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC) and high tumour mutational burden (TMB; ≥10 mutations/megabase). AIM: To evaluate patient-reported outcomes (PROs) in this population. METHODS: Disease-related symptoms and general health status were assessed using the validated PRO questionnaires Lung Cancer Symptom Scale (LCSS) and EQ-5D, respectively. LCSS average symptom burden index (ASBI) and three-item global index (3-IGI) and EQ-5D visual analogue scale (VAS) and utility index (UI) scores and changes from baseline were analysed descriptively. Longitudinal changes were assessed by mixed-effect model repeated measures (MMRMs) and time to first deterioration/improvement analyses. RESULTS: In the high TMB population, PRO questionnaire completion rates were â¼90% at baseline and >80% for most on-treatment assessments. During treatment, mean changes from baseline with nivolumab + ipilimumab showed early, clinically meaningful improvements in LCSS ASBI/3-IGI and EQ-5D VAS/UI; with chemotherapy, symptoms and health-related quality of life remained stable (LCSS ASBI/3-IGI, EQ-5D UI) or improved following induction (EQ-5D VAS). MMRM-assessed changes in symptom burden were improved with nivolumab + ipilimumab versus chemotherapy. Symptom deterioration by week 12 was lower with nivolumab + ipilimumab versus chemotherapy (22.3% versus 35.0%; absolute risk reduction: 12.7% [95% confidence interval 2.4-22.5]), irrespective of discontinuation. Time to first deterioration was delayed with nivolumab + ipilimumab versus chemotherapy across LCSS and EQ-5D summary measures. CONCLUSION: First-line nivolumab + ipilimumab demonstrated early, sustained improvements in PROs versus chemotherapy in patients with advanced NSCLC and high TMB. CLINICAL TRIAL REGISTRATION: NCT02477826.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Medidas de Resultados Relatados pelo Paciente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Nível de Saúde , Humanos , Ipilimumab/administração & dosagem , Masculino , Pessoa de Meia-Idade , Nivolumabe/administração & dosagem , Qualidade de VidaRESUMO
BACKGROUND: No targeted therapies are available for KRAS-mutant non-small-cell lung cancer (NSCLC). Selumetinib is an inhibitor of MEK1/MEK2, downstream of KRAS, with preclinical evidence of synergistic activity with docetaxel in KRAS-mutant cancers. We did a prospective, randomised, phase 2 trial to assess selumetinib plus docetaxel in previously treated patients with advanced KRAS-mutant NSCLC. METHODS: Eligible patients were older than 18 years of age; had histologically or cytologically confirmed stage IIIB-IV KRAS-mutant NSCLC; had failed first-line therapy for advanced NSCLC; had WHO performance status of 0-1; had not received previous therapy with either a MEK inhibitor or docetaxel; and had adequate bone marrow, renal, and liver function. Patients were randomly assigned (in a 1:1 ratio) to either oral selumetinib (75 mg twice daily in a 21 day cycle) or placebo; all patients received intravenous docetaxel (75 mg/m(2) on day 1 of a 21 day cycle). Randomisation was done with an interactive voice response system and investigators, patients, data analysts, and the trial sponsor were masked to treatment assignment. The primary endpoint was overall survival, analysed for all patients with confirmed KRAS mutations. This study is registered with ClinicalTrials.gov, number NCT00890825. FINDINGS: Between April 20, 2009, and June 30, 2010, we randomly assigned 44 patients to receive selumetinib and docetaxel (selumetinib group) and 43 to receive placebo and docetaxel (placebo group). Of these, one patient in the selumetinib group and three in the placebo group were excluded from efficacy analyses because their tumours were not confirmed to be KRAS-mutation positive. Median overall survival was 9·4 months (6·8-13·6) in the selumetinib group and 5·2 months (95% CI 3·8-non-calculable) in the placebo group (hazard ratio [HR] for death 0·80, 80% CI 0·56-1·14; one-sided p=0·21). Median progression-free survival was 5·3 months (4·6-6·4) in the selumetinib group and 2·1 months (95% CI 1·4-3·7) in the placebo group (HR for progression 0·58, 80% CI 0·42-0·79; one-sided p=0·014). 16 (37%) patients in the selumetinib group and none in the placebo group had an objective response (p<0·0001). Adverse events of grade 3 or higher occurred in 36 (82%) patients in the selumetinib group and 28 (67%) patients in the placebo group. The most common grade 3-4 adverse events were neutropenia (29 [67%] of 43 patients in the selumetinib group vs 23 [55%] of 42 patients in the placebo group), febrile neutropenia (eight [18%] of 44 patients in the selumetinib group vs none in the placebo group), dyspnoea (one [2%] of 44 patients in the selumetinib group vs five [12%] of 42 in the placebo group), and asthenia (four [9%] of 44 patients in the selumetinib group vs none in the placebo group). INTERPRETATION: Selumetinib plus docetaxel has promising efficacy, albeit with a higher number of adverse events than with docetaxel alone, in previously treated advanced KRAS-mutant NSCLC. These findings warrant further clinical investigation of selumetinib plus docetaxel in KRAS-mutant NSCLC. FUNDING: AstraZeneca.
Assuntos
Benzimidazóis/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Proteínas Proto-Oncogênicas/genética , Taxoides/administração & dosagem , Proteínas ras/genética , Adulto , Idoso , Benzimidazóis/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Intervalo Livre de Doença , Docetaxel , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/induzido quimicamente , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Prospectivos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas p21(ras) , Taxoides/efeitos adversosRESUMO
O caso de um paciente do sexo masculino, com 54 anos, portador de carcinoma de pequenas células primitivas em terço inferior de esôfago. As manifestações iniciais da doença se caracterizaram por emagracimento acentuado e dores epigástricas com 3 meses de evolução. Ao exame físico observamos sinais evidentes de doença consuntiva. O estadiamento oncológico revelou acometimento secundário de linfonodos para-aórticos, mesentéricos e do tronco celíaco (doença extensa), além de possível invasão de aorta descendente. O tratamento baseou-se na quimioterapia com cisdiaminodicloroplatinum e etoposide, obtendo-se remissão clínica completa com três ciclos. Como consolidação do resultado, o paciente recebeu radioterapia externa dirigida ao local do tumor primário, porém a resposta obtida não se manteve, havendo progressão local e sistêmica após 40 dias do término da radioterapia. O óbito se deu em função de infecção respiratória e múltiplas metástases 9 meses do diagnóstico ...
Assuntos
Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma de Células Pequenas/diagnóstico , Carcinoma de Células Pequenas/patologia , Carcinoma de Células Pequenas/tratamento farmacológico , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/tratamento farmacológico , Quimioterapia CombinadaRESUMO
OBJETIVOS: Análise retrospectiva de pacientes com infertilidade tubária. CASUISTICA E METODOLOGIA: Apresenta-se os dados clínicos de 51 pacientes com infertilidade de causa tubária primária ou secundária, entre fevereiro de 1991 e março de 1994, em acompanhamento no Setor de Infertilidade do Serviço de Ginecologia e Obstetrícia do Hospital de Clínicas de Porto Alegre. Estas foram submetidas à microcirurgia tubária visando à resoluçao da infertilidade. RESULTADOS: Através de rossalpingografia pós-cirúrgica ou gestaçao comprovada, foi observado que em 80,85 por cento dos casos houve permeabilidade uni ou bilateral das tubas uterinas, com um índice de gestaçao de 17,02 por cento. CONCLUSOES: sugere-se que a microcirurgia tubária possa ser método satisfatório para o tratamento de infertilidade de causa tubária.
