RESUMO
BACKGROUND: There is no recommended therapy for malignant pleural mesothelioma that has progressed after first-line pemetrexed and platinum-based chemotherapy. Disease control has been less than 30% in all previous studies of second-line drugs. Preliminary results have suggested that anti-programmed cell death 1 (PD-1) monoclonal antibody could be efficacious in these patients. We thus aimed to prospectively assess the anti-PD-1 monoclonal antibody alone or in combination with anti-cytotoxic T-lymphocyte protein 4 (CTLA-4) antibody in patients with malignant pleural mesothelioma. METHODS: This multicentre randomised, non-comparative, open-label, phase 2 trial was done at 21 hospitals in France. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, histologically proven malignant pleural mesothelioma progressing after first-line or second-line pemetrexed and platinum-based treatments, measurable disease by CT, and life expectancy greater than 12 weeks. Patients were randomly allocated (1:1) to receive intravenous nivolumab (3 mg/kg bodyweight) every 2 weeks, or intravenous nivolumab (3 mg/kg every 2 weeks) plus intravenous ipilimumab (1 mg/kg every 6 weeks), given until progression or unacceptable toxicity. Central randomisation was stratified by histology (epithelioid vs non-epithelioid), treatment line (second line vs third line), and chemosensitivity to previous treatment (progression ≥3 months vs <3 months after pemetrexed treatment) and used a minimisation method with a 0·8 random factor. The primary outcome was the proportion of patients who achieved 12-week disease control, assessed by masked independent central review; the primary endpoint would be met if disease control was achieved in at least 40% of patients. The primary endpoint was assessed in the first 108 eligible patients. Efficacy analyses were also done in the intention-to-treat population and safety analyses were done in all patients who received at least one dose of their assigned treatment. This trial is registered at ClinicalTrials.gov, number NCT02716272. FINDINGS: Between March 24 and August 25, 2016, 125 eligible patients were recruited and assigned to either nivolumab (n=63) or nivolumab plus ipilimumab (n=62). In the first 108 eligible patients, 12-week disease control was achieved by 24 (44%; 95% CI 31-58) of 54 patients in the nivolumab group and 27 (50%; 37-63) of 54 patients in the nivolumab plus ipilimumab group. In the intention-to-treat population, 12-week disease control was achieved by 25 (40%; 28-52) of 63 patients in the nivolumab group and 32 (52%; 39-64) of 62 patients in the combination group. Nine (14%) of 63 patients in the nivolumab group and 16 (26%) of 61 patients in the combination group had grade 3-4 toxicities. The most frequent grade 3 adverse events were asthenia (one [2%] in the nivolumab group vs three [5%] in the combination group), asymptomatic increase in aspartate aminotransferase or alanine aminotransferase (none vs four [7%] of each), and asymptomatic lipase increase (two [3%] vs one [2%]). No patients had toxicities leading to death in the nivolumab group, whereas three (5%) of 62 in the combination group did (one fulminant hepatitis, one encephalitis, and one acute kidney failure). INTERPRETATION: Anti-PD-1 nivolumab monotherapy or nivolumab plus anti-CTLA-4 ipilimumab combination therapy both showed promising activity in relapsed patients with malignant pleural mesothelioma, without unexpected toxicity. These regimens require confirmation in larger clinical trials. FUNDING: French Cooperative Thoracic Intergroup.
Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Ipilimumab/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Mesotelioma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Nivolumabe/administração & dosagem , Neoplasias Pleurais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica , Feminino , Humanos , Masculino , Mesotelioma Maligno , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
Erlotinib maintenance treatment improves progression-free survival compared with observation after first-line chemotherapy in unselected advanced non-small cell lung cancer (NSCLC). Very few cardiac adverse effects have been observed in phase III studies on tyrosine kinase inhibitors (TKI). We report the case of a 71-year-old woman with metastatic NSCLC treated with cisplatin/pemetrexed and then erlotinib maintenance therapy. After 26 months of TKI therapy, she developed dilated cardiomyopathy. Despite symptomatic treatment, left ventricular ejection fraction decreased to 25%. Ischemic heart disease was excluded by coronary angiography and cardiac magnetic resonance imaging, and no other cause was found. Erlotinib was stopped, and cardiac resynchronization therapy by pacemaker was initiated. This case report highlights the possible cardiotoxic effects of long-term erlotinib and suggests the need for close clinical and echocardiographic follow-up of patients receiving long-term TKI therapy.
Assuntos
Antineoplásicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cardiomiopatia Dilatada/induzido quimicamente , Cloridrato de Erlotinib/efeitos adversos , Neoplasias Pulmonares/tratamento farmacológico , Quimioterapia de Manutenção/efeitos adversos , Marca-Passo Artificial , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Tirosina Quinases/antagonistas & inibidores , Volume Sistólico/efeitos dos fármacos , Idoso , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bloqueio de Ramo/complicações , Cardiomiopatia Dilatada/fisiopatologia , Cardiomiopatia Dilatada/terapia , Cisplatino/administração & dosagem , Cloridrato de Erlotinib/administração & dosagem , Feminino , Humanos , Quimioterapia de Manutenção/métodos , Pemetrexede/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Resultado do TratamentoAssuntos
Internet , Neoplasias Pulmonares/mortalidade , Vigilância da População/métodos , Autorrelato , Avaliação de Sintomas/métodos , Autoavaliação Diagnóstica , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/diagnóstico por imagem , Recidiva Local de Neoplasia/diagnósticoRESUMO
BACKGROUND: Sexual dysfunction (erectile dysfunction in males, sexual dissatisfaction, sexual interest/arousal disorders, and dyspareunia in females) has not been the subject of indepth research in people with cystic fibrosis (CF). This study aimed to determine the prevalence of sexual dysfunction in adults with CF, factors associated with sexual dysfunction, and the impact of sexual dysfunction on quality of life. METHOD: We conducted a multicentre study in adults with cystic fibrosis followed in specialist centres in Western France. We assessed erectile dysfunction and its severity using the IIEF5 self-questionnaire (International Index of Erectile Function); the FSFI (Female Sexual Function Index) was used to assess sexual function in females, and we evaluated quality of life in both sexes using the CFQ-R14+ questionnaire. RESULTS: In total, 77 males and 74 females completed the sexual function questionnaire (mean age 32+/- 10 and 25+/- 8,5 years respectively). Among them, 21 % of males and 30 % of females reported sexual dysfunction. CFQ-R14+ score was significantly lower in males with erectile dysfunction than those without (p < 0.001). Faecal incontinence was associated with more frequent sexual dysfunction in females and higher severity of erectile dysfunction in males. CONCLUSION: The prevalence of sexual disorders is relatively high in males and females with cystic fibrosis. Therefore, it seems important to train specialist teams to address the issue of sexuality without embarrassment, and to encourage them to seek out and treat faecal incontinence, which is associated with greater severity or frequency of these symptoms.
RESUMO
INTRODUCTION: Studies have shown improved tolerability with once-weekly versus three-weekly docetaxel in the second-line treatment of advanced non-small cell lung cancer (NSCLC). This study aimed to evaluate the tolerability of nintedanib plus weekly docetaxel in patients with NSCLC. METHODS: This phase I, open-label, dose-escalation study (NCT02668393) enrolled patients with locally advanced/metastatic adenocarcinoma NSCLC that had progressed on first-line platinum chemotherapy. The primary endpoint was to determine the maximum tolerated dose of nintedanib (up to 200 mg twice daily [BID]) combined with weekly docetaxel (35 mg/m2) on days 1, 8, and 15 based on the occurrence of dose-limiting toxicities (DLTs) over a 28-day treatment cycle. Adverse events (AEs) were also evaluated. RESULTS: The trial terminated prematurely due to recruitment challenges. At termination, seven patients had received nintedanib 150 mg BID and seven nintedanib 200 mg BID, in combination with weekly docetaxel. In the first treatment cycle, DLTs were reported for 1/6 evaluable patients (16.7%) in each group. The disease control rates were 57.1% and 42.9%, respectively. Grade ≥3 treatment-related AEs affected three patients in each group (42.9%); neutropenia was reported in one patient (14.3%) in each group. Treatment-related serious AEs were reported in three patients (42.9%) receiving nintedanib 150 mg, and two patients (28.6%) receiving nintedanib 200 mg. CONCLUSIONS: Overall, nintedanib plus weekly docetaxel was well-tolerated in patients with locally advanced or metastatic lung adenocarcinoma who progressed on first-line platinum-based chemotherapy, without loss of efficacy. DLTs were manageable.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Docetaxel/uso terapêutico , Neoplasias Pulmonares/patologia , Resultado do Tratamento , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
BACKGROUND: In cystic fibrosis (CF), coughing is associated with a risk of pelvic floor dysfunction. However, data on the prevalence of symptoms (stress urinary incontinence, bladder overactivity, dysuria, and faecal incontinence) are lacking in males and females with CF. The impact of incontinence on adherence to respiratory care has not been studied. METHODS: We conducted a multicentre study in adults with CF followed in the North-West French CF network. Urinary disorders and their severity were assessed using the Urinary Symptom Profile (USP) self-report questionnaire; the impact of urinary disorders on general quality of life was measured using the SF-Qualiveen questionnaire; faecal incontinence was assessed using the Wexner self-report questionnaire; and the CFQ-R14+ questionnaire was used to assess quality of life. A self-administered questionnaire developed for the study assessed the impact of symptoms on respiratory care. RESULTS: Of the 178 people with CF included, 34 % reported stress urinary incontinence, with a large female predominance (63.5 % of females vs. 7.5 % of males), 65 % bladder overactivity (including 16 % urge incontinence) and 50 % faecal incontinence, also with a female predominance. Neither urinary nor faecal incontinence were related to the severity of the respiratory impairment (FEV1). Quality of life was particularly affected in women. Stress urinary Incontinence symptoms affected respiratory care in both sexes. CONCLUSION: The prevalence of functional urinary and faecal disorders was high in adults with CF and impacted on quality of life and respiratory care. Therefore, multidisciplinary teams must have knowledge of symptoms, the diagnostic tools and management strategies to provide specific treatment.
RESUMO
The consequences of the strict health restrictions during the first wave of COVID-19 on lung cancer (LC) patients are not known. This cohort study evaluated the impact of the initial lockdown on management of and long-term outcome in LC patients. This exposed-unexposed-type study included two evaluation periods of 6 months each in non-selected patients; one began on the first day of lockdown in 2020, and the other in 2019 during the same calendar period. Various indicators were compared: clinical profiles, management delays and overall survival beyond 2 years. A total of 816 patients from 7 public or private centers were enrolled. The clinical characteristics of the patients in 2020 did not differ from those in 2019, except that the population was older (p = 0.002) with more non-smokers (p = 0.006). Delays for pre-therapeutic medical management were generally reduced after the first imaging in 2020 (1.28 [1.1-1.49]). In the multivariate analysis, being part of the 2020 cohort was correlated with better prognosis (HR = 0.71 [0.5-0.84], p < 0.001). The gain observed in 2020 mainly benefited non-smoking patients, along with ECOG PS 0-2 (p = 0.01), stage 4 (p = 0.003), squamous cell carcinoma (p = 0.03) and receiving systemic therapy (p = 0.03). In conclusion, the first lockdown did not exert any deleterious impact on LC patients.
RESUMO
BACKGROUND: Patient self-assessment via a mobile app detects actionable symptoms and has been shown to detect lung cancer relapses early, thereby lengthening survival. OBJECTIVE: The purpose of this study was to assess the incidence of chief symptoms associated with the main tobacco-induced pathologies in both current and ex-smokers through a self-assessment smartphone app and to evaluate the app's capacity to encourage users to quit smoking or reduce consumption, as well as its impact on early lung cancer stages at the time of diagnosis. METHODS: Current and ex-smokers were recruited through an advertising campaign in Sarthe county (France) proposing the free download of a smartphone app. App users were asked to answer 13 questions related to symptoms associated with tobacco-induced diseases (chronic obstructive pulmonary disease [COPD], cardiovascular diseases, cancer). In the event of any positive answer, a message was displayed recommending the user to consult a physician. In addition, they were asked about smoking cessation intention before and after answering these 13 questions. Finally, incidence of stage 1 or 2 lung cancers diagnosed during the launch period of our application was evaluated by comparing data from various sources to those from the same period during the previous year. RESULTS: Of the 5671 users who were eligible for evaluation, an alert was sent to the majority (4118/5671, 72.6%), with a higher incidence for current smokers (2833/3679, 77.0% vs 1298/1992, 65.2%; P<.001). The most frequent symptoms triggering the notifications were fatigue (2023/5671, 35.7%), cough (1658/5671, 29.2%), dyspnea (1502/5671, 26.5%), and persistent chest pain (1286/5671, 22.7%). Of the current smokers, 14.0% (515/3679) showed symptoms suggesting COPD, 15.5% (571/3679) showed symptoms suggesting stable angina, 12.4% (455/3679) probably had lower extremity artery disease, and 6.8% (249/3679) had possible cancer. Of the users, 36.5% (1343/3679) claimed that they thought about quitting smoking, and 48.7% (1795/3679) had thought about reducing their consumption. Surgery-eligible stage 1 and 2 lung cancer incidence was 24% (14/58) during the study period versus 9% (5/54) during the previous year in Sarthe county (P=.04), whereas it remained unchanged in the neighboring county of Maine-et-Loire. CONCLUSIONS: A majority of current and ex-smokers showed worrying symptoms, and the use of a self-assessment smartphone app may drive a majority of smokers toward the intention of smoking cessation or decreasing consumption. A randomized study should be performed to confirm this intention and to support the potential increase of symptomatic lung cancer detection at early, surgery-accessible stages. TRIAL REGISTRATION: ClinicalTrials.gov NCT04048954; https://www.clinicaltrials.gov/ct2/show/NCT04048954.
Assuntos
Doenças Cardiovasculares , Neoplasias Pulmonares , Aplicativos Móveis , Doença Pulmonar Obstrutiva Crônica , Abandono do Hábito de Fumar , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Detecção Precoce de Câncer , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiologia , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/etiologia , Autoavaliação (Psicologia) , Smartphone , NicotianaRESUMO
BACKGROUND: The orally available kinase inhibitor R-roscovitine has undergone clinical trials against various cancers and is currently under clinical evaluation against Cushing disease and rheumatoid arthritis. Roscovitine displays biological properties suggesting potential benefits in CF: it partially corrects F508del-CFTR trafficking, stimulates the bactericidal properties of CF alveolar macrophages, and displays anti-inflammatory properties and analgesic effects. METHODS: A phase 2 trial study (ROSCO-CF) was launched to evaluate the safety and effects of roscovitine in Pseudomonas aeruginosa infected adult CF patients carrying two CF causing mutations (at least one F508del-CFTR mutation) and harboring a FEV1 ≥40%. ROSCO-CF was a multicenter, double-blind, placebo-controlled, dose-ranging study (200, 400, 800 mg roscovitine, orally administered daily for 4 days/week/4 weeks). RESULTS: Among the 34 volunteers enrolled, randomization assigned 11/8/8/7 to receive the 0 (placebo)/ 200/400/800 mg roscovitine doses, respectively. In these subjects with polypharmacy, roscovitine was relatively safe and well-tolerated, with no significant adverse effects (AEs) other than five serious AEs (SAEs) possibly related to roscovitine. Pharmacokinetics of roscovitine were rather variable among subjects. No significant efficacy, at the levels of inflammation, infection, spirometry, sweat chloride, pain and quality of life, was detected in roscovitine-treated groups compared to the placebo-treated group. CONCLUSION: Roscovitine was relatively safe and well-tolerated in CF patients especially at the 200 and 400 mg doses. However, there were 5 subject withdrawals due to SAEs in the roscovitine group and none in the placebo group. The lack of evidence for efficacy of roscovitine (despite encouraging cellular and animal results) may be due to high pharmacokinetics variability, short duration of treatment, and/or inappropriate dosing protocol.
Assuntos
Fibrose Cística , Roscovitina , Animais , Fibrose Cística/diagnóstico , Fibrose Cística/tratamento farmacológico , Fibrose Cística/metabolismo , Fibrose Cística/microbiologia , Método Duplo-Cego , Humanos , Inibidores de Proteínas Quinases/uso terapêutico , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/metabolismo , Pseudomonas aeruginosa , Qualidade de Vida , Roscovitina/uso terapêuticoRESUMO
The main causes of diffuse cystic lung diseases include lymphangioleiomyomatosis, pulmonary Langerhans cell histiocytosis, Birt-Hogg-Dubé syndrome, lymphoid interstitial pneumonia, light chain deposition disease, Pneumocystis jirovecii pneumonia, hypersensitivity pneumonitis, and desquamative interstitial pneumonia. Diffuse cystic lung diseases are rarely caused by a malignant process, which are secondary to metastases from sarcomas and gastrointestinal and gynecologic adenocarcinomas. Here, we present a rare case of invasive pulmonary adenocarcinoma associated with progressive diffusion of cystic lesions, revealed by chronic cough and progressive shortness of breath. It is important for clinicians to be aware of this unusual imaging manifestation of lung cancer, to avoid misdiagnoses.
RESUMO
Viruses are important agents in lung function deterioration in Cystic Fibrosis (CF). To date, no standard operating procedures (SOPs) have been established to determine which sampling method is the most effective for an optimal virological diagnosis of respiratory viral infections in CF. Here we investigated the performances of two sampling sites, sputum samples versus nasopharyngeal (NP) swabs, for thirty participants from three CF centres presenting an acute respiratory infection. Sputum and NP samples were simultaneously collected and multiplex PCR targeting 16 to 18 viruses were performed. Viruses were detected for 18/30 patients (60%). A high concordance between the sputum and NP samples was observed in 25 (83%) paired samples of which 13 tested positive and 12 tested negative. These results highlighted the relevance of sputum sampling for diagnostic of respiratory viruses in CF, which is less invasive and better accepted by CF patients than NP, and allows accurate bacterial detection.
Assuntos
Fibrose Cística/virologia , Nasofaringe/virologia , Infecções Respiratórias/virologia , Escarro/virologia , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Viabilidade , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
PURPOSE: Lipid nanocapsules (LNCs) are solvent-free drug nanocarriers permitting entrapment of paclitaxel and increasing its antitumoural effect in animal models after i.v. injection. The tolerance and efficacy of LNCs after repeated dose i.v. administration were assessed in mice. The maximum tolerated dose (MTD) and 50 percent lethal dose (LD50) were studied. METHODS: Paclitaxel-loaded LNC formulation was given i.v. at the dose of 12 mg/kg per day for 5 consecutive days in comparison with blank LNCs and saline. Histological examination, complete blood counts and biochemical quantification were performed after a recovery of 7 days. Growth of NCI-H460 subcutaneous xenografts in nude mice receiving one of the aforementioned schedules was assessed. MTD and LD50 were determined by Irwin test. RESULTS: No mortality was observed in repeated injections studies. Histological studies revealed no lesions and no accumulation of lipids. Blood studies were normal. The tumoural growth was significantly reduced in the group treated by paclitaxel-loaded LNCs. The MTDs/LD50s of Taxol, paclitaxel-loaded LNCs and blank LNCs were 12/19.5, 96/216 and above 288/288 mg/kg, respectively. CONCLUSIONS: This study demonstrates that a five-day i.v. injection schedule of paclitaxel-loaded LNC dispersions induces no histological or biochemical abnormalities in mice and improves paclitaxel efficacy and therapeutic index in comparison with Taxol.
Assuntos
Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/uso terapêutico , Lipídeos/química , Nanocápsulas/química , Paclitaxel/efeitos adversos , Paclitaxel/uso terapêutico , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Linhagem Celular Tumoral , Feminino , Humanos , Lipídeos/análise , Masculino , Camundongos , Camundongos Nus , Nanocápsulas/ultraestrutura , Paclitaxel/administração & dosagemRESUMO
BACKGROUND: Previous studies have yielded inconsistent findings regarding the association between OSA and cancer in humans. RESEARCH QUESTION: Is there an association between indexes of sleep-disordered breathing severity and cancer incidence in patients investigated for suspected OSA? STUDY DESIGN AND METHODS: Data from a large multicenter cohort of cancer-free patients investigated for OSA were linked to health administrative data to identify new-onset cancer. Kaplan-Meier survival analysis and Cox proportional hazards models were used to evaluate the association of cancer incidence with OSA severity and nocturnal hypoxemia. RESULTS: After a median follow-up period of 5.8 years (interquartile range, 3.8-7.8), 718 of 8,748 patients (8.2%) had received a diagnosis of cancer. On unadjusted Kaplan-Meier survival analyses, cancer incidence was associated with increasing severity of OSA (log-rank test, P < .0005) and nocturnal hypoxemia (log-rank test, P < .0001 for both oxygen desaturation index and percent night time with oxygen saturation < 90% [T90]). After adjustment for anthropomorphic data, smoking and alcohol consumption, comorbid cardiac, metabolic, and respiratory diseases, marital status, type of sleep study, and study site, only T90 was associated with cancer incidence (adjusted hazard ratio, 1.33; 95% CI, 1.05-1.68 for T90 ≥ 13% vs < 0.01%; P = .02). On stratified analyses, the association between T90 and cancer appeared stronger in older patients with obesity and no adequate OSA therapy. Among the most frequent cancer sites, nocturnal hypoxemia was associated with lung and breast malignancies. INTERPRETATION: Nocturnal hypoxemia was associated with all-cancer incidence in patients investigated for OSA. Whether OSA therapy might reduce the risk of cancer needs further evaluation.
Assuntos
Hipóxia , Neoplasias , Oxigênio/sangue , Polissonografia , Apneia Obstrutiva do Sono , Estudos de Coortes , Correlação de Dados , Feminino , França/epidemiologia , Humanos , Hipóxia/diagnóstico , Hipóxia/etiologia , Incidência , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Neoplasias/epidemiologia , Neoplasias/patologia , Polissonografia/métodos , Polissonografia/estatística & dados numéricos , Modelos de Riscos Proporcionais , Fatores de Risco , Índice de Gravidade de Doença , Apneia Obstrutiva do Sono/sangue , Apneia Obstrutiva do Sono/diagnóstico , Apneia Obstrutiva do Sono/epidemiologia , Apneia Obstrutiva do Sono/fisiopatologiaRESUMO
BACKGROUND: Osimertinib, a third-generation tyrosine kinase inhibitor, is a new therapeutic option in epidermal growth factor receptor (EGFR)-mutated non-pretreated advanced non-small-cell lung cancer (NSCLC). The tumor escape mechanisms after first-line treatment with osimertinib are partially known; most of the data being obtained by analysis of circulating tumor DNA (ctDNA) from the FLAURA phase III trial. STUDY DESIGN: The MELROSE study, a French multicentric, open label, phase II trial (ClinicalTrials.govNCT03865511) plans to enroll 150 patients with treatment-naive advanced EGFR-mutated (L858R or exon 19 deletion) NSCLC, age ≥ 18 years, with an Eastern Cooperative Oncology Group performance status 0 or 1. All patients will receive osimertinib at the dose of 80 mg/d. Tumor assessment according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria will be performed every 3 months, with brain and thoracoabdominal computed tomographic scan. The continuation of osimertinib is at the discretion of the referring physician, particularly if clinical benefit is observed. The primary objective is the genetic tumor profile, both on tissue biopsy and ctDNA analyses, at the time of disease progression. Other endpoints include kinetic studies of ctDNA, biological progression-free survival (bPFS) (time from first study dose to first biological event on ctDNA), median PFS according to RECIST criteria 1.1 (called radiological [r] PFS), and median clinical (c) PFS (time from the first study dose to off-osimertinib). This study started in April 2019, and 18 centers in France are participants.
Assuntos
Acrilamidas/administração & dosagem , Compostos de Anilina/administração & dosagem , DNA Tumoral Circulante/genética , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Acrilamidas/farmacologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina/farmacologia , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Biópsia , DNA Tumoral Circulante/sangue , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , França , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Resultado do Tratamento , Adulto JovemRESUMO
INTRODUCTION: A multicenter randomized clinical trial in France found an overall survival benefit of web-based patient-reported outcome (PRO)-based surveillance after initial treatment for lung cancer compared with conventional surveillance. The aim of this study was to assess the cost-effectiveness of this PRO-based surveillance in lung cancer patients. METHODS: This medico-economic analysis used data from the clinical trial, augmented by abstracted chart data and costs of consultations, imaging, transportations, information technology, and treatments. Costs were calculated based on actual reimbursement rates in France, and health utilities were estimated based on scientific literature review. Willingness-to-pay thresholds of 30,000 per quality-adjusted life year (QALY) and 90,000 per QALY were used to define a very cost-effective and cost-effective strategy, respectively. Average annual costs of experimental and control surveillance approaches were calculated. The incremental cost-effectiveness ratio was expressed as cost per life-year gained and QALY gained, from the health insurance payer perspective. One-way and multivariate probabilistic sensitivity analyses were performed. RESULTS: Average annual cost of surveillance follow-up was 362 lower per patient in the PRO arm (941/year/patient) compared to control (1,304/year/patient). The PRO approach presented an incremental cost-effectiveness ratio of 12,127 per life-year gained and 20,912 per QALY gained. The probabilities that the experimental strategy is very cost-effective and cost-effective were 97% and 100%, respectively. CONCLUSIONS: Surveillance of lung cancer patients using web-based PRO reduced the follow-up costs. Compared to conventional monitoring, this surveillance modality represents a cost-effective strategy and should be considered in cancer care delivery.
Assuntos
Internet , Neoplasias Pulmonares/economia , Neoplasias Pulmonares/terapia , Medidas de Resultados Relatados pelo Paciente , Ensaios Clínicos Controlados Aleatórios como Assunto/economia , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Análise Custo-Benefício , França/epidemiologia , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Estudos Multicêntricos como Assunto/economia , Estudos Multicêntricos como Assunto/métodos , Estadiamento de Neoplasias , Resultado do TratamentoRESUMO
BACKGROUND: Immune checkpoint inhibitors (ICI) target T cell inhibitory pathways that are responsible for cancer tolerance by down-modulating immune functions. ICI have revolutionized patients care with lung cancer. Nevertheless, restoring endogenous antitumor T-cell responses can induce immune related adverse events, such as sarcoidosis. CASE PRESENTATION: We report here the first case of a thoracic and cutaneous sarcoid-like reaction in a patient with a relapsing unresectable non-small cell lung cancer (NSCLC) treated with nivolumab, an anti-PD-1 mAb. The expression of PD-1 and its ligands, PD-L1 and PD-L2, was assessed by flow cytometry on peripheral blood mononuclear cells (PBMC) and compared to patients who had discontinued nivolumab therapy without having developed any immune related adverse events. PD-L1 expression was transiently increased on B cells, T cells and monocytes, whereas PD-L2 expression was not modulated. PD-1 was transiently undetectable when PD-L1 was maximal, before returning to basal level. Sarcoidosis spontaneously resolved, without corticotherapy. CONCLUSION: This case sheds the light on a complex regulation of PD-L1 expression in vivo on PBMC after nivolumab arrest and triggers the question of monitoring the expression of immune checkpoint on immune cells during and after treatment with ICI.
Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Nivolumabe/efeitos adversos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Sarcoidose/induzido quimicamente , Dermatopatias/induzido quimicamente , Antígeno B7-H1/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Feminino , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Neoplasias Pulmonares/imunologia , Linfonodos/efeitos dos fármacos , Linfonodos/patologia , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/imunologia , Sarcoidose/patologia , Pele/efeitos dos fármacos , Pele/patologia , Dermatopatias/patologia , TóraxRESUMO
BACKGROUND: Clinical experience suggests that lung cancer (LC) is associated with sleep disturbances that may contribute to impaired daytime functioning and quality of life. Using questionnaires and home actigraphic recordings, we tried to determine whether sleep quality and daytime alertness are impaired in patients with newly diagnosed LC. PATIENTS AND METHODS: Twenty-nine outpatients with newly diagnosed LC and an Eastern Cooperative Oncology Group performance status =2 and 14 age- and sex-matched non-cancer (NC) patients with successfully treated sleep apnea were enrolled in the study. Sleep quality was assessed by the Pittsburgh Sleep Quality Index (PSQI) and by night actigraphic data. Daytime alertness was assessed by the Epworth Sleepiness Scale (ESS) and day actigraphic data. The medical outcomes study 36-item short form (SF-36) was used for quality of life assessment. RESULTS: LC patients had higher PSQI (9.6+/-3.7 versus 5.6+/-3.2; p<0.001) and higher ESS (8.6+/-3.7 versus 5.6+/-3.2; p=0.01) than NC patients indicating worse quality of sleep and more excessive daytime sleepiness. Both physical and mental components score of SF-36 were lower in LC patients (p<0.001) indicating lower quality of life. Wrist actigraphy data showed significantly lower sleep efficiency and a higher sleep fragmentation during the night and lower mean activity during the day in LC patients. CONCLUSIONS: Patients with newly diagnosed LC and performance status =2 present marked sleep disturbances, excessive daytime sleepiness and impaired quality of life. Further studies are required to determine the etiologic factors of sleep disturbances in LC patients and the impact of pharmacologic and non-pharmacologic interventions on sleep and daytime functioning.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma de Células Pequenas/complicações , Neoplasias Pulmonares/complicações , Distúrbios do Início e da Manutenção do Sono/etiologia , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/fisiopatologia , Carcinoma Pulmonar de Células não Pequenas/psicologia , Carcinoma de Células Pequenas/diagnóstico , Carcinoma de Células Pequenas/fisiopatologia , Carcinoma de Células Pequenas/psicologia , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/fisiopatologia , Neoplasias Pulmonares/psicologia , Pacientes Ambulatoriais , Qualidade de Vida , Índice de Gravidade de Doença , Síndromes da Apneia do Sono/etiologia , Síndromes da Apneia do Sono/psicologia , Distúrbios do Início e da Manutenção do Sono/psicologia , Inquéritos e Questionários , Análise e Desempenho de TarefasRESUMO
Two types of immune checkpoint inhibitors, both antibodies that target cytotoxic T-lymphocyte antigen-4 and those that target programmed cell death-protein 1, have been approved for use in melanoma, non-small-cell lung cancer, and renal cell carcinoma as first-line or second-line therapy. Their adverse events are primarily regarded as immune-related adverse events. We felt it was important to pinpoint and discuss certain preconceptions or misconceptions regarding thyroid dysfunction, hypophysitis, and diabetes induced by immune checkpoint inhibitors. We have identified areas of uncertainty and unmet requirements, including essential interaction between endocrinologists and oncologists. Five issues have been identified for discussion: (1) diagnosis of endocrine toxicity, (2) assessment of toxicity severity, (3) treatment of toxicity, (4) withdrawal or continuation of immunotherapy, (5) preventive action.
Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Sistema Endócrino/efeitos dos fármacos , Imunomodulação/efeitos dos fármacos , Anticorpos Monoclonais/efeitos adversos , Antígeno B7-H1/antagonistas & inibidores , Biomarcadores Tumorais , Antígeno CTLA-4/antagonistas & inibidores , Tomada de Decisão Clínica , Gerenciamento Clínico , Doenças do Sistema Endócrino/diagnóstico , Doenças do Sistema Endócrino/etiologia , Doenças do Sistema Endócrino/prevenção & controle , Doenças do Sistema Endócrino/terapia , Endocrinologistas , Humanos , Imunoterapia , Comunicação Interdisciplinar , Oncologistas , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Índice de Gravidade de DoençaRESUMO
Lipid nanocapsules (LNCs) are potential drug carriers for pulmonary delivery since they can be nebulized without any structural or functional changes, and the aerosols produced are highly compatible with pulmonary drug delivery in human beings. The alveolar surface tension, in vitro cytotoxicity, biodistribution and pulmonary toxicity in rats of a single endotracheal spray of LNCs or paclitaxel-loaded LNCs were studied. In vitro cytotoxicity of LNCs after a spray remained unchanged. Biodistribution study showed a homogeneous repartition in the lungs in rats with an improvement in lung retention of the radiolabeled tracer loaded in LNCs compared to the absence of LNCs with a lung half-time of 8.8±0.7 hours. Bronchoalveolar fluid analysis revealed transient 7-day alveolar inflammation, reaching a maximum between days 2 and 4, characterized by a peak of granulocytes at day 1 followed by a peak of lymphocytes at day 3. Alveolar protein levels were increased at days 3 and 7. Acute inflammation was increased with paclitaxel-loaded LNCs in comparison with blank LNCs but dropped out at day 7. No histological pulmonary lesion was observed at day 60. LNCs lowered surface tension to a greater degree than Curosurf® in a physicochemical model of the pulmonary alveolus. A single pulmonary delivery of LNCs induces a short-term alveolar inflammation with no residual lesions in rats at day 60. These data permit to start the study of LNCs in surfactant replacement therapy.