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PURPOSE: Pneumocystis jirovecii pneumonia (PJP) prophylaxis is required by provincial and national drug monographs during glioma treatment using temozolomide (TMZ) concurrently with radiation (TMZ-RT). However, real-world data suggest the potential benefits of PJP prophylaxis may not outweigh its potential harms in this population. METHODS: We conducted a single-center patient survey and a national physician survey to explore the role of PJP prophylaxis amongst glioma patients undergoing TMZ-RT. RESULTS: 23% (31/133) of physicians and 60% (44/73) of patients completed a survey. The median patient age was 42 (range 20-77); 85% (34/40) had completed adjuvant TMZ. Although only 2.4% (1/41) of patients received PJP prophylaxis, only one person (without PJP prophylaxis) was hospitalized for pneumonia. When presented with hypothetical PJP risks, 13.2% (5/38) of patients were concerned about PJP infection, while 26% (10/38) were concerned about potential side effects from prophylactic antibiotics. Most physicians (77%, 17/22) perceived the evidence for PJP prophylaxis as weak; 58% (11/19) did not routinely prescribe prophylaxis, and 73% (16/22) felt that PJP prophylaxis should be limited to patients with additional risk factors. Over 95% of physicians estimated that the incidence of PJP was < 1% in their last 5 years of practice regardless of PJP prophylaxis. For 73% (16/22) of physicians, to prescribe PJP prophylaxis, the risk of PJP infection needed to be 3-8%. CONCLUSION: The current recommendation to routinely prescribe PJP prophylaxis in patients receiving TMZ-RT in the absence of other risk factors warrants reconsideration.
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Antineoplásicos Alquilantes , Neoplasias Encefálicas , Glioma , Pneumocystis carinii , Pneumonia por Pneumocystis , Temozolomida , Humanos , Temozolomida/uso terapêutico , Pessoa de Meia-Idade , Glioma/radioterapia , Glioma/complicações , Pneumonia por Pneumocystis/prevenção & controle , Masculino , Feminino , Adulto , Idoso , Antineoplásicos Alquilantes/uso terapêutico , Antineoplásicos Alquilantes/efeitos adversos , Adulto Jovem , Neoplasias Encefálicas/radioterapia , Inquéritos e Questionários , Médicos , Quimiorradioterapia/efeitos adversos , AntibioticoprofilaxiaRESUMO
BACKGROUND: Standard treatment for patients with newly diagnosed glioblastoma includes surgery, radiotherapy (RT) and temozolomide (TMZ) chemotherapy (TMZ/RTâTMZ). The proteasome has long been considered a promising therapeutic target because of its role as a central biological hub in tumor cells. Marizomib is a novel pan-proteasome inhibitor that crosses the blood brain barrier. METHODS: EORTC 1709/CCTG CE.8 was a multicenter, randomized, controlled, open label phase 3 superiority trial. Key eligibility criteria included newly diagnosed glioblastoma, age > 18 years and Karnofsky performance status > 70. Patients were randomized in a 1:1 ratio. The primary objective was to compare overall survival (OS) in patients receiving marizomib in addition to TMZ/RTâTMZ with patients receiving only standard treatment in the whole population, and in the subgroup of patients with MGMT promoter-unmethylated tumors. RESULTS: The trial was opened at 82 institutions in Europe, Canada and the US. A total of 749 patients (99.9% of planned 750) were randomized. OS was not different between the standard and the marizomib arm (median 17 vs 16.5 months; HR=1.04; p=0.64). PFS was not statistically different either (median 6.0 vs. 6.3 months; HR=0.97; p=0.67). In patients with MGMT promoter-unmethylated tumors, OS was also not different between standard therapy and marizomib (median 14.5 vs 15.1 months, HR=1.13; p=0.27). More CTCAE grade 3/4 treatment-emergent adverse events were observed in the marizomib arm than in the standard arm. CONCLUSIONS: Adding marizomib to standard temozolomide-based radiochemotherapy resulted in more toxicity, but did not improve OS or PFS in patients with newly diagnosed glioblastoma.
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Circulating tumor DNA (ctDNA) has shown promise in capturing primary resistance to immunotherapy. BR.36 is a multi-center, randomized, ctDNA-directed, phase 2 trial of molecular response-adaptive immuno-chemotherapy for patients with lung cancer. In the first of two independent stages, 50 patients with advanced non-small cell lung cancer received pembrolizumab as standard of care. The primary objectives of stage 1 were to ascertain ctDNA response and determine optimal timing and concordance with radiologic Response Evaluation Criteria in Solid Tumors (RECIST) response. Secondary endpoints included the evaluation of time to ctDNA response and correlation with progression-free and overall survival. Maximal mutant allele fraction clearance at the third cycle of pembrolizumab signified molecular response (mR). The trial met its primary endpoint, with a sensitivity of ctDNA response for RECIST response of 82% (90% confidence interval (CI): 52-97%) and a specificity of 75% (90% CI: 56.5-88.5%). Median time to ctDNA response was 2.1 months (90% CI: 1.5-2.6), and patients with mR attained longer progression-free survival (5.03 months versus 2.6 months) and overall survival (not reached versus 7.23 months). These findings are incorporated into the ctDNA-driven interventional molecular response-adaptive second stage of the BR.36 trial in which patients at risk of progression are randomized to treatment intensification or continuation of therapy. ClinicalTrials.gov ID: NCT04093167 .
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Anticorpos Monoclonais Humanizados , Intervalo Livre de ProgressãoRESUMO
[This corrects the article DOI: 10.3389/fonc.2021.671972.].
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PURPOSE: Antitumor activity in preclinical models and a phase I study of patients with dedifferentiated liposarcoma (DD-LPS) was observed with selinexor. We evaluated the clinical benefit of selinexor in patients with previously treated DD-LPS whose sarcoma progressed on approved agents. METHODS: SEAL was a phase II-III, multicenter, randomized, double-blind, placebo-controlled study. Patients age 12 years or older with advanced DD-LPS who had received two-five lines of therapy were randomly assigned (2:1) to selinexor (60 mg) or placebo twice weekly in 6-week cycles (crossover permitted). The primary end point was progression-free survival (PFS). Patients who received at least one dose of study treatment were included for safety analysis (ClinicalTrials.gov identifier: NCT02606461). RESULTS: Two hundred eighty-five patients were enrolled (selinexor, n = 188; placebo, n = 97). PFS was significantly longer with selinexor versus placebo: hazard ratio (HR) 0.70 (95% CI, 0.52 to 0.95; one-sided P = .011; medians 2.8 v 2.1 months), as was time to next treatment: HR 0.50 (95% CI, 0.37 to 0.66; one-sided P < .0001; medians 5.8 v 3.2 months). With crossover, no difference was observed in overall survival. The most common treatment-emergent adverse events of any grade versus grade 3 or 4 with selinexor were nausea (151 [80.7%] v 11 [5.9]), decreased appetite (113 [60.4%] v 14 [7.5%]), and fatigue (96 [51.3%] v 12 [6.4%]). Four (2.1%) and three (3.1%) patients died in the selinexor and placebo arms, respectively. Exploratory RNA sequencing analysis identified that the absence of CALB1 expression was associated with longer PFS with selinexor compared with placebo (median 6.9 v 2.2 months; HR, 0.19; P = .001). CONCLUSION: Patients with advanced, refractory DD-LPS showed improved PFS and time to next treatment with selinexor compared with placebo. Supportive care and dose reductions mitigated side effects of selinexor. Prospective validation of CALB1 expression as a predictive biomarker for selinexor in DD-LPS is warranted.
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Hidrazinas , Lipossarcoma , Triazóis , Criança , Método Duplo-Cego , Humanos , Hidrazinas/efeitos adversos , Lipossarcoma/tratamento farmacológico , Lipossarcoma/patologia , Triazóis/efeitos adversosRESUMO
AIM: Conduct a systematic review of the effectiveness of systemic therapies for adult recurrent glioblastoma (rGBM). METHODS: We electronically searched for randomized controlled trials from three major databases and four conferences from 2009-Dec 2020. Two independent reviewers conducted screening, data extraction, and quality assessment. RESULTS: 48 randomized trials were identified. Outcome reporting was inconsistent: overall survival (OS) in 46 studies, progression free survival in 37 studies, 6-month PFS in 30 studies, objective response rate in 28 studies, and 6-month OS in 7 studies. Network meta-analysis was not feasible due to heterogeneity in outcome reporting and single-study linkages. Most studies compared lomustine (8 studies), bevacizumab (18), or temozolomide (8) with other treatments. The median OS across all studies ranged from 3 to 17.6 months. CONCLUSIONS: Based on level one evidence, there is no superior systemic regimen for rGBM. rGBM is a heterogeneous population with no single regimen demonstrating OS benefit. Registration number: CRD42020148512.
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Neoplasias Encefálicas , Glioblastoma , Adulto , Bevacizumab , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Intervalo Livre de Progressão , Ensaios Clínicos Controlados Aleatórios como Assunto , TemozolomidaRESUMO
BACKGROUND: Glioblastoma (GBM) is known to use both local and systemic immunosuppressive strategies. One such strategy is the expression of the immune checkpoint protein programmed cell death ligand-1 (PD-L1) by both tumor cells and tumor-associated immune cells. Recent phase III trials using IgG4 antibodies targeting PD-1, the ligand for PD-L1, failed to show any benefit. Avelumab is an IgG1 monoclonal antibody targeting PD-L1. In contrast to the previously tested immune checkpoint inhibitors, it can directly bind tumor cells and immune cells expressing PD-L1 and can induce antibody-dependent cellular cytotoxicity. METHODS: We conducted a single center, open label, phase II study where avelumab 10 mg/kg IV Q2W was added concurrently to the first monthly temozolomide cycle in patients with newly diagnosed GBM. Immunohistochemical analyses were performed on surgery samples. The primary objective was safety. Secondary objectives were efficacy outcomes according to the immunotherapy Response Assessment in Neuro Oncology criteria, progression free survival (PFS), and overall survival (OS). Exploratory objectives aimed at determining prognostic biomarkers. RESULTS: Thirty patients were started on therapy and two were lost to follow-up. Median follow-up time (reverse Kaplan-Meier) was 41.7 months (IQR: 28.3-43.4). Three (10.0%) patients had a related or possibly related treatment emergent adverse event that lead to transient or permanent discontinuation of avelumab. Eight (26.7%) patients had one or more immune-related adverse events, and 8 (26.7%) patients had an infusion-related reaction. The overall response rate was 23.3%, median PFS was 9.7 months, and the median OS was 15.3 months. No pretreatment biomarkers showed any predictive value. CONCLUSIONS: The addition of avelumab to standard therapy in patients with GBM was not associated with any new safety signal. There was no apparent improvement in OS. TRIAL REGISTRATION: NCT03047473 Registered February 9, 2017.
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BACKGROUND: Understudied elderly patients comprise a large segment of high-risk patients with glioblastoma (GBM) that are challenging to treat. Tumor Treating Fields (TTFields) is a locoregional, noninvasive, antimitotic therapy delivering low-intensity, intermediate-frequency alternating electric fields to the tumor. In the phase 3 EF-14 clinical trial, TTFields (200 kHz) improved median progression-free survival (PFS) and median overall survival (OS) in patients with newly diagnosed GBM (ndGBM) when added concomitantly to maintenance temozolomide (TMZ). This EF-14 subgroup analysis evaluated the safety and efficacy of TTFields in elderly patients. METHODS: All 134 patients who are ≥65 years of age were included (TTFields/TMZ combination, n=89; TMZ monotherapy, n=45; 2:1 ratio of randomization). PFS and OS were analyzed using Kaplan-Meier methodology (α=0.05). Health-related quality-of-life (HRQoL) was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) quality-of-life questionnaire QLQ-C30 supplemented with the brain tumor module (QLQ-BN20). Adverse events (AEs) were evaluated using Common Terminology Criteria for AEs (CTCAE) v4.0. RESULTS: The PFS was 6.5 months in patients randomized to the treatment group with TTFields/TMZ combination versus 3.9 months in patients treated with TMZ monotherapy (HR, 0.47; 95% CI, 0.30-0.74; P=0.0236). The OS was 17.4 months in patients treated with TTFields/TMZ combination versus 13.7 months in patients treated with TMZ monotherapy (HR, 0.51; 95% CI, 0.33-0.77; P=0.0204). Annual survival rates with TTFields/TMZ versus TMZ monotherapy were 39% (95% CI, 29-50%) versus 27% (95% CI, 15-41%; P=0.072) at 2 years, 19% (95% CI, 11-29%) versus 11% (95% CI, 4-23%; P=0.135) at 3 years, and 15% (95% CI, 7-25%) versus 0% at 5 years, respectively. There were no significant differences between groups in the preselected items of HRQoL assessment. Grade ≥3 systemic AEs were 46% in the TTFields/TMZ group versus 40% in the TMZ monotherapy group, without statistically significant difference between the two groups. The only TTFields-related AEs were reversible scalp skin reactions, with grades 1-2 and grade 3 skin reactions reported by 51% and 2% of patients, respectively. CONCLUSIONS: Combining TTFields with maintenance TMZ significantly improved PFS and OS in elderly patients with ndGBM in the phase 3 EF-14 clinical trial, without significant increases in systemic toxicity or negatively affecting patient HRQoL. TTFields-related skin AEs were low-grade and manageable. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT00916409, identifier: NCT00916409.
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BACKGROUND: A successful lung cancer screening program requires a patient cohort at sufficient risk of developing cancer who are willing to participate. Among other factors, a patient's lung cancer risk perception may inform their attitudes toward screening and smoking cessation programs. RESEARCH QUESTION: This study analyzed data from the Pan-Canadian Early Detection of Lung Cancer (PanCan) Study to address the following questions: Which factors are associated with the perception of lung cancer risk? Is there an association between risk perception for lung cancer and actual calculated risk? Is there an association between risk perception for lung cancer and the intent to quit smoking? Are there potential targets for lung cancer screening awareness? STUDY DESIGN AND METHODS: The PanCan study recruited current or former smokers aged 50 to 75 years who had at least a 2% risk of developing lung cancer over 6 years to undergo low-dose screening CT. Risk perception and worry about lung cancer were captured on a baseline questionnaire. Cumulative logistic regression analysis was used to assess the relationship between baseline risk variables and both lung cancer risk perception and worry. RESULTS: Among the 2,514 individuals analyzed, a higher perceived risk of lung cancer was positively associated with calculated risk (P = .032). Younger age, being a former smoker, respiratory symptoms, lower FEV1, COPD, and a family history of lung cancer were associated with higher perceived risk. Conversely, a consistent relationship between calculated risk and worry was not identified. There was a positive association between risk perception and lung cancer worry and reported intent to quit smoking. INTERPRETATION: Individuals' lung cancer risk perception correlated positively with calculated risk in a screening population. Promotion of screening programs may benefit from focusing on factors associated with higher risk perception; conversely, harnessing worry seemingly holds less value.
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Atitude Frente a Saúde , Neoplasias Pulmonares/diagnóstico , Programas de Rastreamento , Participação do Paciente , Idoso , Canadá , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fumantes , Abandono do Hábito de Fumar/psicologiaRESUMO
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is an underdiagnosed condition sharing risk factors with lung cancer. Lung cancer screening may provide an opportunity to improve COPD diagnosis. Using Pan-Canadian Early Detection of Lung Cancer (PanCan) study data, the present study sought to determine the following: 1) What is the prevalence of COPD in a lung cancer screening population? 2) Can a model based on clinical and screening low-dose CT scan data predict the likelihood of COPD? METHODS: The single arm PanCan study recruited current or former smokers age 50-75 who had a calculated risk of lung cancer of at least 2% over 6 years. A baseline health questionnaire, spirometry, and low-dose CT scan were performed. CT scans were assessed by a radiologist for extent and distribution of emphysema. With spirometry as the gold standard, logistic regression was used to assess factors associated with COPD. RESULTS: Among 2514 recruited subjects, 1136 (45.2%) met spirometry criteria for COPD, including 833 of 1987 (41.9%) of those with no prior diagnosis, 53.8% of whom had moderate or worse disease. In a multivariate model, age, current smoking status, number of pack-years, presence of dyspnea, wheeze, participation in a high-risk occupation, and emphysema extent on LDCT were all statistically associated with COPD, while the overall model had poor discrimination (c-statistic = 0.627 (95% CI of 0.607 to 0.650). The lowest and the highest risk decile in the model predicted COPD risk of 27.4 and 65.3%. CONCLUSIONS: COPD had a high prevalence in a lung cancer screening population. While a risk model had poor discrimination, all deciles of risk had a high prevalence of COPD, and spirometry could be considered as an additional test in lung cancer screening programs. TRIAL REGISTRATION: (Clinical Trial Registration: ClinicalTrials.gov, number NCT00751660 , registered September 12, 2008).
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Neoplasias Pulmonares/diagnóstico por imagem , Programas de Rastreamento/métodos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Fumar/efeitos adversos , Idoso , Canadá/epidemiologia , Detecção Precoce de Câncer , Enfisema/diagnóstico por imagem , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Enfisema Pulmonar/complicações , Fatores de Risco , Espirometria , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Recruitment to clinical trials is suboptimal, increasing costs, and delaying the potential implementation of clinical advances. Among other barriers, the lack of marketing experience among trialists may limit recruitment. In this observational study, in the context of the Pan-Canadian Early Detection of Lung Cancer Trial, we assessed the value of a motivational survey of study participants in planning a tailored advertising campaign and analysed the value of individual components of advertising in generating telephone calls to the study and recruited subjects. METHODS: The Pan-Canadian Early Detection of Lung Cancer Trial was a single arm study assessing risk modelling for lung cancer screening by low-dose computed tomography scan and autofluorescence bronchoscopy. Individuals were recruited to eight sites across Canada without a central marketing plan. On contact with the study, individuals reported how they heard about the study according to a predefined list. One site, the Juravinski Cancer Centre, worked with a marketing expert to develop a survey to assess participant motivations, source of study awareness, and personal habits. The survey was used to develop a media campaign for recruitment. Media events were collected from all sites. The primary analysis assessed the number of telephone contacts and recruited subjects associated with various media factors. Individual print media characteristics were assessed for their effect on recruitment. RESULTS: At all sites, 7059 individuals contacted the study, and 2537 were eligible and recruited. Among 52 individuals completing the Juravinski Cancer Centre survey, motivation included concern for personal risk of lung cancer (71%), followed by desire to contribute to a cure (67%), followed by personal knowledge of a person with lung cancer (50%). Most reported hearing of the study from the newspaper (58%) despite no print ad yet being distributed. With survey input, a newsprint campaign was executed. The number of media events varied by site (median: 13, range: 3-28). Among all recruits, 56.4% reported referral by newspaper followed by family/friend (14%). Telephone contacts and recruited subjects per event varied significantly by site, while unpaid media events appeared superior to paid events. Print media characteristics associated with increased telephone contacts and recruitment included use of a rational appeal (vs a mixed rational-emotional), less use of white space, and larger headline font. CONCLUSION: A survey of trial candidates provides useful information regarding personal motivation, media use, and lifestyle. Unpaid media events appear superior in generating recruitment, while print media may be superior to radio and television in selecting eligible recruits. The utility of individual print media characteristics appears to differ from the commercial advertising literature. Further research on marketing in clinical trials is encouraged to improve recruitment ( ClinicalTrials.gov registration: NCT00751660, https://clinicaltrials.gov/ct2/show/NCT00751660 ).
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Ensaios Clínicos como Assunto/métodos , Detecção Precoce de Câncer/métodos , Neoplasias Pulmonares/terapia , Marketing , Seleção de Pacientes , Idoso , Canadá , Feminino , Humanos , Masculino , Meios de Comunicação de Massa , Pessoa de Meia-Idade , Motivação , Participação do Paciente , Medição de Risco , Inquéritos e QuestionáriosRESUMO
INTRODUCTION: Activation of the RAS/RAF/MEK/ERK pathway may confer resistance to chemotherapy in non-small cell lung cancer (NSCLC). Selumetinib (AZD6244, ARRY142886), a MEK1/2 inhibitor combined with chemotherapy in patients with NSCLC was evaluated in two schedules to evaluate efficacy and toxicity. METHODS: IND.219 was a three-arm study of first line pemetrexed/platinum chemotherapy with two schedules of selumetinib (Arm A: intermittent given on days 2-19; Arm B: continuous given on days 1-21) versus chemotherapy alone (Arm C). The primary endpoint was objective response rate (ORR); secondary objectives were tolerability, progression-free survival (PFS), overall survival (OS). The trial was stopped at the planned interim analysis. RESULTS: Arms A/B/C enrolled 20/21/21 patients, ORR was 35% (95% CI 15-59% median duration 3.8 months), 62% (95% CI 38-82%; median duration 6.3 months), 24% (95% CI 8-47%; median duration 11.6 months) respectively. The PFS (months Arm A, B, C) was 7.5, 6.7, 4.0 respectively (hazard ratio (HR) PFS Arm A over Arm C: 0.76 [95% CI, 0.38-1.51, 2-sided p = 0.42]; Arm B over Arm C 0.75 [95% CI 0.37-1.54, p = 0.43]. Skin and gastrointestinal adverse events were more common with the addition of selumetinib. A high incidence of venous thromboembolism was seen in all arms. CONCLUSIONS: Selumetinib combined with chemotherapy was associated with a higher response rate. Continuous selumetinib appeared to be superior to an intermittent schedule. PFS was prolonged with the addition of selumetinib, however this was not statistically significant.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzimidazóis/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Pemetrexede/uso terapêutico , Compostos de Platina/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Canadá , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Proteínas Proto-Oncogênicas p21(ras)/genética , Análise de SobrevidaRESUMO
BACKGROUND: Most newly diagnosed advanced NSCLC patients have an initial medical oncology consult as an outpatient. Sometimes, the initial consult occurs as an inpatient. We explored differences among NSCLC patients presenting to medical oncology while hospitalized versus as outpatients. METHODS: With ethics approval, we performed a retrospective analysis of all stage IIIB and IV NSCLC patients at our institution consulted by medical oncology between 2009 and 2012. The primary analysis is descriptive, exploring differences in baseline characteristics, treatment choices, and overall survival (OS). RESULTS: In total, 637 patients were included: 123 inpatients and 514 outpatients. Among outpatients, 55% received systemic therapy compared to 21% of inpatients. Among treated patients, inpatients were likely to be younger (81% vs 70% <70 years, pâ¯=â¯0.04), have PS 3-4 (38% vs 5%, p<0.001), have ≥5% weight loss (54% vs 42%, pâ¯=â¯0.01), anemia (19% vs 4%, pâ¯=â¯0.001), leukocytosis (38% vs 32%, pâ¯=â¯0.001), thrombocytosis (27â¯vs 23%, pâ¯=â¯0.001), renal dysfunction (12% vs 5%, pâ¯=â¯0.01) and more rapid onset of symptoms (27% vs 6% for <2 weeks, 35% vs 11% for 2-6 weeks; p<0.001). Inpatients who received systemic therapy were more likely to have a complete or partial response (42% vs 26%, pâ¯=â¯0.007), however had a shorter median OS than treated outpatients (8.4â¯vs 10.5 months, pâ¯=â¯0.003). CONCLUSIONS: Patients initially consulted by medical oncologists while hospitalized were more unwell and fewer received systemic therapy. However, if treated, they had higher response rates than outpatients and reasonable OS. Systemic therapy can be considered in hospitalized advanced NSCLC patients. MICROABSTRACT: A minority of patients with lung cancer have an initial oncology consultation as an inpatient. We compared the characteristics and outcomes of inpatients with their outpatient counterparts. Inpatients were more unwell at diagnosis and fewer received systemic therapy, but among those who did, they were more likely to respond and their overall survival approached that of the outpatient cohort.
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Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma de Células Escamosas/mortalidade , Hospitalização/tendências , Pacientes Internados/estatística & dados numéricos , Neoplasias Pulmonares/mortalidade , Pacientes Ambulatoriais/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Encaminhamento e Consulta , Estudos Retrospectivos , Taxa de Sobrevida , Adulto JovemRESUMO
OBJECTIVES: The impact of lung cancer screening with low-dose chest CT (LDCT) on participants' anxiety levels and health-related quality of life (HRQoL) is an important consideration in the implementation of such programmes. We aimed to describe changes in anxiety and HRQoL in a high-risk Canadian cohort undergoing LDCT lung cancer screening. METHODS: 2537 subjects who had 2% or greater lung cancer risk over 6 years using a risk prediction tool were recruited from eight centres across Canada in the Pan-Canadian Early Detection of Lung Cancer Study (2008-2010). We compared HRQoL and anxiety levels before and after screening of 1237 participants with LDCT (excluding a subset of 1300 participants who also underwent autofluorescence bronchoscopy screening), as well as after investigations performed because of a positive screening examination. The 12-item short-form Physical and Mental Component Scales (SF-12), EQ-5D-3L scores and State Trait Anxiety Inventory-State anxiety were used at each assessment. RESULTS: Overall, there were no clinically significant differences in HRQoL outcomes between baseline and each of the survey time points following initial screening. No mean change in anxiety in the overall cohort was noted following baseline LDCT, but more participants had clinically significant increase in anxiety versus decrease after baseline screening (increase >minimal clinically important difference (MCID) (n=180) vs decrease >MCID (n=50), p<0.001). This finding persisted but to a lesser degree at the 12 month time point (increase >MCID (n=146) vs decrease >MCID (n=87), p<0.001). CONCLUSIONS: CT screening for lung cancer has no major overall impact on HRQoL among participants, although a minority of participants (number-needed-to-harm=7 after baseline screening and 18 at 1 year) demonstrated clinically significant increased anxiety levels. TRIALREGISTRATION NUMBER: NCT00751660; Results.
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Ansiedade/psicologia , Detecção Precoce de Câncer/psicologia , Neoplasias Pulmonares/diagnóstico , Qualidade de Vida/psicologia , Idoso , Canadá , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição de Risco , Tomografia Computadorizada por Raios XRESUMO
PURPOSE: Constitutional mismatch repair deficiency (CMMRD) is a highly penetrant cancer predisposition syndrome caused by biallelic mutations in mismatch repair (MMR) genes. As several cancer syndromes are clinically similar, accurate diagnosis is critical to cancer screening and treatment. As genetic diagnosis is confounded by 15 or more pseudogenes and variants of uncertain significance, a robust diagnostic assay is urgently needed. We sought to determine whether an assay that directly measures MMR activity could accurately diagnose CMMRD. PATIENTS AND METHODS: In vitro MMR activity was quantified using a 3'-nicked G-T mismatched DNA substrate, which requires MSH2-MSH6 and MLH1-PMS2 for repair. We quantified MMR activity from 20 Epstein-Barr virus-transformed lymphoblastoid cell lines from patients with confirmed CMMRD. We also tested 20 lymphoblastoid cell lines from patients who were suspected for CMMRD. We also characterized MMR activity from patients with neurofibromatosis type 1, Li-Fraumeni syndrome, polymerase proofreading-associated cancer syndrome, and Lynch syndrome. RESULTS: All CMMRD cell lines had low MMR activity (n = 20; mean, 4.14 ± 1.56%) relative to controls (n = 6; mean, 44.00 ± 8.65%; P < .001). Repair was restored by complementation with the missing protein, which confirmed MMR deficiency. All cases of patients with suspected CMMRD were accurately diagnosed. Individuals with Lynch syndrome (n = 28), neurofibromatosis type 1 (n = 5), Li-Fraumeni syndrome (n = 5), and polymerase proofreading-associated cancer syndrome (n = 3) had MMR activity that was comparable to controls. To accelerate testing, we measured MMR activity directly from fresh lymphocytes, which yielded results in 8 days. CONCLUSION: On the basis of the current data set, the in vitro G-T repair assay was able to diagnose CMMRD with 100% specificity and sensitivity. Rapid diagnosis before surgery in non-neoplastic tissues could speed proper therapeutic management.
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Biomarcadores Tumorais/genética , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Reparo de Erro de Pareamento de DNA , Enzimas Reparadoras do DNA/genética , Testes Genéticos , Mutação , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/metabolismo , Estudos de Casos e Controles , Linhagem Celular Tumoral , Neoplasias Colorretais/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Predisposição Genética para Doença , Humanos , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Proteína 1 Homóloga a MutL/genética , Proteína 1 Homóloga a MutL/metabolismo , Proteína 2 Homóloga a MutS/genética , Proteína 2 Homóloga a MutS/metabolismo , Síndromes Neoplásicas Hereditárias/metabolismo , Fenótipo , Valor Preditivo dos TestesRESUMO
BACKGROUND: There is a paucity of data about effective interventions to improve happiness and reduce burnout in oncologists. Benjamin Franklin developed a 13-week program of "necessary activities" or "virtues" (temperance, silence, order, resolution, frugality, industry, sincerity, justice, moderation, cleanliness, tranquility, chastity, and humility) to follow, in his attempt at self-improvement. In this pilot study, we explored whether using a modified version of this was associated with any discernable impact on physician happiness, burnout, or compliance with each of the virtues. METHODS: Self-reported happiness (Oxford happiness scores) and burnout (Abbreviated Maslach Burnout Inventory) were completed at baseline (pre-study), week 13, and 1 month after completion of the program. Each day during the 13-week program, oncologists were emailed a list of virtues to focus on and scored how they felt they were complying with them. The oncologist's spouses also assessed how they felt the oncologist was complying with the virtues. RESULTS: Thirteen physicians completed the baseline scores, 11 completed Maslach/Oxford scores at the end of the study, and 8 the 1-month post-study assessment. No significant improvements in happiness and burnout (emotional exhaustion, depersonalization, personal accomplishment) scores were observed. Statistically significant changes in self-rated virtue scores were observed for temperance (p = 0.046), order (p = 0.049), and resolution (p = 0.014). Additionally, although not reaching statistical significance, 11 of 13 virtues (excepting sincerity and chastity) assessed by spouses indicated a positive change over time. CONCLUSION: In this hypothesis generating study, daily reflection on personal virtues was not associated with any statistically significant change in happiness or burnout scores. Alternative strategies should be considered.
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Esgotamento Psicológico/prevenção & controle , Felicidade , Satisfação no Emprego , Oncologistas , Psicoterapia Psicodinâmica , Adulto , Idoso , Esgotamento Profissional/epidemiologia , Esgotamento Profissional/prevenção & controle , Esgotamento Psicológico/epidemiologia , Fadiga/epidemiologia , Fadiga/psicologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Oncologistas/psicologia , Oncologistas/estatística & dados numéricos , Personalidade , Inventário de Personalidade , Médicos/psicologia , Médicos/estatística & dados numéricos , Projetos Piloto , Estudos Prospectivos , Psicoterapia Psicodinâmica/métodos , Inquéritos e QuestionáriosRESUMO
OBJECTIVES: Pelareorep (reolysin), a Dearing strain of reovirus serotype 3, has demonstrated oncolytic activity as single agent and synergy with chemotherapy. We evaluated pelareorep, combined with standard second-line chemotherapy in patients with non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: This randomized phase II trial enrolled patients with advanced or metastatic NSCLC after first line chemotherapy. After a safety run-in, patients were randomized 1:1 to chemotherapy (pemetrexed [500â¯mg/m2, non-squamous], or docetaxel [75â¯mg/m2], day 1 every 21â¯days]) +/- pelareorep (4.5â¯×â¯1010 TCID50, days 1-3 every 21â¯days), stratified by EGFR mutation status. The primary outcome was progression free survival (PFS) of patients randomized to chemotherapyâ¯+â¯pelareorep vs. chemotherapy alone. Secondary outcomes included overall survival, objective response rate and exploratory translational analyses. RESULTS: Between October 2012 and August 2015, 166 patients were enrolled (14 to the safety run in). Pelareorep did not improve the PFS vs. single agent chemotherapy (median PFS 3.0 months, 95% confidence interval [CI] 2.6-4.1) vs. 2.8 months (95% CI 2.5-4.0), hazard ratio (HR) 0.90 (95% CI 0.65-1.25), Pâ¯=â¯0.53). Neither KRAS or EGFR mutation was associated with improved PFS, but STK11 mutations did appear to have an association with improved PFS (HR 0.29 [0.12-0.67); as did PIK3CA mutation (HR 0.45 [0.22-0.93]). The combination was tolerable, although associated with increased rates of neutropenic fever. CONCLUSION: The addition of pelareorep to second-line chemotherapy did not improve the PFS of patients with NSCLC. The three-day pelareorep schedule was tolerable. Further research is needed to evaluate the potential benefit in molecular subtypes of NSCLC.
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Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/terapia , Orthoreovirus Mamífero 3/imunologia , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos , Infecções por Reoviridae/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Canadá , Terapia Combinada , Docetaxel/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pemetrexede/uso terapêutico , Recidiva , Terapia de Salvação , Adulto JovemRESUMO
BACKGROUND: Palliative systemic therapy is frequently underutilized in patients with advanced non-small-cell lung cancer (NSCLC), for many reasons. The aim of this study was to identify patient-reported factors that may predict for treatment decisions and survival in advanced NSCLC, using the Edmonton Symptom Assessment Scale (ESAS), which is a self-reported questionnaire that quantifies symptom burden by asking patients to rate the severity of 9 common symptoms. PATIENTS AND METHODS: With ethics approval, we analyzed ESAS scores at initial oncology consultation for 461 patients with advanced NSCLC seen at The Ottawa Hospital Cancer Centre from 2009 to 2012. Subgroup analysis was performed to determine if treatment strategies or overall survival (OS) were related to the total symptom burden, as defined by the sum of the individual ESAS symptom scores. RESULTS: The severity of the ESAS total symptom burden score was positively correlated with Eastern Cooperative Oncology Group performance status (R = 0.48; P < .0001). Furthermore, patients with a higher symptom burden were less likely to receive systemic chemotherapy than those with fewer symptoms (43% vs. 66%; P < .0001), and had a significantly reduced OS (5.5 vs. 9.9 months; P < .0001). A higher ESAS symptom burden score was also associated with reduced OS by univariate analysis (hazard ratio, 1.78; 95% confidence interval, 1.45-2.18; P < .0001), although multivariate analysis showed only a trend towards significance (hazard ratio, 1.27; 95% confidence interval, 0.99-1.62; P = .06). CONCLUSIONS: Overall, this demonstrates a novel role for the ESAS as a prognostic tool that could complement existing patient assessment models, such as Eastern Cooperative Oncology Group performance status, in the development of optimal treatment plans and estimation of survival, in patients with advanced lung cancer.
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Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/terapia , Estudos de Coortes , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Cuidados Paliativos , Medidas de Resultados Relatados pelo Paciente , Prognóstico , Projetos de Pesquisa , Inquéritos e Questionários , Análise de Sobrevida , Avaliação de SintomasRESUMO
Importance: Tumor-treating fields (TTFields) is an antimitotic treatment modality that interferes with glioblastoma cell division and organelle assembly by delivering low-intensity alternating electric fields to the tumor. Objective: To investigate whether TTFields improves progression-free and overall survival of patients with glioblastoma, a fatal disease that commonly recurs at the initial tumor site or in the central nervous system. Design, Setting, and Participants: In this randomized, open-label trial, 695 patients with glioblastoma whose tumor was resected or biopsied and had completed concomitant radiochemotherapy (median time from diagnosis to randomization, 3.8 months) were enrolled at 83 centers (July 2009-2014) and followed up through December 2016. A preliminary report from this trial was published in 2015; this report describes the final analysis. Interventions: Patients were randomized 2:1 to TTFields plus maintenance temozolomide chemotherapy (n = 466) or temozolomide alone (n = 229). The TTFields, consisting of low-intensity, 200 kHz frequency, alternating electric fields, was delivered (≥ 18 hours/d) via 4 transducer arrays on the shaved scalp and connected to a portable device. Temozolomide was administered to both groups (150-200 mg/m2) for 5 days per 28-day cycle (6-12 cycles). Main Outcomes and Measures: Progression-free survival (tested at α = .046). The secondary end point was overall survival (tested hierarchically at α = .048). Analyses were performed for the intent-to-treat population. Adverse events were compared by group. Results: Of the 695 randomized patients (median age, 56 years; IQR, 48-63; 473 men [68%]), 637 (92%) completed the trial. Median progression-free survival from randomization was 6.7 months in the TTFields-temozolomide group and 4.0 months in the temozolomide-alone group (HR, 0.63; 95% CI, 0.52-0.76; P < .001). Median overall survival was 20.9 months in the TTFields-temozolomide group vs 16.0 months in the temozolomide-alone group (HR, 0.63; 95% CI, 0.53-0.76; P < .001). Systemic adverse event frequency was 48% in the TTFields-temozolomide group and 44% in the temozolomide-alone group. Mild to moderate skin toxicity underneath the transducer arrays occurred in 52% of patients who received TTFields-temozolomide vs no patients who received temozolomide alone. Conclusions and Relevance: In the final analysis of this randomized clinical trial of patients with glioblastoma who had received standard radiochemotherapy, the addition of TTFields to maintenance temozolomide chemotherapy vs maintenance temozolomide alone, resulted in statistically significant improvement in progression-free survival and overall survival. These results are consistent with the previous interim analysis. Trial Registration: clinicaltrials.gov Identifier: NCT00916409.