RESUMO
Clinical pathways have the potential to improve complex clinical decision-making in cancer care. The authors implemented pathways with customized content to assist oncologists to select treatments, aiming for an on-pathway rate of 70%-85%. Treatment decisions were captured as on or off pathway, and metrics were shared monthly with users. Oncologists were categorized into quintiles based on on-pathway performance during the first 90 days of use. On-pathway rates were then calculated for days 91-360 (N = 121). Median on-pathway quintile rates varied from 50% to 100% in the initial 90-day period. During follow-up, median on-pathway rates shifted into the prespecified goal range for all groups. Clinical pathways resulted in greater uniformity in medical oncology practice. Monthly feedback about usage, familiarity with the electronic platform, and regular content updates are some factors that may influence on-pathway rates. Clinical pathways hold promise to manage unwarranted variation in cancer care.
Assuntos
Procedimentos Clínicos , Neoplasias , Tomada de Decisão Clínica , Retroalimentação , Humanos , Oncologia , Neoplasias/terapiaRESUMO
PURPOSE: Nine months after the implementation of a new electronic medical record (EMR) system at a single institution, physicians (MDs), nurse practitioners (NPs), and physician assistants (PAs) expressed frustration with its use. We aimed to test if an individually tailored training approach reduced time spent with the EMR and increased confidence. MATERIALS AND METHODS: Two hours of training were conducted in a one-on-one manner with a trainer. Content was individualized according to the following: provider survey, EMR utilization profile, and shadowing in clinic. Surveys assessed confidence before training and immediately after training. Changes in time spent in various EMR activities before training and after training were compared. RESULTS: Three trainers delivered one-on-one training to 133 MDs, 42 NPs, and 10 PAs who specialized in medical oncology. Participants reported an increase in confidence across all activities, and almost all providers (98%) who responded to our survey agreed that the training enhanced their efficiency. A non-statistically significant trend toward reduction in the overall time in the system was observed. Time in system was reduced primarily in activities such as documentation and ordering of laboratory tests, imaging, medications, and chemotherapy. CONCLUSION: A personalized and data-driven training approach was highly regarded by providers. EMR usage reports provided extensive data to identify and prioritize training content and were valuable to measure the impact of training on provider time in system. With the growth of EMR implementation and the reported relationship of EMR use to burnout, continuous and personalized training after EMR implementation is effective to reduce the time in system and increase confidence.
Assuntos
Registros Eletrônicos de Saúde , Pessoal de Saúde/educação , Capacitação em Serviço , Atitude do Pessoal de Saúde , Eficiência , Pessoal de Saúde/psicologia , Humanos , Oncologia , Avaliação de Programas e Projetos de Saúde , AutoeficáciaRESUMO
Lung cancer is the leading cause of cancer-related mortality in the United States and worldwide. Early detection of lung cancer is an important opportunity for decreasing mortality. Data support using low-dose computed tomography (LDCT) of the chest to screen select patients who are at high risk for lung cancer. Lung screening is covered under the Affordable Care Act for individuals with high-risk factors. The Centers for Medicare & Medicaid Services (CMS) covers annual screening LDCT for appropriate Medicare beneficiaries at high risk for lung cancer if they also receive counseling and participate in shared decision-making before screening. The complete version of the NCCN Guidelines for Lung Cancer Screening provides recommendations for initial and subsequent LDCT screening and provides more detail about LDCT screening. This manuscript focuses on identifying patients at high risk for lung cancer who are candidates for LDCT of the chest and on evaluating initial screening findings.
Assuntos
Neoplasias Pulmonares/diagnóstico , Programas de Rastreamento , Tomografia Computadorizada por Raios X , Tomada de Decisão Clínica , Análise Custo-Benefício , Detecção Precoce de Câncer/métodos , Humanos , Neoplasias Pulmonares/epidemiologia , Programas de Rastreamento/métodos , Imagem Multimodal/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Reprodutibilidade dos Testes , Medição de Risco , Fatores de Risco , Tomografia Computadorizada por Raios X/métodos , Carga Tumoral , Estados UnidosRESUMO
PURPOSE: Increasing costs and medical complexity are significant challenges in modern oncology. We explored the use of clinical pathways to support clinical decision making and manage resources prospectively across our network. MATERIALS AND METHODS: We created customized lung cancer pathways and partnered with a commercial vendor to provide a Web-based platform for real-time decision support and post-treatment data aggregation. Dana-Farber Cancer Institute (DFCI) Pathways for non-small cell lung cancer (NSCLC) were introduced in January 2014. We identified all DFCI patients who were diagnosed and treated for stage IV NSCLC in 2012 (before pathways) and 2014 (after pathways). Costs of care were determined for 1 year from the time of diagnosis. RESULTS: Pre- and postpathway cohorts included 160 and 210 patients with stage IV NSCLC, respectively. The prepathway group had more women but was otherwise similarly matched for demographic and tumor characteristics. The total 12-month cost of care (adjusted for age, sex, race, distance to DFCI, clinical trial enrollment, and EGFR and ALK status) demonstrated a $15,013 savings after the implementation of pathways ($67,050 before pathways v $52,037 after pathways). Antineoplastics were the largest source of cost savings. Clinical outcomes were not compromised, with similar median overall survival times (10.7 months before v 11.2 months after pathways; P = .08). CONCLUSION: After introduction of a clinical pathway in metastatic NSCLC, cost of care decreased significantly, with no compromise in survival. In an era where comparative outcomes analysis and value assessment are increasingly important, the implementation of clinical pathways may provide a means to coalesce and disseminate institutional expertise and track and learn from care decisions.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Tomada de Decisão Clínica , Sistemas de Apoio a Decisões Clínicas , Custos de Cuidados de Saúde , Neoplasias Pulmonares/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Terapia Combinada , Análise Custo-Benefício , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Masculino , Mortalidade , Estadiamento de Neoplasias , Avaliação de Resultados em Cuidados de Saúde , Análise de SobrevidaRESUMO
OBJECTIVES: Accurate assessment of tumor response to chemoradiation has the potential to guide clinical decision-making regarding surgical resection and/or dose escalation for patients. Early assessment has implications for Optimal local therapy for operable locally advanced non-small cell lung cancer (LA-NSCLC) is controversial. This study evaluated quantitative CT-based tumor measurements to predict pathologic response. MATERIALS AND METHODS: Patients with operable LA-NSCLC treated with chemoradiation followed by surgical resection were assessed. Tumor diameter and volume were quantified from CT imaging obtained prior to chemoradiation and post-chemoradiation prior to surgical resection. Univariate and multivariate logistic regression were used to determine association with the primary endpoint of pathologic complete response (pCR). Overall survival, locoregional recurrence, and distant metastasis were assessed as secondary endpoints. RESULTS: 101 LA-NSCLC patients were identified and treated with preoperative chemoradiation and surgical resection. The median RT dose was 54Gy (range, 46-70) and 98% of patients received concurrent chemoradiation as part of their preoperative treatment. Reduction of CT-defined tumor volume was associated with pCR (OR 1.06 [1.02-1.09], p=0.002) and LRR (HR 1.01 [1.00-1.02], p=0.048). Conventional response assessment determined by RECIST (p=0.213) was not associated with pCR or any secondary endpoints. CONCLUSION: CT-measured reductions in tumor volume after chemoradiation are associated with pCR and provide greater clinical information about tumor response than conventional response assessment (RECIST) or absolute tumor sizes or volumes. This study demonstrates that change in tumor volumes provides better radiologic-pathologic correlation and is thus an additional tool to assess tumor response following chemoradiation.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Quimiorradioterapia/métodos , Neoplasias Pulmonares/diagnóstico por imagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Tomada de Decisão Clínica , Terapia Combinada , Estudos de Avaliação como Assunto , Feminino , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacosAssuntos
Biópsia/métodos , Carcinoma Pulmonar de Células não Pequenas/genética , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Progressão da Doença , Cloridrato de Erlotinib/uso terapêutico , Estudos de Viabilidade , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Estudos Prospectivos , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-met/metabolismoRESUMO
PURPOSE: Genotype-directed therapy is the standard of care for advanced non-small cell lung cancer (NSCLC), but obtaining tumor tissue for genotyping remains a challenge. Circulating tumor cell (CTC) or cell-free DNA (cfDNA) analysis may allow for noninvasive evaluation. This prospective trial evaluated CTCs and cfDNA in EGFR-mutant NSCLC patients treated with erlotinib until progression. EXPERIMENTAL DESIGN: EGFR-mutant NSCLC patients were enrolled in a phase II trial of erlotinib. Blood was collected at baseline, every 2 months on study, and at disease progression. Plasma genotyping was performed by droplet digital PCR for EGFR19del, L858R, and T790M. CTCs were isolated by CellSave, enumerated, and analyzed by immunofluorescence for CD45 and pan-cytokeratin and EGFR and MET FISH were also performed. Rebiopsy was performed at disease progression. RESULTS: Sixty patients were enrolled; 44 patients discontinued therapy for disease progression. Rebiopsy occurred in 35 of 44 patients (80%), with paired CTC/cfDNA analysis in 41 of 44 samples at baseline and 36 of 44 samples at progression. T790M was identified in 23 of 35 (66%) tissue biopsies and 9 of 39 (23%) cfDNA samples. CTC analysis at progression identified MET amplification in 3 samples in which tissue analysis could not be performed. cfDNA analysis identified T790M in 2 samples in which rebiopsy was not possible. At diagnosis, high levels of cfDNA but not high levels of CTCs correlated with progression-free survival. CONCLUSIONS: cfDNA and CTCs are complementary, noninvasive assays for evaluation of acquired resistance to first-line EGFR TKIs and may expand the number of patients in whom actionable genetic information can be obtained at acquired resistance. Serial cfDNA monitoring may offer greater clinical utility than serial monitoring of CTCs. Clin Cancer Res; 22(24); 6010-20. ©2016 AACR.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Ácidos Nucleicos Livres/efeitos dos fármacos , Receptores ErbB/deficiência , Cloridrato de Erlotinib/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Células Neoplásicas Circulantes/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Ácidos Nucleicos Livres/genética , DNA de Neoplasias/efeitos dos fármacos , DNA de Neoplasias/genética , Progressão da Doença , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Células Neoplásicas Circulantes/patologia , Estudos Prospectivos , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
INTRODUCTION: Activating mutations in the epidermal growth factor receptor gene (EGFR) predict for prolonged progression-free survival in patients with advanced non-small cell lung cancer (NSCLC) treated with EGFR tyrosine kinase inhibitors (EGFR-TKIs) versus chemotherapy. Long-term survival outcomes, however, remain undefined. The objective of this study was to determine the 5-year survival in these patients and identify clinical factors associated with overall survival (OS). METHODS: Patients with EGFR-mutant metastatic lung adenocarcinoma who had been treated with erlotinib or gefitinib at Dana-Farber Cancer Institute between 2002 and 2009 were included. OS was analyzed. RESULTS: Among 137 patients, median progression-free survival and OS were 12.1 months (95% CI: 10.2-13.5) and 30.9 months (95% CI: 28.2-35.7), respectively. Twenty patients (14.6%) were 5-year survivors. In multivariate analysis, exon 19 deletions (hazard ratio [HR] = 0.63, 95% CI: 0.44-0.91, p = 0.01), absence of extrathoracic (HR = 0.62, 95% CI: 0.41-0.93, p = 0.02) or brain metastasis (HR = 0.48, 95% CI: 0.30-0.77, p = 0.002), and not a current smoker (HR = 0.23, 95% CI: 0.09-0.59, p = 0.002) were associated with prolonged OS. Age; sex; stage at diagnosis; liver, bone, or adrenal metastasis; specific TKI; and line of TKI therapy were not associated with OS. CONCLUSIONS: Our data suggest that the rate of 5-year survival among patients with EGFR-mutant metastatic lung adenocarcinoma treated with erlotinib or gefitinib is 14.6%. Exon 19 deletions and absence of extrathoracic or brain metastasis are associated with prolonged survival. On the basis of our findings, clinicians can gain an enhanced estimation of long-term outcomes in this population.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Receptores ErbB/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Adulto , Idoso , Idoso de 80 Anos ou mais , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Massachusetts/epidemiologia , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Ensaios Clínicos Controlados Aleatórios como Assunto , Análise de SobrevidaRESUMO
PURPOSE: Non-small-cell lung cancers (NSCLCs) harboring mutations in MET exon 14 and its flanking introns may respond to c-Met inhibitors. We sought to describe the clinical, pathologic, and genomic characteristics of patients with cancer with MET exon 14 mutations. PATIENTS AND METHODS: We interrogated next-generation sequencing results from 6,376 cancers to identify those harboring MET exon 14 mutations. Clinical characteristics of MET exon 14 mutated NSCLCs were compared with those of NSCLCs with activating mutations in KRAS and EGFR. Co-occurring genomic mutations and copy number alterations were identified. c-Met immunohistochemistry and real-time polymerase chain reaction to detect exon 14 skipping were performed where sufficient tissue was available. RESULTS: MET exon 14 mutations were identified in 28 of 933 nonsquamous NSCLCs (3.0%) and were not seen in other cancer types in this study. Patients with MET exon 14-mutated NSCLC were significantly older (median age, 72.5 years) than patients with EGFR-mutant (median age, 61 years; P < .001) or KRAS-mutant NSCLC (median age, 65 years; P < .001). Among patients with MET exon 14 mutations, 68% were women, and 36% were never-smokers. Stage IV MET exon 14-mutated NSCLCs were significantly more likely to have concurrent MET genomic amplification (mean ratio of MET to chromosome 7, 4.3) and strong c-Met immunohistochemical expression (mean H score, 253) than stage IA to IIIB MET exon 14-mutated NSCLCs (mean ratio of MET to chromosome 7, 1.4; P = .007; mean H score, 155; P = .002) and stage IV MET exon 14-wild-type NSCLCs (mean ratio of MET to chromosome 7, 1.2; P < .001; mean H score, 142; P < .001). A patient whose lung cancer harbored a MET exon 14 mutation with concurrent genomic amplification of the mutated MET allele experienced a major partial response to the c-Met inhibitor crizotinib. CONCLUSION: MET exon 14 mutations represent a clinically unique molecular subtype of NSCLC. Prospective clinical trials with c-Met inhibitors will be necessary to validate MET exon 14 mutations as an important therapeutic target in NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Mutação , Proteínas Proto-Oncogênicas c-met/genética , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Crizotinibe , Éxons , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Reação em Cadeia da Polimerase em Tempo Real , Fatores de RiscoRESUMO
INTRODUCTION: Clinical responses to immune checkpoint blockade by anti-programmed cell death protein-1 (PD-1)/PD-L1 monoclonal antibodies in non-small-cell lung cancer (NSCLC) are associated with PD-L1 expression and smoking status. We aimed to determine the expression profile of PD-1 and its ligands, PD-L1 and PD-L2, in both smokers and never smokers patients with KRAS-mutant NSCLC. METHODS: We retrospectively analyzed the clinical and molecular characteristics of 114 KRAS-mutant NSCLC patients (84 smokers and 30 never smokers) and their clinical tumor samples for the expression of PD-1, PD-L1, and PD-L2 by immunohistochemistry (IHC). We used murine monoclonal antibodies anti-PD-L1 (clone 9A11) and anti-PD-L2 (clone 9E5) to examine for tumor cell expression (0, negative; 1, weak; 2, moderate; 3, intense) and anti-PD-1 (clone EH33) for tumor-infiltrating lymphocytes. RESULTS: PD-L1 expression was detected in 27 of 114 patients (24%; 95% confidence interval [CI], 16-33%) and associated with smoking status (current smokers, 44%; former smokers, 20%; never smokers, 13%; p = 0.03). Higher intensity of PD-L1 expression (IHC-2+/IHC-3+) was more frequently observed in smokers and associated with more pack-years. PD-L2 was positive in 54 of 114 patients (47%; 95% CI, 38-57%) and not related to smoking status. PD-1-positive tumor-infiltrating lymphocytes were present in 77 of 114 tumor specimens tested (68%; 95% CI, 59-77%) including 21 of 27 samples with PD-L1 expression and 39 of 54 samples with PD-L2-positive expression. We found that PD-L1 expression fades with the age of the specimens used for analyses decreasing beyond 3 years (p = 0.016). CONCLUSIONS: The expression of PD-1 and its ligands PD-L1 and PD-L2 is heterogeneous within KRAS-mutant NSCLC and suggests an inducible expression of PD-L1 by smoking.
Assuntos
Antígeno B7-H1/biossíntese , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Proteína 2 Ligante de Morte Celular Programada 1/biossíntese , Receptor de Morte Celular Programada 1/biossíntese , Proteínas Proto-Oncogênicas p21(ras)/genética , Adulto , Idoso , Antígeno B7-H1/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Imuno-Histoquímica , Ligantes , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Proteína 2 Ligante de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Estudos Retrospectivos , Fumar/genética , Fumar/metabolismoRESUMO
BACKGROUND: Erlotinib is a highly active epidermal growth factor receptor (EGFR) kinase inhibitor that is approved for first-line use in lung cancers harboring EGFR mutations. Anecdotal experience suggests that this drug may provide continued disease control after patients develop objective progression of disease (PD), although this has not been systematically studied to date. METHODS: Patients who had Response Evaluation Criteria In Solid Tumors-defined PD who were participating in 3 prospective trials of first-line erlotinib in advanced lung cancer were studied retrospectively, and the progression characteristics were compared between patients with and without EGFR-sensitizing mutations. Factors were studied that influenced the time until treatment change (TTC), defined as the time from PD to the start of a new systemic therapy or death. The rate of tumor progression was assessed by comparing tumor measurements between the computed tomography scan obtained at the time of PD and the preceding scan. RESULTS: In total, 92 eligible patients were studied, including 42 with and 50 without an EGFR-sensitizing mutation. The EGFR-mutant cohort had a slower rate of progression (P = .003) and a longer TTC (P < .001). Among the patients with EGFR-mutant cancers, 28 (66%) continued single-agent erlotinib after PD, and 21 (50%) were able to delay a change in systemic therapy for >3 months; only 2 patients received local debulking therapy during that period. Multivariate analysis of the patients with EGFR-mutant tumors demonstrated that a longer time to progression, a slower rate of progression, and a lack of new extrathoracic metastases were associated with a longer TTC. CONCLUSIONS: A change in systemic therapy commonly can be delayed in patients with EGFR-mutant lung cancer who objectively progress on first-line erlotinib, particularly in those with a longer time to progression, a slow rate of progression, and a lack of new extrathoracic metastases.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Quinazolinas/uso terapêutico , Tempo para o Tratamento/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Progressão da Doença , Receptores ErbB/genética , Cloridrato de Erlotinib , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Terapia Neoadjuvante , Estudos Retrospectivos , Falha de TratamentoRESUMO
PURPOSE: Programmed death 1 is an immune checkpoint that suppresses antitumor immunity. Nivolumab, a fully human immunoglobulin G4 programmed death 1 immune checkpoint inhibitor antibody, was active and generally well tolerated in patients with advanced solid tumors treated in a phase I trial with expansion cohorts. We report overall survival (OS), response durability, and long-term safety in patients with non-small-cell lung cancer (NSCLC) receiving nivolumab in this trial. PATIENTS AND METHODS: Patients (N = 129) with heavily pretreated advanced NSCLC received nivolumab 1, 3, or 10 mg/kg intravenously once every 2 weeks in 8-week cycles for up to 96 weeks. Tumor burden was assessed by RECIST (version 1.0) after each cycle. RESULTS: Median OS across doses was 9.9 months; 1-, 2-, and 3-year OS rates were 42%, 24%, and 18%, respectively, across doses and 56%, 42%, and 27%, respectively, at the 3-mg/kg dose (n = 37) chosen for further clinical development. Among 22 patients (17%) with objective responses, estimated median response duration was 17.0 months. An additional six patients (5%) had unconventional immune-pattern responses. Response rates were similar in squamous and nonsquamous NSCLC. Eighteen responding patients discontinued nivolumab for reasons other than progressive disease; nine (50%) of those had responses lasting > 9 months after their last dose. Grade 3 to 4 treatment-related adverse events occurred in 14% of patients. Three treatment-related deaths (2% of patients) occurred, each associated with pneumonitis. CONCLUSION: Nivolumab monotherapy produced durable responses and encouraging survival rates in patients with heavily pretreated NSCLC. Randomized clinical trials with nivolumab in advanced NSCLC are ongoing.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Estudos de Coortes , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Nivolumabe , Receptor de Morte Celular Programada 1/metabolismo , Resultado do TratamentoRESUMO
PURPOSE: LKB1 loss is common in lung cancer, but no assay exists to efficiently evaluate the presence or absence of LKB1. We validated an IHC assay for LKB1 loss and determined the impact of LKB1 loss in KRAS-mutant non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: We optimized and validated an IHC assay for LKB1 (clone Ley37D/G6) using a panel of lung cancer cell lines and tumors with known LKB1 mutations, including 2 patients with Peutz-Jeghers syndrome (PJS) who developed lung adenocarcinoma. We retrospectively analyzed tumors for LKB1 using IHC from 154 KRAS-mutant NSCLC patients, including 123 smokers and 31 never-smokers, and correlated the findings with patient and tumor characteristics and clinical outcome. RESULTS: LKB1 expression was lost by IHC in 30% of KRAS-mutant NSCLC (smokers 35% vs. never-smokers 13%, P = 0.017). LKB1 loss did not correlate with a specific KRAS mutation but was more frequent in tumors with KRAS transversion mutations (P = 0.029). KRAS-mutant NSCLC patients with concurrent LKB1 loss had a higher number of metastatic sites at the time of diagnosis (median 2.5 vs. 2, P = 0.01), higher incidence of extrathoracic metastases (P = 0.01), and developed brain metastasis more frequently (48% vs. 25%, P = 0.02). There was a nonsignificant trend to worse survival in stage IV KRAS-mutant NSCLC patients with LKB1 loss. CONCLUSIONS: LKB1 IHC is a reliable and efficient assay to evaluate for loss of LKB1 in clinical samples of NSCLC. LKB1 loss is more common in smokers, and is associated with a more aggressive clinical phenotype in KRAS-mutant NSCLC patients, accordingly to preclinical models.
Assuntos
Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Mutação , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Quinases Proteína-Quinases Ativadas por AMP , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Adulto JovemRESUMO
OBJECTIVE: Interstitial lung diseases are associated with increased risk of lung cancer. The prevalence of ILA at diagnosis of advanced non-small-cell lung cancer (NSCLC) and its impact on overall survival (OS) remain to be investigated. MATERIALS AND METHOD: The study included 120 treatment-naïve stage IV NSCLC patients (53 males, 67 females). ILA was scored on CT prior to any systemic therapy using a 4-point scale [0=no evidence of ILA, 1=equivocal for ILA, 2=suspicious for ILA, 3=ILA] by a sequential reading method previously reported. ILA scores of 2 or 3 indicated the presence of ILA. RESULTS: ILA was present in 17 patients (14%) with advanced NSCLC prior to any treatment (score3: n=2, score2: n=15). These 17 patients were significantly older (median age: 69 vs. 63, p=0.04) and had a heavier smoking history (median: 40 vs. 15.5 pack-year, p=0.003) than those with ILA score 0 or 1. Higher ILA scores were associated with shorter OS (p=0.001). Median OS of the 17 patients with ILA was 7.2 months [95%CI: 2.9-9.4] compared to 14.8 months [95%CI: 11.1-18.4] in patients with ILA score 0 or 1 (p=0.002). In a multivariate model, the presence of ILA remained significant for increased risk for death (HR=2.09, p=0.028) after adjusting for first-line systemic therapy (chemotherapy, p<0.001; TKI, p<0.001; each compared to no therapy) and pack years of smoking (p=0.40). CONCLUSION: Radiographic ILA was present in 14% of treatment-naïve advanced NSCLC patients. Higher ILA scores were associated with shorter OS, indicating that ILA could be a marker of shorter survival in advanced NSCLC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Neoplasias Pulmonares/mortalidade , Fumar/mortalidade , Tomografia Computadorizada por Raios X , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/patologia , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Prevalência , Interpretação de Imagem Radiográfica Assistida por ComputadorRESUMO
INTRODUCTION: There are few effective treatment options for leptomeningeal metastasis (LM) in non-small-cell lung cancer (NSCLC). This study assessed the feasibility of high-dose gefitinib in patients with LM from NSCLC harboring EGFR mutations or prior systemic response to EGFR-TKI. METHODS: This phase I open-label trial of a novel gefitinib dosing schedule employed a 3+3 design. Eligible NSCLC patients with LM had known EGFR mutations and/or prior response to EGFR-TKI. Patients alternated 2 weeks of high-dose daily gefitinib (dose levels: 750 mg, 1000 mg, 1250 mg) with 2 weeks of maintenance therapy (500 mg daily). Primary endpoints were safety and toxicity. Secondary endpoints included overall survival (OS), neurological progression-free survival, radiological response, and cytological response in cerebrospinal fluid (CSF). RESULTS: Seven patients were treated: 3 at 750 mg dose level, 4 at 1000 mg dose level. There were no DLTs at the 750 mg dose level, and one DLT (toxic epidermal necrolysis) at the 1000 mg dose level. The study was closed due to slow accrual. Median neurological PFS was 2.3 months (range 1.6-4.0 months); median OS was 3.5 months (range 1.6-5.1 months). Though there were no radiologically documented remissions of LM disease, four patients had improvement in neurological symptoms. One patient cleared their CSF of NSCLC cells, while 2 others had decrease in malignant cells in CSF. CONCLUSION: Although the MTD was not defined due to slow accrual, this study provides important information about the tolerability and CSF penetration of high-dose gefitinib as a therapeutic option for modest palliation for NSCLC patients with LM and a known EGFR mutation.
Assuntos
Antineoplásicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Meníngeas/tratamento farmacológico , Quinazolinas/administração & dosagem , Idoso , Antineoplásicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/secundário , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Feminino , Gefitinibe , Humanos , Neoplasias Pulmonares/patologia , Masculino , Dose Máxima Tolerável , Neoplasias Meníngeas/secundário , Pessoa de Meia-Idade , Quinazolinas/efeitos adversosRESUMO
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Lung Cancer Screening provide recommendations for selecting individuals for lung cancer screening, and for evaluation and follow-up of nodules found during screening, and are intended to assist with clinical and shared decision-making. These NCCN Guidelines Insights focus on the major updates to the 2015 NCCN Guidelines for Lung Cancer Screening, which include a revision to the recommendation from category 2B to 2A for one of the high-risk groups eligible for lung cancer screening. For low-dose CT of the lung, the recommended slice width was revised in the table on "Low-Dose Computed Tomography Acquisition, Storage, Interpretation, and Nodule Reporting."
Assuntos
Detecção Precoce de Câncer , Neoplasias Pulmonares/diagnóstico , Detecção Precoce de Câncer/métodos , Humanos , Tomografia Computadorizada por Raios XRESUMO
OBJECTIVES: Optimal therapy for patients with non-small cell lung carcinoma (NSCLC) presenting with synchronous brain-only oligometastases (SBO) is not well defined. We sought to analyze the effect of differing therapeutic paradigms in this subpopulation. MATERIALS AND METHODS: We retrospectively analyzed NSCLC patients with 1-4 SBO diagnosed between 1/2000 and 1/2011 at our institution. Patients with T0 tumors or documented Karnofsky Performance Status <70 were excluded. Aggressive thoracic therapy (ATT) was defined as resection of the primary disease or chemoradiotherapy whose total radiation dose exceeded 45 Gy. Cox proportional hazards and competing risks models were used to analyze factors affecting survival and first recurrence in the brain. RESULTS: Sixty-six patients were included. Median follow-up was 31.9 months. Intrathoracic disease extent included 9 stage I, 10 stage II and 47 stage III patients. Thirty-eight patients received ATT, 28 did not. Patients receiving ATT were younger (median age 55 vs. 60.5 years, p=0.027) but were otherwise similar to those who did not. Receipt of ATT was associated with prolonged median overall survival (OS) (26.4 vs. 10.5 months; p<0.001) with actuarial 2-year rates of 54% vs. 26%. ATT remained associated with OS after controlling for age, thoracic stage, performance status and initial brain therapy (HR 0.40, p=0.009). On multivariate analysis, the risk of first failure in the brain was associated with receipt of ATT (HR 3.62, p=0.032) and initial combined modality brain therapy (HR 0.34, p=0.046). CONCLUSION: Aggressive management of thoracic disease in NSCLC patients with SBO is associated with improved survival. Careful management of brain disease remains important, especially for those treated aggressively.
Assuntos
Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/terapia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Terapia Combinada , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Fatores de Risco , Falha de Tratamento , Resultado do Tratamento , Carga TumoralRESUMO
PURPOSE: Although palliative chemotherapy is the standard of care for patients with diagnoses of stage IV non-small cell lung cancer (NSCLC), patients with a small metastatic burden, "oligometastatic" disease, may benefit from more aggressive local therapy. METHODS AND MATERIALS: We identified 186 patients (26% of stage IV patients) prospectively enrolled in our institutional database from 2002 to 2012 with oligometastatic disease, which we defined as 5 or fewer distant metastatic lesions at diagnosis. Univariate and multivariable Cox proportional hazards models were used to identify patient and disease factors associated with improved survival. Using propensity score methods, we investigated the effect of definitive local therapy to the primary tumor on overall survival. RESULTS: Median age at diagnosis was 61 years of age; 51% of patients were female; 12% had squamous histology; and 33% had N0-1 disease. On multivariable analysis, Eastern Cooperate Oncology Group performance status ≥ 2 (hazard ratio [HR], 2.43), nodal status, N2-3 (HR, 2.16), squamous pathology, and metastases to multiple organs (HR, 2.11) were associated with a greater hazard of death (all P<.01). The number of metastatic lesions and radiologic size of the primary tumor were not significantly associated with overall survival. Definitive local therapy to the primary tumor was associated with prolonged survival (HR, 0.65, P=.043). CONCLUSIONS: Definitive local therapy to the primary tumor appears to be associated with improved survival in patients with oligometastatic NSCLC. Select patient and tumor characteristics, including good performance status, nonsquamous histology, and limited nodal disease, may predict for improved survival in these patients.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/secundário , Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/terapia , Neoplasias das Glândulas Suprarrenais/mortalidade , Neoplasias das Glândulas Suprarrenais/secundário , Neoplasias das Glândulas Suprarrenais/terapia , Idoso , Análise de Variância , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/secundário , Neoplasias Ósseas/terapia , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/terapia , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/diagnóstico por imagem , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/secundário , Carcinoma de Células Escamosas/terapia , Bases de Dados Factuais , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Pontuação de Propensão , Radiografia , Estudos Retrospectivos , Índice de Gravidade de DoençaRESUMO
PURPOSE: Tumor genotyping using cell-free plasma DNA (cfDNA) has the potential to allow noninvasive assessment of tumor biology, yet many existing assays are cumbersome and vulnerable to false-positive results. We sought to determine whether droplet digital PCR (ddPCR) of cfDNA would allow highly specific and quantitative assessment of tumor genotype. EXPERIMENTAL DESIGN: ddPCR assays for EGFR, KRAS, and BRAF mutations were developed using plasma collected from patients with advanced lung cancer or melanoma of a known tumor genotype. Sensitivity and specificity were determined using cancers with nonoverlapping genotypes as positive and negative controls. Serial assessment of response and resistance was studied in patients with EGFR-mutant lung cancer on a prospective trial of erlotinib. RESULTS: We identified a reference range for EGFR L858R and exon 19 deletions in specimens from KRAS-mutant lung cancer, allowing identification of candidate thresholds with high sensitivity and 100% specificity. Received operative characteristic curve analysis of four assays demonstrated an area under the curve in the range of 0.80 to 0.94. Sensitivity improved in specimens with optimal cfDNA concentrations. Serial plasma genotyping of EGFR-mutant lung cancer on erlotinib demonstrated pretreatment detection of EGFR mutations, complete plasma response in most cases, and increasing levels of EGFR T790M emerging before objective progression. CONCLUSIONS: Noninvasive genotyping of cfDNA using ddPCR demonstrates assay qualities that could allow effective translation into a clinical diagnostic. Serial quantification of plasma genotype allows noninvasive assessment of response and resistance, including detection of resistance mutations up to 16 weeks before radiographic progression.