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BACKGROUND: Some genomic alterations in non-small cell lung cancer (NSCLC) are known to differ according to race, sex, or age. These studies have been limited in sample size and thus they cannot detect the differences precisely and comprehensively. METHODS: Tissue-based comprehensive genomic profiling was performed on 75,362 patients with NSCLC from the United States during routine clinical care. Additionally, we examined data of a Japanese NSCLC cohort with 1,019 patients. In the US cohort, 296 genes were examined for pathogenic alterations. Predominant genetic ancestry was inferred using a SNP-based approach, and patients were categorized into European (EUR), African (AFR), East Asian (EAS), Admixed American (AMR), and South Asian (SAS) ancestry groups. Patients were additionally stratified by histologic type, age (<40/≥40 years, <75/≥75 years), and sex. The prevalence of high tumor mutational burden (TMB-High) and microsatellite instability status was also calculated. RESULTS: Stratified by ancestry, EGFR alterations were significantly enriched in EAS versus other ancestry groups. The prevalence of ALK was significantly higher in the AMR, EAS, and SAS patients than in AFR and EUR patients. KRAS and STK11 were enriched in EUR and AFR patients versus other groups. TMB-High was significantly enriched in AFR patients versus all other groups. An analysis based on sex revealed differences in prevalence of alterations in 80 genes and TMB-High status. For example, EGFR, ALK, BRAF, and KRAS alterations were significantly enriched in females, whereas TP53, STK11, KEAP1, and TMB-High were significantly enriched in males. With respect to age, the prevalence of alterations in 41 genes, including ALK, RET, MET, EGFR, STK11, KEAP1, BRAF, and KRAS, as well as TMB-High, were significantly different between patients aged <40 years and those aged ≥40 years. CONCLUSIONS: Comprehensive analysis from a large real-world dataset revealed ancestry-associated differences in genomic alterations in NSCLC. Age- and sex-related differences in prevalence of genomic alterations and TMB-High status were also observed.
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BACKGROUND AND OBJECTIVE: Lymphangioleiomyomatosis (LAM) is a rare neoplastic disease associated with the functional tumour suppressor genes TSC1 and TSC2 and causes structural destruction in the lungs, which could potentially increase the risk of lung cancer. However, this relationship remains unclear because of the rarity of the disease. METHODS: We investigated the relative risk of developing lung cancer among patients diagnosed with LAM between 2001 and 2022 at a single high-volume centre in Japan, using data from the Japanese Cancer Registry as the reference population. Next-generation sequencing (NGS) was performed in cases where tumour samples were available. RESULTS: Among 642 patients diagnosed with LAM (sporadic LAM, n = 557; tuberous sclerosis complex-LAM, n = 80; unclassified, n = 5), 13 (2.2%) were diagnosed with lung cancer during a median follow-up period of 5.13 years. All patients were female, 61.5% were never smokers, and the median age at lung cancer diagnosis was 53 years. Eight patients developed lung cancer after LAM diagnosis. The estimated incidence of lung cancer was 301.4 cases per 100,000 person-years, and the standardized incidence ratio was 13.6 (95% confidence interval, 6.2-21.0; p = 0.0008). Actionable genetic alterations were identified in 38.5% of the patients (EGFR: 3, ALK: 1 and ERBB2: 1). No findings suggested loss of TSC gene function in the two patients analysed by NGS. CONCLUSION: Our study revealed that patients diagnosed with LAM had a significantly increased risk of lung cancer. Further research is warranted to clarify the carcinogenesis of lung cancer in patients with LAM.
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Neoplasias Pulmonares , Linfangioleiomiomatose , Humanos , Linfangioleiomiomatose/genética , Linfangioleiomiomatose/epidemiologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/epidemiologia , Feminino , Japão/epidemiologia , Pessoa de Meia-Idade , Fatores de Risco , Adulto , Incidência , Idoso , Estudos de Coortes , Masculino , Sistema de Registros , População do Leste AsiáticoRESUMO
Alectinib, an anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), is the recommended first-line treatment for ALK-positive non-small-cell lung cancer (NSCLC) in Japan. Lorlatinib was approved as a subsequent therapeutic option after progression while receiving ALK TKI treatment. However, data on the use of lorlatinib in the second- or third-line setting after alectinib failure are limited in Japanese patients. This retrospective real-world observational study investigated the clinical effectiveness of lorlatinib in second- or later-line settings after alectinib failure in Japanese patients. Clinical and demographic data collected in the Japan Medical Data Vision (MDV) database between December 2015 and March 2021 were used. Patients diagnosed with lung cancer who received lorlatinib following alectinib failure after the November 2018 marketing approval of lorlatinib in Japan were included. Of 1954 patients treated with alectinib, 221 were identified from the MDV database as receiving lorlatinib after November 2018. The median age of these patients was 62 years. Second-line lorlatinib treatment was reported for 154 patients (70%); third- or later-line lorlatinib treatment was reported for 67 patients (30%). The median duration of treatment (DOT) for all lorlatinib-treated patients was 161 days (95% confidence interval [CI], 126-248), and 83 patients (37.6%) continued treatment after data cut-off (March 31, 2021). Median DOTs of 147 days (95% CI, 113-242) and 244 days (95% CI, 109 to not reached) were reported with second-line and third- or later-line treatment, respectively. Consistent with clinical trial data, this real-world observational study supports data suggesting the effectiveness of lorlatinib after alectinib failure in Japanese patients.
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Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Pessoa de Meia-Idade , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Estudos Retrospectivos , População do Leste Asiático , Antineoplásicos/uso terapêutico , Quinase do Linfoma Anaplásico , Lactamas Macrocíclicas/uso terapêutico , Proteínas Tirosina Quinases , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
For non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations, the initial therapeutic interventions will have crucial impacts on their clinical outcomes. Drug tolerant factors reportedly have an impact on EGFR-tyrosine kinase inhibitor sensitivity. This prospective study investigated the impacts of drug tolerant-related protein expression in tumors based on the efficacy of osimertinib in the first-setting of EGFR-mutated advanced NSCLC patients. A total of 92 patients with EGFR-mutated advanced or postoperative recurrent NSCLC were analyzed and treated with osimertinib at 14 institutions in Japan. AXL, p53, and programmed death-ligand 1 (PD-L1) expression in patient tumors was determined using immunohistochemistry. The AXL signaling pathway was investigated using a cell line-based assay and AXL-related gene expression in The Cancer Genome Atlas (TCGA) database. High levels of AXL and positive-p53 expression were detected in 26.1% and 53.3% of the pretreatment EGFR-mutated NSCLC tumors, respectively. High AXL expression levels were significantly associated with a shorter progression-free survival compared with low AXL expression levels, irrespective of the EGFR activating mutation status (p = 0.026). Cell line-based assays indicated that the overexpression of AXL protein accelerated PD-L1 expression, which induced insensitivity to osimertinib. In the TCGA database, AXL RNA levels were positively correlated with PD-L1 expression in the lung adenocarcinoma cohort. The results show that high AXL expression levels in tumors impact clinical predictions when using osimertinib to treat EGFR-mutated NSCLC patients. Trial Registration: UMIN000043942.
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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 , Antígeno B7-H1/metabolismo , Estudos Prospectivos , Proteína Supressora de Tumor p53/genética , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Receptor Tirosina Quinase Axl , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Receptores ErbB , Compostos de Anilina/farmacologia , Compostos de Anilina/uso terapêutico , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
Background: First-line immune checkpoint inhibitor (ICI) monotherapy for advanced non-small cell lung cancer (NSCLC) was introduced in Japan in February 2017. Limited information is available since that time regarding health care resource use for NSCLC in Japan, where the hospitalization burden is high. Objective: We evaluated health care resource use from first- through third-line systemic anticancer therapy for patients with advanced NSCLC included in a multicenter, retrospective chart review study. Methods: Eligible patients were aged 20 years or older with unresectable locally advanced/metastatic NSCLC with no known actionable genomic alteration who initiated first-line systemic anticancer therapy from July 1, 2017, to December 20, 2018, at 23 Japanese hospitals. We calculated the percentage of patients with a record of each resource used, the total number of each resource, and the resource use per 100 patient-weeks of follow-up from initiation of first-, second-, and third-line therapy, overall and by the 3 most common regimen categories, namely, ICI monotherapy, platinum-doublet chemotherapy (without concomitant ICI), and nonplatinum cytotoxic regimens (nonplatinum). Study follow-up ended September 30, 2019. Results: Among 1208 patients (median ageâ¯=â¯70 years; 975 [81%] men), 463 patients (38%) received ICI monotherapy, 647 (54%) received platinum-doublet chemotherapy, and 98 (8%) received nonplatinum regimens as first-line therapy. During the study, 621 (51%) patients initiated second-line, and 281 (23%) initiated third-line therapy. The majority of patients experienced ≥1 hospitalization (76%-94%) and ≥1 outpatient visit (85%-90%) during each therapy line. The number of hospitalizations increased from 6.5 per 100 patient-weeks in first-line to 8.0 per 100 patient-weeks in third-line. During first-line therapy, the number of hospitalizations per 100 patient-weeks were 4.8, 8.4, and 6.5 for patients receiving ICI monotherapy, platinum-doublet chemotherapy, and nonplatinum regimens, respectively, and the percentages of hospitalizations categorized as attributable to NSCLC treatment administration (no surgery, procedure, treatment of metastasis, or palliative lung radiation) were 64%, 77%, and 73%, respectively. The number of outpatient visits increased from 43.0 per 100 patient-weeks in first-line to 51.4 per 100 patient-weeks in third-line therapy. During first-line therapy, outpatient visits per 100 patient-weeks were 41.0, 46.7, and 33.0 for patients receiving ICI monotherapy, platinum-doublet chemotherapy, and nonplatinum regimens, respectively, and the percentages of outpatient visits for infusion therapy were 48%, 34%, and 36%, respectively. Conclusions: The results of this study, although solely descriptive, showed differing patterns of health care resource use during first-line therapy among the 3 common systemic anticancer therapy regimens for advanced NSCLC in Japan and suggest that further research is needed to investigate these apparent differences by treatment regimen.
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BACKGROUND: The combination of immune-checkpoint inhibitors with chemotherapy has become the standard of treatment for non-small cell lung cancer (NSCLC) patients. However, the association between therapeutic efficacy and the development of immune-related adverse events (irAEs) remains unclear in patients treated with combination therapy. We aimed to investigate the frequency of irAEs, and the association between therapeutic efficacy and the development of irAEs in patients with NSCLC. MATERIALS AND METHODS: We retrospectively surveyed patients with chemo-naïve advanced NSCLC who received pembrolizumab plus platinum-based chemotherapy or pembrolizumab monotherapy at Juntendo University Hospital, Japan, between February 2017 and May 2021. RESULTS: Among 148 patients (median [range] age, 68 (33-85) years; 107 men [72.3%] and 41 women [27.7%]), 74 each received pembrolizumab plus chemotherapy and pembrolizumab monotherapy. IrAEs were observed in 46 (62.2%) and 41 patients (55.4%) in the combination therapy and monotherapy group, respectively. Patients with irAEs showed significantly longer progression-free survival (PFS) than those without irAEs in the combination therapy group (8.9 vs. 5.7 months; Hazard Ratio [HR], 0.53; 95% CI, 0.29-0.98; P = 0.041) and monotherapy group (11.7 vs. 5.0 months; HR, 0.40; 95% CI, 0.22-0.70; P = 0.001). In the multivariable analysis, development of irAEs was positively associated with PFS in both the groups (HR, 0.48; 95% CI, 0.26-0.89; P = 0.019 and HR, 0.38; 95% CI, 0.21-0.68; P < 0.01). In the inverse probability of treatment weighting adjusted analysis, development of irAEs was significantly associated with combination therapy (OR, 0.56; 95% CI, 0.34-0.91; P = 0.019). CONCLUSION: Our study demonstrated that the incidence of irAEs was associated with favorable efficacy in patients treated with pembrolizumab plus chemotherapy, as well as pembrolizumab monotherapy. Also, the addition of chemotherapy to pembrolizumab significantly increased the incidence of irAEs.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Idoso , Anticorpos Monoclonais Humanizados , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Feminino , Humanos , Inibidores de Checkpoint Imunológico , Masculino , Nivolumabe/uso terapêutico , Estudos RetrospectivosRESUMO
BACKGROUND: The prognosis of patients with NSCLC harboring oncogenic driver gene alterations, such as EGFR gene mutations or ALK fusion, has improved dramatically with the advent of corresponding molecularly targeted drugs. As patients were followed up for about five years in most clinical trials, the long-term outcomes beyond 5 years are unclear. The objectives of this study are to explore the clinical course beyond five years of chemotherapy initiation and to investigate factors that lead to long-term survival. METHODS: One hundred and seventy-seven patients with advanced, EGFR-mutated or ALK-rearranged NSCLC who received their first chemotherapy between December 2008 and September 2015 were included. Kaplan Meier curves were drawn for the total cohort and according to subgroups of patients' characteristics. RESULTS: Median OS in the total cohort was 40.6 months, the one-year survival rate was 89%, the three-year survival rate was 54%, and the five-year survival rate was 28%. Median OS was 36.9 months in EGFR-mutated patients and 55.4 months in ALK-rearranged patients. The OS curve seemed to plateau after 72 months, and most of the patients who were still alive after more than five years are on treatment. Female sex, age under 75 years, an ECOG PS of 0 to 1, ALK rearrangement, postoperative recurrence, and presence of brain metastasis were significantly associated with longer OS. CONCLUSIONS: A tail plateau was found in the survival curves of patients with advanced, EGFR-mutated and ALK-rearranged NSCLC, but most were on treatment, especially with EGFR-mutated NSCLC.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Idoso , Quinase do Linfoma Anaplásico/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/genética , Receptores ErbB/uso terapêutico , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , PrognósticoRESUMO
BACKGROUND: Platinum-based chemoradiotherapy is the standard treatment for unresectable stage III non-small-cell lung cancer (NSCLC). However, few studies have evaluated the efficacy of subsequent chemotherapy for relapsed NSCLC following platinum-based chemoradiotherapy. This study aimed to evaluate the efficacy of platinum-doublet chemotherapy as a second-line treatment for patients with unresectable stage III NSCLC. METHODS: We retrospectively evaluated patients with unresectable stage III NSCLC treated with cytotoxic chemotherapy following platinum-based chemoradiotherapy who were registered in a nationwide registry NSCLC database. Patients were divided into the platinum-doublet chemotherapy (platinum) group and single-agent chemotherapy (non-platinum) group based on the type of second-line chemotherapy. RESULTS: The platinum group (n = 119) showed significantly better overall survival (OS) than the non-platinum group (n = 201) (median OS: 21.5 vs. 10.5 months, hazard ratio [HR]: 0.54, 95% confidence interval [CI]: 0.40-0.73, p < 0.001). OS from the beginning of chemoradiotherapy was also significantly better in the platinum group than in the non-platinum group (median OS: 34.9 vs. 21.8 months, HR: 0.58, 95% CI: 0.43-0.79, p = 0.001). In the multivariate analysis, platinum-doublet chemotherapy as second-line therapy, female sex, clinical stage IIIA, and duration of ≥ 8.6 months from the beginning of first-line therapy to the beginning of second-line therapy were associated with significantly better OS. CONCLUSION: Platinum-doublet chemotherapy as a second-line therapy may prolong survival in unresectable stage III NSCLC patients following platinum-based chemoradiotherapy. Thus, re-administration of platinum agents may be a promising treatment for unresectable stage III NSCLC treated with platinum-based chemoradiotherapy.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Quimiorradioterapia , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Platina/uso terapêutico , Estudos RetrospectivosRESUMO
ALK, ROS1, and RET kinase fusions are important predictive biomarkers of tyrosine kinase inhibitors (TKIs) in non-small-cell lung cancer (NSCLC). Analysis of cell-free DNA (cfDNA) provides a noninvasive method to identify gene changes in tumor cells. The present study sought to use cfRNA and cfDNA for identifying fusion genes. A reliable protocol was established to detect fusion genes using cfRNA and assessed the analytical validity and clinical usefulness in 30 samples from 20 cases of fusion-positive NSCLC. The results of cfRNA-based assays were compared with tissue biopsy and cfDNA-based liquid biopsy (Guardant360 plasma next-generation sequencing [NGS] assay). The overall sensitivity of the cfRNA-based assay was 26.7% (8/30) and that of cfDNA-based assay was 16.7% (3/18). When analysis was limited to the samples collected at chemo-naïve or progressive disease status and available for both assays, the sensitivity of the cfRNA-based assay was 77.8% (7/9) and that of cfDNA-based assay was 33.3% (3/9). Fusion gene identification in cfRNA was correlated with treatment response. These results suggest that the proposed cfRNA assay is a useful diagnostic test for patients with insufficient tissues to facilitate effective administration of first-line treatment and is a useful tool to monitor the progression of NSCLC for consideration of second-line treatments.
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Quinase do Linfoma Anaplásico/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Ácidos Nucleicos Livres , Fusão Gênica , Neoplasias Pulmonares/genética , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas c-ret/genética , Proteínas Proto-Oncogênicas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Biópsia , Carbazóis/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Ácidos Nucleicos Livres/isolamento & purificação , Crizotinibe/uso terapêutico , Proteínas do Citoesqueleto/genética , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Gliceraldeído-3-Fosfato Desidrogenase (Fosforiladora)/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Biópsia Líquida/métodos , Pulmão/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/isolamento & purificação , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , RNA Mensageiro/isolamento & purificação , Sensibilidade e EspecificidadeRESUMO
This study provides the benchmark statistics on medically treated patients with non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) in Japan. Demographic background, treatment, and prognosis were obtained from patients with lung cancer pathologically diagnosed in 2012, who received nonsurgical treatment. Descriptive statistics and their associations with survival were analyzed. In total, 12 320 patients were registered from 314 institutions in Japan. The median age was 70 years, and 73% of the patients were male. The number (%) of stages I, II, III, and IV diseases were 468 (3.8%), 421 (3.4%), 3260 (26.5%), and 8171 (66.3%), respectively. NSCLC and SCLC accounted for 9872 (80.1%) and 2353 (19.1%) patients, respectively. Thoracic radiotherapy-based therapy, chemotherapy, and palliative care alone were administered to 2572 (20.9%), 7790 (63.2%), and 1952 (15.8%) patients, respectively. Clinical TNM stage was one of the strongest prognostic factors with the 3-year survival rates of 62.9%, 47.3%, 40.0%, 27.8%, 37.5%, 26.5%, and 18.2% for stages IA, IB, IIA, IIB, IIIA, IIIB, and IV, respectively. Among 6158 patients with NSCLC treated with chemotherapy, the 3-year survival rate was 33.4% in patients receiving epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) at some point in their clinical course, whereas it was 17.4% in patients who did not. The 3-year survival rate of SCLC was only 15.9%. In conclusion, approximately two-thirds of the patients were diagnosed as stage IV at the initial diagnosis. Use of EGFR-TKIs significantly improved the survival of patients with NSCLC.
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Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/terapia , Sistema de Registros/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Benchmarking , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Feminino , Seguimentos , Humanos , Japão/epidemiologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Carcinoma de Pequenas Células do Pulmão/mortalidade , Carcinoma de Pequenas Células do Pulmão/patologia , Carcinoma de Pequenas Células do Pulmão/terapia , Taxa de Sobrevida , Adulto JovemRESUMO
BACKGROUND: Owing to the rarity of this tumor, there is limited information about second-line chemotherapy for patients with previously treated advanced thymic carcinoma. MATERIAL AND METHODS: We performed a multi-institutional, retrospective study named NEJ023 for patients with advanced thymic carcinoma. Patients without indications for curative treatment were treated with chemotherapy from 1995 to 2014 at 40 institutions in the North East Japan Study Group. Demographic and clinicopathologic characteristics, data on treatment methods, and outcomes of second-line chemotherapy were obtained from medical records. RESULTS: In total, 191 patients were enrolled in this study. Second-line chemotherapy included platinum-based doublets in 57.6% of patients, other multidrug chemotherapy (e.g., cisplatin, doxorubicin, vincristine, and cyclophosphamide) in 13.6%, and monotherapy in 28.8%. The median follow-up time was 50.5 months, and the median overall survival (OS) from the start of second-line chemotherapy was 22.4 (95% confidence interval, 17.5-26.7) months. The average response rate (RR) was 20.0% overall; it was 21.6% for patients treated with platinum-based doublet chemotherapy, 13.6% for those treated with other multidrug chemotherapy, and 19.6% for those treated with single agent chemotherapy. There was no significant difference in OS between platinum-based doublet chemotherapy, other multidrug chemotherapy, and monotherapy (the median OS was 22.4, 25.7, and 21.4 months, respectively). CONCLUSION: The median OS was 22.4 months in patients with advanced thymic carcinoma treated with second-line chemotherapy. There were no significant differences in RR and OS between monotherapy and multidrug chemotherapy in this study. IMPLICATIONS FOR PRACTICE: Owing to the rarity of this tumor, there is limited information about second-line chemotherapy for patients with previously treated advanced thymic carcinoma. This is the largest data for those patients treated with second-line chemotherapy. This study suggests there is no significant difference in efficacy between monotherapy and multidrug chemotherapy for previously treated advanced thymic carcinoma. This result can support the adequacy to select monotherapy as treatment of those patients.
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Timoma , Neoplasias do Timo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/uso terapêutico , Humanos , Japão , Estudos Retrospectivos , Timoma/tratamento farmacológico , Neoplasias do Timo/tratamento farmacológico , Resultado do TratamentoRESUMO
BACKGROUND: Hermansky-Pudlak syndrome (HPS) is an extremely rare disease with pulmonary fibrosis (PF), oculocutaneous albinism, induced platelet dysfunction, and granulomatous colitis. Although patients with HPS-associated PF (HPS-PF) often receive treatment with anti-fibrotic agents, including pirfenidone, many HPS-PF cases are progressive. The development of pneumothorax is known to be rare in HPS-PF. Pneumothorax development is generally important for prognosis in patients with interstitial pneumonia. However, there are few reports regarding the development of pneumothorax in patients with HPS-PF. CASE PRESENTATION: A 50-year-old Japanese man with chestnut hair, white skin, and light brown squint eyes visited our hospital for interstitial pneumonia examination. Chest high-resolution computed tomography (HRCT) demonstrated diffuse bilateral reticular opacities along the bronchovascular bundles and traction bronchiectasis predominantly in the upper lung fields. He was definitively diagnosed with HPS because genetic analysis showed that he had a homozygous mutation, c.398 + 5G > A, in the HPS-1 gene. After diagnosis with HPS-PF, he initiated home oxygen therapy due to gradually progressive hypoxemia. Three months after the HPS-PF diagnosis, the patient suddenly developed severe chest pain and dyspnea and was admitted to our hospital on emergency. He was diagnosed with pneumothorax by chest radiological findings. He immediately received chest drainage; however, his pneumothorax did not improve. Therefore, he underwent video-assisted surgery by thoracic surgeons. The leak point was not detected, but multiple bullae were found, mainly in the upper lung lobes. Thus, the surgeons did not perform bullectomy and only covered the apical areas. Fifteen days after the surgery, the patient developed high fever and dyspnea with a new diffuse reticular shadow found through HRCT. We first initiated the patient on broad-spectrum antibiotics; however, the symptoms and radiological findings worsened. Therefore, we started treatment with pirfenidone for inhibition of PF progression. The patient re-developed pneumothorax with severe respiratory failure. Although he re-underwent chest drainage, he died of progressive respiratory failure. CONCLUSIONS: We herein report the case of a rare HPS patient who developed pneumothorax with progressive PF. Pneumothorax may cause rapid progressive respiratory failure and may be associated with PF progression in HPS-PF.
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Síndrome de Hermanski-Pudlak/diagnóstico , Síndrome de Hermanski-Pudlak/patologia , Pneumotórax/etiologia , Fibrose Pulmonar/fisiopatologia , Insuficiência Respiratória/etiologia , Progressão da Doença , Testes Genéticos , Síndrome de Hermanski-Pudlak/complicações , Humanos , Masculino , Proteínas de Membrana , Pessoa de Meia-Idade , Mutação , Pneumotórax/diagnóstico por imagem , Radiografia Torácica , Cirurgia Torácica Vídeoassistida , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Adjuvant tegafur/uracil (UFT) chemotherapy is recommended for patients with completely resected Stage I non-small cell lung cancer (NSCLC) in Japan. A Phase III trial, the Japan Clinical Oncology Group (JCOG) 0707, comparing the survival benefit of UFT and S-1 (tegafur/gimeracil/oteracil) for this population is being conducted. However, the selection of patients in the randomized clinical trial (RCT) may not represent the real-world population. The present study aimed to investigate the pattern of care for patients receiving adjuvant chemotherapy for completely resected NSCLC. METHODS: Patients with completely resected pathological Stage I (T1 > 2 cm and T2 in 6th TNM edition) NSCLC eligible for the JCOG0707 trial but excluded from it during the enrollment period (2008-13) were eligible for this study. Physicians from institutions that participated in the JCOG0707 retrospectively assessed the medical records of each patient. RESULTS: This study enrolled 5006 patients, 85% of those initially considered for participation in the JCOG0707 trial (5006 of 5923 patients). Among them, 2389 were ineligible for the trial and 2617 had not been enrolled despite being eligible. The most frequent reason for non-enrollment despite eligibility was the decline in patients' participation, and the major reasons for trial ineligibility were concomitant malignancy and comorbidities. Of all the patients enrolled in our study, 1659 received adjuvant chemotherapy, mainly UFT. CONCLUSIONS: Our study indicates that only 15% of the real-world patients with completely resected NSCLC were enrolled into the adjuvant chemotherapy RCT, and among those not participating in the trial, one-third received adjuvant chemotherapy.
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Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Quimioterapia Adjuvante/métodos , Neoplasias Pulmonares/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/patologia , Estudos de Coortes , Feminino , Humanos , Japão , Neoplasias Pulmonares/patologia , Masculino , Estadiamento de Neoplasias , Estudos RetrospectivosRESUMO
BACKGROUND: Alectinib, a potent, highly selective, CNS-active inhibitor of anaplastic lymphoma kinase (ALK), showed promising efficacy and tolerability in the single-arm phase 1/2 AF-001JP trial in Japanese patients with ALK-positive non-small-cell lung cancer. Given those promising results, we did a phase 3 trial to directly compare the efficacy and safety of alectinib and crizotinib. METHODS: J-ALEX was a randomised, open-label, phase 3 trial that recruited ALK inhibitor-naive Japanese patients with ALK-positive non-small-cell lung cancer, who were chemotherapy-naive or had received one previous chemotherapy regimen, from 41 study sites in Japan. Patients were randomly assigned (1:1) via an interactive web response system using a permuted-block method stratified by Eastern Cooperative Oncology Group performance status, treatment line, and disease stage to receive oral alectinib 300 mg twice daily or crizotinib 250 mg twice daily until progressive disease, unacceptable toxicity, death, or withdrawal. The primary endpoint was progression-free survival assessed by an independent review facility. The efficacy analysis was done in the intention-to-treat population, and safety analyses were done in all patients who received at least one dose of the study drug. The study is ongoing and patient recruitment is closed. This study is registered with the Japan Pharmaceutical Information Center (number JapicCTI-132316). FINDINGS: Between Nov 18, 2013, and Aug 4, 2015, 207 patients were recruited and assigned to the alectinib (n=103) or crizotinib (n=104) groups. At data cutoff for the second interim analysis, 24 patients in the alectinib group had discontinued treatment compared with 61 in the crizotinib group, mostly due to lack of efficacy or adverse events. At the second interim analysis (data cutoff date Dec 3, 2015), an independent data monitoring committee determined that the primary endpoint of the study had been met (hazard ratio 0·34 [99·7% CI 0·17-0·71], stratified log-rank p<0·0001) and recommended an immediate release of the data. Median progression-free survival had not yet been reached with alectinib (95% CI 20·3-not estimated) and was 10·2 months (8·2-12·0) with crizotinib. Grade 3 or 4 adverse events occurred at a greater frequency with crizotinib (54 [52%] of 104) than alectinib (27 [26%] of 103). Dose interruptions due to adverse events were also more prevalent with crizotinib (77 [74%] of 104) than with alectinib (30 [29%] of 103), and more patients receiving crizotinib (21 [20%]) than alectinib (nine [9%]) discontinued the study drug because of an adverse event. No adverse events with a fatal outcome occurred in either treatment group. INTERPRETATION: These results provide the first head-to-head comparison of alectinib and crizotinib and have the potential to change the standard of care for the first-line treatment of ALK-positive non-small-cell lung cancer. The dose of alectinib (300 mg twice daily) used in this study is lower than the approved dose in countries other than Japan; however, this limitation is being addressed in the ongoing ALEX study. FUNDING: Chugai Pharmaceutical Co, Ltd.
Assuntos
Antineoplásicos/uso terapêutico , Carbazóis/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Piperidinas/uso terapêutico , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Receptores Proteína Tirosina Quinases/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Quinase do Linfoma Anaplásico , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Neoplasias Encefálicas/secundário , Carbazóis/efeitos adversos , Carbazóis/sangue , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/secundário , Crizotinibe , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Piperidinas/efeitos adversos , Piperidinas/sangue , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/efeitos adversos , Pirazóis/sangue , Piridinas/efeitos adversos , Piridinas/sangue , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Método Simples-CegoRESUMO
BACKGROUND: The prognostic factors and the efficacy of first-line chemotherapy remain unclear in patients with advanced thymic carcinoma. MATERIALS AND METHODS: We conducted a multi-institutional retrospective study named NEJ023 for patients with advanced thymic carcinoma. All patients without any indication of curative treatment were treated with chemotherapy from 1995 to 2014 at 40 institutions of the North East Japan Study Group. RESULTS: A total of 286 patients with advanced thymic carcinoma were analyzed. First-line chemotherapy included platinum-based doublets in 62.2% of the patients, monotherapy in 3.5%, and other multidrug chemotherapy (e.g., cisplatin, doxorubicin, vincristine, and cyclophosphamide [ADOC]) in 34.3%. The median follow-up period was 55.5 months, and the median overall survival (OS) from the start of first-line chemotherapy was 30.7 months (95% confidence interval, 25.9-35.9 months). There was no significant difference in OS among different first-line chemotherapy regimens (e.g., between carboplatin/paclitaxel and ADOC, median OS: 27.8 vs. 29.9 months). Masaoka-Koga stage IVa and volume reduction surgery were favorable prognostic factors for OS in the multivariate analysis using the Cox proportional hazards model. CONCLUSION: The efficacy of each first-line chemotherapy regimen for advanced thymic carcinoma did not vary significantly. Our results might support the adequacy of the use of carboplatin/paclitaxel as first-line chemotherapy for these patients. IMPLICATIONS FOR PRACTICE: Because of its rarity, there is limited information about prognostic factors and efficacy of chemotherapy in patients with advanced thymic carcinoma. This is the largest data set for those patients treated with chemotherapy. This study suggests there is no significant difference in efficacy between carboplatin/paclitaxel and cisplatin/doxorubicin/vincristine/cyclophosphamide for advanced thymic carcinoma. This result can support the adequacy of the selection of platinum doublets as treatment for those patients, rather than anthracycline-based multidrug regimen.
Assuntos
Timoma/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Timoma/patologia , Adulto JovemRESUMO
BACKGROUND: Interstitial lung diseases induced by anticancer agents (ILD-AA) are rare adverse effects of anticancer therapy. However, prognostic biomarkers for ILD-AA have not been identified in patients with advanced lung cancer. Our aim was to analyze the association between serum biomarkers sialylated carbohydrate antigen Krebs von den Lungen-6 (KL-6) and surfactant protein D (SP-D), and clinical characteristics in patients diagnosed with ILD-AA. METHODS: Between April 2011 and March 2016, 1224 advanced lung cancer patients received cytotoxic agents and epidermal growth factor receptor tyrosine kinase inhibitors at Juntendo University Hospital and Juntendo University Urayasu Hospital. Of these patients, those diagnosed with ILD-AA were enrolled in this case control study. ΔKL-6 and ΔSP-D were defined as the difference between the levels at the onset of ILD-AA and their respective levels prior to development of ILD-AA. We evaluated KL-6 and SP-D at the onset of ILD-AA, ΔKL-6 and ΔSP-D, the risk factors for death related to ILD-AA, the chest high resolution computed tomography (HRCT) findings, and survival time in patients diagnosed with ILD-AA. RESULTS: Thirty-six patients diagnosed with ILD-AA were enrolled in this study. Among them, 14 patients died of ILD-AA. ΔSP-D in the patients who died was significantly higher than that in the patients who survived. However, ΔKL-6 did not differ significantly between the two groups. Moreover, ΔSP-D in patients who exhibited diffuse alveolar damage was significantly higher than that in the other patterns on HRCT. Receiver operating characteristic curve analysis was used to set the optimal cut off value for ΔSP-D at 398 ng/mL. Survival time for patients with high ΔSP-D (≥ 398 ng/mL) was significantly shorter than that for patients with low ΔSP-D. Multivariate analysis revealed that ΔSP-D was a significant prognostic factor of ILD-AA. CONCLUSIONS: This is the first research to evaluate high ΔSP-D (≥ 398 ng/mL) in patients with ILD-AA and to determine the risk factors for ILD-AA in advanced lung cancer patients. ΔSP-D might be a serum prognostic biomarker of ILD-AA. Clinicians should evaluate serum SP-D during chemotherapy and should carefully monitor the clinical course in patients with high ΔSP-D.
Assuntos
Antineoplásicos/efeitos adversos , Biomarcadores/sangue , Doenças Pulmonares Intersticiais , Neoplasias Pulmonares , Proteína D Associada a Surfactante Pulmonar/sangue , Idoso , Antineoplásicos/uso terapêutico , Estudos de Casos e Controles , Feminino , Humanos , Pulmão , Doenças Pulmonares Intersticiais/induzido quimicamente , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/mortalidade , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Masculino , Prognóstico , Curva ROC , Análise de Sobrevida , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Advanced non-small cell lung cancer (NSCLC) patients often develop thromboembolic events, including cerebral infarction (CI). However, the relationship between advanced NSCLC and CI has not been thoroughly investigated. We examined the association between advanced NSCLC and CI and risk factors for CI in advanced or post-operative recurrent NSCLC patients. METHODS: We retrospectively investigated 515 patients diagnosed with advanced or post-operative recurrent NSCLC at Juntendo University Hospital between April 2009 and March 2014. RESULTS: Among the 515 patients evaluated, 15 patients (2.9%) developed CI after diagnosis of advanced or post-operative recurrent NSCLC. Univariate and multivariate analyses were conducted, and brain metastasis was the only significant independent risk factor for CI (odds ratio 5.24, 95% confidence interval 1.72-16.10, p = 0.004). The incidence was 6.3% in these patients. The median survival time was 36 days, and 1-year survival rate was 6.7% after development of CI. Overall survival from diagnosis of advanced NSCLC or post-operative recurrence was significantly shorter in patients with CI than in patients without CI (223 days versus 895 days; HR, 3.46; 95% confidence interval, 2.04-6.02; p = 0.001). CONCLUSIONS: The incidence of CI is high in advanced or post-operative recurrent NSCLC, and is especially higher in patients with brain metastasis than in those without brain metastasis. Moreover, CI may affect patient's prognosis. Careful monitoring for the development of CI in patients with advanced or post-operative recurrent NSCLC is needed, especially for patients with brain metastasis.
Assuntos
Neoplasias Encefálicas/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Infarto Cerebral/patologia , Recidiva Local de Neoplasia/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/complicações , Estudos de Casos e Controles , Infarto Cerebral/complicações , Feminino , Humanos , Trombose Intracraniana/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Período Pós-Operatório , Prognóstico , Fatores de RiscoRESUMO
BACKGROUND: The combination of nedaplatin, a cisplatin derivative, and docetaxel showed promising activity for advanced squamous cell lung carcinoma in a previous phase 1-2 study. We compared nedaplatin plus docetaxel with cisplatin plus docetaxel in patients with previously untreated advanced or relapsed squamous cell lung carcinoma to determine effects on overall survival. METHODS: We did a randomised, open-label, phase 3 study at 53 institutions in Japan. Eligibility criteria included pathologically proven squamous cell lung cancer with stage IIIB/IV or postoperative recurrence, age 20-74 years, Eastern Cooperative Oncology Group performance status of 0-1, no previous chemotherapy or recurrence more than a year after previous adjuvant chemotherapy, and adequate organ function. Patients were randomly assigned (1:1) to 100 mg/m(2) nedaplatin and 60 mg/m(2) docetaxel intravenously, or 80 mg/m(2) cisplatin and 60 mg/m(2) docetaxel, every 3 weeks for four to six cycles (at the treating oncologist's discretion). Randomisation was done centrally at the West Japan Oncology Group data centre via a computer-generated allocation sequence with dynamic minimisation that balanced stage (IIIB/IV or postoperative recurrent), sex, and institution. The primary endpoint was overall survival in the modified intention-to-treat population (ie, all patients who were randomly assigned and met the inclusion criteria). Safety analyses were done in all randomly assigned patients who received at least one dose of the study regimen. This trial is registered with the UMIN Clinical Trials Registry, number UMIN000002015, and is closed to new participants. FINDINGS: Between July 6, 2009, and July 26, 2012, 355 patients were randomly assigned. 349 patients were included in the modified intention-to-treat analysis (177 in the nedaplatin group and 172 in the cisplatin group). Overall survival was significantly longer in the nedaplatin group (median 13·6 months, 95% CI 11·6-15·6) than in the cisplatin group (11·4 months,10·2-12·2; hazard ratio 0·81, 95% CI 0·65-1·02; p=0·037, one-sided stratified log-rank test). Grade 3 or worse nausea (seven of 177 patients in the nedaplatin group and 25 of 175 in the cisplatin group), fatigue (six vs 20), hyponatraemia (24 vs 53), and hypokalaemia (four vs 15) were more frequent in the cisplatin group than in the nedaplatin group, whereas grade 3 or worse leucopenia (98 vs 77), neutropenia (146 vs 123), and thrombocytopenia (16 vs none) were more frequent in the nedaplatin group than in the cisplatin group. Treatment-related deaths occurred in four and three patients in nedaplatin and cisplatin groups, respectively. INTERPRETATION: Overall survival was significantly longer with nedaplatin plus docetaxel than with cisplatin plus docetaxel, and the regimens had different safety profiles. Nedaplatin plus docetaxel could be a new treatment option for advanced or relapsed squamous cell lung cancer. FUNDING: West Japan Oncology Group and Sanofi.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Cisplatino/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Recidiva Local de Neoplasia , Compostos Organoplatínicos/uso terapêutico , Taxoides/uso terapêutico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Cisplatino/efeitos adversos , Progressão da Doença , Intervalo Livre de Doença , Docetaxel , Feminino , Humanos , Análise de Intenção de Tratamento , Japão , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Compostos Organoplatínicos/efeitos adversos , Modelos de Riscos Proporcionais , Fatores de Risco , Taxoides/efeitos adversos , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Central nervous system (CNS) metastases caused by small-cell lung cancer (SCLC) are incurable and therefore fatal. Although such metastases are usually treated with chemotherapy or radiotherapy, their sensitivity to these treatment measures is unclear. Amrubicin appears to be a promising agent for relapsed SCLC, but its effectiveness in CNS metastases originating from SCLC is unknown. METHODS: Between April 2002 and December 2009, 110 SCLC patients with CNS metastasis were treated at Shizuoka Cancer Center. Of these, we retrospectively reviewed 8 consecutive cases with CNS metastases originating from relapsed SCLC that were treated with amrubicin as a second-line therapy. RESULTS: We recorded three sensitive relapses and five refractory cases. Amrubicin yielded a CNS response rate of 50 % (2 partial responses and 2 complete response; 95 % CI, 21.5-78.5\ %) and the disease control rate for CNS lesions was 87.5 % (95 % CI, 52.9-97.8 %). All of the sensitive relapse patients achieved a partial response. The median time to progression for CNS metastases was 150.5 days (95 % CI, 9-171 days), and the median survival time from the start of amrubicin administration was 230.5 days (95 % CI, 89-619 days). We also report a dramatic improvement in one patient's radiological result of intramedullary spinal cord metastasis and alleviation of her symptoms following amrubicin monotherapy including this case series. CONCLUSIONS: The results of this study suggest that amrubicin is active in patients with CNS metastases originating from SCLC.
Assuntos
Antraciclinas/uso terapêutico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/secundário , Neoplasias Pulmonares/patologia , Carcinoma de Pequenas Células do Pulmão/patologia , Idoso , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Neoplasias do Sistema Nervoso Central/diagnóstico por imagem , Meios de Contraste , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
Post-operative adjuvant chemotherapy has been considered an effective strategy to reduce cancer recurrence and improve survival for resected non-small-cell lung cancer. The Japan Clinical Oncology Group has completed patient accrual for a randomized Phase III study (JCOG0707), which compares the survival benefit of UFT and S-1 for completely resected pathological Stage I (T1 >2 cm and T2 in TNM classification version 6) non-small-cell lung cancer. However, there is a growing concern that those who participated in clinical trials are highly selected patients and do not represent the 'real-world' population. This multicenter observational cohort study aims to analyze the backgrounds, pattern of care and outcomes of the patients who were excluded from the JCOG0707 study during the accrual period. The results of this cohort study will be useful for external validity of the results of clinical trial such as JCOG0707.