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    Genomic landscape of lung adenocarcinoma in East Asians. Chen Jianbin,Yang Hechuan,Teo Audrey Su Min,Amer Lidyana Bte,Sherbaf Faranak Ghazi,Tan Chu Quan,Alvarez Jacob Josiah Santiago,Lu Bingxin,Lim Jia Qi,Takano Angela,Nahar Rahul,Lee Yin Yeng,Phua Cheryl Zi Jin,Chua Khi Pin,Suteja Lisda,Chen Pauline Jieqi,Chang Mei Mei,Koh Tina Puay Theng,Ong Boon-Hean,Anantham Devanand,Hsu Anne Ann Ling,Gogna Apoorva,Too Chow Wei,Aung Zaw Win,Lee Yi Fei,Wang Lanying,Lim Tony Kiat Hon,Wilm Andreas,Choi Poh Sum,Ng Poh Yong,Toh Chee Keong,Lim Wan-Teck,Ma Siming,Lim Bing,Liu Jin,Tam Wai Leong,Skanderup Anders Jacobsen,Yeong Joe Poh Sheng,Tan Eng-Huat,Creasy Caretha L,Tan Daniel Shao Weng,Hillmer Axel M,Zhai Weiwei Nature genetics Lung cancer is the world's leading cause of cancer death and shows strong ancestry disparities. By sequencing and assembling a large genomic and transcriptomic dataset of lung adenocarcinoma (LUAD) in individuals of East Asian ancestry (EAS; n = 305), we found that East Asian LUADs had more stable genomes characterized by fewer mutations and fewer copy number alterations than LUADs from individuals of European ancestry. This difference is much stronger in smokers as compared to nonsmokers. Transcriptomic clustering identified a new EAS-specific LUAD subgroup with a less complex genomic profile and upregulated immune-related genes, allowing the possibility of immunotherapy-based approaches. Integrative analysis across clinical and molecular features showed the importance of molecular phenotypes in patient prognostic stratification. EAS LUADs had better prediction accuracy than those of European ancestry, potentially due to their less complex genomic architecture. This study elucidated a comprehensive genomic landscape of EAS LUADs and highlighted important ancestry differences between the two cohorts. 10.1038/s41588-019-0569-6
    Integrative Analysis of Sirtuins and Their Prognostic Significance in Clear Cell Renal Cell Carcinoma. Tan Ying,Li Bijuan,Peng Fang,Gong Guanghui,Li Ning Frontiers in oncology Sirtuins, class III histone deacetylases, are involved in multiple biological processes in cancer initiation and progression. However, the diverse expression patterns and prognostic values of sirtuins in cancers have yet to be elucidated. In this study, we first evaluated the expression and prognostic values of sirtuins in multiple cancer cohorts using publicly available TCGA pan-cancer datasets. Pan-cancer survival analysis indicated that 6 out of 7 sirtuin family members were significant associated with prognosis of clear cell renal cell carcinoma (KIRC) patients. SIRT1, SIRT3, SIRT4, and SIRT5 were associated with favorable prognosis of KIRC patients, while SIRT6 and SIRT7 were associated with unfavorable prognosis. The expression levels of SIRT4 and SIRT5 in KIRC tissues were lower than that in normal tissues, while SIRT6 and SIRT7 were higher in KIRC tissues. The expression levels of SIRT1, SIRT3, SIRT5, SIRT6, and SIRT7 were significantly correlated with tumor stage and histological grade. DNA methylation may contribute to the dysregulation of sirtuins. Finally, GSEA was conducted to predict the potential functions of sirtuins in KIRC. Our results may provide novel insights for the development of sirtuins-based cancer therapy in KIRC. 10.3389/fonc.2020.00218
    Avelumab versus docetaxel in patients with platinum-treated advanced non-small-cell lung cancer (JAVELIN Lung 200): an open-label, randomised, phase 3 study. Barlesi Fabrice,Vansteenkiste Johan,Spigel David,Ishii Hidenobu,Garassino Marina,de Marinis Filippo,Özgüroğlu Mustafa,Szczesna Aleksandra,Polychronis Andreas,Uslu Ruchan,Krzakowski Maciej,Lee Jong-Seok,Calabrò Luana,Arén Frontera Osvaldo,Ellers-Lenz Barbara,Bajars Marcis,Ruisi Mary,Park Keunchil The Lancet. Oncology BACKGROUND:Antibodies targeting the immune checkpoint molecules PD-1 or PD-L1 have demonstrated clinical efficacy in patients with metastatic non-small-cell lung cancer (NSCLC). In this trial we investigated the efficacy and safety of avelumab, an anti-PD-L1 antibody, in patients with NSCLC who had already received platinum-based therapy. METHODS:JAVELIN Lung 200 was a multicentre, open-label, randomised, phase 3 trial at 173 hospitals and cancer treatment centres in 31 countries. Eligible patients were aged 18 years or older and had stage IIIB or IV or recurrent NSCLC and disease progression after treatment with a platinum-containing doublet, an Eastern Cooperative Oncology Group performance status score of 0 or 1, an estimated life expectancy of more than 12 weeks, and adequate haematological, renal, and hepatic function. Participants were randomly assigned (1:1), via an interactive voice-response system with a stratified permuted block method with variable block length, to receive either avelumab 10 mg/kg every 2 weeks or docetaxel 75 mg/m every 3 weeks. Randomisation was stratified by PD-L1 expression (≥1% vs <1% of tumour cells), which was measured with the 73-10 assay, and histology (squamous vs non-squamous). The primary endpoint was overall survival, analysed when roughly 337 events (deaths) had occurred in the PD-L1-positive population. Efficacy was analysed in all PD-L1-positive patients (ie, PD-L1 expression in ≥1% of tumour cells) randomly assigned to study treatment (the primary analysis population) and then in all randomly assigned patients through a hierarchical testing procedure. Safety was analysed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT02395172. Enrolment is complete, but the trial is ongoing. FINDINGS:Between March 24, 2015, and Jan 23, 2017, 792 patients were enrolled and randomly assigned to receive avelumab (n=396) or docetaxel (n=396). 264 participants in the avelumab group and 265 in the docetaxel group had PD-L1-positive tumours. In patients with PD-L1-positive tumours, median overall survival did not differ significantly between the avelumab and docetaxel groups (11·4 months [95% CI 9·4-13·9] vs 10·3 months [8·5-13·0]; hazard ratio 0·90 [96% CI 0·72-1·12]; one-sided p=0·16). Treatment-related adverse events occurred in 251 (64%) of 393 avelumab-treated patients and 313 (86%) of 365 docetaxel-treated patients, including grade 3-5 events in 39 (10%) and 180 (49%) patients, respectively. The most common grade 3-5 treatment-related adverse events were infusion-related reaction (six patients [2%]) and increased lipase (four [1%]) in the avelumab group and neutropenia (51 [14%]), febrile neutropenia (37 [10%]), and decreased neutrophil counts (36 [10%]) in the docetaxel group. Serious treatment-related adverse events occurred in 34 (9%) patients in the avelumab group and 75 (21%) in the docetaxel group. Treatment-related deaths occurred in four (1%) participants in the avelumab group, two due to interstitial lung disease, one due to acute kidney injury, and one due to a combination of autoimmune myocarditis, acute cardiac failure, and respiratory failure. Treatment-related deaths occurred in 14 (4%) patients in the docetaxel group, three due to pneumonia, and one each due to febrile neutropenia, septic shock, febrile neutropenia with septic shock, acute respiratory failure, cardiovascular insufficiency, renal impairment, leucopenia with mucosal inflammation and pyrexia, infection, neutropenic infection, dehydration, and unknown causes. INTERPRETATION:Compared with docetaxel, avelumab did not improve overall survival in patients with platinum-treated PD-L1-positive NSCLC, but had a favourable safety profile. FUNDING:Merck and Pfizer. 10.1016/S1470-2045(18)30673-9
    Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study. Solomon Benjamin J,Besse Benjamin,Bauer Todd M,Felip Enriqueta,Soo Ross A,Camidge D Ross,Chiari Rita,Bearz Alessandra,Lin Chia-Chi,Gadgeel Shirish M,Riely Gregory J,Tan Eng Huat,Seto Takashi,James Leonard P,Clancy Jill S,Abbattista Antonello,Martini Jean-François,Chen Joseph,Peltz Gerson,Thurm Holger,Ou Sai-Hong Ignatius,Shaw Alice T The Lancet. Oncology BACKGROUND:Lorlatinib is a potent, brain-penetrant, third-generation inhibitor of ALK and ROS1 tyrosine kinases with broad coverage of ALK mutations. In a phase 1 study, activity was seen in patients with ALK-positive non-small-cell lung cancer, most of whom had CNS metastases and progression after ALK-directed therapy. We aimed to analyse the overall and intracranial antitumour activity of lorlatinib in patients with ALK-positive, advanced non-small-cell lung cancer. METHODS:In this phase 2 study, patients with histologically or cytologically ALK-positive or ROS1-positive, advanced, non-small-cell lung cancer, with or without CNS metastases, with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2, and adequate end-organ function were eligible. Patients were enrolled into six different expansion cohorts (EXP1-6) on the basis of ALK and ROS1 status and previous therapy, and were given lorlatinib 100 mg orally once daily continuously in 21-day cycles. The primary endpoint was overall and intracranial tumour response by independent central review, assessed in pooled subgroups of ALK-positive patients. Analyses of activity and safety were based on the safety analysis set (ie, all patients who received at least one dose of lorlatinib) as assessed by independent central review. Patients with measurable CNS metastases at baseline by independent central review were included in the intracranial activity analyses. In this report, we present lorlatinib activity data for the ALK-positive patients (EXP1-5 only), and safety data for all treated patients (EXP1-6). This study is ongoing and is registered with ClinicalTrials.gov, number NCT01970865. FINDINGS:Between Sept 15, 2015, and Oct 3, 2016, 276 patients were enrolled: 30 who were ALK positive and treatment naive (EXP1); 59 who were ALK positive and received previous crizotinib without (n=27; EXP2) or with (n=32; EXP3A) previous chemotherapy; 28 who were ALK positive and received one previous non-crizotinib ALK tyrosine kinase inhibitor, with or without chemotherapy (EXP3B); 112 who were ALK positive with two (n=66; EXP4) or three (n=46; EXP5) previous ALK tyrosine kinase inhibitors with or without chemotherapy; and 47 who were ROS1 positive with any previous treatment (EXP6). One patient in EXP4 died before receiving lorlatinib and was excluded from the safety analysis set. In treatment-naive patients (EXP1), an objective response was achieved in 27 (90·0%; 95% CI 73·5-97·9) of 30 patients. Three patients in EXP1 had measurable baseline CNS lesions per independent central review, and objective intracranial responses were observed in two (66·7%; 95% CI 9·4-99·2). In ALK-positive patients with at least one previous ALK tyrosine kinase inhibitor (EXP2-5), objective responses were achieved in 93 (47·0%; 39·9-54·2) of 198 patients and objective intracranial response in those with measurable baseline CNS lesions in 51 (63·0%; 51·5-73·4) of 81 patients. Objective response was achieved in 41 (69·5%; 95% CI 56·1-80·8) of 59 patients who had only received previous crizotinib (EXP2-3A), nine (32·1%; 15·9-52·4) of 28 patients with one previous non-crizotinib ALK tyrosine kinase inhibitor (EXP3B), and 43 (38·7%; 29·6-48·5) of 111 patients with two or more previous ALK tyrosine kinase inhibitors (EXP4-5). Objective intracranial response was achieved in 20 (87·0%; 95% CI 66·4-97·2) of 23 patients with measurable baseline CNS lesions in EXP2-3A, five (55·6%; 21·2-86·3) of nine patients in EXP3B, and 26 (53·1%; 38·3-67·5) of 49 patients in EXP4-5. The most common treatment-related adverse events across all patients were hypercholesterolaemia (224 [81%] of 275 patients overall and 43 [16%] grade 3-4) and hypertriglyceridaemia (166 [60%] overall and 43 [16%] grade 3-4). Serious treatment-related adverse events occurred in 19 (7%) of 275 patients and seven patients (3%) permanently discontinued treatment because of treatment-related adverse events. No treatment-related deaths were reported. INTERPRETATION:Consistent with its broad ALK mutational coverage and CNS penetration, lorlatinib showed substantial overall and intracranial activity both in treatment-naive patients with ALK-positive non-small-cell lung cancer, and in those who had progressed on crizotinib, second-generation ALK tyrosine kinase inhibitors, or after up to three previous ALK tyrosine kinase inhibitors. Thus, lorlatinib could represent an effective treatment option for patients with ALK-positive non-small-cell lung cancer in first-line or subsequent therapy. FUNDING:Pfizer. 10.1016/S1470-2045(18)30649-1
    Relationship between Overall Survival and Response or Progression-Free Survival in Advanced Non-Small Cell Lung Cancer Patients Treated with Anti-PD-1/PD-L1 Antibodies. Shukuya Takehito,Mori Keita,Amann Joseph M,Bertino Erin M,Otterson Gregory A,Shields Peter G,Morita Satoshi,Carbone David P Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer INTRODUCTION:Alternative predictive end points for overall survival (OS), such as tumor response and progression-free survival (PFS), are useful in the early detection of drug efficacy; however, they have not been fully investigated in patients with advanced NSCLC treated with anti-programmed death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) antibodies. METHODS:In a systematic review of the reported prospective clinical trials, data for response rate, median PFS, and median OS were extracted from 12 arms in 10 reported clinical trials using anti-PD-1/PD-L1 antibody, and their correlation was investigated. In a retrospective analysis at our institution, OS was compared according to tumor response on 5- to 9-week computed tomography scans and status of being progression-free at 8, 16, and 24 weeks by landmark analysis in 71 patients with advanced NSCLC treated with anti-PD-1/PD-L1 antibodies between 2013 and 2015. RESULTS:In a systematic review, moderate correlations between median OS and median PFS (p = 0.120, r = 0.473) and between median OS and response rate (p = 0.141, r = 0.452) were identified using the Spearman correlation coefficient, although these correlations were not statistically significant. In a retrospective analysis of patients treated at our institution, disease control (partial response [PR]/stable disease versus progressive disease/not evaluable), and progression-free status at 8, 16, and 24 weeks significantly predicted OS (Cox proportional hazards model, PR/stable disease versus progressive disease/not evaluable, p = 0.0104, HR = 3.041; 8-week progression-free yes versus no, p = 0.0183, HR = 2.684; 16-week progression-free yes versus no, p = 0.0036, HR = 4.009; and 24-week progression-free yes versus no, p = 0.0002, HR = 12.726). CONCLUSIONS:Both disease control (PR plus stable disease status) and landmark progression-free survival were correlated with OS, with the longer interval landmark PFS being the best predictor of survival in patients with NSCLC treated with anti-PD-1/PD-L1 antibodies. 10.1016/j.jtho.2016.07.017
    Randomized phase III study of docetaxel plus bavituximab in previously treated advanced non-squamous non-small-cell lung cancer. Gerber D E,Horn L,Boyer M,Sanborn R,Natale R,Palmero R,Bidoli P,Bondarenko I,Germonpre P,Ghizdavescu D,Kotsakis A,Lena H,Losonczy G,Park K,Su W-C,Tang M,Lai J,Kallinteris N L,Shan J S,Reck M,Spigel D R Annals of oncology : official journal of the European Society for Medical Oncology Background:Bavituximab is a monoclonal antibody that targets phosphatidylserine in the presence of β2 glycoprotein 1 (β2GP1) to exert an antitumor immune response. This phase III trial determined the efficacy of bavituximab combined with docetaxel in patients with previously treated advanced non-small-cell lung cancer (NSCLC). Patients and methods:Key eligibility criteria included advanced non-squamous NSCLC with disease progression after treatment with platinum-based doublet chemotherapy, evidence of disease control after at least two cycles of first-line therapy, presence of measurable disease, ECOG performance status 0 or 1, adequate bone marrow and organ function, and no recent history of clinically significant bleeding. Eligible patients were randomized 1 : 1 to receive up to six 21-day cycles of docetaxel plus either weekly bavituximab 3 mg/kg or placebo until progression or toxicity. The primary end point was overall survival (OS). Results:A total of 597 patients were enrolled. Median OS was 10.5 months in the docetaxel + bavituximab arm and was 10.9 months in the docetaxel + placebo arm (HR 1.06; 95% CI 0.88-1.29; P = 0.533). There was no difference in progression-free survival (HR 1.00; 95% CI 0.82-1.22; P = 0.990). Toxicities were manageable and similar between arms. In subset analysis, among patients with high baseline serum β2GP1 levels ≥200 µg/ml, a nonsignificant OS trend favored the bavituximab arm (HR 0.82; 95% CI 0.63-1.06; P = 0.134). Among patients who received post-study immune checkpoint inhibitor therapy, OS favored the bavituximab arm (HR 0.46; 95% CI 0.26-0.81; P = 0.006). Conclusions:The combination of bavituximab plus docetaxel is not superior to docetaxel in patients with previously treated advanced NSCLC. The addition of bavituximab to docetaxel does not meaningfully increase toxicity. The potential benefit of bavituximab observed in patients with high β2GP1 levels and in patients subsequently treated with immune checkpoint inhibitors requires further investigation. Clinical trial number:NCT01999673. 10.1093/annonc/mdy177
    Targeted Therapy and Immunotherapy for Lung Cancer. Naylor Evan C,Desani Jatin K,Chung Paul K Surgical oncology clinics of North America Targeted therapy and immunotherapy have changed the treatment paradigm of non-small cell lung cancer (NSCLC). Distinct molecular subtypes of NSCLC have been described over the past 20 years, enabling the emergence of treatments specific to that subtype. Agents targeting the driver mutations in NSCLC have revolutionized the approach to patients with metastatic disease, because oncologists now select a treatment based on the profile of that particular tumor. More recently, an understanding of immune checkpoints has led to the development of checkpoint inhibitors that enable the host immune system to better recognize tumor cells as foreign and to destroy them. 10.1016/j.soc.2016.02.011
    Updates on immunotherapy in non-small cell lung cancer. Shimanovsky Alexei,Dasanu Constantin A Expert opinion on biological therapy Immunotherapy has made significant progress in patients with non-small cell lung cancer (NSCLC) in the last years. Early tumor vaccine studies showed trends toward better clinical outcomes, and larger trial results are currently being awaited. Immune checkpoint inhibitors are promising therapeutic agents in advanced NSCLC. While ipilimumab, a cytotoxic T-lymphocyte antigen 4 inhibitor, has clearly improved outcomes in metastatic malignant melanoma, its safety and efficacy in NSCLC are not yet known. Programmed death-1 (PD-1) and PD-1 ligand inhibitors such as nivolumab, MK3475 and MPDL3280 have demonstrated clinical efficacy in patients with advanced/metastatic NSCLC in early clinical trials. Their validation in larger Phase III trials is anxiously being awaited. Furthermore, exploring efficacy of these molecules in patients with early stages of lung cancer is also necessary. 10.1517/14712598.2014.887675
    Cancer immunotherapy: a future paradigm shift in the treatment of non-small cell lung cancer. Anagnostou Valsamo K,Brahmer Julie R Clinical cancer research : an official journal of the American Association for Cancer Research Emerging evidence on the role of the antitumor activity of the immune system has generated great interest in immunotherapy even for tumors that were historically considered as nonimmunogenic. Immunotherapy is emerging as a major modality in non-small cell lung cancer (NSCLC) treatment focusing on vaccine approaches to elicit specific immune responses and development of inhibitors of the molecular mediators of cancer-induced immunosuppression (immune checkpoints) to boost antitumor immune responses. Amplification of the host response against evolving tumors through vaccination is being investigated in ongoing clinical trials with tumor cell vaccines; however, the clinical efficacy of these agents has been limited. Blocking inhibitory pathways such as the CTL antigen 4 (CTLA-4) and programmed cell death 1 (PD-1) checkpoint pathways with mAbs has generated antitumor immune responses that are transforming cancer therapeutics. PD-1 and programmed cell death ligand 1 (PD-L1) antibodies have shown durable responses in NSCLC, with a favorable safety profile and manageable side effects. The activity of immune checkpoint inhibitors is currently been assessed in treatment-naïve patients with PD-L1-positive advanced NSCLC. Combinatorial approaches with other immune checkpoint inhibitors, chemotherapy, or targeted agents are being explored in ongoing clinical trials, and may improve outcome in NSCLC. 10.1158/1078-0432.CCR-14-1187
    Immunotherapy in the treatment of non-small cell lung cancer. Sundar Raghav,Soong Richie,Cho Byoung-Chul,Brahmer Julie R,Soo Ross A Lung cancer (Amsterdam, Netherlands) Advances in the understanding of the role of the immune system in tumor immunosurveillance have resulted in the recognition that tumors can evade immune destruction via the dysregulation of co-inhibitory or checkpoint signals. This has led to the development of a generation immunotherapeutic agents targeting the immune checkpoint pathway. Recent early phase studies of immune checkpoint modulators, such as CTLA-4, PD-1 and PD-L1 inhibitors in NSCLC have reported promising results with prolonged clinical responses and tolerable toxicity. This article provides an overview of co-stimulatory and inhibitory molecules that regulate the immune response to tumors, recent therapies that have been developed to exploit these interactions and the role of predictive biomarkers in treatment selection. 10.1016/j.lungcan.2014.05.005
    What lies within: novel strategies in immunotherapy for non-small cell lung cancer. Forde Patrick M,Reiss Kim A,Zeidan Amer M,Brahmer Julie R The oncologist Immunotherapy has become an increasingly important therapeutic strategy for those with cancer, with phase III studies demonstrating survival advantages in melanoma and castration-resistant prostate cancer. Non-small cell lung cancer (NSCLC) is a promising target for the next generation of immune-based strategies. In this article, we examine the current state of the art in lung cancer immunotherapy, including vaccines that specifically target lung tumor antigens and immune checkpoint antibodies such as antiprogrammed death 1 (anti-PD-1). Both approaches harness innate immunity against tumors by suppressing tumor-induced immune paresis. Methods. To identify relevant clinical trials of immunotherapy in NSCLC, PubMed and Medline databases were searched using the terms "immunotherapy" and "NSCLC," and several other therapy-specific search terms (e.g., PD-1, NSCLC). Additionally, abstracts presented at international lung cancer symposia, the American Society of Clinical Oncology annual meeting, and the European Society of Medical Oncology annual meeting between 2005 and 2013 were evaluated. Results. Large international phase III trials of NSCLC vaccines have completed accrual in both the adjuvant and metastatic disease settings. Results of the START study were disappointing, but results from other studies are still awaited. Immune checkpoint modulation has shown promise, with separate phase I studies of the anti-PD-1 antibody, nivolumab, and anti-PD-L1 antibody, MPDL3280A, demonstrating good tolerance and durable responses for certain patients with NSCLC who were heavily pretreated. Conclusions. Immune-based strategies have shown initial promise for early- and advanced-stage NSCLC. Validating these findings in randomized studies and discovering durable biomarkers of response represent the next challenges for investigation. 10.1634/theoncologist.2013-0171
    Small-cell lung cancer: what we know, what we need to know and the path forward. Gazdar Adi F,Bunn Paul A,Minna John D Nature reviews. Cancer Small-cell lung cancer (SCLC) is a deadly tumour accounting for approximately 15% of lung cancers and is pathologically, molecularly, biologically and clinically very different from other lung cancers. While the majority of tumours express a neuroendocrine programme (integrating neural and endocrine properties), an important subset of tumours have low or absent expression of this programme. The probable initiating molecular events are inactivation of TP53 and RB1, as well as frequent disruption of several signalling networks, including Notch signalling. SCLC, when diagnosed, is usually widely metastatic and initially responds to cytotoxic therapy but nearly always rapidly relapses with resistance to further therapies. There were no important therapeutic clinical advances for 30 years, leading SCLC to be designated a 'recalcitrant cancer'. Scientific studies are hampered by a lack of tissue availability. However, over the past 5 years, there has been a worldwide resurgence of studies on SCLC, including comprehensive molecular analyses, the development of relevant genetically engineered mouse models and the establishment of patient-derived xenografts. These studies have led to the discovery of new potential therapeutic vulnerabilities for SCLC and therefore to new clinical trials. Thus, while the past has been bleak, the future offers greater promise. 10.1038/nrc.2017.87
    Lung cancer - major changes in the American Joint Committee on Cancer eighth edition cancer staging manual. Rami-Porta Ramón,Asamura Hisao,Travis William D,Rusch Valerie W CA: a cancer journal for clinicians Answer questions and earn CME/CNE The revision for the eighth edition of the tumor, node, and metastasis (TNM) classification of lung cancer was based on analyses of the International Association for the Study of Lung Cancer database, which included 77,156 evaluable patients diagnosed with lung cancer from 1999 to 2010. Among tumor (T) descriptors, the following new tumor-size groups were created: T1a, ≤1 cm; T1b, >1 to 2 cm; T1c, >2 to 3 cm; T2a, >3 to 4 cm; T2b, >4 to 5 cm; T3, >5 to 7 cm; and T4, >7 cm. Tis and T1mi were introduced for adenocarcinoma in situ and minimally invasive adenocarcinoma, respectively. Endobronchial tumors located <2 cm from the carina have better prognosis than those with any other T3 descriptor and were classified as T2. Total atelectasis/pneumonitis was classified as a T2 descriptor, because it has a T2 prognosis. Diaphragmatic invasion is now T4. Visceral pleural invasion remains unchanged, and mediastinal pleura invasion, which is seldom used, disappears as a T descriptor. The lymph node (N) component descriptors are unchanged, but the number of involved nodal stations has prognostic impact. For the metastasis (M) component, M1a (intrathoracic metastases) remains unchanged, but extrathoracic metastases are divided into a single extrathoracic metastasis (new M1b) and multiple extrathoracic metastases in a single organ or multiple organs (M1c). Stage IA is now divided into IA1, IA2, and IA3 to accommodate T1a, T1b, and T1cN0M0 tumors, respectively; all N1 disease is stage IIB except for T3-T4N1M0 tumors, which are stage IIIA; a new stage IIIC is created for T3-T4N3M0 tumors; and stage IV is divided into IVA (M1a and M1b) and IVB (M1c). This revision enhances our capacity for prognostication and will have an important impact in the management of patients with lung cancer and in future research. CA Cancer J Clin 2017;67:138-155. © 2017 American Cancer Society. 10.3322/caac.21390
    European cancer mortality predictions for the year 2017, with focus on lung cancer. Malvezzi M,Carioli G,Bertuccio P,Boffetta P,Levi F,La Vecchia C,Negri E Annals of oncology : official journal of the European Society for Medical Oncology Background:We predicted cancer mortality figures in the European Union (EU) for the year 2017 using most recent available data, with a focus on lung cancer. Materials and methods:We retrieved cancer death certification data and population figures from the World Health Organisation and Eurostat databases. Age-standardized (world standard population) rates were computed for France, Germany, Italy, Poland, Spain, the UK and the EU overall in 1970-2012. We obtained estimates for 2017 by implementing a joinpoint regression model. Results:The predicted number of cancer deaths for 2017 in the EU is 1 373 500, compared with 1 333 400 in 2012 (+3%). Cancer mortality rates are predicted to decline in both sexes, reaching 131.8/100 000 men (-8.2% when compared with 2012) and 84.5/100 000 women (-3.6%). Mortality rates for all selected cancer sites are predicted to decline, except pancreatic cancer in both sexes and lung cancer in women. In men, pancreatic cancer rate is stable, in women it increases by 3.5%. Lung cancer mortality rate in women is predicted to rise to 14.6/100 000 in 2017 (+5.1% since 2012, corresponding to 92 300 predicted deaths), compared with 14.0/100 000 for breast cancer, corresponding to 92 600 predicted deaths. Only younger (25-44) women have favourable lung cancer trends, and rates at this age group are predicted to be similar in women (1.4/100 000) and men (1.2/100 000). In men lung cancer rates are predicted to decline by 10.7% since 2012, and falls are observed in all age groups. Conclusion:European cancer mortality projections for 2017 confirm the overall downward trend in rates, with a stronger pattern in men. This is mainly due to different smoking prevalence trends in different generations of men and women. Lung cancer rates in young European women are comparable to those in men, confirming that smoking has the same impact on lung cancer in the two sexes. 10.1093/annonc/mdx033
    Lung Cancer Screening and Smoking Cessation Clinical Trials. SCALE (Smoking Cessation within the Context of Lung Cancer Screening) Collaboration. Joseph Anne M,Rothman Alexander J,Almirall Daniel,Begnaud Abbie,Chiles Caroline,Cinciripini Paul M,Fu Steven S,Graham Amanda L,Lindgren Bruce R,Melzer Anne C,Ostroff Jamie S,Seaman Elizabeth L,Taylor Kathryn L,Toll Benjamin A,Zeliadt Steven B,Vock David M American journal of respiratory and critical care medicine National recommendations for lung cancer screening for former and current smokers aged 55-80 years with a 30-pack-year smoking history create demand to implement efficient and effective systems to offer smoking cessation on a large scale. These older, high-risk smokers differ from participants in past clinical trials of behavioral and pharmacologic interventions for tobacco dependence. There is a gap in knowledge about how best to design systems to extend reach and treatments to maximize smoking cessation in the context of lung cancer screening. Eight clinical trials, seven funded by the National Cancer Institute and one by the Veterans Health Administration, address this gap and form the SCALE (Smoking Cessation within the Context of Lung Cancer Screening) collaboration. This paper describes methodological issues related to the design of these clinical trials: clinical workflow, participant eligibility criteria, screening indication (baseline or annual repeat screen), assessment content, interest in stopping smoking, and treatment delivery method and dose, all of which will affect tobacco treatment outcomes. Tobacco interventions consider the "teachable moment" offered by lung cancer screening, how to incorporate positive and negative screening results, and coordination of smoking cessation treatment with clinical events associated with lung cancer screening. Unique data elements, such as perceived risk of lung cancer and costs of tobacco treatment, are of interest. Lung cancer screening presents a new and promising opportunity to reduce morbidity and mortality resulting from lung cancer that can be amplified by effective smoking cessation treatment. SCALE teamwork and collaboration promise to maximize knowledge gained from the clinical trials. 10.1164/rccm.201705-0909CI
    Immunological Aspects of Cryoablation of Non-Small Cell Lung Cancer: A Comprehensive Review. Katzman Daniel,Wu Shirley,Sterman Daniel H Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer In cryoimmunotherapy, target tumors are treated with cryoablation to generate antitumor immune responses. Because immune checkpoint inhibitors have demonstrated that lung cancer can be an immunotherapy-responsive disease, there has been renewed interest in the immunological aspects of cryoablation of lung cancer. Herein, we review preclinical and clinical trials of cryoablation of primary lung tumors. We examine the magnitude of cryoablation-induced antitumor immune responses and the synergy between cryoablation and either other immunotherapies or molecular targeted therapies to improve treatment responses in advanced lung cancer. We further discuss a rationale for the addition of cryoablation to immune checkpoint inhibitors for the treatment of advanced lung cancer, which is currently under clinical investigation. 10.1016/j.jtho.2018.01.017
    The IASLC Lung Cancer Staging Project: A Renewed Call to Participation. Giroux Dorothy J,Van Schil Paul,Asamura Hisao,Rami-Porta Ramón,Chansky Kari,Crowley John J,Rusch Valerie W,Kernstine Kemp, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Over the past two decades, the International Association for the Study of Lung Cancer (IASLC) Staging Project has been a steady source of evidence-based recommendations for the TNM classification for lung cancer published by the Union for International Cancer Control and the American Joint Committee on Cancer. The Staging and Prognostic Factors Committee of the IASLC is now issuing a call for participation in the next phase of the project, which is designed to inform the ninth edition of the TNM classification for lung cancer. Following the case recruitment model for the eighth edition database, volunteer site participants are asked to submit data on patients whose lung cancer was diagnosed between January 1, 2011, and December 31, 2019, to the project by means of a secure, electronic data capture system provided by Cancer Research And Biostatistics in Seattle, Washington. Alternatively, participants may transfer existing data sets. The continued success of the IASLC Staging Project in achieving its objectives will depend on the extent of international participation, the degree to which cases are entered directly into the electronic data capture system, and how closely externally submitted cases conform to the data elements for the project. 10.1016/j.jtho.2018.02.012
    The potential to treat lung cancer via inhalation of repurposed drugs. Lee Wing-Hin,Loo Ching-Yee,Ghadiri Maliheh,Leong Chean-Ring,Young Paul M,Traini Daniela Advanced drug delivery reviews Lung cancer is a highly invasive and prevalent disease with ineffective first-line treatment and remains the leading cause of cancer death in men and women. Despite the improvements in diagnosis and therapy, the prognosis and outcome of lung cancer patients is still poor. This could be associated with the lack of effective first-line oncology drugs, formation of resistant tumors and non-optimal administration route. Therefore, the repurposing of existing drugs currently used for different indications and the introduction of a different method of drug administration could be investigated as an alternative to improve lung cancer therapy. This review describes the rationale and development of repositioning of drugs for lung cancer treatment with emphasis on inhalation. The review includes the current progress of repurposing non-cancer drugs, as well as current chemotherapeutics for lung malignancies via inhalation. Several potential non-cancer drugs such as statins, itraconazole and clarithromycin, that have demonstrated preclinical anti-cancer activity, are also presented. Furthermore, the potential challenges and limitations that might hamper the clinical translation of repurposed oncology drugs are described. 10.1016/j.addr.2018.08.012
    Survival Comparison in Patients with Stage IV Lung Cancer in Academic versus Community Centers in the United States. Ramalingam Sendhilnathan,Dinan Michaela A,Crawford Jeffrey Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer INTRODUCTION:Although metastatic NSCLC is widely treated in both academic centers (ACs) and community-based centers (CCs), it is unclear whether outcomes are similar across both settings. A growing variety of chemotherapies and targeted agents for an increasingly histology- and molecular-based treatment strategy could provide an advantage to patients treated in ACs. Using the National Cancer Database, we investigated whether treatment at ACs was associated with a survival advantage in metastatic NSCLC. METHODS:We conducted a retrospective analysis of the National Cancer Database after the introduction of novel NSCLC chemotherapy agents from 1998 to 2010. The primary outcome was 2-year survival, which was analyzed by using a multivariable regression model controlling for age, year of diagnosis, sex, primary payer, histologic type, facility type (AC versus CC), and an interaction term allowing a time-based comparison of survival between ACs and CCs. Alpha was set to 0.001 because of the size of the data set. RESULTS:There were 193,279 patients included in this study. The percentage of patients achieving 2-year survival was higher in ACs versus in CCs in 1998 (11.5% versus 9.2% [+2.3%]), and by 2010, the difference had increased to 17.4% versus 13.1% (+4.3%). Multivariable analysis confirmed a significant relative increase in 2-year survival associated with ACs versus with CCs from 1998 to 2010 (p = 0.0005). A histology-dependent survival difference was also noted in adenocarcinoma versus in squamous cell carcinoma (10.2% versus 9.9% in 1998 [+0.3%], increasing to 17.3% versus 10.1% in 2010 [+7.2%]). Adenocarcinoma survival also varied by treatment facility, with the difference in 2-year survival in ACs versus in CCs increasing from 12.3% versus 9.1% (+3.2%) in 1998 to 20.5% versus 15.5% (+5%) in 2010, with a trend toward significance in our multivariable model (p = 0.005). CONCLUSIONS:A greater increase in survival was noted in ACs than in CCs over this time period, and it was particularly pronounced among patients with adenocarcinoma versus in those with squamous cell carcinoma. Given the known advances in adenocarcinoma treatment compared with in squamous cell lung cancer over this time period, our study suggests that potential treatment-related disparities may exist between ACs and CCs. Further study will be needed to validate this disparity in health care and address opportunities to improve survival in patients with stage IV NSCLC across treatment settings. 10.1016/j.jtho.2018.09.007
    Atezolizumab plus Chemotherapy in Small-Cell Lung Cancer. Diker Omer The New England journal of medicine 10.1056/NEJMc1900123
    Atezolizumab plus Chemotherapy in Small-Cell Lung Cancer. Reply. Horn Leora,Liu Stephen V The New England journal of medicine 10.1056/NEJMc1900123
    Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. Kim Young-Hak The New England journal of medicine 10.1056/NEJMc1900407
    Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. Reply. Antonia Scott J The New England journal of medicine 10.1056/NEJMc1900407
    Lung cancer: diagnosis and management: summary of updated NICE guidance. Maconachie Ross,Mercer Toby,Navani Neal,McVeigh Gary, BMJ (Clinical research ed.) 10.1136/bmj.l1049
    Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Mok Tony S K,Wu Yi-Long,Kudaba Iveta,Kowalski Dariusz M,Cho Byoung Chul,Turna Hande Z,Castro Gilberto,Srimuninnimit Vichien,Laktionov Konstantin K,Bondarenko Igor,Kubota Kaoru,Lubiniecki Gregory M,Zhang Jin,Kush Debra,Lopes Gilberto, Lancet (London, England) BACKGROUND:First-line pembrolizumab monotherapy improves overall and progression-free survival in patients with untreated metastatic non-small-cell lung cancer with a programmed death ligand 1 (PD-L1) tumour proportion score (TPS) of 50% or greater. We investigated overall survival after treatment with pembrolizumab monotherapy in patients with a PD-L1 TPS of 1% or greater. METHODS:This randomised, open-label, phase 3 study was done in 213 medical centres in 32 countries. Eligible patients were adults (≥18 years) with previously untreated locally advanced or metastatic non-small-cell lung cancer without a sensitising EGFR mutation or ALK translocation and with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, life expectancy 3 months or longer, and a PD-L1 TPS of 1% or greater. Randomisation was computer generated, accessed via an interactive voice-response and integrated web-response system, and stratified by region of enrolment (east Asia vs rest of world), ECOG performance status score (0 vs 1), histology (squamous vs non-squamous), and PD-L1 TPS (≥50% vs 1-49%). Enrolled patients were randomly assigned 1:1 in blocks of four per stratum to receive pembrolizumab 200 mg every 3 weeks for up to 35 cycles or the investigator's choice of platinum-based chemotherapy for four to six cycles. Primary endpoints were overall survival in patients with a TPS of 50% or greater, 20% or greater, and 1% or greater (one-sided significance thresholds, p=0·0122, p=0·0120, and p=0·0124, respectively) in the intention-to-treat population, assessed sequentially if the previous findings were significant. This study is registered at ClinicalTrials.gov, number NCT02220894. FINDINGS:From Dec 19, 2014, to March 6, 2017, 1274 patients (902 men, 372 women, median age 63 years [IQR 57-69]) with a PD-L1 TPS of 1% or greater were allocated to pembrolizumab (n=637) or chemotherapy (n=637) and included in the intention-to-treat population. 599 (47%) had a TPS of 50% or greater and 818 patients (64%) had a TPS of 20% or greater. As of Feb 26, 2018, median follow-up was 12·8 months. Overall survival was significantly longer in the pembrolizumab group than in the chemotherapy group in all three TPS populations (≥50% hazard ratio 0·69, 95% CI 0·56-0·85, p=0·0003; ≥20% 0·77, 0·64-0·92, p=0·0020, and ≥1% 0·81, 0·71-0·93, p=0·0018). The median surival values by TPS population were 20·0 months (95% CI 15·4-24·9) for pembrolizumab versus 12·2 months (10·4-14·2) for chemotherapy, 17·7 months (15·3-22·1) versus 13·0 months (11·6-15·3), and 16·7 months (13·9-19·7) versus 12·1 months (11·3-13·3), respectively. Treatment-related adverse events of grade 3 or worse occurred in 113 (18%) of 636 treated patients in the pembrolizumab group and in 252 (41%) of 615 in the chemotherapy group and led to death in 13 (2%) and 14 (2%) patients, respectively. INTERPRETATION:The benefit-to-risk profile suggests that pembrolizumab monotherapy can be extended as first-line therapy to patients with locally advanced or metastatic non-small-cell lung cancer without sensitising EGFR or ALK alterations and with low PD-L1 TPS. FUNDING:Merck Sharp & Dohme. 10.1016/S0140-6736(18)32409-7
    Lung Cancer Worldwide. Adjei Alex A Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 10.1016/j.jtho.2019.04.001
    Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. West Howard,McCleod Michael,Hussein Maen,Morabito Alessandro,Rittmeyer Achim,Conter Henry J,Kopp Hans-Georg,Daniel Davey,McCune Steven,Mekhail Tarek,Zer Alona,Reinmuth Niels,Sadiq Ahad,Sandler Alan,Lin Wei,Ochi Lohmann Tania,Archer Venice,Wang Lijia,Kowanetz Marcin,Cappuzzo Federico The Lancet. Oncology BACKGROUND:Atezolizumab (a monoclonal antibody against PD-L1), which restores anticancer immunity, improved overall survival in patients with previously treated non-small-cell lung cancer and also showed clinical benefit when combined with chemotherapy as first-line treatment of non-small-cell lung cancer. IMpower130 aimed to assess the efficacy and safety of atezolizumab plus chemotherapy versus chemotherapy alone as first-line therapy for non-squamous non-small-cell lung cancer. METHODS:IMpower130 was a multicentre, randomised, open-label, phase 3 study done in 131 centres across eight countries (the USA, Canada, Belgium, France, Germany, Italy, Spain, and Israel). Eligible patients were aged 18 years or older, and had histologically or cytologically confirmed stage IV non-squamous non-small-cell lung cancer, an Eastern Cooperative Oncology Group performance status of 0 or 1, and received no previous chemotherapy for stage IV disease. Patients were randomly assigned (2:1; permuted block [block size of six] with an interactive voice or web response system) to receive atezolizumab (1200 mg intravenously every 3 weeks) plus chemotherapy (carboplatin [area under the curve 6 mg/mL per min every 3 weeks] plus nab-paclitaxel [100 mg/m intravenously every week]) or chemotherapy alone for four or six 21-day cycles followed by maintenance therapy. Stratification factors were sex, baseline liver metastases, and PD-L1 tumour expression. Co-primary endpoints were investigator-assessed progression-free survival and overall survival in the intention-to-treat wild-type (ie, EGFR and ALK) population. The safety population included patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02367781. FINDINGS:Between April 16, 2015, and Feb 13, 2017, 724 patients were randomly assigned and 723 were included in the intention-to-treat population (one patient died before randomisation, but was assigned to a treatment group; this patient was excluded from the intention-to-treat population) of the atezolizumab plus chemotherapy group (483 patients in the intention-to-treat population and 451 patients in the intention-to-treat wild-type population) or the chemotherapy group (240 patients in the intention-to-treat population and 228 patients in the intention-to-treat wild-type population). Median follow-up in the intention-to-treat wild-type population was similar between groups (18·5 months [IQR 15·2-23·6] in the atezolizumab plus chemotherapy group and 19·2 months [15·4-23·0] in the chemotherapy group). In the intention-to-treat wild-type population, there were significant improvements in median overall survival (18·6 months [95% CI 16·0-21·2] in the atezolizumab plus chemotherapy group and 13·9 months [12·0-18·7] in the chemotherapy group; stratified hazard ratio [HR] 0·79 [95% CI 0·64-0·98]; p=0·033) and median progression-free survival (7·0 months [95% CI 6·2-7·3] in the atezolizumab plus chemotherapy group and 5·5 months [4·4-5·9] in the chemotherapy group; stratified HR 0·64 [95% CI 0·54-0·77]; p<0·0001]). The most common grade 3 or worse treatment-related adverse events were neutropenia (152 [32%] of 473 in the atezolizumab plus chemotherapy group vs 65 [28%] of 232 in the chemotherapy group), anaemia (138 [29%] vs 47 [20%]), and decreased neutrophil count (57 [12%] vs 19 [8%]). Treatment-related serious adverse events were reported in 112 (24%) of 473 patients in the atezolizumab plus chemotherapy group and 30 (13%) of 232 patients in the chemotherapy group. Treatment-related (any treatment) deaths occurred in eight (2%) of 473 patients in the atezolizumab plus chemotherapy group and one (<1%) of 232 patients in the chemotherapy group. INTERPRETATION:IMpower130 showed a significant and clinically meaningful improvement in overall survival and a significant improvement in progression-free survival with atezolizumab plus chemotherapy versus chemotherapy as first-line treatment of patients with stage IV non-squamous non-small-cell lung cancer and no ALK or EGFR mutations. No new safety signals were identified. This study supports the benefit of atezolizumab, in combination with platinum-based chemotherapy, as first-line treatment of metastatic non-small-cell lung cancer. FUNDING:F. Hoffmann-La Roche. 10.1016/S1470-2045(19)30167-6
    5-year overall survival in patients with lung cancer eligible or ineligible for screening according to US Preventive Services Task Force criteria: a prospective, observational cohort study. Luo Yung-Hung,Luo Lei,Wampfler Jason A,Wang Yi,Liu Dan,Chen Yuh-Min,Adjei Alex A,Midthun David E,Yang Ping The Lancet. Oncology BACKGROUND:The US Preventive Services Task Force (USPSTF) recommends lung cancer screening among individuals aged 55-80 years with a 30 pack-year cigarette smoking history and, if they are former smokers, those who quit within the past 15 years. Our previous report found that two-thirds of newly diagnosed patients with lung cancer do not meet these criteria; they are reported to be either long-term quitters (≥15 years since quitting) or from a younger age group (age 50-54 years). We aimed to assess survival outcomes in these two subgroups. METHODS:For this prospective, observational cohort study we identified and followed up patients aged 50-80 years with lung cancer, with a smoking history of 30 pack-years or more, and included both current smokers and former smokers who quit within the past 30 years. We identified patients from two cohorts in the USA: a hospital cohort (Mayo Clinic, Rochester, MN) and a community cohort (Olmsted County, MN). Patients were divided into those meeting USPSTF criteria (USPSTF group) versus those not meeting USPSTF criteria (long-term quitters or the younger age group). The main outcome was overall survival at 5 years after diagnosis. 5-year overall survival was analysed with and without matching age and pack-years smoked for long-term quitters. The USPSTF group was subdivided into two age subgroups (55-69 years and 70-80 years) for multivariable regression analysis. FINDINGS:Between Jan 1, 1997, and Dec 31, 2017, 8739 patients with lung cancer were identified and followed up. Median follow-up was 6·5 (IQR 3·8-10·0) years, and median overall survival was 16·9 months (95% CI 16·2-17·5). 5-year overall survival was 27% (95% CI 25-30) in long-term quitters, 22% (19-25) in the younger age group, and 23% (22-24) in the USPSTF group. In both cohorts, 5-year overall survival did not differ significantly between long-term quitters and the USPSTF group (hospital cohort: hazard ratio [HR] 1·02 [95% CI 0·94-1·10]; p=0·72; community cohort: 0·97 [0·75-1·26]; p=0·82); matched analysis showed similar results in both cohorts. 5-year overall survival also did not differ significantly between the younger age group and the USPSTF group in both cohorts (hospital cohort: HR 1·16 [95% CI 0·98-1·38], p=0·08; community cohort: 1·16 [0·74-1·82]; p=0·52); multivariable regression analyses stratified by age group yielded similar findings. INTERPRETATION:Patients with lung cancer who quit 15 or more years before diagnosis and those who are up to 5 years younger than the age cutoff recommended for screening, but otherwise meet USPSTF criteria, have a similar risk of death to those individuals who meet all USPSTF criteria. Individuals in both subgroups could benefit from screening, as expansion of USPSTF screening criteria to include these subgroups could enable earlier detection of lung cancer and improved survival outcomes. FUNDING:National Institutes of Health and the Mayo Clinic Foundation. 10.1016/S1470-2045(19)30329-8
    Lung Cancer Incidence and Mortality with Extended Follow-up in the National Lung Screening Trial. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer INTRODUCTION:The National Lung Screening Trial (NLST) randomized high-risk current and former smokers to three annual screens with either low-dose computed tomography (LDCT) or chest radiography (CXR) and demonstrated a significant reduction in lung cancer mortality in the LDCT arm after a median of 6.5 years' follow-up. We report on extended follow-up of NLST subjects. METHODS:Subjects were followed by linkage to state cancer registries and the National Death Index. The number needed to screen (NNS) to prevent one lung cancer death was computed as the reciprocal of the difference in the proportion of patients dying of lung cancer across arms. Lung cancer mortality rate ratios (RRs) were computed overall and adjusted for dilution effect, with the latter including only deaths with a corresponding diagnosis close enough to the end of protocol screening. RESULTS:The median follow-up times were 11.3 years for incidence and 12.3 years for mortality. In all, 1701 and 1681 lung cancers were diagnosed in the LDCT and CXR arms, respectively (RR = 1.01, 95% confidence interval [CI]: 0.95-1.09). The observed numbers of lung cancer deaths were 1147 (with LDCT) versus 1236 (with CXR) (RR = 0.92, 95% CI: 0.85-1.00). The difference in the number of patients dying of lung cancer (per 1000) across arms was 3.3, translating into an NNS of 303, which is similar to the original NNS estimate of around 320. The dilution-adjusted lung cancer mortality RR was 0.89 (95% CI: 0.80-0.997). With regard to overall mortality, there were 5253 (with LDCT) and 5366 (with CXR) deaths, for a difference across arms (per 1000) of 4.2 (95% CI: -2.6 to 10.9). CONCLUSION:Extended follow-up of the NLST showed an NNS similar to that of the original analysis. There was no overall increase in lung cancer incidence in the LDCT arm versus in the CXR arm. 10.1016/j.jtho.2019.05.044
    Untangling the evolutionary roots of lung cancer. Devarakonda Siddhartha,Govindan Ramaswamy Nature communications 10.1038/s41467-019-10879-6
    Micronodules Detected on Computed Tomography During the National Lung Screening Trial: Prevalence and Relation to Positive Studies and Lung Cancer. Munden Reginald F,Chiles Caroline,Boiselle Phillip M,Sicks JoRean D,Aberle Denise R,Gatsonis Constantine A Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer INTRODUCTION:In the National Lung Screening Trial (NLST) all cases with a 4-mm nodule (micronodule) and no other findings were classified as a negative study. The prevalence and malignant potential of micronodules in the NLST is evaluated to understand if this classification was appropriate. METHODS AND MATERIALS:In the NLST a total of 53,452 participants were enrolled with 26,722 undergoing low-dose computed tomography (CT) screening. To determine whether a micronodule developed into a lung cancer, a list from the NLST database of those participants who developed lung cancer and had a micronodule recorded was selected. The CT images of this subset were reviewed by experienced, fellowship-trained thoracic radiologists (R.F.M., C.C., P.M.B., and D.R.A.), all of whom participated as readers in the NLST. RESULTS:There were 26,722 participants who underwent CT in the NLST, of which 11,326 (42%) participants had at least one CT with a micronodule. Five thousand five hundred sixty (49%) of these participants had at least one positive CT examination, of which 409 (3.6%) subsequently were diagnosed with lung cancer. Of the 409 lung cancer cases with a micronodule recorded, there were 13 cases in which a micronodule developed into lung cancer. Considering the 13 cases, they represent 1.2% (13 of 1089) of the lung cancers diagnosed in the CT arm of the NLST and 0.11% (13 of 11,326) of the total micronodule cases. Additionally they represent 0.23% (13 of 5560) of the micronodule and at least one positive CT examination cases and 3.2% (13 of 409) of the micronodule cases diagnosed with lung cancer. The average size of the nodule at baseline (recorded as maximum diameter by perpendicular diameter) was 3.0 × 2.5 mm (ranges 2 x 4 mm and 2 x 4 mm) and at the positive CT the nodule was 11.1 × 8.6 mm (ranges, 6 x 20 mm and 5 x 14 mm); a difference of average change in size of 8.1 × 6.1 mm. The average number of days from first CT with a micronodule recorded to positive CT was 459 days (range, 338 - 723 days), the mean time from first CT with micronodule to lung cancer diagnosis was 617 days (range, 380 - 1140 days) and the mean time from positive CT to lung cancer diagnosis was 160 days (range, 18 - 417 days). Histologically, there was one small cell carcinoma and 12 non-small cell with stages of IA in 8 (62%), stage IB in 2 (15%), and 1 each stage IIIA, IIIB, and IV. The overall survival of NSCLC cases with a micronodule was not significantly different than the survival of the CT subset diagnosed with NSCL (p = 0.36). CONCLUSIONS:Micronodules are common among lung cancer-screened participants and are capable of developing into lung cancer; however, following micronodules by annual CT screening surveillance is appropriate and does not impact overall survival or outcome. 10.1016/j.jtho.2019.05.045
    Systemic Therapy for Locally Advanced and Metastatic Non-Small Cell Lung Cancer: A Review. Arbour Kathryn C,Riely Gregory J JAMA Importance:Non-small cell lung cancer remains the leading cause of cancer death in the United States. Until the last decade, the 5-year overall survival rate for patients with metastatic non-small cell lung cancer was less than 5%. Improved understanding of the biology of lung cancer has resulted in the development of new biomarker-targeted therapies and led to improvements in overall survival for patients with advanced or metastatic disease. Observations:Systemic therapy for metastatic non-small cell lung cancer is selected according to the presence of specific biomarkers. Therefore, all patients with metastatic non-small cell lung cancer should undergo molecular testing for relevant mutations and expression of the protein PD-L1 (programmed death ligand 1). Molecular alterations that predict response to treatment (eg, EGFR mutations, ALK rearrangements, ROS1 rearrangements, and BRAF V600E mutations) are present in approximately 30% of patients with non-small cell lung cancer. Targeted therapy for these alterations improves progression-free survival compared with cytotoxic chemotherapy. For example, somatic activating mutations in the EGFR gene are present in approximately 20% of patients with advanced non-small cell lung cancer. Tyrosine kinase inhibitors such as gefitinib, erlotinib, and afatinib improve progression-free survival in patients with susceptible EGFR mutations. In patients with overexpression of ALK protein, the response rate was significantly better with crizotinib (a tyrosine kinase inhibitor) than with the combination of pemetrexed and either cisplatin or carboplatin (platinum-based chemotherapy) (74% vs 45%, respectively; P < .001) and progression-free survival (median, 10.9 months vs 7.0 months; P < .001). Subsequent generations of tyrosine kinase inhibitors have improved these agents. For patients without biomarkers indicating susceptibility to specific targeted treatments, immune checkpoint inhibitor-containing regimens either as monotherapy or in combination with chemotherapy are superior vs chemotherapy alone. These advances in biomarker-directed therapy have led to improvements in overall survival. For example, the 5-year overall survival rate currently exceeds 25% among patients whose tumors have high PD-L1 expression (tumor proportion score of ≥50%) and 40% among patients with ALK-positive tumors. Conclusions and Relevance:Improved understanding of the biology and molecular subtypes of non-small cell lung cancer have led to more biomarker-directed therapies for patients with metastatic disease. These biomarker-directed therapies and newer empirical treatment regimens have improved overall survival for patients with metastatic non-small cell lung cancer. 10.1001/jama.2019.11058
    PD-L1 Status and Survival in Patients With Lung Cancer. Yang Xin,Qi Chuang,Ji Mei JAMA 10.1001/jama.2019.9177
    Immunotherapy: a new era in small-cell lung cancer. Goetze Thorsten Oliver Lancet (London, England) 10.1016/S0140-6736(19)32235-4
    Lung Cancer Incidence in Nonmetropolitan and Metropolitan Counties - United States, 2007-2016. O'Neil Mary Elizabeth,Henley S Jane,Rohan Elizabeth A,Ellington Taylor D,Gallaway M Shayne MMWR. Morbidity and mortality weekly report Lung and bronchus (lung) cancer is the leading cause of cancer death in the United States (1). In 2016, 148,869 lung cancer deaths were reported.* Most lung cancers can be attributed to modifiable exposures, such as tobacco use, secondhand smoke, radon, and asbestos (1). Exposure to lung cancer risk factors vary over time and by characteristics such as sex, age, and nonmetropolitan or metropolitan residence that might affect lung cancer rates (1,2). A recent report found that lung cancer incidence rates were higher and decreased more slowly in nonmetropolitan counties than in metropolitan counties (3). To examine whether lung cancer incidence trends among nonmetropolitan and metropolitan counties differed by age and sex, CDC analyzed data from U.S. Cancer Statistics during 2007-2016, the most recent years for which data are available. During the 10-year study period, lung cancer incidence rates were stable among females aged <35, 45-64, and ≥75 years in nonmetropolitan counties, were stable among females aged <35 years in metropolitan counties, and decreased in all other groups. Overall, among males, lung cancer incidence rates decreased from 99 to 82 per 100,000 in nonmetropolitan areas and from 83 to 63 in metropolitan areas; among females, lung cancer incidence rates decreased from 61 to 58 in nonmetropolitan areas and from 57 to 50 in metropolitan areas. A comprehensive approach to lung cancer prevention and control includes such population-based strategies as screening for tobacco dependence, promoting tobacco cessation, implementing comprehensive smoke-free laws, testing all homes for radon and using proven methods to lower high radon levels, and reducing exposure to lung carcinogens such as asbestos (1). Increasing the implementation of these strategies, particularly among persons living in nonmetropolitan counties, might help to reduce disparities in the decline of lung cancer incidence. 10.15585/mmwr.mm6844a1
    Lung cancer staging: a concise update. Rami-Porta Ramón,Call Sergi,Dooms Christophe,Obiols Carme,Sánchez Marcelo,Travis William D,Vollmer Ivan The European respiratory journal Diagnosis and clinical staging of lung cancer are fundamental to planning therapy. The techniques for clinical staging, anatomic and metabolic imaging, endoscopies and minimally invasive surgical procedures, should be performed sequentially and with an increasing degree of invasiveness. Intraoperative staging, assessing the magnitude of the primary tumour, the involved structures, and the loco-regional lymphatic spread by means of systematic nodal dissection, is essential in order to achieve a complete resection. In resected tumours, pathological staging, with the systematic study of the resected specimens, is the strongest prognostic indicator and is essential to make further decisions on therapy. In the present decade, the guidelines on lung cancer staging of the American College of Chest Physicians and the European Society of Thoracic Surgeons are based on the best available evidence and are widely followed. Recent advances in the classification of the adenocarcinoma of the lung, with the definition of adenocarcinoma , minimally invasive adenocarcinoma and lepidic predominant adenocarcinoma, and the publication of the eighth edition of the tumour, node and metastasis classification of lung cancer, have to be integrated into the staging process. The present review complements the latest guidelines on lung cancer staging by providing an update of all these issues. 10.1183/13993003.00190-2018
    Smoking and Lung Cancer Mortality in the United States From 2015 to 2065: A Comparative Modeling Approach. Jeon Jihyoun,Holford Theodore R,Levy David T,Feuer Eric J,Cao Pianpian,Tam Jamie,Clarke Lauren,Clarke John,Kong Chung Yin,Meza Rafael Annals of internal medicine Background:Tobacco control efforts implemented in the United States since the 1960s have led to considerable reductions in smoking and smoking-related diseases, including lung cancer. Objective:To project reductions in tobacco use and lung cancer mortality from 2015 to 2065 due to existing tobacco control efforts. Design:Comparative modeling approach using 4 simulation models of the natural history of lung cancer that explicitly relate temporal smoking patterns to lung cancer rates. Setting:U.S. population, 1964 to 2065. Participants:Adults aged 30 to 84 years. Measurements:Models were developed using U.S. data on smoking (1964 to 2015) and lung cancer mortality (1969 to 2010). Each model projected lung cancer mortality by smoking status under the assumption that current decreases in smoking would continue into the future (status quo trends). Sensitivity analyses examined optimistic and pessimistic scenarios. Results:Under the assumption of continued decreases in smoking, age-adjusted lung cancer mortality was projected to decrease by 79% between 2015 and 2065. Concomitantly, and despite the expected growth, aging, and longer life expectancy of the U.S. population, the annual number of lung cancer deaths was projected to decrease from 135 000 to 50 000 (63% reduction). However, 4.4 million deaths from lung cancer are still projected to occur in the United States from 2015 to 2065, with about 20 million adults aged 30 to 84 years continuing to smoke in 2065. Limitation:Projections assumed no changes to tobacco control efforts in the future and did not explicitly consider the potential effect of lung cancer screening. Conclusion:Tobacco control efforts implemented since the 1960s will continue to reduce lung cancer rates well into the next half-century. Additional prevention and cessation efforts will be required to sustain and expand these gains to further reduce the lung cancer burden in the United States. Primary Funding Source:National Cancer Institute. 10.7326/M18-1250