Non-small cell lung cancer: current treatment and future advances.

Lung cancer has a poor prognosis; over half of people diagnosed with lung cancer die within one year of diagnosis and the 5-year survival is less than 18%. Non-small cell lung cancer (NSCLC) accounts for the majority of all lung cancer cases. Risk factors for developing NSCLC have been identified, with cigarette smoking being a major factor along with other environmental and genetic risk factors. Depending on the staging of lung cancer, patients are eligible for certain treatments ranging from surgery to radiation to chemotherapy as well as targeted therapy. With the advancement of genetics and biomarkers testing, specific mutations have been identified to better target treatment for individual patients. This review discusses current treatments including surgery, chemotherapy, radiotherapy, and immunotherapy as well as how biomarker testing has helped improve survival in patients with NSCLC.

[1]  M. Sporn,et al.  Effects of transforming growth factor beta on the functions of natural killer cells: depressed cytolytic activity and blunting of interferon responsiveness. , 1986, Journal of immunology.

[2]  N. Dubrawsky Cancer statistics , 1989, CA: a cancer journal for clinicians.

[3]  H. Hansen,et al.  Lung cancer. , 1990, Cancer chemotherapy and biological response modifiers.

[4]  P. Linsley,et al.  Binding of the B cell activation antigen B7 to CD28 costimulates T cell proliferation and interleukin 2 mRNA accumulation , 1991, The Journal of experimental medicine.

[5]  J. Troppmair,et al.  The ins and outs of Raf kinases. , 1994, Trends in biochemical sciences.

[6]  S. Hirohashi,et al.  Small adenocarcinoma of the lung. Histologic characteristics and prognosis. , 1995, Cancer.

[7]  O. Brodin,et al.  Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials , 1995 .

[8]  E. Wynder,et al.  Impact of filter cigarette smoking on lung cancer histology. , 1997, Preventive medicine.

[9]  R. Goldbohm,et al.  Occupational exposure to carcinogens and risk of lung cancer: results from The Netherlands cohort study. , 1997, Occupational and environmental medicine.

[10]  A. Neugut,et al.  Cigarette smoking and large cell carcinoma of the lung. , 1997, Cancer Epidemiology, Biomarkers and Prevention.

[11]  R. Steinman,et al.  Dendritic cells and the control of immunity , 1998, Nature.

[12]  S. Hecht,et al.  Tobacco smoke carcinogens and lung cancer. , 1999, Journal of the National Cancer Institute.

[13]  R. Clough,et al.  Plasma transforming growth factor‐β1 level before radiotherapy correlates with long term outcome of patients with lung carcinoma , 1999, Cancer.

[14]  Y Iwasaki,et al.  [Large cell carcinoma]. , 2000, Nihon rinsho. Japanese journal of clinical medicine.

[15]  A. Darnton,et al.  The quantitative risks of mesothelioma and lung cancer in relation to asbestos exposure. , 2000, The Annals of occupational hygiene.

[16]  J. Crowley,et al.  Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non--small-cell lung cancer: a Southwest Oncology Group trial. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[17]  E. Hersh,et al.  Transduction of human dendritic cells with a recombinant modified vaccinia Ankara virus encoding MUC1 and IL-2 , 2001, Cancer Immunology, Immunotherapy.

[18]  G. Coukos,et al.  Regulatory CD4(+)CD25(+) T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer. , 2001, Cancer research.

[19]  C. June,et al.  Cutting Edge: Regulatory T Cells from Lung Cancer Patients Directly Inhibit Autologous T Cell Proliferation1 , 2002, The Journal of Immunology.

[20]  A. Nicholson,et al.  Mutations of the BRAF gene in human cancer , 2002, Nature.

[21]  David Harrington,et al.  Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. , 2002, The New England journal of medicine.

[22]  G. Scagliotti,et al.  Phase III randomized trial comparing three platinum-based doublets in advanced non-small-cell lung cancer. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[23]  R. Burnett,et al.  Lung cancer, cardiopulmonary mortality, and long-term exposure to fine particulate air pollution. , 2002, JAMA.

[24]  Richard Wooster,et al.  BRAF and RAS mutations in human lung cancer and melanoma. , 2002, Cancer research.

[25]  S. Coca,et al.  Prognostic significance of tumor infiltrating natural killer cells subset CD57 in patients with squamous cell lung cancer. , 2002, Lung cancer.

[26]  M. Meyerson,et al.  Missense mutations of the BRAF gene in human lung adenocarcinoma. , 2002, Cancer research.

[27]  T. Crombet,et al.  Epidermal growth factor-based cancer vaccine for non-small-cell lung cancer therapy. , 2003, Annals of oncology : official journal of the European Society for Medical Oncology.

[28]  Thomas A. Davis,et al.  Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[29]  Christopher I. Amos,et al.  Lung cancer risk in germline p53 mutation carriers: association between an inherited cancer predisposition, cigarette smoking, and cancer risk , 2003, Human Genetics.

[30]  R. Ramlau,et al.  Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[31]  L. Pilotto,et al.  Environmental exposure to carcinogens causing lung cancer: Epidemiological evidence from the medical literature , 2003, Respirology.

[32]  G. Kalemkerian,et al.  Small cell lung cancer , 2010, Seminars in Respiratory and Critical Care Medicine.

[33]  Patricia L. Harris,et al.  Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. , 2004, The New England journal of medicine.

[34]  S. Gabriel,et al.  EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy , 2004, Science.

[35]  R. Wilson,et al.  EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[36]  A. Vlad,et al.  MUC1 immunobiology: from discovery to clinical applications. , 2004, Advances in immunology.

[37]  C. Gridelli,et al.  Treatment of advanced non-small-cell lung cancer patients with ECOG performance status 2: results of an European Experts Panel. , 2004, Annals of oncology : official journal of the European Society for Medical Oncology.

[38]  Daniel Krewski,et al.  Residential Radon and Risk of Lung Cancer: A Combined Analysis of 7 North American Case-Control Studies , 2005, Epidemiology.

[39]  R Doll,et al.  Radon in homes and risk of lung cancer: collaborative analysis of individual data from 13 European case-control studies , 2004, BMJ : British Medical Journal.

[40]  P. Ellis,et al.  Randomized phase IIB trial of BLP25 liposome vaccine in stage IIIB and IV non-small-cell lung cancer. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[41]  P. Vineis,et al.  Air pollution and cancer: biomarker studies in human populations. , 2005, Carcinogenesis.

[42]  E. Feuer,et al.  SEER Cancer Statistics Review, 1975-2003 , 2006 .

[43]  N. Senzer,et al.  Phase II study of belagenpumatucel-L, a transforming growth factor beta-2 antisense gene-modified allogeneic tumor cell vaccine in non-small-cell lung cancer. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[44]  E. G. Letourneau,et al.  A Combined Analysis of North American Case-Control Studies of Residential Radon and Lung Cancer , 2006, Journal of toxicology and environmental health. Part A.

[45]  M. Kris,et al.  Cancer Care Ontario and American Society of Clinical Oncology Adjuvant Chemotherapy and Adjuvant Radiation Therapy for Stages I-IIIA Resectable Non-Small-Cell Lung Cancer Guideline. , 2007, Journal of oncology practice.

[46]  T. Okazaki,et al.  PD-1 and PD-1 ligands: from discovery to clinical application. , 2007, International immunology.

[47]  J. Dement,et al.  An epidemiological study of the role of chrysotile asbestos fibre dimensions in determining respiratory disease risk in exposed workers , 2007, Occupational and Environmental Medicine.

[48]  W. Scott,et al.  Treatment of non-small cell lung cancer stage I and stage II: ACCP evidence-based clinical practice guidelines (2nd edition). , 2007, Chest.

[49]  J. Jassem,et al.  Final results of a multi-center, double-blind, randomized, placebo-controlled phase II study to assess the efficacy of MAGE-A3 immunotherapeutic as adjuvant therapy in stage IB/II non-small cell lung cancer (NSCLC) , 2007 .

[50]  H. Aburatani,et al.  Identification of the transforming EML4–ALK fusion gene in non-small-cell lung cancer , 2007, Nature.

[51]  A. de la Torre,et al.  Phase II randomized controlled trial of an epidermal growth factor vaccine in advanced non-small-cell lung cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[52]  R. Ramlau,et al.  A Phase II Study of Tg4010 (Mva-Muc1-Il2) in Association with Chemotherapy in Patients with Stage III/IV Non-small Cell Lung Cancer , 2008, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[53]  T. D. de Gruijl,et al.  Whole-cell cancer vaccination: from autologous to allogeneic tumor- and dendritic cell-based vaccines , 2008, Cancer Immunology, Immunotherapy.

[54]  Paolo Vineis,et al.  A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25 , 2008, Nature.

[55]  Daniel F. Gudbjartsson,et al.  A variant associated with nicotine dependence, lung cancer and peripheral arterial disease , 2008, Nature.

[56]  M. Ladanyi,et al.  KRAS mutations: an old oncogene becomes a new predictive biomarker. , 2008, The Journal of molecular diagnostics : JMD.

[57]  G A Colditz,et al.  Comparison of aspects of smoking among the four histological types of lung cancer , 2008, Tobacco Control.

[58]  Y. Ishikawa,et al.  Multiplex Reverse Transcription-PCR Screening for EML4-ALK Fusion Transcripts , 2008, Clinical Cancer Research.

[59]  Yuki Togashi,et al.  EML4-ALK Fusion Is Linked to Histological Characteristics in a Subset of Lung Cancers , 2008, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[60]  G. Mills,et al.  Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1 , 2008, Nature Genetics.

[61]  William Pao,et al.  Genetic predictors of MEK dependence in non-small cell lung cancer. , 2008, Cancer research.

[62]  D. Berman,et al.  A Meta-Analysis of Asbestos-Related Cancer Risk That Addresses Fiber Size and Mineral Type , 2008, Critical reviews in toxicology.

[63]  E. Tartour,et al.  Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[64]  M. Ladanyi,et al.  Frequency and Distinctive Spectrum of KRAS Mutations in Never Smokers with Lung Adenocarcinoma , 2008, Clinical Cancer Research.

[65]  S. Ramalingam,et al.  Systemic chemotherapy for advanced non-small cell lung cancer: recent advances and future directions. , 2008, The oncologist.

[66]  Derek Y. Chiang,et al.  EML4-ALK Fusion Gene and Efficacy of an ALK Kinase Inhibitor in Lung Cancer , 2008, Clinical Cancer Research.

[67]  W. Pao,et al.  KRAS mutations in non-small cell lung cancer. , 2009, Proceedings of the American Thoracic Society.

[68]  Lech Papiez,et al.  Stereotactic body radiation therapy for early-stage non-small-cell lung carcinoma: four-year results of a prospective phase II study. , 2009, International journal of radiation oncology, biology, physics.

[69]  Y. Ishikawa,et al.  EML4-ALK lung cancers are characterized by rare other mutations, a TTF-1 cell lineage, an acinar histology, and young onset , 2009, Modern Pathology.

[70]  B. Mirakhur,et al.  MAGRIT: the largest-ever phase III lung cancer trial aims to establish a novel tumor-specific approach to therapy. , 2009, Clinical lung cancer.

[71]  N. Shan,et al.  A High Number of CD8+ T Cells Infiltrated in NSCLC Tissues is Associated With a Favorable Prognosis , 2010, Applied immunohistochemistry & molecular morphology : AIMM.

[72]  Andrea Bezjak,et al.  Stereotactic body radiation therapy for inoperable early stage lung cancer. , 2010, JAMA.

[73]  D. Schadendorf,et al.  Improved survival with ipilimumab in patients with metastatic melanoma. , 2010, The New England journal of medicine.

[74]  Alfons G H Kessels,et al.  Comparison of the effectiveness of radiotherapy with photons, protons and carbon-ions for non-small cell lung cancer: a meta-analysis. , 2010, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[75]  Jeffrey W. Clark,et al.  Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. , 2010, The New England journal of medicine.

[76]  Y. Bang,et al.  Clinicopathologic Characteristics and Outcomes of Patients with Anaplastic Lymphoma Kinase-Positive Advanced Pulmonary Adenocarcinoma: Suggestion for an Effective Screening Strategy for These Tumors , 2011, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[77]  M. Buyse,et al.  Therapeutic vaccination with TG4010 and first-line chemotherapy in advanced non-small-cell lung cancer: a controlled phase 2B trial. , 2011, The Lancet. Oncology.

[78]  P. Ellis,et al.  Updated survival analysis in patients with stage IIIB or IV non-small-cell lung cancer receiving BLP25 liposome vaccine (L-BLP25): phase IIB randomized, multicenter, open-label trial , 2011, Journal of Cancer Research and Clinical Oncology.

[79]  R. Schreiber,et al.  Cancer Immunoediting: Integrating Immunity’s Roles in Cancer Suppression and Promotion , 2011, Science.

[80]  Hiroki Shirato,et al.  Stereotactic body radiotherapy (SBRT) for operable stage I non-small-cell lung cancer: can SBRT be comparable to surgery? , 2011, International journal of radiation oncology, biology, physics.

[81]  M. Ladanyi,et al.  Clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[82]  A. Tsao Ipilimumab in Combination With Paclitaxel and Carboplatin As First-Line Treatment in Stage IIIB/IV Non–Small-Cell Lung Cancer: Results From a Randomized, Double-Blind, Multicenter Phase II Study , 2012 .

[83]  Sébastien Couraud,et al.  Lung cancer in never smokers--a review. , 2012, European journal of cancer.

[84]  Drew M. Pardoll,et al.  The blockade of immune checkpoints in cancer immunotherapy , 2012, Nature Reviews Cancer.

[85]  T. Nakajima,et al.  KLC1-ALK: A Novel Fusion in Lung Cancer Identified Using a Formalin-Fixed Paraffin-Embedded Tissue Only , 2012, PloS one.

[86]  Yoshimasa Tanaka,et al.  Immunotherapies: The Blockade of Inhibitory Signals , 2012, International journal of biological sciences.

[87]  C. Drake,et al.  Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. , 2012, Current opinion in immunology.

[88]  Suresh Senan,et al.  Outcomes of stereotactic ablative radiotherapy in patients with potentially operable stage I non-small cell lung cancer. , 2012, International journal of radiation oncology, biology, physics.

[89]  Ioanna Kougioumtzi,et al.  Occupational exposure and lung cancer. , 2013, Journal of thoracic disease.

[90]  P. Iyengar,et al.  Locally Advanced Lung Cancer: An Optimal Setting for Vaccines and Other Immunotherapies , 2013, Cancer journal.

[91]  Kevan M. Shokat,et al.  K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions , 2013, Nature.

[92]  A. Chang,et al.  Treatment of stage I and II non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. , 2013, Chest.

[93]  Jeanne Shen,et al.  Clinical, Pathologic, and Biologic Features Associated with BRAF Mutations in Non–Small Cell Lung Cancer , 2013, Clinical Cancer Research.

[94]  M. Dolled-Filhart,et al.  Safety and Clinical Activity of MK-3475 as Initial Therapy in Patients With Advanced Non-Small Cell Lung Cancer (NSCLC) , 2014 .

[95]  M. Socinski,et al.  Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial. , 2014, The Lancet. Oncology.

[96]  A. Jemal,et al.  Cancer statistics, 2014 , 2014, CA: a cancer journal for clinicians.

[97]  F. Cappuzzo,et al.  First-line crizotinib versus chemotherapy in ALK-positive lung cancer. , 2014, The New England journal of medicine.

[98]  Oar,et al.  Health Risk of Radon , 2014 .

[99]  A. Amini,et al.  Stereotactic Body Radiation Therapy (SBRT) for lung cancer patients previously treated with conventional radiotherapy: a review , 2014, Radiation oncology.

[100]  B. Lushniak,et al.  The Health consequences of smoking—50 years of progress : a report of the Surgeon General , 2014 .

[101]  C. Rudin,et al.  Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. , 2015, The New England journal of medicine.

[102]  G. Giaccone,et al.  A phase III study of belagenpumatucel-L, an allogeneic tumour cell vaccine, as maintenance therapy for non-small cell lung cancer. , 2015, European journal of cancer.

[103]  Gideon Blumenthal,et al.  FDA Approval Summary: Nivolumab for the Treatment of Metastatic Non-Small Cell Lung Cancer With Progression On or After Platinum-Based Chemotherapy , 2016, The oncologist.

[104]  Tobias Faust Pathology And Genetics Of Tumours Of The Lung Pleura Thymus And Heart , 2016 .

[105]  S. Temin,et al.  Systemic Therapy for Stage IV Non-Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. , 2016, Journal of oncology practice / American Society of Clinical Oncology.