With the advances in surgery, chemotherapy, and radiotherapy over the last decades, the treatment strategies of lung cancer has been largely changed. In this review, we summarize recent advances in lung cancer and treatment research. We discuss current clinical management, highlight stage-specific therapy approaches, chemotherapy options for advanced-stage of non-small-cell lung cancer (NSCLC) patients, along with new agents such as epidermal growth factor receptor (EGFR)-targeting tyrosine kinase inhibitors erlotinib and gefitinib, and the anaplastic lymphoma kinase (ALK) inhibitor crizotinib. We also give an outlook into NSCLC disease biology, focus e on the importance of EGFR activating mutations and the role of the tumor-microenvironment. Finally we summarize the new recommendations in treating small-cell-lung cancer (SCLC).
KeywordsNSCLCEGFR-Targeting Tyrosine Kinase
A. Jemal, F. Bray, M. M. Center, J. Ferlay, E. Ward, et al., “Global Cancer Statistics,” CA: A Cancer Journal for Clinicians, Vol. 61, No. 2, 2011, pp. 69-90. doi:10.3322/caac.20107
C. J. Langer, B. Besse, A. Gualberto, et al., “The Evolving Role of Histology in the Management of Advanced Non-Small-Cell Lung Cancer,” Journal of Clinical Oncology, Vol. 28, No. 36, 2010, pp. 5311-5320. doi:10.1200/JCO.2010.28.8126
W. D. Travis, E. Brambilla, M. Noguchi, et al., “International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society International Multidisciplinary Classification of Lung Adenocarcinoma,” Journal of Thoracic Oncology, Vol. 6, No. 2, 2011, pp. 244-285. doi:10.1097/JTO.0b013e318206a221
W. D. Travis, E. Brambilla and G. J. Riely, “New Pathologic Classification of Lung Cancer: Relevance for Clinical Practice and Clinical Trials,” Journal of Clinical Oncology, Vol. 31, No. 8, 2013, pp. 992-1001. doi:10.1200/JCO.2012.46.9270
P. McCloskey, B. Balduyck, P. E. Van Schil, et al., “Radical Treatment of Non-Small Cell Lung Cancer during the Last 5 Years,” European Journal of Cancer, Vol. 49, No. 7, 2013, pp. 1555-1564. doi:10.1016/j.ejca.2012.12.023
S. Senan, D. A. Palma and F. J. Lagerwaard, “Stereotactic Ablative Radiotherapy for Stage I NSCLC: Recent Advances and Controversies,” Journal of Thorac Disease, Vol. 3, No. 3, 2011, pp. 189-196.
B. E. Lally, D. Zelterman, J. M. Colasanto, et al., “Postoperative Radiotherapy for Stage II or III Non-Small-Cell Lung Cancer Using the Surveillance, Epidemiology, and End Results Database,” Journal of Clinical Oncology, Vol. 24, No. 19, 2006, pp. 2998-3006. doi:10.1200/JCO.2005.04.6110
D. W. Andrews, C. B. Scott, P. W. Sperduto, et al., “Whole Brain Radiation Therapy with or without Stereotactic Radiosurgery Boost for Patients with One to Three Brain Metastases: Phase III Results of the RTOG 9508 Randomised Trial,” Lancet, Vol. 363, No. 9422, 2004, pp. 1665-1672. doi:10.1016/S0140-6736(04)16250-8
J. P. Pignon, H. Tribodet, G. V. Scagliotti, et al., “Lung Adjuvant Cisplatin Evaluation: A Pooled Analysis by the LACE Collaborative Group,” Journal of Clinical Oncology, Vol. 26, No. 21, 2008, pp. 3552-3559. doi:10.1200/JCO.2007.13.9030
G. M. Strauss, J. E. Herndon II, M. A. Maddaus, et al., “Adjuvant Paclitaxel plus Carboplatin Compared with Observation in Stage IB Non-Small-Cell Lung Cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups,” Journal of Clinical Oncology, Vol. 26, No. 31, 2008, pp. 5043-5051. doi:10.1200/JCO.2008.16.4855
T. Ciuleanu, T. Brodowicz, C. Zielinski, et al., “Maintenance Pemetrexed plus Best Supportive Care versus Placebo plus Best Supportive Care for Non-Small-Cell Lung Cancer: A Randomised, Double-Blind, Phase 3 Study,” Lancet, Vol. 374, No. 9699, 2009, pp. 1432-1440. doi:10.1016/S0140-6736(09)61497-5
F. Cappuzzo, T. Ciuleanu, L. Stelmakh, et al., “Erlotinib as Maintenance Treatment in Advanced Non-Small-Cell Lung Cancer: A Multicentre, Randomised, Placebo-Controlled Phase 3 Study,” Lancet Oncology, 11, No. 6, 2010, pp. 521-529. doi:10.1016/S1470-2045(10)70112-1
L. Paz-Ares, F. de Marinis, M. Dediu, et al., “Maintenance Therapy with Pemetrexed plus Best Supportive Care versus Placebo plus Best Supportive Care after Induction Therapy with Pemetrexed plus Cisplatin for Advanced Non-Squamous Non-Small-Cell Lung Cancer (PARAMOUNT): A Double-Blind, Phase 3, Randomised Controlled Trial,” Lancet Oncology, Vol. 13, No. 3, 2012, pp. 247-255.
NSCLC Meta-Analyses Collaborative Group, “Chemotherapy in Addition to Supportive Care Improves Survival in Advanced Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis of Individual Patient Data from 16 Randomized Controlled Trials,” Journal of Clinical Oncology, Vol. 26, No. 28, 2008, pp. 4617-4625. doi:10.1200/JCO.2008.17.7162
C. G. Azzoli, S. Baker Jr., S. Temin, et al., “American Society of Clinical Oncology Clinical Practice Guideline Update on Chemotherapy for Stage IV Non-Small-Cell Lung Cancer,” Journal of Clinical Oncology, Vol. 27, No. 36, 2009, pp. 6251-6266. doi:10.1200/JCO.2009.23.5622
T. J. Lynch, D. W. Bell, R. Sordella, et al., “Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non-Small-Cell Lung Cancer to Gefitinib,” New England Journal of Medicine, Vol. 350, 2004, pp. 2129-2139. doi:10.1056/NEJMoa040938
J. G. Paez, P. A. J?nne, J. C. Lee, et al., “EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy,” Science, Vol. 304, No. 5676, 2004, pp. 1497-1500. doi:10.1126/science.1099314
T. Mitsudomi, S. Morita, Y. Yatabe, et al., “Gefitinib versus Cisplatin plus Docetaxel in Patients with NonSmall-Cell Lung Cancer Harbouring Mutations of the Epidermal Growth Factor Receptor (WJTOG3405): An Open Label, Randomised Phase 3 Trial,” Lancet Oncology, Vol. 11, No. 2, 2010, pp. 121-128. doi:10.1016/S1470-2045(09)70364-X
M. Maemondo, A. Inoue, K. Kobayashi, et al., “Gefitinib or Chemotherapy for Non-Small-Cell Lung Cancer with Mutated EGFR,” New England Journal of Medicine, Vol. 362, 2010, pp. 2380-2388. doi:10.1056/NEJMoa0909530
C. Zhou, Y. L. Wu, G. Chen, et al., “Erlotinib versus Chemotherapy as First-Line Treatment for Patients with Advanced EGFR Mutation-Positive Non-Small-Cell Lung Cancer (OPTIMAL, CTONG-0802): A Multicentre, OpenLabel, Randomised, Phase 3 Study,” Lancet Oncology, Vol. 12, No. 8, 2011, pp. 735-742. doi:10.1016/S1470-2045(11)70184-X
R. Rosell, E. Carcereny, R. Gervais, et al., “Erlotinib versus Standard Chemotherapy as First-Line Treatment for European Patients with Advanced EGFR MutationPositive Non-Small-Cell Lung Cancer (EURTAC): A Multicentre, Open-Label, Randomised Phase 3 Trial,” Lancet Oncology, Vol. 13, No. 3, 2012, pp. 239-246. doi:10.1016/S1470-2045(11)70393-X
M. Shiota and S. Mori, “The Clinicopathological Features of Anaplastic Large Cell Lymphomas Expressing p80NPM/ ALK,” Leuk Lymphoma, Vol. 23, 1996, pp. 25-32. doi:10.3109/ 10428199609054798
M. Soda, Y. L. Choi, M. Enomoto, et al., “Identification of the Transforming EML4-ALK Fusion Gene in NonSmall-Cell Lung Cancer,” Nature, Vol. 448, No. 7153, 2007, pp.561-566.
E. L. Kwak, Y. J. Bang, D. R. Camidge, et al., “Anaplastic Lymphoma Kinase Inhibition in Non-Small-Cell Lung Cancer,” New England Journal of Medicine, Vol. 363, 2010, pp. 1693-1703. doi:10.1056/ NEJMoa1006448
G. M. Stella, R. Scabini, S. Inghilleri, et al., “EGFR and KRAS Mutational Profiling in Fresh Non-Small Cell Lung Cancer (NSCLC) Cells,” Journal of Cancer Research and Clinical Oncology, Vol. 139, No. 8, 2013, pp. pp. 1327-1335. doi:10.1007/s00432-013-1444-y
S. Kobayashi, T. J. Boggon, T. Dayaram, et al., “EGFR Mutation and Resistance of Non-Small-Cell Lung Cancer to Gefitinib,” New England Journal of Medicine, Vol. 352, 2005, pp. 786-792. doi:10.1056/NEJMoa044238
W. Pao, V. A. Miller, K. A. Politi, et al., “Acquired Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib Is Associated with a Second Mutation in the EGFR Kinase Domain,” PLoS Medicine, Vol. 2, No. 3, 2005, p. e73.
J. A. Engelman, K. Zejnullahu, T. Mitsudomi, et al., “MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling,” Science, Vol. 316, No. 5827, 2007, pp. 1039-1043. doi:10.1126/science.1141478
J. Bean, C. Brennan, J. Y. Shih, et al., “MET Amplification Occurs with or without T790M Mutations in EGFR Mutant Lung Tumors with Acquired Resistance to Gefitinib or Erlotinib,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 52, 2007, pp. 20932-20937. doi:10.1073/pnas.0710370104
W. Zhou, D. Ercan, L. Chen, et al., “Novel Mutant-Selective EGFR Kinase Inhibitors against EGFR T790M,” Nature, Vol. 462, 2009, pp. 1070-1074. doi:10.1038/nature08622
J. A. Engelman, K. Zejnullahu, T. Mitsudomi, et al., “MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling,” Science, Vol. 316, No. 5827, 2007, pp. 1039-1043. doi:10.1126/science.1141478
C. Belani, “The Role of Irreversible EGFR Inhibitors in the Treatment of Non-Small Cell Lung Cancer: Overcoming Resistance to Reversible EGFR Inhibitors,” Cancer Investigation, Vol. 28, No. 4, 2010, pp. 413-423.
G. J. Riely, M. G. Kris, B. Zhao, et al., “Prospective Assessment of Discontinuation and Reinitiation of Erlotinib or Gefitinib in Patients with Acquired Resistance to Erlotinib or Gefitinib Followed by the Addition of Everolimus,” Clinical Cancer Research, Vol. 13, 2007, pp. 5150-5155. doi:10.1158/1078-0432.CCR-07-0560
K. Pietras and A. Ostman, “Hallmarks of Cancer: Interactions with the Tumor Stroma,” Experimental Cell Research, Vol. 316, No. 8, 2010, pp. 1324-1331. doi:10.1016/j.yexcr.2010.02.045
Y. Shaked and E. E. Voest, “Bone Marrow Derived Cells in Tumor Angiogenesis and Growth: Are They the Good, the Bad or the Evil?” Biochimica et Biophysica Acta, Vol. 1796, No. 1, 2009, pp. 1-4.
O. Casanovas, D. J. Hicklin, G. Bergers and D. Hanahan, “Drug Resistance by Evasion of Antiangiogenic Targeting of VEGF Signaling in Late-Stage Pancreatic Islet Tumors,” Cancer Cell, Vol. 8, No. 4, 2005, pp. 299-309. doi:10.1016/j.ccr.2005.09.005
D. Bonnet, “Biology of Human Bone Marrow Stem Cells,” Clinical and Experimental Medicine, Vol. 3, No. 3, 2003, pp. 140-149. doi:10.1007/s10238-003-0017-9
H. N. LeBlanc and A. Ashkenazi, “Apo2L/TRAIL and Its Death and Decoy Receptors,” Cell Death & Differentiation, Vol. 10, No. 1, 2003, pp. 66-75. doi:10.1038/sj.cdd.4401187
L. G. Menon, K. Kelly, H. W. Yang, et al., “Human Bone Marrow-Derived Mesenchymal Stromal Cells Expressing S-TRAIL as a Cellular Delivery Vehicle for Human Glioma Therapy,” Stem Cells, Vol. 27, No. 9, 2009, pp. 2320-2330. doi:10.1002/stem.136
A. Mohr, S. M. Albarenque, L. Deedigan, et al., “Targeting of XIAP Combined with Systemic Mesenchymal Stem Cell-Mediated Delivery of sTRAIL Ligand Inhibits Metastatic Growth of Pancreatic Carcinoma Cells,” Stem Cells, Vol. 28, No. 11, 2010, pp. 2109-2120. doi:10.1002/stem.533
L. Kucerova, V. Altanerova, M. Matuskova, et al., “Adipose Tissue-Derived Human Mesenchymal Stem Cells Mediated Prodrug Cancer Gene Therapy,” Cancer Research, Vol. 67, No. 13, 2007, pp. 6304-6313. doi:10.1158/0008-5472.CAN-06-4024
F. Guddo, A. Giatromanolaki, M. I. Koukourakis, et al., “MUC1 (Episialin) Expression in Non-Small Cell Lung Cancer Is Independent of EGFR and c-erbB-2 Expression and Correlates with Poor Survival in Node Positive Patients,” Journal of Clinical Pathology, Vol. 51, No. 9, 1998, pp. 667-671. doi:10.1136/jcp.51.9.667
A. Ohgami, T. Tsuda, T. Osaki, et al., “MUC1 Mucin mRNA Expression in Stage I Lung Adenocarcinoma and Its Association with Early Recurrence,” The Annals of Thoracic Surgery, Vol. 67, No. 3, 1999, pp. 810-814. doi:10.1016/S0003-4975(99)00041-7
C. Butts, A. Maksymiuk, G. Goss, et al., “Updated Survival Analysis in Patients with Stage IIIB or IV NonSmall-Cell Lung Cancer Receiving BLP25 Liposome Vaccine (L-BLP25): Phase IIB Randomized, Multicenter, Open-Label Trial,” Journal of Cancer Research and Clinical Oncology, Vol. 137, No. 9, 2011, pp. 1337-1342. doi:10.1007/s00432-011-1003-3
R. Govindan, N. Page, D. Morgensztern, et al., “Changing Epidemiology of Small-Cell Lung Cancer in the United States over the Last 30 Years: Analysis of the Surveillance, Epidemiologic, and End Results Database,” Journal of Clinical Oncology, Vol. 24, No. 28, 2006, pp. 4539-4544. doi:10.1200/JCO.2005.04.4859
V. Kut, W. Spies, S. Spies, et al., “Staging and Monitoring of Small Cell Lung Cancer Using [18F]Fluoro-2-DeoxyD-Glucose-Positron Emission Tomography (FDG-PET),” American Journal of Clinical Oncology, Vol. 30, No. 1, 2007, pp. 45-50. doi:10.1097/01.coc.0000239095.09662.19
J. van Loon, D. de Ruysscher, R. Wanders, et al., “Selective Nodal Irradiation on Basis of (18)FDG-PET Scans in Limiteddisease Small-Cell Lung Cancer: A Prospective Study,” International Journal of Radiation Oncology Biology Physics, Vol. 77, No. 2, 2010, pp. 329-336. doi:10.1016/ j.ijrobp.2009.04.075
S. G. Spiro, L. E. James, R. M. Rudd, et al., “Early Compared with Late Radiotherapy in Combined Modality Treatment for Limited Disease Small-Cell Lung Cancer: A London Lung Cancer Group Multicenter Randomized Clinical Trial and Meta-Analysis,” Journal of Clinical Oncology, Vol. 24, No. 24, 2006, pp. 3823-3830. doi:10.1200/JCO.2005.05.3181
D. B. Fried, D. E. Morris, C. Poole, et al., “Systematic Review Evaluating the Timing of Thoracic Radiation Therapy in Combined Modality Therapy for LimitedStage Small-Cell Lung Cancer,” Journal of Clinical Oncology, Vol. 22, No. 23, 2004, pp. 4837-4845. doi:10.1200/JCO.2004.01.178
D. de Ruysscher, M. Pijls-Johannesma, S. M. Bentzen, et al., “Time between the First Day of Chemotherapy and the Last Day of Chest Radiation Is the Most Important Predictor of Survival in Limited-Disease Small-Cell Lung Cancer,” Journal of Clinical Oncology, Vol. 24, No. 7, 2006, pp. 1057-1063. doi:10.1200/JCO.2005.02.9793
D. de Ruysscher, M. Pijls-Johannesma, J. Vansteenkiste, et al., “Systematic Review and Meta-Analysis of Randomised, Controlled Trials of the Timing of Chest Radiotherapy in Patients with Limited-Stage, Small-Cell Lung Cancer,” Annals of Oncology, Vol. 17, No. 4, 2006, pp. 543-552. doi:10.1093/ annonc/mdj094
M. Huncharek, and R. McGarry, “A Meta-Analysis of the Timing of Chest Irradiation in the Combined Modality Treatment of Limited-Stage Small Cell Lung Cancer,” Oncologist, Vol. 9, No. 6, 2004, pp. 665-672. doi:10.1634/theoncologist.9-6-665
B. Slotman, C. Faivre-Finn, G. Kramer, et al., “Prophylactic Cranial Irradiation in Extensive Small-Cell Lung Cancer,” The New England Journal of Medicine, Vol. 357, 2007, pp. 664-672. doi:10.1056/NEJMoa071780
J. R. Jett, S. E. Schild, K. A. Kesler and G. P. Kalemkerian, “Treatment of Small Cell Lung Cancer: Diagnosis and Management of Lung Cancer, 3rd ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines,” Chest, 2013, Vol. 143, Suppl. 5, pp. e400S-e419S.
S. M. Lee, P. J. Woll, R. Rudd, et al., “Anti-Angiogenic Therapy Using Thalidomide Combined with Chemotherapy in Small Cell Lung Cancer: A Randomized, Double-Blind, Placebo-Controlled Trial,” Journal of the National Cancer Institute, Vol. 101, No. 15, 2009, pp. 1049-1057. doi:10.1093/ jnci/djp200
N. E. Ready, A. Z. Dudek, H. H. Pang, et al., “Cisplatin, Irinotecan, and Bevacizumab for Untreated ExtensiveStage Small-Cell Lung Cancer: CALGB 30306, a Phase II Study,” Journal of Clinical Oncology, Vol. 29, No. 33, 2011, pp. 4436-4441. doi:10.1200/JCO.2011.35.6923
D. R. Spigel, F. A. Greco, J. D. Zubkus, et al., “Phase II Trial of Irinotecan, Carboplatin, and Bevacizumab in the Treatment of Patients with Extensive-Stage Small-Cell Lung Cancer,” Journal of Thoracic Oncology, Vol. 4, No. 12, 2009, pp. 1555-1560. doi:10.1097/JTO.0b013e3181bbc540
A. Inoue, S. Sugawara, K. Yamazaki, et al., “Randomized Phase II Trial Comparing Amrubicin with Topotecan in Patients with Previously Treated Small-Cell Lung Cancer: North Japan Lung Cancer Study Group Trial 0402,” Journal of Clinical Oncology, Vol. 26, No. 33, 2008, pp. 5401-5406. doi:10.1200/JCO.2008.18.1974
R. Jotte, P. Conkling, C. Reynolds, et al., “Randomized Phase II Trial of Single-Agent Amrubicin or Topotecan as Second-Line Treatment in Patients with Small-Cell Lung Cancer Sensitive to First-Line Platinum-Based Chemotherapy,” Journal of Clinical Oncology, Vol. 29, No. 3, 2011, pp. 287-293. doi:10.1200/JCO.2010.29.8851
E. D. Pleasance, P. J. Stephens, S. O’Meara, et al., “A Small-Cell Lung Cancer Genome with Complex Signatures of Tobacco Exposure,” Nature, Vol. 463, No. 7278, 2010, pp. 184-190. doi:10.1038/ nature08629