Skip to main content
SpringerLink
Log in

Locally Advanced Non-small Cell Lung Cancer and Targeted Therapy

  • Chapter
  • First Online:
Molecular Targeted Therapy of Lung Cancer

Abstract

Locally advanced unresectable non-small cell lung cancer (NSCLC), stage IIIA with bulky N2 and stage IIIB diseases, has been treated with concurrent chemoradiotherapy using a platinum doublet, but the effect of this conventional therapy has reached a plateau. Current research focuses on molecular targeted agents, especially epidermal growth factor receptor (EGFR)-directed agents and angiogenesis inhibitors. Although many preclinical experiments showed promising synergistic effects of EGFR-directed agents and radiation, no clinical trials have yet demonstrated the reproducibility of the preclinical results. Numerous preclinical models also showed synergistic effects of angiogenesis inhibitors and radiation without excessive toxicity. However, early clinical investigations of bevacizumab and chemoradiotherapy were closed early due to serious and unacceptable toxicities such as tracheoesophageal fistula and potentially fatal pneumonitis. The current review disclosed and discussed many issues on incorporation of molecular targeted agents into the treatment of unresectable stage III NSCLC.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Goldstraw P, Crowley J, Chansky K et al (2007) The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours. J Thorac Oncol 2:706–714

    Article  PubMed  Google Scholar 

  2. Groome PA, Bolejack V, Crowley JJ et al (2007) The IASLC Lung Cancer Staging Project: validation of the proposals for revision of the T, N, and M descriptors and consequent stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours. J Thorac Oncol 2:694–705

    Article  PubMed  Google Scholar 

  3. Furuse K, Fukuoka M, Kawahara M et al (1999) Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer. J Clin Oncol 17:2692–2699

    CAS  PubMed  Google Scholar 

  4. Curran WJ Jr, Paulus R, Langer CJ et al (2011) Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst 103:1452–1460

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Horinouchi H, Sekine I, Sumi M et al (2013) Long-term results of concurrent chemoradiotherapy using cisplatin and vinorelbine for stage III non-small-cell lung cancer. Cancer Sci 104:93–97

    Article  CAS  PubMed  Google Scholar 

  6. Segawa Y, Kiura K, Takigawa N et al (2010) Phase III trial comparing docetaxel and cisplatin combination chemotherapy with mitomycin, vindesine, and cisplatin combination chemotherapy with concurrent thoracic radiotherapy in locally advanced non-small-cell lung cancer: OLCSG 0007. J Clin Oncol 28:3299–3306

    Article  CAS  PubMed  Google Scholar 

  7. Yamamoto N, Nakagawa K, Nishimura Y et al (2010) Phase III study comparing second- and third-generation regimens with concurrent thoracic radiotherapy in patients with unresectable stage III non-small-cell lung cancer: West Japan Thoracic Oncology Group WJTOG0105. J Clin Oncol 28:3739–3745

    Article  PubMed  Google Scholar 

  8. Senan S, Brade A, Wang LH et al (2016) PROCLAIM: randomized Phase III trial of Pemetrexed-Cisplatin or Etoposide-Cisplatin Plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer. J Clin Oncol 34:953–962

    Article  CAS  PubMed  Google Scholar 

  9. Bradley JD, Paulus R, Komaki R et al (2015) Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol 16:187–199

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Roskoski R Jr (2014) The ErbB/HER family of protein-tyrosine kinases and cancer. Pharmacol Res 79:34–74

    Article  CAS  PubMed  Google Scholar 

  11. Nyati MK, Morgan MA, Feng FY, Lawrence TS (2006) Integration of EGFR inhibitors with radiochemotherapy. Nat Rev Cancer 6:876–885

    Article  CAS  PubMed  Google Scholar 

  12. Baumann M, Krause M, Dikomey E et al (2007) EGFR-targeted anti-cancer drugs in radiotherapy: preclinical evaluation of mechanisms. Radiother Oncol 83:238–248

    Article  CAS  PubMed  Google Scholar 

  13. Milas L, Fan Z, Andratschke NH, Ang KK (2004) Epidermal growth factor receptor and tumor response to radiation: in vivo preclinical studies. Int J Radiat Oncol Biol Phys 58:966–971

    Article  CAS  PubMed  Google Scholar 

  14. Akimoto T, Hunter NR, Buchmiller L et al (1999) Inverse relationship between epidermal growth factor receptor expression and radiocurability of murine carcinomas. Clin Cancer Res 5:2884–2890

    CAS  PubMed  Google Scholar 

  15. Liang K, Ang KK, Milas L et al (2003) The epidermal growth factor receptor mediates radioresistance. Int J Radiat Oncol Biol Phys 57:246–254

    Article  CAS  PubMed  Google Scholar 

  16. Huang SM, Harari PM (2000) Modulation of radiation response after epidermal growth factor receptor blockade in squamous cell carcinomas: inhibition of damage repair, cell cycle kinetics, and tumor angiogenesis. Clin Cancer Res 6:2166–2174

    CAS  PubMed  Google Scholar 

  17. Raben D, Helfrich B, Chan DC et al (2005) The effects of cetuximab alone and in combination with radiation and/or chemotherapy in lung cancer. Clin Cancer Res 11:795–805

    CAS  PubMed  Google Scholar 

  18. Bonner JA, Harari PM, Giralt J et al (2006) Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354:567–578

    Article  CAS  PubMed  Google Scholar 

  19. Ang KK, Zhang Q, Rosenthal DI et al (2014) Randomized phase III trial of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III to IV head and neck carcinoma: RTOG 0522. J Clin Oncol 32:2940–2950

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Suntharalingam M, Winter K, Ilson D et al (2014) The initial report of RTOG 0436: a phase III trial evaluating the addition of cetuximab to paclitaxel, cisplatin, and radiation for patients with esophageal cancer treated without surgery. J Clin Oncol 32:(suppl 3; abstr LBA6)

    Google Scholar 

  21. Hughes S, Liong J, Miah A et al (2008) A brief report on the safety study of induction chemotherapy followed by synchronous radiotherapy and cetuximab in stage III non-small cell lung cancer (NSCLC): SCRATCH study. J Thorac Oncol 3:648–651

    Article  PubMed  Google Scholar 

  22. Hallqvist A, Wagenius G, Rylander H et al (2011) Concurrent cetuximab and radiotherapy after docetaxel-cisplatin induction chemotherapy in stage III NSCLC: satellite—a phase II study from the Swedish Lung Cancer Study Group. Lung Cancer 71:166–172

    Article  CAS  PubMed  Google Scholar 

  23. Ramalingam SS, Kotsakis A, Tarhini AA et al (2013) A multicenter phase II study of cetuximab in combination with chest radiotherapy and consolidation chemotherapy in patients with stage III non-small cell lung cancer. Lung Cancer 81:416–421

    Article  CAS  PubMed  Google Scholar 

  24. Dingemans AM, Bootsma G, van Baardwijk A et al (2014) A phase I study of concurrent individualized, isotoxic accelerated radiotherapy and cisplatin-vinorelbine-cetuximab in patients with stage III non-small-cell lung cancer. J Thorac Oncol 9:710–716

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. van den Heuvel MM, Uyterlinde W, Vincent AD et al (2014) Additional weekly Cetuximab to concurrent chemoradiotherapy in locally advanced non-small cell lung carcinoma: efficacy and safety outcomes of a randomized, multi-center phase II study investigating. Radiother Oncol 110:126–131

    Article  PubMed  Google Scholar 

  26. Blumenschein GR Jr, Paulus R, Curran WJ et al (2011) Phase II study of cetuximab in combination with chemoradiation in patients with stage IIIA/B non-small-cell lung cancer: RTOG 0324. J Clin Oncol 29:2312–2318

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Govindan R, Bogart J, Stinchcombe T et al (2011) Randomized phase II study of pemetrexed, carboplatin, and thoracic radiation with or without cetuximab in patients with locally advanced unresectable non-small-cell lung cancer: Cancer and Leukemia Group B trial 30407. J Clin Oncol 29:3120–3125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Liu D, Zheng X, Chen J et al (2015) Induction chemotherapy with cetuximab, vinorelbine-cisplatin followed by thoracic radiotherapy and concurrent cetuximab, vinorelbine-cisplatin in patients with unresectable stage III non-small cell lung cancer. Lung Cancer 89:249–254

    Article  PubMed  Google Scholar 

  29. Lynch TJ, Bell DW, Sordella R et al (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129–2139

    Article  CAS  PubMed  Google Scholar 

  30. Paez JG, Janne PA, Lee JC et al (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304:1497–1500

    Article  CAS  PubMed  Google Scholar 

  31. Das AK, Sato M, Story MD et al (2006) Non-small-cell lung cancers with kinase domain mutations in the epidermal growth factor receptor are sensitive to ionizing radiation. Cancer Res 66:9601–9608

    Article  CAS  PubMed  Google Scholar 

  32. Das AK, Chen BP, Story MD et al (2007) Somatic mutations in the tyrosine kinase domain of epidermal growth factor receptor (EGFR) abrogate EGFR-mediated radioprotection in non-small cell lung carcinoma. Cancer Res 67:5267–5274

    Article  CAS  PubMed  Google Scholar 

  33. Bianco C, Tortora G, Bianco R et al (2002) Enhancement of antitumor activity of ionizing radiation by combined treatment with the selective epidermal growth factor receptor-tyrosine kinase inhibitor ZD1839 (Iressa). Clin Cancer Res 8:3250–3258

    CAS  PubMed  Google Scholar 

  34. She Y, Lee F, Chen J et al (2003) The epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 selectively potentiates radiation response of human tumors in nude mice, with a marked improvement in therapeutic index. Clin Cancer Res 9:3773–3778

    CAS  PubMed  Google Scholar 

  35. Tanaka T, Munshi A, Brooks C et al (2008) Gefitinib radiosensitizes non-small cell lung cancer cells by suppressing cellular DNA repair capacity. Clin Cancer Res 14:1266–1273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zhuang HQ, Sun J, Yuan ZY et al (2009) Radiosensitizing effects of gefitinib at different administration times in vitro. Cancer Sci 100:1520–1525

    Article  CAS  PubMed  Google Scholar 

  37. Park SY, Kim YM, Pyo H (2010) Gefitinib radiosensitizes non-small cell lung cancer cells through inhibition of ataxia telangiectasia mutated. Mol Cancer 9:222

    Article  PubMed  PubMed Central  Google Scholar 

  38. Chinnaiyan P, Huang S, Vallabhaneni G et al (2005) Mechanisms of enhanced radiation response following epidermal growth factor receptor signaling inhibition by erlotinib (Tarceva). Cancer Res 65:3328–3335

    CAS  PubMed  Google Scholar 

  39. Stinchcombe TE, Morris DE, Lee CB et al (2008) Induction chemotherapy with carboplatin, irinotecan, and paclitaxel followed by high dose three-dimension conformal thoracic radiotherapy (74 Gy) with concurrent carboplatin, paclitaxel, and gefitinib in unresectable stage IIIA and stage IIIB non-small cell lung cancer. J Thorac Oncol 3:250–257

    Article  PubMed  Google Scholar 

  40. Okamoto I, Takahashi T, Okamoto H et al (2011) Single-agent gefitinib with concurrent radiotherapy for locally advanced non-small cell lung cancer harboring mutations of the epidermal growth factor receptor. Lung Cancer 72:199–204

    Article  PubMed  Google Scholar 

  41. Rothschild S, Bucher SE, Bernier J et al (2011) Gefitinib in combination with irradiation with or without cisplatin in patients with inoperable stage III non-small cell lung cancer: a phase I trial. Int J Radiat Oncol Biol Phys 80:126–132

    Article  CAS  PubMed  Google Scholar 

  42. Choong NW, Mauer AM, Haraf DJ et al (2008) Phase I trial of erlotinib-based multimodality therapy for inoperable stage III non-small cell lung cancer. J Thorac Oncol 3:1003–1011

    Article  PubMed  PubMed Central  Google Scholar 

  43. Ready N, Janne PA, Bogart J et al (2010) Chemoradiotherapy and gefitinib in stage III non-small cell lung cancer with epidermal growth factor receptor and KRAS mutation analysis: cancer and leukemia group B (CALEB) 30106, a CALGB-stratified phase II trial. J Thorac Oncol 5:1382–1390

    Article  PubMed  Google Scholar 

  44. Niho S, Ohe Y, Ishikura S et al (2012) Induction chemotherapy followed by gefitinib and concurrent thoracic radiotherapy for unresectable locally advanced adenocarcinoma of the lung: a multicenter feasibility study (JCOG 0402). Ann Oncol 23:2253–2258

    Article  CAS  PubMed  Google Scholar 

  45. Komaki R, Allen PK, Wei X et al (2015) Adding erlotinib to chemoradiation improves overall survival but not progression-free survival in Stage III non-small cell lung cancer. Int J Radiat Oncol Biol Phys 92:317–324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Kelly K, Chansky K, Gaspar LE et al (2008) Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG S0023. J Clin Oncol 26:2450–2456

    Article  CAS  PubMed  Google Scholar 

  47. Keedy VL, Arteaga CL, Johnson DH (2008) Does gefitinib shorten lung cancer survival? Chaos redux. J Clin Oncol 26:2428–2430

    Article  PubMed  Google Scholar 

  48. Casal Rubio J, Firvida-Perez JL, Lazaro-Quintela M et al (2014) A phase II trial of erlotinib as maintenance treatment after concurrent chemoradiotherapy in stage III non-small-cell lung cancer (NSCLC): a Galician Lung Cancer Group (GGCP) study. Cancer Chemother Pharmacol 73:451–457

    Article  CAS  PubMed  Google Scholar 

  49. Wachsberger P, Burd R, Dicker AP (2003) Tumor response to ionizing radiation combined with antiangiogenesis or vascular targeting agents: exploring mechanisms of interaction. Clin Cancer Res 9:1957–1971

    CAS  PubMed  Google Scholar 

  50. Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3:721–732

    Article  CAS  PubMed  Google Scholar 

  51. Moeller BJ, Cao Y, Li CY, Dewhirst MW (2004) Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules. Cancer Cell 5:429–441

    Article  CAS  PubMed  Google Scholar 

  52. Moeller BJ, Dreher MR, Rabbani ZN et al (2005) Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity. Cancer Cell 8:99–110

    Article  CAS  PubMed  Google Scholar 

  53. Garcia-Barros M, Paris F, Cordon-Cardo C et al (2003) Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science 300:1155–1159

    Article  CAS  PubMed  Google Scholar 

  54. Kleibeuker EA, Griffioen AW, Verheul HM et al (2012) Combining angiogenesis inhibition and radiotherapy: a double-edged sword. Drug Resist Updat 15:173–182

    Article  CAS  PubMed  Google Scholar 

  55. Winkler F, Kozin SV, Tong RT et al (2004) Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6:553–563

    CAS  PubMed  Google Scholar 

  56. Dings RP, Loren M, Heun H et al (2007) Scheduling of radiation with angiogenesis inhibitors anginex and Avastin improves therapeutic outcome via vessel normalization. Clin Cancer Res 13:3395–3402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Cao C, Albert JM, Geng L et al (2006) Vascular endothelial growth factor tyrosine kinase inhibitor AZD2171 and fractionated radiotherapy in mouse models of lung cancer. Cancer Res 66:11409–11415

    Article  CAS  PubMed  Google Scholar 

  58. Geng L, Donnelly E, McMahon G et al (2001) Inhibition of vascular endothelial growth factor receptor signaling leads to reversal of tumor resistance to radiotherapy. Cancer Res 61:2413–2419

    CAS  PubMed  Google Scholar 

  59. Spigel DR, Hainsworth JD, Yardley DA et al (2010) Tracheoesophageal fistula formation in patients with lung cancer treated with chemoradiation and bevacizumab. J Clin Oncol 28:43–48

    Article  CAS  PubMed  Google Scholar 

  60. Socinski MA, Stinchcombe TE, Moore DT et al (2012) Incorporating bevacizumab and erlotinib in the combined-modality treatment of stage III non-small-cell lung cancer: results of a phase I/II trial. J Clin Oncol 30:3953–3959

    Article  CAS  PubMed  Google Scholar 

  61. Lind JS, Senan S, Smit EF (2012) Pulmonary toxicity after bevacizumab and concurrent thoracic radiotherapy observed in a phase I study for inoperable stage III non-small-cell lung cancer. J Clin Oncol 30:e104–e108

    Article  CAS  PubMed  Google Scholar 

  62. Wozniak AJ, Moon J, Thomas CR Jr et al (2015) A pilot trial of cisplatin/etoposide/radiotherapy followed by consolidation docetaxel and the combination of bevacizumab (NSC-704865) in patients with inoperable locally advanced stage III non-small-cell lung cancer: SWOG S0533. Clin Lung Cancer 16:340–347

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medical Oncology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan

    Ikuo Sekine

Authors
  1. Ikuo Sekine
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ikuo Sekine .

Editor information

Editors and Affiliations

  1. Department of Medical Oncology Graduate School of Medicine, Chiba University, Chiba, Japan

    Yuichi Takiguchi

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer Science+Business Media Singapore

About this chapter

Cite this chapter

Sekine, I. (2017). Locally Advanced Non-small Cell Lung Cancer and Targeted Therapy. In: Takiguchi, Y. (eds) Molecular Targeted Therapy of Lung Cancer. Springer, Singapore. https://doi.org/10.1007/978-981-10-2002-5_9

Download citation

  • DOI: https://doi.org/10.1007/978-981-10-2002-5_9

  • Published:

  • Publisher Name: Springer, Singapore

  • Print ISBN: 978-981-10-2000-1

  • Online ISBN: 978-981-10-2002-5

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation