Skip to main content
SpringerLink
Log in

Multimodality Treatment of Stage IIIA/N2 NSCLC: Why Always NO to Surgery?

  • Chapter
  • First Online:
Advances in Radiation Oncology in Lung Cancer

Part of the book series: Medical Radiology ((Med Radiol Radiat Oncol))

  • 323 Accesses

Abstract

The highest level of evidence from prospective randomized clinical trials (PRCTs) and meta-analyses (MAs) which have asked the question about optimal treatment approach in patients with Stage IIIA/pN2 non-small cell lung cancer (NSCLC) accumulated slowly in the past 25 years. They have mostly focused on the question of induction chemotherapy (CHT) or induction radiochemotherapy (RT-CHT) both followed by surgery and frequently compared it with exclusive RT-CHT. Seven PRCTs and five MAs which currently exist have investigated this issue. None of them showed any benefit for surgical multimodality approach over exclusive RT-CHT, except an unplanned, post-hoc analysis coming from a single PRCT, which concerned lobectomy-suitable candidates. While there are many retrospective studies which tried to identify patient subgroups favoring induction therapies followed by surgery, their results have never been reproduced even in retrospective setting. Importantly, no PRCT ever investigated potential pretreatment patient and/or tumor-related predictors favoring surgical multimodality and it remained unknown which, if any, patients may actually benefit from surgical multimodality approach. Exclusive RT-CHT achieves similar results to induction therapies followed by surgery but with less morbidity and mortality. Together with the lack of identified pretreatment predictors pointing towards surgery, they suggest that surgical bi- or trimodality approach should not be practiced outside well planned clinical trial.

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 189.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 249.99
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

  • Albain KS, Swann RS, Rusch VW et al (2009) Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet 374:379–386

    Google Scholar 

  • Allen AM, Shochat T, Flex D et al (2018) High-dose radiotherapy as neoadjuvant treatment in non-small-cell lung cancer. Oncology 95:13–19

    Google Scholar 

  • Andre F, Grunenwald D, Pignon JP et al (2000) Survival of patients with resected N2 non-small-cell lung cancer: evidence for a subclassification and implications. J Clin Oncol 18:2981–2989

    Google Scholar 

  • Aupérin A, Le Péchoux C, Rolland E et al (2010) Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. J Clin Oncol 28:2181–2190

    Google Scholar 

  • Boffa D, Fernandez FG, Kim S et al (2017) Surgically managed clinical stage IIIA-clinical N2 lung cancer in the society of thoracic surgeons database. Ann Thorac Surg 104:395–403

    Google Scholar 

  • Candela SC, Detterbeck FC (2010) A systematic review of restaging after induction therapy for stage IIIa lung cancer prediction of pathologic stage. J Thorac Oncol 5:389–398

    Google Scholar 

  • Casiraghi M, Maisonneuve P et al (2017) Salvage surgery after definitive chemoradiotherapy for non-small cell lung cancer. Semin Thorac Cardiovasc Surg 29:233–241

    Google Scholar 

  • Cerfolio RJ, Bryant AS, Spencer SA, Bartolucci AA (2005) Pulmonary resection after high-dose and low-dose chest irradiation. Ann Thorac Surg 80:1224–1230

    Google Scholar 

  • Chen Y, Peng X, Zhou Y, Xia K, Zhuan W (2018) Comparing the benefits of chemoradiotherapy and chemotherapy for resectable stage III A/N2 non-small cell lung cancer: a meta-analysis. World J Surg Oncol 16:8

    Google Scholar 

  • Cho HJ, Kim SR, Kim HR et al (2014) Modern outcome and risk analysis of surgically resected occult N2 non-small cell lung cancer. Ann Thorac Surg 97:1920–1925

    Google Scholar 

  • Clark GM (2008) Prognostic factors versus predictive factors: examples from a clinical trial of erlotinib. Mol Oncol 1:406–412

    Google Scholar 

  • Clark GM, Zborowski DM, Culbertson JL et al (2006) Clinical utility of epidermal growth factor receptor expression for selecting patients with advanced non-small cell lung cancer for treatment with erlotinib. J Thorac Oncol 1:837–846

    Google Scholar 

  • Daly BDT, Fernando HC, Ketchedjian A et al (2006) Pneumonectomy after high-dose radiation and concurrent chemotherapy for nonsmall cell lung cancer. Ann Thorac Surg 82:227–231

    Google Scholar 

  • De Leyn P, Lardinois D, Van Schil PE et al (2007) ESTS guidelines for preoperative lymph node staging for non-small cell lung cancer. Eur J Cardiothorac Surg 32:1–8

    Google Scholar 

  • De Leyn P, Dooms C, Kuzdzal J et al (2014) Revised ESTS guidelines for preoperative mediastinal lymph node staging for non-small-cell lung cancer. Eur J Cardiothorac Surg 45:787–798

    Google Scholar 

  • De Waele M, Serra-Mitjans M, Hendriks J et al (2008) Accuracy and survival of repeat mediastinoscopy after induction therapy for non-small cell lung cancer in a combined series of 104 patients. Eur J Cardiothorac Surg 33:824–828

    Google Scholar 

  • Decaluwé H, De Leyn P, Vansteenkiste J et al (2009) Surgical multimodality treatment for baseline resectable stage IIIA-N2 non-small cell lung cancer. Degree of mediastinal lymph node involvement and impact on survival. Eur J Cardiothorac Surg 36:433–439

    Google Scholar 

  • Detterbeck F (2008) What to do with ‘surprise’ N2?: intraoperative management of patients with non-small-cell lung cancer. J Thorac Oncol 3:289–302

    Google Scholar 

  • Ding X, Hui Z, Dai H et al (2016) A proposal for combination of lymph node ratio and anatomic location of involved lymph nodes for nodal classification in non-small cell lung cancer. J Thorac Oncol 11:1565–1573

    Google Scholar 

  • Donington JS, Paulus R, Edelman MJ, for the NRG Oncology Lung Group et al (2020) Resection following concurrent chemotherapy and high-dose radiation for stage IIIA non–small cell lung cancer. J Thorac Cardiovasc Surg 160:1331–1345.e1

    Google Scholar 

  • Douillard JY, Rosell R, De Lena M et al (2006) Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol 7:719–727

    Google Scholar 

  • Eberhardt WE, Pöttgen C, Gauler TC et al (2015) Phase III study of surgery versus definitive concurrent chemoradiotherapy boost in patients with resectable stage IIIA(N2) and selected IIIB non-small-cell lung cancer after induction chemotherapy and concurrent chemoradiotherapy (ESPATUE). J Clin Oncol 33:4194–4201

    Google Scholar 

  • Ellis MC, Diggs BS, Vetto JT et al (2011) Intraoperative oncologic staging and outcomes for lung cancer resection vary by surgeon specialty. Ann Thorac Surg 92:1958–1963

    Google Scholar 

  • Evison M, Clive A, Castle L et al (2017) Resectable clinical N2 non-small cell lung cancer; what is the optimal treatment strategy? An update by the British Thoracic Society Lung Cancer Specialist Advisory Group. J Thorac Oncol 12:1434–1341

    Google Scholar 

  • Farjah F, Flum DR, Varghese TK Jr et al (2009) Surgeon specialty and long-term survival after pulmonary resection for lung cancer. Ann Thorac Surg 87:995–1004

    Google Scholar 

  • Funakoshi Y, Takeuchi Y, Kusumoto H et al (2012) Which subgroup of patients with pathologic N2 non-small cell lung cancer benefit from surgery? J Cancer Res Clin Oncol 138:1027–1033

    Google Scholar 

  • Gao SJ, Corso CD, Wang EH et al (2017) Timing of surgery after neoadjuvant chemoradiation in locally advanced non–small cell lung cancer. J Thorac Oncol 12:314–322

    Google Scholar 

  • 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

    Google Scholar 

  • Goldstraw P, Chansky K, Crowley J et al (2016) The IASLC lung cancer staging project: proposals for revision of the TNM stage groupings in the forthcoming (eighth) edition of the TNM classification for lung cancer. J Thorac Oncol 11:39–51

    Google Scholar 

  • Guo SX, Jian Y, Chen YL et al (2016) Neoadjuvant chemoradiotherapy versus chemotherapy alone followed by surgery for resectable stage III non-small-cell lung cancer: a meta-analysis. Sci Rep 6:34388

    Google Scholar 

  • Hancock J, Rosen J, Moreno A et al (2014) Management of clinical stage IIIA primary lung cancers in the National Cancer Database. Ann Thorac Surg 98:424–432

    Google Scholar 

  • Jeremic B, Milicic B, Milisavljevic S (2013) Radiotherapy alone versus radiochemotherapy in patients with favorable prognosis clinical stage IIIa non small-cell lung cancer (NSCLC). Clin Lung Cancer 14:172–180

    Google Scholar 

  • Jeremic B, Casas F, Dubinsky P et al (2016) Surgery in stage IIIA nonsmall cell lung cancer: lack of predictive and prognostic factors identifying any patient subgroup benefiting from it. Clin Lung Cancer 17:107–112

    Google Scholar 

  • Johnstone DW, Byhardt RW, Ettinger D, Scott CB (2002) Phase III study comparing chemotherapy and radiotherapy with preoperative chemotherapy and surgical resection in patients with non-small-cell lung cancer with spread to mediastinal lymph nodes (N2); final report of RTOG 89-01. Radiation therapy oncology group. Int J Radiat Oncol Biol Phys 54:365–369

    Google Scholar 

  • Kamel MK, Rahouma M, Ghaly G et al (2017) Clinical predictors of persistent mediastinal nodal disease after induction therapy for stage IIIA N2 non-small cell lung cancer. Ann Thorac Surg 103:281–286

    Google Scholar 

  • Kim AW, Boffa DJ, Wang Z et al (2012) An analysis, systematic review, and meta-analysis of the perioperative mortality after neoadjuvant therapy and pneumonectomy for non-small cell lung cancer. J Thorac Cardiovasc Surg 143:55–63

    Google Scholar 

  • Kumar P, Herndon J II, Langer M et al (1996) Patterns of disease failure after trimodality therapy of nonsmall cell lung carcinoma pathologic stage IIIA (N2): analysis of cancer and leukemia group B protocol 8935. Cancer 77:2393–2399

    Google Scholar 

  • Legras A, Mordant P, Arame A et al (2014) Long-term survival of patients with pN2 lung cancer according to the pattern of lymphatic spread. Ann Thorac Surg 97:1156–1162

    Google Scholar 

  • Liang H-Y, Zhou H, Li H-L et al (2010) Chemo-radiotherapy for advanced non-small cell lung cancer: concurrent or sequential? It’s no longer the question: a systematic review. Int J Cancer 127:718–728

    Google Scholar 

  • Livingston RB (1997) Combined modality therapy of lung cancer. Clin Cancer Res 3:2638–2647

    Google Scholar 

  • Louie BE, Kapur S, Farivar AS et al (2011) Safety and utility of mediastinoscopy in non-small cell lung cancer in a complex mediastinum. Ann Thorac Surg 92:278–283

    Google Scholar 

  • MacManus MP, Everitt S, Bayne M et al (2013) The use of fused PET/CT images for patient selection and radical radiotherapy target volume definition in patients with non-small cell lung cancer: results of a prospective study with mature survival data. Radiother Oncol 106:292–298

    Google Scholar 

  • Matsunaga T, Suzuki K, Takamochi K et al (2014) Time to refine N2 staging? cN2α and cN2β based on local regional involvement provide a more accurate prognosis in surgically treated IIIA non-small-cell lung cancer than N2 alone or the number of node stations involved. Eur J Cardiothorac Surg 46:86–91

    Google Scholar 

  • McElnay PJ, Choong A, Jordan E et al (2015) Outcome of surgery versus radiotherapy after induction treatment in patients with N2 disease: systematic review and meta-analysis of randomised trials. Thorax 70:764–768

    Google Scholar 

  • Misthos P, Sepsas E, Kokotsakis J, Skottis I, Lioulias A (2008) The significance of one-station N2 disease in the prognosis of patients with nonsmall-cell lung cancer. Ann Thorac Surg 86:1626–1630

    Google Scholar 

  • Nagai K, Tsuchiya R, Mori T et al (2003) A randomized trial comparing induction chemotherapy followed by surgery with surgery alone for patients with stage IIIA N2 non-small cell lung cancer (JCOG 9209). J Thorac Cardiovasc Surg 125:254–260

    Google Scholar 

  • O’Rourke N, Roqué I, Figuls M et al (2010) Concurrent chemoradiotherapy in non-small cell lung cancer. Cochrane Database Syst Rev 6:CD002140

    Google Scholar 

  • Obiols C, Call S, Rami-Porta R et al (2014) Survival of patients with unsuspected pN2 non-small cell lung cancer after an accurate preoperative mediastinal staging. Ann Thorac Surg 97:957–964

    Google Scholar 

  • Pass HI, Pogrebniak HW, Steinberg SM et al (1992) Randomized trial of neoadjuvant therapy for lung cancer: interim analysis. Ann Thorac Surg 53:992–998

    Google Scholar 

  • Pöttgen C, Eberhardt W, Stamatis G, Stuschke M (2017) Definitive radiochemotherapy versus surgery with multimodality treatment in stage III non-small cell lung cancer (NSCLC) - a cumulative meta-analysis of the randomized evidence. Oncotarget 8 41670–41678.

    Google Scholar 

  • Rami-Porta R, Bolejack V, Giroux DJ et al (2014) International association for the study of lung cancer Staging and Prognostic Factors Committee, Advisory Board Members and Participating Institutions The IASLC lung cancer staging project: the new database to inform the eighth edition of the TNM classification of lung cancer. J Thorac Oncol 9:1618–1624

    Google Scholar 

  • Ramnath N, Dilling TJ, Harris LJ et al (2013) Treatment of stage III non-small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 143:e314S–e340S

    Google Scholar 

  • Ren Z, Zhou S, Liu Z et al (2015) Randomized controlled trials of induction treatment and surgery versus combined chemotherapy and radiotherapy in stagesIIIA-N2 NSCLC: a systematic review and meta-analysis. J Thorac Dis 7:1414–1422

    Google Scholar 

  • Rice JD, Heidel J, Trivedi JR, van Berkel VH (2020) Optimal surgical timing after neoadjuvant therapy for stage IIIa non-small cell lung cancer. Ann Thorac Surg 109:842–847

    Google Scholar 

  • Rocco G, Nason K, Brunelli A et al (2016) Management of stage IIIA (N2) non-small cell lung cancer: a transatlantic perspective. Ann Thorac Surg 101:1247–1250

    Google Scholar 

  • Romero-Vielva L, Viteri S, Moya-Hornoc I et al (2019) Salvage surgery after definitive chemo-radiotherapy for patients with non-small cell lung cancer. Lung Cancer 133:117–122

    Google Scholar 

  • Rosell R, Gomez-Codina J, Camps C et al (1994) A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small-cell lung cancer. N Engl J Med 330:153–158

    Google Scholar 

  • Roth JA, Fossella F, Komaki R et al (1994) A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer. J Natl Cancer Inst 86:673–680

    Google Scholar 

  • Schreiner W, Dudek W, Lettmaier S, Fietkau R, Sirbu H (2018) Long-term survival after salvage surgery for local failure after definitive chemoradiation therapy for locally advanced non-small cell lung cancer. Thorac Cardiovasc Surg 66:135–141

    Google Scholar 

  • Shah AA, Berry MF, Tzao C et al (2012) Induction chemoradiation is not superior to induction chemotherapy alone in stage IIIA lung cancer. Ann Thorac Surg 93:1807–1812

    Google Scholar 

  • Shepherd FA, Johnston MR, Payne D et al (1998) Randomized study of chemotherapy and surgery versus radiotherapy for stage IIIA non-small-cell lung cancer: a National Cancer Institute of Canada Clinical Trials Group Study. Br J Cancer 78:683–685

    Google Scholar 

  • Sher DJ, Fidler MJ, Seder CW, Liptay MJ, Koshy M (2015) Relationship between radiation therapy dose and outcome in patients treated with neoadjuvant chemoradiation therapy and surgery for stage IIIA non-small cell lung cancer: a population-based, comparative effectiveness analysis. Int J Radiat Oncol Biol Phys 92:307–316

    Google Scholar 

  • Shi Y, Sun Y, Yu J et al (2017) China experts consensus on the diagnosis and treatment of advanced stage primary lung cancer. (2016 version). Asia Pac J Clin Oncol 13:87–103

    Google Scholar 

  • Shields TW (1990) The significance of ipsilateral mediastinal lymph node metastasis (N2 disease) in non-small cell carcinoma of the lung: a commentary. J Thorac Cardiovasc Surg 99:48–53

    Google Scholar 

  • Silvestri GA, Gonzalez AV, Jantz MA et al (2013) Methods for staging non-small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 143:e211S–e250S

    Google Scholar 

  • Sonett JR, Suntharalingam M, Edelman MJ et al (2004) Pulmonary resection after curative intent radiotherapy (>59 Gy) and concurrent chemotherapy in non-small-cell lung cancer. Ann Thorac Surg 78:1200–1205

    Google Scholar 

  • Sorensen JB, Riska H, Ravn J et al (2013) Scandinavian phase III trial of neoadjuvant chemotherapy in NSCLC stages IB-IIIA/T3. J Clin Oncol 31(Suppl):abstract 7504

    Google Scholar 

  • Stephens RJ, Girling DJ, Hopwood P et al (2005) A randomised controlled trial of pre-operative chemotherapy followed, if feasible, by resection versus radiotherapy in patients with inoperable stage T3, N1, M0 or T1-3, N2, M0 non-small cell lung cancer. Lung Cancer 49:395–400

    Google Scholar 

  • Sugarbaker DJ, Herndon J, Kohman LJ, Krasna MJ, Green MR, and the Cancer and Leukemia Group B Thoracic Surgery Group (1995) Results of cancer and leukemia group B protocol 8935: a multiinstitutional phase II trimodality trial for stage IIIA (N2) non-small-cell lung cancer. J Thorac Cardiovasc Surg 109:473–485

    Google Scholar 

  • Suntharalingam M, Paulus R, Edelman MJ et al (2012) Radiation therapy oncology group protocol 02-29: a phase II trial of neoadjuvant therapy with concurrent chemotherapy and full-dose radiation therapy followed by surgical resection and consolidative therapy for locally advanced nonsmall cell carcinoma of the lung. Int J Radiat Oncol 84:456–463

    Google Scholar 

  • SEER (2010) Surveillance, epidemiology and end results. US National Institutes of Health, National Cancer Institute, Bethesda, MD

    Google Scholar 

  • Taylor NA, Liao ZX, Cox JD et al (2004) Equivalent outcome of patients with clinical Stage IIIA non-small-cell lung cancer treated with concurrent chemoradiation compared with induction chemotherapy followed by surgical resection. Int J Radiat Oncol Biol Phys 58:204–212

    Google Scholar 

  • Tong S, Qin Z, Wan M, Zhang L, Cui Y, Yao Y (2018) Induction chemoradiotherapy versus induction chemotherapy for potentially resectable stage IIIA (N2) non-small cell lung cancer: a systematic review and meta-analysis. J Thorac Dis 10:2428–2436

    Google Scholar 

  • van Meerbeeck JP, Kramer GW, van Schil PE et al (2007) Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small-cell lung cancer. J Natl Cancer Inst 99:442–450

    Google Scholar 

  • Xu Y-P, Li B, Xu X-L et al (2015) Is there a survival benefit in patients with stage IIIA (N2) non- cell lung cancer receiving neoadjuvant chemotherapy and/or radiotherapy prior to surgical resection. A systematic review and meta-analysis. Medicine (Baltimore) 94:e879

    Google Scholar 

  • Xu X-L, Dan L, Chen W et al (2016) Neoadjuvant chemoradiotherapy or chemotherapy followed by surgery is superior to that followed by definitive chemoradiation or radiotherapy in stage IIIA(N2) nonsmall-cell lung cancer: a meta-analysis and system review. Onco Targets Ther 9:845–853

    Google Scholar 

  • Ye JC, Ding L, Atay SM et al (2020) Trimodality vs chemoradiation and salvage resection in cN2 stage IIIA non_small cell lung cancer. Semin Thorac Cardiovasc Surg 32:153–159

    Google Scholar 

  • Yoshino I, Yoshida S, Miyaoka E et al (2012) Surgical outcome of stage IIIAcN2_ pN2 non-small-cell lung cancer patients in Japanese lung cancer registry study in 2004. J Thorac Oncol 7:850–855

    Google Scholar 

  • Zeng X, Karnon J, Wang S, Wu B, Wan X, Peng L (2012) The cost of treating advanced non-small cell lung cancer: estimates from the Chinese experience. PLoS One 7:e48323

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. School of Medicine, University of Kragujevac, Kragujevac, Serbia

    Branislav Jeremić

  2. Caucasus Medical Center, Tbilisi, Georgia

    Ivane Kiladze

  3. University Clinical Center, School of Medicine, Kragujevac, Serbia

    Slobodan Milisavljevic

Authors
  1. Branislav Jeremić
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ivane Kiladze
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Slobodan Milisavljevic
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Branislav Jeremić .

Editor information

Editors and Affiliations

  1. School of Medicine, University of Kragujevac, Kragujevac, Serbia

    Branislav Jeremić

Rights and permissions

Reprints and permissions

Copyright information

© 2021 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Jeremić, B., Kiladze, I., Milisavljevic, S. (2021). Multimodality Treatment of Stage IIIA/N2 NSCLC: Why Always NO to Surgery?. In: Jeremić, B. (eds) Advances in Radiation Oncology in Lung Cancer. Medical Radiology(). Springer, Cham. https://doi.org/10.1007/174_2021_275

Download citation

  • DOI: https://doi.org/10.1007/174_2021_275

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-031-34846-4

  • Online ISBN: 978-3-031-34847-1

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation