Review Article|Articles in Press

Current Management of Stage IIIA (N2) Non-Small-Cell Lung Cancer

Role of Perioperative Immunotherapy, and Tyrosine Kinase Inhibitors
Published:February 26, 2023DOI:


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribers receive full online access to your subscription and archive of back issues up to and including 2002.

      Content published before 2002 is available via pay-per-view purchase only.


      Subscribe to Thoracic Surgery Clinics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Siegel R.L.
        • et al.
        Cancer Statistics, 2021.
        CA A Cancer J Clin. 2021; 71: 7-33
        • Yotsukura M.
        • et al.
        Recent advances and future perspectives in adjuvant and neoadjuvant immunotherapies for lung cancer.
        Jpn J Clin Oncol. 2020; 51: 28-36
        • Ramnath N.
        • et al.
        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. 2013; 143: e314S-e340S
        • AJCC
        AJCC cancer staging manual.
        8th Ed. Springer, New York2016
        • Brahmer J.
        • et al.
        Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer.
        N Engl J Med. 2015; 373: 123-135
        • Borghaei H.
        • et al.
        Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer.
        N Engl J Med. 2015; 373: 1627-1639
        • Mok T.S.K.
        • et al.
        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.
        Lancet. 2019; 393: 1819-1830
        • Herbst R.S.
        • et al.
        Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial.
        Lancet. 2016; 387: 1540-1550
        • Herbst R.S.
        • et al.
        Atezolizumab for First-Line Treatment of PD-L1–Selected Patients with NSCLC.
        N Engl J Med. 2020; 383: 1328-1339
        • Ramalingam S.S.
        • et al.
        Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC.
        N Engl J Med. 2019; 382: 41-50
        • Antonia S.J.
        • et al.
        Durvalumab after Chemoradiotherapy in Stage III Non–Small-Cell Lung Cancer.
        N Engl J Med. 2017; 377: 1919-1929
        • Antonia S.J.
        • et al.
        Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC.
        N Engl J Med. 2018; 379: 2342-2350
        • Felip E.
        • et al.
        Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial.
        Lancet. 2021; 398: 1344-1357
      1. Felip, E., Overall Survival Interim Analysis of a Phase III Study of Atezolizumab vs Best Supportive Care in Resected NSCLC, in World Conference on Lung Cancer. 2022: Vienna, Austria.

        • O'Brien M.
        • et al.
        Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB-IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): an interim analysis of a randomised, triple-blind, phase 3 trial.
        Lancet Oncol. 2022; 23: 1274-1286
        • Kosaka T.
        • et al.
        Mutations of the epidermal growth factor receptor gene in lung cancer: biological and clinical implications.
        Cancer Res. 2004; 64: 8919-8923
        • Russo A.
        • et al.
        Heterogeneous responses to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patients with uncommon EGFR mutations: new insights and future perspectives in this complex clinical scenario.
        Int J Mol Sci. 2019; 20: 1431
        • Kobayashi Y.
        • et al.
        EGFR exon 18 mutations in lung cancer: molecular predictors of augmented sensitivity to afatinib or neratinib as compared with first-or third-generation TKIs.
        Clin Cancer Res. 2015; 21: 5305-5313
        • Wu Y.-L.
        • et al.
        Osimertinib in Resected EGFR-Mutated Non–Small-Cell Lung Cancer.
        N Engl J Med. 2020; 383: 1711-1723
        • Tsuboi M.
        • et al.
        LBA47 Osimertinib as adjuvant therapy in patients (pts) with resected EGFR-mutated (EGFRm) stage IB-IIIA non-small cell lung cancer (NSCLC): Updated results from ADAURA.
        Ann Oncol. 2022; 33: S1413-S1414
        • Forde P.M.
        • et al.
        Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer.
        N Engl J Med. 2022; 386: 1973-1985
        • Provencio-Pulla M.
        • et al.
        Nivolumab + chemotherapy versus chemotherapy as neoadjuvant treatment for resectable stage IIIA NSCLC: Primary endpoint results of pathological complete response (pCR) from phase II NADIM II trial.
        J Clin Oncol. 2022; 40: 8501
        • Provencio M.
        • et al.
        PL03.12 Progression Free Survival and Overall Survival in NADIM II Study.
        J Thorac Oncol. 2022; 17: S2-S3
        • Spigel D.R.
        • et al.
        Five-year survival outcomes with durvalumab after chemoradiotherapy in unresectable stage III NSCLC: an update from the PACIFIC trial.
        J Clin Oncol. 2021; 39: 8511
        • Bryan D.S.
        • Donington J.S.
        The role of surgery in management of locally advanced non-small cell lung cancer.
        Curr Treat Options Oncol. 2019; 20: 1-13
        • Tanner N.T.
        • et al.
        Physician preferences for management of patients with stage IIIA NSCLC: impact of bulk of nodal disease on therapy selection.
        J Thorac Oncol. 2012; 7: 365-369
        • Suntharalingam M.
        • et al.
        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 non-small cell carcinoma of the lung.
        Int J Radiat Oncol Biol Phys. 2012; 84: 456-463
        • Albain K.S.
        • et al.
        Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial.
        Lancet. 2009; 374: 379-386
        • Cheung M.C.
        • et al.
        Impact of teaching facility status and high-volume centers on outcomes for lung cancer resection: an examination of 13,469 surgical patients.
        Ann Surg Oncol. 2009; 16: 3-13
        • Kim A.W.
        • et al.
        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. 2012; 143: 55-63
        • Spicer J.
        • et al.
        Surgical outcomes from the phase 3 CheckMate 816 trial: Nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo alone as neoadjuvant treatment for patients with resectable non-small cell lung cancer (NSCLC).
        J Clin Oncol. 2021; 39: 8503
        • Liu J.
        • et al.
        Improved Efficacy of Neoadjuvant Compared to Adjuvant Immunotherapy to Eradicate Metastatic Disease.
        Cancer Discov. 2016; 6: 1382-1399
        • Blank C.U.
        • et al.
        Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma.
        Nat Med. 2018; 24: 1655-1661
        • Donington J.S.
        Neoadjuvant Immunotherapy for Resectable Non-small Cell Lung Cancer: Exciting New Horizon in Early-Stage Lung Cancer Care.
        Ann Surg Oncol. 2022; 29: 5344-5346
        • Patel S.
        • et al.
        LBA6 Neoadjvuant versus adjuvant pembrolizumab for resected stage III-IV melanoma (SWOG S1801).
        Ann Oncol. 2022; 33: S1408
        • Pless M.
        • et al.
        Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial.
        Lancet. 2015; 386: 1049-1056
        • Katakami N.
        • et al.
        A phase 3 study of induction treatment with concurrent chemoradiotherapy versus chemotherapy before surgery in patients with pathologically confirmed N2 stage IIIA nonsmall cell lung cancer (WJTOG9903).
        Cancer. 2012; 118: 6126-6135
        • Chen Y.
        • et al.
        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. 2018; 16: 8
        • Higgins K.
        • et al.
        Preoperative chemotherapy versus preoperative chemoradiotherapy for stage III (N2) non-small-cell lung cancer.
        Int J Radiat Oncol Biol Phys. 2009; 75: 1462-1467
        • Altorki N.K.
        • et al.
        Neoadjuvant durvalumab with or without stereotactic body radiotherapy in patients with early-stage non-small-cell lung cancer: a single-centre, randomised phase 2 trial.
        Lancet Oncol. 2021; 22: 824-835