Is the routine use of trimodality therapy for selected patients with non-small cell lung cancer supported by long-term clinical outcomes?
Authors: C. Dickhoff, K.J. Hartemink, J. Kooij, P.M. van de Ven, M.A. Paul, E.F. Smit, M. Dahele
Journal: Annals of Oncology (2016)

Induction chemo-radiotherapy followed by surgical resection (trimodality therapy, TT) in patients with non-small cell lung cancer remains controversial, in particular for non-Pancoast tumors. Studies comparing TT with definitive chemo-radiotherapy have failed to show an advantage for either strategy [1.Eberhardt W.E. Pöttgen C. Gauler T.C. et al.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. 2015; 33: 4194-4201Crossref PubMed Scopus (226) Google Scholar, 2.Albain K.S. Swann R.S. Rusch V.W. 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: 379-386Abstract Full Text Full Text PDF PubMed Scopus (1142) Google Scholar]. As a result, TT continues to be used outside clinical trials for patients with stage IIB (chest wall invasion) and stage III (locally advanced, node positive) non-small cell lung cancer [3.Kawaguchi K. Yokoi K. Niwa H. et al.Trimodality therapy for lung cancer with chest wall invasion: initial results of a phase II study.Ann Thorac Surg. 2014; 98: 1184-1191Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar, 4.Koshy M. Fedewa S.A. Malik R. et al.Improved survival associated with neoadjuvant chemoradiation in patients with clinical stage IIIA(N2) non-small-cell lung cancer.J Thorac Oncol. 2013; 8: 915-922Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 5.Dickhoff C. Dahele M. de Langen A.J. et al.Population-based patterns of surgical care for stage IIIA NSCLC in the Netherlands between 2010 and 2013.J Thorac Oncol. 2016; 11: 566-572Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar]. However, randomized studies have been challenging to conduct. For example, the recently published ESPATUE study closed early due to poor accrual, and outcomes in the trimodality arm were based on 80 patients enrolled in multiple centers over a decade [1.Eberhardt W.E. Pöttgen C. Gauler T.C. et al.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. 2015; 33: 4194-4201Crossref PubMed Scopus (226) Google Scholar]. This raises uncertainties in the extrapolation of such data to routine practice. It is therefore necessary to ensure that results of TT in routine clinical practice are not worse than expected. We audited long-term outcomes after TT for non-Pancoast tumors in 54 consecutive patients treated over 5 years starting in 2007. All surgery was performed in one center. Thirteen patients (24.1%) had stage IIB disease (all T3N0), 37 (68.5%) IIIA, and 4 (7.4%) IIIB (7th edition TNM). Median age was 57 (40–72) years; 33/54 (61.1%) and 16/54 (29.6%) were American Society of Anesthesiologists II and III, respectively; and 33 were male (61.6%). Nineteen of 54 had clinical N2 (14 confirmed). Forty-eight of 54 (88.9%) received concurrent chemo-radiotherapy, and 32/54 (59.3%) <50 Gy of radiation (87.5% of whom had <cN2 disease). Surgery was an average of 47 days after final day of radiotherapy and comprised 38 lobectomies (6 bronchial sleeve resections), 7 bi-lobectomies, 5 pneumonectomies, and 4 sublobar resections. Ten patients underwent chest wall resection, seven pulmonary artery sleeve resection, two superior vena cava, one subclavian artery, and one complete vertebral resection. Forty-four of 54 (81.5%) patients had bronchial stump coverage. Complete (R0) resection was achieved in 48/54 (88.9%) and 21/54 (38.9%) had a pathologic complete response. Postsurgical mortality at 30/90 days was 1.9/5.5%, respectively (none after pneumonectomy). Median follow-up was 80.4 months [95% confidence interval (CI): 66.6–94.1] during which 27/54 (50.0%) experienced recurrent disease of whom 20 died of disease. Median overall survival (OS) and event-free survival were 75.9 and 58.7 months, respectively. Eighteen patients (33.3%) had distant recurrence (brain in 9/18, of whom 7/9 diagnosed within 14 months of surgery), six (11.1%) locoregional, and three both (5.6%). Of the six patients without a radical resection, four had locoregional recurrence/persistent disease. Median survival after locoregional and distant relapse was 5.1 months (95% CI: 3.2–7.0) and 11.8 months (95% CI: 0.0–32.3), respectively. Univariate predictors for improved OS and event-free survival included radical resection and the absence of pre-induction mediastinal metastasis. Accepting that there will be differences in tumor stage and patient characteristics between the population presented here and published studies, the median OS > 6 years, low peri-operative mortality, and high R0 resection rate after TT compare favorably with what has been reported in trials and support the careful use of TT for selected patients [1.Eberhardt W.E. Pöttgen C. Gauler T.C. et al.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. 2015; 33: 4194-4201Crossref PubMed Scopus (226) Google Scholar, 2.Albain K.S. Swann R.S. Rusch V.W. 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: 379-386Abstract Full Text Full Text PDF PubMed Scopus (1142) Google Scholar, 3.Kawaguchi K. Yokoi K. Niwa H. et al.Trimodality therapy for lung cancer with chest wall invasion: initial results of a phase II study.Ann Thorac Surg. 2014; 98: 1184-1191Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar]. Clinical audit is essential to ensure that outcomes in routine practice are acceptable. None declared.