MTE05.01 Where is the Place of Surgery for N2 Disease?

Abstract

The diagnostic and management strategies for stage IIIA-N2 non-small cell lung cancer (NSCLC), which represents locally advanced disease with involvement of ipsilateral mediastinal lymph nodes, remain controversial despite results from several randomized controlled trials.1,2 There are various reasons for this ongoing debate. First, stage IIIA-N2 represents a very heterogeneous patient population ranging from incidental discovery of positive N2 nodes during lung resection, to single mediastinal nodal involvement and bulky N2 disease where individual lymph nodes are hard to identify. In this setting, the precise diagnostic algorithm remains controversial. Currently, patients with proven or suspected lung cancer are mainly staged by integrated positron emission tomography – computed tomography (PET-CT). However pathological proof of nodal involvement should be obtained by a minimally invasive or invasive technique due to a relatively high rate of false positive nodes, owing to mainly inflammation.3 Secondly, the optimal restaging strategy after induction therapy is heavily debated. Thirdly, specific controversy relates to the role of surgery versus radiotherapy and the precise extent of resection after induction therapy. Randomized trials included different subsets of N2 disease making the interpretation of results quite difficult. As a result of the limitations of available data heated discussions have been taking place for several decades on the optimal treatment strategy for this subset of patients. When N2 disease is detected during thoracotomy, this is referred to as incidental, unsuspected, unforeseen or “surprise” N2.4 When found intraoperatively, a resection should be performed as long as it can be complete. Adjuvant chemotherapy prolongs survival and is currently recommended in this setting. However the role of radiotherapy remains controversial and is currently evaluated in the randomized LungART trial (NCT00410683).5 In quite a large subgroup of patients, N2 disease is suspected on PET-CT scanning and subsequently confirmed by minimally invasive or invasive staging techniques. Although the term “potentially resectable N2” is often utilized, no precise, internationally accepted definition is available. Most patients in this sub-group will be treated by concurrent chemo-radiotherapy alone or induction therapy followed by surgery or definitive radiotherapy. Whether induction chemo-radiotherapy yields better results than chemotherapy alone was studied in the recently published, randomized trial NCT00030771 of the Swiss Cancer League.6 No significant differences were found. However, this study was not adequately powered to show non-inferiority between the two strategies. There are different restaging techniques to evaluate response after induction therapy. In contrast to imaging or functional studies, remediastinoscopy provides pathological evidence but is technically more difficult and less accurate than mediastinoscopy done prior to induction treatment.3 An alternative approach consists of the use of minimally invasive staging procedures to obtain an initial proof of mediastinal nodal involvement. Mediastinoscopy is subsequently performed after induction therapy to evaluate response.3 In patients with proven mediastinal downstaging after induction who can preferentially treated by lobectomy, surgical resection may be recommended. Whether radiotherapy yields similar results has not been established yet. One of the reasons is that in patients undergoing chemo-radiotherapy pathology to evaluate response is not available making comparison with surgery quite difficult. A recent meta-analysis tried to better clarify the outcome of surgery compared to radiotherapy after induction treatment in patients with N2 disease.7 Six trials including a total of 868 patients were included. Main outcome was overall survival. The authors concluded that when bimodality treatment is applied, both surgery and radiotherapy options are valid with a pooled hazard ratio for mortality in the surgery group of 1.01 (p not significant). In contrast, in trimodality regimens results support surgical resection as part of multimodality management with a pooled hazard ratio for mortality in the surgery group of 0.87 indicating a 13% relative improvement in overall survival (p= 0.068). In the recently published ESPATUE trial, patients with resectable stage IIIA-N2 and selected stages IIIB NSCLC were included.2 No significant differences were found between the control arm consisting of induction chemotherapy followed by definitive chemo-radiotherapy, and the experimental arm administering induction chemotherapy followed by chemo-radiotherapy with a dose of 45 Gy, followed by surgical resection. Both treatment options are considered acceptable strategies for these highly selected patients with a relatively good prognosis. North American (American College of Chest Physicians 2013)8 and European guidelines (European Society of Medical Oncology 2015)1 recommend that in NSCLC patients with N2 involvement the treatment plan should be made with the input of an experienced multidisciplinary team. The ESMO guidelines include induction chemotherapy followed by surgery, induction chemoradiotherapy followed by surgery, or concurrent definitive chemoradiotherapy as possible treatment strategies for potentially resectable stage IIIA-N2 However bulky N2 disease is mostly treated with chemo-radiotherapy as these patients do not qualify for surgical resection due to extensive extracapsular involvement.1 Furthermore complete resection, which is a major prognostic factor, is mostly not achievable in this subset of N2 disease. The standard of care in patients with good performance status is concurrent chemoradiotherapy.1 Of particular interest to thoracic surgeons is the relatively new concept of “salvage” surgery after full-dose chemo-radiotherapy in stage IIIA-N2 NSCLC.9,10 These patients present with recurrent or progressive locally advanced disease, in some cases complicated by an infected cavity, rendering surgical resection technically difficult. Furthermore, a systematic nodal dissection may be challenging, especially when bulky lymph nodes were initially present. In conclusion, although randomized controlled trials are available, no definite answer can be provided regarding the optimal strategy for staging, restaging and treatment of the different subsets of stage IIIA-N2 disease. Every patient with locally advanced NSCLC should be discussed within a multidisciplinary tumor board including radiation oncologists and thoracic surgeons who have a large experience with major lung resections. The best available diagnostic and treatment strategies should be discussed with the patient. Salvage surgery should be reserved for those centers having a large experience in thoracic surgery where a dedicated team is available as management of these patients requires multidisciplinary cooperation preoperatively, intraoperatively and postoperatively. 1. Eberhardt WE, De Ruysscher D, Weder W, Le Péchoux C, De Leyn P, Hoffmann H et al. 2nd ESMO Consensus Conference in Lung Cancer: locally advanced stage III non-small-cell lung cancer. Ann Oncol 2015; 26:1573-88. 2. Eberhardt WE, Pöttgen C, Gauler TC, Friedel G, Veit S, Heinrich V 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; 33:4194-201. 3. De Leyn P, Dooms C, Kuzdzal J, Lardinois D, Passlick B, Rami-Porta R et al. Revised ESTS guidelines for preoperative mediastinal lymph node staging for non-small-cell lung cancer. Eur J Cardiothorac Surg 2014; 45:787-98. 4. Van Schil P. Stage IIIA-N2 non-small-cell lung cancer: from “surprise” involvement to surgical nightmare. Eur J Cardiothorac Surg 2016; 49:1613-4. 5. Le Péchoux C, Dunant A, Faivre-Finn C, Thomas PA, Pourel N, Lerouge D et al. Postoperative radiotherapy for pathologic N2 non-small cell lung cancer treated with adjuvant chemotherapy: need for randomized evidence. J Clin Oncol 2015;33:2930-1. 6. Pless M, Stupp R, Ris HB, Stahel RA, Weder W, Thierstein S et al. Induction chemo-radiotherapy in stage IIIA/N2 non-small cell lung cancer: a phase 3 randomised trial. Lancet 2015; 386(9998):1049-56. 7. McElnay PJ, Choong A, Jordan E, Song F, Lim E. Outcome of surgery versus radiotherapy after induction treatment in patients with N2 disease: systematic review and meta-analysis of randomised trials. Thorax 2015;70:764-8. 8. Ramnath N, Dilling TJ, Harris LJ, Kim AW, Michaud GC, Balekian AA 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(5 Suppl): e314-30S. 9. Van Schil P. Salvage surgery after stereotactic radiotherapy: a new challenge for thoracic surgeons. J Thorac Oncol 2010;5:1881-2. 10. Schreiner W, Dudek W, Sirbu H. Is salvage surgery for recurrent non-small-cell lung cancer after definitive non-operative therapy associated with reasonable survival? Interact Cardiovasc Thorac Surg 2015;21:682-4. induction therapy, Chemo-radiotherapy, Surgery, stage IIIA-N2 disease