Is surgery indicated in patients with stage IIIa lung cancer and mediastinal nodal involvement?

doi:10.1510/icvts.2011.267872 Interactive CardioVascular and Thoracic Surgery 13 (2011) 303-310 www.icvts.org Best evidence topic - Thoracic oncologic Is surgery indicated in patients with stage IIIa lung cancer and mediastinal nodal involvement? Mohammed Bakir a, Stephanie Fraser b, Tom Routledge b, Marco Scarci c, * a King s College London School of Medicine, First Floor, Hodgkin Building, Guy s Campus, London, SE1 1UL, UK b Department of Cardio-thoracic Surgery, Guys Hospital, Great Maze Pond, London, SE1 9RT, UK c Department of Thoracic Surgery, St Joseph s Healthcare, Hamilton, ON, Canada Received 3 February 2011; received in revised form 19 May 2011; accepted 30 May 2011 Summary The role of surgery in the treatment of patients with stage IIIa non-small cell lung cancer (NSCLC) and mediastinal node involvement is examined in this best evidence topic according to a structured protocol. A total of 579 papers were identified using the outlined search, 12 of which were deemed to represent the best available evidence. From the data summarized, we conclude that surgery, as part of a multimodality therapeutic approach, offers a survival benefit for patients with resectable N2 NSCLC. Overall five-year survival rates following primary resection ranged from 17% to 20% (four studies). Improved five-year survival was demonstrated with multimodality therapy (19 45%; 13 studies). Subgroup analysis demonstrates a five-year survival of 30.5% with postoperative chemo-radiotherapy, 22.2% with chemotherapy alone, and 27% with radiotherapy alone. In our review, we address three major issues regarding the management of stage IIIa NSCLC, the first of which is primary vs. postinduction surgery. The largest cohort series to date is the International Association for the Study of Lung Cancer Staging Committee paper on nodal disease, which reports that patients with single-zone N2 disease had the same survival outcome as patients with multizone N1 disease. The second issue is that of randomized vs. cohort studies: there have been five randomized trials reporting similar outcomes and hence equipoise. The third issue is postinduction staging. All studies evaluated reported a better outcome in patients with ypn0 (i.e. postinduction N0 disease). However, surgery should not be denied to patients with ypn1 N2, as there is evidence to demonstrate a significant improvement in survival time in all patients able to undergo surgery after induction chemo-radiotherapy. In conclusion, although some of the evidence available is equivocal regarding the survival benefit of resection for stage IIIa N2 disease, the authors believe surgery should be considered as part of a multimodality therapeutic strategy for patients with advanced nodal disease. 2011 Published by European Association for Cardio-Thoracic Surgery. All rights reserved. Keywords: N2; Lung cancer; Stage III 1. Introduction A best evidence topic was constructed according to a structured protocol. This is fully described in ICVTS [1]. 2. Three-part question In patients with [lung cancer involving the mediastinal nodes], is [surgery] superior to [conventional chemo-radiotherapy] in terms of [improved survival rates]? 3. Clinical scenario A 54-year-old lifelong smoker is diagnosed with T2N2M0 non-small cell lung cancer (NSCLC) of the right upper lobe (RUL), confirmed by positron emission tomography. Mediastinoscopy of stations 4R, 4L, 2R, 2L and 7 has found a *Corresponding author. Department of Thoracic Surgery, St Joseph s Healthcare, Hamilton, ON L8N 4A6, Canada. Tel.: +1-905-906-9131; fax: +1-905-540-6512. E-mail address: marco.scarci@mac.com (M. Scarci). 2011 Published by European Association for Cardio-Thoracic Surgery single microscopic metastatic deposit in the station 7 node. The tumor is otherwise technically resectable on computed tomography scan. Balancing the risks and benefits of surgery against the patient s relatively young age and good health, you wish to consider whether surgical resection after induction chemotherapy would confer a survival benefit compared to chemotherapy/radiotherapy alone. 4. Search strategy A Medline search from 1948 to January 2011 was performed using the OVID interface [non-small cell lung cancer.ti OR stage III lung cancer.mp OR N2.ti NOT N0.mp NOT stage I.mp] AND [resect$.ti OR operat$.ti] 5. Search outcome A total of 579 papers were identified using the reported search; in addition, the reference lists of all the relevant articles were searched. From these, 12 papers were identified as the best evidence available (Table 1). Best Evidence Topic

304 M. Bakir et al. / Interactive CardioVascular and Thoracic Surgery 13 (2011) 303-310 Table 1. Best evidence papers Van Meerbeeck Three hundred and Median overall survival, 15.4 months (95% CI=14.2 17.3) For inductionet al., (2007), thirty-two patients with months (n=579) responsive but J Natl Cancer Inst, cytologically/histologically unresectable stage Belgium, [2] proven unresectable stage Radiotherapy arm Surgery arm P-value IIIA N2 NSCLC, IIIA N2 NSCLC Median survival, 17.5 (15.8 23.2) 16.4 (13.3 19.0) surgery did not improve Randomized underwent induction months (95% CI) survival compared control trial chemotherapy and to radiotherapy The low (level 1b) showed a response; 165 Five-year survival, % 14 (9 20) 15.7 (10 22) morbidity and mortality were randomized to (95% CI) of radiotherapy suggests radiotherapy and 167 to that it is preferable surgery. Sixty-two Hazard ratio (95% CI) 1 1.06 (0.84 1.35) 0.6 for unresectable patients in the surgical arm lymph node involvement received PORT Variable Five-year P-value overall survival Definition of Surgery arm Resection type: 0.009 unresectability: (Bi-)lobectomy 27% any N2 involvement by a Pneumonectomy 12% non-squamous carcinoma pn postinduction: <0.001 in case of squamous cell N0 N1 29% carcinoma, any N2 N2 7% involvement exceeding Resection extent: <0.001 level 4R for a right-sided Complete 27% tumor and level 5 and 6 for Incomplete 7% a left-sided tumor. Incidental N2 was not necessarily considered unresectable Johnstone et al., Forty-three patients Progression-free No statistically The patient accrual to (2002), randomized survival rate significant this trial made its Int J Radiat Oncol by the RTOG and Eastern difference was results inconclusive, Biol Phys, USA, [3] Cooperative Oncology found among but several observations Group between April the treatment are notable. In this Randomized 1990 and April 1994 to arms. The overall trial, histological control trial receive induction progression-free confirmation of (level 1b) chemotherapy followed by survival rate was N2 disease in the surgery or radiotherapy 53% at one year surgical and non-surgical and 17% at arms eliminated the three years. usual biases from The median clinical staging. In this progression-free setting, local control survival was 14 and survival were months essentially equal between the surgical and One-year survival (70% vs. 66%) or radiotherapy arms. The median survival time three- and five-year (19.4 vs. 17.4 survival rates of nonmonths) between surgical therapy were the surgery and comparable to radiotherapy arms published surgical trials of N2 disease Albain et al., Three hundred and Trimodality Bimodality P-value Overall survival was not (2009), ninty-six patients with no Median overall survival 23.6 22.2 significantly different in Lancet, USA, [4] progression of stage (months) the two groups, although IIIA N2 (T1 T3) NSCLC HR (95% CI) 0.87 (0.7 1.1) 1 0.24 trimodality treatment Randomized following chemo- conferred a significant control trial radiotherapy; 202 patients Median progression- 12.8 10.5 improvement in (level 1b) were randomized to free survival (months) progression-free resection (trimodality), HR (95% CI) 0.77 (0.62 0.96) 1 0.017 survival. However, 194 continued exploratory analysis radiotherapy (bimodality) suggested that overall survival significantly improved following trimodality treatment with (Continued on next page)

M. Bakir et al. / Interactive CardioVascular and Thoracic Surgery 13 (2011) 303-310 305 Table 1. (Continued) lobectomy vs. bimodality treatment, but not following pneumonectomy Shepherd et al., Thirty-one patients with Response rate Response rates to Median survival times (1998), stage IIIA induction were 16.2 and 18.7 Br J Cancer, (N2) NSCLC were chemotherapy months for radiotherapy Canada, [5] randomized to receive and radiotherapy alone and radiotherapy alone or were 50% chemotherapy- Randomized chemotherapy with and 53.3%, surgery, respectively control trial cisplatin and vinblastine respectively (P=NS), with (level 1b) followed by surgery no long-term Complete resection 62.5% improvement in survival seen with combined-modality treatment Stephens et al., Forty-eight patients with Median survival 13.8 months in the Complete No evidence of an (2005), T3N1 or T1 T3N2 NSCLC chemotherapy/ resection in only improved survival in the Lung Cancer, UK, were randomized to either surgery group four out of the chemotherapy/surgery [6] neoadjuvant chemotherapy compared to 11.3 24 patients in group, but because the (MIC or MVP) followed months in the the surgical arm trial failed to recruit Randomized by surgery, or to radical radiotherapy sufficient numbers of control trial radiotherapy alone group patients, they were (level 1b) unable to reach reliable conclusions about the two treatment options Rusch et al., An international lung Survival was calculated Lymph node stations could be grouped together into No change was advised (2007), cancer database of 67,725 by the Kaplan Meier six zones : peripheral or hilar for N1, and upper to the current NSCLC J Thorac Oncol, patients was developed method or lower mediastinal, aortopulmonary, and staging system; USA, [7] and analyzed subcarnial for N2 nodes however, further prospective study was Retrospective Three distinct prognostic groups (single-zone N1, suggested to validate cohort study multizone N1 or single N2, and multizone N2 disease) amalgamating (level 2B) were identified in patients undergoing resection lymph node without induction therapy stations into zones and subdividing n descriptors Casali et al., One hundred and eighty- Variable Median survival Five-year P-value Significant prognostic (2005), three patients with proven time (months) survival (%) factors were used to Eur J Cardiothorac N2 NSCLC underwent Overall survival 24 20 identify homogeneous Surg, Italy, [8] complete surgical N clinical status: 0.001 subgroups,including: resection. All patients cn0 N1 33.9 35.4 incidental N2; number Retrospective received adjuvant cn2 19.4 17.4 of node levels involved; cohort study chemotherapy, but not N2 levels: 0.034 and pattern of (level 2b) induction therapy Single 25.2 23.8 lymphatic spread to Multiple 16.0 14.7 mediastinal nodes, Topography N2: 0.037 although skip Superior 32.0 37.8 metastases were not Aortic 24.3 17.4 associated with improved Lower 16.3 17.1 survival. Individual N2 metastatic patterns: 0.002 subgroups may benefit RUL/RML+ 37.7 31.8 from customized superior nodes therapeutic strategies LUL+aortic nodes 43.1 26.9 for the timing of surgery Lower lobes+lower 17.8 15.7 and chemotherapy nodes Lymphatic spread: 0.163 Sequential 22.9 18.5 Skipped (skip-n2) 25.2 26.4 Best Evidence Topic (Continued on next page)

306 M. Bakir et al. / Interactive CardioVascular and Thoracic Surgery 13 (2011) 303-310 Table 1. (Continued) Andre et al., Seven hundred and two Variable Three-year event- Three-year Two homogeneous stage (2000), J Clin patients with resectable free survival overall survival IIIA N2 NSCLC Oncol, France, [9] stage IIIA N2 were defined: RR S.E. P-value RR S.E. P-value prognostic subgroups clinical N2 pt stage: were identified: Prospective disease (cn2) and pt1 T2 1.62 0.09 <0.0001 1.5 0.1 <0.0001 mn2l1 patients, cohort study minimal pt3 T4 in whom surgery is (level 2b) (incidental) N2 disease Preoperative beneficial; and mn2l2+ (mn2). Induction N2 status: and cn2 patients, in chemotherapy was mn2 1.9 0.09 <0.0001 1.8 0.1 <0.0001 whom surgery is administered to 124 cn2 indicated if patients from both groups No. of lymph responsive to induction node levels chemotherapy involved: One (L1) 1.6 0.09 <0.0001 1.6 0.1 <0.0001 Multiple (L2+) Neoadjuvant chemotherapy: Yes 1.55 0.1 0.0006 1.4 0.1 <0.005 No Five-year survival (%) mn2 preoperative 29.5 status cn2 preoperative 7 status: Primary surgery 5 Surgery+induction chemotherapy Responsive 20 Not responsive 5 Downstaged disease 30 Ratto et al., Two hundred and seventy- Preoperative variables Median P-value HR 95% CI Different patient (2009), seven patients with survival subgroups J Thorac confirmed potentially time are identified based on Cardiovasc operable N2 NSCLC; (months) preoperative and Surg, Italy, [10] 192 patients underwent No. of N2 nodes <0.0001 postoperative prognostic primary resection, and 85 involved: factors that may be Prospective underwent induction 1 22.7 1 used to select patients population study chemotherapy followed 2 16.8 1.744 1.256 2.422 for surgery (level 2b) by surgery >2 11.1 3.109 1.869 5.173 Symptom severity: 0.0129 None 23.6 1 Mild 21.2 1.311 0.842 2.042 Moderate 20.6 1.116 0.727 1.712 Severe 12.8 1.987 1.243 2.896 Clinical T: 0.0688 T1 23.3 T2 22.0 T3 14.6 T4 18.0 1.236 1.011 1.510 Induction 0.0012 chemotherapy: No 18.7 1 Yes 27.1 0.543 0.380 0.778 Symptom grading: mild cough, asthenia; moderate dyspnea on exertion, fever, blood-tinged/blood-streaked sputum, weight loss <5% body weight; severe hemoptysis (whole-blood sputum), pain, dyspnea at rest, weight loss >5% body weight Postoperative Median P-value HR 95% CI P-value variables survival time (months) Pathological T: <0.0001 0.003 T0 (reference) 70.2 1 T1 25.4 1.085 0.352 3.349 (Continued on next page)

M. Bakir et al. / Interactive CardioVascular and Thoracic Surgery 13 (2011) 303-310 307 Table 1. (Continued) T2 23.6 1.198 0.404 T3 14.5 3.552 T4 12.4 1.678 0.551 5.113 2.564 0.854 7.699 Resection <0.0001 0.034 completeness: R0 (reference) 23.6 1 R1 12.4 1.487 0.998 R2 8.6 2.214 1.954 1.069 3.574 No. of N2 nodes: <0.0001 <0.001 involved 0 (reference) 75.1 1 1 3 24.6 2.11 0.856 4 9 16.6 5.202 >9 12.7 3.446 1.405 8.443 4.83 1.892 12.33 Lorent et al., One hundred and thirty-one Surgical cohort variables Five-year P-value Complete resection (2004), Ann IIIA N2 patients survival (%) following induction Oncol, Belgium, underwent induction Surgical group 34.6 chemotherapy improves [11] chemotherapy; of those Resection extent: 0.004 prognosis when with at least stable disease, Complete 38.6 compared with surgery Prospective 70 underwent surgical Incomplete 0 alone. However, patients cohort study resection Pathological T-stage: 0.03 with subcarinal nodal (level 2b) 0+1+2 41.3 involvement 3+4 0 and those without Subcarnial nodes: 0.03 postinduction Absent 38 nodal down staging may Present 15.9 preferably be treated pn down staging: 0.0008 with non-surgical Present 43.6 bimodality treatment Absent 13.7 Decaluwé et al., Ninety-two patients with Five-year P-value Surgical multimodality (2009), Eur J response/stable disease survival treatment of resectable Cardiothorac Surg, after induction time (%) N2 disease has Belgium, [12] chemotherapy for All patients 33.5 acceptable morbidity resectable stage IIIA N2 Extent of resection <0.005 and mortality. Degree Retrospective NSCLC underwent R0 43.2 of baseline and cohort study surgery R1 R2 19.9 postinduction (level 2b) Mediastinal N2 <0.005 mediastinal nodal involvement prior to involvement were induction independent prognostic Single level 39.5 variables Multiple levels 17 of survival, as was Mediastinal N2 involvement <0.005 extent of resection after induction Single level 37 Multiple levels 7.1 N status after induction 0.095 N0 N1 (downstaged) 49.1 N2 27.5 Best Evidence Topic R0, complete resection of tumor with free margins and negative highest mediastinal lymph nodes; R1, uncertain resection; R2, macroscopic incomplete resection (Continued on next page)

308 M. Bakir et al. / Interactive CardioVascular and Thoracic Surgery 13 (2011) 303-310 Table 1. (Continued) Stefani et al., One hundred and seventy- Variable Five-year P-value Surgery following (2010), J Thorac five patients with survival (%) chemotherapy provides Cardiovasc Surg, resectable N2 NSCLC Predicted postoperative FEV 1 0.015 favorable long-term France, [13] received neoadjuvant <40 8 survivals in selected chemotherapy and 40 29 patients, even Retrospective subsequent Clinical N2 levels 0.067 after pneumonectomy. cohort study surgical resection [96 (bi) Single 34 Clinical response (level 2b) lobectomies and 79 Multiple 22 and nodal downstaging pneumonectomies] No. of chemotherapy cycles 0.0001 are the best predictors <3 17 of survival For 3 38 responders, survival Chemotherapy response 0.0001 remains satisfying even Objective response 42 if persistent N2 Stable disease 10 For non-responders, Resection type 0.054 surgery is Pneumonectomy 23 contraindicated when (Bi)lobectomy 33 pneumonectomy is Pathological T 0.001 required T0+T1 49 T2 34 T3+T4 17 Pathological N 0.003 N0 44 N1 42 N2 Pathological stage 0.0008 0+I+II 44 IIIA 27 IIIB+IV Resection extent 0.002 R0 32 R1+R2 0 N downstaging 0.0008 Yes 45 No 22 Histopathological response 0.038 >90% 47 90% 17 Multivariate analysis of survival Variable HR P-value Predicted postoperative FEV 1 (%) (<40 vs. 40) 2.34 0.012 cn2 levels (single vs. multiple) 0.71 0.146 No. of chemotherapy cycles (<3 vs. 3) 2.08 0.001 Type of resection (lobectomy vs. 0.91 0.676 pneumonectomy) pstage (0, I, II vs. III, IV) 0.55 0.029 Extent of resection (R0 vs. R1, R2) 0.59 0.173 Response to chemotherapy (none vs. stable disease) 0.47 0.002 N downstaging (yes vs. no) 0.51 0.007 Histopathological response (>90% vs. 90%) 0.35 0.005 CI, confidence interval; FEV 1, forced expiratory ventilation in one second; HR, hazard ratio; LUL, left upper lobe; NS, not significant; NSCLC, non-small cell lung cancer; RML, right middle lobe; RR, risk ratio; RTOG, Radiation Therapy Oncology Group; RUL, right upper lobe; S.E., standard error. 6. Results 6.1. Randomized controlled trials One of the largest randomized controlled trials (RCTs) to date, by Van Meerbeeck et al. (European Organisation for Research and Treatment of Cancer study) [2], compared survival outcomes between surgery and radiotherapy in 332 responders to induction chemotherapy with stage IIIa N2 disease. A statistically non-significant difference in five-year survival [15.7% following surgery vs. 14% following radiotherapy, hazard ratio (HR) 1.06, 95% confidence interval (CI) 0.84 1.35; P=0.6] led the authors to conclude that radiotherapy was a more suitable treatment for N2 disease due to the lower morbidity and mortality. The findings of Johnstone et al. [Radiation Therapy Oncology Group (RTOG) 89-01 trial] [3] supported this conclusion. A total of 45 patients with mediastinoscopy-verified N2 NSCLC were randomized to either surgery or radiotherapy following

M. Bakir et al. / Interactive CardioVascular and Thoracic Surgery 13 (2011) 303-310 309 induction chemotherapy. The authors demonstrated no significant difference in the one-year survival rate (70% vs. 66%) or median survival time (19.4 vs. 17.4 months) between surgery and radiotherapy. However, the trial accrued only a small number of patients and was concluded early due to the initiation of the Intergroup 0139 study. Albain et al. (Intergroup 0139 study) [4] conducted an RCT of 396 patients with stage IIIa NSCLC and no progression after chemo-radiotherapy. They reported no significant differences in overall five-year survival following surgery vs. further radiotherapy (27% vs. 20%; HR 0.87, 95% CI 0.70 1.10; P=0.24). The study did, however, demonstrate improved progression-free survival in the surgery arm of the trial (22% vs. 11%; HR 0.77, 95% CI 0.62 0.96; P=0.017), and an improvement in the five-year survival of patients undergoing lobectomy (36% vs. 18%; P=0.002). Pneumonectomy, however, was associated with a lower five-year survival when compared to chemo-radiotherapy (22% vs. 24%). Two trials by Shepherd et al. [5] and Stephens et al. [6], randomized small numbers of patients with stage IIIa NSCLC to radiotherapy alone or chemotherapy followed by surgery. These studies failed to demonstrate a statistically significant improvement in median survival time; however, both trials were terminated early, the former due to the results of the RTOG study, which demonstrated improved survival with chemo-radiotherapy vs. radiotherapy alone, and the latter due to poor accrual over a three-year period. 6.2. Cohort studies Two important retrospective cohort studies evaluated the significance of patterns of nodal spread on survival time after surgical resection. Rusch et al. [7] compiled a database of 67,725 cases of non-metastatic NSCLC. Their analysis suggested that prognosis varied with the pattern of N2 involvement and advised that multizone N1 disease could be grouped together with single-zone N2 disease. However, the study concluded that prospective RCTs were required to validate this finding. Casali et al. [8] demonstrated further N2-related prognostic variables following complete resection with adjuvant chemotherapy, including incidental vs. clinical N2 disease (35.4% vs. 17.4%; P=0.001), single- vs. multiple-level N2 disease (23.8% vs. 14.7%; P=0.034), superior/aortic vs. lower nodal involvement (37.8%/17.4% vs. 17.1%; P=0.037) and specific patterns of lymphatic spread (P=0.002). Andre et al. [9] advocate surgery for patient with incidental single-station N2 disease in their prospective cohort study, and suggest that multistation N2 disease is an adverse prognostic factor [risk ratio (RR) 1.6, standard error (S.E.) 0.1; P<0.0001]. 6.3. Post-induction staging Ratto et al. [10] found induction chemotherapy was associated with improved median survival compared to surgery alone in patients with N2 NSCLC (27.1 vs. 18.7 months; P=0.0012). Lorent et al. [11] reported five-year survival rates of 35% after induction chemotherapy followed by surgery, compared to 21% with chemotherapy alone (P=0.022). Decaluwé et al. [12] report that single-level N2 disease and nodal downstaging postchemotherapy were independent predictors of survival (P<0.005 and P=0.095, respectively). Stefani et al. [13] demonstrated that response to induction chemotherapy was a predictor of survival following surgical resection (P=0.0001), but recommended that surgery might be contraindicated when pneumonectomy was required vs. lobectomy (23% vs. 33%; P=0.054). 6.4. Clinical guidelines Despite the clinical and statistical heterogeneity of the available data, two British institutions have produced guidelines regarding the management of NSCLC with N2 involvement in the past year. The National Institute for Health and Clinical Excellence update for the management of NSCLC [14] advises that patients with non-bulky N2 disease should be considered for trials of surgical resection. It reiterates that the lack of comparable data renders it difficult to construct a compelling argument for surgical resection of stage IIIa N2 NSCLC, but highlights that the prognosis associated with subgroups of nodal involvement has not yet been fully elucidated. The British Thoracic Society guidelines by Lim et al. [15] go further and suggest that surgeons should consider not only surgical resection in patients with non-bulky, singlezone N2 disease, but also trials of surgery in multizone N2 disease. 7. Clinical bottom line There is a convincing argument for the consideration of surgery as part of a multimodality treatment approach for resectable N2 NSCLC. Improved survival rates have been demonstrated, particularly if complete resection is achieved with lobectomy, there is a single-zone of mediastinal node involvement, and mediastinal downstaging occurs after induction chemotherapy. References [1] Dunning J, Prendergast B, Mackway-Jones K. Towards evidence-based medicine in cardiothoracic surgery: best BETS. Interact CardioVasc Thorac Surg 2003;2:405 409. [2] Van Meerbeeck JP, Kramer GW, van Schil PE, Legrand C, Smit EF, Schramel F, Tjan-Heijnen VC, Biesma B, Debruyne C, van Zandwijk N, Splinter TA, Giaccone G. Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-smallcell lung cancer. J Natl Cancer Inst 2007;99:442 450. [3] Johnstone DW, Byhardt RW, Ettinger D, Scott CB. 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 2002;54:365 369. [4] Albain KS, Swann RS, Rusch VW, Turrisi AT 3rd, Shepherd FA, Smith C, Chen Y, Livingston RB, Feins RH, Gandara DR, Fry WA, Darling G, Johnson DH, Green MR, Miller RC, Ley J, Sause WT, Cox JD. Radiotherapy plus chemotherapy with or without surgical resection for stage III nonsmall-cell lung cancer: a phase III randomised controlled trial. Lancet 2009;374:379 386. [5] Shepherd FA, Johnston MR, Payne D, Burkes R, Deslauriers J, Cormier Y, de Bedoya LD, Ottaway J, James K, Zee B. 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 1998;78:683 685. Best Evidence Topic

310 M. Bakir et al. / Interactive CardioVascular and Thoracic Surgery 13 (2011) 303-310 [6] Stephens RJ, Girling DJ, Hopwood P, Thatcher N. 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 2005;49:395 400. [7] Rusch VW, Crowley J, Giroux DJ, Goldstraw P, Im JG, Tsuboi M, Tsuchiya R, Vansteenkiste J. International Staging Committee; Cancer Research and Biostatistics; Observers to the Committee; Participating; Institutions. The IASLC Lung Cancer Staging Project: proposals for the revision of the N descriptors in the forthcoming seventh edition of the TNM classification for lung cancer. J Thorac Oncol 2007;2:603 612. [8] Casali C, Stefani A, Natali P, Rossi G, Morandi U. Prognostic factors in surgically resected N2 non-small cell lung cancer: the importance of patterns of mediastinal lymph nodes metastases. Eur J Cardiothorac Surg 2005;28:33 38. [9] Andre F, Grunenwald D, Pignon JP, Dujon A, Pujol JL, Brichon PY, Brouchet L, Quoix E, Westeel V, Le Chevalier T. Survival of patients with resected N2 non-small cell lung cancer: evidence for a subclassification and implications. J Clin Oncol 2000;18:2981 2989. [10] Ratto GB, Costa R, Maineri P, Alloisio A, Bruzzi P, Dozin B. Is there a subset of patients with preoperatively diagnosed N2 non-small cell lung cancer who might benefit from surgical resection? J Thorac Cardiovasc Surg 2009;138:849 858. [11] Lorent N, De Leyn P, Lievens Y, Verbeken E, Nackaerts K, Dooms C, Van Raemdonck D, Anrys B, Vansteenkiste J. Long-term survival of surgically staged IIIA-N2 non-small-cell lung cancer treated with surgical combined modality approach: analysis of a 7-year prospective experience. Ann Oncol 2004;15:1645 1653. [12] Decaluwé H, De Leyn P, Vansteenkiste J, Dooms C, Van Raemdonck D, Nafteux P, Coosemans W, Lerut T. 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 2009;36:433 439. [13] Stefani A, Alifano M, Bobbio A, Grigoroiu M, Jouni R, Magdeleinat P, Regnard JF. Which patients should be operated on after induction chemotherapy for N2 non-small cell lung cancer? Analysis of a 7-year experience in 175 patients. J Thorac Cardiovasc Surg 2010;140:356 363. [14] National Institute for Health and Clinical Excellence (NICE). The Diagnosis and Treatment of Lung Cancer (Update): Full Guideline London:NICE; 2011. [15] Lim E, Baldwin D, Beckles M, Duffy J, Entwisle J, Faivre-Finn C, Kerr K, Macfie A, McGuigan J, Padley S, Popat S, Screaton N, Snee M, Waller D, Wharburton C, Win T. Guidelines on the radical management of patients with lung cancer: British Thoracic Society and the Society for Cardiothoracic surgery in Great Britain and Ireland. Thorax 2010;65(Suppl III).