Lymph Node Assessment and Impact on Survival in Video-Assisted Thoracoscopic Lobectomy or Segmentectomy Haiyu Zhou, MD, Luis F. Tapias, MD, Henning A. Gaissert, MD, Ashok Muniappan, MD, Cameron D. Wright, MD, John C. Wain, MD, Dean M. Donahue, MD, Christopher R. Morse, MD, Douglas J. Mathisen, MD, and Michael Lanuti, MD Department of Thoracic Surgery, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Southern Medical University, GuangZhou, GuangDong, China; and Division of Thoracic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
Background. The objective of this study was to evaluate the influence of total number of resected lymph nodes, lymph node ratio, and the number of lymph node stations sampled on prognosis in patients with early stage non-small cell lung cancer (NSCLC) treated with videoassisted thoracoscopic surgery (VATS). Methods. Five hundred and fifty patients who underwent VATS lobectomy or segmentectomy for early clinical stage NSCLC were retrospectively analyzed from 2006 to 2012. Disease-free survival (DFS) and overall survival (OS) were compared for cutoff values of total number of resected lymph nodes (RNs) and lymph node stations (LNS) using Kaplan-Meier methods and Cox proportional hazard models. Results. Lobectomy was performed in 493 (90%) patients with a median follow-up of 2.7 years. Median age was 68 (range, 29 to 92 years) and 342 (62%) were female. Pathologic stage I, II, and III was observed in 434 (79%),
80 (14.5%) and 36 (6.5%) patients, respectively. The N0, N1, and N2 pathologic nodal status was observed in 485 (88%), 38 (7%), and 27 (5%) patients, respectively. Nodal upstaging was observed in 11.3% (59 of 550) in the total cohort and 15% (49 of 332) in patients who underwent LNS greater than 3 compared with 5% (10 of 218) in patients with LNS 3 or less (p < 0.01). Multivariate analysis identified LNS greater than 3 as a negative independent predictor for DFS (hazard ratio 2.36, p [ 0.003) and OS (hazard ratio 1.77, p [ 0.046). Conclusions. Sampling greater than 3 LNS and greater than 10 RNs was associated with an increase in nodal upstaging. Only LNS greater than 3 was found to be an independent predictor of mortality in VATS lobectomy and segmentectomy in clinical early-stage NSCLC.
C
prognostic role for the total number of resected lymph nodes (RNs), regardless of their metastatic involvement [9–11]. Other studies invoke lymph node ratio (LNR ¼ number of positive lymph nodes divided by RNs) as a predictor of poor survival in resected, node-positive NSCLC [12, 13]. Because RNs may be confounded by fragmentation at the time of surgery, the total number of lymph node stations sampled (LNS) may be another surrogate for outcome. These 3 measures (RNs, LNR, and LNS) depend directly on the surgeon’s technique (ie, hilar and mediastinal lymph node sampling) and the pathologist’s diligence (ie, the systematic collection of peribronchial and intrapulmonary nodes). Recent studies have demonstrated that systematic lymph node dissection by VATS was not inferior and the number of lymph nodes dissected was equivalent to thoracotomy [14–16]. Interestingly, these studies did not show any significant prognostic role for RNs, LNR, or LNS in patients undergoing VATS. Whether VATS or thoracotomy is a better approach has been debated intensively and remains controversial, which is why investigations of surgical lymph node evaluation during a
linical stage I lung cancer accounts for approximately 18% of patients who present with non-small cell lung cancer (NSCLC) [1]. As a minimally invasive alternative to open thoracotomy, video-assisted thoracic surgery (VATS) is the preferred modality in the latest American College of Chest Physicians Evidence Based Guidelines for early-stage NSCLC [2]. VATS lobectomy is an accepted oncologic approach to early-stage NSCLC [3, 4]. Previous studies have demonstrated that pathologic nodal stage is the strongest predictor of long-term survival after surgical treatment of early-stage NSCLC [5, 6]. Patients who harbor multiple lymph node metastases or have disease in multiple lymph node stations have a worse prognosis [7, 8]. Recent reports have suggested a Accepted for publication April 7, 2015. Presented at the Poster Session of the Fiftieth Annual Meeting of The Society of Thoracic Surgeons, Orlando, FL, Jan 25–29, 2014. Winner of the Blue Ribbon as the top General Thoracic Poster. Address correspondence to Dr Lanuti, Division of Thoracic Surgery, Massachusetts General Hospital, 55 Fruit St, Blake 1570, Boston, MA 02114; e-mail: [email protected].
Ó 2015 by The Society of Thoracic Surgeons Published by Elsevier
(Ann Thorac Surg 2015;-:-–-) Ó 2015 by The Society of Thoracic Surgeons
0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2015.04.034
2
ZHOU ET AL LYMPH NODE ASSESSMENT IN VATS LOBECTOMY
VATS lobectomy for NSCLC are relevant [17]. This controversy has prompted us to investigate the impact of RNs, LNS, LNR, and nodal upstaging on survival in clinical early-stage NSCLC where only VATS lobectomy or segmentectomy were implemented.
Patients and Methods A retrospective analysis was performed in all patients who underwent VATS lobectomy or segmentectomy for clinical early-stage NSCLC from February 2006 to December 2012 at the Massachusetts General Hospital. Patients with a positive mediastinoscopy, small cell lung cancer or small cell mixed histology, carcinoid tumor, clinical stage III or greater disease, second primary lesions in different lungs, multi-lobe resection (pneumonectomy or bilobectomy), and R1/R2 resections were excluded. For all patients included in the study smoking status was characterized as the following: (1) never smokers, fewer than 100 cigarettes in their lifetime; (2) past smokers, quit more than 1 year before diagnosis; and (3) current smokers, ongoing smoking habit or quit less than 1 year before diagnosis. Selective staging tests were chosen for different patients based on the targets suggested by the positron emission tomography (PET), the contrast-enhanced chest computed tomography (CT) scan, and any magnetic resonance imaging (MRI). Mediastinoscopy was primarily used for invasive staging. Endobronchial ultrasound-guided fine needle aspiration (EBUS-FNA) was used to biopsy suspicious N1 lymph nodes in the stations 10, 11, and 12 in only 3 cases. Dedicated pulmonary pathologists reviewed all lung and lymph node specimens. Pathology reports were staged using the 7th edition of the American Joint Committee on Cancer criteria. Data were obtained from the medical records, including office charts, anesthesia records, and in-hospital chart. This study was approved by the Institutional Review Board (IRB) at Massachusetts General Hospital. The IRB specifically considered this retrospective chart review, including subject selection and confidentiality, and waived the need for patient consent.
Postoperative Follow-Up Patients were assessed for recurrence, disease-free survival (DFS), and overall survival (OS). Recurrence was defined as radiographic evidence of cancer relapse on surveillance imaging (CT chest, CT-PET, or MRI) or pathologic evidence of tumor on biopsy. The DFS was defined as the time from surgery until the date of recurrence; OS was defined as time from surgery until death from any cause. Patients were censored at their last known alive date. Date of death was obtained from the electronic medical record and confirmed on the Social Security Death Index website.
Statistical Analysis Data were analyzed using Stata 11 (Stata Corp LP, College Station, TX). Continuous variables were categorized based on clinical experience and statistical analysis. Threshold values for RNs, LNS, and LNR were
Ann Thorac Surg 2015;-:-–-
determined by constructing receiver operator characteristic (ROC) curves to establish the cutoff point that provided the best discriminatory capacity for the outcomes of interest (death in this case, as a surrogate for OS). Threshold values from ROC curves were compared with median values and with cutoff values previously used in the literature for RNs, LNS, and LNR [13, 18, 19]. Survival probability was calculated using the Kaplan-Meier method and the log-rank test was used for univariate survival analysis of variables of interest, particularly RNs, LNS, and LNR. The impact of these lymph node assessment variables was established by constructing a multivariate survival analysis for DFS and OS using the Cox proportional hazards model, while controlling for patient age, history of smoking, comorbidities (ie, coronary artery disease, peripheral vascular disease, diabetes), pulmonary function tests (ie, DLCO [diffusing capacity of lung for carbon monoxide]), clinical T status, the occurrence of nodal upstaging, histopathologic blood vessel invasion, and the occurrence of postoperative complications (ie, atelectasis requiring bronchoscopy and pneumonia). For all comparisons, a 2-sided p value less than 0.05 was considered statistically significant.
Results The study cohort consisted of 550 patients; 493 patients underwent VATS lobectomy and 57 VATS segmentectomy for curative intent. The median age was 68 years (range, 29 to 92) with 62% (342 of 550) females. Mean tumor size was 2.3 1.3 cm (range, 0.2 to 8 cm). Demographic, surgical treatment, and histopathologic characteristics of the entire cohort (including distribution of tumor size and location) are listed in Table 1. Pathologic stage I, II, and III was observed in 434 (79%), 80 (14.5%), and 36 (6.5%) patients, respectively (Fig 1A). Nodal stage N0, N1, and N2 was observed in 485 (88.2%), 38 (6.9%), and 27 (4.9%) patients, respectively (Fig 1B). Therefore, a total of 65 (11.8%) patients had involved nodes. Nodal upstaging was observed in 3 groups: N0 to N1 (32, 5.8%), N0 to N2 (24, 4.1%), and N1 to N2 (3, 0.5%) (Fig 1C). After a median follow-up of 2.7 years (include interquartile range), 5-year OS for p-stages I, II, and III were 82.7%, 79%, and 25.3%, respectively (survival curves not shown). Because this patient cohort represented clinical stage I NSCLC with routine use of CT-PET, invasive mediastinal staging was employed in only 27.5% patients. Endobronchial ultrasound was not typically used for complete mediastinal staging (0.5%, 3 of 550) and often reserved for sampling suspicious N1 nodes. Lymph node assessment of all patients was stratified by RNs, LNS, and LNR. The median RNs was 9 (interquartile range [IQR], 5 to 14) while median LNS was 4 (IQR, 3 to 5). Approximately 41% of patients had greater than 10 lymph nodes analyzed while 26% had 5 or less RNs and 0.7% had 0 RNs sampled. Inspection of ROC curves for RNs and LNS showed that RNs ¼ 10, LNS ¼ 3, and LNR ¼ 0.12 rendered the best discriminatory performance to predict events for OS and DFS, and were therefore used as cutoff values to stratify patients for further analysis. The area
Ann Thorac Surg 2015;-:-–-
ZHOU ET AL LYMPH NODE ASSESSMENT IN VATS LOBECTOMY
Table 1. Demographics of All Patients Variable
Value (%)
Age (years), mean SD Sex Male Female Tobacco history Never smoker Past smoker Current smoker Pack-years, mean SD Comorbidity Hypertension CAD PVD CVD Diabetes Pulmonary functions tests, mean SD FEV1 (% predicted) DLCO (% predicted) Tumor size cm 2 cm 2–3 cm >3 cm Mean (cm) SD Histologic type Adenocarcinoma Squamous cell carcinoma Other Localization LUL LLL RUL RML RLL Surgical procedure Lobectomy Segmentectomy Length of stay (days), mean SD Complication Postoperative events Air leak > 5 days Atelectasis requiring bronchoscopy Pneumonia Empyema
67.7 10.5 208 (38) 342 (62) 98 (18) 313 (59) 120 (23) 32 28.9 264 53 24 30 54
(48) (10) (4) (5) (10)
86.6 21.4 78.2 22.0 281 (51) 138 (25) 131 (24) 2.3 1.3 408 (74) 82 (15) 34 (6) 135 77 188 38 112
(26) (14) (34) (7) (20)
493 (90) 57 (10) 5.0 3.8 136 30 33 10 8
(25) (6) (6) (2) (1)
CAD ¼ coronary disease; CVD ¼ cerebral vascular disease; DLCO ¼ carbon monoxide diffusing capacity; FEV1 ¼ forced expiratory volume in 1 second; LLL ¼ left lower lobe; LUL ¼ left upper lobe; PVD ¼ peripheral vascular disease; RLL ¼ right lower lobe; RML ¼ right middle lobe; RUL ¼ right upper lobe.
under the ROC curve (AUC-ROC) for RNs was 0.521 for tumor recurrence (DFS) and 0.546 for death (OS). The AUC-ROC for LNS were 0.584 (DFS) and 0.529 (OS), and for LNR were 0.513 (DFS) and 0.585 (OS), respectively. The RNs greater than 10 was associated with more tobacco exposure (p ¼ 0.03), larger tumors (p < 0.01),
3
lobectomy (p < 0.01), and more frequent postoperative events (p ¼ 0.01) (Table 2). The frequency of nodal upstaging was 17% (38 of 224) in patients who had greater than 10 RNs compared with 6% (21 of 326) in patients with RNs 10 or less (p < 0.01). Patients who had LNS greater than 3 were associated with larger tumors (p < 0.01) and lobectomy (p < 0.01) as opposed to segmentectomy. Nodal upstaging was 15% (49 of 332) in patients who underwent LNS greater than 3 compared with 5% (10 of 218) in patients with LNS 3 or less (p < 0.01). The median LNR in our patient population was 0.12 (range, 0.02 to 1.0) and did not show any associations with age, sex, smoking, and tumor size, nor did it predict disease-free or overall survival. The influence of tumor size on type of procedure, RNs, and LNS are also summarized in Table 2. The frequency of tumor recurrence in the entire cohort was 14.4% (79 of 550) where 16.5% (21 of 127) was observed in tumors greater than 3 cm and 13.7% (58 of 423) in tumors 3 cm or less (p ¼ 0.47). Tumor size greater than 3 cm represented 24% patients in our study and was not statistically associated with nodal upstaging (p ¼ 0.20). Nodal upstaging was not statistically associated with any particular anatomic lobe. The impact of lymph node assessment variables and other important clinical and pathologic variables on DFS and OS (Table 3) were evaluated using logistic regression. On univariate analysis, only LNS greater than 3 showed a significant association with worse DFS (hazard ratio [HR], 2.35; 95% confidence interval [CI], 1.41% to 3.91%, p ¼ 0.001; Fig 2) and OS (HR, 2.00; 95% CI, 1.19% to 3.35%, p ¼ 0.01; Fig 3). On multivariate analysis for DFS, LNS greater than 3 was associated with worse outcome (HR, 2.34; 95% CI, 1.35% to 4.87%, p ¼ 0.003) while controlling for tumor size and smoking status. The LNS greater than 3 was also associated with worse OS on multivariate analysis (HR, 1.80; 95% CI, 1.00% to 3.16%, p ¼ 0.046) while controlling for age, tumor size, nodal upstaging, smoking history, DLCO, comorbidities, and postoperative complications. Nodal upstaging was associated with worse OS on univariate (p ¼ 0.004) and multivariate analysis (HR, 2.49; 95% CI, 1.29% to 4.79%, p ¼ 0.006).
Comment Lymph node metastasis is a strong predictor of recurrence and survival in NSCLC patients; however, the prognostic value of the total number of lymph nodes harvested (RNs) or the total number of lymph node stations sampled (LNS) remains under investigation. There is no accepted recommendation for RNs; however, the 2013 National Comprehensive Cancer Network guidelines recommend sampling at least 3 mediastinal lymph node stations at the time of pulmonary resection [20]. In a secondary analysis of the American College of Surgeons Oncology Group Z0030 trial (where w 1,023 stage I patients were randomized to mediastinal lymph node sampling versus mediastinal lymph node dissection), the median RNs were similar between VATS and open (15 [range, 5 to 48]) vs 19 [range, 2 to 83], p ¼ 0.147) [21]. As this trial greatly influenced surgeon assessment of mediastinal lymph
4
ZHOU ET AL LYMPH NODE ASSESSMENT IN VATS LOBECTOMY
Ann Thorac Surg 2015;-:-–-
Fig 1. (A) Pathologic stage I, II, and III was observed in 79% (434 of 550), 14.5% (80 of 550), and 6.5% (36 of 550) patients, respectively. (B) Nodal stage (N0, N1, N2) was observed in 485, 38, and 27 patients, respectively. (C) A total of 65 (11.8%) patients had involved nodes. Nodal upstaging was observed in 3 groups: N0 to N1 (32, 5.8%); N0 to N2 (24, 4.1%); and N1 to N2 (3, 0.5%). (LNR ¼ lymph node ratio; LNS ¼ lymph node station; RNs ¼ total number of resected lymph nodes.)
nodes during pulmonary resection, it may serve as a potential benchmark for RNs and LNS in VATS lobectomy. Despite the lack of enthusiasm to adopt RNs, LNS, or LNR into standard practice, there are a number of single-
center series that have examined the impact of these parameters on survival after resection of early-stage NSCLC. Ou and Zell [22] reported on 2,545 patients who underwent lobectomy for stage IA NSCLC and found that removal of
Table 2. Assessment of Important Variables Stratified by Resected Lymph Nodes (RNs) and Lymph Node Stations (LNS) RNs Characteristics
10
>10
Age (years), mean SD 67.3 10.9 Sex, n (%) Male 108 (33) Female 218 (67) Tobacco history, n (%) Never smoker 68 (22) Past smoker 171 (55) Current smoker 73 (23) Pulmonary functions tests, mean SD 87.4 22 FEV1 (% predicted) 78.1 23.1 DLCO (% predicted) Tumor size, n (%) 2 cm 183 (56) 2–3cm 88 (27) >3cm 55 (17) Mean (cm) SD 2.1 1.3 Surgical procedure, n (%) Lobectomy 279 (86) Segmentectomy 47 (14) Nodal upstaging No 305 (94) Yes 21 (6) Complications, n (%) Postoperative events 67 (21) Air leak > 5days 12 (4) Need for bronchoscopy 14 (4) Pneumonia 5 (2) Empyema 5 (2) DLCO ¼ carbon monoxide diffusing capacity;
68.2 9.8
LNS p Value 0.33 0.01
100 (45) 124 (55)
3
>3
p Value
65.8 10.9
68.9 10.0
10 resected lymph nodes), (B) LNS (sampling > 3 lymph node stations), (C) LNR (sampling lymph node ratios > 0.12).
patients found to have occult lymph node metastases compared with those that were lymph node negative. The inherent limitation of this study aside from its retrospective nature is the phenomenon of fragmentation
Ann Thorac Surg 2015;-:-–-
of lymph nodes, which can affect how the pathologists report total lymph node counts (RNs). Other limitations include a relatively small number of patients with positive lymph nodes, 11.8% (65 of 550), which weakens the lymph node ratio (LNR) assessment, and the notion that only 41% of the cases were associated with RNs greater than 10. Only 27.5% (151 of 550) of these clinical stage I patients underwent cervical mediastinoscopy because CT-PET was routinely used to exonerate mediastinal lymph nodes metastases. In conclusion, sampling greater than 3 lymph node stations and greater than 10 RNs were associated with an increase in nodal upstaging in this VATS series of clinical early-stage NSCLC where the mean tumor size was 2.3 cm. The LNS greater than 3 was prognostic of worse DFS and OS by virtue of improved staging accuracy. These observations should caution thoracic surgeons not to be complacent about aggressive lymph node sampling despite a rigorous preoperative evaluation that suggests clinical stage I NSCLC with no mediastinal metastases. Although our data do not support achieving RNs greater than 10 to predict survival during VATS anatomic resection, more lymph node analysis needs to be conducted prospectively in large series to better understand if there is a prognostic threshold value. Lastly, the identification of peribronchial lymph nodes also greatly influences the detection of occult N1 disease, prompting our profession to foster a careful collaboration with our pathology colleagues to improve handling of resected specimens. Financial support for this study was provided by the Division of Thoracic Surgery at the Massachusetts General Hospital. We would like to acknowledge our data manager and research coordinator, Sheila Knoll and Diane Davies, respectively, for their diligence and dedication toward compiling and maintaining the Thoracic Surgery Database.
ZHOU ET AL LYMPH NODE ASSESSMENT IN VATS LOBECTOMY
8.
9.
10. 11.
12. 13.
14.
15.
16.
17.
18.
19.
References 1. Groome PA, Bolejack V, Crowley JJ, et al. The IASLC lung cancer staging project: validation of the proposals for revision of the T, N, and M descriptors and consequent stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours. J Thorac Oncol 2007;2:694–705. 2. Detterbeck FC, Postmus PE, Tanoue LT. The stage classification of 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):e191S–210S. 3. McKenna RJ Jr, Houck W, Fuller CB. Video-assisted thoracic surgery lobectomy: experience with 1,100 cases. Ann Thorac Surg 2006;81:421–6. 4. Takagi H, Matsui M, Umemoto T. Long-term survival of VATS versus open lobectomy. Ann Thorac Surg 2011;92:408–10. 5. Rusch VW, Giroux DJ. Nodal staging in lung cancer: lymph node location or number? J Thorac Oncol 2011;6:237–8. 6. van Velzen E, Snijder RJ, Brutel de la Rivi ere A, Elbers HJ, van den Bosch JM. Type of lymph node involvement influences survival rates in t1n1m0 non-small cell lung carcinoma. Lymph node involvement by direct extension compared with lobar and hilar node metastases. Chest 1996;110:1469–73. 7. Lardinois D, Suter H, Hakki H, Rousson V, Betticher D, Ris HB. Morbidity, survival, and site of recurrence after
20. 21.
22. 23. 24.
25. 26.
7
mediastinal lymph-node dissection versus systematic sampling after complete resection for non-small cell lung cancer. Ann Thorac Surg 2005;80:268–75. Macia I, Ramos R, Moya J, et al. Survival of patients with non-small cell lung cancer according to lymph node disease: single PN1 vs multiple PN1 vs single unsuspected PN2. Ann Surg Oncol 2013;20:2413–8. Ludwig MS, Goodman M, Miller DL, Johnstone PA. Postoperative survival and the number of lymph nodes sampled during resection of node-negative non-small cell lung cancer. Chest 2005;128:1545–50. Nwogu CE, Groman A, Fahey D, et al. Number of lymph nodes and metastatic lymph node ratio are associated with survival in lung cancer. Ann Thorac Surg 2012;93:1614–20. Jonnalagadda S, Smith C, Mhango G, Wisnivesky JP. The number of lymph node metastases as a prognostic factor in patients with n1 non-small cell lung cancer. Chest 2011;140: 433–40. Jonnalagadda S, Arcinega J, Smith C, Wisnivesky JP. Validation of the lymph node ratio as a prognostic factor in patients with N1 nonsmall cell lung cancer. Cancer 2011;117:4724–31. Wisnivesky JP, Arciniega J, Mhango G, Mandeli J, Halm EA. Lymph node ratio as a prognostic factor in elderly patients with pathological n1 non-small cell lung cancer. Thorax 2011;66:287–93. D’Amico TA, Niland J, Mamet R, Zornosa C, Dexter EU, Onaitis MW. Efficacy of mediastinal lymph node dissection during lobectomy for lung cancer by thoracoscopy and thoracotomy. Ann Thorac Surg 2011;92:226–32. Boffa DJ, Kosinski AS, Paul S, Mitchell JD, Onaitis M. Lymph node evaluation by open or video-assisted approaches in 11, 500 anatomic lung cancer resections. Ann Thorac Surg 2012;94:347–53. Ramos R, Girard P, Masuet C, Validire P, Gossot D. Mediastinal lymph node dissection in early-stage non-small cell lung cancer: totally thoracoscopic vs thoracotomy. Eur J Cardiothorac Surg 2012;41:1342–8. Licht PB, Jorgensen OD, Ladegaard L, Jakobsen E. A national study of nodal upstaging after thoracoscopic versus open lobectomy for clinical stage I lung cancer. Ann Thorac Surg 2013;96:943–50. Gajra A, Newman N, Gamble GP, Kohman LJ, Graziano SL. Effect of number of lymph nodes sampled on outcome in patients with stage I non-small-cell lung cancer. J Clin Oncol 2003;21:1029–34. Varlotto JM, Recht A, Nikolov M, Flickinger JC, Decamp MM. Extent of lymphadenectomy and outcome for patients with stage I nonsmall cell lung cancer. Cancer 2009;115:851–8. Ettinger DS, Akerley W, Borghaei H, et al. Non-small cell lung cancer, version 2.2013. J Natl Compr Canc Netw 2013;11:645–53. Scott WJ, Allen MS, Darling G, et al. Video-assisted thoracic surgery versus open lobectomy for lung cancer: s secondary analysis of data from the American College of Surgeons Oncology Group Z0030 randomized clinical trial. J Thorac Cardiovasc Surg 2010;139:976–83. Ou SH, Zell JA. Prognostic significance of the number of lymph nodes removed at lobectomy in stage IA non-small cell lung cancer. J Thorac Oncol 2008;3:880–6. Whitson BA, Groth SS, Maddaus MA. Surgical assessment and intraoperative management of mediastinal lymph nodes in non-small cell lung cancer. Ann Thorac Surg 2007;84:1059–65. Zhong W, Yang X, Bai J, Yang J, Manegold C, Wu Y. Complete mediastinal lymphadenectomy: the core component of the multidisciplinary therapy in resectable non-small cell lung cancer. Eur J Cardiothorac Surg 2008;34:187–95. Cho S, Song IH, Yang HC, Kim K, Jheon S. Predictive factors for node metastasis in patients with clinical stage I non-small cell lung cancer. Ann Thorac Surg 2013;96:239–45. Veeramachaneni NK, Battafarano RJ, Meyers BF, Zoole JB, Patterson GA. Risk factors for occult nodal metastasis in clinical T1N0 lung cancer: a negative impact on survival. Eur J Cardiothorac Surg 2008;33:466–9.
Background. The objective of this study was to evaluate the influence of total number of resected lymph nodes, lymph node ratio, and the number of lymph node stations sampled on prognosis in patients with early stage non-small cell lung cancer (NSCLC) treated with videoassisted thoracoscopic surgery (VATS). Methods. Five hundred and fifty patients who underwent VATS lobectomy or segmentectomy for early clinical stage NSCLC were retrospectively analyzed from 2006 to 2012. Disease-free survival (DFS) and overall survival (OS) were compared for cutoff values of total number of resected lymph nodes (RNs) and lymph node stations (LNS) using Kaplan-Meier methods and Cox proportional hazard models. Results. Lobectomy was performed in 493 (90%) patients with a median follow-up of 2.7 years. Median age was 68 (range, 29 to 92 years) and 342 (62%) were female. Pathologic stage I, II, and III was observed in 434 (79%),
80 (14.5%) and 36 (6.5%) patients, respectively. The N0, N1, and N2 pathologic nodal status was observed in 485 (88%), 38 (7%), and 27 (5%) patients, respectively. Nodal upstaging was observed in 11.3% (59 of 550) in the total cohort and 15% (49 of 332) in patients who underwent LNS greater than 3 compared with 5% (10 of 218) in patients with LNS 3 or less (p < 0.01). Multivariate analysis identified LNS greater than 3 as a negative independent predictor for DFS (hazard ratio 2.36, p [ 0.003) and OS (hazard ratio 1.77, p [ 0.046). Conclusions. Sampling greater than 3 LNS and greater than 10 RNs was associated with an increase in nodal upstaging. Only LNS greater than 3 was found to be an independent predictor of mortality in VATS lobectomy and segmentectomy in clinical early-stage NSCLC.
C
prognostic role for the total number of resected lymph nodes (RNs), regardless of their metastatic involvement [9–11]. Other studies invoke lymph node ratio (LNR ¼ number of positive lymph nodes divided by RNs) as a predictor of poor survival in resected, node-positive NSCLC [12, 13]. Because RNs may be confounded by fragmentation at the time of surgery, the total number of lymph node stations sampled (LNS) may be another surrogate for outcome. These 3 measures (RNs, LNR, and LNS) depend directly on the surgeon’s technique (ie, hilar and mediastinal lymph node sampling) and the pathologist’s diligence (ie, the systematic collection of peribronchial and intrapulmonary nodes). Recent studies have demonstrated that systematic lymph node dissection by VATS was not inferior and the number of lymph nodes dissected was equivalent to thoracotomy [14–16]. Interestingly, these studies did not show any significant prognostic role for RNs, LNR, or LNS in patients undergoing VATS. Whether VATS or thoracotomy is a better approach has been debated intensively and remains controversial, which is why investigations of surgical lymph node evaluation during a
linical stage I lung cancer accounts for approximately 18% of patients who present with non-small cell lung cancer (NSCLC) [1]. As a minimally invasive alternative to open thoracotomy, video-assisted thoracic surgery (VATS) is the preferred modality in the latest American College of Chest Physicians Evidence Based Guidelines for early-stage NSCLC [2]. VATS lobectomy is an accepted oncologic approach to early-stage NSCLC [3, 4]. Previous studies have demonstrated that pathologic nodal stage is the strongest predictor of long-term survival after surgical treatment of early-stage NSCLC [5, 6]. Patients who harbor multiple lymph node metastases or have disease in multiple lymph node stations have a worse prognosis [7, 8]. Recent reports have suggested a Accepted for publication April 7, 2015. Presented at the Poster Session of the Fiftieth Annual Meeting of The Society of Thoracic Surgeons, Orlando, FL, Jan 25–29, 2014. Winner of the Blue Ribbon as the top General Thoracic Poster. Address correspondence to Dr Lanuti, Division of Thoracic Surgery, Massachusetts General Hospital, 55 Fruit St, Blake 1570, Boston, MA 02114; e-mail: [email protected].
Ó 2015 by The Society of Thoracic Surgeons Published by Elsevier
(Ann Thorac Surg 2015;-:-–-) Ó 2015 by The Society of Thoracic Surgeons
0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2015.04.034
2
ZHOU ET AL LYMPH NODE ASSESSMENT IN VATS LOBECTOMY
VATS lobectomy for NSCLC are relevant [17]. This controversy has prompted us to investigate the impact of RNs, LNS, LNR, and nodal upstaging on survival in clinical early-stage NSCLC where only VATS lobectomy or segmentectomy were implemented.
Patients and Methods A retrospective analysis was performed in all patients who underwent VATS lobectomy or segmentectomy for clinical early-stage NSCLC from February 2006 to December 2012 at the Massachusetts General Hospital. Patients with a positive mediastinoscopy, small cell lung cancer or small cell mixed histology, carcinoid tumor, clinical stage III or greater disease, second primary lesions in different lungs, multi-lobe resection (pneumonectomy or bilobectomy), and R1/R2 resections were excluded. For all patients included in the study smoking status was characterized as the following: (1) never smokers, fewer than 100 cigarettes in their lifetime; (2) past smokers, quit more than 1 year before diagnosis; and (3) current smokers, ongoing smoking habit or quit less than 1 year before diagnosis. Selective staging tests were chosen for different patients based on the targets suggested by the positron emission tomography (PET), the contrast-enhanced chest computed tomography (CT) scan, and any magnetic resonance imaging (MRI). Mediastinoscopy was primarily used for invasive staging. Endobronchial ultrasound-guided fine needle aspiration (EBUS-FNA) was used to biopsy suspicious N1 lymph nodes in the stations 10, 11, and 12 in only 3 cases. Dedicated pulmonary pathologists reviewed all lung and lymph node specimens. Pathology reports were staged using the 7th edition of the American Joint Committee on Cancer criteria. Data were obtained from the medical records, including office charts, anesthesia records, and in-hospital chart. This study was approved by the Institutional Review Board (IRB) at Massachusetts General Hospital. The IRB specifically considered this retrospective chart review, including subject selection and confidentiality, and waived the need for patient consent.
Postoperative Follow-Up Patients were assessed for recurrence, disease-free survival (DFS), and overall survival (OS). Recurrence was defined as radiographic evidence of cancer relapse on surveillance imaging (CT chest, CT-PET, or MRI) or pathologic evidence of tumor on biopsy. The DFS was defined as the time from surgery until the date of recurrence; OS was defined as time from surgery until death from any cause. Patients were censored at their last known alive date. Date of death was obtained from the electronic medical record and confirmed on the Social Security Death Index website.
Statistical Analysis Data were analyzed using Stata 11 (Stata Corp LP, College Station, TX). Continuous variables were categorized based on clinical experience and statistical analysis. Threshold values for RNs, LNS, and LNR were
Ann Thorac Surg 2015;-:-–-
determined by constructing receiver operator characteristic (ROC) curves to establish the cutoff point that provided the best discriminatory capacity for the outcomes of interest (death in this case, as a surrogate for OS). Threshold values from ROC curves were compared with median values and with cutoff values previously used in the literature for RNs, LNS, and LNR [13, 18, 19]. Survival probability was calculated using the Kaplan-Meier method and the log-rank test was used for univariate survival analysis of variables of interest, particularly RNs, LNS, and LNR. The impact of these lymph node assessment variables was established by constructing a multivariate survival analysis for DFS and OS using the Cox proportional hazards model, while controlling for patient age, history of smoking, comorbidities (ie, coronary artery disease, peripheral vascular disease, diabetes), pulmonary function tests (ie, DLCO [diffusing capacity of lung for carbon monoxide]), clinical T status, the occurrence of nodal upstaging, histopathologic blood vessel invasion, and the occurrence of postoperative complications (ie, atelectasis requiring bronchoscopy and pneumonia). For all comparisons, a 2-sided p value less than 0.05 was considered statistically significant.
Results The study cohort consisted of 550 patients; 493 patients underwent VATS lobectomy and 57 VATS segmentectomy for curative intent. The median age was 68 years (range, 29 to 92) with 62% (342 of 550) females. Mean tumor size was 2.3 1.3 cm (range, 0.2 to 8 cm). Demographic, surgical treatment, and histopathologic characteristics of the entire cohort (including distribution of tumor size and location) are listed in Table 1. Pathologic stage I, II, and III was observed in 434 (79%), 80 (14.5%), and 36 (6.5%) patients, respectively (Fig 1A). Nodal stage N0, N1, and N2 was observed in 485 (88.2%), 38 (6.9%), and 27 (4.9%) patients, respectively (Fig 1B). Therefore, a total of 65 (11.8%) patients had involved nodes. Nodal upstaging was observed in 3 groups: N0 to N1 (32, 5.8%), N0 to N2 (24, 4.1%), and N1 to N2 (3, 0.5%) (Fig 1C). After a median follow-up of 2.7 years (include interquartile range), 5-year OS for p-stages I, II, and III were 82.7%, 79%, and 25.3%, respectively (survival curves not shown). Because this patient cohort represented clinical stage I NSCLC with routine use of CT-PET, invasive mediastinal staging was employed in only 27.5% patients. Endobronchial ultrasound was not typically used for complete mediastinal staging (0.5%, 3 of 550) and often reserved for sampling suspicious N1 nodes. Lymph node assessment of all patients was stratified by RNs, LNS, and LNR. The median RNs was 9 (interquartile range [IQR], 5 to 14) while median LNS was 4 (IQR, 3 to 5). Approximately 41% of patients had greater than 10 lymph nodes analyzed while 26% had 5 or less RNs and 0.7% had 0 RNs sampled. Inspection of ROC curves for RNs and LNS showed that RNs ¼ 10, LNS ¼ 3, and LNR ¼ 0.12 rendered the best discriminatory performance to predict events for OS and DFS, and were therefore used as cutoff values to stratify patients for further analysis. The area
Ann Thorac Surg 2015;-:-–-
ZHOU ET AL LYMPH NODE ASSESSMENT IN VATS LOBECTOMY
Table 1. Demographics of All Patients Variable
Value (%)
Age (years), mean SD Sex Male Female Tobacco history Never smoker Past smoker Current smoker Pack-years, mean SD Comorbidity Hypertension CAD PVD CVD Diabetes Pulmonary functions tests, mean SD FEV1 (% predicted) DLCO (% predicted) Tumor size cm 2 cm 2–3 cm >3 cm Mean (cm) SD Histologic type Adenocarcinoma Squamous cell carcinoma Other Localization LUL LLL RUL RML RLL Surgical procedure Lobectomy Segmentectomy Length of stay (days), mean SD Complication Postoperative events Air leak > 5 days Atelectasis requiring bronchoscopy Pneumonia Empyema
67.7 10.5 208 (38) 342 (62) 98 (18) 313 (59) 120 (23) 32 28.9 264 53 24 30 54
(48) (10) (4) (5) (10)
86.6 21.4 78.2 22.0 281 (51) 138 (25) 131 (24) 2.3 1.3 408 (74) 82 (15) 34 (6) 135 77 188 38 112
(26) (14) (34) (7) (20)
493 (90) 57 (10) 5.0 3.8 136 30 33 10 8
(25) (6) (6) (2) (1)
CAD ¼ coronary disease; CVD ¼ cerebral vascular disease; DLCO ¼ carbon monoxide diffusing capacity; FEV1 ¼ forced expiratory volume in 1 second; LLL ¼ left lower lobe; LUL ¼ left upper lobe; PVD ¼ peripheral vascular disease; RLL ¼ right lower lobe; RML ¼ right middle lobe; RUL ¼ right upper lobe.
under the ROC curve (AUC-ROC) for RNs was 0.521 for tumor recurrence (DFS) and 0.546 for death (OS). The AUC-ROC for LNS were 0.584 (DFS) and 0.529 (OS), and for LNR were 0.513 (DFS) and 0.585 (OS), respectively. The RNs greater than 10 was associated with more tobacco exposure (p ¼ 0.03), larger tumors (p < 0.01),
3
lobectomy (p < 0.01), and more frequent postoperative events (p ¼ 0.01) (Table 2). The frequency of nodal upstaging was 17% (38 of 224) in patients who had greater than 10 RNs compared with 6% (21 of 326) in patients with RNs 10 or less (p < 0.01). Patients who had LNS greater than 3 were associated with larger tumors (p < 0.01) and lobectomy (p < 0.01) as opposed to segmentectomy. Nodal upstaging was 15% (49 of 332) in patients who underwent LNS greater than 3 compared with 5% (10 of 218) in patients with LNS 3 or less (p < 0.01). The median LNR in our patient population was 0.12 (range, 0.02 to 1.0) and did not show any associations with age, sex, smoking, and tumor size, nor did it predict disease-free or overall survival. The influence of tumor size on type of procedure, RNs, and LNS are also summarized in Table 2. The frequency of tumor recurrence in the entire cohort was 14.4% (79 of 550) where 16.5% (21 of 127) was observed in tumors greater than 3 cm and 13.7% (58 of 423) in tumors 3 cm or less (p ¼ 0.47). Tumor size greater than 3 cm represented 24% patients in our study and was not statistically associated with nodal upstaging (p ¼ 0.20). Nodal upstaging was not statistically associated with any particular anatomic lobe. The impact of lymph node assessment variables and other important clinical and pathologic variables on DFS and OS (Table 3) were evaluated using logistic regression. On univariate analysis, only LNS greater than 3 showed a significant association with worse DFS (hazard ratio [HR], 2.35; 95% confidence interval [CI], 1.41% to 3.91%, p ¼ 0.001; Fig 2) and OS (HR, 2.00; 95% CI, 1.19% to 3.35%, p ¼ 0.01; Fig 3). On multivariate analysis for DFS, LNS greater than 3 was associated with worse outcome (HR, 2.34; 95% CI, 1.35% to 4.87%, p ¼ 0.003) while controlling for tumor size and smoking status. The LNS greater than 3 was also associated with worse OS on multivariate analysis (HR, 1.80; 95% CI, 1.00% to 3.16%, p ¼ 0.046) while controlling for age, tumor size, nodal upstaging, smoking history, DLCO, comorbidities, and postoperative complications. Nodal upstaging was associated with worse OS on univariate (p ¼ 0.004) and multivariate analysis (HR, 2.49; 95% CI, 1.29% to 4.79%, p ¼ 0.006).
Comment Lymph node metastasis is a strong predictor of recurrence and survival in NSCLC patients; however, the prognostic value of the total number of lymph nodes harvested (RNs) or the total number of lymph node stations sampled (LNS) remains under investigation. There is no accepted recommendation for RNs; however, the 2013 National Comprehensive Cancer Network guidelines recommend sampling at least 3 mediastinal lymph node stations at the time of pulmonary resection [20]. In a secondary analysis of the American College of Surgeons Oncology Group Z0030 trial (where w 1,023 stage I patients were randomized to mediastinal lymph node sampling versus mediastinal lymph node dissection), the median RNs were similar between VATS and open (15 [range, 5 to 48]) vs 19 [range, 2 to 83], p ¼ 0.147) [21]. As this trial greatly influenced surgeon assessment of mediastinal lymph
4
ZHOU ET AL LYMPH NODE ASSESSMENT IN VATS LOBECTOMY
Ann Thorac Surg 2015;-:-–-
Fig 1. (A) Pathologic stage I, II, and III was observed in 79% (434 of 550), 14.5% (80 of 550), and 6.5% (36 of 550) patients, respectively. (B) Nodal stage (N0, N1, N2) was observed in 485, 38, and 27 patients, respectively. (C) A total of 65 (11.8%) patients had involved nodes. Nodal upstaging was observed in 3 groups: N0 to N1 (32, 5.8%); N0 to N2 (24, 4.1%); and N1 to N2 (3, 0.5%). (LNR ¼ lymph node ratio; LNS ¼ lymph node station; RNs ¼ total number of resected lymph nodes.)
nodes during pulmonary resection, it may serve as a potential benchmark for RNs and LNS in VATS lobectomy. Despite the lack of enthusiasm to adopt RNs, LNS, or LNR into standard practice, there are a number of single-
center series that have examined the impact of these parameters on survival after resection of early-stage NSCLC. Ou and Zell [22] reported on 2,545 patients who underwent lobectomy for stage IA NSCLC and found that removal of
Table 2. Assessment of Important Variables Stratified by Resected Lymph Nodes (RNs) and Lymph Node Stations (LNS) RNs Characteristics
10
>10
Age (years), mean SD 67.3 10.9 Sex, n (%) Male 108 (33) Female 218 (67) Tobacco history, n (%) Never smoker 68 (22) Past smoker 171 (55) Current smoker 73 (23) Pulmonary functions tests, mean SD 87.4 22 FEV1 (% predicted) 78.1 23.1 DLCO (% predicted) Tumor size, n (%) 2 cm 183 (56) 2–3cm 88 (27) >3cm 55 (17) Mean (cm) SD 2.1 1.3 Surgical procedure, n (%) Lobectomy 279 (86) Segmentectomy 47 (14) Nodal upstaging No 305 (94) Yes 21 (6) Complications, n (%) Postoperative events 67 (21) Air leak > 5days 12 (4) Need for bronchoscopy 14 (4) Pneumonia 5 (2) Empyema 5 (2) DLCO ¼ carbon monoxide diffusing capacity;
68.2 9.8
LNS p Value 0.33 0.01
100 (45) 124 (55)
3
>3
p Value
65.8 10.9
68.9 10.0
10 resected lymph nodes), (B) LNS (sampling > 3 lymph node stations), (C) LNR (sampling lymph node ratios > 0.12).
patients found to have occult lymph node metastases compared with those that were lymph node negative. The inherent limitation of this study aside from its retrospective nature is the phenomenon of fragmentation
Ann Thorac Surg 2015;-:-–-
of lymph nodes, which can affect how the pathologists report total lymph node counts (RNs). Other limitations include a relatively small number of patients with positive lymph nodes, 11.8% (65 of 550), which weakens the lymph node ratio (LNR) assessment, and the notion that only 41% of the cases were associated with RNs greater than 10. Only 27.5% (151 of 550) of these clinical stage I patients underwent cervical mediastinoscopy because CT-PET was routinely used to exonerate mediastinal lymph nodes metastases. In conclusion, sampling greater than 3 lymph node stations and greater than 10 RNs were associated with an increase in nodal upstaging in this VATS series of clinical early-stage NSCLC where the mean tumor size was 2.3 cm. The LNS greater than 3 was prognostic of worse DFS and OS by virtue of improved staging accuracy. These observations should caution thoracic surgeons not to be complacent about aggressive lymph node sampling despite a rigorous preoperative evaluation that suggests clinical stage I NSCLC with no mediastinal metastases. Although our data do not support achieving RNs greater than 10 to predict survival during VATS anatomic resection, more lymph node analysis needs to be conducted prospectively in large series to better understand if there is a prognostic threshold value. Lastly, the identification of peribronchial lymph nodes also greatly influences the detection of occult N1 disease, prompting our profession to foster a careful collaboration with our pathology colleagues to improve handling of resected specimens. Financial support for this study was provided by the Division of Thoracic Surgery at the Massachusetts General Hospital. We would like to acknowledge our data manager and research coordinator, Sheila Knoll and Diane Davies, respectively, for their diligence and dedication toward compiling and maintaining the Thoracic Surgery Database.
ZHOU ET AL LYMPH NODE ASSESSMENT IN VATS LOBECTOMY
8.
9.
10. 11.
12. 13.
14.
15.
16.
17.
18.
19.
References 1. Groome PA, Bolejack V, Crowley JJ, et al. The IASLC lung cancer staging project: validation of the proposals for revision of the T, N, and M descriptors and consequent stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours. J Thorac Oncol 2007;2:694–705. 2. Detterbeck FC, Postmus PE, Tanoue LT. The stage classification of 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):e191S–210S. 3. McKenna RJ Jr, Houck W, Fuller CB. Video-assisted thoracic surgery lobectomy: experience with 1,100 cases. Ann Thorac Surg 2006;81:421–6. 4. Takagi H, Matsui M, Umemoto T. Long-term survival of VATS versus open lobectomy. Ann Thorac Surg 2011;92:408–10. 5. Rusch VW, Giroux DJ. Nodal staging in lung cancer: lymph node location or number? J Thorac Oncol 2011;6:237–8. 6. van Velzen E, Snijder RJ, Brutel de la Rivi ere A, Elbers HJ, van den Bosch JM. Type of lymph node involvement influences survival rates in t1n1m0 non-small cell lung carcinoma. Lymph node involvement by direct extension compared with lobar and hilar node metastases. Chest 1996;110:1469–73. 7. Lardinois D, Suter H, Hakki H, Rousson V, Betticher D, Ris HB. Morbidity, survival, and site of recurrence after
20. 21.
22. 23. 24.
25. 26.
7
mediastinal lymph-node dissection versus systematic sampling after complete resection for non-small cell lung cancer. Ann Thorac Surg 2005;80:268–75. Macia I, Ramos R, Moya J, et al. Survival of patients with non-small cell lung cancer according to lymph node disease: single PN1 vs multiple PN1 vs single unsuspected PN2. Ann Surg Oncol 2013;20:2413–8. Ludwig MS, Goodman M, Miller DL, Johnstone PA. Postoperative survival and the number of lymph nodes sampled during resection of node-negative non-small cell lung cancer. Chest 2005;128:1545–50. Nwogu CE, Groman A, Fahey D, et al. Number of lymph nodes and metastatic lymph node ratio are associated with survival in lung cancer. Ann Thorac Surg 2012;93:1614–20. Jonnalagadda S, Smith C, Mhango G, Wisnivesky JP. The number of lymph node metastases as a prognostic factor in patients with n1 non-small cell lung cancer. Chest 2011;140: 433–40. Jonnalagadda S, Arcinega J, Smith C, Wisnivesky JP. Validation of the lymph node ratio as a prognostic factor in patients with N1 nonsmall cell lung cancer. Cancer 2011;117:4724–31. Wisnivesky JP, Arciniega J, Mhango G, Mandeli J, Halm EA. Lymph node ratio as a prognostic factor in elderly patients with pathological n1 non-small cell lung cancer. Thorax 2011;66:287–93. D’Amico TA, Niland J, Mamet R, Zornosa C, Dexter EU, Onaitis MW. Efficacy of mediastinal lymph node dissection during lobectomy for lung cancer by thoracoscopy and thoracotomy. Ann Thorac Surg 2011;92:226–32. Boffa DJ, Kosinski AS, Paul S, Mitchell JD, Onaitis M. Lymph node evaluation by open or video-assisted approaches in 11, 500 anatomic lung cancer resections. Ann Thorac Surg 2012;94:347–53. Ramos R, Girard P, Masuet C, Validire P, Gossot D. Mediastinal lymph node dissection in early-stage non-small cell lung cancer: totally thoracoscopic vs thoracotomy. Eur J Cardiothorac Surg 2012;41:1342–8. Licht PB, Jorgensen OD, Ladegaard L, Jakobsen E. A national study of nodal upstaging after thoracoscopic versus open lobectomy for clinical stage I lung cancer. Ann Thorac Surg 2013;96:943–50. Gajra A, Newman N, Gamble GP, Kohman LJ, Graziano SL. Effect of number of lymph nodes sampled on outcome in patients with stage I non-small-cell lung cancer. J Clin Oncol 2003;21:1029–34. Varlotto JM, Recht A, Nikolov M, Flickinger JC, Decamp MM. Extent of lymphadenectomy and outcome for patients with stage I nonsmall cell lung cancer. Cancer 2009;115:851–8. Ettinger DS, Akerley W, Borghaei H, et al. Non-small cell lung cancer, version 2.2013. J Natl Compr Canc Netw 2013;11:645–53. Scott WJ, Allen MS, Darling G, et al. Video-assisted thoracic surgery versus open lobectomy for lung cancer: s secondary analysis of data from the American College of Surgeons Oncology Group Z0030 randomized clinical trial. J Thorac Cardiovasc Surg 2010;139:976–83. Ou SH, Zell JA. Prognostic significance of the number of lymph nodes removed at lobectomy in stage IA non-small cell lung cancer. J Thorac Oncol 2008;3:880–6. Whitson BA, Groth SS, Maddaus MA. Surgical assessment and intraoperative management of mediastinal lymph nodes in non-small cell lung cancer. Ann Thorac Surg 2007;84:1059–65. Zhong W, Yang X, Bai J, Yang J, Manegold C, Wu Y. Complete mediastinal lymphadenectomy: the core component of the multidisciplinary therapy in resectable non-small cell lung cancer. Eur J Cardiothorac Surg 2008;34:187–95. Cho S, Song IH, Yang HC, Kim K, Jheon S. Predictive factors for node metastasis in patients with clinical stage I non-small cell lung cancer. Ann Thorac Surg 2013;96:239–45. Veeramachaneni NK, Battafarano RJ, Meyers BF, Zoole JB, Patterson GA. Risk factors for occult nodal metastasis in clinical T1N0 lung cancer: a negative impact on survival. Eur J Cardiothorac Surg 2008;33:466–9.
