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Survival of Patients With Resected N2 Non–Small-Cell Lung Cancer: Evidence for a Subclassification and Implications

From the Departments of Medicine and Biostatistics, Institut Gustave Roussy, Villejuif; Department of Thoracic Surgery, Institut Mutualiste Montsouris, Paris; Department of Thoracic Surgery, Clinique des Cèdres, Bois Guillaume; Department of Thoracic Oncology, Hopital Arnaud de Villeneuve, Montpellier; Department of Thoracic Surgery, Hopital Michallon, Grenoble; Department of Thoracic Surgery, Hopital Purpan, Toulouse; Department of Pneumology, Hopital de Strasbourg, Strasbourg; Department of Pneumology, Hopital de Besançon, Besançon, France.

Address reprint requests to Fabrice Andre, MD, Department of Medicine, comité 031 Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif, France; email UIMMUNOC{at}igr.fr

	ABSTRACT

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PURPOSE: Patients who suffer from non–small-cell lung cancer (NSCLC) with ipsilateral mediastinal lymph node involvement (N2) belong to a heterogeneous subgroup of patients. We analyzed the prognosis of patients with resected N2 NSCLC to propose homogeneous patient subgroups.

PATIENTS AND METHODS: The present study comprised 702 consecutive patients from six French centers who underwent surgical resection of N2 NSCLC. Initially, two groups of patients were defined: patients with clinical N2 (cN2) and those with minimal N2 (mN2) disease were patients in whom N2 disease was and was not detected preoperatively at computed tomographic scan, respectively.

RESULTS: The median duration of follow-up was 52 months (range, 18 to 120 months). A multivariate analysis using Cox regression identified four negative prognostic factors, namely, cN2 status (P < .0001), involvement of multiple lymph node levels (L2+; P < .0001), pT3 to T4 stage (P < .0001), and no preoperative chemotherapy (P < .01). For patients treated with primary surgery, 5-year survival rates were as follows: mN2, one level involved (mN2L1, n = 244): 34%; mN2, multiple level involvement (mN2L2+, n = 78): 11%; cN2L1 (n = 118): 8%; and cN2L2+ (n = 122): 3%. When only patients with mN2L1 disease were considered, the site of lymph node involvement according to the American Thoracic Society numbering system had no prognostic significance (P = .14). Preoperative chemotherapy was associated with a better prognosis for those with cN2 (P < .0001). Five-year survival rates were 18% and 5% for cN2 patients treated with and without preoperative chemotherapy, respectively.

CONCLUSION: This study has identified homogeneous N2 NSCLC prognostic subgroups and suggests different therapeutic approaches according to the subgroup profile.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PATIENTS SUFFERING from N2 non–small-cell lung cancer (NSCLC), ie, with ipsilateral mediastinal lymph node involvement, are considered by most physicians to be a heterogeneous subgroup of patients.¹ A number of controversies plague this subgroup of patients with respect to staging and treatment, which often makes it difficult to interpret the large amount of literature data concerning these patients. Two decades ago, Naruke et al,² Martini et al,³ and Pearson et al⁴ reported that surgery could cure a small proportion of these patients. Since then, many series⁵ have reported 5-year survival rates ranging from 6% to 35% after surgery. These series suggested that preoperative detection of N2 disease, involvement of multiple lymph node levels, subcarinal involvement, and an adenocarcinoma subtype were associated with a worse prognosis.⁵ The small number of patients included in these studies and the differences in inclusion criteria clearly account for the heterogeneity of these results and for the confusion concerning the prognosis of N2 patients. Against this background, the indications for surgery for N2 NSCLC remain somewhat ambiguous. Two randomized trials^6,7 suggested that preoperative chemotherapy improved the survival of patients in whom N2 disease was detected preoperatively at computed tomographic (CT) scan. These results became controversial when another randomized trial reported no statistically significant survival advantage for clinical N2 (cN2) patients treated with preoperative chemotherapy.⁸ A recent meta-analysis⁹ found no benefit for resected N2 disease treated with postoperative radiotherapy. Despite this lack of benefit, some groups^10-12 propose preoperative radiotherapy delivered concomitantly with chemotherapy for bulky N2 disease. What has emerged from such confusion concerning the management of N2 is the need to classify patients with N2 disease into homogeneous subgroups according to the prognosis. This subclassification should improve the interpretation of clinical trials. One subclassification was recently proposed¹³ in which two subgroups were defined: patients with minimal N2 (mN2) are those with no preoperative detection of N2 disease, and patients with cN2 are those in whom N2 disease is preoperatively detected at CT scan and confirmed by mediastinoscopy. This subclassification corroborates well animal models. Indeed, a mice model of mediastinal lymph node metastasis suggests that the weight of mediastinal lymph node increased in a time-dependant manner and that clinically detectable N2 disease represents a more advanced disease compared with mN2.¹⁴ Another subclassification according to the number of lymph node levels involved at mediastinoscopy was proposed by Ruckdeshel et al.¹⁵ This subclassification corroborates well anatomic studies^16,17 that suggest that involvement of multiple lymph node stations usually traduces a spreading from one mediastinal lymph node station and a more advanced disease. Moreover, these studies strongly suggest that the invasion of the circulation by tumor cells is more frequent when multiple lymph node stations are involved.

In the present study, we analyzed prognostic factors and survival rates of a cohort of patients with resected N2 disease. The main objective of the present study was to propose a subclassification of N2 NSCLC patients into homogenous subgroups. A secondary objective was to analyze the results of surgery and preoperative chemotherapy.

	PATIENTS AND METHODS

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Patients
From January 1989 to June 1996, 702 consecutive patients with histologically proven N2M0 NSCLC underwent resection with a curative intent in six French centers and were included in the present study. All patients had an apparently resectable disease at preoperative staging and thoracotomy. Eleven other patients with mN2 and 50 others with cN2 disease were seen in our institutions but were considered to have unresectable N2 NSCLC. These latter patients were not included in the present study. Patients with metastatic NSCLC, a prior history of metastatic malignancy, a palliative resection, or a neuroendocrine tumor were excluded. Centers were selected if they performed prospective registration of patients, mediastinoscopy, and radical mediastinal lymph node dissection. All data were collected prospectively but were analyzed retrospectively.

Pretreatment Staging
Pretreatment staging included a clinical history, clinical examination, blood tests, chest x-ray, CT scan of the thorax, fiberoptic bronchoscopy, and upper abdominal CT scan in all patients. The indications for liver ultrasound, brain CT scan, and bone scan were based on clinical symptoms and center-specific recommendations. Mediastinal lymph nodes with a diameter of 10 mm or more on the CT scan were considered abnormal. A mediastinoscopy was performed when assessable mediastinal lymph nodes were 1 cm at CT scan.

Patients with no mediastinal lymph node enlargement (< 10 mm) at CT scan were classified as having mN2 disease. Patients with an enlarged mediastinal lymph node at CT scan whose mediastinoscopy was negative were classified as having mN2 disease. Patients with mediastinal lymph node enlargement at CT scan and a positive mediastinoscopy or in whom mediastinoscopy was not performed were considered as having cN2 lesions, if the histologic analysis of enlarged lymph nodes revealed malignant cells.

Postoperative Staging
All patients were staged postsurgically according to the 1997 tumor-node-metastasis classification.¹⁸ All lymph nodes removed were examined by a histopathologist. Lymph node levels were classified according to their anatomic location and the American Thoracic Society numbering system.¹⁹ The lymph node size was defined as the diameter of the largest node. Tumor extension (pT) was classified according to the 1997 tumor-node-metastasis classification.¹⁸ Complete resection was defined as resection of all macroscopic tumor and resection margins free of tumor at microscopic analysis.

Treatment Modalities
The extent of the tumor resection (wedge resection, lobectomy, or pneumonectomy) was at the discretion of the surgeon. Extensive mediastinal lymph node dissection was performed when possible and consisted of resection of all ipsilateral mediastinal lymph nodes. Adjuvant chemotherapy and postoperative radiotherapy were recorded. During this period, preoperative chemotherapy was considered as a viable option in France. The decision to administer this treatment was therefore at the discretion of the medical oncologist who cared for the patient. Inclusion criteria for patients who received preoperative chemotherapy were similar to those of the other patients included in the study.

Locoregional Tumor Response After Induction Treatment
A radiologic complete response (CR) to preoperative treatment was defined as the complete disappearance of all objective disease. A pathologic CR was defined as the absence of malignant cells at pathologic examination after preoperative treatment. A partial response was defined as a 50% or greater decrease in the sum of the products of the two largest perpendicular diameters of all measurable lesions. Downstaging was defined as the disappearance of mediastinal lymph node enlargement at CT scan. Stable disease was defined as a less than 50% decrease or a less than 25% increase in the sum of the products of the two largest perpendicular diameters of all measurable lesions. Progressive disease was defined as an increase of 25% or more in the sum of the products of the two longest perpendicular diameters of all measurable lesions.

Statistical Analysis
Overall survival (OS) denotes the time from the first treatment to death or the last follow-up visit. Event-free survival (EFS) denotes the time from diagnosis to relapse, death, or the last follow-up visit. Cumulative survival rates were calculated by the Kaplan-Meier method.²⁰ Univariate analyses of prognostic factors were performed using the log-rank test, and multivariate analyses were performed using Cox regression models.²¹ Three-year EFS and 5-year OS rates were selected before analysis for Results and Discussion sections, because they were considered legitimate end points for evaluating the prognosis.

	RESULTS

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Patient Characteristics
Among the 702 consecutive patients, 16 (2.3%) were lost to follow-up and excluded from the analysis. Patients’ characteristics (n = 686) are listed in Table 1. A mediastinoscopy was performed in 70% of patients who presented with lymph node enlargement at levels 1, 2, 3, 4, and 7 at CT scan. The main reason that mediastinoscopy was not performed was that some enlarged lymph nodes in the left mediastinum or in the subcarinal area seemed readily amenable to surgery but seemed to be difficult to assess with this technique. The adrenal gland and the liver were explored in all patients. Seventy percent of the patients had brain CT scans, and 80% of the patients had bone scans. Ninety percent of patients whose performance status was greater than 1 or whose lactate dehydrogenase levels exceeded the upper threshold were assessed by brain CT scan and bone scan. Performance status was 1 in 91% of patients. Three hundred fifty-four patients (52%) were classified as having mN2 lesions and 332 as having cN2. Four hundred seventeen patients (62%) had a single lymph node level involved (L1), and 260 patients (38%) had multiple lymph node levels involved (L2+). Twenty-four percent of mN2 and 53% of cN2 cases had multiple lymph node levels involved (P < .001). The lymph node levels most frequently involved by metastasis were the tracheobronchial (station 4; n = 272) and subcarinal areas (station 7; n = 240). Resection was partial in 156 patients (23%). The partial resection rate was higher in the cN2 subgroup than in the mN2 subgroup (29% v 16%; P = .0005). The partial resection rate was 23% for mN2L2+ and 13% for mN2L1 patients (P = .001). The success rate for extensive mediastinal lymph node sampling was 89% for the mN2 group and 80% for the cN2 group (P = .002). Ninety-five patients with cN2 disease and 29 with mN2 received preoperative chemotherapy. The CR and partial response rates were 2% and 70%, respectively, for cN2 disease treated with preoperative chemotherapy. Thirty-seven cases were downstaged, but a pathologic CR occurred in only one patient. Thirty-two patients (5%) received adjuvant chemotherapy, 389 (57%) postoperative radiotherapy, and 57 (8%) postoperative radiochemotherapy.

View larger version (19K): [in this window] [in a new window]   Fig 1. Survival of patients with N2 disease treated with primary surgery according to N2 status and number of levels involved.

View larger version (17K): [in this window] [in a new window]   Fig 2. (A) Survival of patients with cN2 disease according to treatment. (B) Survival according to response after neoadjuvant treatment in cN2 patients.

	DISCUSSION

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The present results raise several questions: is it relevant to classify N2 NSCLC into subgroups? If such is the case, what is the definition of each subgroup? What are the implications for preoperative staging of NSCLC? Will the treatment strategy differ according to the N2 NSCLC subgroups?

Patients who suffer from N2 NSCLC are a heterogeneous subgroup of patients as regards the prognosis and treatment. To guide preoperative staging and to select appropriate treatment options, some authors have proposed new tumor-node-metastasis classifications to classify N2 disease into subcategories. A subclassification of N2 according to preoperative staging has recently been proposed¹³ but not validated. In this subclassification, mN2 cases, ie, patients with no preoperative evidence of N2 disease at CT scan, and cN2 cases, ie, patients with N2 disease detected preoperatively at CT scan, are considered as distinct N2 NSCLC patient subgroups. Long ago Martini et al³ and Pearson et al⁴ claimed that there was a difference between mN2 and cN2. In the study of Martini et al (n = 151 cases), preoperative staging was based on chest x-ray, CT scan, and bronchoscopy. The 5-year OS rates of mN2 and cN2 patients were 34% and 9%, respectively (P = .002). In the study of Pearson et al (n = 76 cases), preoperative mediastinoscopy was systematically performed. The 5-year OS rates were 41% and 15% for mediastinoscopy-negative N2 and mediastinoscopy-positive N2 patients, respectively (P = .01). No large series were conducted during the CT scan era to confirm these findings. In the present study, the 5-year OS rates were 29% and 7% for mN2 and cN2 patients, respectively (P < .0001; relative risk = 1.8, by multivariate analysis). These results demonstrate that mN2 and cN2 are basically two distinct stages of NSCLC. Of note, the survival of patients with apparently resectable cN2 disease (median survival time, 14 months; 3-year OS rate, 15%; 5-year OS rate, 7%) was close to that of stage IIIB disease reported in randomized trials.^22,23 The prognosis of cN2 disease remains poor despite complete resection, because the 5-year OS rate is only 8%. These findings justify the inclusion of cN2 with stage IIIB disease in clinical trials that evaluate multimodality treatment.^10-12 Our results validate the relevance of a subclassification of N2 NSCLC based on the cN2 status.¹³

In another recent classification,¹⁵ mN2 disease was subclassified according to the number of involved lymph node levels. The number of involved mediastinal lymph node levels was an independent prognostic factor in six previously published series, whereas it had no significant impact in six other studies.^24-35 Overall, the difference in survival between single and multiple lymph node level involvement (L1 and L2+) in the literature is statistically significant.⁵ In the present study, the 5-year OS rates were 34% and 11% for patients with mN2L1 and mN2L2+ disease (P < .0001). In our series, the survival of patients with mN2L2+ disease (median, 16 months; 3-year OS rate, 17%; 5-year OS rate, 11%) was close to that of patients with cN2 and stage IIIB disease.^22,23 On the other hand, 5-year OS rates of patients with mN2L1 disease (34%) were close to those of cases with stage IIB reported by Mountain (39%) in his updated classification.¹⁸ These results confirm the relevance of a subclassification based on the number of lymph node levels involved.¹⁵ We have shown that a preoperative N2 status and the number of involved lymph node levels are the most relevant prognostic factors for N2 NSCLC and that it is wise to classify N2 NSCLC into two basically distinct patient subgroups. It could be contended that the exclusion of unresectable N2 NSCLC led to a bias in the subclassification proposed. Such was not the case, however, because the rate of mN2 disease considered as unresectable at preoperative staging was low (n = 11; 3.4% of overall mN2) and did not influence the survival analysis. The exclusion of unresectable cN2 disease does not bias our results either, because it is well known that the survival of these patients is similar to that of patients with stage IIIB disease.^22,23 The immediate implication of this finding is that there is a need for optimal preoperative detection of mN2L2+ and cN2 disease and for different treatment strategies in line with each subgroup profile.

As mN2L2+/cN2 NSCLC is a distinct category from mN2L1 NSCLC, the former subgroup of patients should be determined preoperatively. This signifies finding a good definition of mN2/cN2 and accurate procedures for the diagnosis and detection of mN2L2+ and cN2. Distinguishing mN2 from cN2 must be a goal of preoperative staging because treatment options and outcome are totally different. In our study, we performed preoperative thoracic staging according to American Thoracic Society/European Respiratory Society³⁶ and American Society of Clinical Oncology³⁷ recommendations. Mediastinoscopy was therefore performed only in patients who presented with mediastinal lymph node enlargement at CT scan (> 1 cm). Some authors recommend systematic mediastinoscopy for preoperative staging of NSCLC¹⁰ and define unforeseen N2 as N2 that was not detected at systematic mediastinoscopy. Whether systematic mediastinoscopy is better than CT scan ± mediastinoscopy for classifying N2 patients into subgroups has never been addressed. Because the specificity of CT scan in detecting malignant lymph nodes is only 70% and preoperative differentiation between cN2 and earlier stages is warranted, mediastinal lymph node enlargement at CT scan must be diagnosed preoperatively. Conventional mediastinoscopy is accurate for sampling levels 1, 2, 3, 4, and 7 but not levels 5, 6, 8, and 9.³⁸ New staging procedures are therefore required to confirm the malignancy of enlarged lymph node at levels 5, 6, 8, and 9 preoperatively. Mediastinotomy, parasternal mediastinoscopy,³⁹ transesophageal echoendoscopy,⁴⁰ and transtracheal echoendoscopy should be developed in this setting. Another major goal of preoperative staging should be the distinction between mN2L1 and mN2 L2+, because we have demonstrated that the results of primary surgery are different for these two entities. The positron emission tomography scan could be a useful technique in this context, because studies show that it is able to detect both mN2 and the level involved accurately.^41-43

Previous short series suggested that surgery is beneficial in patients with mN2.^3,4 Because the 5-year OS rate is 34% for patients with resected mN2L1 NSCLC, surgery seems to be the key treatment procedure in these cases. On the other hand, the results of primary surgery for mN2L2+ and cN2 are much more disappointing (5-year OS rates, 11% and 5%, respectively). Two randomized trials, each of which included 60 patients, demonstrated improved survival for patients with cN2 treated with preoperative chemotherapy.^6,7 A recently reported randomized trial, however, found no statistically significant survival benefit for patients with N2 disease treated with preoperative chemotherapy.⁸ In the present study, the multivariate analysis shows that preoperative chemotherapy is associated with a better prognosis (relative risk = 1.5; P < .005). The 5-year OS rate was 18% for patients with cN2 disease treated with preoperative chemotherapy and 5% for those with cN2 disease who were not. Differences in patient characteristics and chemotherapy regimens could explain the divergent results observed in the study of Depierre et al⁸ and our own. Overall, if preoperative chemotherapy seems to be associated with a benefit for cN2 NSCLC, it cannot currently be considered as standard therapy because results are inconsistent. New cytotoxic drugs included in a multimodality approach should be tested in this setting. Downstaging after preoperative chemotherapy is associated with a better survival in our study (5-year OS rate, 30%) and in other trials^11,44; this is another argument in favor of administering induction chemotherapy.

The long-term results for cN2 treated with preoperative chemotherapy are not different from those reported for selected stage IIIB patients treated with radiochemotherapy.⁴⁵ Whether surgery has an edge over radiotherapy in cN2 disease still needs to be established in a randomized trial. Nevertheless, the 26% 5-year OS rate observed in our series for patients with cN2 disease who achieved a tumor response after preoperative chemotherapy and who were treated with complete resection, argues in favor of surgery in this setting to improve local control.⁴⁶

In conclusion, this study was centered on the prognosis of resected N2 NSCLC, according to which two distinct homogeneous subgroups were identified. The first subgroup of N2 NSCLC is represented by mN2L1. The 5-year OS rate was 34% for these patients. Surgery is mandatory in these patients, in whom the prognosis is close to that of patients with stage IIB disease. This is a good population in which adjuvant systemic strategies can be tested. mN2L2+ and cN2 represent the second subgroup of N2 NSCLC. The prognosis is close to that of stage IIIB disease. Considering that primary surgery only marginally cures these patients (5-year OS rates range from 3% to 11%), the challenge is to identify them at clinical staging and to include them in clinical trials that test multimodality treatments.^10,11 Our series suggests that preoperative chemotherapy is of interest for these patients. This finding is controversial but is an incentive to explore new drugs in this context. The impact of surgery compared with that of radiotherapy needs to be clarified by randomized trials. Nevertheless, although the results of ongoing clinical trials are still awaited, it seems reasonable to consider surgery for cN2 lesions that respond to preoperative chemotherapy, because the 5-year OS rate is 26% for patients treated with complete resection.

	ACKNOWLEDGMENTS

 
We are grateful to Lorna Saint Ange for editing, Claire Billard for statistical analysis, and P. Girard and C. Le Pechoux for helpful discussions.

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Submitted October 18, 1999; accepted April 25, 2000.

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				P. Misthos, E. Sepsas, J. Kokotsakis, I. Skottis, and A. Lioulias The Significance of One-Station N2 Disease in the Prognosis of Patients With Nonsmall-Cell Lung Cancer Ann. Thorac. Surg., November 1, 2008; 86(5): 1626 - 1630. [Abstract] [Full Text] [PDF]

				C. H. Kang, Y. J. Ra, Y. T. Kim, S.-H. Jheon, S.-w. Sung, and J. H. Kim The impact of multiple metastatic nodal stations on survival in patients with resectable N1 and N2 nonsmall-cell lung cancer. Ann. Thorac. Surg., October 1, 2008; 86(4): 1092 - 1097. [Abstract] [Full Text] [PDF]

				C. Dooms, E. Verbeken, S. Stroobants, K. Nackaerts, P. De Leyn, and J. Vansteenkiste Prognostic Stratification of Stage IIIA-N2 Non-Small-Cell Lung Cancer After Induction Chemotherapy: A Model Based on the Combination of Morphometric-Pathologic Response in Mediastinal Nodes and Primary Tumor Response on Serial 18-Fluoro-2-Deoxy-Glucose Positron Emission Tomography J. Clin. Oncol., March 1, 2008; 26(7): 1128 - 1134. [Abstract] [Full Text] [PDF]

				M. J. Liptay Sentinel Node Mapping in Lung Cancer: The Holy Grail? Ann. Thorac. Surg., February 1, 2008; 85(2): S778 - S779. [Full Text] [PDF]

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				J. P. van Meerbeeck, G. W. P. M. Kramer, P. E. Y. Van Schil, C. Legrand, E. F. Smit, F. Schramel, V. C. Tjan-Heijnen, B. Biesma, C. Debruyne, N. van Zandwijk, et al. Randomized Controlled Trial of Resection Versus Radiotherapy After Induction Chemotherapy in Stage IIIA-N2 Non-Small-Cell Lung Cancer J Natl Cancer Inst, March 21, 2007; 99(6): 442 - 450. [Abstract] [Full Text] [PDF]

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				J. A. Bogart and J. N. Aronowitz Localized Non-Small Cell Lung Cancer: Adjuvant Radiotherapy in the Era of Effective Systemic Therapy Clin. Cancer Res., July 1, 2005; 11(13): 5004s - 5010s. [Abstract] [Full Text] [PDF]

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				N. Lorent, P. De Leyn, Y. Lievens, E. Verbeken, K. Nackaerts, C. Dooms, D. Van Raemdonck, B. Anrys, J. Vansteenkiste, and The Leuven Lung Cancer Group 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. Onc., November 1, 2004; 15(11): 1645 - 1653. [Abstract] [Full Text] [PDF]

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				M. B. Faries, R. J. Bleicher, X. Ye, R. Essner, and D. L. Morton Lymphatic Mapping and Sentinel Lymphadenectomy for Primary and Metastatic Pulmonary Malignant Neoplasms Arch Surg, August 1, 2004; 139(8): 870 - 877. [Abstract] [Full Text] [PDF]

				S. M. Keller, M. G. Vangel, H. Wagner, J. H. Schiller, A. Herskovic, R. Komaki, R. S. Marks, M. C. Perry, R. B. Livingston, and D. H. Johnson Prolonged survival in patients with resected non-small cell lung cancer and single-level N2 disease J. Thorac. Cardiovasc. Surg., July 1, 2004; 128(1): 130 - 137. [Abstract] [Full Text] [PDF]