Ann Thorac Surg 2008;86:1092-1097. doi:10.1016/j.athoracsur.2008.06.056
© 2008 The Society of Thoracic Surgeons
Original Articles: General Thoracic
The Impact of Multiple Metastatic Nodal Stations on Survival in Patients With Resectable N1 and N2 Nonsmall-Cell Lung Cancer
Chang Hyun Kang, MDa,*,
Yong Joon Ra, MDa,
Young Tae Kim, MDa,
Sang-Hoon Jheon, MDb,
Sook-whan Sung, MDb,
Joo Hyun Kim, MDa
a Department of Thoracic and Cardiovascular Surgery, Cancer Research Institute, Seoul National University Hospital, Seoul
b Department of Thoracic and Cardiovascular Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea
Accepted for publication June 18, 2008.
* Address correspondence to Dr Kang, Department of Thoracic and Cardiovascular Surgery, Seoul National University Hospital, 28 Yongon-dong, Chongro-gu, Seoul, 110-744, South Korea (Email: chkang{at}snuh.org).
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Abstract
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Background: The aim of the study was to identify common prognostic factors in nonsmall-cell lung cancer (NSCLC) with N1 and N2 nodal involvement.
Methods: A retrospective review of NSCLC patients who underwent primary surgical resection without neoadjuvant chemotherapy was performed. In all, 280 patients were included in this study, and there were 132 patients with N1 disease (N1 group) and 148 patients with N2 disease (N2 group). The median follow-up period was 26 months, and complete follow-up was possible in 269 patients (96%).
Results: Lobectomy was performed in 194 patients (69%), bilobectomy was performed in 43 (15%), and pneumonectomy was performed in 43 (15%). Complete resection was possible in 273 patients (98%), and operative death occurred in 5 patients (2%). The overall and disease-free 5-year survival rates were 63% and 55%, respectively, in the N1 group, and 44% and 32%, respectively, in the N2 group (p < 0.05). The prognostic factors for overall survival in both the N1 and N2 groups were age and the number of metastatic nodal stations; however, N2 metastasis was not a significant prognostic factor in the multivariate analysis. The poor prognosis of the patients in the N2 group was due to the greater incidence of multiple node involvement in comparison with the N1 group (73% versus 15%; p < 0.05).
Conclusions: Multiple metastatic nodal stations was the common prognostic factor in resectable NSCLC patients with nodal metastasis, and mediastinal nodal involvement was associated with a higher chance of multiple-station metastasis in this study.
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Introduction
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Lymph node metastasis is the most important prognostic factor in resectable nonsmallcell lung cancer (NSCLC). The prognoses of patients with metastatic lymph nodes are expected to be poor, especially in those with N2 disease [1–3]. Owing to the relatively high frequency of distant failure after surgical resection of NSCLC with nodal metastasis, it has been generally accepted that nodal metastasis would be an indicator of systemic metastasis. The most widely accepted treatment strategy for N2 disease is the pathologic confirmation of mediastinal nodal metastasis by mediastinoscopy or other modality and the subsequent initiation of multimodality treatment, including neoadjuvant chemotherapy followed by surgery or chemoradiation [4]. However, N2 disease is a mixture of heterogeneous stages of NSCLC. Although it is classified as stage IIIA by American Joint Committee on Cancer (AJCC) staging, N2 disease ranges from single nodal involvement with occult metastasis to bulky multiple-station mediastinal metastasis.
It has been reported that the prognosis of N2 disease varies according to the extent of lymph node involvement, from good prognosis in single-skip metastasis to poor prognosis in bulky N2 disease [2, 4]. However, most of the studies reporting multimodality treatment did not differentiate between the types of N2 disease based on the extent of lymph node involvement [5–7]. In this study, we hypothesized that nodal metastasis in NSCLC represents a continuum of disease extent of NSCLC; therefore, in the early N2 stages, N2 disease (mainly occult N2 disease) would share a prognostic feature similar to that of N1 disease. The aim of this study was to identify the common prognostic factors in N1 and early N2 nodal disease in surgically resected NSCLC.
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Material and Methods
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Patients who underwent curative resection because of NSCLC were enrolled in this study. The inclusion criteria for this study were the patients (1) who underwent curative resection, including lobectomy, bilobectomy, or pnuemonectomy; (2) in whom complete mediastinal lymphadenectomy was performed; (3) with pathologically confirmed N1 or N2 nodal metastasis; (4) who did not receive neoadjuvant chemotherapy; and (5) with pathologic T1, T2, or T3 lesions. From February 2000 to September 2006, 280 patients who met the inclusion criteria were enrolled in the study. There were 132 patients with N1 nodal metastasis (N1 group) and 148 patients with N2 nodal metastasis (N2 group). This study was approved by the Institutional Review Board of our hospital, and patient consent was waived.
Preoperative staging was performed by chest computed tomography (CT), bronchoscopy, bone scan, integrated positron emission tomography (PET)–CT scan, and mediastinoscopy. Since 2004, PET-CT scan has been performed as a part of routine staging evaluation in our institute; before that, it was only performed for selected patients. Mediastinoscopy was performed only for selected patients with suspected N2 disease, advanced primary lesions, and significant comorbidity. Clinical N2 was defined as a lymph node with a short diameter of more than 1 cm on chest CT or maximum standardized uptake value more than 2.5 on PET-CT. Routine mediastinoscopy was not performed for patients with clinical N0 and N1 disease. A small portion of patients with clinical N2 disease received primary surgery without pathologic evaluation of the mediastinal lymph node owing to old age, obstructive pneumonitis, or the patient's need.
Surgery was performed through standard thoracotomy. Anatomical resections were performed in all patients. Complete lymphadenectomy was performed in all patients. All mediastinal stations were numbered separately by the surgeons according to the American Joint Committee on Cancer classification. However, lymph node number 13 (segmental) was not numbered separately from lymph node number 12 (lobar). The lobar lymph node in another lobe was counted as a separate station from the lobar lymph node in the lobe in which the primary tumor was located.
The patient follow-up examinations were performed by surgeons or a medical oncologist. The patients were evaluated every 3 months by chest radiograph, and chest CT scans were obtained every 6 months for the first 2 years after surgery and annually thereafter. Sputum cytology and bronchoscopy were performed for selected patients during the follow-up period. The median follow-up period was 26 months (range, 1 to 90).
Statistical Analysis
All statistical analyses were performed using SPSS statistical software (version 11.0, SPSS, Chicago, Illinois). Continuous variables are expressed as the mean ± SD. Discrete variables were described as a number of ratios. Comparisons of continuous variables between groups were made using the independent t test. Pearson's 
2 test or Fisher's exact test were used for comparisons among discrete variables. Survival rates were calculated according to the Kaplan-Meier method, and the differences between subgroups were compared using the log-rank test. Univariate analysis for the prognostic factors of survival was performed using the log-rank test. Multivariate analysis of the prognostic factors was performed using Cox's proportional hazard model. A statistically significant difference was defined as a p value of less than 0.05.
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Results
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The study group included 280 patients, and there were 132 patients with N1 disease and 148 patients with N2 disease. During the study period, 135 patients with clinical N2 disease were treated with neoadjuvant chemotherapy followed by surgical resection in our hospital; however, those patients were not included in this study. The pathologic N2 patients who were treated by primary surgical resection and included in this study constituted 52.3% of the entire population of N2 patients who underwent surgical resection in our hospital. Of the 148 patients with pathologic N2 disease, 109 patients had occult N2 disease, which was not detected in the preoperative staging evaluation. Thirty-nine patients had clinical N2 disease; 21 of them were confirmed as having pathologic N2 disease by thoracotomy after negative mediastinoscopy, and 18 of them underwent primary resectional surgery without mediastinoscopy.
The median age of the patients was 61 years (range, 29 to 85). There were 206 men (74%) and 74 women (26%). Lobectomy was performed in 194 patients (69%), bilobectomy in 43 (15%), and pneumonectomy in 43 (15%). Complete resection was possible in 273 patients (98%), and operative mortality occurred in 5 patients (2%). Adjuvant chemotherapy and radiotherapy were administered to 103 patients (37%) and 89 patients (32%), respectively. During the follow-up period, recurrence occurred in 118 patients (42%), and late death occurred in 103 patients (37%). The locations of metastatic lymph node stations are listed in Figure 1.
The comparison of the clinical features between the N1 and N2 groups is presented in Table 1. There were more females and more adenocarcinoma patients in the N2 group. Clinical N2 constituted 14% of the N1 group and 23% of the N2 group. The number of metastatic lymph nodes and stations was higher in the N2 group than in the N1 group (p < 0.001). Adjuvant radiation was more frequently administered in the N2 group than in the N1 group (p < 0.001). However, there was no difference in age, type of operation performed, and the number of dissected lymph nodes between the two groups.
The 5-year overall survival rate was 53% in all patients: 63% in the N1 group, and 44% in the N2 group (Fig 2;
p = 0.007). In the univariate analysis, age, clinical nodal stage (cN), cell type, pathologic nodal stage (pN), the number of positive lymph nodes, the number of positive stations, and adjuvant chemotherapy were significant prognostic factors for overall survival. In the multivariate analysis, age and the number of positive stations were significant prognostic factors for overall survival (Table 2). The 5-year disease-free survival rates were 43% in all patients: 55% in the N1 group and 32% in the N2 group. In the univariate analysis, clinical nodal stage, cell type, pathologic nodal stage, the number of metastatic lymph nodes, and the number of metastatic nodal stations were significant prognostic factors for disease-free survival. In the multivariate analysis, clinical nodal stage, cell type, primary tumor size, and the number of metastatic nodal stations were significant prognostic factors for disease-free survival (Table 3). Pathologic nodal stage (N1 or N2) was not a significant prognostic factor for overall or disease-free survival in the multivariate analysis.
To compare the patterns of lymph node metastasis and survival between the N1 and N2 groups, both groups were subdivided according to the number of stations of nodal metastasis. Most of the patients in the N1 group had single-station metastasis (85%); however, only 27% of the patients in the N2 group had single-station metastasis. Of the patients in the N2 group, 41% showed multiple-station metastasis with involvement of more than 3 stations (Fig 3). Overall and disease-free survivals were compared according to the number of metastatic stations. There was no difference in overall and disease-free survival between the N1 and N2 groups according to the number of metastatic stations (Fig 4).
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Fig 3. Number of metastatic nodal stations in patients with N1 disease (black bars) and N2 disease (gray bars).
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Fig 4. Comparison of patients with N1 disease (solid line) and N2 disease (dotted line) according to the multiplicity of metastatic nodal stations.
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Comment
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Lymph node metastasis is the most important prognostic factor in resectable NSCLC patients, and the treatment strategy for patients with resectable NSCLC is usually determined by mediastinal nodal involvement. Current standard treatments in NSCLC are surgical resection followed by adjuvant chemotherapy in N1 disease and multimodality treatment, including neoadjuvant chemotherapy followed by surgery or chemoradiation in N2 disease [4, 8]. Therefore, the importance of precise evaluation of mediastinal nodal status has been emphasized for the determination of treatment strategy in patients with suspected nodal metastasis.
However, although numerous studies have focused on the prethoracotomy evaluation of mediastinal nodal metastasis, other features of nodal metastasis, including the concomitant involvement of the N1 lymph node or the extent of mediastinal involvement, have not been considered to be important factors for determining the treatment. In many prospective studies of NSCLC with N2 disease, the presence of mediastinal nodal involvement was the only criteria for inclusion in multimodality treatment. However, the distinction between N1 and N2 disease is just an imaginary classification. Therefore, N1 and N2 disease can share similar prognostic features. Okada and colleagues [9] reported their analysis of survival according to the location of metastasis in N1 and N2 disease. In their study, the survival rates of patients with interlobar N1, hilar N1, lower mediastinal N2, and upper mediastinal N2 were 71%, 60%, 38%, and 24%, respectively. This study showed that nodal metastasis might be a spectrum of the disease. There are also several reports that the survival of patients with hilar nodal metastasis was equal to that of patients with single N2 disease [10, 11]. According to those studies, it seems likely that N1 and N2 diseases are spectrums of the same disease progression rather than distinctly different stages of diseases. The purpose of this study was to identify common prognostic factors that can be used to predict survival in both N1 and N2 NSCLC.
In this study, the common prognostic factor for overall and disease-free survival in both N1 and N2 NSCLC was the number of metastatic nodal stations. Other factors, such as clinical nodal stage, pathologic nodal stage, cell type, and the number of positive lymph nodes, were prognostic factors for overall survival in the univariate analysis; however, those factors were not significant in the multivariate analysis. The significance of multiplicity of metastatic nodal stations has been reported as an important risk factor in both N1 and N2 disease in previous studies. In patients with N1 disease, multiple-station N1 has been known to be a significant risk factor for overall and recurrence-free survival. Fujimoto and colleagues [12] reported that multiple-station N1 was a significant risk factor for distant recurrence after surgical resection. According to their study, the recurrence-free survival rates were significantly affected by the number of metastatic nodes, and the rates of single-station N1 disease and multiple-station N1 disease were 69% and 48%, respectively. Osaki and colleagues [13] also reported that the 5-year overall survival in single-node N1 metastasis was 61%, while that of multiple-node N1 metastasis was just 29%.
Other studies concerning N1 disease have emphasized the location of metastatic nodes. Hilar nodal involvement was shown to be a poor prognostic factor in those studies. However, the location itself is also an indication of multiple-node metastases. A study performed by Sawyer and colleagues [14] showed that hilar nodal metastasis was a poor prognostic factor; however, hilar metastasis was associated with multiple-station metastasis in most of the patients (74.7%), suggesting a high probability of multiple-station N1 metastasis in patients with hilar nodal involvement.
In N2 disease, studies concerning the multiple-node metastasis have also been reported, and patients with single nodal involvement in N2 disease has been considered to be a subgroup with a favorable prognosis. Ichinose and colleagues [15] reported that the 5-year survival rate of patients with single N2 station involvement was 47%, while that of multiple N2 station involvement was 17%. Sawabata and colleagues[16]reported that N2 station multiplicity was also significant a risk factor after neoadjuvant chemotherapy. However, the prognostic significance of multiple-station N2 disease was not revealed in other studies. Several studies reported that there were no statistically significant differences between single-station and multiple-station N2 disease [17, 18]. However, even though it was not statistically significant, single-station N2 disease did show a trend toward better survival than multiple-station N2 disease. Therefore, it is generally accepted that multiplicity is an important prognostic factor in N2 disease, and the newly revised AJCC staging systems are trying to modify the N category according to the multiplicity of nodal involvement [19].
The most striking finding in this study is that the location of metastatic nodes (N1 or N2) was a significant risk factor only in the univariate analysis, but not in multivariate analysis. On the other hand, multiplicity of nodal involvement was a common risk factor in both N1 and N2 disease in the multivariate analysis. We believe that there can be several explanations for these results. The first is the heterogeneity of N2 disease. As previously mentioned, most of the patients with N2 disease in this study could be regarded as being in the early stages of the N2 disease. According to the classification system of Ruckdeschel [20], most patients with N2 disease have stage IIIA1 or IIIA2 disease. A small proportion of patients (12%) with clinical N2 (stage IIIA3) were included in this study; however, no patients with bulky N2 disease (stage IIIA4) were included. Therefore, the clinical and prognostic feature of the patients with N2 disease in this study could be similar to that of patients with N1 disease rather than bulky N2 disease. Similar results were reported by the study of Andre and colleagues [21] who performed a combined analysis of multiplicity and occult metastasis. They reported that the 5-year survival rates in occult single-station N2, occult multiple-station N2, clinical single-station N2 and clinical multiple-station N2 were 34%, 11%, 8% and 3%, respectively.
The prognosis of the patients in the N2 group in this study was favorable compared with that of patients in other studies reporting primary resection of N2 disease [22, 23]. We believe that the effect of patient selection was the most important factor contributing to the improved survival. As previously mentioned, most of the patients with pathologic N2 included in this study could not represent all of the patients with N2 disease because most of the patients in this study had occult N2 disease. Those patients have the most favorable prognosis of all patients with pathologic N2 NSCLC. Other factors that could have affected the overall survival were the relatively low rate of surgical mortality, moderate rate of pneumonectomy and high rate of complete resection. All of the factors mentioned are known to be significant prognostic factors of survival after surgical resection of N2 NSCLC.
In this study, we did not perform routine mediastinoscopy in clinical N0 or N1 patients. Mediastinoscopy was performed only in patients with suspicious mediastinal nodal involvement on chest CT or PET-CT scan. The evaluation of mediastinal nodal involvement was performed by chest CT scan in most of the earlier cases, and routine PET-CT scan was used in the more recent cases in this study. The indication of mediastinoscopy in patients with occult N2 metastasis is still controversial. Recent improvements in the use of PET-CT scan for the detection of mediastinal nodal metastasis have made the routine use of mediastinoscopy in the early stages of clinical NSCLC questionable. Lee and colleagues [24] investigated the prevalence of mediastinal nodal metastasis in clinical stage I NSCLC after CT and PET scans and found that only 11 of 224 cases were detected by mediastinoscopy. The incidences of occult N2 metastasis were 6.5% in T1N0 and 8.7% in T2N0. Furthermore, the prognosis of occult N2 metastasis has been known to be better than that of patients with clinical N2 disease after surgical resection [21]. The role of mediastinoscopy and the evidence of a survival benefit of neoadjuvant treatment in this subset of patients had not yet been established. Therefore, routine mediastinoscopy in the clinically early stages of lung cancer was not performed in our institute traditionally; therefore, a relatively high incidence of primary resection in pathologic N2 patients was inevitable. However, in our institute, most of the clinical N2 patients received neoadjuvant chemotherapy, and the results were reported previously [25].
Multiple-station metastasis was the most important risk factor in both N1 and N2 disease in this study. However, current staging work-ups mainly focus on the presence or absence of mediastinal metastasis. Prethoracotomy pathologic evaluation of the multiplicity of lymph node metastasis is not possible with the current staging work-up system, especially in multiple N1 metastases. Therefore, we believe that the evaluation of the presence or absence of mediastinal metastasis is still important because multiple-station involvement was identified in 73% of the pathologic N2 patients in this study.
There are several limitations to this study. The first limitation is the different proportion of cell type between the N1 and N2 groups. The higher incidence of adenocarcima in N2 group might represent the early metastatic property of adenocarcinoma, however; other unrecognized patient selection strategies might influence the final results. The second limitation is the relatively short follow-up period. We think that further studies with longer follow-up periods will be necessary.
In this study, the patients with N2 disease showed a poorer prognosis than patients with N1 disease. However, there was a higher possibility of multiple node involvement in N2 disease than in N1 disease, and multiple node involvement was a significant risk factor in the multivariate analysis. Considering that the optimal treatment strategy for patients with NSCLC has been determined on the basis of N2 lymph node metastasis, future studies concerning multiple-node metastases are necessary for the proper selection of treatment modalities in patients with resectable NSCLC.
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Abstract
Introduction
