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Ann Thorac Surg 2006;81:1028-1032
© 2006 The Society of Thoracic Surgeons

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Original article: General thoracic

Selective Mediastinal Lymphadenectomy for Clinico-Surgical Stage I Non–Small Cell Lung Cancer

Department of Thoracic Surgery, Hyogo Medical Center for Adults, Akashi City, Hyogo, Japan

Accepted for publication September 30, 2005.

^_* Address correspondence to Dr Okada, Department of Thoracic Surgery, Hyogo Medical Center for Adults, Kitaohji-cho, 13-70, Akashi City 673-8558, Hyogo, Japan (Email: morihito1217jp{at}aol.com).

	Abstract

Top Abstract Introduction Patients and Methods Results Comment References

 
BACKGROUND: Improved radiologic imaging provides earlier detection of non–small cell lung cancer, but controversy exists regarding the need for complete lymph node dissection. This study was designed to evaluate the possibility of lesser mediastinal dissection for early-stage lung cancer.

METHODS: Selective mediastinal dissection is defined as follows: Dissection of the upper mediastinum for upper-lobe tumors is performed but it is not needed for lower-lobe tumors with intact hilar and lower mediastinal nodes. Also, dissection of the lower mediastinum for an upper-lobe tumor is not routinely required when the nodes in the hilum and upper mediastinum are negative. From 1997 through 2002, 377 patients with clinico-surgical stage I non–small cell lung cancer underwent curative-intent surgery with selective dissection (group S). In addition, 358 patients with the same-stage disease who underwent complete lymphadenectomy by the same surgical team served as historic controls (group C).

RESULTS: The characteristics of the two groups were well balanced. There was no significant difference in disease-free survival (p = 0.376) or overall survival (p = 0.060). Multivariate analysis showed that the dissection mode did not significantly influence either disease-free survival (p = 0.636) or overall survival (p = 0.119). The postoperative morbidity rates were 17.3% and 10.1% for group C and group S, respectively (p = 0.005). One operative death occurred in each group (0.3%). The rates of distant metastasis and local recurrence were similar in the two groups.

CONCLUSIONS: Selective mediastinal dissection for clinico-surgical stage I non–small cell lung cancer proved to be as effective as complete dissection, and although large multicenter trials are warranted, it might be considered as an alternative for curative surgery in this era of minimally invasive surgery.

	Introduction

Top Abstract Introduction Patients and Methods Results Comment References

 
Up to the present, there has been no consensus among thoracic surgical oncologists regarding the optimal dissection of mediastinal lymph nodes for patients with early-stage non–small cell lung carcinoma (NSCLC). There have been two contrasting opinions concerning its significance. On the one hand, it has been traditionally advocated that lymphadenectomy is important for survival as well as for staging. On the other hand, lymphadenectomy has been considered to be only useful for staging with no influence on the prognosis because cancer is a systemic disease even at its origin. Current surgical practice varies from mere visual inspection of the unopened mediastinum to radical lymphadenectomy. Although for an accurate staging of NSCLC it is necessary to examine the mediastinal lymph nodes, the extent of their removal has been a matter of debate. Whereas lymphadenectomy may contribute to prolong the time to recurrence and survival, the operative time, blood loss, and the frequency of recurrent laryngeal nerve injury, chylothorax, and bronchopleural fistula are increased.

As a result of the development of radiographic tools such as high-resolution computed tomography, the frequency of detection of early-stage lung cancer has been dramatically increasing. If the use of low-dose helical computed tomography to screen patients for the presence of lung cancer becomes a more widespread practice, we will probably encounter an escalating number of very early cancers with indolent biologic behavior in the near future and find ourselves in a tremendous dilemma regarding the extent of nodal dissection as well as of lung tissue removal. Thus, it is important to develop a more reasonable approach for dissecting mediastinal lymph nodes.

In 1997, we reviewed the clinical records of patients with completely resected NSCLC to assess the features and patterns of mediastinal spread of the tumor cells to lymph nodes, and reported the validation and the utility of selective mediastinal lymph node dissection [1]. Then, we initiated a prospective cohort study of this type of dissection in patients with clinical and surgical stage I disease. We thus sought to evaluate selective mediastinal dissection from the viewpoint of postoperative prognosis to open the gate for large trials.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Comment References

 
Selective dissection of mediastinal lymph nodes refers to the dissection of the upper mediastinum including aortic regions, performed regardless of the operative appearance when the tumor is located in the upper lobe, but not when it is located in the lower lobe and the hilar and lower mediastinal nodes are negative. Besides, dissection of the lower mediastinum in patients with an upper-lobe tumor is not needed when the nodes in both the hilum and upper mediastinum are intact. During the operation, dissected lymph nodes were aggressively sent to the pathologist for rapid examination of frozen sections.

Patients
Between January 1997 and December 2002, 463 consecutive patients with clinical stage I NSCLC except in the middle lobe, were enrolled into this study. Among them, 377 patients underwent curative-intent surgery with selective dissection of mediastinal lymph nodes. Twenty-six patients were excluded from the study during the operation because of pleural dissemination including positive pleural lavage cytology. The remaining 60 patients, 35 with surgical N1 disease and 25 with surgical N2 disease, underwent complete mediastinal dissection and therefore were excluded. Three hundred fifty-eight patients with clinical and surgical stage I NSCLC were identified as historic controls; these patients had been subjected to curative resection of the tumor and complete dissection of the mediastinum consecutively performed by the same surgical team from January 1985 through December 1996.

Informed consent was obtained from the patients or surrogates. Patients were excluded if they were assigned to chemoradiotherapy, mediastinoscopy was performed to assess nodal status, or they did not meet the definition of stage I disease [2]. Moreover, patients who exhibited residual tumor at the resection margin or had evidence of malignant effusion were excluded. The patients who were excluded from the study were equally allocated to the two groups. Resected specimens were examined histopathologically, and histologic typing was done according to the World Health Organization classification. Local recurrence was defined as any recurrence within the ipsilateral chest cavity, and all other recurrences were classified as distant metastases. Recurrence was evaluated on the basis of clinical findings or images at the follow-up visit, which took place every 3 months. Second primary tumors were excluded from the analysis of recurrence [3]. Operative mortality included all deaths occurring within 30 days after resection.

Grouping of Lymph Node Sites
The sites of N2 lymph nodes were grouped as follows: upper mediastinal (1, highest mediastinal nodes; 2, paratracheal nodes; 3, pretracheal nodes; and 4, tracheobronchial angle nodes), aortic (5, Botallo's nodes; and 6, ascending aortic nodes), and lower mediastinal (7, subcarinal nodes; 8, paraesophageal nodes; and 9, pulmonary ligament nodes) lymph nodes, and N1 comprised hilar (10, main bronchus nodes; 11, interlobar nodes; and 12, lobar nodes) and intrapulmonary (13, segmental nodes; and 14, subsegmental nodes) lymph nodes. Mediastinal metastases were considered as so-called skipping ones if any of the N2 nodes, but no N1 nodes, were involved. Basically, three stations (numbers 10, 11, and 12) of N1 lymph nodes and one station of N2 nodes (number 4 for right upper-lobe tumors, number 5 for left upper-lobe tumors, number 7 for lower-lobe tumors) were examined by frozen section to select the type of dissection. Actually, however, the surgeons decided intraoperatively which stations were to be examined according to the surgical findings of each case.

Statistical Methods
Differences between the two groups were compared using Fisher's exact test for categorical data and Student's t test for continuous variables. Disease-free survival was defined as the time from surgery to first locoregional or distant recurrence. An observation was censored at last follow-up if the patient was alive or if the patient had died from a cause other than the original NSCLC. The overall survival was calculated from the date of surgery to every death. Distribution of disease-free survival and overall survival was estimated with the Kaplan-Meier method and compared using the log-rank test. Cox regression analysis was used to simultaneously determine the relationship between survival and one of the following factors with a potential prognostic value: sex, age, histologic type, size of the tumor, pathologic nodal status, and mode of the dissection.

	Results

Top Abstract Introduction Patients and Methods Results Comment References

 
The median follow-up time was 62 months (range, 28 to 98 months) for the selective dissection group (group S) and 111 months (range, 67 to 207 months) for the complete dissection group (group C). The characteristics of the groups, listed in Table 1, show that the baseline features were well balanced. In group S, 36 patients were diagnosed as having bronchioloalveolar carcinoma, in which the proportion of the bronchioloalveolar carcinoma component was more than 50%. The postoperative complications are shown in Table 2. The morbidity rates were 17.3% and 10.1% for group C and group S, respectively (p = 0.005). Dysrhythmia, such as atrial fibrillation, was the most common morbidity after either type of dissection. One operative death secondary to myocardial infarction or cardiogenic shock occurred in group C (0.3%), whereas one operative death owing to septic shock occurred in group S (0.3%).

Among the 21 patients with pN1 disease in group S, none had recurrence of mediastinal lymph nodes postoperatively. The recurrence patterns of the two groups are presented in Table 3. Although the difference in follow-up period should be duly considered, recurrence rates regarding distant metastases and local involvement, including mediastinal lymph nodes, were approximately equal in the two groups or a little lower in group S. Statistically, no significant differences were observed.

View larger version (23K): [in this window] [in a new window]   Fig 1. Disease-free (A) and overall (B) survival curves of all patients with clinical and surgical stage I disease, stratified by the type of mediastinal dissection.

View larger version (22K): [in this window] [in a new window]   Fig 2. Disease-free (A) and overall (B) survival curves of patients with clinical and surgical stage I disease except those with bronchioloalveolar carcinoma, stratified by the type of mediastinal dissection.

	Comment

Top Abstract Introduction Patients and Methods Results Comment References

Nowadays, early-stage lung cancer is being frequently detected, and thus thoracic surgeons wonder whether complete dissection of mediastinal lymph nodes is uniformly required in radical surgery for such lesions. Up to now, there have been two randomized studies published, and neither of them has shown any significant difference of outcome in patients subjected to complete lymphadenectomy when compared with those having undergone sampling [8, 9]. Izbicki and coworkers [8] reported in their randomized trial that complete dissection did not improve survival compared with sampling in patients with no nodal involvement, despite finding that complete dissection had led to better staging of lung cancer. The other randomized study performed by Sugi and colleagues [9] showed that survival of the sampling group was better than that of the dissection group (overall 5-year survival 84% versus 81%); the authors concluded that clinically evaluated lung cancer smaller than 2 cm in diameter did not require radical systematic mediastinal lymph node dissection. They also reported that the morbidity associated with complete dissection was significantly higher than that seen with sampling (23.8% versus 3.4%). Our serious concern regarding these studies is the considerably small number of evaluated cases.

In 1997 we analyzed the patterns of lymph node metastases, including skipping ones, in patients who underwent complete dissection for NSCLC and suggested the possibility of a rational and practical lesser mediastinal dissection, for which sampling and examination of a sufficient number of key lymph nodes were extremely important [1, 10]. In case of upper-lobe tumors, we decided lower mediastinal lymphadenectomy was not needed if the hilar and upper mediastinal nodes were found to be tumor-free, and in case of lower-lobe tumors, upper mediastinal lymphadenectomy was not considered necessary when the hilar and subcarinal nodes were found to be tumor-free. Exceptionally, when patients were suspected of having an advanced disease based on their intraoperative findings, such as extent of invasion, a complete lymphadenectomy was routinely performed. Since then, we have introduced such selective mediastinal dissection for clinical and surgical stage I NSCLC. This report describes the first large series representing all patients treated with selective dissection, and compares selective dissection with complete lymphadenectomy. Although this study is limited by factors inherent to all nonrandomized studies that compare data from historic controls operated on by the same team, such as a potential selection bias, it presents two characteristics reinforcing the meaning of its results: the comparison of the two groups of patients proved to be relatively homogeneous regarding the main clinical variables, and the high follow-up rate of treated patients strongly indicates that the patients studied are highly representative of clinical and surgical stage I NSCLC patients surgically treated at our institution. The consecutive nature of the two groups of patients reduces the extent of possible bias.

In our series, the 5-year disease-free survival rate of patients who underwent selective dissection was 76.4% and that of patients who underwent complete dissection was 73.4%. In addition, the 5-year overall survival rate of patients who underwent selective dissection was 83.2% while that of patients who underwent complete dissection was 79.7%. Even when patients diagnosed as having bronchioloalveolar carcinoma, whose number has been increasing with recent advances of radiologic imaging and who would have better prognosis, were excluded from the selective dissection group, there were no significant differences in survival between the two groups. These data demonstrated that selective dissection was not inferior to a complete one regarding prognosis. Although only 1 patient in each group (0.3% each) died during the perioperative period, the postoperative morbidity was significantly higher in the complete dissection group, suggesting that the extent of dissection influenced the frequency of complications. The complications can possibly arise from injury of the bronchial arteries and nerves, recurrent nerves, laryngeal nerves, and the thoracic duct and lymphatic backflow, resulting in ischemic tissue changes, pulmonary edema, and pneumonia as well as respiratory distress syndrome. These results were consistent with those of other studies [9] and suggested that removing healthy lymph nodes should be minimized. At present, we cannot draw definite conclusions about the advantage of selective dissection because of the nonrandomized nature of this study, the lack of a prospective control group, and the fact that more recently treated patients were more likely to have undergone selective dissection. The improved results may be related to improved surgical or postoperative care, improved staging techniques, or other unknown variables that may have led to improved patient outcome in this study. However, we can conclude that although these data may not show the superiority of selective dissection to a complete one, they at least show our approach is not inferior to complete lymphadenectomy.

The question of the extent of mediastinal dissection will become even more important in the future as many surgeons become interested in a minimally invasive surgery such as video-assisted thoracic surgery to treat patients with early-stage NSCLC. We have adopted this type of dissection in case of video-assisted thoracic surgery, during which complete mediastinal dissection is a complex procedure. Therefore, when following the minamally invasive approach, a simpler dissection technique is easier to apply, and recently its need is more keenly felt. However, the current practice of using selective mediastinal lymphadenectomy in curative surgery for clinico-surgical stage I NSCLC should be reevaluated through randomized multicenter trials.

	References

Top Abstract Introduction Patients and Methods Results Comment References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Noriaki Tsubota Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Okada, M. Articles by Tsubota, N. Search for Related Content PubMed PubMed Citation Articles by Okada, M. Articles by Tsubota, N. Related Collections Lung - cancer