Treatment Strategy for Patients With Surgically Discovered N2 Stage IIIA Non-Small Cell Lung Cancer

Treatment Strategy for Patients With Surgically Discovered N2 Stage IIIA Non-Small Cell Lung Cancer Ryoichi Nakanishi, MD, Toshihiro Osaki, MD, Kozo Nakanishi, MD, Ichiro Yoshino, MD, Takashi Yoshimatsu, MD, Hideyuki Watanabe, MD, Hajime Nakata, MD, and Kosei Yasumoto, MD Second Department of Surgery, and Department of Radiology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan Background. The treatment strategy for patients with non-small cell lung cancer and clinically negative, but surgically detected mediastinal lymph node metastasis (surgically discovered N2 disease) is controversial. Methods. From August 1979 through December 1994, 53 patients with non-small cell lung cancer were found to have surgically discovered N2 disease. We retrospectively studied the clinical characteristics and the factors that influenced the prognosis in these patients. Results. The 3-year and 5-year survival rates and the median survival for the 53 patients with surgically discovered N2 disease were 44%, 21%, and 26 months. Two thirds of the patients had adenocarcinoma. Only complete resection affected long-term survival; adjuvant ther- apy had no effect on survival. In regard to lymph node status, a single metastatic focus in the aortic area was associated with long-term survival. Conclusions. Patients with adenocarcinoma may require histologic determination of N2 disease. Complete resection, including extensive and complete mediastinal lymph node dissection, is warranted in patients with surgically discovered N2 disease. In particular, when the aortic lymph node (including stations 5 and 6) alone is involved, the patients should undergo as complete a resection as possible. (Ann Thorac Surg 1997;64:342-8) 1997 by The Society of Thoracic Surgeons M etastases to mediastinal lymph nodes (N2 disease) are present in nearly one half of all patients with non-srnau cell lung cancer. Most physicians consider this an incurable disease. Recently, there have been reports [1, 2] of improved survival with induction treatment followed by surgical intervention in patients with clinical N2 disease (positive mediastinoscopy or bulky lymph node enlargement on radiographic examination). Operation alone is associated with poor survival in these patients [1, 2]. On the other hand, many patients with a clinically normal mediastinum are found to have N2 disease at pathologic examination. The prognoses for these patients are better than those for patients with clinical N2 disease [3] but are still unsatisfactory [4]. There is no established treatment strategy for surgically discovered N2 disease. In this study, we defined the clinical characteristics of patients with surgically discovered N2 disease by comparing them with patients with clinical N2 disease and retrospectively studied the factors that influenced survival in patients with N2 disease at pathologic examination. We suggest a treatment strategy for these patients. Accepted for publication Feb 6, 1997. Address reprint requests to Dr Ryoichi Nakanishi, Second Department of Surgery, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 87, Japan. Material and Methods From August 1979 through December 1994, 88 patients with non-small cell lung cancer were found to have metastases to ipsilateral mediastinal lymph nodes (N2 disease). There were 64 men and 24 women with N2 stage IIIA disease. The median age was 63 years and the age range, 33 to 86 years. Twelve patients (13.6%) were less than 5 years old; 16 (18.2%) were aged 5 through 59 years; 32 (36.4%) were aged 6 through 69 years; 26 (29.5%) were aged 7 through 79 years; and 2 (2.3%) were 8 years old or older. The tumor was on the right in 62 patients (7.5%) and on the left in 26 (29.5%). The right upper lobe was involved in 31 patients (35.2%), the right middle lobe in 4 (4.5%), the right lower lobe in 27 (3.7%), the left upper lobe in 16 (18.2%), and the left lower lobe in 1 (11.4%). The tumor was an adenocarcinoma in 48 patients (54.5%), a squamous cell carcinoma in 27 (3.7%), a large cell carcinoma in 1 (11.4%), an adenosquamous carcinoma in 2 (2.3%), and a carcinoid in 1 (1.1%). After pathologic evaluation, 25 patients (28.4%) were found to have T1 lesions, 44 (5.%) to have T2 lesions, and 19 (21.6%) to have T3 lesions. Extensive direct invasion to the mediastinum (T4 disease) was excluded in this series. Mediastinoscopy was performed in 32 patients. The indications for mediastinoscopy included enlarged mediastinal lymph nodes on a chest roentgenogram or computed tomogram and a central neoplasm. The results 1997 by The Society of Thoracic Surgeons 3-4975/97/$17. Published by Elsevier Science Inc PII S3-4975(97)535-3

Ann Thorac Surg NAKANISHI ET AL 343 1997;64:342-8 SURGICALLY DISCOVERED N2 STAGE IIIA NSCLC were positive in 11 patients (34.4%) and negative in 21. Many of the patients with negative results had inaccessible metastatic lymph nodes. Pneumonectomy was performed in 18 patients (2.5%), bilobectomy in 14 (15.9%), lobectomy in 53 (6.2%), sleeve pneumonectomy in 1 (1.1%), and sleeve lobectomy in 2 (2.3%). The mediastinal pleura was opened in every patient, and all accessible nodes in the superior and inferior mediastinum, as well as in the aortopulmonary window for left-sided lesions, were removed. A complete resection, defined as cancerfree surgical margins, was performed in 72 patients (81.8%). Each of the remaining 16 patients underwent an incomplete resection. As adjuvant therapy, 49 patients (55.7%) received chemotherapy; 23 (26.1%), radiation therapy; and 14 (15.9%), both. None of the patients in the study received induction or neoadjuvant therapy. There were two operative deaths (mortality rate, 2.3%). One patient died of an acute myocardial infarction, and the other died of respiratory failure after the development of a bronchopleural fistula. Both patients had a clinically normal mediastinum. Thirty-four patients (39.%) are alive at the time of writing. Of the others, 38 (7.4%) died of recurrent lung cancer, 1 (18.5%) died of other causes, and 4 (7.4%) died of unknown causes. Forty-six patients (52.3%) had recurrence. It was initially local in 15 patients (32.6%) and distant in 31 (67.4%). The overall 3-year and 5-year survival rates and the median survival for the 88 patients were 39%, 23%, and 24 months, respectively. The medical record of each patient was examined for patient's age and sex, location of the primary tumor, histologic type, tumor stage, lymph node status, surgical procedure, and whether or not complete resection, adjuvant chemotherapy, or adjuvant irradiation was performed. Comparisons between patients with surgically discovered N2 disease and those with clinical N2 disease were made using clinical variables, prognosis, and metastatic lymph node status, including size, location, and involved station number, to clarify the characteristics of surgically discovered disease. The factors that influenced survival in patients with surgically discovered N2 disease were then examined. Clinical N2 disease was identified on computed tomography as nodes with a short-axis diameter of more than 1 mm [5]. Mediastinal lymph nodes were labeled to 11 stations according to their location and submitted for histologic study [6]. Mediastinal lymph node metastases were grouped into four locations for comparison: (1) superior mediastinal lymph nodes, which included the highest mediastinal (station 1), paratracheal (station 2), pretracheal (station 3), posterior mediastinal (station 3p), anterior mediastinal (station 3a), and tracheobronchial (station 4) nodes; (2) aortic lymph nodes, which included the subaortic (station 5) and para-aortic (station 6) nodes; (3) inferior mediastinal lymph nodes, which included the subcarinal (station 7), paraesophageal (station 8), and pulmonary ligament (station 9) nodes; and (4) extended lymph nodes, which included lymph nodes in two or more locations. All patients were staged postsurgically according to the international system for staging lung cancer [7]. Operative mortality was defined as deaths occurring within the first 3 days after operation. The )(2 test, Fisher's exact test, or Student's t test was used to compare several clinical variables between patients with a clinically negative mediastinum and patients with a clinically positive mediastinum. Survival was estimated by the Kaplan-Meier method, using the date of pulmonary resection as the starting point and the date of death or last follow-up as the end point [8]. The significance of differences in survival was computed by the log-rank test [9]. The influence of variables on survival was analyzed using the Cox proportional hazards model for continuous variables and for multivariate analyses [1]. Statistical analysis was performed using the SAS software package (SAS Institute, Cary, NC). A p value of less than.5 was considered significant. Results Of the 88 patients, 53 (6.2%) with a clinically negative mediastinum were found to have surgically discovered N2 disease. In contrast, clinical N2 disease was found in 35 patients (39.8%). Surgically discovered N2 disease had no characteristic findings in regard to age or sex, whereas clinical N2 disease often was seen in younger men (Table 1). There was no difference in the distribution of patients between the two N2 groups in regard to primary tumor location or pathologic T stage. In terms of histology, however, there were significantly more patients with adenocarcinoma with surgically discovered N2 disease than clinical N2 disease (see Table 1). Mediastinoscopy was performed in 15 patients with surgically discovered N2 disease. Eight (53.3%) of these 15 patients had inaccessible metastatic lymph nodes. Among the 53 patients with surgically discovered N2 disease, pneumonectomy was performed in 6 patients (11.3%), bilobectomy in 11 (2.8%), and lobectomy in 36 (67.9%). The proportion of patients with surgically discovered N2 disease who did not require pneumonectomy (88.7%) was significantly higher than in patients with clinical N2 disease. There was no difference in the number of dissected lymph nodes or the rate of surgical curability between the two N2 groups. The number of dissected lymph nodes averaged 24 in the patients with surgically discovered N2 disease. A complete resection was performed in 45 patients (84.9%) with surgically discovered N2 disease and 27 (77.1%) with clinical N2 disease. The remaining 8 patients with surgically discovered N2 disease had incomplete resections because cancer cells were left at the bronchial stump in 4 patients, in lymph nodes in 3, and in the chest wall in 1 patient. There were two operative deaths (mortality rate, 3.8%) among the patients with surgically discovered N2 disease. Twenty-three patients (43.%) are alive at the time of writing. Of the others, 2 (66.7%) died of recurrent lung cancer, 6 (2.%) died of other causes, and 2 (6.7%) died of unknown causes. Twenty-five (47.2%) of the 53 patients had recurrence. The recurrence was initially local in 7 patients (28.%) and distant in 18 (72.%). The overall 5-year survival rate for the 53 patients with surgically

344 NAKANISHI ET AL Ann Thorac Surg SURGICALLY DISCOVERED N2 STAGE IIIA NSCLC 1997;64:342-8 Table 1. Demographic Characteristics of Patients With Pathologic N2 Non-Small Cell Lung Cancer" Surgically Discovered N2 Clinical N2 Variable (n = 53) (n = 35) Probability Age (y) Range 33-86 41-75 NS Median 66 62 Sex p =.74 Male 33 31 Female 2 4 Primary site NS Right 37 (69.8) 25 (71.4) Upper 16 (43.2) 15 (6.) Middle 3 (8.1) 1 (4.) Lower 18 (48.6) 9 (36.) Left 16 (3.2) 1 (28.6) Upper 11 (68.8) 5 (5.) Lower 5 (31.3) 5 (5.) Histology Adenocarcinoma 35 (66.) 13 (37.1) p -.235 Squamous cell 14 (26.4) 13 (37.1) carcinoma Large cell 3 (5.7) 7 (2.) carcinoma Adenosquamous 1 (1.9) 1 (2.9) carcinoma Carcinoid () 1 (2.9) Pathologic T stage T1 18 (34.) 7 (2.) NS T2 27 (5.9) 17 (48.6) T3 8 (15.1) 11 (31.4) a Numbers in parentheses are percentages. NS = not significant. discovered N2 disease was 21.3% (Fig 1). On the other hand, 21 (6.%) of the 35 patients with clinical N2 disease had recurrences, which were initially local in 8 patients (38.1%) and distant in 13 (61.9%). The 3-year and 5-year survival rates and the median survival for clinical N2 disease were 31%, 25%, and 19 months, respectively. There was no difference in the pattern of recurrence or the overall 5-year survival between the two N2 groups, although clinical N2 disease showed a higher recurrence rate. The metastatic lymph node status of all 88 patients was investigated in detail. The short-axis diameter of lymph nodes in which metastases were pathologically documented were measured on computed tomograms obtained preoperatively. The appearance of the lymph nodes on the computed tomograms was also evaluated as follows: (1) round or flat in shape and (2) smooth or rough in margin. A retrospective study of metastatic lymph nodes was feasible in 45 patients with surgically discovered N2 disease and 29 with clinical N2 disease. The following computed tomographic scanners were used: SOMATOM 2 (Siemens Co, Ltd, Erlangen, Germany) from June 1981 to June 199; TCT 6A (Toshiba Co, Ltd, % survival 1 8 6 4-2- O" ' ' I 1 44% ~.~ 21% 2 3 4 5 Years after surgery Fig 1. Probability of survival (death from any cause) for the 53 patients with surgically discovered N2 disease. Zero time on abscissa represents date of pulmonary resection. Median survival for the group is 26 months. Tokyo, Japan) from June 199 to August 1991; and TCT 9S (Toshiba) from August 1991 to the present. The mean short-axis diameter of metastatic lymph nodes in surgically discovered N2 disease was significantly smaller than that in clinical N2 disease (7.24 _+ 2.4 mm versus 15.26 + 4.1 ram; p =.1). Almost all patients with surgically discovered N2 disease had flat and smooth nodes in contrast to round and rough nodes in patients with clinical N2 disease. The location of the metastatic lymph nodes did not differ between the N2 groups (Table 2). There also was no difference in the number of metastatic lymph node stations (Table 3). We evaluated the prognosis for the patients with surgically discovered N2 disease according to histologic type, pathologic T stage, and metastatic lymph node status. There was no difference in survival between patients with adenocarcinoma and patients with squamous cell carcinoma. The 3-year and 5-year survival rates and the median survival for each group were as follows: Table 2. Metastatic Lymph Node Location a'b Surgically Discovered N2 Clinical N2 Location Station No. (n = 53) (n = 35) Superior 1, 2, 3, 3a, 3p, 4 2 (37.7) 14 (4.) Aortic 5, 6 9 (17.) 4 (11.4) Inferior 7, 8, 9 14 (26.4) 11 (31.4) Extended (two 1-9 1 (18.9) 6 (17.1) or more locations) a Numbers in parentheses are percentages, cant differences between the two groups. b There were no signifi- I

Ann Thorac Surg NAKANISHI ET AL 345 1997;64:342-8 SURGICALLY DISCOVERED N2 STAGE IIIA NSCLC Table 3. Number of Metastatic Lymph Node Stations "b No. of Lymph Surgically Node Stations Discovered N2 Clinical N2 Involved (n = 53) (n = 35) One 28 (52.8) 14 (4.) Two 15 (28.3) 1 (28.6) Three 6 (11.3) 7 (2.) Four or more 4 (7.5) 4 (11.4)... -- Superior % survival ---.- Aortic I 8O l L-.rf I -.-Ir erior Numbers in parentheses are percentages, cant differences between the two groups. b There were no signifi- 6- Ili~ m limr~. adenocarcinoma (n = 35), 45%, 28%, and 26 months, respectively, and squamous cell carcinoma (n = 14), 49%, %, and 24 months. There also was no difference in survival among patients with T1, T2, or T3 stage tumors. The 3-year and 5-year survival rates and the median survival for each group were as follows: T1 (n = 18), 49%, 36%, and 36 months, respectively; T2 (n = 27), 44%, 16%, and 26 months; and T3 (n = 8) unknown, unknown, and 1 months. The prognosis for patients with surgically discovered N2 disease showed no difference in terms of superior, aortic, inferior, or extended mediastinal lymph node metastases. The 3-year and 5-year survival rates and the median survival for each group were as follows: superior (n = 2), 37 37%, and 24 months, respectively; aortic (n = 9), 63%, 32%, and 41 months; inferior (n = 14), 51%, %, and 37 months; and extended (n = 1), 37%, 37%, and 36 months. There was no difference between a single positive station and two or more positive stations. The 3-year and 5-year survival rates and the median survival for each group were as follows: one lymph node station involved (n = 28), 37%, 37%, and 24 months, respectively, and two or more stations (n = 25), 37%, 37%, and 36 months. However, among the 28 patients with a single metastatic station, patients with aortic lymph node metastases did significantly better than patients with inferior lymph node metastases. The 3-year and 5-year survival rates and the median survival for each group were as follows: superior (n = 11), 36%, 36%, and 24 months, respectively; aortic (n = 6), 8%, 8%, and unknown; and inferior (n = 11), 4%, %, and 26 months (Fig 2). With respect to treatment regimen, complete resection was associated with a significantly better survival rate than was incomplete resection. The 3-year and 5-year survival rates and the median survival rate for each group were as follows: complete resection, 51%, 21%, and 37 months, respectively, and incomplete resection, 13%, 13%, and 11 months (Fig 3). Thirty-one (58.5%) of the 53 patients with surgically discovered N2 disease received adjuvant chemotherapy, and 12 (22.6%) received radiation therapy. Many patients were given chemotherapy because a considerable number of patients with N2 disease die of distant metastases. A platinum agent (cisplatin or carboplatin) was used in 18 (58.1%) of the 31 patients. Mitomycin C played a central role in 6 patients seen early in the series. The remaining 7 patients received oral chemotherapy using UFT (combination of 4- L- 1 ' ' I ' ' I ' ' I ' ~ I ' ' I... 1 2 3 4 5 Years after surgery Fig 2. Probability of survival (death from any cause) for the 28 patients with one positive lymph node station and surgically discovered N2 disease grouped by metastatic lymph node locations. Zero time on abscissa represents date of pulmonary resection. The aortic group has significantly better survival than the inferior group (p =.391); there are no other significant differences among the groups. uracil and tegafur in a 4:1 molar concentration) or cyclophosphamide. We examined the association between adjuvant therapy and survival in the 45 patients who % survival 1-8O 6-4- m 2- alg~jwa~,~ Complete resection...- Incomplete resection L..._... ; ' I ; I ' ' I ' ' I ' ' I 1 2 3 4 5 Years after surgery Fig 3. Probability of survival (death from any cause) for the 45 patients with surgically discovered N2 disease undergoing complete resection compared with the 8 patients who underwent incomplete resection. Zero time on abscissa represents date of pulmonary resection. The complete resection group has significantly better survival than the incomplete resection group (p =.34).

346 NAKANISHI ET AL Ann Thorac Surg SURGICALLY DISCOVERED N2 STAGE [IIA NSCLC 1997;64:342-8 Table 4. Univariate Analysis of Various Prognostic Factors in Patients With Surgically Discovered N2 Stage IliA Non- Small Cell Lung Cancer 5-Year Survival No. of Rate Prognostic Factor Patients (%) Probability Age (y).3346 ~6 26 27.19 ->6 27 13.16 Sex.9725 Male 33 21.57 Female 2 18.97 Histology.3335 Adenocarcinoma 35 28.8 Others 18 Pathologic T stage.268 T1 18 36.43 T2 and T3 35 14.5 Metastatic Lymph Node.3838 Location Single 43 19.53 Extended (two or 1 36.57 more) No. of metastatic stations.577 One 28 22.36 Two or more 25 17.6 Surgical procedure.2987 Lobectomy 36 26.74 Bilobectomy or 17 pneumonectomy Curability.35 Complete resection 45 21.29 Incomplete resection 8 12.5 Chemotherapy.249 Received 31 27.76 Not received 22 Radiation therapy.2245 Received 12 11.11 Not received 41 26.74 underwent complete resection. We did not analyze the results for radiation therapy because only a few patients were involved. This therapy usually was given in combination with chemotherapy to patients with uncontrolled local tumors. There was no difference in survival among patients receiving adjuvant chemotherapy and patients receiving no further treatment. The overall 3-year and 5-year survival rates and the median survival were 66%, 47%, and 38 months, respectively, for the patients receiving chemotherapy and 55%, %, and 41 months for the patients receiving no treatment. The effect of several potential prognostic factors was analyzed by univariate and multivariate analyses using the Cox proportional hazards model (Tables 4, 5). After univariate analysis, the two prognostic factors sex and metastatic lymph node location were excluded from the multivariate analysis because of the improvement in statistical accuracy (see Table 5). Both univariate and multivariate analyses of various prognostic factors in the 53 patients with surgically discovered N2 disease revealed that surgical curability alone affected survival. Age, sex, histology, pathologic T stage, metastatic lymph node status, surgical procedure, and adjuvant chemotherapy or radiation therapy did not significantly affect survival (see Tables 4, 5). Incomplete resection appeared to increase the risk of death approximately threefold (see Table 5). Comment Generally, the prognosis for patients with a clinically negative mediastinum and pathologically diagnosed N2 disease is better than that for patients with clinically diagnosed N2 disease [4, 11]. The 5-year survival rate of patients with surgically discovered N2 disease ranges from 13.5% to 34% in contrast to 6.6% to 18% for those with clinical N2 disease [4, 11]. However, our results did not show any difference in pattern of recurrence or survival between surgically discovered N2 and clinical N2 disease. We also found no difference in surgical curability or metastatic lymph node status, such as locat-ion or station number, despite apparent differences in surgical procedure and metastatic lymph node size on computed tomography. The prognosis for patients with Table 5. Multivariate Analysis of Various Prognostic Factors in Patients With Surgically Discovered N2 Stage IliA Non- Small Cell Lung Cancer Risk 95% Confidence Prognostic Factor Probability Ratio Interval Age (y) <6 ->6.8859.942.416-2.135 Histology Adenocarcinoma Others.6871 1.32.483-3.58 Pathologic T stage T1 T2 and T3.339 1.393.579-3.347 No. of metastatic stations One Two or more.4436 1.228.81-1.88 Surgical procedure Lobectomy Bilobectomy or.6495 1.226.55-2.971 pneumonectomy Curability Complete resection Incomplete resection.21 2.856 1.179-6.915 Chemotherapy Received Not received.1179.54.249-1.169 Radiation therapy Received Not received.4464 1.296.456-3.683

Ann Thorac Surg NAKANISHI ET AL 347 1997;64:342-8 SURGICALLY DISCOVERED N2 STAGE IIIA NSCLC clinical N2 disease may show spurious improvement compared with other series because patients with symptomatic N2 or bulky N2 disease, which are considered nonresectable, were excluded from this series. Our results suggest that if clinical N2 disease is asymptomatic and resectable, there may be no difference in prognosis between clinical N2 disease and surgically discovered N2 disease. Recently, for symptomatic or nonresectable N2 disease, a new strategy of induction chemotherapy followed by surgical intervention has resulted from the need to improve the poor results with operation alone. This combined treatment strategy improves the median survival and 3-year survival rate for these patients to 18.6 to 19 months and 26% to 28%, respectively [1, 2]. We have also applied the same treatment for advanced N2 disease. Even patients with clinical N2 disease that is asymptomatic and resectable can receive this regimen. However, this strategy is not applicable to patients with surgically discovered N2 disease because the N2 disease is not found before thoracotomy. Most patients with surgically discovered N2 disease have no recourse but postoperative chemotherapy, radiation therapy, or both. The number of patients with surgically discovered N2 disease is still high, regardless of the recent development of diagnostic techniques [11]. New strategies are required for surgically discovered N2 disease to improve the prognosis for all patients with N2 disease. First, we looked at whether patients with surgically discovered N2 disease have some defining clinical characteristics. Two thirds of these patients had adenocarcinoma. There were no specific characteristics involving metastatic lymph node status. Adenocarcinoma is known to often have normal-sized lymph nodes with micrometastases [11]. Therefore, adenocarcinoma may require a histologic determination to make as accurate a diagnosis of mediastinal lymph node metastases (N staging) as possible. Accurate N staging subsequently decreases the number of patients with surgically discovered N2 disease and may lead to promising treatment, such as induction therapy plus operation. For this modality, histologic evidence of N2 disease is needed because the histopathologic diagnosis and staging after induction treatment are potentially false. Currently, the clinical determination of N staging in almost all institutions is based on computed tomographic findings and is assessed chiefly by the diameter of the nodes [4, 5, 11]. We assessed the radiologic morphology as well as the size of the lymph nodes in this series. We could not find characteristics consistently suggestive of metastases. A considerable number of patients still have false-positive and false-negative results after noninvasive staging [11]. The size criteria for metastatic adenopathy remain controversial. Another technique used in the evaluation of N staging in lung cancer is cervical mediastinoscopy. Mediastinoscopy can lead to a definitive tissue diagnosis of metastatic lymph node disease [12]. However, some nodes are inaccessible to cervical mediastinoscopy, such as the nodes of the subaortic, para-aortic, subcarinal, and para- esophageal stations and the nodes of the pulmonary ligament [13]. Approximately half of the patients in whom mediastinoscopy was performed had inaccessible metastatic lymph nodes in our series. The diagnosis of metastatic disease in these mediastinal nodes therefore requires other methods for histopathologic evaluation. Video-assisted thoracoscopy is the technique of choice with respect to accessibility and visualization [14]. This method can determine the presence of other lesions or ipsilateral lymph node metastases, which may influence operability. Thus, combined thoracoscopy and rnediastinoscopy after a basic computed tomographic scan potentially leads to a complete diagnosis of mediastinal lymph node metastases [15, 16]. However, it is controversial whether these approaches to N staging are applicable for all patients with non-small cell lung cancer. Our results in this series suggest that adenocarcinoma may be an indication, even if there is no evidence of mediastinal lymph node enlargement. Second, we retrospectively studied the factors that influenced prognosis in patients with surgically discovered N2 disease to establish the treatment strategy. We found that only a single metastatic station in the aortic area or a complete resection affected long-term survival in these patients. Patterson and colleagues [17] reported that patients with metastatic disease in subaortic lymph nodes alone have a comparatively good 5-year survival rate (42%) after complete resection. The subaortic nodes constitute an important pathway of lymph drainage for the upper lobe of the left lung and may be equivalent to hilar lymph nodes, unlike the other mediastinal lymph nodes. In contrast, Miller and associates [181 found no difference in 5-year survival between patients with positive nodes and patients with negative nodes in the aortic stations. The 5-year survival rate of the aortic nodepositive group was less than 3% in their series. However, this group included patients with other positive nodal stations. Moreover, early in the series, these authors did biopsies only of enlarged lymph nodes. The presence of multiple areas of positive mediastinal nodes and the low rates of resection of the lymph nodes may have caused the unfavorable results. As the average number of resected lymph nodes was 24 in our series, our data are highly reliable. Prospective research into the survival of patients with a single metastatic station in the aortic area is needed; we had only 6 such patients in our series. No new treatment strategy may be required for patients with a single metastatic station in the aortic area if the favorable survival results are confirmed in a larger series. Our results demonstrate that complete resection is warranted when N2 disease is unexpectedly detected by pathologic examination. This is in agreement with the observations of Martini and Flehinger [4] and Miller and co-workers [18]. Adjuvant therapy was not effective in our series. This result is similar to the observations of several other investigators [19, 2]. Postoperative chemotherapy has never been shown to increase the 5-year survival of patients with N2 disease [19]. Postoperative radiation therapy improves local tumor control, but its

348 NAKANISHI ET AL Ann Thorac Surg SURGICALLY DISCOVERED N2 STAGE IIIA NSCLC 1997;64:342-8 effect on survival remains unclear [2]. More effective chemotherapy is required for systemic control, as systemic recurrence is common in patients with unexpected N2 disease. Randomized trials of chemotherapy are currently under way. In conclusion, complete resection, including extensive and complete mediastinal lymph node dissection, is recommended when N2 disease is unexpectedly detected at the time of operation for non-small cell lung cancer. In particular, when the aortic lymph node alone is involved and other mediastinal nodes are negative, the patient should undergo as complete a resection as possible. As a preoperative strategy, the histologic determination for an accurate N staging should be performed in patients with adenocarcinoma. References 1. Martini N, Kris MG, Flehinger BJ, et al. Preoperative chemotherapy for stage IIIa (N2) lung cancer: the Sloan-Kettering experience with 136 patients. Ann Thorac Surg 1993;55: 1365-74. 2. Burkes RL, Ginsberg RJ, Shepherd FA, et al. Induction chemotherapy with mitomycin, vindesine, and cisplatin for stage III unresectable non-small-cell lung cancer: results of the Toronto phase II trial. J Clin Oncol 1992;1:58-6. 3. Martini N, Flehinger BJ, Zaman MB, Beattie EJ Jr. Results of resection in non-oat cell carcinoma of the lung with mediastinal lymph node metastases. Ann Surg 1983;198:386-97. 4. Martini N, Flehinger BJ. The role of surgery in N2 lung cancer. Surg Clin North Am 1987;67:137-49. 5. Aronchick JM. CT of mediastinal lymph nodes in patients with non-small cell lung carcinoma. Radiol Clin North Am 199;28:573-81. 6. Naruke T, Suemasu K, Ishikawa S. Lymph node mapping and curability at various levels of metastasis in resected lung cancer. J Thorac Cardiovasc Surg 1978;76:832-9. 7. Mountain CF. A new international staging system for lung cancer. Chest 1986;89 (Suppl):225S-33S. 8. Kaplan E, Meier P. Non-parametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457-81. 9. Peto R, Pike MC, Armitage P, et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. Br J Cancer 1976;34:585-612. 1. Cox DR. Regression models and life-tasks. J R Stat Soc [B] 1972;34:187-22. 11. Cybulsky IJ, Lanza LA, Ryan MB, Putnam JB Jr, McMurtrey MM, Roth JA. Prognostic significance of computed tomography in resected N2 lung cancer. Ann Thorac Surg 1992;54: 533-7. 12. Patterson GA, Ginsberg RJ, Poon PY, et al. A prospective evaluation of magnetic resonance imaging, computed tomography, and mediastinoscopy in the preoperative assessment of mediastinal node status in bronchogenic carcinoma. J Thorac Cardiovasc Surg 1987;94:679-84. 13. Ginsberg RJ. Evaluation of the mediastinum by invasive techniques. Surg Clin North Am 1987;67:125-35. 14. Landreneau RJ, Hazelrigg SR, Mack MJ, et al. Thoracoscopic mediastinal lymph node sampling. Useful for mediastinal lymph node stations inaccessible by cervical mediastinoscopy. J Thorac Cardiovasc Surg 1993;16:554-8. 15. Nakanishi R, Mitsudomi T, Osaki T, Yasumoto K. Combined thoracoscopy and mediastinoscopy for the evaluation of mediastinal lymph node metastasis in left upper lobe lung cancer. J Cardiovasc Surg (Torino) 1994;35:347-9. 16. Nakanishi R, Yasumoto K. Combined thoracoscopy and mediastinoscopy for mediastinal lymph node staging of lung cancer. Int Surg 1996;81:359-61. 17. Patterson GA, Piazza D, Pearson FG, et al. Significance of metastatic disease in subaortic lymph nodes. Ann Thorac Surg 1987;43:155-9. 18. Miller DL, McManus KG, Allen MS, et al. Results of surgical resection in patients with N2 non-small cell lung cancer. Ann Thorac Surg 1994;57:195-11. 19. Ohta M, Tsuchiya IK Shimoyama M, et al. Adjuvant chemotherapy for completely resected stage III non-small cell lung cancer. Results of a randomized prospective study. J Thorac Cardiovasc Surg 1993;16:73-9. 2. Lung Cancer Study Group. Effects of postoperative mediasfinal radiation on completely resected stage II and stage IIl epidermoid cancer of the lung. N Engl J Med 1986;315: 1377-81.