S promise of long-term survival for patients with nonsmall

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1 Aggressive Surgical ntervention in N Non-Small Cell Cancer of the Lung Yoh Watanabe, MD, Junzo Shimizu, MD, Makoto Oda, MD, Yoshinobu Hayashi, MD, Shinichiro Watanabe, MD, Yasuhiko Tatsuzawa, MD, Takashi wa, MD, Masayuki Suzuki, MD, and Tsutomu Takashima, MD Departments of Surgery and Radiology, Kanazawa University School of Medicine, Kanazawa, Japan An aggressive attitude toward surgical treatment was taken in patients with N non-small cell lung cancer in the past years. Computed tomographic scanning was employed in the diagnosis of N disease, and had a true-positive rate of 7%. Among patients with N disease detected by computed tomographic scanning, surgical intervention was attempted except for those with unresectable disease. Of patients with clinical N disease, underwent surgical exploration: patients had only an exploratory thoracotomy, patients underwent a curative operation, and had a noncurative operation. The overall -year survival rate of these patients was 6% and that of curatively resected patients was %. There were 7 patients whose N disease was not recognized before operation. The -year survival rate of this group was % overall and % in curatively resected cases. The overall -year survival rate of patients with N disease who underwent resection (6 with clinical N disease and 7 with clinically unrecognized N disease) was 7%, and that of the 8 patients undergoing curative operations was %. An aggressive attitude toward surgical intervention can be advocated for patients with N disease on the basis of our present results. (Ann Thorac Surg ;:-6) urgical treatment is the only method that holds the S promise of long-term survival for patients with nonsmall cell lung cancer, and the role of the surgeon is to select appropriate surgical candidates so as to ensure the greatest possible benefit to the individual cancer patients. There are differences of opinion regarding the indications for operation in patients with ipsilateral mediastinal lymph node metastasis (N disease) discovered at thoracotomy. Some authors insist that all patients having preoperatively detected N disease should not be operated on. Others say that surgical candidates who may have N disease should undergo mediastinoscopy and that those with histologically proven N disease should be excluded from thoracotomy [-6]. n contrast, there are some authors who believe that N disease does not contraindicate surgical resection [7-. Recently, Shields [lo] reported on the significance of N disease in non-small cell lung carcinoma. He collected and analyzed many papers on the results of treatment in patients with N disease and concluded that a small subset of patients with resectable N disease discovered at thoracotomy or mediastinoscopy should be considered as potential surgical candidates. Unfortunately, the survivors from this group of patients represent only % to 6% of all patients with N disease, so N disease must be considered to have a very poor prognosis. Accepted for publication Oct,. Address reprint requests to Dr Watanabe, Department of Surgery, Kanazawa University School of Medicine, - Takara-machi, Kanazawa, Japan. t has been our policy that all patients with marginally resectable N non-small cell lung carcinoma should be carefully evaluated with the possibility of surgical therapy in mind. As an operative procedure for N disease, extensive mediastinal lymph node dissection with some modification of the standard operation was done in the past years. As a result, aggressive resection has been performed in patients with N disease whenever it was thought to be feasible after the preoperative work-up. At our institution, the routine use of computed tomographic (CT) scanning in the preoperative evaluation of N disease was started in 8. This paper reports a clinical analysis of patients having N disease detected by preoperative CT scanning, by thoracotomy, or by postsurgical analysis of the resected specimens. Material and Methods Since 8, all admitted lung cancer patients were examined by chest CT scanning to evaluate their T and N factors. n addition, evaluation of metastases to the brain, bone, and abdominal organs was performed by CT scanning, radioisotope scanning, and ultrasonography. Lymphadenopathy was routinely investigated by CT scanning and mediastinal lymph nodes larger than mm along their short axis (except for subcarinal nodes) were defined as metastatic lymph nodes (N disease). For subcarinal lymph nodes, nodes larger than mm along their short axis were defined as metastatic nodes. Calcified lymph nodes were not defined as metastatic nodes, even if their sizes fulfilled the criteria for N disease. by The Society of Thoracic Surgeons -7//$.

2 WATANABE ET AL N NON-SMALL CELL LUNG CANCER Ann Thorac Surg ::-6 Table. Patients With Clinical N Disease and Their Postoperative Diagnoses Clinically N Curative Noncurative No (n = 78) Oueration Oueration Resection" Total Postoperatively NO (n = ) T- NO MO T NO MO T NO MO T NO M Postoperatively N (n = 6) T- N MO T N MO T N MO T N M Postoperatively N (n = ) T N MO T N MO T N MO T N MO T N M T N M T N M T N M Postoperatively N (n = ) T- N MO T N MO T N MO T N M T N M Total a Nine patients with exploratory thoracotomy without resection were included. Staging of patients not undergoing resection was performed clinically. From 8 to June, 7 patients with proven non-small cell lung cancer were admitted to the Department of Surgery at Kanazawa University School of Medicine. All patients underwent CT scanning for evaluation of the N factors and the other factors needed for staging of the disease. There were 78 patients who were clinically diagnosed as having N disease (cn) by preoperative CT scanning (Table ). Among the patients who were shown to have N disease by preoperative CT scanning, surgical intervention was attempted, except in the following cases: patients with distant metastases to extrathoracic organs; patients with unresectable T lesions, such as malignant pleural effusion, or extensive invasion of the great vessel, vertebral bodies, trachea, or carina; patients with bulky N disease; and patients regarded as unsuitable for other reasons. Among the 78 cn patients, were operated on and (7% of cn patients) underwent resection. Nine patients only had an exploratory thoracotomy because of the extensiveness of their disease. On pathological examination of the resected specimens, patients still had N disease (postsurgical histopathological N, pn), comprising 7% (/) of the N patients undergoing exploration. f N disease that was not detected by preoperative CT scanning was discovered at thoracotomy by examination of frozen section, resection still proceeded unless other unresectable disease existed. After operation, all of the dissected lymph nodes were sent for pathological examination [ll]. There were 7 patients whose preoperative diagnosis was NO or N, but who were verified to have N disease by intraoperative or postoperative pathology studies (Table ). A total of pn patients have been accumulated in the past years: 6 patients were cn patients and 7 were cno or cn patients. n addition, there were 8 cn patients in whom resection was not performed. Although N disease could not be verified by pathological examination in these unresected cases, they were defined as having actual N disease. The histology of these 6 N patients is shown in Table. Routine systematic dissection of the mediastinal lymph nodes was performed in every case (even if the preoperative evaluation was NO or Nl), in accordance with the lymph node map proposed by the Japan Lung Cancer Society []. On the right side, the mediastinal pleura was longitudinally incised along the trachea and esophagus from the apex to the base of the right hemithorax. For node dissection in the superior mediastinum, the azygos vein was cut to mobilize the trachea, esophagus, and superior vena cava. All of the accessible lymph nodes in the superior mediastinurn, ie, the superior mediastinal (#l), paratracheal (#), pretracheal (#), retrotracheal (#p), and tracheobronchial angle (#) nodes, were removed with the surrounding fat pad. The node anterior to the superior vena cava (#a) was also routinely removed, Table. Preoperative Staging of 7 Patients With Postoperatively N Disease That Was Not Detected by Preoperative Evaluation Preoperative Curative Noncurative Staging Operation Operation Total Stage T NO MO 7 T NO MO Stage T N MO Stage A T NO MO 7 T N MO Stage B T NO MO T N MO Total 6 7

3 Ann Thorac Surg!;:-6 WATANABE ET AL N NON-SMALL CELL LUNG CANCER Table. Histological Diagnosis and Operative Radicality of 7 Patients With N Disease Epidermoid Adenosquamous Large Cell Mucoepidermoid Diagnosis Adenocarcinoma Carcinoma Carcinoma Carcinoma Carcinoma Total Clinically NO- (n = 7) Curative operation Noncurative operation No resection Clinically N (n = ) Curative operation Noncurative operation No resection Total with N disease (n = 7) Curative operation Noncurative operation No resection Total including thymic tissue. By these procedures all of the lymph nodes and fat pad located around the subclavian artery, trachea, right main bronchus, ascending aortic arch, superior vena cava, and upper thoracic esophagus could be completely removed. For node dissection in the inferior mediastinum, the incised posterior mediastinal pleura was reflected and the pulmonary ligament was cut to expose the tracheal bifurcation, both main bronchi, the pericardium, and the lower thoracic esophagus. All of the lymph nodes in this compartment, ie, subcarinal (#7), paraesophageal (#8), and pulmonary ligament (#) nodes, were dissected out with their surrounding fat pad. On the left side, lymph node dissection in the inferior mediastinum was performed similarly to that on the right side, excluding subcarinal node dissection. However, in the superior mediastinum, there were great anatomical limitations on node dissection, in contrast to the right side. As the routine procedure before the present series, the mediastinal pleura was incised just beneath the aortic arch and the subaortic (#), paraaortic (#6), subcarinal (#7), paraesophageal (#8), pretracheal (#), and paratracheal (#) nodes were removed as far as it was possible. However, in the present series, the operative procedure was modified to allow more complete dissection of the lymph nodes in the left superior mediastinum. When left-sided N lung cancer was diagnosed by preoperative CT scanning or discovered at thoracotomy, two kinds of adjunctive procedures were performed in addition to the previous dissection method. For the earlier half of this series, the aortic arch and part of the descending aorta were mobilized by cutting a few intercostal arteries to allow more extensive removal of the superior mediastinal nodes. By this procedure, lymph nodes,, and p were completely dissected. n the later half of this series, to allow a far more extensive node dissection, median sternotomy was performed after procedures in the left hemithorax had been completed using the left posterolatera approach []. By this procedure, nodes,,, a,, and 7 in the ipsilateral side and also mediastinal and hilar lymph nodes in the contralateral side could be completely dissected. For the comparison of surgical results, operative radicality was divided into two categories. Curative operations were defined as those in which the tumor and accessible mediastinal lymph nodes were completely removed, whereas noncurative operations were those in which the tumor, metastatic lymph nodes, or both were incompletely excised. Staging of all the patients was performed using the new TNM classification proposed by the Union nternationale Contre le Cancer in 86 []. There exists disagreement regarding the definition of M disease in the case of intrapulmonary metastasis. The American Joint Committee defines pulmonary metastasis only to the contralateral lung as M disease [], whereas the Union nternationale Contre le Cancer [] and the Japan Lung Cancer Society [] define both ipsilateral and contralateral pulmonary metastases as M disease. n this study, we adopted the latter definition. All of the patients with postsurgical stage V disease in the present series (see Table ) had microscopic ipsilateral pulmonary metastases, which were discovered at postsurgical examination of the resected lung. Radiation therapy was not done as routine postoperative treatment but was performed in some patients who underwent noncurative operations or in those in whom mediastinal nodal recurrence developed. For calculation of the survival rate, we included six postoperative deaths occurring within days of operation: all of them occurred in cn-pn patients, with being in the curative operation group and the other in the noncurative operation group. The survival rate was calculated by the Kaplan-Meier method and statistical significance was evaluated by the Cox-Mantel and generalized Wilcoxon tests. When these two tests gave values of p less than., the difference was defined as statistically significant.

4 6 WATANABE ET AL N NON-SMALL CELL LUNG CANCER Ann Thorac Surg ;:-6 * cn explored (%) (%)... 6(%) ( 6%) Fig. Postoperative staging of the N factor in clinical N patients submitted for surgical exploration. (* Nine patients having an exploratory thoracotomy were included.) (c = clinical stage; p = postoperative stage.) Results Diagnostic Value of Preoperative Computed Tomographic Scanning in Assessing N Disease This evaluation was made only in the resected non-small cell lung cancer patients, so were eligible. The sensitivity, specificity, and accuracy of CT scanning in detecting N disease were 6%, 7%, and 76%, respectively. Predictive value of positive and negative tests were 8% and 86%, respectively. Among the patients who were diagnosed to have N disease in the preoperative evaluation by CT scanning and underwent exploration, patients (7%) had actual N disease, which was verified by postoperative histopathological examination (Fig ). Another patients (% of explored cn patients) were pno, 6 patients (%) were pn, and patients were pn, so the true-positive rate of CT scanning in the evaluation of N disease was only 7% and the falsepositive rate was % among the explored patients. Surgical Results in Clinically N Patients Among the 78 patients who were diagnosed to have N disease by preoperative evaluation by CT scanning, there were 8 patients in whom resection was not performed, including patients undergoing only exploratory thoracotomy due to extensive disease (see Table ). The reasons in the 7 patients who did not undergo surgical intervention were as follows: distant metastasis, 6; malignant pleural effusion, ; bulky N disease, 7; extensive invasion of mediastinal structures, 7; complications in major organs, ; and refusal of operation,. The most common histological cell type in the nonresection group was adenocarcinoma (8/8), followed by epidermoid carcinoma (/8) (see Table ). Excluding the cases of exploratory thoracotomy, 6 patients with true N disease (cn-pn) underwent curative and noncurative operations (% each) (see Table ). When their cell types were compared, curative operation could be more frequently accomplished in patients with epidermoid carcinoma (/, 7%) than in those with adenocarcinoma (/, %). The survival curves of the patients in this group are shown in Figure. The -year survival rate of the patients with pn and pn disease were 68% and %, respectively. On the other hand, the -year survival rate of patients with pn disease was 6%, including six operative deaths, and it was % in curatively resected patients, including three operative deaths. There were significant differences between pn and pno disease, and between pn and pn disease, respectively. There were no -year survivors among the patients with cn-pn disease who were incompletely resected, but patients ( with adenocarcinoma and with adenosquamous carcinoma; who underwent postoperative radiotherapy and who did not) have survived more than years after the operation. Surgical Results of Clinically N& but Postoperatively N Patients. There were 7 patients whose preoperative stage was NO or N, but in whom N disease was discovered at thoracotomy or by postoperative pathological examination of the lymph nodes removed (see Table ). Their preoperative evaluations of the N factor were NO in patients and N in patients, and their preoperative staging was as follows: stage in patients, stage in patients, stage A in patients, and stage B in patients. Thirty-one patients (66%) underwent curative operations, and this rate was higher than that in patients with cn-pn disease (%). Noncurative operation was more common in the preoperatively stage A and B group than in those with stage and disease. Histological diagnoses for these 7 patients are shown in Table. Adenocarcinoma was the most frequent, followed by epidermoid carcinoma. Of the 7 patients, had a curative operation and 6 had a noncurative operation. The survival curve of the 7 patients in this group is shown in Figure. The -year survival rate of this group overall (n = 7) was 7%, and it was % if the 6 patients who underwent noncurative operations (the longest survival was 8 months) were excluded. Overall Surgical Results of Patients With Postoperatively N Disease n all, there were 7 patients with N disease including 8 (% of N patients) inoperable N patients (Fig ). There were resected patients (6%) with postoperatively N disease, and of these patients 6 had truepositive disease and 7 had false-negative disease on CT. Their histological diagnoses are shown in Table. Seventy-five had adenocarcinoma and had epidermoid carcinoma. Eighty-four patients underwent curative operation (% of N patients) and 6 had a noncurative operation. The survival curves are shown in Figure. The overall -year survival rate of the patients was 7%, and that of the 8 patients undergoing curative operation was %. When the -year survival rates of the curatively resected patients with true-positive disease (n = ) and

5 Ann Thorac Surg ;:?-6 WATANABE ET AL 7 N NON-SMALL CELL LUNG CANCER cn 68% % pn(curative op.) c... (overall) % 6% 6 8 months 6o Fig. Survival curves of clinically N patients classified by the postoperative N factor. Operative deaths were included in the calculation of all survival rates in this and the other figures. (A = alive with no evidence of disease; A = dead with no evidence of disease; pno = patients with clinical N disease but postsurgically NO [n = ; pn = patients with clinical N disease but postsurgically N fn = 6; pn = patients with clinical N disease and postsurgically N [n = 6.) those with compared, there was groups. false-negative disease (n = ) on CT were they were % and %, respectively, but no significant difference between the two The -year survival rates of the patients with adenocarcinoma (n = ) and epidermoid carcinoma (n = 6) were % and %, respectively, showing no significant difference between the two. The -year survival rates of the Q) - E - a.- > v) 8- - c-: 6- i - *'!..., c... CNO-- (curative op.) pn +...:... (overall) L% % 6 8 months6' Fig. Survival curves of patients with clinically unrecognized N disease (clinical stage NO or N). (curative op. = patients undergoing curative operation fn = ; overall = patients undergoing curative operation plus those with noncurative operation [n = 7.)

6 8 WATANABE ET AL N NON-SMALL CELL LUNG CANCER Ann Thorac Surg ;: PN Total 7(%) patients with metastases confined within one level and those with metastases extending more than two levels were % and 7%, respectively, but there was no significant difference between the two groups. 8(%)... Noncurative op. (%) J Comment A major factor affecting the prognosis of patients undergoing operation for lung cancer is the presence of lymph node metastases and their location. There should be no objection to the statement that definitive surgical treat ment is the treatment of first choice for patients with stage Fig. Distribution of 7 patients with N disease. f* Nine patients undergoing explorato y thoracotomy were included.) (cn = patients with clinically proven N disease; cn- = patients with clinically unrecognized N disease.) patients with T N MO (n = ) and T N MO disease (n = ) were % and %, respectively, whereas those of patients with T N MO (n = 6) and T N MO disease (n = ) were % and, respectively. However, there were no significant differences between either T N MO versus T N MO, T N versus T N MO, or T N MO versus T N MO. Excluding T N MO patients, a comparison was made in respect to number of metastatic levels (there were patients who had multiple metastatic lymph nodes within one level; however, they were calculated as one metastatic focus in this comparison). The -year survival rates of the and non-small cell lung cancer. However, there exists considerable controversy regarding the treatment of patients with mediastinal lymph node metastases. There are many physicians who do not regard surgical treatment as a valid option in patients with mediastinal node metastases, but we do not support this concept. Even among surgeons, there still exists controversy regarding the selection criteria for surgical intervention in patients with N disease [lo, 6. We have been taking an aggressive attitude toward surgical treatment in patients with mediastinal lymph node metastases. To allow more complete dissection of the mediastinal lymph nodes, extensive operative procedures have been applied in the past years. As a result, there definitively was a group of patients with N disease who could undergo curative operations and gained long-term survival, even though it was a small part of the whole patient population with N disease. n the preoperative evaluation of N disease, two alternative methods are used. One is noninvasive, using cn months % % % Fig. Survival curves of patients with N disease undergoing curative operation. (cn- = patients with clinically unrecognized N disease fn = ; cn = patients with clinically proven N disease fn = ; symbols as in Figure.)

7 Ann Thorac Surg ::-6 WATANABE ET AL N NON-SMALL CELL LUNG CANCER conventional tomograms, CT scanning, scintiscanning, or magnetic resonance imaging. The other is the use of invasive procedures, such as mediastinal exploration or mediastinoscopy. We did not employ mediastinoscopy, and CT scanning was used for the selection of our surgical candidates. Except for patients with bulky N disease, an aggressive attitude toward surgical intervention was taken, even if N disease was found preoperatively by CT scanning. t should be mentioned that the true-positive rate of CT in our present series was only 7% ( of explored patients), and the false-positive rate was 8%. Among these explored cn-pn patients, only patients (7.8%) had a exploratory thoracotomy due to unresectable disease. f all the patients in our series with N disease detected by preoperative CT scanning were uniformly excluded from operation (as some physicians are doing), % of pno or pn patients would have been excluded. Because these patients have respective -year survival rates of 68% and % (including incompletely resected patients), they should not be denied the most appropriate treatment modality. t should be remembered that the reported values of the sensitivity, accuracy, and predictive value of CT scanning in detecting N disease are relatively low, as was also observed in our present study. Whittlesey [ 7 employed CT scanning in the staging of lung cancer and reported that mediastinal lymph nodes larger than. cm were positive for tumor in 6.6%, nodes between. and. cm were positive in.8%, and nodes less than. cm were positive in.7%. He concluded that all patients with otherwise resectable disease and eblarged mediastinal lymph nodes (greater than. cm) should undergo surgical exploration before resection is ruled out, as the false-positive rate for enlarged nodes was significant. Moreover, Martini and Flehinger [] have also reported that even when enlarged lymph nodes are found by CT scanning, many lung cancers are still resectable, and that more importantly, % to % of enlarged nodes detected by CT scanning are found to be hyperplastic and without metastasis. Magnetic resonance imaging has been expected to improve the accuracy of diagnosis of N disease, but Martini and associates [8] reported that there was no advantage of magnetic resonance imaging over CT scanning. Thus, both our present results and the data from these reports indicate that an aggressive attitude to surgical intervention is justified, even if lymphadenopathy is demonstrated in the mediastinum by preoperative CT scanning, provided that the suspected N disease is not unresectably bulky. There were only 7 patients with bulky unresectable N disease who did not undergo operation in our series. Although the accuracy of preoperative diagnosis may be increased by the combined use of preoperative mediastinal exploration (eg, mediastinoscopy), we did not use mediastinoscopy as a routine method of preoperative investigation. Pearson and co-workers [, employed mediastinoscopy in selecting patients for surgical exploration and reported that the -year survival rate of the patients with N disease detected by mediastinoscopy (n = 7) was %. However, when mediastinoscopy was negative and N nodal involvement was found only at thoracotomy (n = 6), the actuarial survival rate was %. They did not mention the overall -year survival rate of their patients, but these results were not so different from those obtained in our series without mediastinoscopy in selection of surgical candidates (7% overall and % for curatively resected patients). Our data showed little difference in survival rates between patients whose N disease was detected before operation and those whose N disease was discovered at thoracotomy or by postoperative pathology studies, provided complete resection could be accomplished. We think, therefore, that bulky unresectable N disease can be satisfactorily detected by CT scanning alone, as there were only patients found to be unresectable at thoracotomy. Of course, there would be no objection to the use of mediastinoscopy in patient selection. Mediastinoscopy can be helpful in determining which clinically N patients may benefit from surgical exploration. However, there are some long-term survivors among mediastinoscopypositive patients [l,. Mediastinoscopy does not cover all the known lymph node stations, and it is not yet clear who is a surgical candidate among mediastinoscopypositive patients. n some reports, all medistinoscopypositive patients were not surgical candidates [], whereas other authors have stated that mediastinal node metastasis without fixation in one station was no contraindication to exploration []. f all of mediastinoscopypositive patients are uniformly excluded from operation, some patients who otherwise might be salvaged by surgical therapy will undergo inappropriate treatment. Various results of surgical treatment of N disease have been reported. Pearson [l] collected the reported results of resection in patients with mediastinal lymph node metastases identified preoperatively and found a range from % to % for the -year survival rate. Survival of patients with N disease identified intraoperatively ranges from % to %, and is better than that of those with clinically evident N disease. We would like to emphasize that the surgical indications for N disease should not be discussed only on the basis of the reported survival rates, and that it is vital to make a correct interpretation of these confusing reports of the results of operation. t is worth noting that the patient populations vary greatly between institutions and that these differences are even more marked between Japan and western countries. The different results reported from Japan and western countries are thought to depend on the following reasons. The first reason is a difference in the method of selection of patients with clinically proven N disease for operation. Many Japanese institutions (including our hospital) have a rather more aggressive attitude toward performing operation for clinically evident N disease than is evident in western countries. Second, our present series reports the experience of a surgical department, so most of the patients who had obviously inoperable disease (such as clinical evidence of metastasis to distant

8 6 WATANABE ET AL N NON-SMALL CELL LUNG CANCER Ann Thorac Surg ;:-6 organs, hoarseness, superior vena cava syndrome, palpable supraclavicular lymph nodes, or other unresectable disease) were excluded from admission. Owing to these reasons, among the patients with clinically evident N disease, 6 of patients (6%) underwent surgical resection. This rate is higher than that reported in the literature. Luke and colleagues [] explored only % of 86 patients positive for N disease before thoracotomy, and Martini and Flehinger [] explored 8% of 8 patients with clinically evident N disease. By the aggressive inclusion of surgical patients in our series, the ratio of resected patients with clinically proven N disease to all pn patients undergoing resection was increased. This could greatly bias the results of the overall surgical outcomes for N disease, because the rate of complete resection was much higher in the clinically unrecognized N group than in the clinically evident N group. f the number of patients with clinically evident N disease is much higher than the number with clinically unrecognized N disease (as it was in our series), the overall survival rate would be worse than if the series included a high incidence of patients with clinically unrecognized N disease. n our present series, the pn patients undergoing resection comprised 6 (6%) with clinically evident N disease and 7 (%) with clinically unrecognized N disease. n contrast, in Martini and Flehinger s series [], the pn patients undergoing resection comprised 7 (%) with clinically evident N disease and (6%) with clinically unrecognized N disease. When the survival rates were compared, the overall -year survival rate for the pn patients in our series was 7%, which corresponded with the result of Naruke and associates [8] of % (n = 6). However, the -year survival rates for N patients reported by Mountain [7] and Martini and Flehinger [] were 6%, and %, respectively. t must be remembered that both these reports gave the survival rates of the curatively resected group and not those of all patients, including the patients undergoing incomplete resection. The results for the 7 patients in Martini and Flehinger s [] series with incomplete resection were not described, but they could greatly reduce the survival rate if the overall survival rate of resected patients were calculated. n addition, their series contained a rather small number of patients with detectable N disease, which generally shows a worse prognosis than clinically unrecognized N disease. Another reason for the difference in the reported survival rate may concern the definitions of complete resection or curative operation. Martini and Flehinger [] reported that the -year survival rate of patients with completely resected N disease was %, whereas the figures obtained by Naruke and associates [8] and in our present series were % and %, respectively. However, survival rates can be greatly modified by the selection of the complete resection group at the time of evaluating the survival data. n our present series, the frequency of curative operation in patients with clinically evident N disease was 8% overall and 6% of explored patients. The frequency of curative operation in the patients with clinically unrecognized N disease was 66%. n total, 8 of N patients (%) undergoing resection underwent curative operation (see Fig ). n contrast, in the series of Martini and Flehinger [], only 7% (Y8) of clinically recognized N patients and 8% (7) of explored patients underwent complete resection. Furthermore, even among the patients with clinically unrecognized N disease, only out of resected patients (%) underwent complete resection. n all, only 8% (/) of their N patients undergoing resection had a complete resection procedure, a rate far lower than that in our series. The relatively high rate of curative resection in our present series might be partly due to our operative procedure of extensive mediastinal lymph node dissection, but there must also be some differences among these series in the definition of curative operation. Mountain [7] reported a 6% -year survival in patients with completely resected N disease, and defined complete resection as being achieved when the most distal nodes within each major lymphatic drainage region are microscopically free of tumor. f the farthest node in the dissection is positive for tumor, they defined the resection as incomplete. This definition, although it is not described in detail, is markedly different from our definition []. We defined complete resection as a procedure in which all accessible metastatic lymph nodes were removed, even if the most distal node was found to be involved. f we use Mountain s criteria to define complete resection, a considerable number of our patients are then excluded from the complete resection group, which results in an improvement of the survival rate of the complete resection group. There is thus an urgent need for international agreement regarding the definition of operative radicality so as to allow a more rational comparison of the surgical results. We have been adopting an aggressive attitude to clinically evident N disease, because the reported survival rates of nonsurgical treatment in patients with N disease were extremely low. The $year and -year survival rates of nonsurgically treated N patients in our series were 7% and %, respectively, and their % survival length was 6 months. Our present series supports the value of an aggressive attitude toward resection in patients with N disease. However, the results of surgical treatment of N disease shown by the present series were not satisfactory. To improve the resectability rate and ultimately the survival of patients with clinically evident N disease, neoadjuvant therapy has been attempted in several preliminary trials [,. We also have started such a clinical trial recently, but it is too early yet to make any clear conclusions regarding the survival rate. However, such therapy seems to improve the resection rate of bulky N disease. n conclusion, an aggressive attitude toward surgical intervention for N disease can be advocated. n patients with N disease detected either by preoperative investigations or at thoracotomy, complete resection should be performed whenever possible by employing extended surgical procedures to allow complete dissection of the mediastinal lymph nodes.

9 Ann Thorac Surg ;:-6 WATANABE ET AL 6 N NON-SMALL CELL LUNG CANCER References. Pearson FG. Mediastinal adenopathy-the N lesion. n: DeLarue NC. Eschapasse H, eds. nternational trends in general thoracic surgery, vol. Lung cancer. Philadelphia: WB Saunders, 8:.. Pearson FG, DeLarue NC, lves R, Todd TRJ, Cooper JD. Significance of positive superior mediastinal nodes identified at mediastinoscopy in patients with resectable cancer of the lung. J Thorac Cardiovasc Surg 8;8:-.. Coughlin M, Deslauriers JD, Beaulieu M, et al. Role of mediastinoscopy in pretreatment staging of patients with primary lung cancer. Ann Thorac Surg 8;:6-6.. Ratto GB, Mereu C, Motta G. The prognostic significance of preoperative assessment of mediastinal lymph nodes in patients with lung cancer. Chest 88;:87-.. Luke WP, Pearson FG, Todd TRJ, Patterson GA, Cooper JD. Prospective evaluation of mediastinoscopy for assessment of carcinoma of the lung. J Thorac Cardiovasc Surg 86;:. 6. Backer CL, Shields TW, Lockhart CG, Volgelzang R, LoCicero J. Selective preoperative evaluation for possible N disease in carcinoma of the lung. J Thorac Cardiovasc Surg 87;: Mountain CF. The biological operability of stage non-small cell lung cancer. Ann Thorac Surg 8;: Naruke T, Goya T, Tsuchiya R, Suemasu K. The importance of surgery to non-small cell carcinoma of lung with mediastinal lymph node metastasis. Ann Thorac Surg 88;6: 6-.. Martini N, Flehinger BJ. The role of surgery in N lung cancer. Surg Clin N Am 87;67:7-.. Shields TW. The significance of ipsilateral mediastinal lymph node metastasis (N disease) in non-small cell carcinoma of the lung. J Thorac Cardiovasc Surg ;:8-.. Watanabe Y, Shimizu J, Tsubota M, wa T. Mediastinal spread of metastatic lymph nodes in bronchogenic carcinoma. Chest ;7: -6.. The Japan Lung Cancer Society. General rule for clinical and pathological records of lung cancer. Tokyo: Kanahara Publishing Company, 86.. Watanabe Y, chihashi T, wa T. Median sternotomy as an approach for pulmonary surgery. Thorac Cardiovasc Surg 88;6:7-.. nternational Union Against Cancer. TNM classification of malignant tumours. th ed. New York: Springer-Verlag, 87.. American Joint Committee for Cancer Staging and End- Results Reporting. Staging of lung cancer 7. Chicago: American Joint Committee, Shields TW. Carcinoma of the lung. n: Shields TW, ed. General thoracic surgery. Philadelphia: Lea & Febiger, Whittlesey D. Prospective computed tomographic scanning in the staging of bronchogenic carcinoma. J Thorac Cardiovasc Surg 88;: Martini N, Heelan R, Westcott J, et al. Comparative merits of conventional, computed tomographic, and magnetic resonance imaging in assessing mediastinal involvement in surgically confirmed lung carcinoma. J Thorac Cardiovasc Surg 8;:6-.. Faber LP, Kittle CF, Warren WH, et al. Preoperative chemotherapy and irradiation for stage non-small cell lung cancer. Ann Thorac Surg 8; Martini N, Kris MG, Gralla RJ, et al. The effects of preoperative chemotherapy on the resectability of non-small cell lung carcinoma with mediastinal lymph node metastases (NMO). Ann Thorac Surg 88;:7-.