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Clinical Investigations: CANCER |

Unfavorable Prognosis of Patients With Stage II Non-small Cell Lung Cancer Associated With Macroscopic Nodal Metastases* FREE TO VIEW

Ichiro Yoshino, MD; Ryoichi Nakanishi, MD; Toshihiro Osaki, MD; Mitsuhiro Takenoyama, MD; Satoshi Taga, MD; Takeshi Hanagiri, MD; Kosei Yasumoto, MD
Author and Funding Information

*From the Department of Surgery II, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.

Correspondence to: Ichiro Yoshino, MD, Department of Surgery II, School of Medicine, University of Occupational and Environmental Health, Iseigaoka 1–1, Yahatanishi-ku, Kitakyushu 807, Japan; e-mail: ichiroy@med.uoeh-u.ac.jp



Chest. 1999;116(1):144-149. doi:10.1378/chest.116.1.144
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Background: Patients with stage II-N1 non-small cell lung cancer (NSCLC) make up an intermediate group of patients with an unsatisfactory prognosis even though complete resection is usually possible. We retrospectively analyzed postoperative prognostic factors to devise guidelines for the proper management of this patient population.

Study design: Among 546 patients with NSCLC who underwent surgical resection from 1979 to 1995, 43 patients were pathologically defined to be at stage II-N1 (T1–2N1M0). The influence of the following variables on postoperative survival was analyzed: gender, age, cell type, pathologic T factor, number of metastatic nodes, station of metastatic nodes (hilar or pulmonary nodes), status of nodal metastasis (macroscopic, gross involvement confirmed histologically; or microscopic, metastasis first defined by histologic examination), surgical methods, and adjuvant therapy (including 18 of chemotherapy and 2 of radiotherapy).

Results: The 5-year survival rates (5YSRs) of patients with microscopic (n = 21) and macroscopic nodal metastasis (n = 22) were 76.0% and 27.6%, respectively (p = 0.001). The 5YSRs of 20 patients who received adjuvant therapy and 23 who did not receive adjuvant therapy were 57.6% and 46.6%, respectively (p = 0.036). Other variables did not affect survival. The Cox proportional hazards model analysis indicated that the presence of a macroscopic nodal metastasis and postoperative adjuvant therapy were independent prognostic factors. Among patients with macroscopic N1 NSCLC, 9 patients who had undergone adjuvant therapy showed a more favorable prognosis than the 13 patients who had not received adjuvant therapy (3-year survival rate, 55.6% vs 18.5%; p = 0.037; and recurrence rate, 30.0% vs 77.8%), whereas no significant influence of adjuvant therapy on survival was observed among patients with microscopic N1 NSCLC.

Conclusions: Stage II-N1 NSCLC was categorized into microscopic and macroscopic N1 diseases. The latter had a poor prognosis, which might be improved by adjuvant therapy, although a suitable regimen has not been established.

Figures in this Article

Abbreviations: 5YSR = 5-year survival rate; MST = median survival time; NSCLC = non-small cell lung cancer

Non -small cell lung cancer (NSCLC) with the main tumor not invading neighboring organs, and with involvement of hilar or pulmonary nodes as the sole site of metastasis (stage II-N1, referred to as stage II in the former TNM classification1), is well suited for surgical resection; however, the outcome is still considered unsatisfactory, with a high rate of recurrence at both local and distant sites and an overall survival rate of 30 to 50% at 5 years.25 These facts indicate that tumor cells have already spread systematically beyond the intrathoracic lymphatic system at the time of surgery in a certain population of the stage II-N1 patients. The characteristics of such a small (approximately 10% of all resected NSCLC cases) and intermediate population remain to be investigated.

Radiotherapy or systemic chemotherapy has been performed as an adjuvant therapy for stage II NSCLC in a number of institutes, but the efficacy of adjuvant therapy remains to be determined.4,67 To make it more effective, it may be essential to select and characterize the subpopulation that is best suited for surgical adjuvant treatment. Until recently, pathologic T factor,3larger size of main tumor,4 multiplicity of nodal metastases,4 and hilar nodal involvement5 have been suggested as indicators of a poor prognosis for stage II-N1 NSCLC, although such factors still remain controversial. In this study, we investigated the prognostic factors in an attempt to classify subgroups for a proper management of stage II disease.

Patients

From January 1979 to December 1995, 546 patients with NSCLC underwent surgical resection at the Department of Surgery II, University Hospital of Occupational and Environmental Health, Kitakyushu, Japan. Of these patients, 43 were defined as having stage II-N1 disease by pathologic determination of T1–2, and intrapulmonary (Nos. 12 and 13) or hilar lymph node (Nos. 10 and 11) metastases (N1).8Mean observation time was 1,240 days. The profile of the stage II-N1 patients is given in Table 1 . The histologic diagnosis of the tumors was based on the criteria of the World Health Organization.9 The mean age of the patients (32 men, 11 women) was 67.5 ± 7.5 years (range, 47 to 81 years). Histologically, 27 patients had squamous cell carcinomas, 13 had adenocarcinomas, and 3 had large cell carcinomas. A standard surgical procedure, such as a lobectomy or pneumonectomy with complete dissection of the hilar and mediastinal lymph nodes, was performed in all patients except one who underwent segmentectomy with mediastinal dissection. Postoperative adjuvant chemotherapy included platinum-based combination chemotherapy for 14 patients (two to three courses); mitomycin for one patient (two shots); cyclophosphamide for one patients (two courses); and oral administration of tegafur and uracil for two patients (daily for 2 years). Irradiation was performed for the ipsilateral hilum (60 Gy) in two patients. TNM stage10 was determined by preoperative examinations comprising chest radiograph; CT of the brain, chest, and abdomen; bone scan; and pathologic examination of surgical specimens. When nodal involvement was macroscopically recognized at thoracotomy and confirmed by subsequent histologic examination, the nodal metastasis was defined as macroscopic (macroscopic N1). When the nodal metastasis was first diagnosed by postoperative histologic examination of resected specimens, the metastasis was defined as microscopic (microscopic N1). Fifteen out of 22 patients with macroscopic N1 disease could be diagnosed as clinical N1 based on preoperative imaging.

Follow Up of Patients

Serial follow-up examinations were, in general, done every 1 or 2 months for the first 2 years and every 3 to 4 months thereafter. The examinations included physical examination, hematology, blood biochemistry, and chest radiography. All patients routinely received screening examinations for recurrence by CT or radionuclide bone scanning once or twice per year after the operation. Recurrent disease was then confirmed by biopsy specimen if clinically feasible. In patients for whom a biopsy was not feasible, radiographic confirmation (radiography, CT, or radionuclide scan) was accepted. The final date for evaluation was December 31, 1997.

Statistical Analysis

Survival rates were calculated by the Kaplan-Meier method,11and comparisons among the survival curves were made using the log-rank test.12The Cox proportional hazards model was used to identify the factors (gender, age, cell type, pathologic T factor, number of metastatic nodes, station of metastatic nodes, status of nodal metastases, surgical methods, and adjuvant therapy) that had a jointly significant influence on survival.13 The data were considered to be significant when the p value did not exceed 0.05.

Overall Survival of Stage II-N1 Patients

There was no event with morbidity or mortality at the time of surgery and/or adjuvant therapies. For all 43 patients with stage II-N1 disease, the cumulative postoperative 5-year survival rate (5YSR) and median survival time (MST) were 50.2% and 2,205 days, respectively (Fig 1 ). These values were significantly different (p < 0.001) from those for the 217 patients with stage I disease (5YSR, 67.4%; MST, 4,581 days), and for the 94 patients with stage IIIa-N2 disease (5YSR, 25.7%; MST, 730 days), who underwent surgical resection at our department during the same period (Fig 1). The survival curves of stage II-N1 patients and stage II-T3 patients (5YSR, 43.2%; MST, 769 days) were very similar (p = 0.430; Fig 1).

Postoperative Prognostic Factors for Stage II-N1 Patients

The influence of various factors on the postoperative prognosis of patients was examined by a univariate analysis (Table 2 ). There was no association between postoperative survival and the following variables: gender (male vs female); age (≥ 65 years vs< 65 years); cell type (squamous cell carcinoma vs others); pathologic T factor (T1 vs T2); number of metastatic nodes (one vs two or more); station of metastatic nodes (hilar vs pulmonary nodes); surgical methods (lobectomy or segmentectomy vs bilobectomy or pneumonectomy). A significant influence was observed only with regard to the extent of nodal involvement (macroscopic vs microscopic metastasis) and adjuvant therapy. The 5YSR and MST of 21 patients in whom microscopic N1 disease was diagnosed and 22 patients in whom macroscopic N1 disease was diagnosed were 76.0%/3,123 days and 27.6%/632 days, respectively (p = 0.001; Fig 2 ). The 5YSR and MST of 20 patients who received adjuvant therapy (chemotherapy in 18 patients and radiotherapy in 2 patients) were 57.6% and 1,155 days, respectively, compared with 46.6% and 854 days in the 23 patients who did not receive adjuvant therapy (p = 0.036; Fig 3 ).

A multivariate analysis revealed that macroscopic N1 disease was an independent factor for poor prognosis at a hazard ratio of 7.87 (p = 0.001); postoperative adjuvant therapy was an independent factor for favorable prognosis, and the hazard ratio was 8.70 when no adjuvant therapy was performed after resection (p = 0.002; Table 2).

Significance of Postoperative Adjuvant Therapy for Patients With Macroscopic Stage II-N1 NSCLC

Considering the results described above, the effect of adjuvant therapy on the survival of the microscopic and macroscopic N1 subgroups was examined. Postoperative adjuvant therapy did not influence the survival of the 21 patients with microscopic N1 disease. The 5YSR of 11 patients who underwent adjuvant therapy (chemotherapy for 11 patients) was 72.9%, and that of the other 10 patients was 80.0% (p = 0.316; Fig 4top, a). On the other hand, in the subgroup with macroscopic N1 disease, significant survival benefits were observed in 9 patients who received adjuvant therapy (7 chemotherapy and 2 radiotherapy), as compared with the 13 patients who did not receive any adjuvant therapy after resection (3-year survival rates, 55.6% with adjuvant therapy vs 18.5% without adjuvant therapy; p = 0.037; Fig 4bottom, b).

Occurrence and First Site of Recurrence

Postoperative recurrence was frequently observed in the patients who did not receive any adjuvant therapy. Recurrence was observed in only 2 of the 11 patients with microscopic N1 disease who underwent adjuvant therapy (recurrence rate, 9.1%), whereas 5 of the 10 patients with microscopic N1 disease who did not receive any adjuvant therapy developed recurrent tumors (recurrence rate, 50.0%; Table 3 ). Among patients with macroscopic N1 disease, the recurrence rate was higher for the 13 patients who did not receive any adjuvant therapy (53.9%) than for the 9 patients who received adjuvant therapy (chemotherapy in 7 patients and radiotherapy in 2 patients), in whom the recurrence rate was 33.3% (Table 3). Among 13 patients in whom the first site of recurrence was identified, distant metastases (10 patients) including the lungs, brain, and liver were more frequent than local relapses (3 patients; Table 3).

Until recently, several prognostic factors have been suggested for patients with stage II-N1 NSCLC. Several authors stated that stage II-N1 patients with adenocarcinoma had a significantly less favorable prognosis than patients with squamous cell carcinoma.1416 Martini et al4reported that tumor size > 3 cm and multiplicity of nodal involvement were associated with a poor prognosis. Recently, Yano et al5 reported that hilar nodal involvement revealed advanced disease, whereas intrapulmonary nodal involvement revealed early disease. In our study, the extent of nodal involvement (macroscopic or microscopic), but not the station of metastatic nodes (hilar or pulmonary nodes), was a strong factor for the postoperative prognosis, even in a relatively small number of patients. In N2 disease, a relatively better prognosis has been reported when mediastinal nodal involvement is first identified at the time of thoracotomy, with a survival of approximately 20% at 5 years after resection; conversely, surgical outcome of clinically diagnosed N2 disease was extremely poor, with a 5YSR of almost 0%.8,1718 Similarly, in the case of N1 disease, microscopic N1 disease showed a favorable outcome with a 5YSR of 76.0% and a recurrence rate of 28.6% (6 of 21 patients), while macroscopic N1 disease showed a poor outcome with a 5YSR of 27.6% and a recurrence rate of 43.4% (10 of 23 patients). Therefore, gross nodal metastases may reveal the existence of systemically widespread occult cancer cells. The microscopic N1 and the stage I populations showed similar prognoses (5YSRs of 76.0% and 67.6%, respectively), and the macroscopic N1 and stage IIIa-N2 subpopulations also showed similar prognoses (5YSRs of 27.6% and 23.7%, respectively). Therefore, stage II-N1 disease is a complex of local disease (microscopic N1) and systemic disease (macroscopic N1).

Recently, we have reported that micrometastatic cancer cells in the dissected lymph nodes that are overlooked by conventional histologic examination are frequently detected by immunohistochemical staining using monoclonal antibody for p53 in patients with p53-positive NSCLC, and the incidence of micrometastasis in the lymph nodes was associated with a poor prognosis.19In an additional recent study by us, micrometastatic cancer cells (cytokeratin 18-positive cells) were also detected in the bone marrow in 39% of the patients with completely resected NSCLC; of the four patients with stage II-N1 (the former stage II) disease, two patients tested positive for micrometastases,20 suggesting that in certain populations of patients with NSCLC, it is already a systemic disease even though no distant metastasis is observed by conventional preoperative examinations such as body and brain CT or bone scan. Such micrometastases probably are more frequent in macroscopic N1 than in microscopic N1 disease.

Another influencing factor identified in this study was postoperative adjuvant therapy. Ferguson et al6also reported an improvement of postoperative survival for stage II-N1 NSCLC when adjuvant radiotherapy and/or chemotherapy were administered. In the prospective randomized studies performed by the Lung Cancer Study Group, however, the efficacy of both adjuvant radiotherapy and chemotherapy for the former stage II (stage II-N1) disease was not studied. In one of those studies in which 42% of the study population had stage II-N1 disease, a significant benefit of postoperative chemotherapy was observed regarding disease-free survival but not overall survival.7 In another series concerning adjuvant radiotherapy, there was no significant improvement of the rate of local recurrence in N1 disease.21Of the adjuvant therapies performed in this study, platinum-based combination chemotherapy was performed in 14 patients for more than two courses. Mild chemotherapy using daily oral administration of tegafur and uracil for 1 year, which was recently reported by Wada et al,22 was administered in two patients. The two patients who received adjuvant radiotherapy are long survivors (2,321 days and 1,974 days for each). These adjuvant therapies seem to improve the prognosis of the stage II-N1 NSCLC, especially that of patients with macroscopic N1 disease, although such an improvement in survival rate should be demonstrated by a randomized trial.

Table Graphic Jump Location
Table 1. Profile of the Stage II–N1 Patients*
* 

Data are given as mean ± SD (range) or No.

Figure Jump LinkFigure 1. The overall survival curves of patients with stage I (n = 217), II-N1 (n = 43), II-T3 (n = 38), and IIIa-N2 (n = 94) NSCLC.Grahic Jump Location
Table Graphic Jump Location
Table 2. Analysis of Factors Associated With the Postoperative Prognosis*
* 

Squamous = squamous cell carcinoma; others = 13 adenocarcinomas and 3 large cell carcinomas; Lob/Seg = lobectomy or segmentectomy; Bi/Pn = bilobectomy/pneumonectomy.

 

Including one patient who underwent lobectomy combined with resection of other lobe.

Figure Jump LinkFigure 2. The survival curves for the microscopic N1 (n = 21) and macroscopic N1 (n = 22) subsets of patients with stage II-N1 disease.Grahic Jump Location
Figure Jump LinkFigure 3. The survival curves of the patients who underwent postoperative adjuvant therapy (n = 20) and those who received no anticancer treatment after surgery (n = 23).Grahic Jump Location
Figure Jump LinkFigure 4. Top, a: the survival curves of the subgroups of patients with microscopic N1 disease who received adjuvant therapy (n = 11) and those with microscopic N1 disease who did not receive adjuvant therapy (n = 10). Bottom, b: the survival curves of the subgroups of patients with macroscopic N1 disease who received adjuvant therapy (n = 9) and those with macroscopic N1 disease who did not receive adjuvant therapy (n = 13).Grahic Jump Location
Table Graphic Jump Location
Table 3. The Incidence and the Site of the First Recurrence

ACKNOWLEDGMENT: We thank Ms. Miki Kiyofuji for her expert help during preparation of the manuscript.

American Joint Committee on Cancer. Manual for staging of cancer. 4th ed. Philadelphia, PA: JB Lippincott, 1992; 116.
 
Naruke, T, Goya, T, Tuchiya, R, et al Prognosis and survival in resected lung carcinoma based on the new international staging system.J Thorac Cardiovasc Surg1988;96,440-447. [PubMed]
 
Martini, N, Flehinger, BJ, Nagasaki, F, et al Prognostic significance of N1 disease carcinoma of the lung.J Thorac Cardiovasc Surg1983;86,646-653. [PubMed]
 
Martini, N, Burt, ME, Bains, MS, et al Survival after resection of stage II non-small cell lung cancer.Ann Thorac Surg1992;54,460-466. [PubMed] [CrossRef]
 
Yano, T, Yokoyama, H, Inoue, T, et al Surgical results and prognostic factors of pathologic N1 disease in non-small-cell carcinoma of the lung.J Thorac Cardiovasc Surg1994;107,503-507
 
Ferguson, MF, Little, AG, Golomb, HM, et al The role of adjuvant therapy after resection of T1N1M0 and T2N1M0 non-small cell lung cancer.J Thorac Cardiovasc Surg1986;91,344-349. [PubMed]
 
Holmes, EC, Gail, M, Lung Cancer Study Group. Surgical adjuvant therapy for Stage II and Stage III adenocarcinoma and large cell undifferentiated carcinoma.J Clin Oncol1986;4,710-715. [PubMed]
 
Naruke, T, Suemasu, K, Ishikawa, S Lymph node mapping and curability at various levels of metastasis in resected lung cancer.J Thorac Cardiovasc Surg1978;76,832-839. [PubMed]
 
World Health Organization.. Histological typing of lung tumors.Am J Clin Pathol1982;57,471-476
 
Mountain, CF Revisions in the international system for staging lung cancer.Chest1997;111,1710-1717. [PubMed]
 
Kaplan, EL, Meier, P Nonparametric estimation from incomplete observations.J Am Stat Assoc1958;53,457-481
 
Peto, R, Peto, J Asymptotically efficient rank and invariant procedures.J R Stat Soc (A)1972;135,185-207
 
Cox, DR Regression models and life tables.J R Stat Soc (B)1972;34,187-220
 
Newman, SB, DeMeester, TR, Golomb, HM, et al Treatment of modified Stage II (T1 N1 M0, T2 N1 M0) non-small cell bronchogenic carcinoma.J Thorac Cardiovasc Surg1983;86,180-185. [PubMed]
 
Vincent, RG, Takita, H, Lane, WW, et al Surgical therapy of lung cancer.J Thorac Cardiovasc Surg1976;71,581-591. [PubMed]
 
Mountain, CF Assessment of the role of surgery in control of lung cancer.Ann Thorac Surg1977;24,365-373. [PubMed]
 
Martini, N, Flehinger, BJ, Zaman, MB, et al Prospective study of 455 lung carcinomas with mediastinal lymph node metastases.J Thorac Cardiovasc Surg1980;80,390-399. [PubMed]
 
Nakanishi, R, Osaki, T, Nakanishi, K, et al Treatment strategy for patients with surgically discovered N2 stage IIIA non-small cell lung cancer.Ann Thorac Surg1997;64,342-348. [PubMed]
 
Dobashi, K, Sugio, K, Osaki, T, et al Micrometastatic p53-positive cells in the lymph nodes of non-small-cell lung cancer: prognostic significance.J Thorac Cardiovasc Surg1997;114,339-346. [PubMed]
 
Ohgami, A, Mitsudomi, T, Sugio, K, et al Micrometastatic tumor cells in the bone marrow of patients with non-small cell lung cancer.Ann Thorac Surg1997;64,363-367. [PubMed]
 
Weisenburger, TH, Gail, M, Lung Cancer Study Group. Effects of postoperative mediastinal irradiation on completely resected Stage II and Stage III epidermoid cancer of the lung.N Engl J Med1986;315,1377-1381. [PubMed]
 
Wada, H, Hitomi, S, Teramatsu, T, et al Adjuvant chemotherapy after complete resection in non-small-cell lung cancer.J Clin Oncol1996;14,1048-1054. [PubMed]
 

Figures

Figure Jump LinkFigure 1. The overall survival curves of patients with stage I (n = 217), II-N1 (n = 43), II-T3 (n = 38), and IIIa-N2 (n = 94) NSCLC.Grahic Jump Location
Figure Jump LinkFigure 2. The survival curves for the microscopic N1 (n = 21) and macroscopic N1 (n = 22) subsets of patients with stage II-N1 disease.Grahic Jump Location
Figure Jump LinkFigure 3. The survival curves of the patients who underwent postoperative adjuvant therapy (n = 20) and those who received no anticancer treatment after surgery (n = 23).Grahic Jump Location
Figure Jump LinkFigure 4. Top, a: the survival curves of the subgroups of patients with microscopic N1 disease who received adjuvant therapy (n = 11) and those with microscopic N1 disease who did not receive adjuvant therapy (n = 10). Bottom, b: the survival curves of the subgroups of patients with macroscopic N1 disease who received adjuvant therapy (n = 9) and those with macroscopic N1 disease who did not receive adjuvant therapy (n = 13).Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Profile of the Stage II–N1 Patients*
* 

Data are given as mean ± SD (range) or No.

Table Graphic Jump Location
Table 2. Analysis of Factors Associated With the Postoperative Prognosis*
* 

Squamous = squamous cell carcinoma; others = 13 adenocarcinomas and 3 large cell carcinomas; Lob/Seg = lobectomy or segmentectomy; Bi/Pn = bilobectomy/pneumonectomy.

 

Including one patient who underwent lobectomy combined with resection of other lobe.

Table Graphic Jump Location
Table 3. The Incidence and the Site of the First Recurrence

References

American Joint Committee on Cancer. Manual for staging of cancer. 4th ed. Philadelphia, PA: JB Lippincott, 1992; 116.
 
Naruke, T, Goya, T, Tuchiya, R, et al Prognosis and survival in resected lung carcinoma based on the new international staging system.J Thorac Cardiovasc Surg1988;96,440-447. [PubMed]
 
Martini, N, Flehinger, BJ, Nagasaki, F, et al Prognostic significance of N1 disease carcinoma of the lung.J Thorac Cardiovasc Surg1983;86,646-653. [PubMed]
 
Martini, N, Burt, ME, Bains, MS, et al Survival after resection of stage II non-small cell lung cancer.Ann Thorac Surg1992;54,460-466. [PubMed] [CrossRef]
 
Yano, T, Yokoyama, H, Inoue, T, et al Surgical results and prognostic factors of pathologic N1 disease in non-small-cell carcinoma of the lung.J Thorac Cardiovasc Surg1994;107,503-507
 
Ferguson, MF, Little, AG, Golomb, HM, et al The role of adjuvant therapy after resection of T1N1M0 and T2N1M0 non-small cell lung cancer.J Thorac Cardiovasc Surg1986;91,344-349. [PubMed]
 
Holmes, EC, Gail, M, Lung Cancer Study Group. Surgical adjuvant therapy for Stage II and Stage III adenocarcinoma and large cell undifferentiated carcinoma.J Clin Oncol1986;4,710-715. [PubMed]
 
Naruke, T, Suemasu, K, Ishikawa, S Lymph node mapping and curability at various levels of metastasis in resected lung cancer.J Thorac Cardiovasc Surg1978;76,832-839. [PubMed]
 
World Health Organization.. Histological typing of lung tumors.Am J Clin Pathol1982;57,471-476
 
Mountain, CF Revisions in the international system for staging lung cancer.Chest1997;111,1710-1717. [PubMed]
 
Kaplan, EL, Meier, P Nonparametric estimation from incomplete observations.J Am Stat Assoc1958;53,457-481
 
Peto, R, Peto, J Asymptotically efficient rank and invariant procedures.J R Stat Soc (A)1972;135,185-207
 
Cox, DR Regression models and life tables.J R Stat Soc (B)1972;34,187-220
 
Newman, SB, DeMeester, TR, Golomb, HM, et al Treatment of modified Stage II (T1 N1 M0, T2 N1 M0) non-small cell bronchogenic carcinoma.J Thorac Cardiovasc Surg1983;86,180-185. [PubMed]
 
Vincent, RG, Takita, H, Lane, WW, et al Surgical therapy of lung cancer.J Thorac Cardiovasc Surg1976;71,581-591. [PubMed]
 
Mountain, CF Assessment of the role of surgery in control of lung cancer.Ann Thorac Surg1977;24,365-373. [PubMed]
 
Martini, N, Flehinger, BJ, Zaman, MB, et al Prospective study of 455 lung carcinomas with mediastinal lymph node metastases.J Thorac Cardiovasc Surg1980;80,390-399. [PubMed]
 
Nakanishi, R, Osaki, T, Nakanishi, K, et al Treatment strategy for patients with surgically discovered N2 stage IIIA non-small cell lung cancer.Ann Thorac Surg1997;64,342-348. [PubMed]
 
Dobashi, K, Sugio, K, Osaki, T, et al Micrometastatic p53-positive cells in the lymph nodes of non-small-cell lung cancer: prognostic significance.J Thorac Cardiovasc Surg1997;114,339-346. [PubMed]
 
Ohgami, A, Mitsudomi, T, Sugio, K, et al Micrometastatic tumor cells in the bone marrow of patients with non-small cell lung cancer.Ann Thorac Surg1997;64,363-367. [PubMed]
 
Weisenburger, TH, Gail, M, Lung Cancer Study Group. Effects of postoperative mediastinal irradiation on completely resected Stage II and Stage III epidermoid cancer of the lung.N Engl J Med1986;315,1377-1381. [PubMed]
 
Wada, H, Hitomi, S, Teramatsu, T, et al Adjuvant chemotherapy after complete resection in non-small-cell lung cancer.J Clin Oncol1996;14,1048-1054. [PubMed]
 
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