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J Thorac Cardiovasc Surg 2001;122:803-808
© 2001 The American Association for Thoracic Surgery

General Thoracic Surgery

Completely resected stage IIIA non–small cell lung cancer: The significance of primary tumor location and N2 station

From the National Kyushu Cancer Center, Fukuoka,^a Tokyo Medical University, Tokyo,^b Niigata Cancer Center Hospital, Niigata,^c National Cancer Center Hospital, Tokyo,^d Chiba University School of Medicine, Chiba,^e Okayama University School of Medicine, Okayama,^f Kanazawa University School of Medicine, Ishikawa,^g Aichi Cancer Center Hospital, Aichi,^h and Hyogo Prefectural Adult Diseases Center, Hyogo, Japan.ⁱ

Supported by a Grant-in-Aid (S11-2) for Cancer Research from the Ministry of Health and Welfare, Japan.

Received for publication Feb 1, 2001. Revisions requested March 6, 2001. revisions received March 19, 2001. Accepted for publication April 12, 2001. Address for reprints: Yukito Ichinose, MD, Department of Chest Surgery, National Kyushu Cancer Center, 3-1-1, Notame, Minami-ku, Fukuoka 811-1395, Japan.

	Abstract

Top Abstract Introduction Patients and methods Results Discussion Appendix References

 
Background: The number of N2 stations (single vs multiple N2 stations) is an important prognostic factor in patients with completely resected stage IIIA-N2 non–small cell lung cancer. However, the significance of both the N2 station(s) actually involved and the primary tumor location remains unclear.
Methods: The database was built with the use of a questionnaire survey on the survival of patients with pathologic stage IIIA-N2 non–small cell lung cancer completely resected between January 1992 and December 1993. The survey was performed by the Japan Clinical Oncology Group as of July 1999. The data include information on the survival and N2 stations of 402 patients.
Results: A frequently metastasized single N2 station was the lower pretracheal station in primary tumors in the right upper lobe, the subaortic station in the left upper lobe, and the subcarinal station in the right middle or lower lobe and the left lower lobe. In multiple N2 stations, the frequency of metastasis of the N2 station observed in a single N2 station was as high as 72% to 89%, and one or two other frequently metastasized stations were added to each group. Regarding the survival of patients with a primary tumor in each lobe except for the left lower lobe, a single N2 station resulted in a significantly better survival than did multiple N2 stations. Furthermore, the overall survivals classified according to each primary site showed a significant difference among the four primary sites (P = .04).
Conclusions: The primary tumors in each lobe showed a prevalence of N2 station(s). The number of N2 stations is a good prognosticator except in patients with a primary tumor in the left lower lobe. In addition, the site of a primary tumor itself is also considered to influence the survival of the patients.

	Introduction

Top Abstract Introduction Patients and methods Results Discussion Appendix References

 
Survival of patients with stage IIIA-N2 disease is known to be variable. Even if the subjects are limited to patients with completely resected pathologic stage IIIA-N2 non–small cell lung cancer (NSCLC), that situation does not change. Therefore, extensive clinical research has been done to elucidate the prognostic factors that are useful for identifying a homogeneous survival subgroup among patients undergoing resection. The prognostic factors ^1-7 identified so far are the pathologic characteristics of the tumor, the extent of the primary tumor, the clinical N status, the number of N2 stations, the presence of subcarinal N2 disease, the extracapsular spread in N2 disease, and the extent of the resection. Among these prognostic factors, the number of N2 stations (single vs multiple) has been recognized as one of the most important. ^1,6 In our previous study using the same subjects as in the present study, the number of N2 stations was also found to be the most important prognostic factor on the basis of a multivariate analysis. ⁸ To our knowledge, however, the site of N2 station(s) actually involved when comparing a single N2 station with multiple N2 stations has not been reported. In addition, whether the importance of the number of N2 stations as a prognostic factor is influenced by the location of the primary tumor remains to be elucidated. In the present study, we therefore attempted to clarify these issues.

	Patients and methods

Top Abstract Introduction Patients and methods Results Discussion Appendix References

 
Subjects
Patients with NSCLC and pathologic stage IIIA-N2 disease completely resected by either a lobectomy or a pneumonectomy from January 1992 to December 1993 who did not receive preoperative chemotherapy or radiotherapy were the subjects of a questionnaire survey on survival. The survey was conducted by the Lung Cancer Surgical Study Group of the Japan Clinical Oncology Group (JCOG) as of July 1999. The data included information on the survival and the involved N2 station(s) from 406 patients. ⁸ All patients underwent computed tomographic scanning of the chest, but mediastinoscopy was not routinely used. Four patients were excluded from the present study because the primary tumor was located in only the main bronchus or the truncus intermedius. The characteristics of all 402 patients are shown in Table 1.

Survival and local recurrence
The overall survival was defined as the time from the operation until death from any cause. Survival curves were drawn by means of the Kaplan-Meier method and a statistical evaluation of the curves was done by means of a log-rank test.

	Results

Top Abstract Introduction Patients and methods Results Discussion Appendix References

 
General
The 3- and 5-year survivals of all 402 patients were 42% (95% confidence interval [CI]: 37%-47%) and 31% (95% CI: 26%-35%), respectively. The 3- and 5-year survivals of the 209 patients with a single N2 station were 51% (95% CI: 44%–58%) and 43% (95% CI: 36%–49%), whereas those of the 193 patients with multiple N2 stations were 32% (95% CI: 25%–39%) and 17% (95% CI: 12%–22%), respectively. The survival of patients with a single N2 station was significantly better than that of patients with multiple N2 stations (P < .0001).

Right upper lobe (table 2 and figure 1)
A frequently metastasized N2 station was station 3 in patients with a single N2 station and stations 1, 3, and 4 in patients with multiple N2 stations. Although the frequency of station 7 involvement was as low as 3% in patients with a single N2 station, it reached as high as 30% in patients with multiple N2 stations.

View larger version (15K): [in this window] [in a new window]   Fig. 1. Survival curves of patients with a primary tumor in the right upper lobe. Each bar represents a 95% confidence interval of the survival.

Right middle or lower lobe (table 3 and figure 2)
A frequently metastasized N2 station was station 7 in patients with a single N2 station and stations 3 and 7 in patients with multiple N2 stations. Although the frequency of station 1 involvement was only 2% in patients with a single N2 station, that increased to 39% in those with multiple N2 stations.

View larger version (15K): [in this window] [in a new window]   Fig. 2. Survival curves of patients with a primary tumor in the right middle or lower lobe. Each bar represents a 95% confidence interval of the survival.

Left upper lobe (table 4 and figure 3)
A frequently metastasized N2 station was station 5 in patients with a single N2 station and stations 4, 5, and 6 in patients with multiple N2 stations. Although no involvement was observed in the superior mediastinal N2 stations, including stations 1 to 3 in patients with a single N2 station, the frequency of involvement in stations 1 plus 2 and station 3 increased to 10% and 37% in those with multiple N2 stations, respectively.

View larger version (15K): [in this window] [in a new window]   Fig. 3. Survival curves of patients with a primary tumor in the left upper lobe. Each bar represents a 95% confidence interval of the survival.

Left lower lobe (Table 5 and Figure 4)
A frequently metastasized N2 station was station 7 in patients with a single N2 station and stations 5 and 7 in patients with multiple N2 stations.

View larger version (15K): [in this window] [in a new window]   Fig. 4. Survival curves of patients with a primary tumor in the left lower lobe. Each bar represents a 95% confidence interval of the survival.

Comparison of survival between primary sites (Figure 5)
The 5-year survival was 43% (95% CI: 33%-52%) in patients with a primary tumor in the right upper lobe, 23% (95% CI: 16%-31%) in the right middle or lower lobe, 30% (95% CI: 21%-39%) in the left upper lobe, and 23% (95% CI: 12%-35%) in the left lower lobe. A statistically significantly difference in survival was observed among the four primary sites (P = .0378). The prognosis was not influenced by the side of the primary tumor (P = .2969); the 5-year survival was 33% (95% CI: 26%-39%) in right-sided tumors and 28% (95% CI: 21%-35%) in left-sided tumors.

View larger version (19K): [in this window] [in a new window]   Fig. 5. Survival curves of the patients classified by the primary tumor site. RUL, Right upper lobe; RMLL, right middle and lower lobes; LUL, left upper lobe; LLL, left lower lobe.

	Discussion

Top Abstract Introduction Patients and methods Results Discussion Appendix References

The relatively high frequency of skip mediastinal lymph node metastasis, in which the affected lymph nodes were not in the prevalent location for metastasis, in patients with a single N2 station was an interesting finding in this study. In particular, in cancer of the right middle or lower lobe and of the left lower lobe, 30% of the patients with a single N2 station had metastasis to abnormal sites: to the right-sided superior mediastinal nodes, including stations 1 to 4, and to the left-sided nodes, including stations 4 to 6, respectively. Takizawa, ⁹ Riquet, ¹² and their associates reported that among the dissected lymph nodes that were determined to have metastasis on the basis of a postoperative pathologic examination, 68% and 20% of these nodes, respectively, were judged to have no metastasis according to intraoperative macroscopic examinations. On the basis of the above findings and our present data, a systemic nodal dissection is thus thought to be necessary, not only to obtain a precise staging of the disease but also to eradicate the intrathoracic disease.

The present study demonstrated that the number of N2 stations (single vs multiple N2 stations) is an important prognostic factor in patients with a primary tumor in the right lung and the left upper lobe but not in the left lower lobe. However, at the same time, the prognosis of patients with a single N2 and multiple N2 stations was demonstrated to be influenced by the location of the primary tumor. Among patients with a primary tumor in the right upper lobe, the 5-year survival was 60% in patients with a single N2 station and 23% in those with multiple N2 stations. On the other hand, the 5-year survival among patients with a primary tumor in the right middle or lower lobe was 37% in patients with a single N2 station and 9% in those with multiple N2 stations.

To our knowledge, whether the location of the primary tumor in patients with completely resected pathologic stage IIIA-N2 NSCLC influences survival has yet to be elucidated. In the present study, the prognosis of patients was significantly different depending on which of the four primary sites was affected. The 5-year survival was 23% in patients with a primary tumor in either the right middle and lower lobes or the left lower lobe. This figure was worse than the 43% survival in right upper lobe tumors or the 30% survival in left upper lobe tumors. These observations indicate that lung cancer in the lower lobe with N2 disease may be more advanced than cancer in the upper lobe with N2 disease.

Subcarinal lymph node metastasis, which is most frequently observed among the metastasized mediastinal lymph nodes of patients with cancer in the lower lobe including the middle lobe, is thus reported to adversely influence survival. ^7,13,14 However, these poor results may reflect the poor prognosis of patients with cancer in the lower lobe. In fact, the survival of patients with a single N2 station whose primary tumor was located in the middle or lower lobes in the present study was not influenced by the presence or absence of the subcarinal lymph node metastasis: the 5-year survival of cancer in the right middle or lower lobe was 36% (95% CI: 20%-51%) in the 38 patients with subcarinal nodal involvement as a single N2 station and 34% (95% CI: 14%-53%) in the 23 patients with the nodal involvement of the other sites as a single N2 station (P = .3738; data not shown in the "Results"). In patients with cancer in the left lower lobe, the 5-year survival was 22% (95% CI: 1%-43%) in the 17 patients with the subcarinal nodal involvement as a single N2 station and 23% (95% CI: 0%-46%) in the 13 patients with the nodal involvement of the other sites as a single N2 station (P = .9064; data not shown in the "Results").

In conclusion, the number of N2 stations (single N2 vs multiple N2 stations) and the location of the primary tumor was found to influence the survival of patients with completely resected stage IIIA-N2 NSCLC. Therefore, these factors should be included as a stratified factor in a prospective clinical trial of such patients.

	Appendix

Top Abstract Introduction Patients and methods Results Discussion Appendix References

 
Additional participating institutions and principal investigators
Nagasaki University School of Medicine (Hiroyoshi Ayabe, MD)

Osaka Prefectural Adult Disease Center (Ken Kodama, MD)

Iwaki Kyoritsu Hospital (Yoshio Yamane, MD)

Tochigi Cancer Center (Kohei Yokoi, MD)

Tohoku University School of Medicine (Shigefumi Fujimura, MD)

Saitama Cancer Center (Mitsunobu Yamamoto, MD)

Keio University School of Medicine (Koichi Kobayashi, MD)

National Okinawa Hospital (Keiichiro Gengka, MD)

Gunma Cancer Center (Sachio Shimizu, MD)

National Cancer Center, East (Kanji Nagai, MD)

Kumamoto Central Hospital (Noboru Fujino, MD)

Cancer Institute (Ken Nakagawa, MD)

Shikoku Cancer Center (Masao Nakata, MD)

National Kure Hospital (Kenji Nakamura, MD)

Takatsuki Red-Cross Hospital (Wataru Chiba, MD)

Ibaragi Cancer Center (Ryuta Amamiya, MD)

Osaka City General Hospital (Hirohito Tada, MD)

Kyorin University School of Medicine (Tomoyuki Goya, MD)

	Acknowledgments

 
We thank Masanori Shimoyama, MD, chairperson of the Japan Clinical Oncology Group; Nagahiro Saijo, MD, chairperson of the Lung Cancer Study Group of the Japan Clinical Oncology Group for his support in this study; Satoru Inutsuka, MD, of Kyushu University for his help with the statistical analysis; Brian Quinn for his critical review; and Yumiko Oshima for her help in preparing the manuscript.

	References

Top Abstract Introduction Patients and methods Results Discussion Appendix References

 

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