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Eur J Cardiothorac Surg 2001;19:555-561
© 2001 Elsevier Science NL

Prognostic factors in patients with resected pathologic (p-) T1-2N1M0 non-small cell lung cancer (NSCLC)

Department of Thoracic Surgery, Faculty of Medicine, Kyoto University, Shogoin-kawahara-cho 54, Sakyo-ku, Kyoto 606-8507, Japan

Received 9 October 2000; received in revised form 12 February 2001; accepted 8 March 2001.

Corresponding author. Tel.: +81-75-751-3835; fax: +81-75-751-4647
e-mail: wadah{at}kuhp.kyoto-u.ac.jp

	Abstract

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion References

 
Objectives: To clarify prognostic factors in resected pathologic (p-) T1-2N1M0 non-small cell lung cancer (NSCLC). Methods: A total of 95 consecutive patients who underwent complete tumor resection and mediastinal dissection for pT1-2N1M0 NSCLC between 1976 and 1997 were retrospectively reviewed. p53 status and proliferative activity were evaluated immunohistochemically. Results: The extent of N1 stations and p53 status proved to be significant prognostic factors. The 5-year survival rate for tumor without hilar node (#10) involvement was 66%, significantly higher than that for tumor with #10 involvement (39%, P<0.01). The 5-year survival rate for tumor with aberrant p53 expression was 37%, significantly lower than that for tumor without aberrant p53 expression (74%, P<0.01). There proved to be no significant difference in the prognosis between pT1 disease and pT2 disease; the 5-year survival rates for pT1 and pT2 diseases were 62 and 56%, respectively. Age, gender, performance status, grade of tumor differentiation, histological type, or proliferative activity were not significant factors. Multivariate analysis of prognostic factors using Cox's proportional hazard model confirmed these results. Conclusions: Involvement of the hilar node and aberrant p53 expression were significant factors to predict a worse prognosis in resected T1-2N1M0 NSCLC.

Key Words: Lung cancer • Stage II • N1 • Prognosis • Nodal station • p53

	1. Introduction

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion References

 
Postoperative survival for non-small cell lung cancer (NSCLC) remains poor [1–3]. The identification of prognostic factors is important in order to improve the prognosis, and many studies on prognostic factors in pathologic (p-)stage I NSCLC have been conducted. However, only a few studies have focused on the postoperative prognosis of pT1-2N0M0 (p-stage II, N1) disease [4–7], probably because of the relatively small number of patients.

In addition to a variety of clinical characteristics, it has recently been demonstrated that biological features of the tumor may affect the postoperative survival. Among these biomarkers, abnormality of the p53 gene, a tumor suppressor gene, is the most common disorder shown in a variety of malignant tumors, including NSCLC [8,9]. p53 status has been reported to be clinically important in that an abnormal p53 status may serve not only as a significant factor to predict poor prognosis [10], but also as a factor to determine sensitivity to radiation therapy and/or chemotherapy [11]. However, the clinical significance of biological features of tumor tissues, including p53 status, has not been established in NSCLC, and decision-making in therapy for NSCLC patients based on these biological factors is not recommended [12].

In the present study, therefore, we reviewed several prognostic factors, including biomarkers (p53 status and proliferative activity), in completely resected pT1-2N1M0 NSCLC.

	2. Patients and methods

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion References

 
A total of 95 consecutive patients with pT1-2N1M0 NSCLC who underwent thoracotomy with a complete mediastinal lymph node dissection without any preoperative therapy at the Department of Thoracic Surgery, Kyoto University, from January 1976 through December 1997, were retrospectively reviewed (Table 1). Preoperative clinical staging (c-stage) and postoperative p-stage were re-evaluated and determined by the current tumor-node-metastasis (TNM) classification as revised in 1997 [2]. The histological type and cell differentiation were determined using the classification by the World Health Organization. Performance status (PS) was determined according to the ECOG scale as follows: grade 0, fully active, able to carry on all pre-disease activities without restriction; grade 1, restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature, e.g. light house work or office work; grade 2, ambulatory and capable of all self-care, but unable to carry work activities, up and about >50% of waking hours; grade 3, capable of only limited self-care, confirmed to bed or chair 50% of waking hours; grade 4, completely disabled, cannot carry on any self-care, totally confirmed to bed or chair [12]. For all of these patients, the inpatient medical records, chest X-ray films, whole-body CT films, bone and gallium scanning data, and records of surgery were reviewed. Follow-up survey was performed on 31st March 2000, which was successfully completed for 100% of the patients; the mean follow-up period was 2011 days.

p53 status and proliferative activity were examined in patients operated between 1985 and 1997, because tumor specimens had not been stored and could not serve for evaluation in patients operated before 1985. p53 status was determined by immunohistochemical staining (IHS) [11]. Cell proliferation was also evaluated by immunohistochemical detection of proliferating cell nuclear antigen (PCNA) which is expressed in the cell nucleus during late G1 and S stages of cell cycle [13]. All tumor specimens cut from the primary tumor were immediately fixed in 10% (v/v) formalin, and then embedded in paraffin. Serial 4 µm sections were prepared from each sample, and served for routine hematoxylin and eosin (HE) staining and IHS. The procedure of IHS using streptoavidin–biotinylated horseradish peroxidase complex method (LSAB kit; DAKO Japan, Kyoto, Japan) was described in the previous paper [11,14,15]. In brief, dewaxed sections were heated in a microwave oven for 5 min, three times each, to retrieve their antigeneities. Mouse anti-human p53 monoclonal antibody (MoAb) DO-7 (mouse IgG2b, kappa, 250 µg/ml, DAKO Japan) diluted at 1:50 and mouse anti-human PCNA, MoAb PC-10 (mouse IgG2a, kappa, 400 µg/ml, DAKO Japan) diluted at 1:50 were used as the primary antibody. A total of 1000 tumor cells were counted for positive staining, and the percentages of positive cells were determined. The aberrant p53 expression was judged, when the percentage of cancer cells with nuclear positive staining exceeded 5%. Proliferative activity was represented by the percentage of PCNA-positive cancer cells (proliferative index, PI).

2.1. Statistical methods
Counts were compared using the Chi-square test. Continuous data were compared using the unpaired t-test if the distribution of samples was normal, or using the Mann–Whitney test if the sample distribution was asymmetrical. The postoperative survival rate was analyzed by the Kaplan–Meier method, and the differences in survival rates were assessed by the log-rank test. Multivariate analysis of prognostic factors was performed using Cox's regression model. Variables that achieved statistical significance (P<0.05) in the univariate analysis were sequentially included in a multivariate analysis using a stepwise forward Cox regression model [16]. All statistical manipulations were performed using the SPSS for Windows software system (SPSS, Inc., Chicago, IL, 1993).

	3. Results

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion References

 
3.1. Characteristics of patients and postoperative survival
The characteristics of patients and the influence of those characteristics on the postoperative survival are shown in Table 1. Univariate analysis demonstrated that the proximal extent of involved nodal station proved to be a significant factor. The 5-year survival rate was 39% when the hilar node (#10) was involved, whereas the 5-year survival rate was 62% when the proximal end of the involved nodal station was an inter-lobar node (#11). When the proximal end was a lobar (#12) or segmental (#13) node, the 5-year survival rate was 72%. There was significant differences in the survival between these three diseases (P=0.05 between disease with #10 involvement and disease with #11 involvement; P=0.02 between disease with #10 involvement and disease with #12–13 involvement). Since there was no significant difference in the prognosis between disease with #11 involvement and that with #12–13 involvement, postoperative survival was analyzed according to whether or not #10 was involved (Fig. 1). There proved to be a significant difference between disease with and disease without #10 involvement (5-year survival rates, 39 vs. 66%; and 95% confidence interval of survival time, 1122–2896 vs. 3555–5122 days; P<0.01). The number of involved nodes did not influence the postoperative survival.

View larger version (18K): [in this window] [in a new window]   Fig. 1. Postoperative survival of patients with completely resected p-stage II, N1 NSCLC. Comparison between survival for disease with involvement of the hilar node (#10-positive) and that for disease without #10 involvement (#10-negative).

3.2. p53 status and proliferative activity and postoperative survival
Aberrant expression of p53 was seen in 33 (49%) of 67 patients (Table 2). p53 aberrant expression was more frequently seen in pT2 disease (25 of 42 patients (60%)) than in pT1 disease (eight of 25 patients (32%); P=0.04). There was no significant correlation between p53 status and age, sex, PS, histological type, grade of tumor differentiation, involved nodal station, or number of involved nodes. The 5-year survival rate for tumors with p53 aberrant expression was 37% (95% confidence interval of survival time, 935–1637 days), significantly lower than that for tumors without p53 aberrant expression (74%; 95% confidence interval of survival time, 3555–5122 days; Fig. 2).

View larger version (18K): [in this window] [in a new window]   Fig. 2. Postoperative survival of patients with completely resected p-stage II, N1 NSCLC. Comparison between survival for tumor with p53 aberrant expression (p53-positive) and that for tumor without p53 aberrant expression (p53-negative).

View larger version (18K): [in this window] [in a new window]   Fig. 3. Postoperative survival of patients with completely resected p-stage II, N1 NSCLC. Comparison between survival for tumor with a lower proliferative index (lower-PI) and that for tumor with a higher proliferative index (higher-PI).

	4. Discussion

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion References

 
In the present study, we demonstrated that involvement of the hilar node (#10) and p53 aberrant expression were significant factors to predict a poor prognosis in completely resected pT1-2N0M0 NSCLC. According to the current TNM system, T1N1M0, T2N1M0 and T3N0M0 diseases were classified as stage II. Among them, T1N1M0 and T2N1M0 diseases were subdivided into stages IIA and IIB, respectively, according to the T-factor [2]. However, it was not demonstrated in the present study that pT-factor affected the postoperative survival of p-stage II, N1 disease. Yoshino and coworkers reported that the 5-year survival rates for pT1N1M0 and pT2N1M0 were 54.2 and 48.8%, and documented no difference [7]. Ichinose and coworkers also reported that the 5-year survival rate for pT2N1M0 (48.9%) was comparable with that for pT1N1M0 (50.0%) [8]. Ferguson and coworkers also demonstrated no difference in the postoperative survival between pT1N1M0 and pT2N1M0 [5]. Since the number of pT1N0M0 patients is extremely small, the validity of subdividing of pT1N0M0 into an independent stage (IIA) should be examined in further studies.

According to the current TNM system, hilar (#10), lobar (#11), inter-lobar (#12), and segmental (#13) nodes were classified into N1 nodes. Yano and coworkers reviewed resected N1, NSCLC, and revealed that the postoperative survival associated with lobar N1 was significantly better than that for hilar N1 disease (64.5 vs. 39.7% at 5 years; P=0.014) [17]. Riquet and coworkers also documented a significant difference in the postoperative survival between N1 diseases of different nodal involvement [18]. van Velzen and coworkers also demonstrated that the 5-year survival rate of patients with lobar node involvement was superior to that of patients with hilar node involvement in pT1N1M0 disease (67.3 vs. 29.9%; P=0.016), as well as in pT2N1M0 disease (57.3 vs. 30.3%; P=0.0028) [19,20]. All of these studies, as well as the present study, clearly demonstrated that N1 disease was a heterogeneous group that should be subdivided according to the level of N1 station involved. Although further review of the prognosis in a larger patient-group of pT1-2N0M0 NSCLC should be conducted, p-stage II disease may be subdivided according to N1 level involved, not T-factor.

Recent advances in molecular biology have revealed a variety of biological and genetic disorders involved in the development and progress of malignant tumors, including NSCLC. However, the clinical significance of biomarkers, including p53 status, has not been established in NSCLC [12]. We have already revealed that p53 status is not a significant prognostic factor, but also a significant predictive factor of postoperative adjuvant therapy in resected NSCLC [11]. In the present study, p53 aberrant expression proved to be a significant factor to predict a poor survival in resected pT1-2N0M0 NSCLC. To establish the clinical value, mutations of p53 gene, as well as p53 aberrant expression, should be examined in a larger patient-population of N1 disease.

We have already demonstrated that oral administration of UFT, a 5-fluorouracil derivative chemotherapeutic agent, is effective in completely resected NSCLC, especially p-stage I disease [21–23]. There has been no study demonstrating the efficacy of UFT for pT1-2N0M0 disease, probably because of the small number of patients. A multi-institutional, prospective randomized study should be conducted to examine the efficacy for such patients. In conclusion, p-stage II, N1 disease (T1-2N0M0) was a mixed group with nodes of different involvement, and different nodal and p53 status.

	Acknowledgments

 
The authors thank Drs Yozo Kawano, Tatsuo Nakagawa, Tetsuya Takata, Hiroki Oyanagi, and Hiromichi Katakura for technical assistance in this work. Part of this study is supported by ‘Ueda-Tahei Momorial Fund’.

	Footnotes

 
Presented at the 14th Annual Meeting of the European Association for Cardio-thoracic Surgery, Frankfurt, Germany, October 7–11, 2000.

	References

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion References

 

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