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Ann Thorac Surg 1999;67:927-932
© 1999 The Society of Thoracic Surgeons

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Original Articles

Prognostic factors in clinical stage I non–small cell lung cancer

^a Division of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan

Accepted for publication October 17, 1998.

Address reprint requests to Dr Suzuki, Division of Thoracic Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
e-mail: kjsuzuki{at}east.ncc.go.jp

	Abstract

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Background. Management of patients with early-stage lung cancer but a poor prognosis is controversial.

Methods. Between January 1987 and December 1994, 365 patients with clinical stage I disease underwent surgical resection at our hospital. Eight preoperative clinical variables were entered into univariate and multivariate analyses to determine their impacts on 5-year survival.

Results. The 3-year and 5-year survival rates were 78.1% and 66.5%, respectively. In the multivariate analysis, clinical T2 status and preoperative high serum carcinoembryonic antigen levels were independent significant factors indicative of a poor prognosis (hazard ratio, 2.20 and 1.88, respectively). Patients with both of these factors had 3-year and 5-year survival rates of 65% and 38% (p < 0.001), and the risk of death for this subgroup was 4.14 times greater than that of the overall clinical stage I population.

Conclusions. A subgroup with clinical T2 disease and preoperative high serum carcinoembryonic antigen levels had a significantly poorer prognosis among patients with clinical stage I lung cancer. For this subgroup, a complete preoperative staging workup and multimodal therapy, especially induction chemotherapy, instead of surgical intervention alone could be beneficial.

	Introduction

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The prognosis for patients with surgically resected lung cancer has not been satisfactory, as the 5-year survival rate is no more than 70% even for patients in stage I [1]. This means that approximately 30% of patients have recurrence, generally in distant organs [2]. For these patients, surgical resection has not been curative, but multimodality treatment might be beneficial. Because encouraging results have been seen in patients with locally advanced disease, the combined modality approach is now being applied to the patient population with early-stage lung cancer [3, 4]. Although postoperative adjuvant therapy in patients with completely resected stage I non–small cell lung cancer failed to show prognostic benefit [5], induction (preoperative) treatment may be effective in these patients, as it was in patients with stage III disease [6, 7].

One of the major problems in this setting is the unnecessary additional treatment given to a large number of patients who could have been cured by surgical resection alone. Therefore, clinical factors to identify the early-stage lung cancer subgroup with a poor prognosis are necessary. Although many prognostic factors have been reported [1, 8, 9], most have been pathologic findings. As stage migration, ie, disagreement between clinical and pathologic staging, is frequent in all stages of lung cancer, clinical factors are essential for the preoperative identification of the subgroup with a poor prognosis.

In regard to patients suspected of having disease limited to one hemithorax, there has been much debate about the minimum number of investigations required to prove metastatic spread [10]. In Japan, plain chest roentgenography, chest computed tomography (CT), abdominal CT or ultrasonography, brain CT or magnetic resonance imaging, and bone scanning are routinely done preoperatively in most centers. The cost has not been a problem in Japan to date. However, if the patient with a poor prognosis could be identified by a few clinical markers, some of these preoperative studies for metastatic spread would be indicated for only this subgroup, which would save money.

We performed a retrospective study involving patients with surgically resected clinical stage I lung cancer to try to identify a subgroup with a poor prognosis, as those patients might benefit from neoadjuvant therapy or a complete preoperative staging workup.

	Material and methods

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Between January 1987 and December 1994, 572 patients underwent surgical resection of primary lung cancer at our hospital. Of them, 365 patients (63.8%) were classified clinically as stage I. There were 216 men and 149 women, a male to female ratio of 1.4:1. Age ranged from 25 years to 85 years (median age, 64 years). Plain chest roentgenography, chest CT, abdominal CT or ultrasonography, brain CT or magnetic resonance imaging, and bone scanning were routinely performed preoperatively in all patients. Clinical mediastinal and hilar node status was considered positive if the results of chest CT showed a shortest axis larger than 1.0 cm. Histologic typing was determined according to the World Health Organization classification [11], and stage of disease was based on the TNM classification of the International Union Against Cancer [12]. The following were excluded from the study: patients with an incomplete resection or conservative resection, ie, partial resection or segmentectomy; patients with multiple lung tumors; patients who did not undergo mediastinal sampling or dissection; patients with small cell carcinoma or low-grade malignancy, such as bronchial carcinoid; patients with hilar squamous cell carcinoma; and patients receiving preoperative therapy.

Methods
The medical record of each patient was examined for age (<70 years versus 70 years), sex, pack-years of smoking (<5 versus 5), serum carcinoembryonic antigen (CEA) level (<5.0 versus 5.0 ng/mL), serum squamous cell carcinoma antigen (SCC) level (<1.5 versus 1.5 mg/mL), tumor location (left versus right), clinical T status (cT1 versus cT2), and histologic typing (adenocarcinoma versus others). These factors were entered into univariate and multivariate analyses to determine their impact on the 5-year survival of clinical stage I patients. Discrepancy between clinical and pathologic TNM stages, ie, stage migration, was also examined on the basis of the significant prognostic factors.

Statistical analysis
The median follow-up for the 267 patients alive at the time of the study was 48 months. The length of survival was defined as the interval in months between the day of surgical resection of lung carcinoma and the date of death from any cause or last follow-up visit. The survival rates were calculated by the Kaplan-Meier method [13], and univariate analyses were performed by means of the log-rank test. Because the median potential follow-up was less than 5 years, we calculated 3-, 4-, and 5-year survivals separately. Multivariate analyses were performed by means of the Cox proportional hazards model on Stat View J 4.11 with a Power Macintosh 8100/100 AV [14].

Because CEA values, SSC values, or both were not available for all patients, we initially performed multivariate analyses for all patients with clinical stage I lung cancer using the six variables other than serum CEA and SCC levels. We also performed multivariate analyses using patients in whom serum CEA levels or SCC levels, or both were available. The CEA value was obtained in 269 (73.7%) and the SCC in 272 (74.5%) of the 365 clinical stage I lung carcinoma patients. As there were no differences in clinical background between patients with and without CEA or SCC values, the results of the multivariate analysis for patients with CEA or SCC data were considered to represent all patients. Statistical analysis was considered to be significant when the probability value was less than 0.01.

	Results

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Overall survival
The prognosis for the 365 patients with clinical stage I non–small cell lung cancer is shown in Figure 1. The 3-year and 5-year survival rates were 78.1% and 66.5%, respectively.

View larger version (18K): [in this window] [in a new window]   Fig 1. Survival curve for patients with clinical stage I non–small cell lung cancer. Bars indicate 99% confidence intervals (CI).

Multivariate analysis among patients for whom serum CEA or SCC levels or both were available was also performed using the eight clinical variables. Clinical T2 status was again a significant factor (p = 0.002; HR, 2.20; 99% confidence interval, 1.15 to 4.20), and a high serum CEA level was also an independent factor for a poor prognosis (p = 0.009; HR, 1.88; 99% confidence interval, 1.01 to 3.51) (Table 2). Figures 2 and 3 show survival curves based on the clinical T status and serum CEA status, respectively. The 5-year survival rate was only 38% for patients with both of these factors versus 84.8% for patients with neither of them. The difference in survival among patients with clinical stage I non–small cell lung cancer with reference to these two clinical prognostic factors was extremely significant (p < 0.001) (Table 3). The survival curves are shown in Figure 4.

View larger version (22K): [in this window] [in a new window]   Fig 2. Survival by clinical T status patients with clinical stage I non–small cell lung cancer. A significant differences was observed (p < 0.001, log-rank test).

View larger version (22K): [in this window] [in a new window]   Fig 3. Survival by serum carcinoembryonic antigen (CEA) level for patients with clinical stage I non–small cell lung cancer. A significant difference was observed (p = 0.005, log-rank test).

View larger version (28K): [in this window] [in a new window]   Fig 4. Survival by clinical T status and serum carcinoembryonic antigen levels patients with clinical stage I non–small cell lung cancer. A significant difference was observed (p < 0.001, log-rank test).

	Comment

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

Like Icard and coworkers [17], we found preoperative serum CEA level to be a significant prognostic factor in lung cancer patients. Although univariate analysis showed several other significant prognostic factors, only clinical T2 status was an additional factor for a poor prognosis in our multivariate analyses. According to our results, the risk of death could be estimated for patients with clinical stage I non–small cell lung cancer by multiplying the HRs for all factors present. For clinical stage I lung cancer patients with a high serum CEA level and a clinical T2 status, the risk of death is 4.14 (2.20 x 1.88) times greater than that for the overall population (see Table 2). The 5-year survival rate for this subgroup was 38%, which is almost equal to that of stage IIIA disease. Further, stage migration was frequently observed in this subgroup, and nearly half of them were upstaged to stage III postoperatively. In addition, most stage III disease was due to pathologic N2 disease. The prognosis for patients undergoing surgical resection for clinical N0/pathologic N2 lung cancer is better than that for patients with clinical N2/pathologic N2 lung cancer [18], and the former subgroup of patients might also benefit from preoperative multimodal therapy [19]. Therefore, induction chemotherapy or chemoradiotherapy followed by surgical intervention might be a therapeutic option for the subgroup with clinical T2 disease and high serum CEA levels among clinical stage I non–small cell lung cancer patients. Otherwise, mediastinoscopy is indicated for patients with T2 tumor and high serum CEA levels, because upstaging was common (especially to stage IIIA) in this population. Positron emission tomography with a tracer of ¹⁸F-fluorodeoxyglucose has been reported to be useful to evaluate mediastinal nodal status [20]. If positron emission tomography is available, it is indicated for patients with a high probability of N2 disease, ie, patients with high serum CEA levels and T2 tumor. Future clinical trials are mandatory to evaluate this strategy for this category of patients, ie, those with early clinical-stage lung cancer with a poor prognosis.

When serum CEA level was excluded, multivariate analyses revealed two other significant factors for a poor prognosis: clinical T2 status and age of 70 years or older. More than 5 pack-years of smoking was a marginally independent prognostic factor. However, serum CEA level was a more potent prognostic factor than smoking status. Maximum tumor dimension has been considered one of the strongest prognostic indicators [1, 8], which is consistent with our results. Clinical T2 status and serum CEA levels are independent prognostic factors that can be obtained preoperatively. In the future, molecular analysis on genomic deoxyribonucleic acid or ribonucleic acid extracted from the preoperative pathologic specimens, such as transbronchial biopsy tissue and exfoliated sputum cells, may provide more precise predictive information [21].

We also attempted to clarify the indications for preoperative staging of patients with clinical stage I non–small cell lung cancer. In patients suspected of having disease limited to one hemithorax, controversies exist as to the minimum number of studies necessary to establish the presence or absence of metastatic spread [10]. In our study, patients with T1 tumor and normal serum CEA levels had a 5-year survival rate of 85%, whereas that of patients with T2 tumor and high serum CEA levels was 38%. Although these patients are in the same clinical stage I, it is only reasonable to manage these two groups differently. For patients in clinical stage I, we now evaluate only a plain chest roentgenogram and chest computed tomogram preoperatively unless T2 tumor and high serum CEA levels are present.

In conclusion, two clinical prognostic factors, clinical T2 status and high serum CEA levels, could be used to stratify lung cancer patients with clinical stage I disease. Patients with both of these factors might benefit from preoperative multimodal therapy. A complete preoperative workup for clinical stage I non–small cell lung cancer is necessary if the patients have clinical T2 disease and high serum CEA levels.

	Acknowledgments

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
We thank Dr Satoshi Sasaki, Epidemiology and Biostatistics Division, National Cancer Center Research Institute East, for technical support in the statistical analyses. We also thank Drs Koichi Goto and Hidenori Kawasaki, Division of Thoracic Oncology, National Cancer Center Hospital East, for their critical reviews.

The study was supported in part by a grant-in-aid for cancer research from the Ministry of Health and Welfare, Japan.

	References

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 

1. Harpole D.H., Jr, Herndon J.E., II, Young W.G., Jr, Wolfe W.G., Sabiston D.C., Jr Stage I nonsmall cell lung cancer. A multivariate analysis of treatment methods and patterns of recurrence. Cancer 1995;76:787-796.[Medline]
2. Feld R., Rubinstein L.V., Weisenberger T.H. Sites of recurrence in resected stage I non-small-cell lung cancer: a guide for future studies. J Clin Oncol 1984;2:1352-1358.[Abstract]
3. Pisters K.M.W., Ginsberg R.J. Phase II trial of induction paclitaxel and carboplatin in early stage (T2N0, T1-2N1, and selected T3N0-1) non–small cell lung cancer. Proc Am Soc Clin Oncol 1998;17:451a.
4. Martini N., Kris M.G., Ginsberg R.J. The role of multimodality therapy in locoregional non–small cell lung cancer. Surg Oncol Clin North Am 1997;6:769-791.[Medline]
5. Feld R., Rubinstein L., Thomas P.A. Adjuvant chemotherapy with cyclophosphamide, doxorubicin, and cisplatin in patients with completely resected stage I non-small-cell lung cancer. The Lung Cancer Study Group. J Natl Cancer Inst 1993;85:299-306.[Abstract/Free Full Text]
6. Roth J.A., Fossella F., Komaki R., et al. A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer. J Natl Cancer Inst 1994;86:673-680.[Abstract/Free Full Text]
7. Rosell R., Gomez-Codina J., Camps C., et al. A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small-cell lung cancer. N Engl J Med 1994;330:153-158.[Abstract/Free Full Text]
8. Kurokawa T., Matsuno Y., Noguchi M., Mizuno S., Shimosato Y. Surgically curable "early" adenocarcinoma in the periphery of the lung. Am J Surg Pathol 1994;18:431-438.[Medline]
9. Ichinose Y., Yano T., Asoh H., Yokoyama H., Yoshino I., Katsuda Y. Prognostic factors obtained by a pathologic examination in completely resected non-small-cell lung cancer. An analysis in each pathologic stage. J Thorac Cardiovasc Surg 1995;110:601-605.[Abstract/Free Full Text]
10. Ginsberg R. Diagnosis and staging: NSCLC. In: DeVita V.T., ed. Cancer: principles and practice in oncology. New York: Lippincott-Raven Publishers, 1997:868-877.
11. World Health Organization. Histological typing of lung tumors, 2nd ed. Geneva: World Health Organization, 1981.
12. Hermanek P., Sobin L.H. UICC TNM classification of malignant tumours, 4th ed. Berlin: Springer-Verlag, 1992.
13. Kaplan E.L., Meier P. Nonparametric estimation for incomplete observations. J Am Stat Assoc 1958;53:457-481.
14. Cox D.R. Regression models and life-tables. J R Stat Soc [B] 1972;34:187-220.
15. PORT Meta-analysis Trialists Group. Postoperative radiotherapy in non-small-cell lung cancer: systematic review and meta-analysis of individual patient data from nine randomised controlled trials. Lancet 1998;352:257-263.[Medline]
16. Non–Small Cell Lung Cancer Collaborative Group. Chemotherapy in non–small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Br Med J 1995;311:899-909.[Abstract/Free Full Text]
17. Icard P., Regnard J.-F., Essomba A., Panebianco V., Magdeleinat P., Levasseur P. Preoperative carcinoembryonic antigen level as a prognostic indicator in resected primary lung cancer. Ann Thorac Surg 1994;58:811-814.[Abstract]
18. Cybulsky I.J., Lanza L.A., Ryan M.B., Putnam J.B., Jr, McMurtrey M.M., Roth J.A. Prognostic significance of computed tomography in resected N2 lung cancer. Ann Thorac Surg 1992;54:533-537.[Abstract]
19. Reed M.F., Sugarbaker D.J. Mediastinal staging of lung cancer. In: Pass H.I., Mitchel J.B., Johnson D.H., Turrisi A.W., eds. Lung cancer: principles and practice. Philadelphia: Lippincott-Raven, 1996:537-544.
20. Vansteenkiste J.F., Stroobants S.G., De Leyn P.R., et al. Lymph node staging in non-small-cell lung cancer with FDG-PET scan: a prospective study on 690 lymph node stations from 68 patients. J Clin Oncol 1998;16:2142-2149.[Abstract]
21. Murakami I., Fujiwara Y., Yamaoka N., Hiyama K., Ishioka S., Yamakido M. Detection of p53 gene mutations in cytopathology and biopsy specimens from patients with lung cancer. Am J Respir Crit Care Med 1996;154:1117-1123.[Abstract]

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