The prognosis for patients with surgically resected

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1 Prognostic Factors in Clinical Stage I Non Small Cell Lung Cancer Kenji Suzuki, MD, Kanji Nagai, MD, Junji Yoshida, MD, Eiji Moriyama, MD, Mitsuyo Nishimura, MD, Kenro Takahashi, MD, and Yutaka Nishiwaki, MD Division of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan 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. (Ann Thorac Surg 1999;67:927 32) 1999 by The Society of Thoracic Surgeons Accepted for publication Oct 17, Address reprint requests to Dr Suzuki, Division of Thoracic Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, , Japan; kjsuzuki@east.ncc.go.jp. 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 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 1999 by The Society of Thoracic Surgeons /99/$20.00 Published by Elsevier Science Inc PII S (99)00140-X

2 928 SUZUKI ET AL Ann Thorac Surg PROGNOSTIC FACTORS IN CLINICAL STAGE I NSCLC 1999;67: 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 Fig 1. Survival curve for patients with clinical stage I non small cell lung cancer. Bars indicate 99% confidence intervals (CI). Results 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. Univariate Analysis of Clinical Prognostic Factors The survival rates of lung cancer patients with reference to the various clinical variables are shown in Table 1. Of these eight variables, five were significant for a poor prognosis: older age, male sex, heavier smoking status, high serum CEA level, and clinical T2 status. The 120 patients 70 years of age or older had a 5-year survival rate of 48.8% versus 74.1% in the younger group ( p 0.002). Men had a 5-year survival rate of 60.3%, whereas that of women was 75.5% ( p 0.006). If patients had a smoking history of 5 pack-years or more, the 5-year survival rate was 60.3% compared with 76.3% for patients who smoked less or not at all ( p 0.002). The 5-year survival rate was 53% for patients with a high serum CEA level and 78.5% for patients with a normal CEA level ( p 0.005). Patients with clinical T2 disease had a significantly poorer prognosis (5-year survival rate, 53.8%) than those with clinical T1 disease (5-year survival rate, 77.1%) ( p 0.001). Multivariate Analysis of Clinical Prognostic Factors Multivariate analysis using all factors except serum CEA and SCC levels revealed two that were significant for a poor prognosis: clinical T2 status ( p 0.001; hazard ratio [HR], 2.26; 99% confidence interval, 1.30 to 3.90) and age of 70 years or older ( p 0.007; HR, 1.74; 99% confidence interval, 1.02 to 2.95). Smoking status of more than 5 pack-years was a marginally independent prognostic factor ( p 0.017; HR, 1.74; 99% confidence interval, 0.96 to 3.16). 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

3 Ann Thorac Surg SUZUKI ET AL 1999;67: PROGNOSTIC FACTORS IN CLINICAL STAGE I NSCLC 929 Table 1. Relationship Between Clinical Variables and Survival for Patients With Surgically Resected Clinical Stage I Peripheral Non Small Cell Lung Cancer Variable No. of Patients a (n 365) Survival Rates (%) 3 Years 4 Years 5 Years 2 p Value (log-rank test) Age (y) Sex Male Female Smoking status 0 PY PY CEA (ng/ml) SCC (ng/ml) Location Left Right Clinical T status ct ct Histology Adenocarcinoma Other Overall survial a Numbers of patients in subgroups do not always equal 365 because of missing data. CEA carcinoembryonic antigen; PY pack-years of smoking; SCC squamous cell carcinoma antigen. 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. Discrepancy Between Clinical and Pathologic TNM Stages Stage migration was examined on the basis of the two prognostic factors in patients with clinical stage I non Table 2. Results of Multivariate Analyses of Prognostic Factors in Surgically Resected Clinical Stage I Peripheral Non Small Cell Lung Cancer Variables Beta SE Hazard Ratio a p Value Clinical T status ct2 versus ct ( ) Serum CEA (ng/ml) 5.0 versus ( ) a Numbers in parentheses are 99% confidence interval. CEA carcinoembryonic antigen; SE standard error. 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).

4 930 SUZUKI ET AL Ann Thorac Surg PROGNOSTIC FACTORS IN CLINICAL STAGE I NSCLC 1999;67: 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). 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). small cell lung cancer (Table 4). Postoperative pathologic stage was in agreement with clinical stage in 73% of patients with clinical T1 disease versus only 52% of these with clinical T2 disease. Similarly, pathologic stage agreed with clinical stage in 68% of patients with a low serum CEA level versus 49% with a high serum CEA level. In the subgroup with clinical T2 disease and a high serum CEA level, (n 48) clinical and pathologic stages concurred in only 35% of patients, and stage migration was frequently observed in this subgroup. The most frequent postoperative pathologic stage was stage III (22 patients, 46%), and in most of these patients, it was due to pathologic N2 disease (17 patients). Comment The most common therapeutic option for patients with clinical stage I non small cell lung cancer is surgical resection. The prognosis is best predicted by postoperative pathologic TNM staging [9]. Many reports have dealt with other pathologic prognostic factors [1, 8, 9]. On the basis of pathologic staging, several clinical trials employing multimodal therapy have been conducted for advanced diseases, but the benefits of postoperative chemotherapy or radiotherapy have been considered small to date [5, 15, 16]. Recent phase III trials of preoperative chemotherapy for stage III non small cell lung cancer, however, have suggested possible advantages of this strategy [6, 7]. Even among patients with pathologic stage I disease, more than 20% have recurrence [1]. Because of the encouraging results seen in locally advanced disease, the combined modality approach is now being applied to patients with early-stage lung cancer [3, 4]. To conduct preoperative therapy, patients in a clinically early stage should be stratified using preoperative variables. Otherwise, the majority of patients with surgically curable lung carcinoma [8] would undergo unnecessary preoperative therapy. This background led us to investigate clinical prognostic factors among patients with clinical stage I non small cell lung cancer. 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 ( ) 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 Table 3. 5-Year Survival Rates in Subgroups Determined by Two Significant Factors a Subgroup No. of Patients Survival Rates (%) 3 Years 4 Years 5 Years 2 p Value (log-rank test) Both factors present Either factor present Neither factor present a The two factors are high serum levels of carcinoembryonic antigen and clinical T2 status. ]

5 Ann Thorac Surg SUZUKI ET AL 1999;67: PROGNOSTIC FACTORS IN CLINICAL STAGE I NSCLC 931 Table 4. Relationship Between Clinical and Pathologic Stages by Preoperative T Status and Serum Carcinoembryonic Antigen Level Clinical Stage I Subgroup No. of Patients Pathologic Stage I II III IV 2 p Value ( 2 test) Clinical T status T (73) 17 (9) 27 (14) 10 (5) T (52) 14 (8) 52 (31) 14 (8) Serum CEA level Low ( 5.0 ng/ml) (68) 15 (8) 29 (16) 13 (7) High ( 5.0 ng/ml) (49) 9 (10) 30 (34) 6 (7) Clinical T status and serum CEA level ct1 and low CEA (75) 7 (7) 11 (11) 7 (7) ct2 and high CEA (35) 4 (8) 22 (46) a 5 (10) a Seventeen of these 22 patients were in pathologic stage III because of pathologic N2 disease. 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 18 F-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. 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 1. Harpole DH Jr, Herndon JE II, Young WG Jr, Wolfe WG, Sabiston DC Jr. Stage I nonsmall cell lung cancer. A multivariate analysis of treatment methods and patterns of recurrence. Cancer 1995;76: Feld R, Rubinstein LV, Weisenberger TH. Sites of recurrence in resected stage I non-small-cell lung cancer: a guide for future studies. J Clin Oncol 1984;2: Pisters KMW, Ginsberg RJ. Phase II trial of induction paclitaxel and carboplatin in early stage (T2N0, T1-2N1, and selected T3N0-1) non small cell lung cancer [Abstract]. Proc Am Soc Clin Oncol 1998;17:451a.

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Lancet 1998;352: 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: 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: Cybulsky IJ, Lanza LA, Ryan MB, Putnam JB Jr, McMurtrey MM, Roth JA. Prognostic significance of computed tomography in resected N2 lung cancer. Ann Thorac Surg 1992;54: Reed MF, Sugarbaker DJ. Mediastinal staging of lung cancer. In: Pass HI, Mitchel JB, Johnson DH, Turrisi AW, eds. Lung cancer: principles and practice. Philadelphia: Lippincott- Raven, 1996: Vansteenkiste JF, Stroobants SG, De Leyn PR, 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: 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: REVIEW OF RECENT BOOKS Landmarks in Cardiac Surgery Edited by Stephen Westaby with Cecil Bosher United Kingdom, Oxford University Press, pp, illustrated, $ ISBN: Reviewed by James J. Rams, MD Landmarks of Cardiac Surgery began in antiquity, as this volume pointedly outlines throughout each of its chapters. The observation illustrated by each landmark initially provides the impetus to elaborate further on topics. Just as in the present, the leader, even among physician groups, who is able to forcefully express his opinion will often carry the day, right or wrong. The surgeon ahead of the time has either to wait for peers to stumble ahead or needs to be propelled forward to accomplish the development of much-needed operative techniques. These items are well illustrated by stories about surgeons at the turn of the 20th century; many medical-surgical luminaries were obstructed from making progress in cardiac surgery. In contrast, Taussig had to cajole Blalock to develop the blue-baby shunt. Many vignettes are scattered throughout each chapter to remind us that success is not easy. Opportunity was taken to reward the leaders in the field of cardiac surgery with an explanation of their landmark. Also, nicely appraised are all the multiple contributors to each landmark of surgical correction that allowed the momentous effort to succeed. We all cling mightily to our peers to attain the ultimate in patient improvement. The author spent some time in the United States to contact many of the pioneering cardiac physicians and to acquire many unusual details that contribute to the descriptions of each landmark. A poignant aspect of each leader was his ability to put everything else aside and concentrate in the animal laboratory, the clinical milieu, or anatomic studies to determine the problem and elucidate the means for correcting it. Despite the intense egotism needed to survive and succeed, somehow the dissemination of knowledge was quickly implemented for patient benefit. Two appendices provide references of original articles, tabulated for each chapter, and an alphabetic outline of the names and accomplishments of many individuals. This book has been a difficult accomplishment, but it is a great benefit to all interested in the history of cardiac surgery. The efforts by the author and his associates will benefit all cardiac surgeons to help patients with cardiac disease. The volume allows us to return to the fundamental difficulties, their solutions, and aides for further improvement. Pittsburgh, PA 1999 by The Society of Thoracic Surgeons Ann Thorac Surg 1999;67: /99/$20.00 Published by Elsevier Science Inc PII S (99)