Surgery for non-small cell lung cancer: postoperative survival based on the revised tumor-node-metastasis classi cation and its time trend q

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1 European Journal of Cardio-thoracic Surgery 18 (2000) 147±155 Surgery for non-small cell lung cancer: postoperative survival based on the revised tumor-node-metastasis classi cation and its time trend q Fumihiro Tanaka, Kazuhiro Yanagihara, Yohsuke Otake, Ryo Miyahara, Yozo Kawano, Tatsuo Nakagawa, Tsuyoshi Shoji, Hiromi Wada* Department of Thoracic Surgery, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto , Japan Received 8 September 1999; received in revised form 11 April 2000; accepted 10 May 2000 Abstract Objective: To clarify results of surgery for non-small cell lung cancer (NSCLC) based on the new tumor-node-metastasis (TNM) classi cation revised in 1997 and its time trend. Methods: A total of 921 patients operated from 1980±1994 were retrospectively reviewed. For analysis of time trend, they were grouped into three periods by the year of operation (period (1): 1980±1984, period (2): 1985±1989, and period (3): ). Results: Concerning patients' characteristics, recent increase in the ratio of patients whose tumor was discovered at mass screening (31% in period (1), 40% in period (2), and 50% in period (3)), and increase in the ratio of p-stage IA patient (16, 20, and 29%, respectively) were marked. Decrease in the ratio of operation-related death and the ratio of exploratory thoracotomy was signi cant. Concerning level of operation, decrease in the ratio of pneumonectomy, increase in the ration of sublober resection and that of tracheal or bronchoplastic procedures were signi cant. Postoperative survival for all patients was signi cantly better in period (2) or (3) than that in period (1); no signi cant difference was demonstrated between period (2) and (3) (5-year survival rates: 35% for period (1), 56% for period (2), and 56% for period (3)). Strati ed p-stage, improvement of postoperative survival in recent years was demonstrated in p-stage IIA, IIB, IIIA, and IIIB diseases. Conclusions: Postoperative survival for all NSCLC patients has been improved with signi cant increase of earlystage (p-stage IA) patients. Concerning level of resection, recent increase in patients who underwent sublobar resection and bronchoplastic procedures was marked. q 2000 Elsevier Science B.V. All rights reserved. Keywords: Non-small cell lung cancer; Surgery; Time trend; New tumor-node-metastasis; Postoperative survival 1. Introduction q Presented at the 13th Annual Meeting of the European Association for Cardio-thoracic Surgery, Glasgow, Scotland, UK, September 5±8, * Corresponding author. Department of Thoracic Surgery, Faculty of Medicine, Kyoto University, Shogoin-kawara-cho 54, Sakyo-ku, Kyoto, , Japan. Tel.: ; fax: address: wadah@kuhp.kyoto-u.ac.jp (H. Wada). Non-small cell lung cancer (NSCLC) is a malignant tumor with the poorest prognosis. Although surgery is the most effective modality for cure of NSCLC, the 5-year survival rate after surgery remained to be only 20±35% [1]. Particularly, postoperative survival of patients with histological evidence of mediastinal lymph nodes metastasis (pn2) have been reported to be very poor [2±6]. However, there had been only one report on time trends or recent progress in survival after surgery for NSCLC [7]. We have already analyzed time trends in survival operated for primary lung cancer from 1976 to 1990, and have revealed a signi cant improvement of the postoperative survival particularly in the later years (1985±1990) [8]. And the improvement of postoperative survival proved to be realized by a recent development of medical imaging techniques such as computed tomography (CT) and a recent improvement of preoperative and postoperative management [8]. Moreover, we have revealed a signi cant improvement of the postoperative survival of patients with pathologic stage (pstage) IIIA, pn2, NSCLC in the later years (1985±1990), and have revealed that the improvement was realized by decrease of T3N2M0 patients having poor prognosis with careful and exact preoperative evaluation [9]. All these reports were based on the previous tumor-nodemetastasis (TNM) staging system revised in 1986 [4]. Now, the TNM system has been revised in 1997 [10], and it is dif cult to compare a postoperative survival classi ed based on the current staging system with that classi ed based on the previous one. Therefore, in the present paper, postoperative survival based on the revised TNM system was assessed. Moreover, postoperative survival after 1980 was reviewed by dividing patients according to the operation period to clarify the time trends in more recent years /00/$ - see front matter q 2000 Elsevier Science B.V. All rights reserved. PII: S (00)

2 148 F. Tanaka et al. / European Journal of Cardio-thoracic Surgery 18 (2000) 147± Patients and methods Nine-hundred and twenty-one patients who underwent thoracotomy for NSCLC in the Department of Thoracic Surgery, Kyoto University Hospital from January 1st, 1980 to December 31st, 1994 (Table 1). There were 662 males and 259 females, ranging in age from 20 to 83 years with an average of 62 ^ 10 (mean ^ SD). These patients were divided into three groups by the period of operation (period (1): 1980±1984, period (2): 1985±1989, and period (3): 1990±1994), and were retrospectively reviewed. All the in-patients records, chest roentgenogram, whole body CT, bone and gallium scan, operation records, and pathological specimens were examined. Whole body CT, bone scan, and gallium scan were performed in all patients operated from 1981, and in most patients operated in For the preoperative assessment of mediastinal lymph node status, chest roentgenogram and tomogram had been performed in some patients operated in 1980, and chest CT has been employed in most patients operated in 1980 and in all patients operated from Mediastinoscopy or magnetic resonance imaging (MRI) for preoperative evaluation was not routinely performed with some exceptions. Among all 921 patients studied, 400 patients (43%) had complained of subjective symptoms and their lung tumors were discovered. In 139 patients (15%), their lung tumors were revealed by chest roentgenogram taken during followup of other diseases. In the other 382 patients (42%), their lung tumors were revealed at the mass screening; sputum cytology at the mass screening revealed the lung cancers in only ten cases and chest roentgenogram revealed them in the other 372 patients. Mass examination using sputum cytology was performed for the heavy smoker, and that using chest roentgenogram for non-selected population. Histological typing was determined based on the classi- cation system of World Health Organization [11]. Performance status (PS) was determined according to the ECOG performance status scale as follows; Grade 0: fully active, able to carry on all predisease 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 of ce 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, con ned to bed or chair $50% of waking hours, Grade 4: completely disabled, cannot carry on any self-care, totally con ned to bed or chair [12]. The clinical and the pathologic stages of the patients were re-evaluated based on the current staging system revised in 1997 [10]. Lobectomy with radical lymphadenectomy was Table 1 Patients' characteristics and postoperative survival

3 F. Tanaka et al. / European Journal of Cardio-thoracic Surgery 18 (2000) 147± employed as a standard operation throughout the study periods. Sublobar resection was performed for patients who were judged not to be candidates for standard lobectomy because of high age, poor PS, poor lung function, or other complications. In patients who had no radical lymph node dissection, routine sampling of various lymph node stations was intraoperatively performed in order to determine the pathologic staging. Metastatic sites of 76 p-stage IV patients were lung in 41, brain in 15, bone in 15, adrenal gland in four, and liver in one patient. Complete tumor resection was de ned when no microscopic cancer were identi ed either in the resection margins of the tumor nor in the highest mediastinal lymph nodes [8]. Operation-related death was de ned as death of any causes within 30 days after thoracotomy or that without discharge from hospital. Follow-up of the postoperative clinical course was conducted by outpatient medical records and by inquiries using telephone or letters. In patients referred to other hospitals for postoperative follow-up, medical information concerning the cause and date of death was reported from the hospital. Thus, follow-up was complete and death could be identi ed accurately and reliably across the three time periods of the study. The day of the thoracotomy for the primary pulmonary lesion was regarded as the starting day for counting the postoperative survival days. In principle, preoperative radiation was offered to ct3 patients, and preoperative chemotherapy to cn2±3 patients. Similarly, postoperative radiation was offered to pt3 patients, and intravenous chemotherapy to pn1 or pn2±3 patients. Oral administration of UFT (tegafur and uracil), a 5- uorouracil derivative chemetherapeutic drug [13], was administrated to patients with all stages when informed consent was taken. Details of postoperative adjuvant therapy performed were described in previous manuscript [14] Statistical methods Statistical comparisons of counts were made using the chi-square analysis or chi-square test for trend was employed for analysis of time trends [15], when all expected cell frequencies were $5 in a two times two table or three in a two times three tables. Otherwise, P-value was calculated using Fischer's exact-test. Statistical comparisons of continuous data were made using the unpaired t-test when normal distribution was obtained, or using the Mann±Whitney U- test when not. Survival after surgery was analyzed by Kaplan±Meier method [16], and the evaluation of the survival difference was conducted using the log-rank test [17]. Multivariate analyses of the prognostic factors were made using the Cox's regression model [18]. Difference with P- value less than 0.05 was regarded as statistically signi cant. In comparison among three study groups, difference with P- value not greater than was regarded as statistically signi cant (a Bonferroni correction) [9]. All the abovementioned statistical analysis was performed using `SPSS for Windows' software system (SPSS Inc. Chicago, IL, 1993). 3. Results 3.1. Postoperative survival based on the revised TNM staging system Five-year survival rate for all patients operated for the entire study period, that is from 1980 to 1994, was 50%. Results of univariative analysis of prognostic factors were shown in Table 1. Female patients demonstrated signi cantly better prognosis as compared with male patients. Patients having better PS demonstrated better prognosis as compared with those having worse PS. Five-year survival rate of patients with NSCLC discovered at the mass screening was 63%, which was signi cantly higher than that of patients with NSCLC discovered during follow-up of other diseases or discovered complaining of subjective symptoms. Concerning histologic types, patients with squamous cell carcinoma (Sq) had a signi cantly poorer survival than adenocarcinoma (Ad) patients. Postoperative survival of each p-stage was shown in Table 2. Five-year survival rate of p-stage IA disease was 79%, which proved to be signi cantly higher than that of p- stage IB disease (66%). Five-year survival rate of p-stage IIA disease was 58%, and seemed to be higher than that of p-stage IIB disease (50%) or that of p-stage IIIA disease (37%). However, because of small number of p-stage IIA disease (n ˆ 24), there proved to be no statistical signi cant differences. Five-year survival rates of pt2n1m0, pt3n0m0, pt3n1m0, and pt1±3n2m0 diseases which have been classi ed into p-stage IIB or IIIA were 58, 45, 34, and 37%, respectively (Table 2, and Fig. 1). Postoperative prognosis of pt2n1m0 disease classi ed into p-stage IIB proved to be signi cantly better than pt3n1m0 and pt1±3n2m0 diseases classi ed into p-stage IIIA. However, difference in the postoperative prognosis between pt3n0 M0 disease and pt3n1m0 disease or that between pt3n0m0 disease and pt1±3n2m0 disease proved not to be statistically signi cant Analysis of time trends Postoperative survival or all patients Five-year survival rates of all patients operated in period (1), (2), and (3) were 35, 56, and 56%, respectively, which demonstrated a signi cant improvement of the postoperative survival in period (2) and (3) (Table 1 and Fig. 2). There proved to be no difference in the postoperative survival between period (2) and (3) Patients' characteristics (Table 3) There was no signi cant difference in an average age and distribution of sex or performance status among three periods. There proved to be a marked difference in the cause of

4 150 F. Tanaka et al. / European Journal of Cardio-thoracic Surgery 18 (2000) 147±155 Table 2 Pathologic stage based on the new TNM classi cation revised in 1997 and postoperative survival Pathologic stage TNM classi cation Number of patients (%) Five-year survival rate (%) a P-value for survival IA IB IIA IIB IIIA IIIB IA T1N0M0 208 (23) 79 IB T2N0M0 176 (19) IIA T1N1M0 24 (2.6) IIB 118 (13) 50, 0.001, T2N1M0 45 (4.9) 58 T3N0M0 73 (7.9) 48 IIIA 178 (19) 37, 0.001, T3N1M0 18 (1.9) 34 T1±3N2M0 160 (18) 37 IIIB 141 (15) 19, 0.001, 0.001, 0.001, 0.001, T4N0±2M0 116 (13) 23 Any TN3M0 25 (2.7) 0 IV Any TNM1 76 (8.3) 3.3, 0.001, 0.001, 0.001, 0.001, Total of patients 921 (100) 50 a Five year survival rates are obtained using the Kaplan±Meier method and P-values using the log-rank test. A difference with a P-value less than was regarded as statistically signi cant. discovery of lung cancer among the periods. The number of patients whose tumors were discovered at the mass examination was 77 (31%) among 250 patients operated in period (1), 119 (40%) among 295 patients in period (2), and 186 (50%) among 376 patients in period (3), which demonstrated a signi cant increase in the percentage. The number of patients who complained of subjective symptoms was 135 in period (1), 123 in period (2), and 142 in period (3), which demonstrated no apparent changes; the percentage of the patients was 54, 42, and 38% in each operation period, which demonstrated a signi cant decrease in the percentage. In the histologic type, a signi cant increase in the ratio of patients with adenocarcinoma (Ad), and a signi cant decrease in the ratio of patients with squamous cell carcinoma (Sq) were noted over the time period. With regard to the p-stage, there proved to be a signi cant increase in the ratio of p-stage IA patients (16%: 41/250 patients, 20%: 59/295 patients, and 29%: 108/376 patients, in period (1), (2), and (3), respectively. Also, a signi cant decrease in the ratio of pt3n2m0 patients (6.4% in period (1), 3.7%, in period (2), and 2.1% in period (3)) was also revealed Level of resection, rate of exploratory thoracotomy, rate of complete resection (Table 4) In all operation periods studied, lobectomy including bilobectomy was the most common operation procedure. Sublobar resection including partial resection and segmentectomy was performed in only two patients (0.8%) in period (1), in nine patients (3.1%) in period (2), and 29 patients (7.7%) in period (3), demonstrating a signi cant increase especially in period (3). A signi cant increase in the ratio of patients who underwent tracheal or bronchoplastic procedures, and a signi cant decrease in the ratio of Fig. 1. Postoperative survival of patients with pathologic stage IIB, IIIA non-small cell lung cancer (NSCLC) according to the new TNM classi cation revised in Comparison of postoperative survival among T2N1M0, T3N0M0, T3N1M0, and T1±3N2M0 diseases. Fig. 2. Comparison of postoperative survival of patients with pathologic stage IA-IV non-small cell lung cancer (NSCLC) according to the operation period. Postoperative survival in period (1) (1985±1990) and that in period (2) (1990±1994) were signi cantly better than that in period (2) (1980± 1984) (P, 0:001). There were no signi cant difference in the postoperative survival between period (2) and period (3) (P ˆ 0:900).

5 F. Tanaka et al. / European Journal of Cardio-thoracic Surgery 18 (2000) 147± Table 3 Time trend of patients' characteristics according to the operation period Operation period Number of patients (%) P-value for time trend (1) (1980±1984) (2) (1985±1989) (3) ( ) All patients Gender Male (%) 179 (72) 218 (74) 265 (71) 0.62 Female (%) 71 (28) 77 (26) 111 (30) Age (mean ^ SD, years) 61.7 ^ ^ ^ Performance status (%) (77) 245 (83) 308 (82) 1 56 (22) 47 (16) 59 (16) ±3 2 (0.8) 3 (1.0) 9 (2.4) Cause of discovery Asymptomatic At mass screening 77 (31) a 119 (40) 186 (50), During follow-up of other diseases 38 (15) 53 (18) 48 (13) 0.18 During follow-up of other malignancies 2 (0.8) 11 (3.7) 8 (2.1) 0.19 Subjective complaints or symptoms 135 (54) a,b 123 (42) 142 (38), Histology Squamous cell 119 (48) a 113 (38) 113 (30), Adenocarcinoma 111 (44) a 158 (54) 234 (62), Large cell 13 (5.2) 18 (6.1) 20 (5) 0.88 Others 7 (2.8) 6 (2.0) 9 (2.4) Pathologic stage IA 41 (16) a 59 (20) c 108 (29), IB 38 (15) 69 (23) 69 (18) IIA 8 (3.2) 9 (3.1) 7 (1.9) 0.50 IIB 45 (18) a 42 (14) 31 (8.2) T2N1M0 16 (6.4) 16 (5.4) 13 (3.5) 0.22 T3N0M0 29 (12) a 26 (8.8) 18 (4.8) IIIA 60 (24) b 44 (15) 74 (20) T31N0M 6 (2.4) 1 (0.3) 11 (2.9) T13N2M0 54 (22) 43 (15) 63 (17) T3N2M0 16 (6.4) a 11 (3.7) 8 (2.1) IIIB 33 (13) 52 (18) 56 (15) 0.35 T4N0±1M0 29 (12) 44 (15) 43 (11) 0.35 Any TN3M0 4 (1.6) 8 (2.7) 13 (3.5) 0.38 IV 25 (10) 20 (6.8) 31 (8.2) 0.40 a P, 0:017 (period (1) vs. period (3)). b P, 0:017 (period (1) vs. period (2)). c P, 0:017 (period (2) vs. period (3)). patients who underwent pneumonectomy were noted over the time period. In an attempt to resect tumors by thoracotomy, the operation ended in exploratory thoracotomy in 14 (5.6%), nine (3.1%), and six (1.6%) patients in period (1), (2) and (3), respectively, showing a statistically signi cant decrease in period (2) and (3). In contrast to the number of patients who underwent exploratory thoracotomy, the number of patients who had complete resection was 173 (69%), 233 (79%), and 297 (79%), in period (1), (2), and (3), respectively, demonstrating a statistically signi cant increase in period (2) and (3) Rate of operation-related death Operation-related death rates were 4.0, 1.0, and 1.1%, in period (1), (2) and (3), respectively, demonstrating a statistically signi cant decrease in period (2) and (3) (Table 4) Postoperative survival according to p-stage (Table 5) Five-year survival rates of p-stage IA patients in all the study periods were over 70%, showing no signi cant difference. There proved to be no signi cant differences in the postoperative survival of p-stage IB patients or p-stage IIA patients. Five-year survival rates of p-stage IIB patients in period (2) and (3) were 64 and 53%, respectively, showing signi cant improvement of the prognosis as compared with that in period (1) (5-year survival rate: 38%). Five-year survival rates of p-stage IIIA patients in period (2) and (3) were 51 and 40%, respectively, showing signi cant improvement of the prognosis as compared with that in period (1) (5-year survival rate: 21%); 5-year survival

6 152 F. Tanaka et al. / European Journal of Cardio-thoracic Surgery 18 (2000) 147±155 Table 4 Time trend of level of resection, rate of exploratory thoracotomy, rate of complete resection post-mortality according to the operation period, and preoperative/ postoperative therapy Operation period Number of patients (%) P-value for time trend (1) (1980±1984) (2) (1985±1989) (3) (1990±1994) Level of resection Sublobar resection 2 (0.8) 9 (3.1) a 29 (7.7), Lobectomy or bilobectomy 198 (79) 245 (83) 298 (79) 0.40 Pneumonectomy 35 (14) b 29 (9.8) 26 (6.9) Tracheal or bronchoplastic procedures 1 (0.4) b 3 (1.0) 17 (4.5) Exploratory thoracotomy 14 (5.6) b 9 (3.1) 6 (1.6) Resection (complete, incomplete) Complete resection 173 (69) b,c 233 (79) 297 (79) 0.08 Incomplete resection 77 (31) 62 (21) 79 (21) Operation mortality d 10 (4.0) 3 (1.0) 4 (1.1) Preoperative/postoperative therapy Surgery alone 114 (46) b 137 (46) a 240 (53), Surgery with preoperative therapy 19 (7.6) b 38 (13) a 78 (21), Chemotherapy 5 (2.0) 11 (3.7) 17 (4.5) 0.25 Radiation 13 (5.2) b 23 (7.8) a 57 (15), Chemo-radiation 1 (0.4) 4 (1.4) 4 (1.1) 0.52 Surgery with postoperative radiation 117 (47) b 120 (41) a 58 (15), Chemotherapy 59 (24) b 73 (25) a 20 (5.3), Radiation 38 (15) b 37 (13) 33 (8.8) Chemo-radiation 20 (8.0) b 10 (3.4) 5 (3.8), a P, 0:017 (period (2) vs. period (3)). b P, 0:017 (period (1) vs. period (3)). c P, 0:017 (period (1) vs. period (2)). d Both death of any cause within 30 days after thoracotomy and that without discharge were included. rates of p-stage IIIA, pn2 patients showed marked improvement in period (2) and (3), whereas those of p-stage IIIA, pt3n1 patients showed no signi cant improvement. Fiveyear survival rates of p-stage IIIB, pt4 (N0-2) patients in period (2) and (3) showed signi cant improvement as compared with that in period (1), whereas those of p-stage IIIB, pn3 were equally 0% at all the study periods Multivariate analyses of prognostic factors (Cox's proportional hazard model) (Table 6) Factors which in uenced on the outcome of operation most signi cantly were performance status, whether complete resection was achieved or not, p-stage, and operation periods (P, 0:001). Age and gender was also a significant factor. Histologic type or cause of discovery proved not to be a signi cant prognostic factor. 4. Discussion The current TNM staging system for primary lung cancer has been revised in In the present study, postoperative prognosis of p-stage IA patients proved to be signi cantly better than that of p-stage IB patients (5-year survival rates: 79 and 66%, respectively, P ˆ 0:007), which suggested the validity of the current TNM system in dividing p-stage I disease into IA and IB diseases. Postoperative prognosis of p-stage IIA patients seemed to be better than that of p- stage IIB patients (5-year survival rates: 58 and 50%, respectively), but there proved to be no signi cant differences probably because of a small number of p-stage IIA patients (n ˆ 24). As the number of T2N1M0 patients may be small, whether T2N1M0 disease should be separated as an independent pathologic stage (stage IIA) may be discussed. Among pt2n1m0, pt3n0m0, pt3n1m0, and pt1±3n2m0 diseases which had been classi ed into p-stage IIB or IIIA in the previous TNM system, pt3n0m0 disease proved to have an intermediate prognosis between pt2n1m0 and pt3n1m0/pt3±1n2m0 diseases (5-year survival rates: 45, 58, 34, and 37%, respectively). As the difference between pt3n0m0 and pt2n1m0 diseases (P ˆ 0:18), that between pt3n0m0 and pt3n1m0 diseases (P ˆ 0:20), or that between pt3n0m0 disease and pt1±3n2m0 disease (P ˆ 0:51) was not statistically signi cant, the classi cation of pt3n0m0 disease may also be discussed. Univariative analysis of prognostic factors revealed that patients with Ad had better prognosis as compared with

7 F. Tanaka et al. / European Journal of Cardio-thoracic Surgery 18 (2000) 147± Table 5 Time trend of postoperative survival according to the operation period Operation period Five-year survival rate (%) a (1) (1980±1984) (2) (1985±1989) (3) (1990±1994) All patients 35 b,c Pathologic stage IA IB IIA IIB 38 b T2N1M T3N0M IIIA 21 b,c T3N1M T1-3N2M0 18 b,c IIIB 6.1 c T4N0-1M0 6.9 b,c Any TN3M IV 0 c 0 15 a Five-year survival rates are obtained using Kaplan±Meier method and P-values using the log-rank test. b P, 0:017 (period (1) vs. period (2)). c P, 0:017 (period (1) vs. period (3)). those with Sq. However, multivariative analysis did not revealed that Ad was an independent prognostic factor to predict better prognosis. Concerning the correlation between histologic type and p-stage, the ratio of p-stage IA disease among Ad patients (130/503, 26%) was signi cantly higher than that among the other histologic type patients (78/418, 19%, P ˆ 0:011). Moreover, the ratio of well-differentiated tumor among Ad (182/503, 36%) was signi cantly higher than that among other histologic types (115/418, 28%, P ˆ 0:006). Thus, histologic type proved not to be a signi cant factor. Univariative analysis also revealed that patients whose lung cancer was discovered at mass screening had better survival. The better survival may be mainly due to the fact that the ratio of p-stage I disease among NSCLC discovered at mass screening (205/382, 54%) was signi cantly higher than that among NSCLC discovered at the other situations (179/539, 33%). In fact, multivariative analysis failed to demonstrate that cause of discovery was an independent prognostic factor. Although mass screening for early detection of lung cancer has not evaluated to be effective [19], a possible ef cacy of mass screening using CT has been recently reported [20]. According to the results, CT could detect more early-stage lung cancers as compared with chest roentgenogram. Ef cacy of mass screening, especially screening using CT for high-risk population, should be examined. We have already reported that postoperative survival for primary lung cancer have been improved particularly in latter half of 1980s [8,9]. Moreover, we have also revealed that the improvement was achieved with a signi cant increase of the number of p-stage I patients [8] and/or improvement of preoperative evaluation especially with introduction of CT [9]. In the present analysis as well, postoperative prognosis in period (2) (1985±1989) and in period (3) (1990±1994) proved to be signi cantly better than that in period (1) (1980±1984). However, no improvement of the postoperative prognosis has been demonstrated in period (3) as compared with that in period (2). Roughly speaking, whereas postoperative survival for p-stage IA or IB disease is good in all study periods, that for more progressive stages remains to be poor. As clari ed by a prospective randomized study conducted by Rosell and co-workers demonstrating that 5-year survival rate of patients who underwent surgery alone for p-stage IIIA, NSCLC was 0% [21], improvement in the prognosis by surgery alone is limited even with progress in surgical techniques. We have already conducted a retrospective analysis on postoperative adjuvant therapy in our institute, and have already reported the ef cacy of oral administration of UFT [13] as a postoperative adjuvant therapy in a retrospective study [14]. Whereas the ef cacy have been established in prospective randomized studies [22,23], UFT alone has failed to improve postoperative survival of higher stage NSCLC. We have performed cisplatin-based intravenous combination chemotherapy for higher stage diseases as a postoperative adjuvant therapy. However, as described in the previous manuscript, cisplatin-based intravenous chemotherapy proved not to be effective [14]. To improve the prognosis, establishment of more effective adjuvant therapy should be needed in future. Although improvement of postoperative survival after 1990 was not demonstrated as mentioned above, introduction and prevalence of new operation techniques such as limited operation and bronchoplastic procedures were noted. Sublobar resection was performed in 29 patients (7.7%) in period (3) whereas in only two patients (0.8%) in period (1). In principle, we have performed sublobar resection only for patients in whom standard operation, that is lobectomy, can not be safely performed. Now, we Table 6 Multivariative analysis of prognostic factors Prognostic factors a P-value Odds ratio (95% CI) Gender (male, female) (0.55±0.90) Age (1.00±1.02) Performance status (0, 1, 2, 3), (1.23±1.84) Cause of discovery (at mass (0.64±1.02) examination, others) Histologic type (non-adenocarcinoma, adenocarcinoma) (0.83±1.27) Operation:complete tumor resection, (0.47±0.77) (not done, done) Pathologic stage (IA, IB, IIA, IIB, IIIA,, (1.33±1.50) IIIB, IV) Operation period (earlier: 1980±1984,, (0.61±0.80) middle: 1985±1989, later: 1990±1994) a Variables were analyzed as normal or continuous.

8 154 F. Tanaka et al. / European Journal of Cardio-thoracic Surgery 18 (2000) 147±155 have conducted a prospective study of segmentectomy with lymph nodes dissection as a curative operation for p-stage IA tumor less than 2 cm in diameter. Lymph nodes dissected are judged to be positive or negative for metastasis on the frozen sections during operation, and standard lobectomy instead of segmentectomy will be performed if lymph node metastases are con rmed pathologically. Ginsberg and co-corkers reported results of prospective randomized study of lobectomy vs. sublobar resection for T1N0M0, NSCLC, and concluded that sublobar resection could not be a preferred surgical procedure because of higher death rate and locoregional recurrence rate as compared with lobectomy [24]. Warren and co-workers also reported that segmentectomy was not a preferred surgical procedure for patients with p-stage I tumors larger than 3 cm in diameter [25]. 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Intentional limited resection for selected patients with T1N0M0 non-small cell lung cancer: a single-institutional study. J Thorac Cardiovasc Surg 1997;114:347±353. [27] Tsubota N, Ayabe K, Doi O, Mori T, Mamikawa S, Taki T, Watanabe Y. Ongoing prospective study of segmentectomy for small lung tumors. Study group of extended segmentectomy for small lung tumor. Ann Thorac Surg 1998;66:1787±1790. Appendix A. Conference discussion Dr P. Van Schil (Antwerp, Belgium): My question relates to the early screening. In contrast to earlier studies, you found more patients in an early stage, stage I disease. How exactly do you perform your screening? Do you screen high risk population groups like heavy smokers? Do you use radiographs of the thorax, sputum cytology or some other tools? Dr Tanaka: In our study, most patients were screened by routine chest X-ray, not sputum cytology for all populations, including no high risk population, also including a healthy population. Dr D. Skinner (New York, NY, USA): Do you think we need to change the TNM classi cation yet again, Dr Ferguson? Dr M. Ferguson (Chicago, IL, USA): There is a relatively small number of patients in that classi cation. The number is too small to make valid statistical conclusions. Larger numbers of patients would be necessary to see whether the T1, N1 group should be subcombined with another group.

9 F. Tanaka et al. / European Journal of Cardio-thoracic Surgery 18 (2000) 147± You observed some stage migration over the three time periods with larger numbers of patients in stage 1 disease. I am wondering whether some of the improvement in survival might be due to improved pathologic staging in these patients. Did you change your operative techniques over the years, using more mediastinoscopy or more lymph node dissection, for example? Dr Tanaka: I don't know exactly the answer, but improvement of surgical technique does not contribute to the progress of improvement of survival. Perhaps described in a previous paper as shown in 1997 in this annual meeting, postoperative adjuvant therapy using UFT, an oral therapeutic agent, may contribute to improvement of survival.