Impact of Large Tumor Size on Survival After Resection of Pathologically Node Negative (pn0) Non Small Cell Lung Cancer

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1 Impact of Large Tumor Size on Survival After Resection of Pathologically Node Negative (pn0) Non Small Cell Lung Cancer Shin-ichi Takeda, MD, Shimao Fukai, MD, Hikotaro Komatsu, MD, Etsuo Nemoto, MD, Kenji Nakamura, MD, and Masaru Murakami, MD, for the Japanese National Chest Hospital Study Group Toneyama National Hospital, Osaka, Ibaragi East National Hospital, Ibaragi, Tokyo National Hospital, Tokyo, Minami Yokohama National Hospital, Yokohama, Ehime National Hospital, Ehime, and Tenryu National Hospital, Shizuoka, Japan Staging and classification in lung cancer are important for deciding on patient management and estimating prognosis. The TNM staging system is composed of T (characteristics of primary tumor), N (status of regional lymph nodes), and M (presence or absence of distant metastasis). After several reversions, Union Internationale Contre le Cancer (UICC) published the fifth edition of the TNM staging system for lung cancer in 1997 [1]. However, after considering recent trends in patient characteristics, it is now considered necessary to establish a new and more complete classification system that could be applied internationally. In lung cancer patients, several variables, including anatomic extension of disease, histologic classification, other demographic data, and molecular biologic markers, are known or suspected to influence survival [2 6]. We believe that the TNM system should be described by using common variables such as tumor size, local extension, and lymph node involvement, and that the pathologic TNM Accepted for publication Sept 7, Address reprint requests to Dr Takeda, Toneyama National Hospital, Toneyama 5 1 1, Toyonaka, Osaka, Japan; stakeda@ toneyama.hosp.go.jp. Background. The current TNM staging system first adopted the tumor size of 3 cm for subdivision of stage I and II disease. The aim of the present study was to evaluate the impact of tumor size on survival in patients with pathologically node negative (pn0) non small cell lung cancer after complete resection. Methods. We retrospectively reviewed the records of 603 patients with pn0 non small cell lung cancer patients (403 men and 200 women) who underwent a complete resection in five national chest hospitals between 1992 and 1996, with follow-up duration of more than 5 years, and analyzed tumor size and survival. Survival rate was estimated by the Kaplan-Meier method, and differences were compared by log-rank test. For the multivariate analysis, the Cox proportional hazard model was used to identify variables that significantly affected survival. Results. There were 355 adenocarcinomas, 208 squamous cell carcinomas, and 40 large cell carcinomas completely resected. No significant prognostic differences were seen among three groups with smallersized tumors (<2 cm[n 171], 2.1 to 3 cm [n 202], and 3.1 to 5 cm [n 170]); however, patients with a tumor size greater than 5 cm (n 60) showed a significantly worse prognosis. The 5-year survival rates were 79.6%, 72.7%, 68.1%, and 46.6%, respectively, in these four groups. Multivariate analysis showed the tumor size to be an independent prognostic predictor in patients with pn0 tumors. Conclusions. We found that a tumor size of greater than 5 cm was an independent prognostic predictor in pn0 disease; therefore, upgrading the T factor of tumor diameter to greater than 5 cm may be necessary in the next reversion of the TNM staging system. (Ann Thorac Surg 2005;79:1142 6) 2005 by The Society of Thoracic Surgeons should be consistent with the clinical TNM as an initial discriminator and for reflecting prognostic prediction, as tumor size may roughly reflect the number of tumor cells. The current TNM staging system in 1997 proposed stage I and II subdivision according to a tumor diameter of 3 cm as a cutoff point. However, there are conflicting reports with regard to the correlation of tumor size and survival in terms of further subdivision in stage I disease [7 12]. In addition, the prognostic value of larger tumor size in patients with N0 disease has not been fully determined. To evaluate the correlation of tumor size and survival in patients with pn0 and pathologic stage I lung cancer and to assess whether the current TNM has a prognostic relevance, the records of 603 patients who underwent complete pulmonary resection in five National Chest Hospitals in Japan were retrospectively analyzed. Material and Methods Between 1992 and 1996, 1,047 patients with a non small cell lung cancer (NSCLC) underwent complete resection in five National Chest Hospitals in Japan and had a follow-up duration of more than 5 years. We retrospec by The Society of Thoracic Surgeons /05/$30.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg TAKEDA ET AL 2005;79: TUMOR SIZE AND SURVIVAL tively reviewed the records of 603 patients with pathologically node negative (pn0) NSCLC patients (403 men and 200 women). The age distribution ranged from 21 to 89 years old (mean, 62.9 years). These cases, including operation records and extent of cancer growth, were classified according to the fifth edition of the TNM staging system, published in 1997 [1]. Follow-up was complete in all patients through June 2002, and the median follow-up duration is 7.8 years. For the present analysis, zero time was the date of operation. Evaluation of pathologic nodal status (pn) classification was determined from pathologic examination of the resected lymph nodes. Evaluation of M1 disease included results from abdominal computed tomography, bone scan, brain computed tomography, or magnetic resonance imaging, and laboratory tests. Surgical and pathologic reports from each institution were reviewed to confirm the size of the primary lesion in each case. The degree of pleural involvement was defined as a P factor according to the following Japanese definition: P0, no tumor invasion of the visceral pleura; P1, suspected invasion but no penetration of the visceral pleura; P2, invasion through the visceral pleura; and P3, invasion to the chest wall, diaphragm, mediastinal structures, or adjacent lobes [13]. We analyzed tumor size and prognosis in 603 surgical cases with pn0 status, including 540 patients with pathologic stage I NSCLC. Operative-related deaths in hospital (n 4, 0.7%) were also included in survival calculation. Excluded from the analysis were patients with small cell carcinomas and unclassified carcinomas. There were 355 adenocarcinomas, 208 squamous cell carcinomas, and 40 large cell carcinomas. Survival rate was estimated by the Kaplan-Meier methods, and a log-rank test was used to compare survival rates among the groups. The following variables Fig 1. Survival rates for 603 patients with pathologic-negative nodes (pn0) according to tumor size. There were no significant differences between group S ( 2 cm, n 171) and group M (2.1 to 3 cm, n 202; p 0.293), or between group M (2.1 to 3 cm, n 202) and group L (3.1 to 5 cm, n 170; p 0.092). A significant difference was found between group L (3.1 to 5 cm, n 170) and group XL ( 5 cm, n 60; p 0.004). Fig 2. Survival rates for 540 patients with pathologic stage I disease according to tumor size. There were no differences between group S ( 2 cm, n 160) and group M (2.1 to 3 cm, n 193; p 0.403), or group M (2.1 to 3 cm, n 193) and group L (3.1 to 5 cm, n 147; p 0.204). A significant difference was found between group L (3.1 to 5 cm, n 147) and group XL ( 5 cm, n 40; p 0.014). were considered as prognostic variables for survival in univariate and multivariate analyses with the Cox proportional hazard model: age, sex, tumor location, operative procedure, histologic classification, pleural involvement, T factor, and tumor size. A multivariate analysis was performed with the variables found to be significant in the univariate analysis. Results 1143 With regard to the current pathologic TNM staging system for all patients in the National Chest Hospital database, the survival rates are as follows: stage IA (n 329), 77.6%; stage IB (n 222), 68.4%; stage IIA (n 35), 60.3%; stage IIB (n 132), 46.8%; stage IIIA (n 250), 27.8%; stage IIIB (n 57), 19.9%; and stage IV (n 22), 10.5%. We analyzed the tumor diameter and survival in 603 pn0 patients, which included 63 T3 or T4 tumors. The cases with pn0 were classified into four groups according to the tumor size (group S: 2 cm, n 171; group M: 2.1 to 3 cm, n 202; group L: 3.1 to 5 cm, n 170; group XL: 5 cm, n 60), and the 5-year survival rates were 79.6% for group S, 72.7% for group M, 68.1% for group L, and 46.6% for group XL (Fig 1). When we excluded T3 and T4 lesions from pn0 tendencies for the influence of tumor size and prognosis were noted; however, there were no statistical significance between groups S and M and between groups M and L. The 5-year survival rates after excluding T3 and T4 lesions were 80.9% for group S (n 160), 74.2% for group M (n 193), 71.3% for group L (n 147), and 51.3% for group XL (n 40; Fig 2). In the analyses for pn0 and pathologic stage I patients, we found no statistical differences between patients with tumors with 2 cm or less in size and those with tumors from 2 to 3 cm, indicating that there is no need to divide patients GENERAL THORACIC

3 1144 TAKEDA ET AL Ann Thorac Surg TUMOR SIZE AND SURVIVAL 2005;79: Table 1. Univariate Analysis of Factors That Influence Postoperative Survival of Patients With Pathologic-Negative Nodes (pn0) a Variable Subset 5-Year Survival (%) Relative Risk (95% Confidence Interval) p Value b Age (y) 60 (n 222) ( ) (n 381) 65.8 Sex Female (n 200) ( ) Male (n 403) 69.3 Location Right (n 375) ( ) Left (n 228) 74.1 Procedure Lobectomy (n 592) ( ) Pneumonectomy (n 11) 69.9 Histology Adenocarcinoma (n 355) ( ) Not adenocarcinoma (n 248) 70.6 T factor pt1,t2 (n 540) ( ) pt3,t4 (n 63) 49.2 P factor p0p1 (n 512) ( ) p2p3 (n 91) 54.9 Size 30 mm (n 373) , 50 mm (n 170) ( ) mm (n 60) ( ) a Univariate analysis was performed with the Cox proportional hazard model. b p 0.05 is statistically significant. with a tumor size 3 cm or less (Figs 1, 2). Therefore, we conducted the univariate analysis for the tumor diameter of 3 cm and 5 cm as cutoff points. Univariate analysis for pn0 disease revealed a significantly worse prognosis for patients with the following variables: older than 60 years of age, male, T factor, P factor (pleural involvement), and tumor diameters of 3 cm and 5 cm (Table 1). In the multivariate analyses, age and tumor size were also independent prognostic predictors, and tumor size, in particular 5 cm or greater, showed the most significant difference (Table 2). In addition, the 5-year survival rate of patients with pt2n0 and a tumor size of 5 cm or less (71.3%) was better than that of stage IIA patients, whereas that of pt2n0 patients with a tumor size of more than 5 cm (51.3%) fell between that of patients with stage IIA (60.8%) and IIB (46.8%) disease. Comment In the present univariate and multivariate analyses, tumor size was the most significant prognostic predictor in patients with pn0 NSCLC after complete resec- Table 2. Multivariate Analysis of Factors That Predict Postoperative Survival in Patients With Pathologic-Negative Nodes (pn0) a Variable Subset Relative Risk 95% Confidence Interval p Value b Age (y) 60 (n 222) (n 381) Sex Female (n 200) Male (n 403) T factor pt1,t2 (n 540) pt3,t4 (n 63) P factor p0p1 (n 512) p2p3 (n 91) Size mm (n 373) , 50 mm (n 170) mm (n 60) a Multivariate analysis was performed with the Cox proportional hazard model. b p 0.05 is statistically significant.

4 Ann Thorac Surg TAKEDA ET AL 2005;79: TUMOR SIZE AND SURVIVAL 1145 tion. In particular, patients with a tumor size greater than 5 cm showed poor postoperative survival. In another multicenter study analysis, a prognostic difference was seen according to tumor size greater than 5 cm in clinical N0 patients as well as those with clinical N1 disease [14]. Cancer patient prognosis is affected by tumor-related factors, which are represented as T factors. Further, in the TNM classification for lung cancer, tumor size is also considered to have an effect [3, 7, 9, 11, 12], as the current TNM staging system in 1997 has proposed a stage I and II subdivision according to a tumor diameter of 3 cm. A stage I subdivision into IA and IB is acceptable, as noted earlier in our multicenter studies [11, 15], which found differences in prognosis according to size of tumor and the extent of pleural involvement. Recently the prevalence of early stage lung cancer increased because of the nationwide mass screening system. In our institutional experience, 50% of patients who underwent surgery in 1991 had stage I lung cancer, whereas the percentage climbed to nearly 70% in 2001, similar to the report from Duke University [15]. This trend also has prompted us to reconsider further subdivision of stage I disease from a prognostic viewpoint. Several studies, mostly from Japanese institutions, have shown a difference in survival for patients with stage IA disease when using 2 cm as a breakpoint [16 22], and some have promoted acceptance of a segmentectomy or lesser resection for these lesions [17 20] based on the long-term follow-up study and recurrence patterns. However, pathologically discovered nodal metastasis was found in 13.2% of patients with a tumor 2 cm or less, and in 21.0% with a tumor size of 2.1 to 3 cm [14]. All patients in that current series received a standard lobectomy with lymph node resection, regardless of the tumor size. Miller and associates [23] concluded a lobectomy with standard lymph node dissection is warranted, even in cases of tumors with a diameter of less than or equal to 1 cm. The prognostic value of tumor size has been documented for many years on the basis of prognostic clinical aspects; tumor size itself may have a strong influence on potential local progression or metastasis. Padilla and associates [16] stated that the tumor size, at a breakpoint of 2 cm, was the only predictor in stage I NSCLC after univariate analysis with sex, age, cell type, amount of resection, and visceral invasion used as variables. However, Harpole and coworkers [3] found that a 3-cm breakpoint was slightly better in reflecting survival than 2 cm, with other factors showing better prognostic ability. In the present study, we did not find that a breakpoint of 2 cm had prognostic impact; however, our population consisted of patients who were treated with a standard lobectomy. At that time, the entity of small peripheral lung cancer was not fully established. However, a breakpoint of 2 cm is expected to be useful with the increasing number of small-sized lung cancer including roentgenogram-negative ground-glass opacity lesions, which have different clinical characteristics compared with small solid masses [19, 24]. Considering the trend of an increased prevalence of early stage lung cancer, a subgrouping of stage IA according to the tumor size may have clinical impact for predicting survival in a revised TNM system. Controversy exists regarding the prognosis of stage IB and stage IIA patients. In a report of 1,310 Japanese patients, Inoue and colleagues [25] confirmed the validity of the current TNM classification, such as noting differences between stage IA and IB, as well as between stage IIA and IIB. However, no prognostic differences were found between stage IB and IIA [25, 26], and a similar tendency was also reported by Naruke and associates [11] and Adebonojo and coworkers [27]. Together these results imply that the prognosis of stage IB patients with a large size tumor is poor enough that this population should be upgraded in the revised TNM. In contrast, few studies have focused on the impact of larger tumor sizes on the prognosis of N0 [11, 12] patients. Watanabe and colleagues [9] were the first to emphasize that patients with a tumor larger than 5 cm in diameter showed a significantly worse survival rate than those with tumors smaller than 5 cm, indicating that tumors greater than 5 cm should be classified as stage II disease. Further, a recent report published by Carbone and associates [12] also found that the survival of patients with a tumor diameter greater than 5 cm was between that for patients with T3 and T4 tumors. Our present analysis showed that tumor size of greater than 5 cm was the most significant independent prognostic value, which strongly supports these findings [9, 12]. In addition, we previously demonstrated that a tumor diameter of greater than 5 cm was a negative prognostic factor in patients with N1 disease, whose survival rate was similar to that of patients with stage IIIA disease [14]. Taken together, these results reinforce the contention that a tumor size of more than 5 cm in diameter is indicative of a poor prognosis in NSCLC patients and should be considered as a potential factor for upgrading T factors in a revised TNM system. Further, on the basis of this clinical need and current retrospective reviews of multicenter studies, we urge reconsideration of stage I, as well as reclassification of IB and IIA, in the next TNM system. We also emphasize that the clinical TNM should be relevant to the pathologic TNM [28] as well as reflect prognostic predictors and planning therapeutic strategies. In conclusion, tumor size was found to be an independent prognostic predictor in patients with N0 disease; therefore, in addition to a breakpoint of 3 cm, upgrading tumor diameter to greater than 5 cm is reasonable in the next revision of the TNM staging system. The authors wish to thank Hajime Maeda, MD, Shodayu Takashima, MD, Noriyoshi Sawabata (Toneyama National Hospital), Masaaki Kawahara, MD (Kinki National Hospital), and Kazunori Shimada, MD (Ehime National Hospital), for contributing to this project and for critical review of the manuscript. GENERAL THORACIC

5 1146 TAKEDA ET AL Ann Thorac Surg TUMOR SIZE AND SURVIVAL 2005;79: References 1. Mountain CF. Reversions in the international system for staging lung cancer. Chest 1997;111: Ichinose Y, Yano T, Yokoyama H, Inoue T, Asoh H, Katsuda Y. The correlation between tumor size and lymphatic vessel invasion in resected peripheral stage I non-small-cell lung cancer: a potential risk of limited resection. J Thorac Cardiovasc Surg 1994;108: Harpole DH Jr, Herndon JE, Young WG Jr, Wollfe WG, Sabiston DC Jr. Stage I non-small cell lung cancer. A multivariate analysis of treatment methods and patterns of recurrence. Cancer 1995;76: Ohta Y, Oda M, Wu J, et al. Can tumor size be a guide for surgical intervention in patients with peripheral non-small cell lung cancer? Assessment from the point of view of nodal micrometastasis. J Thorac Cardiovasc Surg 2001;122: Buccheri G, Ferrigno D. Serum biomarkers facilitate the recognition of early-stage cancer and may guide the selection of surgical candidates: a study of carcinoembryonic antigen and tissue polypeptide antigen in patients with operable non-small cell lung cancer. J Thorac Cardiovasc Surg 2001;122: Sawabata N, Ohta M, Takeda S, Okumura Y, Asada H, Maeda H. Serum carcinoembryonic antigen (CEA) level in surgically resected clinical-stage I patients with non-small lung cancer. Ann Thorac Surg 2002;74: Teasure T, Belcher JR. Prognosis of peripheral lung tumors related to size of the primary. Thorax 1981;35: Soorae AS, Smith RA. Tumor size as a prognostic factor after resection of lung carcinoma. Thorax 1977;32: Watanabe Y, Shimizu J, Oda M, et al. Proposals regarding some deficiencies in the New International Staging System for non-small cell lung cancer. Jpn J Clin Oncol 1991;21: Patz EF Jr, Rossi S, Harpole DH Jr, Herndon JE, Goodman PC. Correlation of tumor size and survival in patients with stage IA non-small-cell lung cancer. Chest 2000;117: Naruke T, Tsuchiya R, Kondo H, Asamura H. Prognosis and survival after resection for bronchogenic carcinoma based on the1997 TNM-staging classification: Japanese experience. Ann Thorac Surg 2001;71: Carbone E, Asamura H, Takei H, et al. T2 tumors larger than five centimeters in diameter can be upgraded to T3 in non-small cell lung cancer. J Thorac Cardiovasc Surg 2001; 122: Suzuki K, Asamura H, Kusumoto M, Kondo H, Tsuchiya R. Early peripheral lung cancer: prognostic significance of ground glass opacity on thin-section computed tomographic scan. Ann Thorac Surg 2002;74: Takeda S, Maeda H, Ohta M, Tada H, Nakagawa K, Matsumura A. Tumor size and survival after resection of cn0 and cn1 non-small cell lung cancer [Abstract]. Jpn J Lung Cancer 2001; 41:A Heyneman LE, Herndon JE, Goodman PC, Patz EF. Stage distribution in patients with a small ( 3cm) primary nonsmall cell lung carcinoma. Implication for lung carcinoma screening. Cancer 2001;92: Pardilla J, Calvo V, Penalver JC, Sales G, Morcillo A. Surgical results and prognostic factors in early non-small cell lung cancer. Ann Thorac Surg 1997;63: Koike T, Terashima M, Takizawa T, Watanabe T, Kurita Y, Yokoyama A. Clinical analysis of small-sized peripheral lung cancer. J Thorac Cardiovasc Surg 1998;115: Kodama K, Doi O, Higashiyama M, Yokouchi H. Intentional limited resection for selected patients with T1N0M0 nonsmall-cell lung cancer: a single-institutional study. J Thorac Cardiovasc Surg 1997;114: Higashiyama M, Kodama K, Yokouchi H, et al. Prognostic value of bronchiolo-alveolar carcinoma component of small lung adenocarcinoma. Ann Thorac Surg 1999;68: Okada M, Yoshikawa K, Hatta T, Tsubota N. Is segmentectomy with lymph node assessment an alternative to lobectomy for non-small cell lung cancer of 2 cm or smaller? Ann Thorac Surg 2001;71: Sugi K, Nawata K, Fujita N, et al. Systemic lymph node dissection for clinically diagnosed peripheral non-small-cell lung cancer less than 2 cm in diameter. World J Surg 1998;22: Asamura H, Nakayama H, Kondo H, Tsuchiya R, Shimosato Y, Naruke T. Lymph node involvement recurrence, and prognosis in resected small peripheral non-small cell carcinomas: are these carcinomas candidates for video-assisted lobectomy? J Thorac Cardiovasc Surg 1996;111: Miller DL, Rawland CM, Deschamps C, Allen MS, Trastek VF, Pairolero PC. Surgical treatment of non-small cell lung cancer 1 cm or less in diameter. Ann Thorac Surg 2002;73: Kodama K, Higashiyama M, Yokouchi H, et al. Natural history of pure ground-glass opacity after long term follow-up of more than 2 years. Ann Thorac Surg 002;73: Inoue K, Sato M, Fujimura S, Sakurada A, Takahashi S, Usuda K. Prognostic assessment of 1310 patients with nonsmall-cell lung cancer who underwent complete resection from J Thorac Cardiovasc Surg 1998;116: Jassem J, Skokowski J, Dziadziuszko R, et al. Results of surgical treatment of non-small cell lung cancer: validation of the new postoperative pathologic TNM classification. J Thorac Cardiovascular Surg 2000;119: Adebonojo SA, Bower A, Moritz DM, Corcoran PC. Impact of revised stage classification of lung cancer on survival: a military experience. Chest 1999;115: Bulzebruck H, Bopp R, Drings P, et al. New aspects in the staging lung cancer. Prospective validation of the international union against cancer TNM classification. Cancer 1992; 70: