Lung cancer is the leading cause of cancer deaths worldwide.

ORIGINAL ARTICLE Predictors of Death, Local Recurrence, and Distant Metastasis in Completely Resected Pathological Stage-I Non Small-Cell Lung Cancer Jung-Jyh Hung, MD, PhD,* Wen-Juei Jeng, MD, Wen-Hu Hsu, MD,* Teh-Ying Chou, MD, PhD, Biing-Shiun Huang, MD, PhD,* and Yu-Chung Wu, MD* Objective: This study investigated the factors predicting recurrence and death in patients with resected stage-i non small-cell lung cancers according to the 7th edition of tumor, node, metastasis (TNM) classification for lung cancer. Methods: All patients undergoing surgical resection for pathological stage-i non small-cell lung cancers at Taipei Veterans General Hospital between 1980 and 2000 were retrospectively reviewed. Those undergoing sublobar resection were excluded. The factors predicting overall survival (OS), overall recurrence, local recurrence, and distant metastasis were investigated. Results: A total of 756 patients were eligible. The 5-year OS rate and probability of freedom from recurrence were 57.3% and 70.2%, respectively. The 2-year local-recurrence free and distant-metastasis free rates were 90.7% and 82.1%, respectively. In multivariable analysis, the new T descriptor (T1a, T1b, and T2a) was the common factor that significantly affected OS (p = 0.003), overall recurrence (p = 0.004), and distant metastasis (p < 0.001). Smoking index more than 20, and number of mediastinal lymph nodes dissected/sampled of 15 or fewer were common factors that significantly predicted worse OS (p < 0.001, p < 0.001, respectively), lower probability of freedom from overall recurrence (p = 0.025, p = 0.009, respectively), and higher risk of local recurrence (p < 0.001, p = 0.030, respectively). Non squamous-cell histology predicted higher risk of distant metastasis (p = 0.006). Conclusions: Risks of death and recurrence increase as the T descriptor upgrades in the new TNM system. The combination of risk factors can be used to identify high-risk subgroups of local recurrence and distant metastasis. Key Words: Non small-cell lung cancer, Survival, Local recurrence, Distant metastasis. (J Thorac Oncol. 2012;7: 1115 1123) *Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital and School of Medicine, National Yang-Ming University, Taipei, Taiwan; Department of Internal Medicine, Chang Gung Memorial Hospital and School of Medicine, Chang Gung University, Taipei, Taiwan; and Institute of Clinical Medicine, National Yang-Ming University, and Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan. Disclosure: The authors declare no conflict of interest. Address for correspondence: Yu-Chung Wu, MD, Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital, No. 201, Section 2, Shih-Pai Road, Taipei 112, Taiwan. E-mail: wuyc@vghtpe.gov.tw. Copyright 2012 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/12/0707-1115 Journal of Thoracic Oncology Volume 7, Number 7, July 2012 Lung cancer is the leading cause of cancer deaths worldwide. Surgical resection is the treatment of choice for early-stage non small-cell lung cancer (NSCLC). 1,2 Five-year survival in patients with resected stage-i NSCLC according to the 6th edition of the TNM classification (TNM 6) for lung cancer 3 ranges between 55% and 80%. 4 7 Tumor recurrence is the most common cause of disease failure after surgical resection. 5 9 Postrecurrence survival in resected stage-i NSCLC is poor. 8 11 The 7th edition of the TNM classification (TNM 7) for lung cancer was published in 2009. 12,13 In the TNM 7, the T1 descriptor has been classified into T1a ( 2 cm) and T1b (>2 to 3 cm), whereas size-based T2 descriptor has been classified into T2a (>3 to 5 cm), T2b (>5 to 7 cm), and T3 (>7 cm). 14 Stage-I NSCLC was subdivided into IA (T1aN0M0 and T1bN0M0) and IB (T2aN0M0). 15 T2bN0M0 and T3N0M0 were classified as stage IIA and stage IIB, respectively. 15 Although some randomized clinical trials have evaluated the role of adjuvant chemotherapy in patients with resected stage-i NSCLC, the benefits remain uncertain. 16 18 Only a few studies reported the survival and patterns of recurrence in resected stage-i NSCLC (TNM 7) in the literature. The risk factors separately predicting local recurrence and distant metastasis in resected stage-i (TNM 7) NSCLC have not been demonstrated. Identification of factors associated with the development of local recurrence or distant metastasis after surgical resection may be useful to stratify patients with higher risks in the future design of clinical trials for aggressive adjuvant therapy. In this report, we focused on the analysis of the factors predicting survival, local recurrence, and distant metastasis in patients with stage-i NSCLC (TNM 7) after complete resection. PATIENTS AND METHODS All patients who underwent surgical resection for pathological stage-i NSCLC at Taipei Veterans General Hospital between January 1980 and December 2000 were reviewed. Those undergoing sublobar resection were excluded. A total of 916 patients were eligible according to the TNM 6 for lung cancer. Among them 756 patients (82.5%) were reclassified as pathological stage-i NSCLC according to the TNM 7 for lung cancer, and were included in this retrospective study. This study has been approved by the Institutional Review Board of Taipei Veterans General Hospital. 1115

Hung et al. Journal of Thoracic Oncology Volume 7, Number 7, July 2012 The preoperative staging work-up, including chest and upper-abdomen computed tomographic scans, bronchoscopic examination, and nuclear medicine survey (bone and brain), was done as previously described. 19,20 Mediastinoscopy was not a routine preoperative staging procedure, and was performed only when enlarged mediastinal lymph nodes (LNs) (diameter > 1.0 cm) were shown by the computed tomographic scan. During the study period, positron emission tomography scan was not available as a staging modality. All patients underwent complete resection of lung cancer with mediastinal LN dissection/sampling as previously described. 19,20 None of the patients had received adjuvant therapy after initial surgical resection. Histological typing was determined according to the World Health Organization classification, 21 and all the histological cases were reviewed. Determination of disease stages were based on the TNM classification (7th edition) of the American Joint Committee on Cancer and the International Union Against Cancer. 12,13 All patients were followed up at our outpatient department as previously described. 19,20 Secondary primary lung cancer was differentiated from recurrent NSCLC according to the criteria proposed by Martini and Melamed. 5,22 Local recurrence was defined as tumor recurrence in contiguous anatomical sites, including the ipsilateral hemithorax and mediastinum after surgical resection. Distant recurrence was defined as tumor recurrence in the contralateral lung or outside the hemithorax and mediastinum after surgical resection. To investigate their impact on overall survival (OS), overall recurrence, local recurrence, and distant metastasis, clinicopathologic factors were analyzed in univariate and multivariate analyses. The length of OS is defined as the interval between the date of surgical resection and the date of either death or the last follow-up. Pattern of recurrence is defined as all recurrences (including local recurrence, distant metastasis, or both local and distant) discovered from the initial operation to death or last follow-up. Time to recurrence (the period of freedom from recurrence) is defined as the interval between the date of surgical resection and the date of the first recurrence or the last follow-up. An observation was censored at the last follow-up session when the patient was alive with recurrence-free status, or had died without recurrence. In the analysis of prognostic factors for time to recurrence, recurrence (local or distant) is defined by the first recurrence. If both local and distant diseases are noted within a time frame of 3 months, they will be defined as both local recurrence and distant metastasis. Patients with both local recurrence and distant metastasis were excluded from analysis of freedom from local recurrence or distant metastasis. The OS and probabilities of freedom from overall recurrence, local recurrence, and distant metastasis were calculated by the Kaplan-Meier method. 23 To compare between the groups with respect to categorical and continuous variables, the χ 2 test or the independent sample t test was used as appropriate. Univariate and multivariate analyses were performed by means of the Cox proportional hazards model using SPSS software (version 16.0; SPSS, Chicago, IL). Only variables with p < 0.1 after the univariate analysis were entered into the multivariate analysis. Statistical significance was defined as p < 0.05. RESULTS Among the 916 surgically resected stage-i NSCLC patients (TNM 6), 756 (82.5%) patients were reclassified as pathological stage I, 108 (11.8%) were as stage IIA, and 52 (5.7%) were as stage IIB according to the TNM 7. Stage distribution for both TNM 6 and TNM 7 is listed in Table 1. Conversion from the 6 th to the 7th edition resulted in 17.5% stage migration. The median follow-up time for all the 756 surgically resected stage-i NSCLC (TNM 7) patients was 67.7 months (mean, 75.7 ± 57.0 months). The characteristics of these 756 patients are listed in Table 2. Nineteen postoperative deaths (2.5%) occurred. The 5- and 10-year OS rates were 57.3% and 36.4%, respectively (Fig. 1A). The 5- and 10-year disease-free survival rates were 55.1% and 36.1%, respectively (Fig. 1B). Among these 756 patients, 509 (67.3%) were free of tumor recurrence, 213 (28.2%) developed recurrence, and 34 patients (4.5%) were with unknown recurrent status during follow-up. The 5- and 10-year probabilities from recurrence were 70.2 % and 69.4%, respectively (Fig. 2A). The relationship between disease-free status and clinicopathological variables is shown in Table 3. The recurrent group consisted of more T2a tumor (p = 0.004), and a higher frequency of patients with 15 or lesser mediastinal LNs dissected/sampled (p = 0.030). As the T descriptors upgrade from T1a, T1b, to T2a, tumor recurrence rates increase from 19.5% (31/159), 29.6% (66/223), to 34.1% (116/224), respectively. The patterns of recurrence included local recurrence only in 51 patients (23.9%), distant metastasis only in 126 (59.2%), and both local recurrence and distant metastasis in 36 patients (16.9%). The relationship between pattern of recurrence (local recurrence only or distant metastasis only) and clinicopathological variables is shown in Table 4. As compared with the distant-metastasis only group, the local-recurrence only group consisted of more squamous cell carcinoma (p = 0.013), a higher frequency of patients with smoking index greater than 20 pack-years (p = 0.015), and a higher frequency of T1a and T1b tumors (p = 0.048). The distant-metastasis only group consisted of more never smokers, more adenocarcinomas, and a higher frequency of T2a tumors. TABLE 1. Change of Stage Distribution According to the TNM Classification, 6th and 7th Editions Stage 6th Edition TNM TNM Classification 7th Edition No. of Patients Stage TNM No. of Patients Stage IA T1N0M0 406 Stage IA T1aN0M0 168 T1bN0M0 238 Stage IB T2N0M0 510 Stage IB T2aN0M0 350 Stage IIA T2bN0M0 108 Stage IIB T3N0M0 52 1116 Copyright 2012 by the International Association for the Study of Lung Cancer

Journal of Thoracic Oncology Volume 7, Number 7, July 2012 Predictors of Death and Recurrence in Stage I Lung Cancer TABLE 2. Characteristics of 756 Patients with Resected Stage-I Non Small-Cell Lung Cancer Variables Data Age, yrs (mean ± SD) 65.1 ± 9.4 Sex, no. (%) Male 589 (77.9) Female 167 (22.1) Sm oking index, pack-years (median [IQR]) 20.0 (0.0 40.0) Tumor location, no. (%) Left lung 185 (24.5) Right lung 571 (75.5) Histological type, no. (%) Squamous cell carcinoma 287 (38.0) Adenocarcinoma 357 (47.2) Bronchioloalveolar carcinoma 49 (6.5) Large cell carcinoma 57 (7.5) Adenosquamous carcinoma 6 (0.8) Extent of pulmonary resection, no. (%) Lobectomy 603 (79.7) Bilobectomy 78 (10.4) Pneumonectomy 75 (9.9) T status, no. (%) T1a 168 (22.2) T1b 238 (31.5) T2a 350 (46.3) Visceral pleural invasion, no. (%) Absent 565 (74.7) Present 155 (20.5) Unknown 36 (4.8) Nu mber of LNs dissected/sampled 15.3 ± 9.7 (mean ± SD) IQR, interquartile range; LN, lymph node. Overall Survival Univariate analysis indicated that older age (p < 0.001), male sex (p < 0.001), higher smoking index (p < 0.001), squamous cell carcinoma (p = 0.003), bilobectomy or pneumonectomy (p = 0.015), and 15 or fewer mediastinal LNs dissected/sampled (p = 0.001) were predictors of worse OS (Table 5). As compared with T1a, T1b (p = 0.001) and T2a (p < 0.001) were significant predictors of worse OS. Order age (p < 0.001), higher smoking index (p < 0.001), bilobectomy or pneumonectomy (p = 0.039), and 15 or lesser mediastinal LNs dissected/sampled (p < 0.001) were still significant predictors of worse OS in multivariate analysis (Table 6). As compared with T1a, T1b (p = 0.010) and T2a (p = 0.001) were significant predictors of worse OS. Overall Recurrence Univariate analysis indicated that higher smoking index (p = 0.035) and number of mediastinal LNs dissected/sampled being 15 or fewer (p = 0.023) were predictors of lower probability of freedom from recurrence (Table 5). As compared with T1a, T1b (p = 0.018) and T2a (p < 0.001) were significant predictors of lower probability of freedom from recurrence. FIGURE 1. Cumulative probability of (A) overall survival and (B) disease-free survival in 756 patients with resected stage-i non small-cell lung cancer. Higher smoking index (p = 0.025), advanced T status (p = 0.004), and number of mediastinal LNs dissected/sampled less than or equal to 15 (p = 0.009) were still significant predictors of lower probability of freedom from recurrence in multivariate analysis (Table 6). As compared with T1a, T1b (p = 0.028) and T2a (p = 0.001) were significant predictors of lower probability of freedom from recurrence. Local Recurrence For analysis of time to recurrence, recurrence (local or distant) is defined by the first recurrence. Local recurrence Copyright 2012 by the International Association for the Study of Lung Cancer 1117

Hung et al. Journal of Thoracic Oncology Volume 7, Number 7, July 2012 TABLE 3. Relationship Between Disease-Free Status and Clinicopathologic Variables in Patients of Pathological Stage I Non Small-Cell Lung Cancer Variables Disease-Free Status No Recurrence (n = 509) With Recurrence (n = 213) p Value Age, yrs (mean ± SD) 65.1 ± 9.5 64.9 ± 9.3 0.785 Sex, no. (%) Male 392 (77.0) 169 (79.3) 0.493 Female 117 (23.0) 44 (20.7) Smoking index, pack-years, no. (%) a Never 177 (37.2) 63 (31.2) 0.076 1 20 85 (17.8) 29 (14.3) >20 214 (45.0) 110 (54.5) Histological type, no. (%) Squamous cell carcinoma 201 (39.5) 73 (34.3) 0.420 Adenocarcinoma 266 (52.2) 121 (56.8) Others 42 (8.3) 19 (8.9) T descriptor, no. (%) T1a 128 (25.1) 31 (14.5) 0.004 T1b 157 (30.8) 66 (31.0) T2a 224 (44.1) 116 (54.5) Extent of pulmonary resection, no. (%) Lobectomy 400 (78.6) 173 (81.2) 0.425 Pneumonectomy or bilobectomy 109 (21.4) 40 (18.8) Visceral pleural invasion, no. (%) a Absent 381 (79.0) 158 (77.1) 0.293 Present 101 (21.0) 47 (22.9) Number of LNs dissected/sampled, no. (%) a 15 272 (53.8) 132 (62.6) 0.030 >15 234 (46.2) 79 (37.4) a Data are lacking in some patients for these variables. LN, lymph node. only, distant metastasis only, and both local recurrence and distant metastasis were identified in 59, 131, and 19 patients, respectively. The 2- and 5-year local-recurrence free rates were 90.7% and 87.8%, respectively (Fig. 2B). Univariate analysis indicated that higher smoking index (p = 0.001) was a significant predictor of lower probability of freedom from local recurrence (Table 5). Number of mediastinal LNs dissected/sampled less than or equal to 15 (p = 0.072) tended to be a significant predictor of local recurrence. Higher smoking index (p < 0.001) and number of mediastinal LNs dissected/ sampled less than or equal to 15 (p = 0.030) were significant predictors of lower probability of freedom from local recurrence in multivariate analysis (Table 6). FIGURE 2. Cumulative probability of freedom from (A) overall recurrence, (B) local recurrence, and (C) distant metastasis in 756 patients with resected stage-i non small cell lung cancer. Distant Metastasis The 2- and 5-year distant-metastasis free rates were 82.1% and 78.3%, respectively (Fig. 2C). Univariate analysis indicated that adenocarcinoma (p = 0.014) and T2a (p < 0.001) were significant predictors of lower probability of freedom from distant metastasis (Table 5). T1b (p = 0.084) and number of mediastinal LNs dissected/sampled less that 1118 Copyright 2012 by the International Association for the Study of Lung Cancer

Journal of Thoracic Oncology Volume 7, Number 7, July 2012 Predictors of Death and Recurrence in Stage I Lung Cancer TABLE 4. Relationship Between Pattern of Recurrence and Clinicopathologic Variables in Patients of Pathological Stage-I Non Small-Cell Lung Cancer Variables Pattern of Recurrence Local Recurrence Only (n = 51) Distant Metastasis Only (n = 126) p Value Age, yrs (mean ± SD) 63.0 ± 10.5 65.5 ± 9.2 0.114 Age at recurrence, 64.6 ± 10.2 66.4 ± 9.3 0.267 years (mean ± SD) Sex, no. (%) Male 43 (84.3) 97 (77.0) 0.277 Female 8 (15.7) 29 (23.0) Smoking index, pack-years, no. (%) a Never 10 (20.4) 46 (39.0) 0.015 1 20 5 (10.2) 19 (16.1) >20 34 (69.4) 53 (44.9) Histological type, no. (%) Squamous cell 25 (49.0) 33 (26.2) 0.013 carcinoma Adenocarcinoma 22 (43.1) 80 (63.5) Others 4 (7.9) 13 (10.3) T descriptor, no. (%) T1a 9 (17.7) 16 (12.7) 0.048 T1b 22 (43.1) 35 (27.8) T2a 20 (39.2) 75 (59.5) Extent of pulmonary resection, no. (%) Lobectomy 38 (74.5) 105 (83.3) 0.177 Pneumonectomy or bilobectomy 13 (25.5) 21 (16.7) Visceral pleural invasion, no. (%) Absent 38 (74.5) 88 (69.8) 0.515 Present 11 (21.6) 33 (26.2) Unknown 2 (3.9) 5 (4.0) Number of LNs dissected/sampled, no. (%)* 15 34 (66.7) 79 (63.2) 0.663 >15 17 (33.3) 46 (36.8) a Data are lacking in some patients for these variables. LN, lymph node. or equal to 15 (p = 0.057) tended to be significant predictors for distant metastasis. Adenocarcinoma (p = 0.002) and T2a (p < 0.001) were still significant predictors of lower probability of freedom from distant metastasis in multivariate analysis (Table 6). Application of the Number of Risk Factors in Predicting Local Recurrence and Distant Metastasis To examine the cumulative predictive value of local recurrence, a smoking index of more than 20 pack-years and number of mediastinal LNs dissected/sampled equal to or lesser than 15 were used as risk predictors for local recurrence. We divided all patients into three groups according to the number of positive risk predictors: none positive (group 1), one positive (group 2), and two positive (group 3). Kaplan-Meier analysis showed that the possibility of local recurrence was significantly associated with the number of risk predictors (Fig. 3A). Patients with two positive risk predictors had the highest possibility of local recurrence. To examine the cumulative effect predicting distant metastasis, non squamous-cell histology and T2a were used as risk predictors for distant metastasis. We divided all patients into three groups according to the number of positive risk predictors: none or one positive (group 1), two positive (group 2), and three predictors positive (group 3). Kaplan-Meier analysis showed that patients with both risk predictors had significantly higher possibility of distant metastasis (Fig. 3B). DISCUSSION This study investigated the common and distinct factors predicting local recurrence, distant metastasis, and death in patients with completely resected pathological stage-i NSCLC (TNM 7). The extent of pulmonary resection for T1N0 NSCLC remains controversial. The Lung Cancer Study Group randomized controlled trial recommended lobectomy over limited resection for T1N0 NSCLC. 24 Patients undergoing limited resection had significantly increased local recurrence rate than those undergoing lobectomy. 24 However, several recent studies showed that limited resection may be equally effective for the treatment of stage-ia tumors with a diameter of 2 cm or lesser. 25 27 Exclusion of patients undergoing sublobar resection in our cohort avoided the controversies and reduced the possibility of local recurrence because of inadequate resection margin. The T descriptor was a common factor that significantly predicted OS, overall recurrence, and distant metastasis in our study. The smoking index and number of mediastinal LNs dissected/sampled being 15 or fewer were factors significantly predicting OS, overall recurrence, and local recurrence. Non squamous-cell histology was a factor predicting distant metastasis. The TNM 7 has been published in 2009, 12,13 and stage-i NSCLC was reclassified as IA (T1aN0M0, T1bN0M0) and IB (T2aN0M0). Stage IA was not changed to that of TNM 6, whereas stage IB was restricted to T2aN0M0. T2bN0M0 was reclassified as stage IIA. Pepek et al. 28 reported 15.1% stage migration of stage-i NSCLC (TNM 6). Maeda et al. 29 reported 6.8% stage migration of stage-i NSCLC (TNM 6). In our study, 108 patients (11.8%) of T2bN0M0 were restaged as stage IIA, and 52 patients (5.7%) of T3N0M0 were regrouped as stage IIB. Conversion from TNM 6 to TNM 7 resulted in 17.5% stage migration. The prognostic factors of stage-i NSCLC (TNM 6) have been widely reported in the literature. 5 7,30,31 However, only several studies reported the prognostic factors of stage-i NSCLC (TNM 7). 29,32 In the report by Maeda et al. 29 5-year OS rates for stage IA and IB (TNM 7) were 89.9% and 72.3%, respectively. They also demonstrated that older age, intratumoral vascular invasion, and visceral pleural invasion were poor prognostic factors in stage-ib NSCLC. 29 In the current study, we investigated the prognostic factors of stage-i NSCLC (TNM 7). The factors predicting poor OS included order age, higher smoking index, bilobectomy or pneumonectomy, T1b or T2a, and number of LNs dissected/sampled being 15 or fewer. Copyright 2012 by the International Association for the Study of Lung Cancer 1119

Hung et al. Journal of Thoracic Oncology Volume 7, Number 7, July 2012 TABLE 5. Univariate Analysis of Overall Survival, Cancer-Specific Survival, Local Recurrence and Distant Metastasis in 756 Patients with Resected Stage-I Non Small-Cell Lung Cancer Variables Overall Survival Overall Recurrence Local Recurrence Distant Metastasis HR 95% CI p Value HR 95% CI p Value HR 95% CI p Value HR 95% CI p Value Age, yrs a 1.028 1.017 1.039 <0.001 1.002 0.988 1.016 0.798 0.985 0.960 1.010 0.231 1.007 0.989 1.026 0.450 Sex Female 1 1 1 1 Male 1.637 1.287 2.083 <0.001 1.192 0.855 1.658 0.301 1.572 0.797 3.106 0.192 1.056 0.703 1.587 0.793 Smoking index, <0.001 0.035 0.001 0.925 pack-years Never 1 1 1 1 1 20 1.484 1.114 1.976 0.007 1.039 0.672 1.604 0.864 1.033 0.359 2.972 0.953 0.899 0.528 1.529 0.694 >20 1.987 1.597 2.473 <0.001 1.457 1.069 1.986 0.017 3.159 1.620 6.158 0.001 0.978 0.665 1.438 0.910 Location Left lung 1 1 1 1 Right lung 0.927 0.759 1.133 0.460 0.947 0.697 1.287 0.728 0.778 0.443 1.367 0.383 0.804 0.550 1.177 0.262 Histological type 0.014 0.582 0.262 0.043 Squamous cell 1 1 1 1 carcinoma Adenocarcinoma 0.752 0.624 0.907 0.003 0.829 0.500 1.373 0.465 0.640 0.376 1.092 0.102 1.639 1.104 2.432 0.014 Others 0.826 0.574 1.189 0.304 0.954 0.588 1.547 0.849 0.789 0.305 2.043 0.625 1.661 0.879 3.139 0.118 Extent of pulmonary resection Lobectomy 1 1 1 1 Bilobectomy or 1.299 1.051 1.604 0.015 1.034 0.733 1.458 0.850 1.506 0.838 2.705 0.171 0.878 0.555 1.388 0.577 pneumonectomy T status <0.001 <0.001 0.360 0.001 T1a 1 1 1 1 T1b 1.582 1.205 2.078 0.001 1.677 1.094 2.570 0.018 1.602 0.797 3.219 0.186 1.667 0.934 2.976 0.084 T2a 1.869 1.450 2.410 <0.001 2.183 1.469 3.244 <0.001 1.181 0.590 2.361 0.639 2.623 1.553 4.431 < 0.001 Visceral pleural invasion Absent 1 1 1 1 Present 1.014 0.920 1.118 0.783 0.912 0.741 1.123 0.387 0.858 0.546 1.349 0.507 0.970 0.784 1.201 0.782 Number of LNs dissected/sampled 15 1 1 1 1 >15 0.727 0.602 0.877 0.001 0.724 0.548 0.957 0.023 0.609 0.355 1.045 0.072 0.708 0.496 1.010 0.057 a The HR associated with age is that the increase in hazard is associated with a 1-year increase in age. Bold indicates significance. HR, hazard ratio; CI, confidence interval; LN, lymph node. The 5-year recurrence rate in stage-i NSCLC (TNM 6) ranges between 76% and 85%. 5,30,33 Maeda et al. 34,35 reported that the 5-year recurrence-free rate in patients with stage-ia NSCLC (TNM 7) ranges between 84% to 87%. In another article by Maeda et al. 32 they report that 5-year recurrence-free rate in patients with stage-i NSCLC (TNM 7) was 84.2%. In the current study, the 5-year recurrence-free rate was 70.2%. The factors predicting overall recurrence included smoking index more than 20, T1b or T2a, and number of LNs dissected/ sampled no more than 15. We also examined recurrence-free rates in local recurrence and distant metastasis separately. The 2- and 5-year local recurrence-free rates were 90.2% and 86.8%, respectively. The 2- and 5-year distant metastasis-free rates were 81.2% and 77.6%, respectively. The localrecurrence free rate was higher than distant-metastasis free rate. We showed that the recurrent group consisted of more T2a tumor and a higher frequency of patients with number of mediastinal LNs dissected/sampled being 15 or fewer. We further examined the relationship between local recurrence and distant metastasis. The local-recurrence only group consisted of more squamous cell carcinoma, a higher frequency of patients with smoking index greater than 20 pack-years, and a higher frequency of T1a and T1b tumors. The distantmetastasis only group consisted of more never smokers, more adenocarcinomas, and a higher frequency of T2a tumors. The predictors for recurrence in resected stage-i NSCLC (TNM 6) has been well demonstrated in the literature. 5,30,33 However, only few studies evaluated the risk factors 1120 Copyright 2012 by the International Association for the Study of Lung Cancer

Journal of Thoracic Oncology Volume 7, Number 7, July 2012 Predictors of Death and Recurrence in Stage I Lung Cancer TABLE 6. Multivariate Analysis of Overall Survival, Cancer- Specific Survival, Local Recurrence and Distant Metastasis in 756 Patients with Resected Stage-I Non Small-Cell Lung Cancer Variables HR 95% CI p value Overall survival Age, yrs a 1.023 1.011 1.035 <0.001 Smoking index, pack-years <0.001 Never 1 1 20 1.276 0.936 1.739 0.123 >20 1.744 1.337 2.275 <0.001 Extent of pulmonary resection Lobectomy 1 Bilobectomy or 1.271 1.012 1.590 0.039 pneumonectomy T status 0.003 T1a 1 T1b 1.446 1.093 1.913 0.010 T2a 1.583 1.217 2.059 0.001 Number of LNs dissected/sampled 15 1 >15 0.683 0.562 0.831 <0.001 Overall recurrence Smoking index, pack-years 0.025 Never 1 1 20 0.980 0.631 1.522 0.928 >20 1.460 1.069 1.993 0.017 T status 0.004 T1a 1 T1b 1.632 1.055 2.522 0.028 T2a 1.985 1.324 2.977 0.001 Number of LNs dissected/sampled 15 1 >15 0.670 0.508 0.908 0.009 Local recurrence Smoking index, pack-years <0.001 Never 1 1 20 1.047 0.364 3.013 0.932 >20 3.250 1.666 6.339 0.001 Number of LNs dissected/sampled 15 1 >15 0.538 0.307 0.943 0.030 Distant metastasis Histological type 0.006 Squamous cell carcinoma 1 Adenocarcinoma 1.888 1.260 2.828 0.002 Others 1.994 1.049 3.793 0.035 T status <0.001 T1a 1 T1b 1.590 0.889 2.844 0.118 T2a 2.780 1.638 4.717 <0.001 a The HR associated with age is that the increase in hazard is associated with a 1-year increase in age. HR, hazard ratio; CI, confidence interval; LN, lymph node. for local recurrence and distant metastasis separately. Sawyer et al. 30 reported that the number of LNs dissected being less than 15, and T2 tumor were the factors predicting local recurrence in resected stage-i NSCLC (TNM 6). Tumor size of more than 5 cm and nonsquamous histology predicted a poor distant-metastasis free rate in resected stage-i NSCLC. 30 The predictors for recurrence in resected stage-i NSCLC (TNM 7) has not been widely investigated in the literature. Reports by Maeda et al. 32,35 have demonstrated that histologic differentiation, intratumoral vascular invasion, and visceral of pleural invasion were significant predictors for recurrence in stage-i NSCLC (TNM 7). In our study, the predictors of local recurrence or distant metastasis were examined separately. The factors predicting local recurrence included a smoking index more than 20 and the number of LNs dissected/sampled being 15 or lesser. The factors predicting distant metastasis included non squamous-cell carcinoma and T2a. We further developed a model to stratify high-risk subgroups of local recurrence and distant metastasis by using a combination of distinct risk factors. The possibility of local recurrence was significantly associated with increased number of risk predictors. Patients with smoking index more than 20 and number of LNs dissected/ sampled being 15 or fewer had the highest possibility of local recurrence. Although the possibility of distant metastasis was not associated with increased number of risk predictors (nonsquamous-cell carcinoma or T2a), the group of patients with both risk factors had a significantly higher possibility of distant metastasis. Our results showed that the new T descriptor (T1a, T1b, and T2a) in TNM 7 was a significant factor predicting OS and overall recurrence in stage-i NSCLC. As the T descriptor (T1a, T1b, and T2a) upgrades, tumor-recurrence rates also increase (20%, 30%, and 34%). Furthermore, the new T descriptor predicts distant metastasis in stage-i NSCLC. Increase of risks in death, recurrence, and distant metastasis could be predicted as T descriptor upgrades in the new TNM system. Cigarette smoking has been shown to be a prognostic factor in patients with NSCLC in the literature. 36 39 Hanagiri et al. 36 reported that smoking was a significant postoperative prognostic factor in patients with NSCLC. Bryant et al. 37 reported that a 5-year survival rate was significantly better for never smokers compared to smokers in stage-i NSCLC (TNM 6). Maeda et al. 38 reported that OS and recurrence-free survival in never smokers were significantly better than those of ever smokers in patients with stage-i NSCLC (TNM 7). These authors 39 also discovered that a greater smoking extent was associated with the presence of solid components in stage-i lung adenocarcinoma, which may have more aggressive biological features resulting in poorer outcomes. In our study, smoking index was a significant prognostic factor for OS and overall recurrence, and a predictor of local recurrence. The number of mediastinal LNs dissected/sampled alternatively represents the quality of lymphadenectomy, and affects the survival rate for patients with resected stage-i NSCLC. 19,31 Sawyer et al. 30 reported that factors predicting poor OS in resected stage-i NSCLC (TNM 6) included Copyright 2012 by the International Association for the Study of Lung Cancer 1121

Hung et al. Journal of Thoracic Oncology Volume 7, Number 7, July 2012 FIGURE 3. A, Kaplan-Meier analysis (log-rank test) for local recurrence. The patients were divided into three groups according to number of positive risk predictors (smoking index > 20 and number of mediastinal lymph nodes dissected/sampled 15): none positive (group 1), one positive (group 2), and two positive (group 3). The possibility of local recurrence increased as the number of risk predictors increased. B, Kaplan- Meier analysis (log-rank test) for distant metastasis. The patients were divided into three groups according to number of positive risk predictors (nonsquamous cell histology and T2a): none positive (group 1), one positive (group 2), and two positive (group 3). Patients with both positive risk predictors had higher possibility of distant metastasis. fewer than 15 LNs dissected and a tumor size greater than 3 cm. Varlotto et al. 31 also reported that lymphadenectomy was associated with improved OS and disease-free survival in resected stage-i NSCLC (TNM 6). The current study showed that number of mediastinal LNs dissected/sampled was a predictor of OS and overall recurrence in stage-i NSCLC (TNM 7). Furthermore, we showed that number of LNs dissected/ sampled was also a predictor of local recurrence in stage-i NSCLC (TNM 7). There are some limitations and biases of this study that should be mentioned. As a retrospective, single-institute study, patient-selection bias and time-trend bias were inevitable. Although the patients were not selected according to location (right or left side), only 24% of the tumors were left-sided in our study. That may be a result of the bias from conducting a single-institute study. However, we showed that location (right versus left side) did not influence OS and probability of freedom from recurrence. As a retrospective study, it was difficult to obtain performance status from the charts. Although performance status is clearly an important factor in stage-iv NSCLC, its importance in stage-i disease has not yet been established. Lack of data about performance status might have little significance in the analysis of death and recurrence in our study. Furthermore, the fact that the predictors demonstrated in our study were not all consistent with other reports highlights the possibility of false positive findings. Prospective multi-institutional studies are mandatory to further validate the predictors of recurrence and death in resected stage-i NSCLC (TNM 7). The new T descriptor was a common factor predicting OS, overall recurrence, and distant metastasis in resected stage-i NSCLC of the new TNM 7 system. Smoking index and number of mediastinal LNs dissected/sampled being 15 or fewer were predictors of local recurrence, whereas non squamous-cell histology and T2a were predictors of distant metastasis. The combination of distinct risk factors is useful in specifically predicting local recurrence or distant metastasis. A risk-guided strategy focusing on OS, overall recurrence, local recurrence and/or distant metastasis could be used in the future design of clinical trials for adjuvant chemotherapy and/ or radiation therapy. ACKNOWLEDGMENTS The authors thank Dr. Liang-Shun Wang of Shuang Ho Hospital, Taipei, Taiwan for contributing to this article. 1122 Copyright 2012 by the International Association for the Study of Lung Cancer

Journal of Thoracic Oncology Volume 7, Number 7, July 2012 Predictors of Death and Recurrence in Stage I Lung Cancer They also thank Mr. Jung-Hsing Lin for his assistance in data collection. Supported in part by National Science Council (NSC-100 2314-B-075-001) (JJ Hung), National Science Council (NSC 100 2314-B-075-004-MY2) (YC Wu), Center of Excellence for Cancer Research at Taipei Veterans General Hospital (DOH100-TD-C-111-007) (YC Wu), Yen Tjing Ling Medical Foundation (CI-100-15) (JJ Hung) and Taipei Veterans General Hospital (V101B-038) (JJ Hung). REFERENCES 1. Spira A Ettinger DS. Multidisciplinary management of lung cancer. N Engl J Med 2004;350:379 392. 2. Scott WJ, Howington J, Feigenberg S, Movsas B, Pisters K; American College of Chest Physicians. Treatment of non-small cell lung cancer stage I and stage II: ACCP evidence-based clinical practice guidelines (2 nd edition). Chest 2007;132(3 Suppl):234S 242S. 3. Sobin L, Wittekind Ch, eds. 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