Poor Prognostic Factors in Patients With Stage IB Non-small Cell Lung Cancer According to the Seventh Edition TNM Classification

CHEST Original Research Poor Prognostic Factors in Patients With Stage IB Non-small Cell Lung Cancer According to the Seventh Edition TNM Classification LUNG CANCER Ryo Maeda, MD ; Junji Yoshida, MD, PhD ; Genichiro Ishii, MD, PhD ; Tomoyuki Hishida, MD, PhD ; Mitsuyo Nishimura, MD, PhD ; and Kanji Nagai, MD, PhD Background: This study investigated poor prognostic factors in patients with stage IB non-small cell lung cancer (NSCLC) according to the seventh edition of the TNM classification. Methods: Between July 1992 and December 2004, 1,204 consecutive patients with stage I NSCLC diagnosed based on the sixth edition TNM classification underwent complete resection with systematic node dissection. Of these patients, 434 were reclassified as stage IB according to the seventh edition TNM classification. Univariate analyses were performed using the log-rank test to select prognostic factors. The Cox proportional hazards regression model was used for multivariate analyses to identify independent factors indicating an unfavorable prognosis. Results: On multivariate analyses, two variables were independent significant factors indicating an unfavorable prognosis: presence of intratumoral vascular invasion and presence of visceral pleural invasion. According to subgroup analyses combining these two risk factors, 5-year disease-specific survival probabilities were 93%, 83%, and 73% for patients with zero, one, or two risk factors, respectively. The 5-year disease-specific survival of patients without risk factors was not statistically different from that of patients with stage IA cancer. In addition, the 5-year diseasespecific survival curve of patients with two risk factors lay beneath that of patients with T2b or T3N0M0, stage II cancer, and there were no statistically significant differences between them. Conclusions: We identified the presence of intratumoral vascular invasion and the presence of visceral pleural invasion as independent poor prognostic factors in patients with stage IB NSCLC. When these two factors are combined, higher- and lower-risk subgroups can be identified, which will help to personalize adjuvant chemotherapy. CHEST 2011; 139(4):855 861 Abbreviations: CEA 5 serum carcinoembryonic antigen; HR 5 hazard ratio; IVI 5 intratumoral vascular invasion; NSCLC 5 non-small cell lung cancer; VPI 5 visceral pleura invasion In the seventh edition of the TNM Classification for Lung and Pleural Tumors, patients with N0M0 lung cancers that are. 5 cm are separated from patients with stage IB cancer as a group with a poorer prognosis and are upgraded to stage II. 1 Although adjuvant chemotherapy after resection of stage II to stage IIIA Manuscript received June 14, 2010; revision accepted July 24, 2010. Affiliations: From the Department of Thoracic Oncology (Drs Maeda, Yoshida, Hishida, Nishimura, and Nagai), National Cancer Center Hospital East; and Department of Pathology (Dr Ishii), Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan. Funding/Support: This work was supported in part by a Grantin-Aid for Cancer Research from the Ministry of Health, Labour and Welfare, Japan. non-small cell lung cancer (NSCLC) is the standard of care, 2-5 the role of adjuvant chemotherapy in stages according to the seventh edition classification has not been established. Identifying prognostic factors on the basis of the current classification will help to select patients who may benefit from adjuvant therapy or for whom adjuvant therapy need not be used. Correspondence to: Junji Yoshida, MD, PhD, Department of Thoracic Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba 277-8577, Japan; e-mail: jyoshida@ east.ncc.go.jp. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( http://www.chestpubs.org/ site/misc/reprints.xhtml ). DOI: 10.1378/chest.10-1535 www.chestpubs.org CHEST / 139 / 4 / APRIL, 2011 855

We reviewed a large series of consecutive patients with stage I NSCLC with diagnoses based on the sixth edition TNM classification. 6 The purpose of this study was to identify poor prognostic factors in patients with stage IB NSCLC who were reclassified according to the seventh edition TNM classification. Patients Materials and Methods A total of 1,244 consecutive patients with pathologic stage I NSCLC diagnosed according to the sixth edition TNM classification underwent complete resection with systematic node dissection between July 1992 and December 2004 at the National Cancer Center Hospital East (Kashiwa, Chiba, Japan). Complete resection was defined as cancer-free surgical margins identified by both gross and histologic examinations. Among these patients, we excluded 40 from our study because of preoperative or postoperative chemotherapy, radiation therapy, or both (n 5 18) or because of low-grade pulmonary malignancies (n 5 22), including carcinoids, mucoepidermoid carcinomas, and adenoid cystic carcinomas. The remaining 1,204 patients were the subjects of this study. Pathologic Evaluation Statistical Analysis Statistical analysis was performed using SPSS, version 11.0, software (SPSS Inc; Chicago, Illinois) and Prism for Windows version 5.02 (GraphPad Software Inc; La Jolla, California). The length of overall survival probability was calculated in months from the date of resection to the date of death of any cause or last follow-up. The length of disease-specific survival was defined as the interval in months between the date of surgical resection and the date of either lung cancer-related death or the last follow-up. To calculate disease-specific survival probability, patients who died without recurrence were censored. For univariate analyses, all cumulative survival probabilities were estimated using the Kaplan-Meier method, and differences in variables were evaluated using the log-rank test. Cox proportional hazard regression models were used to ascertain the association between individual factors and survival. Statistical significance was assumed at P,.05. Approval was given to collect and analyze the data. The need to obtain informed consent from each patient was waived by the institutional review board in April 2010. Results Figures 1A and 1B show overall and disease-specific survival curves of 764 patients with stage IA NSCLC and 440 patients with stage IB NSCLC with diagnoses according to the sixth edition TNM classification. Histologic type was determined according to the World Health Organization classification, 7 and the histologic grade was categorized by a single pathologist (G. I.) as being well differentiated, moderately differentiated, or poorly differentiated carcinomas according to the degree of structural and cytologic atypia. We diagnosed squamous cell carcinoma on the basis of findings of keratinization and intercellular bridges. These features varied with degree of differentiation, being prominent in well-differentiated tumors, focal in poorly differentiated tumors, and intermediate in moderately differentiated tumors. For adenocarcinomas, bronchioloalveolar carcinoma was categorized as a well-differentiated component, acinar and papillary adenocarcinomas as moderately differentiated components, and solid carcinoma with mucin production as a poorly differentiated component. When more than one differentiation component was identified in a tumor, the differentiation of the most predominant component was registered as its histologic grade of differentiation. Large-cell and pleomorphic carcinomas were classified as poorly differentiated tumors. Disease stages were based on the seventh edition TNM classification. 1 Intratumoral vascular invasion (IVI) and visceral pleural invasion (VPI) were evaluated by hematoxylin-eosin and elastin (Victoria blue-van Gieson) staining. Clinicopathologic Data We reviewed the medical records of each patient for clinicopathologic data, which included age (dichotomized at the median age of 68 years), sex, smoking history (nonsmokers or ever smokers), preoperative FEV 1 (. 70% or, 70%), preoperative serum carcinoembryonic antigen (CEA) level (cutoff at the normal upper limit of 5 ng/ml), diameter of the tumor on the resected specimens (dichotomized at the median diameter of 3.5 cm), histologic differentiation (well differentiated or moderately/poorly differentiated), IVI (present or absent), lymphatic permeation (present or absent), and VPI (as defined in the seventh edition TNM classification6 as present or absent). Figure 1. A, Overall survival curves for patients with stage I cancer according to the sixth edition TNM classification. B, Diseasespecific survival curves for patients with stage I cancer according to the sixth edition TNM classification. 856 Original Research

Table 1 Comparisons of Number of Patients According to the TNM Classification, Sixth and Seventh Editions TNM Classification Sixth Edition Seventh Edition Stage TNM Stage TNM No. of Patients Stage IA T1 (, 3 cm without VPI) N0M0 Stage IA T1a (, 2 cm without VPI) N0M0 384 T1b (. 2 cm but, 3 cm without VPI) N0M0 294 Stage IA T1 (, 3 cm with VPI) N0M0 Stage IB T2aN0M0 86 Stage IB T2 (. 3 cm, but, 5 cm) N0M0 Stage IB T2aN0M0 348 Stage IB T2 (. 5 cm, but, 7 cm) N0M0 Stage IIA T2bN0M0 65 Stage IB T2 (. 7 cm) N0M0 Stage IIB T3N0M0 27 VPI 5 visceral pleural invasion. There was statistically significant difference in overall or disease-specific survival probability between patients with stage IA and stage IB NSCLC (5-year overall survival probability, 88.6% and 68.3%, respectively [ Fig 1A ]; 5-year disease-specific survival probability, 94.1% and 79.5%, respectively [ Fig 1B ]). According to the seventh edition TNM classification, 1,204 patients with stage I cancer were reclassified as follows: T1aN0M0 (stage IA, n 5 384), T1bN0M0 (stage IA, n 5 294), T2aN0M0 (stage IB, n 5 434), T2bN0M0 (stage IIA, n 5 65), and T3N0M0 (stage IIB, n 5 27) ( Table 1 ). The 5-year overall probabilities by the seventh edition TNM classification were stage IA, 89.9%; stage IB, 72.3%; and stage II, 57.8% ( Fig 2A ). For disease-specific survival, the probabilities were stage IA, 93.1%; stage IB, 82.9%; and stage II, 73.3% ( Fig 2B ). There were statistically significant differences in overall survival probabilities between stage IA and stage IB, stage IB and stage II, and stage IA and stage II patients ( Fig 2A ). The 5-year disease-specific survival probabilities were also statistically different from each other ( Fig 2B ). Table 2 lists 5-year overall and disease-specific survival probabilities according to clinicopathologic features in the patients reclassified as having stage IB NSCLC according to the seventh edition TNM classification. For overall survival, univariate analysis identified 10 statistically significant prognostic factors: age, sex, smoking history, FEV 1 percent, CEA, histology, histologic differentiation, IVI, lymphatic permeation, and VPI. On multivariate analysis with the Cox regression model, older age, presence of IVI, and presence of VPI remained as statistically significant independent poor prognostic factors ( Table 3 ). For diseasespecific survival, smoking history, CEA, IVI, lymphatic permeation, and VPI were statistically significant factors identified by univariate analysis ( Table 3 ). On multivariate analysis, presence of IVI and presence of VPI remained as statistically significant independent risk factors for cancer-related death ( Table 3 ). Subgroup analysis (using the seventh edition TNM classification) with a combination of these two prog- nostic factors in the patients with stage IB cancer revealed a 5-year disease-specific survival of 93.1%, 82.9%, and 73.3% for patients with zero, one, or two risk factors, respectively ( Fig 3 ). The differences in disease-specific survival were statistically significant between the zero (curve B) and one (curve C) risk factor groups and between the one- (curve C) and two- (curve D) risk factor groups. The 5-year disease-specific survival of patients without any risk factor (curve B) was not statistically different from that of patients Figure 2. A, Overall survival curves for patients with stage IA, IB, and II cancer according to the seventh edition TNM classification. B, Disease-specific survival curves for patients with stage IA, IB, and II cancer according to the seventh edition TNM classification. www.chestpubs.org CHEST / 139 / 4 / APRIL, 2011 857

Table 2 Clinicopathologic Characteristics and Univariate Analysis of Overall and Disease-Specific Survival Probabilities Using the Seventh Edition for Patients Reclassified as Stage IB Characteristic No. of Patients Overall 5-y Survival Probability, % Univariate P Value Disease-Specific 5-y Survival Probability, % Univariate P Value Overall 434 72.3 82.0 Age, y, 68 224 79.2,.001 a 85.4.152. 68 210 65.0 78.2 Sex Female 174 78.9.019 a 84.1.397 Male 260 68.1 80.6 Smoking history Nonsmoker 149 83.8,.001 a 88.2.041 a Ever smoker 285 66.4 78.7 FEV 1. 70% 315 74.6.014 a 82.8.706, 70% 116 66.3 79.3 Not performed 3 CEA Within normal range 256 76.5,.001 a 85.3.027 a Elevated 178 68.2 77.0 Tumor size, mm, 35 260 73.9.286 83.7.434. 35 174 70.1 79.4 Histologic type Adenocarcinoma 294 77.8,.001 a 83.4.799 Nonadenocarcinoma 140 60.9 78.8 Histologic differentiation Well differentiated 122 82.5.017 a 88.7.086 Moderately/poorly differentiated 312 68.2 79.1 IVI Absent 193 83.8,.001 a 91.2,.001 a Present 241 63.1 74.2 Lymphatic permeation Absent 300 75.5.039 a 85.0.007 a Present 134 65.2 75.0 Visceral pleural invasion Absent 216 78.4,.001 a 86.8,.001 a Present 218 63.6 77.1 CEA 5 preoperative serum carcinoembryonic antigen level, normal upper limit at 5 ng/ml; IVI 5 intratumoral vascular invasion. asignificant at P,.05. with stage IA cancer (curve A), and that of patients with two risk factors (curve D) was not statistically different from that of patients with T2b or T3N0M0, stage II cancer (curve E). The 5-year disease-specific survival of patients with one risk factor (curve C) was statistically different from those of patients with stage IA cancer ( P,.001) (curve A) and patients with T2b or T3N0M0, stage II cancer ( P 5.005) (curve E). Discussion In the sixth edition TNM classification, 6 stage IB NSCLC comprised a heterogeneous group of nodenegative tumors with different prognoses. 8-10 In the seventh edition TNM classification, 1 the T2 (. 3 cm) lung cancer category is subdivided into T2a (. 3 cm but, 5 cm), T2b (. 5 cm but, 7 cm), and T3 (. 7 cm), with each classification based on the largest dimen- sion of the tumor ( Table 1 ). T2bN0M0 tumors are upstaged from stage IB to stage IIA and T3N0M0 tumors to stage IIB. Thus, sixth edition stage IB tumors are divided in the seventh edition into stage IB, IIA, and IIB according to tumor size. In addition, VPI is clearly defined, and T1 tumors are upgraded to T2a when the visceral pleural elastic layer is invaded, regardless of tumor exposure on the pleural surface. Therefore, in the seventh edition, stage IB comprises node-negative tumors. 3 cm but, 5 cm and tumors, 3 cm with VPI ( Table 1 ). Recently, three randomized phase III 2-4 trials and the Lung Adjuvant Cisplatin Evaluation, 11 which was based on a pooled analysis of five randomized trials, showed a significant survival benefit of adjuvant cisplatin-based chemotherapy for patients with completely resected stage II and IIIA NSCLC tumors. For the management of these patients, postoperative adjuvant cisplatin-based chemotherapy represents 858 Original Research

Table 3 Multivariable Analysis: Overall and Disease-Specific Prognostic Factors Factors Unfavorable Favorable HR 95% CI P Value Independent factors that affect overall survival Age, y. 68, 68 2.094 1.502-2.921,.001 a Sex Male Female 1.106 0.719-1.700.647 Smoking history Ever smoker Nonsmoker 1.323 0.809-2.165.265 FEV 1, %, 70. 70 1.038 0.732-1.472.835 CEA Elevated Within normal range 1.315 0.952-1.818.097 Histologic type Nonadenocarcinoma Adenocarcinoma 1.232 0.872-1.741.236 Histologic differentiation Moderately/poorly differentiated Well differentiated 1.020 0.691-1.506.920 IVI Present Absent 1.622 1.125-2.338.010 a Lymphatic permeation Present Absent 1.330 0.952-1.858.094 Visceral pleural invasion Present Absent 1.499 1.096-2.050.011 a Independent factors that affect disease-specific survival Smoking history Nonsmoker Ever smoker 1.316 0.813-2.129.264 CEA Elevated Within normal range 1.319 0.870-2.000.192 IVI Present Absent 1.982 1.221-3.217.006 a Lymphatic permeation Present Absent 1.400 0.911-2.151.125 Visceral pleural invasion Present Absent 1.691 1.090-2.623.019 a HR 5 hazard ratio. See Table 2 legend for expansion of other abbreviations. asignificant at P,.05. the standard of care. 2-5 The Cancer and Leukemia Group B 9633 study showed a statistically significant survival advantage of adding adjuvant chemotherapy for patients with N0 tumors. 4 cm (hazard ratio [HR], 0.69; P 5.043), 12 which suggests that adjuvant chemotherapy also may be beneficial for node-negative patients with large tumors. In the current study, the 5-year disease-specific survival probability of patients upstaged to stage IIA and IIB according to the seventh edition TNM classification because of their tumor size being. 5 cm was confirmed to be significantly lower than that of patients with stage IB cancer. Although the role of adjuvant chemotherapy for the patients reclassified according to the seventh edition has not been established, patients with tumors. 5 cm but without lymph node metastases may be candidates for platinum-based adjuvant chemotherapy. Figure 3. Disease-specific survival curves according to the number of prognostic factors. By multivariate analyses, we identified two independent poor prognostic factors in patients with stage IB cancer according to the seventh edition TNM classification: presence of IVI (HR, 1.982) and presence of VPI (HR, 1.691). Of these factors, VPI is clearly defined, and tumors, 3 cm with VPI is upgraded to T2a in the seventh edition. 1 In the current study, we showed that the presence of VPI was an unfavorable prognostic factor also in patients with T2aN0M0 (stage IB cancer). Yoshida et al 13 reported poorer prognosis of T2 tumors with VPI (5-year overall survival rate, 53.0%) than that of T2 tumors without VPI (61.6%; P,.001) and concluded that T2 tumors with VPI should be classified as T3 in the next edition of the TNM classification. We also propose that VPI should be examined in tumors of 3.1 to 5 cm, similar to the tumors 3.0 cm in size, and VPI status should be studied and taken into consideration in T classification for these larger tumors. IVI has been reported to be a strong independent factor for a poor prognosis in patients with pathologic stage I cancer in most studies that included this factor in analyses ( Table 4 ). 10,14-20 In the current study, IVI (HR, 1.982) rather than VPI was the most powerful prognostic factor in patients with stage IB cancer according to the seventh edition TNM classification. Several authors reported that elastic stains in lung cancer pathologic evaluation was very helpful in IVI determination. 21,22 We recommend the routine use of elastic stains in patients with tumors of 3.1 to 5.0 cm, not only for VPI determination but also for IVI determination, to identify groups among patients with stage IB cancer with poorer prognosis for survival. When we divided the patients staged as IB according to the seventh edition TNM classification into www.chestpubs.org CHEST / 139 / 4 / APRIL, 2011 859

Table 4 Survival of Patients With Stage I Cancer With or Without IVI in Previous Series Series Stage IVI No. of Patients Overall 5-y Survival Probability, % Univariate P Value Multivariate Analysis HR 95% CI P Value Hsu et al 10 Stage IB Absent 246 63 Present 26 30,.001 1.73 1.00-2.98.05 Harpole et al 14 Stage I Absent 257 68 Present 32 35,.001 2.19 Unknown,.01 Ichinose et al 15 Stage I Absent 216 79 Present 27 48,.001 2.16 1.19-3.94.012 Suzuki et al 16 Stage I Absent 276 90 Present 152 69,.001 3.8 2.07-6.80,.001 Ogawa et al 17 Stage I Absent 73 Unknown Present 55 Unknown,.001 4.84 2.15-10.91,.001 Miyoshi et al 18 Stage I Absent 134 93 Present 124 74,.001 2.7 1.3-5.8.009 Tsuchiya et al 19 Stage IA Absent 198 90 Present 19 72,.001 2.84 1.56-5.16,.001 Li et al 20 Stage I Absent 309 71 Present 16 50.021 2.25 1.18-4.29.014 See Table 2 and 3 legends for expansion of abbreviations. zero, one, or two risk factor groups combining these two independent poor prognostic factors (presence of IVI and presence of VPI), the 5-year disease-specific survival probabilities were 93.1%, 82.9%, and 73.3%, respectively. Our results highlighted considerable outcome disparity even among patients with stage IB NSCLC reclassified according to the latest TNM classification. The difference in disease-specific survival was statistically significant between the zero and one risk factor groups and between the one and two risk factor groups. In addition, the 5-year diseasespecific survival curve of patients without risk factors overlapped with that of patients with stage IA cancer. The 5-year disease-specific survival curve of patients with two risk factors lay beneath that of patients with T2b or T3N0M0, stage II cancer, and there was no statistically significant difference between them ( P 5.731). The patients with two risk factors accounted for 37% of the patients with stage IB cancer according to the seventh edition, and these patients, being similar to patients with stage II cancer in outcome, may be good candidates for adjuvant chemotherapy. In contrast, patients with stage IB cancer without risk factors had a favorable outcome comparable to patients with stage IA cancer, and adjuvant chemotherapy may be unnecessary for these patients. Because the survival curve for patients with stage IB cancer with one risk factor lay between those of zero and two risk factors, it is unclear whether adjuvant chemotherapy is beneficial, and further study is necessary. Conclusions We identified two independent poor prognostic factors in patients with stage IB NSCLC according to the seventh edition TNM classification: presence of IVI and presence of VPI. When these two factors are combined, higher- and lower-risk subgroups can be identified, which will help to personalize adjuvant chemotherapy. Acknowledgments Author contributions: Dr Maeda: contributed to study design, data management, data analysis, and writing the manuscript. Dr Yoshida: contributed to study design, data management, data analysis, and writing the manuscript. Dr Ishii: contributed to data management. Dr Hishida: contributed to data management. Dr Nishimura: contributed to data management. Dr Nagai: contributed to study design, data management, data analysis, and writing the manuscript. Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Other contributions: All work included in the manuscript was performed at the National Cancer Center Hospital East, Kashiwa, Chiba, Japan. The research was approved by the internal review board of the institution. No patient consent was required as the research was a retrospective chart review, and no personally identifiable information was included in the manuscript. References 1. Goldstraw P, Crowley J, Chansky K, et al ; International Association for the Study of Lung Cancer International Staging Committee ; Participating Institutions. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol. 2007 ;2(8):706-714. 2. Winton T, Livingston R, Johnson D, et al ; National Cancer Institute of Canada Clinical Trials Group ; National Cancer Institute of the United States Intergroup JBR.10 Trial Investigators. Vinorelbine plus cisplatin vs. observation in 860 Original Research

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