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Original Research: LUNG CANCER |

Long-term Survival and Risk Factors for Recurrence in Stage I Non-small Cell Lung Cancer Patients With Tumors up to 3 cm in Maximum Dimension FREE TO VIEW

Ryo Maeda, MD; Junji Yoshida, MD; Genichiro Ishii, MD; Tomoyuki Hishida, MD; Keiju Aokage, MD; Mitsuyo Nishimura, MD; Yutaka Nishiwaki, MD; Kanji Nagai, MD; International Association for the Study of Lung Cancer International Staging Committee
Author and Funding Information

From the Department of Thoracic Oncology (Drs Maeda, Yoshida, Hishida, Aokage, Nishimura, Nishiwaki, and Nagai), and the Department of Pathology, Research Center for Innovative Oncology (Dr Ishii), National Cancer Center Hospital East, Kashiwa, Chiba, Japan.

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


Funding/Support: This work was supported in part by a Grant-in-Aid for Cancer Research from the Ministry of Health, Labour and Welfare, Japan.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).


© 2010 American College of Chest Physicians


Chest. 2010;138(2):357-362. doi:10.1378/chest.09-3046
Text Size: A A A
Published online

Background:  The purpose of this study was to evaluate patients with stage I non-small cell lung cancer (NSCLC) and tumors up to 3 cm in maximum dimension who underwent surgical resection on the revised TNM classification and to investigate the risk factors for recurrence.

Methods:  Between 1994 and 2003, 713 consecutive stage I NSCLC patients with tumors up to 3 cm in maximum dimension underwent complete resection. Recurrence-free probability was estimated from the date of the primary tumor resection to the date of the first recurrence or the last follow-up using the Kaplan-Meier method.

Results:  The recurrence-free probability of stage I NSCLC patients with tumors up to 3 cm in maximum dimension was 87% at 5 years. On multivariate analyses, three variables were shown to be independently significant recurrence risk factors: histologic differentiation (hazard ratio, 2.3), intratumoral vessel invasion (hazard ratio, 2.9), and visceral pleural invasion (VPI) (hazard ratio, 1.8). According to subgroup analyses combining these three risk factors, the 5-year recurrence-free probability was 94% for patients with zero or one factor (n = 492) and 71% for patients with two or three factors (n = 221), respectively (P < .001).

Conclusion:  In stage I NSCLC patients with tumors up to 3 cm in maximum dimension, we identified three risk factors for recurrence that independently increase their risk of recurrence. In addition to VPI, histologic differentiation and intratumoral vessel invasion should be examined and their data collected for the next revision of the TNM staging system.

Figures in this Article

In the International Association for the Study of Lung Cancer proposal for the seventh edition of the International Union Against Cancer (UICC) TNM for lung and pleural tumors,1 T1 (< 3 cm) non-small cell lung cancer (NSCLC) tumors are subdivided into two groups according to tumor size: T1a (< 2 cm) and T1b (> 2 cm but < 3 cm). Visceral pleura invasion (VPI) is clearly defined, and T1 tumors continue to be upgraded to T2 when the visceral pleura elastic layer is invaded. However, a considerable number of otherwise small tumor patients without VPI develop recurrence, resulting in cancer death. Other than tumor size or VPI, various clinicopathologic factors in patients with small tumors have been reported to predict a poor outcome. Identifying recurrence risk factors in these patients will help select patients who may benefit from adjuvant therapy. We reviewed a large series of consecutive stage I NSCLC patients with tumors up to 3 cm in maximum dimension resected at our hospital. The purpose of this study was to evaluate these patients based on the revised TNM classification and to investigate the risk factors for recurrence.

Patients

A total of 734 consecutive Japanese pathologic stage I NSCLC patients with tumors up to 3 cm in maximum dimension who underwent complete resection between January 1994 and December 2003 at the National Cancer Center Hospital East were identified in our departmental database. Complete resection was defined as cancer-free surgical margins both grossly and histologically. Among these patients, 21 were excluded because of (1) preoperative or postoperative chemotherapy or radiation therapy, or both (n = 6), and (2) low-grade pulmonary malignancies including carcinoids, mucoepidermoid carcinomas, or adenoid cystic carcinomas (n = 15). The remaining 713 patients were the subjects of this study.

Pathologic Evaluations

Histologic type was determined according to the World Health Organization classification,2 and the histologic differentiation grade was categorized into well- and moderately/poorly differentiated carcinomas by a single pathologist (G. I.) who was blinded to the clinical outcome. We diagnosed squamous cell carcinoma based on the findings of keratinization, intercellular bridges, and squamous pearl formation. 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, we registered the differentiation of the most predominant component as its histologic differentiation. We classified large cell and pleomorphic carcinomas as poorly differentiated tumors. Disease stages were based on the TNM classification of the UICC, seventh edition.1 Intratumoral vessel invasion (ie, lymphatic permeation and vascular invasion) was evaluated by hematoxylin-eosin and Elastica-van Gieson stainings. Vascular invasion and lymphatic permeation were often analyzed separately in previous studies.3-8 However, because differentiation between vascular invasion and lymphatic permeation can be difficult,9 and D2-40 staining to specify lymphatic ducts was occasionally not performed in the present series, we analyzed vascular invasion and lymphatic permeation collectively as vessel invasion.

Patient Follow-up

We examined the patients on an outpatient basis at 3-month intervals for the first 2 years and typically at 6-month intervals thereafter. The follow-up evaluation included physical examination, chest radiography, and blood examination, including pertinent tumor markers. Whenever any symptoms or signs of recurrence were detected, further evaluations were performed, including CT scans of the chest and abdomen, brain MRI, and bone scintigraphy. After 2004, integrated PET and CT imaging were also performed when appropriate. We diagnosed recurrence on the basis of compatible physical examination and diagnostic imaging findings, and confirmed the diagnosis histologically when clinically feasible. The date of recurrence was defined as the date of histologic proof or, in cases diagnosed based on clinicoradiologic findings, the date of identification by a physician.

Clinicopathologic Information

We reviewed the medical records of each patient for clinicopathologic information, including age (dichotomized at the median age of 65), gender, smoking history (non- or ever-smoker), preoperative FEV1/FVC; > 70% or < 70%), preoperative serum carcinoembryonic antigen (CEA) level (cut off at the normal upper limit of 5 ng/mL), extent of resection, diameter of the tumor on the resected specimen (≤ 2 cm or > 2 cm), histologic differentiation (well differentiated or moderately/poorly differentiated), intratumoral vessel invasion (presence or absence), and pleural invasion (as defined in the TNM classification, seventh edition: presence or absence).

Statistical Analysis

The length of survival was defined as the interval in months between the date of surgical resection and the date of either death or the last follow-up. The length of the recurrence-free period was calculated in months from the date of resection to the date of the first recurrence or the last follow-up. To calculate recurrence-free probability, patients who died without recurrence or who were known to be recurrence free at the date of last contact were censored. For univariate analyses, all cumulative survival rates were estimated using the Kaplan-Meier method, and differences in variables were determined using the log-rank test. Multivariate analyses were performed using Cox’s proportional hazard regression model. Forward and backward stepwise procedures were used to determine independent predictors. All P values reported were two sided, and the significance level was set at < .05. Analyses were performed using the statistical software SPSS II for Windows, 11.0 (SPSS Inc.; Chicago, IL) and GraphPad Prism for Windows, version 5.02 (GraphPad Software, Inc.; La Jolla, CA). Data collection and analyses were approved and the need to obtain informed consent from each patient was waived by the institutional review board in August 2009.

The 5- and 10-year overall survival rates of the 713 patients were 85.8% and 71.3%, respectively. Recurrence-free probability was 86.7% at 5 years and 79.7% at 10 years after resection. Table 1 lists the recurrence-free probabilities at 5 and 10 years after surgical resection according to clinicopathologic features in all patients.

Table Graphic Jump Location
Table 1 —Recurrence-Free Probability and Clinicopathologic Characteristics

CEA = serum carcinoembryonic antigen level.

a 

Indicates significance.

Univariate analysis (log-rank test) identified nine significant risk factors for recurrence: age, gender, smoking habits, FEV1/FVC ratio, preoperative serum CEA level, tumor diameter, histologic differentiation, intratumoral vessel invasion, and pleural invasion (Table 1). On multivariate analysis using the Cox regression model, histologic differentiation, presence of intratumoral vessel invasion, and presence of VPI remained statistically significant independent predictors for recurrence (Table 2). Subgroup analysis with a combination of these three independent recurrence risk factors (histologic differentiation, presence of intratumoral vessel invasion, and presence of pleural invasion for recurrence) revealed 10-year recurrence-free probabilities of 93.1%, 84.0%, 61.8%, and 42.6% for patients with zero, one, two, or three risk factors, respectively (Fig 1). The difference in recurrence-free probability was statistically significant between the zero- and one-risk-factor groups (P < .001) and between the one- and two-risk-factor groups (P < .001), but not between the two- and three-risk-factor groups (P = .073). When we divided the patients into two groups with either two or three factors or zero or one risk factor, the 10-year recurrence-free probabilities were 56.0% and 89.5%, respectively (P < .001) (Fig 2).

Table Graphic Jump Location
Table 2 —Multivariate Analysis of Risk Factors for Recurrence

See Table 1 for expansion of abbreviation.

a 

Normal upper limit at 5 ng/mL.

b 

Indicates significance.

Figure Jump LinkFigure 1. Recurrence-free probability curves according to the number of risk factors.Grahic Jump Location
Figure Jump LinkFigure 2. Recurrence-free probability curves according to the combined number of prognostic factors: zero or one, and two or three.Grahic Jump Location

Of the 713 patients, 605 patients without VPI were diagnosed as stage IA based on the TNM classification of the UICC, seventh edition. Also in this subset of patients, multivariate analysis showed that histologic differentiation and presence of intratumoral vessel invasion were statistically significant independent predictors for recurrence (Table 3).

Table Graphic Jump Location
Table 3 —Multivariate Analysis of Risk Factors for Recurrence in Stage IA Patients

See Table 1 for expansion of abbreviation.

a 

Normal upper limit at 5 ng/mL.

b 

Indicates significance.

Subgroup analysis combining these two independent recurrence risk factors in stage IA patients revealed 10-year recurrence-free probabilities of 93.2%, 85.0%, and 58.9% for patients with zero, one, or two risk factors, respectively (Fig 3). The 10-year recurrence-free probability of subgroups stratified according to both T subclassification (T1a or T1b) and number of risk factors was as follows: A: T1a/zero risk factors (n = 198), 92.0%; B: T1a/one risk factor (n = 105), 86.3%; C: T1a/two risk factors (n = 54), 53.8%; D: T1b/zero risk factors (n = 93), 95.3%; E: T1b/one risk factor (n = 81), 83.8%; F: T1b/two risk factors (n = 74), 62.7% (Fig 4). The difference in recurrence-free probability stratified by the number of recurrence risk factors was statistically significant both in the T1a (A vs B and B vs C) (P = .018 and P < .001, respectively) and T1b (C vs D and D vs E) (P = .019 and P = .004, respectively) groups. In contrast, in each risk factor number group, there was no difference in survival due to T subclassification, and the recurrence-free probability curves mostly overlapped within each risk factor number group.

Figure Jump LinkFigure 3. Recurrence-free probability curves in stage IA patients according to the number of risk factors.Grahic Jump Location
Figure Jump LinkFigure 4. Recurrence-free probability curves of subgroups stratified according to T subclassification (T1a or T1b) and combined number of risk factors.Grahic Jump Location

Previous studies have reported several factors associated with poor prognosis in patients with small NSCLC, including tumor size,1,3 preoperative serum CEA level,10,11 VPI,3,4,12 intratumoral vessel invasion,3-6,9 and histologic differentiation.4 Among these factors, the maximum tumor dimension is a valuable and readily available prognostic factor. Larger tumor size (> 2 cm) is a known poor prognostic factor in patients with surgically resected stage IA NSCLC. In the UICC’s seventh edition of TNM for lung and pleural tumors, T1 NSCLC tumors are divided into two subgroups according to tumor size: T1a (< 2 cm) and T1b (> 2 cm but < 3 cm).1 However, a considerable number of T1a patients develop recurrence, which results in cancer death. In our study of stage I NSCLC patients with tumors of 3 cm or less, multivariate analysis found that tumor size was not a significant risk factor for recurrence. Patients with a 2- to 3-cm tumor may include a subgroup with good prognosis, whereas patients with a tumor of 2 cm or less may include a subgroup with poor prognosis.

By multivariate analyses, we identified three independently significant predictors for recurrence: histologic differentiation (hazard ratio, 2.310), presence of intratumoral vessel invasion (hazard ratio, 2.913), and presence of pleural invasion (hazard ratio, 1.829). Of these three risk factors, VPI had already been adopted as a specific description in the TNM classification of the UICC staging system in the mid-1970s, and has remained unchanged: a tumor 3 cm in maximum dimension, if it is associated with VPI, is upgraded to T2.13 In the UICC’s seventh edition of TNM for lung and pleural tumors, VPI is clearly defined, and T1 tumors continue to be upgraded to T2 when the visceral pleura elastic layer is invaded.1 Our results supported the concept of upgrading due to VPI.

Ichinose et al4 reported that poorly differentiated histology was an independent prognostic factor for poor survival in stage I NSCLC patients. The 10-year recurrence-free probability was significantly lower in patients with moderately/poorly differentiated tumors (67.8%) than in patients with well-differentiated tumors (90.1%). These results indicate that tumor differentiation has a significant impact on clinical outcome. In the current study, the histologic grade was determined by a single pathologist (G. I.) throughout the trial, which should have contributed to diagnostic consistency. However, no objective criteria have been established for standardized differentiation grade diagnoses. The World Health Organization’s Histologic Typing of Lung and Pleural Tumors2 merely makes brief reference to the histologic grade in adenocarcinoma and squamous cell carcinoma. Objective differentiation-grading criteria need to be established for reproducible assessment.

In most studies that included this factor in analyses, intratumoral vessel invasion has also been reported to be a strong independent recurrence predictor in pathologic stage I disease,3-6,9 with some exceptions.7,8 The current study also suggested that intratumoral vessel invasion status is a significant risk factor for recurrence in stage I NSCLC patients with tumors up to 3 cm in maximum dimension.

Although T1 tumors are upgraded to T2 due to VPI in the seventh edition of TNM classification, neither histologic differentiation grade nor intratumoral vessel invasion have been incorporated into the TMN classifications, including the seventh edition. In the present study, however, multivariate analysis demonstrated that these two factors were significantly stronger recurrence predictors than was VPI (hazard ratio, 1.829) in the new TNM staging system in Japanese patients.We therefore propose that, in addition to VPI, histologic differentiation (hazard ratio, 2.310) and intratumoral vessel invasion (hazard ratio, 2.913) should be examined and data concerning them collected for the next revision of the TNM staging system.

On multivariate analysis using the Cox regression model, histologic differentiation and presence of intratumoral vessel invasion were also statistically significant independent predictors for recurrence in 605 stage IA patients without VPI. Recent randomized controlled trials have shown a survival benefit from platinum-based adjuvant chemotherapy in stage II or higher NSCLC patients.14,15 For stage IB adenocarcinoma patients, based on a large adjuvant trial and metaanalyses on oral uracil-tegafur (UFT), UFT adjuvant chemotherapy is recommended as the standard treatment in Japan.16 Although surgery alone remains the standard treatment of stage IA patients, recent Japanese studies16,17 showed that oral UFT may improve stage IA-T1b patient survival. High-risk small tumor N0 patients, identified by factors other than tumor size and VPI, such as differentiation and vessel involvement, may also benefit from adjuvant chemotherapy in improving survival. Improved quantification of recurrence risk should improve clinical decision making and help design future trials. This study highlighted considerable outcome disparity in stage IA NSCLC patients based on the TNM classification of the UICC, seventh edition. When we divided stage IA patients into zero-, one-, or two-risk-factor groups, we found 10-year recurrence-free probabilities of 93.2%, 85.0%, and 58.9%, respectively. The two-risk-factor patients accounted for 15% of T1a patients and 30% of T1b patients, and these patients may be good candidates for adjuvant chemotherapy.

In 713 stage I NSCLC patients with tumors up to 3 cm in maximum dimension, we identified three risk factors for recurrence that independently increase risk of recurrence: poor or moderate histologic differentiation, presence of intratumoral vessel invasion, and presence of VPI. Poor or moderate histologic differentiation and presence of intratumoral vessel invasion were significantly better recurrence predictors than was VPI. These factors should be examined and their data collected for the next revision of the TNM staging system. Poor or moderate histologic differentiation and presence of intratumoral vessel invasion were also shown to be independently significant recurrence risk factors in stage IA patients without VPI. When two of these factors are combined, a high-risk subgroup of stage IA NSCLC patients can be identified, and this group may benefit from adjuvant chemotherapy.

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 Aokage: contributed to data management.

Dr Nishimura: contributed to data management.

Dr Nishiwaki: 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: The authors thank Professor J. Patrick Barron and Roderick J. Turner of the Department of International Medical Communications of Tokyo Medical University for their review of this manuscript.

CEA

serum carcinoembryonic antigen

NSCLC

non-small cell lung cancer

UFT

uracil-tegafur

UICC

International Union Against Cancer

VPI

visceral pleura invasion

Goldstraw P, Crowley J, Chansky K, et al; International Association for the Study of Lung Cancer International Staging Committee International Association for the Study of Lung Cancer International Staging Committee Participating Institutions 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;28:706-714. [CrossRef] [PubMed]
 
Travis WD, Brambilla E, Muller-Hermelink HK, et al. World Health Organization Classification of Tumors: Pathology and Genetics of Tumors of the Lung, Pleura, Thymus and Heart. 2004; Lyon, France IARC Press
 
Harpole DH Jr, Herndon JE II, Young WG Jr, Wolfe WG, Sabiston DC Jr. Stage I nonsmall cell lung cancer. A multivariate analysis of treatment methods and patterns of recurrence. Cancer. 1995;765:787-796. [CrossRef] [PubMed]
 
Ichinose Y, Yano T, Asoh H, Yokoyama H, Yoshino I, Katsuda Y. Prognostic factors obtained by a pathologic examination in completely resected non-small-cell lung cancer. An analysis in each pathologic stage. J Thorac Cardiovasc Surg. 1995;1103:601-605. [CrossRef] [PubMed]
 
Suzuki K, Nagai K, Yoshida J, et al. Conventional clinicopathologic prognostic factors in surgically resected nonsmall cell lung carcinoma. A comparison of prognostic factors for each pathologic TNM stage based on multivariate analyses. Cancer. 1999;8610:1976-1984. [CrossRef] [PubMed]
 
Ogawa J, Tsurumi T, Yamada S, Koide S, Shohtsu A. Blood vessel invasion and expression of sialyl Lewisx and proliferating cell nuclear antigen in stage I non-small cell lung cancer. Relation to postoperative recurrence. Cancer. 1994;734:1177-1183. [CrossRef] [PubMed]
 
Matsuguma H, Nakahara R, Igarashi S, et al. Pathologic stage I non-small cell lung cancer with high levels of preoperative serum carcinoembryonic antigen: clinicopathologic characteristics and prognosis. J Thorac Cardiovasc Surg. 2008;1351:44-49. [CrossRef] [PubMed]
 
Poleri C, Morero JL, Nieva B, et al. Risk of recurrence in patients with surgically resected stage I non-small cell lung carcinoma: histopathologic and immunohistochemical analysis. Chest. 2003;1236:1858-1867. [CrossRef] [PubMed]
 
Miyoshi K, Moriyama S, Kunitomo T, Nawa S. Prognostic impact of intratumoral vessel invasion in completely resected pathologic stage I non-small cell lung cancer. J Thorac Cardiovasc Surg. 2009;1372:429-434. [CrossRef] [PubMed]
 
Okada M, Sakamoto T, Nishio W, Uchino K, Tsubota N. Characteristics and prognosis of patients after resection of nonsmall cell lung carcinoma measuring 2 cm or less in greatest dimension. Cancer. 2003;983:535-541. [CrossRef] [PubMed]
 
Sawabata N, Ohta M, Takeda S, et al. Serum carcinoembryonic antigen level in surgically resected clinical stage I patients with non-small cell lung cancer. Ann Thorac Surg. 2002;741:174-179. [CrossRef] [PubMed]
 
Shimizu K, Yoshida J, Nagai K, et al. Visceral pleural invasion classification in non-small cell lung cancer: a proposal on the basis of outcome assessment. J Thorac Cardiovasc Surg. 2004;1276:1574-1578. [CrossRef] [PubMed]
 
UICCUICC TNM Classification of Malignant Tumors. 2002;5th ed Geneva, Switzerland UICC
 
Winton T, Livingston R, Johnson D, et al; National Cancer Institute of Canada Clinical Trials Group National Cancer Institute of Canada Clinical Trials Group National Cancer Institute of the United States Intergroup JBR.10 Trial Investigators National Cancer Institute of the United States Intergroup JBR.10 Trial Investigators Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med. 2005;35225:2589-2597. [CrossRef] [PubMed]
 
Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J. International Adjuvant Lung Cancer Trial Collaborative Group International Adjuvant Lung Cancer Trial Collaborative Group Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004;3504:351-360. [CrossRef] [PubMed]
 
Kato H, Ichinose Y, Ohta M, et al; Japan Lung Cancer Research Group on Postsurgical Adjuvant Chemotherapy Japan Lung Cancer Research Group on Postsurgical Adjuvant Chemotherapy A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung. N Engl J Med. 2004;35017:1713-1721. [CrossRef] [PubMed]
 
Hamada C, Tsuboi M, Ohta M, et al. Effect of postoperative adjuvant chemotherapy with tegafur-uracil on survival in patients with stage IA non-small cell lung cancer: an exploratory analysis from a meta-analysis of six randomized controlled trials. J Thorac Oncol. 2009;412:1511-1516. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. Recurrence-free probability curves according to the number of risk factors.Grahic Jump Location
Figure Jump LinkFigure 2. Recurrence-free probability curves according to the combined number of prognostic factors: zero or one, and two or three.Grahic Jump Location
Figure Jump LinkFigure 3. Recurrence-free probability curves in stage IA patients according to the number of risk factors.Grahic Jump Location
Figure Jump LinkFigure 4. Recurrence-free probability curves of subgroups stratified according to T subclassification (T1a or T1b) and combined number of risk factors.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Recurrence-Free Probability and Clinicopathologic Characteristics

CEA = serum carcinoembryonic antigen level.

a 

Indicates significance.

Table Graphic Jump Location
Table 2 —Multivariate Analysis of Risk Factors for Recurrence

See Table 1 for expansion of abbreviation.

a 

Normal upper limit at 5 ng/mL.

b 

Indicates significance.

Table Graphic Jump Location
Table 3 —Multivariate Analysis of Risk Factors for Recurrence in Stage IA Patients

See Table 1 for expansion of abbreviation.

a 

Normal upper limit at 5 ng/mL.

b 

Indicates significance.

References

Goldstraw P, Crowley J, Chansky K, et al; International Association for the Study of Lung Cancer International Staging Committee International Association for the Study of Lung Cancer International Staging Committee Participating Institutions 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;28:706-714. [CrossRef] [PubMed]
 
Travis WD, Brambilla E, Muller-Hermelink HK, et al. World Health Organization Classification of Tumors: Pathology and Genetics of Tumors of the Lung, Pleura, Thymus and Heart. 2004; Lyon, France IARC Press
 
Harpole DH Jr, Herndon JE II, Young WG Jr, Wolfe WG, Sabiston DC Jr. Stage I nonsmall cell lung cancer. A multivariate analysis of treatment methods and patterns of recurrence. Cancer. 1995;765:787-796. [CrossRef] [PubMed]
 
Ichinose Y, Yano T, Asoh H, Yokoyama H, Yoshino I, Katsuda Y. Prognostic factors obtained by a pathologic examination in completely resected non-small-cell lung cancer. An analysis in each pathologic stage. J Thorac Cardiovasc Surg. 1995;1103:601-605. [CrossRef] [PubMed]
 
Suzuki K, Nagai K, Yoshida J, et al. Conventional clinicopathologic prognostic factors in surgically resected nonsmall cell lung carcinoma. A comparison of prognostic factors for each pathologic TNM stage based on multivariate analyses. Cancer. 1999;8610:1976-1984. [CrossRef] [PubMed]
 
Ogawa J, Tsurumi T, Yamada S, Koide S, Shohtsu A. Blood vessel invasion and expression of sialyl Lewisx and proliferating cell nuclear antigen in stage I non-small cell lung cancer. Relation to postoperative recurrence. Cancer. 1994;734:1177-1183. [CrossRef] [PubMed]
 
Matsuguma H, Nakahara R, Igarashi S, et al. Pathologic stage I non-small cell lung cancer with high levels of preoperative serum carcinoembryonic antigen: clinicopathologic characteristics and prognosis. J Thorac Cardiovasc Surg. 2008;1351:44-49. [CrossRef] [PubMed]
 
Poleri C, Morero JL, Nieva B, et al. Risk of recurrence in patients with surgically resected stage I non-small cell lung carcinoma: histopathologic and immunohistochemical analysis. Chest. 2003;1236:1858-1867. [CrossRef] [PubMed]
 
Miyoshi K, Moriyama S, Kunitomo T, Nawa S. Prognostic impact of intratumoral vessel invasion in completely resected pathologic stage I non-small cell lung cancer. J Thorac Cardiovasc Surg. 2009;1372:429-434. [CrossRef] [PubMed]
 
Okada M, Sakamoto T, Nishio W, Uchino K, Tsubota N. Characteristics and prognosis of patients after resection of nonsmall cell lung carcinoma measuring 2 cm or less in greatest dimension. Cancer. 2003;983:535-541. [CrossRef] [PubMed]
 
Sawabata N, Ohta M, Takeda S, et al. Serum carcinoembryonic antigen level in surgically resected clinical stage I patients with non-small cell lung cancer. Ann Thorac Surg. 2002;741:174-179. [CrossRef] [PubMed]
 
Shimizu K, Yoshida J, Nagai K, et al. Visceral pleural invasion classification in non-small cell lung cancer: a proposal on the basis of outcome assessment. J Thorac Cardiovasc Surg. 2004;1276:1574-1578. [CrossRef] [PubMed]
 
UICCUICC TNM Classification of Malignant Tumors. 2002;5th ed Geneva, Switzerland UICC
 
Winton T, Livingston R, Johnson D, et al; National Cancer Institute of Canada Clinical Trials Group National Cancer Institute of Canada Clinical Trials Group National Cancer Institute of the United States Intergroup JBR.10 Trial Investigators National Cancer Institute of the United States Intergroup JBR.10 Trial Investigators Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med. 2005;35225:2589-2597. [CrossRef] [PubMed]
 
Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J. International Adjuvant Lung Cancer Trial Collaborative Group International Adjuvant Lung Cancer Trial Collaborative Group Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004;3504:351-360. [CrossRef] [PubMed]
 
Kato H, Ichinose Y, Ohta M, et al; Japan Lung Cancer Research Group on Postsurgical Adjuvant Chemotherapy Japan Lung Cancer Research Group on Postsurgical Adjuvant Chemotherapy A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung. N Engl J Med. 2004;35017:1713-1721. [CrossRef] [PubMed]
 
Hamada C, Tsuboi M, Ohta M, et al. Effect of postoperative adjuvant chemotherapy with tegafur-uracil on survival in patients with stage IA non-small cell lung cancer: an exploratory analysis from a meta-analysis of six randomized controlled trials. J Thorac Oncol. 2009;412:1511-1516. [CrossRef] [PubMed]
 
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