Japanese Journal of Clinical Oncology Advance Access published online on December 1, 2006
Japanese Journal of Clinical Oncology, doi:10.1093/jjco/hyl119
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© 2006 Foundation for Promotion of Cancer Research
Revisit of 1997 TNM Staging System—Survival Analysis of 1112 Lung Cancer Patients in Taiwan
1 Chest Department
2 Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei
3 Cancer Center, Taipei
4 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine
5 Division of Chest Surgery, Department of Surgery, China Medical University Hospital, Taichung
6 Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung
7 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chang Gung Memorial Hospital, Taipei
8 Department of Oncology
9 Department of Internal Medicine, National Taiwan University Hospital, Taipei
10 Division of Chest Medicine, Department of Internal Medicine, Buddhist Tzu Chi General Hospital, Hualien
11 Division of Thoracic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
For reprints and all correspondence: Chao-Hua Chiu, Chest Department, Taipei Veterans General Hospital, No. 201, Section 2, Shih-Pai Road, Taipei, 112, Taiwan. E-mail: jhchiou{at}vghtpe.gov.tw
Received June 13, 2006; accepted August 28, 2006
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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BACKGROUND: There is neither a nation-wide nor a large-scale, multi-institutional lung cancer database available for stage-by-stage survival analysis in Taiwan at present.
METHODS: Using the data element provided by the International Association for the Study of Lung Cancer, the Taiwan Lung Cancer Society initiated a project to include native lung cancer patients into a global database. A total of 1112 Taiwan lung cancer patients treated in 7 medical centers were enrolled.
RESULTS: In small cell lung cancer, patients with ipsilateral pleural effusion had a survival between those with locoregional disease alone and those with distant metastasis; however, the difference was not statistically significant (P = 0.204). In non-small cell lung cancer, tumor size had significant survival influence for patients as a whole (P<0.001) but it did not support the further division of stage IA according to tumor size (P = 0.122). The survival was compatible in stage IIIB and IV patients and therefore, the survival impact of pleural effusion cannot be determined. In patients with pIIIA-N2 disease, those who had station 8 nodal metastasis had inferior survival (P = 0.020) and station 5 superior survival (P = 0.010). In patients with distant metastasis, bone, liver, or distant lymph node metastasis predicted an inferior survival (all P values<0.05).
CONCLUSIONS: The present study provides for comparison in this area a stage-by-stage reference for the survival of lung cancer patients. Some factors other than current TNM descriptors need to be further investigated in constructing the next version of the staging system.
Key Words: TNM staging system • Taiwan • lung cancer • survival analysis
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Lung cancer is the leading cause of cancer-related death in the world (1). In Taiwan, an area with high prevalence of hepatitis B viral infection, hepatocellular carcinoma and lung cancer are the two leading causes of cancer mortality (2). The prognosis of lung cancer is poor and according to the reports from western countries, the overall 5-year survival is only 12–15% (3). However, there is still neither nation-wide nor large-scale multi-institutional lung cancer survival data according to stage in Taiwan at present. We frequently apply the results obtained in western countries directly without taking into consideration internal or external ethnic factors. Therefore, there is an urgent need to establish the long term survival data of lung cancer patients in Taiwan.
Accurate and reproducible cancer staging is important for patient management and clinical research. It enables universal communication and has implications for prognosis and recommendations for the treatment and design of clinical research. The latest version of TNM staging of lung cancer is published in 1997 (4) and now is planned for revision in 2009. The International Association for the Study of Lung Cancer (IASLC) is the organization responsible for constructing a worldwide database and proposing final recommendations. The Taiwan Lung Cancer Society (TLCS) was invited to enroll patients into this global database. In this report, we present the survival data of 1112 lung cancer patients from seven medical centers distributed throughout the island.
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PATIENTS AND METHODS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Responding to the invitation from TLCS, a total of seven medical centers participated in this project. They included three centers in the northern, two in the middle, and one each in the southern and eastern parts of Taiwan. The format of data elements was provided by IASLC. There were a total of 50 items, including eight regarding patient characteristics, eight regarding disease description, 16 regarding TNM staging, 13 regarding treatment and five regarding outcome. For data concerning patients who had undergone surgical resection, information of both pathological and clinical staging was required. Otherwise, data of clinical staging was obtained. The tumors were classified according to the 1999 World Health Organization Histological Typing. The International System for Staging Lung Cancer revised in 1997 was used for both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). In addition, SCLC was also categorized into limited disease (LD) or extensive disease (ED) according to the IASLC consensus (5). In the present study, LD was further classified into LD-L (locoregional disease alone) and LD-PE (locoregional disease with ipsilateral pleural effusion).
The decision on number and indication of patients to be included was up to each medical center. The raw data on each patient were manually recorded at individual centers. All data were sent to the Data Management Center of TLCS in Taipei and were transformed into electronic format and analyzed independently by TLCS. The raw data were also sent to IASLC for final pooled analysis.
Correlation analysis of patient characteristics was performed by the 
2 test and the Fisher's exact test. Using 2, 3 and 5 cm as cutoff values, tumors were stratified into 4 groups (<2 cm, 2–3 cm, 3–5 cm and 
5 cm) by their longest diameter on image study. Survival curves were constructed using the Kaplan–Meier method and compared by log-rank test. Gender, age (
70 versus >70-years old), smoking status (never smoking versus ever smoking), body weight loss (BWL) (<5 versus 5%), performance status (PS) (ambulatory versus limited self-care), serum albumin (<3.5 versus 3.5 g/dl), and LDH level (300 versus >300 IU/l) and T, N and M status were used in univariate analysis. Values of P less than 0.05 were considered statistically significant. While there were more than two strata, Bonferroni correction was used to calculate P values compared between strata. Factors that showed statistically significant differences were used in multivariate analysis where the Cox regression model with a backward stepwise procedure was performed. Analyses and figures were carried out with SPSS for Windows version 12.0 (SPSS Inc., Chicago, IL).
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RESULTS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Patient Characteristics
Data of 1122 lung cancer patients who were newly diagnosed in the seven medical centers between 1990 and 2004 were collected and sent to the Data Management Center of TLCS. Ten cases were excluded because of incomplete survival information or inappropriate diagnosis. There were 813 (73.1%) male and 299 (26.9%) female. Most male patients were former or current smokers; however, only a few female patients had a smoking history (69.5 versus 9.4%; P<0.001). The median age was 67.5 years (range: 19–99). Nine hundred and seventy-two (87.5%) patients had NSCLC and adenocarcinoma (48.2%) was the most frequent histological subtype. Females were more likely to have adenocarcinoma than males (71.6 versus 39.7%; P<0.001).
Never-smoking and younger age (<70-years old) were also associated with higher incidence of adenocarcinoma (65.8 versus 34.8% and 52.3 versus 42.1%, P<0.001 and P=0.001, respectively). In multivariate analysis, gender and smoking status were two independent factors for adenocarcinoma. Patient characteristics were summarized in Table 1.
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Survival Analysis in SCLC
There were 67 males and nine female SCLC patients and only five of them (6.6%) were non-smokers. Six patients underwent pulmonary resection, 29 received regional radiotherapy, 32 took systemic chemotherapy and 37 had supportive care only. Two patients had incomplete staging information and then were excluded in the survival analysis. Among 74 patients, 38 had ED and 36 had LD, including 25 LD-L and 11 LD-PE. There was a significant difference in overall survival between patients with LD and ED (median=15.5 months versus 7.3 months, P=0.002). When LD was further stratified into LD-L and LD-PE, there was a trend showing intermediate survival of LD-PE between LD-L and ED; however, the difference did not reach statistical significance (LD-L versus LD-PE, P=0.102; LD-PE versus ED, P=0.204) (Fig. 1). There was no survival difference by gender, age, smoking status, BWL and serum LDH level; however, patients with low baseline serum albumin levels and poor PS had inferior survival time (P=0.025 and <0.001, respectively). In multivariate analysis, serum albumin level and PS persisted to be independent factors for overall survival.
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Survival Analysis in NSCLC
A total of 972 patients had NSCLC and nine patients were excluded in survival analysis because they experienced peri-operative mortality. Among 963 patients, there were 693 male and 270 female and the median age was 67 years (range, 19–99 years). Of patients, 20% were ex-smokers, 31% were current smokers and 42% never smoked. About a third of patients had BWL of more than 5% at presentation. The most common cell type was adenocarcinoma (55%), followed by squamous cell carcinoma (37%). In this series, 51% of patients underwent pulmonary resection, 31% received regional radiotherapy, 33% took systemic chemotherapy and 5% had supportive care only. Three-modality treatment was applied in 7% of patients and two-modality treatment in 23%. The clinical and pathological staging and the respective 5-year survival rates of these patients are summarized in Table 2.
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In univariate analysis, age, smoking status, BWL, PS, serum albumin and LDH levels and overall TNM staging were all predictors for overall survival (all P values <0.05); however gender and histological subtype were not. In multivariate analysis, overall TNM staging, age, smoking status and PS were independent prognostic factors.
To confirm the importance of the down staging of T3N0M0 from IIIA to IIB in the revised staging system in 1997, we compared the survival curves among pT2N1N0, pT3N0M0 and pIIIA. Although it did not reach statistical significance (P = 0.290), the survival curve of pT3N0M0 lay between the curves of pT2N1M0 and pIIIA and seemed to be closer to the former. In addition, the 5-year survival rates also favored grouping pT3N0M0 and pT2N1M0 together (46.7%, 41.0% and 34.3% for pT2N1M0, pT3N0M0 and pIIIA respectively).
M status, as expected, was a strong predictor for survival with a median of 2.9 years for cM0 and 0.6 years for cM1 (P<0.001). In patients without distant metastasis, both clinical T and N and pathological T and N status were predictors for survival (all P values <0.001) (Figs 2 and 3). The survival curves stratified by overall clinical and pathological staging are plotted in Figs 4 and 5 (both P values <0.001) and the 5-year survival rates of individual stages are summarized in Table 2.
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To characterize the T descriptor further, the tumor size and the presence of pleural effusion were analyzed. There was a significant survival difference among patients stratified by the longest diameter of their tumors measured by imaging study (P<0.001). However, the difference was no more significant in a subgroup of patients with stage IA disease (n=57, P=0.122). Similarly, the presence of pleural effusion predicted an inferior survival time in all patients (P<0.001), but not in a subgroup of patients with stage IIIB disease (n=123, P=0.412).
In a total of 371 pI-IIIA patients, 331 had detailed pathological information on each resected mediastinal lymph node. The median number of examined lymph node stations were 3 (range, 1–8) and 70.1% of patients had 3 stations examined. The frequency of pathological examination varied greatly among different nodal stations: stations 5 and 7 were frequently examined (73.3–74.5%); stations 3, 4, 6 and 9 were sometimes examined (45.1–58.3%); stations 8 and 2 were examined in 35.5 and 26.7% of patients respectively, and station 1 was examined in only 5.9%. In patients with pIIIA-N2 disease (n=82), tumor metastasis in station 8 resulted in inferior survival (P=0.020). However, interestingly, patients with station 5 lymph node metastasis had superior survival to patients with N2 metastasis other than at station 5 (P=0.010). All other N2 lymph node stations did not have survival impact, including subcarinal node (P = 0.701). There was no survival difference between patients with single versus multiple station metastasis (P=0.757) and between patients with and without metastasis in their highest examined mediastinal lymph node station (P=0.809).
In patients with cM1 disease, the most common metastatic site was bone, followed by lung, brain, liver, distal lymph node and adrenal gland. Patients with bone, liver or distal lymph node metastasis had inferior survival than patients without (P=0.020, 0.008 and 0.041, respectively). Other metastatic sites did not have survival influence, including brain (P = 0.225). Patients with single-organ metastasis had a longer survival time than those with multi-organ metastases (P=0.007). In patients with single-organ metastasis, bone and distal lymph node metastasis predicted a poorer outcome (P=0.029 and 0.007, respectively). However, patients with isolated ipsilateral lung metastasis had superior survival than patients with single-site metastasis to other organs (P<0.001).
In 297 patients who underwent operation with complete tumor resection, 274 received extended resection (lobectomy or pneumonectomy) and 23 received limited resection (segmentectomy or wedge resection). There was no survival difference between these two types of surgery (P=0.852). Systemic chemotherapy was performed in 198 patients with advanced disease and 161 of them received platinum-containing regimens. There was no survival difference among patients in terms of gender, age, histological subtype, smoking status, BW loss and serum LDH level; however, patients with normal serum albumin level and good PS had a longer survival time (P=0.002 and 0.015, respectively).
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Cancer staging is the cornerstone for universal communication of patient management and clinical research design. For lung cancer, the latest version of the staging system was built upon a database from 4351 consecutive patients treated at the MD Anderson and 968 patients treated by the National Cancer Institute cooperative Lung Cancer Study Group in which data had been sent to MD Anderson for confirmation of stage and histology (4). The accuracy of this staging system is questioned, because the database suffered not only from a low number of patients but also a limited variety of ethnicities. The next version is planned for issue in 2009 and IASLC is the organization responsible for proposing recommendations for revision. As the first step, IASLC initiated a project to construct a worldwide lung cancer patient database. In fact, the database was finalized in 2005 and a total of about 80 000 cases are being analyzed. Therefore, the present study not only contributed to this important worldwide project but also gave a chance, using a same data element, to compare several aspects of lung cancer treatment in Taiwan with those from the global database that will be published in the near future.
In the revised staging system of 1997, stage I and II were further divided into IA/IB and IIA/IIB because of the survival impact of T status in the same stage. In this study, we confirmed the importance of T status in stage I disease. The 5-year survival rates for cIA and cIB were 82.9 and 53.5%, and pIA and pIB were 89.8 and 67.2%, respectively. We cannot determine the impact of T status on stage II disease because of the very limited number of stage IIA patients in this series (n=3 for cIIA and n=9 for pIIA). Tumors of T1N1M0 are infrequently seen in clinical practice, therefore, a larger sample size are needed to estimate the accurate 5-year survival rate. Another important issue in the 1997 revision was the down staging of T3N0M0 from IIIA to IIB. In this series, although it did not reach statistical significance, the survival curve for pT3N0M0 was more approximate to pT2N1M0 than to pIIIA and the 5-year survival rates were 41.0, 46.7 and 34.3%, respectively.
In this series, the 5-year survival rates for each stage, both clinical and pathological staging, are better than those from which the 1997 staging system derived, except stage IIA. The inferior outcome of stage IIA was most likely biased by the small sample size as previously discussed. The 1997 database was derived from a cohort of patients diagnosed during 1975–1988. The current study included patients diagnosed between 1990 and 2004. Therefore, there are two possible explanations for the superior outcome of this series: (i) better treatment result and (ii) stage migration by improved technology for staging investigation. The adventure of diagnostic tools in the past few decades, such as CT scan, MRI and PET scan, has dramatically improved the sensitivity of detecting local or distant disease and therefore resulted in more accurate staging. It is well documented that better staging tools would move some patients from lower stages to upper stages and result in improved outcome in both stages, the so-called ‘Will Rogers phenomenon’ (6). Therefore, more delicate statistical methodology is needed in comparing survival data between two cohorts that were diagnosed and staged at very different periods of time.
There were several reports addressing the prognostic importance of tumor size (7–9). In this series, where all NSCLC patients were analyzed, we did find a significant survival advantage in patients whose tumors were less than 2 cm. However, our data did not support the idea of having a substage in stage IA patients according to their tumor size. Some recommended to up-stage patients with malignant pleural effusion from stage IIIB to IV, because the presence of pleural effusion usually precludes a curative local treatment and the survival is closer to stage IV than IIIB (10,11). In this analysis, we did not find survival difference in stage IIIB patients when they were stratified by the presence of pleural effusion or not. In fact, there was no survival difference between stage IIIB and IV in this series. Therefore, these results should be cautiously interpreted.
Because it was a multi-institutional retrospective case analysis, the pattern of operations for mediastinal lymph nodes varied widely in this series. Roughly 70% of operations fulfilled the requirement that at least three N2 stations be examined as recommended by National Comprehensive Cancer Network (12). Subcarinal lymph node, station 7, locates at the midline in mediastinum and the prognosis of metastasis in this lymph node provoked great debate in the past (13–15). In this series, there was no survival difference in pIIIA-N2 patients with or without subcarinal lymph node metastasis. However, although only few patients were included, we found a statistically significant prognostic impact of station 8 (paraesophageal) nodal metastasis. Interestingly, we also found that left-sided NSCLC patients with station 5 (subaortic) nodal metastasis had better a outcome than those with other N2 nodal metastasis. There were some studies arguing the prognostic values of single versus multiple N2 station metastasis and the presence versus absence of metastasis at the highest examined mediastinal lymph node (15–18); however, we did not find differences in this series. On the contrary, we raised the question of the importance on the lower mediastinal lymph nodes (station 8 and 9), i.e. the clinical significance of ‘retrograde’ lymph node metastasis. It deserves further investigation.
Regarding patients with distant metastasis, liver, bone and distant lymph node metastasis predicted a poor prognosis but brain metastasis did not. As expected, patients with single-organ metastasis had better survival than those with multiple organ metastases. In consideration of patients with single-organ metastasis, bone and distant lymph node metastasis were still the signs for poor prognosis. We found patients with distant metastasis in the same side of lung had better outcome than those with other organ metastasis. It may be attributable to the fact that some of them were diagnosed during thoracotomy and had undergone complete resection of both primary and metastatic tumors.
The most commonly used clinical staging for SCLC is a two-stage system, LD and ED. However, there are several controversies regarding the definition of this staging system, mostly concerning the role of pleural effusion (19,20). Some authors considered ipsilateral pleural effusion as LD, others considered it representing a systemic disease which could not be controlled with radiation. Although this study included only a small number of SCLC patients and so the statistical power is limited, we did find that the survival curve of patients with LD-PE was between curves of patients with LD-L and ED (Fig. 1). However, the difference did not reach a statistical significance. In addition to staging, some reports had shown PS, BWL and serum LDH level were prognostic factors. In this study, we confirmed the importance of PS but not BWL and serum LDH level. However, we found serum albumin level an independent prognostic factor.
This is the first collaborative, multi-institutional and stage-by-stage survival analysis of lung cancer patients in Taiwan. Because of the study design, the stage distribution in this series is not representative for the whole of Taiwan. However, it may stand for the best reference of survival data comparison within this country. Most importantly, it also provides a chance, using the same inclusion criteria and data elements, to compare the treatment outcomes of lung cancer patients in Taiwan with those in the world outside. In addition, although the patient number was limited, we did find some prognostic factors that were not included in the current staging system and therefore we consider them deserving further investigation in constructing the next version of the lung cancer staging system.
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Acknowledgment |
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This work was supported by Taiwan Lung Cancer Society.
Conflict of interest
None declared.
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References |
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