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Ann Thorac Surg 2005;79:1142-1146
© 2005 The Society of Thoracic Surgeons

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Original articles: General thoracic

Impact of Large Tumor Size on Survival After Resection of Pathologically Node Negative (pN0) Non–Small Cell Lung Cancer

^a Toneyama National Hospital, Osaka
^b Ibaragi East National Hospital, Ibaragi
^c Tokyo National Hospital, Tokyo
^d Minami Yokohama National Hospital, Yokohama
^e Ehime National Hospital, Ehime
^f Tenryu National Hospital, Shizuoka, Japan

Accepted for publication September 7, 2004.

^_* Address reprint requests to Dr Takeda, Toneyama National Hospital, Toneyama 5–1–1, Toyonaka, Osaka, 560–8552 Japan (E-mail: stakeda{at}toneyama.hosp.go.jp).

	Abstract

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BACKGROUND: The current TNM staging system first adopted the tumor size of 3 cm for subdivision of stage I and II disease. The aim of the present study was to evaluate the impact of tumor size on survival in patients with pathologically node negative (pN0) non–small cell lung cancer after complete resection.

METHODS: We retrospectively reviewed the records of 603 patients with pN0 non–small cell lung cancer patients (403 men and 200 women) who underwent a complete resection in five national chest hospitals between 1992 and 1996, with follow-up duration of more than 5 years, and analyzed tumor size and survival. Survival rate was estimated by the Kaplan-Meier method, and differences were compared by log-rank test. For the multivariate analysis, the Cox proportional hazard model was used to identify variables that significantly affected survival.

RESULTS: There were 355 adenocarcinomas, 208 squamous cell carcinomas, and 40 large cell carcinomas completely resected. No significant prognostic differences were seen among three groups with smaller-sized tumors (2 cm [n = 171], 2.1 to 3 cm [n = 202], and 3.1 to 5 cm [n = 170]); however, patients with a tumor size greater than 5 cm (n = 60) showed a significantly worse prognosis. The 5-year survival rates were 79.6%, 72.7%, 68.1%, and 46.6%, respectively, in these four groups. Multivariate analysis showed the tumor size to be an independent prognostic predictor in patients with pN0 tumors.

CONCLUSIONS: We found that a tumor size of greater than 5 cm was an independent prognostic predictor in pN0 disease; therefore, upgrading the T factor of tumor diameter to greater than 5 cm may be necessary in the next reversion of the TNM staging system.

	Introduction

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Staging and classification in lung cancer are important for deciding on patient management and estimating prognosis. The TNM staging system is composed of T (characteristics of primary tumor), N (status of regional lymph nodes), and M (presence or absence of distant metastasis). After several reversions, Union Internationale Contre le Cancer (UICC) published the fifth edition of the TNM staging system for lung cancer in 1997 [1]. However, after considering recent trends in patient characteristics, it is now considered necessary to establish a new and more complete classification system that could be applied internationally.

In lung cancer patients, several variables, including anatomic extension of disease, histologic classification, other demographic data, and molecular biologic markers, are known or suspected to influence survival [2–6]. We believe that the TNM system should be described by using common variables such as tumor size, local extension, and lymph node involvement, and that the pathologic TNM should be consistent with the clinical TNM as an initial discriminator and for reflecting prognostic prediction, as tumor size may roughly reflect the number of tumor cells.

The current TNM staging system in 1997 proposed stage I and II subdivision according to a tumor diameter of 3 cm as a cutoff point. However, there are conflicting reports with regard to the correlation of tumor size and survival in terms of further subdivision in stage I disease [7–12]. In addition, the prognostic value of larger tumor size in patients with N0 disease has not been fully determined. To evaluate the correlation of tumor size and survival in patients with pN0 and pathologic stage I lung cancer and to assess whether the current TNM has a prognostic relevance, the records of 603 patients who underwent complete pulmonary resection in five National Chest Hospitals in Japan were retrospectively analyzed.

	Material and Methods

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Between 1992 and 1996, 1,047 patients with a non–small cell lung cancer (NSCLC) underwent complete resection in five National Chest Hospitals in Japan and had a follow-up duration of more than 5 years. We retrospectively reviewed the records of 603 patients with pathologically node negative (pN0) NSCLC patients (403 men and 200 women). The age distribution ranged from 21 to 89 years old (mean, 62.9 years). These cases, including operation records and extent of cancer growth, were classified according to the fifth edition of the TNM staging system, published in 1997 [1]. Follow-up was complete in all patients through June 2002, and the median follow-up duration is 7.8 years. For the present analysis, zero time was the date of operation. Evaluation of pathologic nodal status (pN) classification was determined from pathologic examination of the resected lymph nodes. Evaluation of M1 disease included results from abdominal computed tomography, bone scan, brain computed tomography, or magnetic resonance imaging, and laboratory tests. Surgical and pathologic reports from each institution were reviewed to confirm the size of the primary lesion in each case. The degree of pleural involvement was defined as a P factor according to the following Japanese definition: P0, no tumor invasion of the visceral pleura; P1, suspected invasion but no penetration of the visceral pleura; P2, invasion through the visceral pleura; and P3, invasion to the chest wall, diaphragm, mediastinal structures, or adjacent lobes [13].

We analyzed tumor size and prognosis in 603 surgical cases with pN0 status, including 540 patients with pathologic stage I NSCLC. Operative-related deaths in hospital (n = 4, 0.7%) were also included in survival calculation. Excluded from the analysis were patients with small cell carcinomas and unclassified carcinomas. There were 355 adenocarcinomas, 208 squamous cell carcinomas, and 40 large cell carcinomas.

Survival rate was estimated by the Kaplan-Meier methods, and a log-rank test was used to compare survival rates among the groups. The following variables were considered as prognostic variables for survival in univariate and multivariate analyses with the Cox proportional hazard model: age, sex, tumor location, operative procedure, histologic classification, pleural involvement, T factor, and tumor size. A multivariate analysis was performed with the variables found to be significant in the univariate analysis.

	Results

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With regard to the current pathologic TNM staging system for all patients in the National Chest Hospital database, the survival rates are as follows: stage IA (n = 329), 77.6%; stage IB (n = 222), 68.4%; stage IIA (n = 35), 60.3%; stage IIB (n = 132), 46.8%; stage IIIA (n = 250), 27.8%; stage IIIB (n = 57), 19.9%; and stage IV (n = 22), 10.5%.

We analyzed the tumor diameter and survival in 603 pN0 patients, which included 63 T3 or T4 tumors. The cases with pN0 were classified into four groups according to the tumor size (group S: 2 cm, n = 171; group M: 2.1 to 3 cm, n = 202; group L: 3.1 to 5 cm, n = 170; group XL: >5 cm, n = 60), and the 5-year survival rates were 79.6% for group S, 72.7% for group M, 68.1% for group L, and 46.6% for group XL (Fig 1). When we excluded T3 and T4 lesions from pN0 tendencies for the influence of tumor size and prognosis were noted; however, there were no statistical significance between groups S and M and between groups M and L. The 5-year survival rates after excluding T3 and T4 lesions were 80.9% for group S (n = 160), 74.2% for group M (n = 193), 71.3% for group L (n = 147), and 51.3% for group XL (n = 40; Fig 2). In the analyses for pN0 and pathologic stage I patients, we found no statistical differences between patients with tumors with 2 cm or less in size and those with tumors from 2 to 3 cm, indicating that there is no need to divide patients with a tumor size 3 cm or less (Figs 1, 2). Therefore, we conducted the univariate analysis for the tumor diameter of 3 cm and 5 cm as cutoff points.

View larger version (24K): [in this window] [in a new window]   Fig 1. Survival rates for 603 patients with pathologic-negative nodes (pN0) according to tumor size. There were no significant differences between group S (2 cm, n = 171) and group M (2.1 to 3 cm, n = 202; p = 0.293), or between group M (2.1 to 3 cm, n = 202) and group L (3.1 to 5 cm, n = 170; p = 0.092). A significant difference was found between group L (3.1 to 5 cm, n = 170) and group XL (>5 cm, n = 60; p = 0.004).

View larger version (23K): [in this window] [in a new window]   Fig 2. Survival rates for 540 patients with pathologic stage I disease according to tumor size. There were no differences between group S (2 cm, n = 160) and group M (2.1 to 3 cm, n = 193; p = 0.403), or group M (2.1 to 3 cm, n = 193) and group L (3.1 to 5 cm, n = 147; p = 0.204). A significant difference was found between group L (3.1 to 5 cm, n = 147) and group XL (>5 cm, n = 40; p = 0.014).

	Comment

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Cancer patient prognosis is affected by tumor-related factors, which are represented as T factors. Further, in the TNM classification for lung cancer, tumor size is also considered to have an effect [3, 7, 9, 11, 12], as the current TNM staging system in 1997 has proposed a stage I and II subdivision according to a tumor diameter of 3 cm. A stage I subdivision into IA and IB is acceptable, as noted earlier in our multicenter studies [11, 15], which found differences in prognosis according to size of tumor and the extent of pleural involvement.

Recently the prevalence of early stage lung cancer increased because of the nationwide mass screening system. In our institutional experience, 50% of patients who underwent surgery in 1991 had stage I lung cancer, whereas the percentage climbed to nearly 70% in 2001, similar to the report from Duke University [15]. This trend also has prompted us to reconsider further subdivision of stage I disease from a prognostic viewpoint. Several studies, mostly from Japanese institutions, have shown a difference in survival for patients with stage IA disease when using 2 cm as a breakpoint [16–22], and some have promoted acceptance of a segmentectomy or lesser resection for these lesions [17–20] based on the long-term follow-up study and recurrence patterns. However, pathologically discovered nodal metastasis was found in 13.2% of patients with a tumor 2 cm or less, and in 21.0% with a tumor size of 2.1 to 3 cm [14]. All patients in that current series received a standard lobectomy with lymph node resection, regardless of the tumor size. Miller and associates [23] concluded a lobectomy with standard lymph node dissection is warranted, even in cases of tumors with a diameter of less than or equal to 1 cm.

The prognostic value of tumor size has been documented for many years on the basis of prognostic clinical aspects; tumor size itself may have a strong influence on potential local progression or metastasis. Padilla and associates [16] stated that the tumor size, at a breakpoint of 2 cm, was the only predictor in stage I NSCLC after univariate analysis with sex, age, cell type, amount of resection, and visceral invasion used as variables. However, Harpole and coworkers [3] found that a 3-cm breakpoint was slightly better in reflecting survival than 2 cm, with other factors showing better prognostic ability. In the present study, we did not find that a breakpoint of 2 cm had prognostic impact; however, our population consisted of patients who were treated with a standard lobectomy. At that time, the entity of small peripheral lung cancer was not fully established. However, a breakpoint of 2 cm is expected to be useful with the increasing number of small-sized lung cancer including roentgenogram-negative ground-glass opacity lesions, which have different clinical characteristics compared with small solid masses [19, 24]. Considering the trend of an increased prevalence of early stage lung cancer, a subgrouping of stage IA according to the tumor size may have clinical impact for predicting survival in a revised TNM system.

Controversy exists regarding the prognosis of stage IB and stage IIA patients. In a report of 1,310 Japanese patients, Inoue and colleagues [25] confirmed the validity of the current TNM classification, such as noting differences between stage IA and IB, as well as between stage IIA and IIB. However, no prognostic differences were found between stage IB and IIA [25, 26], and a similar tendency was also reported by Naruke and associates [11] and Adebonojo and coworkers [27]. Together these results imply that the prognosis of stage IB patients with a large size tumor is poor enough that this population should be upgraded in the revised TNM. In contrast, few studies have focused on the impact of larger tumor sizes on the prognosis of N0 [11, 12] patients. Watanabe and colleagues [9] were the first to emphasize that patients with a tumor larger than 5 cm in diameter showed a significantly worse survival rate than those with tumors smaller than 5 cm, indicating that tumors greater than 5 cm should be classified as stage II disease. Further, a recent report published by Carbone and associates [12] also found that the survival of patients with a tumor diameter greater than 5 cm was between that for patients with T3 and T4 tumors. Our present analysis showed that tumor size of greater than 5 cm was the most significant independent prognostic value, which strongly supports these findings [9, 12]. In addition, we previously demonstrated that a tumor diameter of greater than 5 cm was a negative prognostic factor in patients with N1 disease, whose survival rate was similar to that of patients with stage IIIA disease [14].

Taken together, these results reinforce the contention that a tumor size of more than 5 cm in diameter is indicative of a poor prognosis in NSCLC patients and should be considered as a potential factor for upgrading T factors in a revised TNM system. Further, on the basis of this clinical need and current retrospective reviews of multicenter studies, we urge reconsideration of stage I, as well as reclassification of IB and IIA, in the next TNM system. We also emphasize that the clinical TNM should be relevant to the pathologic TNM [28] as well as reflect prognostic predictors and planning therapeutic strategies.

In conclusion, tumor size was found to be an independent prognostic predictor in patients with N0 disease; therefore, in addition to a breakpoint of 3 cm, upgrading tumor diameter to greater than 5 cm is reasonable in the next revision of the TNM staging system.

	Acknowledgments

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The authors wish to thank Hajime Maeda, MD, Shodayu Takashima, MD, Noriyoshi Sawabata (Toneyama National Hospital), Masaaki Kawahara, MD (Kinki National Hospital), and Kazunori Shimada, MD (Ehime National Hospital), for contributing to this project and for critical review of the manuscript.

	References

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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