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Eur J Cardiothorac Surg 2007;32:440-444. doi:10.1016/j.ejcts.2007.06.011
Copyright © 2007, European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved

The prognostic value of carcinoembryonic antigen in T1N1M0 and T2N1M0 non-small cell carcinoma of the lung

Ryuta Fukai*, Yukinori Sakao, Motoki Sakuraba, Shiaki Oh, Kazu Shiomi, Satoshi Sonobe, Yuichi Saitoh, Hideaki Miyamoto

Department of General Thoracic Surgery, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8431, Japan

Received 15 January 2007; received in revised form 5 June 2007; accepted 11 June 2007.

* Corresponding author. Tel.: +81 55 948 3111; fax: +81 55 948 5088. (Email: ryuta.f{at}hotmail.co.jp).


   Abstract
Top
 Abstract
1. Introduction
 2. Patients and methods
 3. Results
 4. Comment
 References
 
Objective: To evaluate the significance of preoperative clinicopathological factors, including serum carcinoembryonic antigen (CEA), as well as postoperative clinicopathological factors in T1-2N1M0 patients with non-small cell lung cancer who underwent curative pulmonary resection. Methods: Twenty T1N1M0 disease patients and 25 T2N1M0 patients underwent standard surgical procedures between September 1996 and December 2005, and were found to have non-small lung cancer. As prognostic factors, we retrospectively investigated age, sex, Brinkman index, histologic type, primary site, tumor diameter, clinical T factor, clinical N factor, pathological T factor, preoperative serum CEA levels, surgical procedure, visceral pleural involvement, and the status of lymph node involvement (level and number). Results: The overall 5-year survival rate of all patients was 59.6%. In univariate analysis, survival was related to age (<70/≥70 years, p = 0.0079), site (peripheral/central, p = 0.043), and CEA level (<5.0/≥5.0 ng/ml, p = 0.0015). However, in multivariate analysis, CEA (<5.0/≥5.0 ng/ml) was the only independent prognostic factor; the 5-year survival of the patients with an elevated serum CEA level (≥5.0 ng/ml) was only 33.2% compared to 79.9% in patients with a lower serum CEA level (<5.0 ng/ml). Conclusions: An elevated serum CEA level (≥5.0 ng/ml) was an independent predictor of survival in pN1 patients except for T3 and T4 cases. Therefore, even in completely resected pN1 non-small cell lung cancer, patients with a high CEA level might be candidates for multimodal therapy.

Key Words: Lung cancer • Stage II • N1 • Carcinoembryonic antigen


   1. Introduction
Top
 Abstract
 1. Introduction
2. Patients and methods
 3. Results
 4. Comment
 References
 
The 5-year survival rate of pN1 non-small cell lung cancer (NSCLC) patients after curative operation is 40–60% [1–6]. N1 disease encompasses a heterogeneous subgroup with different outcomes according to various prognostic factors [1–6]. It has been reported that postoperative pathological findings, such as status of nodal involvement (single vs multiple, intralobar vs extralobar, and direct invasion vs metastasis), pleural involvement, tumor diameter, and histologic type were important prognostic factors [1–10]. In contrast, the impact of preoperative factors (cT, cN, tumor marker, etc.) for prognosis in N1 patients remains unclear.

The carcinoembryonic antigen (CEA) is one of the most common serum tumor markers in NSCLC patients. It has been reported that the elevation of preoperative serum CEA levels is associated with more advanced disease and poorer prognosis even after successful surgical procedure [11–12]. However, there are few reports that focused on the serum CEA level in N1 NSCLC patients [13].

In this retrospective study, we evaluated the significance of preoperative clinicopathological factors, including serum CEA, as well as postoperative clinicopathological factors in T1-2N1M0 NSCLC patients who underwent curative pulmonary resection.


   2. Patients and methods
Top
 Abstract
 1. Introduction
 2. Patients and methods
3. Results
 4. Comment
 References
 
This is a retrospective study and individual patients are not identified. Therefore, our institutional review board did not require patient consent for this study. Between September 1996 and December 2005, 646 patients underwent pulmonary resection at the Department of Thoracic Surgery of Juntendo University for bronchogenic carcinoma. Of these patients, 72 patients (11.1%) were diagnosed with pathologic N1 disease according to mapping by Naruke and associates: hilar (#10), inter lobar (#11), lobar (#12), segmental (#13), and subsegmental (#14) [14]. We excluded a small number of T3 and T4 cases that showed a very poor prognosis with a dramatically reduced survival rate. We also excluded palliative operation cases, small cell lung cancer cases, and second primary lung cancer cases; consequently, 20 T1N1M0 disease patients and 25 T2N1M0 patients remained. We identified pathological stages post-surgery by the international TNM criteria for lung cancer [15]. These 45 patients underwent systematic hilar and mediastinal lymph node dissection and were found to have non-small lung cancer with the potential of complete curative resection. In all cases, the resection margin was negative for tumor cells both on gross and microscopic examination. The characteristics of the 45 patients are listed in Table 1 . There were 24 men and 21 women with median age of 64.1 years (range, 37–80 years). The average size of the primary tumor was 31.5 mm. Thirteen patients received oral uracil-tegafur (200 mg of tegafur and 448 mg of uracil) twice daily as adjuvant therapy for 2 years.


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  		Table 1 Patient characteristics in pathological T1N1M0 and T2N1M0 non-small-cell lung cancer (N = 45)
 
For prognostic factors, we retrospectively investigated the following variables: age, sex, Brinkman index, histologic type, primary site, tumor diameter, clinical T factor, clinical N factor, pathological T factor, preoperative serum CEA level, surgical procedure, visceral pleural involvement, and the status of lymph node involvement (level and number). The clinical investigation section of our hospital measured the CEA level using a two-site immunoenzymatic assay that has a normal upper limit of 3 ng/ml. The time-interval between serum CEA measurement and surgical operation was less than a month in all patients. The follow-up duration ranged from 5 to 113 months (median: 39.8 months).

2.1 Statistical analysis
The duration of survival was defined as the interval between the date of surgery and the date of death. Survival rates were calculated using the Kaplan–Meier method, and survival curves were compared using the log-rank test. Prognostic factors that were found to significantly influence survival in univariate analysis (log-rank test) were entered into a multivariate Cox proportional hazards model. Statistical significance was assumed when p-value was <0.05. Stat View J 5.0 (SAS Institute Inc, Cary, NC) was used to perform all statistical analyses.


   3. Results
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
4. Comment
 References
 
3.1 Survival rate
The mean observation period after curative operation was 39.8 months, and the overall 5-year survival rate was 59.6% as shown in Fig. 1 (‘zero time’ was the date of surgery and May 31, 2006 was the end date). Survival rate for the 45 patients according to postoperative stage was 49.8% in stage IIA (N = 20) and 65.8% in stage IIB (N = 25).


Figure 1
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  		Fig. 1. Survival curve of all patients.

 
3.2 Univariate analysis
Univariate analysis was performed to investigate the relationship between prognostic factors and survival. A univariate analysis using the variables summarized in Table 2 showed that age (<70/≥70 years, p = 0.0079), site (peripheral/central, p = 0.043), and CEA (<5.0/≥5.0 ng/ml, p = 0.0015) were significant prognostic factors.


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  		Table 2 Survival in T1N1M0 and T2N0M0 patients by univariate analysis (log-rank test)
 
3.3 Multivariate analysis
The variables in Table 3 that were significant predictors of survival (p < 0.05) in univariate analyses were evaluated in a multivariate Cox proportional hazards model. CEA (<5.0/≥5.0 ng/ml) was an independent prognostic factor, the 5-year survival of the patients with elevated serum CEA level (≥5.0 ng/ml) was only 33.2% compared with 79.9% in patients with serum CEA level less than 5.0 ng/ml (Fig. 2 ). For adenocarcinoma cases (N = 29), the results were similar (38.1% and 80.8%, respectively, Fig. 3 ).


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  		Table 3 Multivariate analysis (Cox proportional hazards model) of factors associated with survival in T1N1M0 and T2N1M0 disease
 

Figure 2
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  		Fig. 2. Survival rate in pT1-2N1M0 NSCLC patients according to preoperative serum CEA concentration. CEA < 5.0, preoperative CEA concentration <5.0 ng/ml. CEA ≥ 5.0, preoperative CEA concentration ≥5.0 ng/ml.

 

Figure 3
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  		Fig. 3. Survival rate in pT1-2N1M0 adenocarcinoma patients according to preoperative serum CEA concentration. CEA < 5.0, preoperative CEA concentration <5.0 ng/ml. CEA ≥ 5.0, preoperative CEA concentration ≥5.0 ng/ml.

 

   4. Comment
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Comment
References
 
N1 disease consists of oncologically heterogeneous subgroups that are determined by various prognostic factors [1–6]. Sayar et al. reported that survival associated with multiple-station N1 disease was significantly worse than that of single-station N1 disease [6]. In addition, Riquet et al. reported that the survival rate with intralobar N1 disease was significantly better compared with extralobar hilar N1 disease [3]. In contrast, in the present study, neither the number of metastatic stations (single vs multiple, p = 0.26) nor the sites of metastatic lymph node (intralobar vs extralobar, p = 0.69) were significant prognostic factors. Similar to our results, Khan et al. reported that the number and site of involved nodes were not significant prognostic factors [10]. Thus, the impact of metastatic site and number of metastatic stations on prognosis in pN1 patients still remains controversial. In this study, we examined preoperative factors (Brinkman index, cT, cN, and serum CEA level) as well as several postoperative factors that were examined previously [1–10]. We found that preoperative serum CEA level was a significant prognostic factor in N1 disease; the 5-year survival of the patients with a lower CEA level (<5.0 ng/ml) was 79.9%, compared to 33.2% in patients with a higher CEA level (≥5.0 ng/ml).

The CEA is one of the most common serum tumor markers in NSCLC patients. Many authors reported that NSCLC patients with a high serum CEA concentration have a poor prognosis [16–20], but there are few reports in N1 disease. Tomita et al. reported that a serum CEA level of more than 10 ng/ml was an independent overall prognostic factor in pN1 patients and was significantly related to survival in pT1-2N1M0 NSCLC (the normal upper limit of CEA level was 5 ng/ml) [13]. In our study, serum CEA cutoff levels of both 3 ng/ml and 5 ng/ml showed prognostic significance (p = 0.0148 and 0.0015, respectively). Moreover, the results of multivariate analysis indicated that a serum CEA level of ≥5 ng/ml was an independent prognostic determinant even in pT1-2N1M0 NSCLC patients. Since 44.4% of our patients had a serum CEA level ≥5.0 ng/ml, it would appear that 5.0 ng/ml is a valid cut-off value. In contrast, Tomita et al. did not report the frequency of patients with an elevated serum CEA level (≥10 ng/ml). There were only six patients with a serum CEA level of ≥10 ng/ml in our study (13.3%). Two of these patients had recurrent disease and died; one died 11 months after the operation, and the other died 27 months after the operation. The remainders have had no recurrence and are still alive; two of them have survived more than 2 years since the operation. Thus, in our study, a CEA cut-off level of 10 ng/ml was not a significant factor for postoperative prognosis in pN1 patients.

A correlation between smoking and serum CEA level has been reported previously, Alexander et al. reported the mean CEA level was significantly higher in smokers than nonsmokers [21]. In our study, there was a similar tendency for a higher mean CEA level in smokers (6.8 ng/ml) than in nonsmokers (3.5 ng/ml), but the difference was not statistically significant (p = 0.08). Moreover, a history of smoking and the Brinkman Index were not significant predictors of survival. Accordingly, further investigation is needed to determine the appropriate CEA cut-off value in NSCLC patients who smoke.

The beneficial effect of induction or adjuvant chemotherapy in pN1 NSCLC patients is still under investigation. Since a 1995 meta-analysis favored adjuvant chemotherapy with cisplatin-based regimens [22], several large randomized adjuvant cisplatin-based trials have been conducted, and some demonstrated a clear survival advantage [23–24]. Therefore, adjuvant postoperative systemic chemotherapy may be beneficial in the treatment of NSCLC patients with N1 disease, especially in pT1-2N1M0 patients with high CEA levels.

A limitation of the present study was the small number of patients, although the statistical power of the preoperative serum CEA level was sufficient to show significance. An additional limitation was that the study was retrospective rather than prospective.

In summary, an elevated serum CEA level (≥5.0 ng/ml) was an independent prognostic determinant of survival in pN1 patients except for T3 and T4 cases. Therefore, even in completely resected pN1 non-small cell lung cancer, patients with a high CEA level might be candidates for multimodal therapy. However, further evaluation will be needed to determine the benefit of multimodal treatment in these patients.


   References
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Comment
 References
 

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