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Eur J Cardiothorac Surg 2007;32:435-439. doi:10.1016/j.ejcts.2007.05.014
Copyright © 2007, European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved

Prognostic value of carcinoembryonic antigen and CYFRA21-1 in patients with pathological stage I non-small cell lung cancer

Katsunari Matsuoka*, Shinichi Sumitomo, Nariyasu Nakashima, Daisuke Nakajima, Noriyuki Misaki

Department of Thoracic Surgery, Japanese Red Cross Society Wakayama Medical Center, Japan

Received 2 February 2007; received in revised form 9 May 2007; accepted 23 May 2007.

* Corresponding author. Address: 640-8550 Komatsubara-Tori 4-20, Wakayama City, Wakayama, Japan. Tel.: +81 73 422 4171; fax: +81 73 426 1168. (Email: katccha{at}hera.eonet.ne.jp).


   Abstract
Top
 Abstract
1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 
Background: The aim of this retrospective study was to assess the prognostic value of serum tumor markers (carcinoembryonic antigen (CEA) and CYFRA21-1) in patients with pathologic (p-) stage I non-small cell lung cancer (NSCLC) undergoing complete resection. Methods: Two hundred and seventy-five patients (163 males, 112 females, mean age 67.1 years) with p-stage I NSCLC who underwent complete resection at our institution between April 1999 and October 2004 were examined. Patients who had received preoperative chemotherapy or radiotherapy were excluded, as were patients who had multiple malignancies including multiple lung cancer. The serum levels of tumor markers were measured using commercially available immunoassays within 1 month before surgical resection. Serum levels of CEA and CYFRA21-1 higher than 5.0 and 2.8 ng/ml, respectively, were considered as positive according to the manufacture's instructions. Results: The histological classification was adenocarcinoma in 193 patients, squamous cell carcinoma in 71, large cell carcinoma in 5, and other histological type in 6. One hundred and fifty-seven patients had T1 disease and 118 patients had T2 disease. The positive ratio of CEA and CYFRA21-1 was 25.7% and 13.7%, respectively, and in relation to histological type was 27.8% and 7.8% in adenocarcinoma, and 20.6% and 28.4% in squamous cell carcinoma. The overall 5-year survival rate was 79.3%. With a median follow-up of 35.5 month for surviving patients, those with initial CYFRA21-1 serum levels higher than 2.8 ng/ml had a significantly worse prognosis (p = 0.0041). Patients with an elevated preoperative CEA level exceeding 5.0 ng/ml had a shorter disease-free survival period (p = 0.0003). In patients with adenocarcinoma, a CEA level above 5.0 ng/ml was associated with shorter survival and early recurrence, whereas CYFRA21-1 showed no such association. In patients with squamous cell carcinoma, elevated preoperative CEA was not related to survival and recurrence. In these patients, preoperative CYFRA21-1 level exceeding 2.8 ng/ml was associated with a poorer outcome, whereas preoperative CYFRA21-1 level was not associated with cancer recurrence. Conclusion: The patients with p-stage I adenocarcinoma whose preoperative CEA level was high might be considered as good candidates for adjuvant chemotherapy. The prognostic value of CYFRA21-1 could not be confirmed for stage I NSCLC, and preoperative CYFRA21-1 level was not useful in selecting the candidates for adjuvant chemotherapy.

Key Words: Lung cancer • Tumor markers • Outcomes • Surgery


   1. Introduction
Top
 Abstract
 1. Introduction
2. Patients and methods
 3. Results
 4. Discussion
 References
 
Pathological (p-) stage I non-small cell lung cancer (NSCLC) is considered to represent early disease, and no further therapy is recommended for NSCLC stage I patients who undergo complete resection. However, the 5-year survival rate at this stage has been reported to be only 60–70%, which is still unsatisfactory. Recently, several meta-analyses have revealed that adjuvant chemotherapy is effective even in stage I patients [1]. However, it remains unknown which patients might benefit from systemic treatment such as adjuvant chemotherapy. Therefore, it is required that prognostic factors that would be useful for identifying those patients who are at increased risk and require adjuvant chemotherapy are clarified.

There is growing evidence that tumor markers provide prognostic information in patients with NSCLC [2]. It has been shown that patients with elevated marker levels have a higher hazard ratio than patients with normal levels of marker expression. Therefore, we investigated prognostic factors for patients undergoing complete resection of stage I NSCLC and demonstrated the prognostic significance of the tumor markers carcinoembryonic antigen (CEA) and CYFRA21-1.


   2. Patients and methods
Top
 Abstract
 1. Introduction
 2. Patients and methods
3. Results
 4. Discussion
 References
 
Between April 1999 and October 2004, 596 NSCLC patients underwent complete surgical resection at our institution. Of these patients, 368 were defined as having stage I disease by pathological examination. Patients who had received induction chemotherapy or radiotherapy before surgery were excluded, as were patients who had multiple primary lung cancer or a history of cancers in other organs, as other malignancies might have affected to the values of preoperative tumor markers. A final total of 275 patients were entered into the current retrospective study. For clinical staging, all patients underwent a physical examination; chest radiography; computed tomography of the thorax, brain, and upper abdomen; bone scintigraphy; and fiberbronchoscopy preoperatively. All of the patients underwent total dissection or sampling of the regional lymph nodes (ipsilateral hilar and mediastinal lymph nodes). The diagnosis of lung cancer was confirmed by pathological examination and classified according to the World Health Organization criteria. The postoperative tumor stage was determined using the revised International System for Staging of Lung Cancer. Last actualization of survival data was done in September 2005. All patients except 10 were completely followed. The median follow-up period for survival patients was 35.5 month (3.7–75.5 months).

The characteristics of the study population are listed in Table 1 . One hundred and sixty-three patients were male and 112 were female. The mean age was 67.1 years (range 18–90 years). The histological classification was adenocarcinoma in 193 patients, squamous cell carcinoma in 71, large cell carcinoma in 5, adenosquamous cell carcinoma in 3, and other histological types in 3. One hundred and fifty-seven patients had pathological T1 disease and 118 had pathological T2 disease. Two hundred and thirty-four patients underwent lobectomy and 41 underwent smaller resections, including segmentectomy in 19 and wedge resection in 22.


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  		Table 1 Patients’ characteristics and the results of univariate survival analysis
 
Forty-five patients suffered tumor recurrence during follow-up. The site of recurrence sites was the lung in 21 patients, the brain in 5, bone in 4, liver in 3, trachea/bronchus in 3, pancreas in 2, and other site in 7. Thirty-two patients died during follow-up: 21 of lung cancer and 11 of other diseases.

Blood samples for measuring CEA and CYFRA21-1 levels were collected within 1 month before surgery. The serum levels of tumor markers were measured using commercially available immunoassay ELISA kit. The serum levels of CEA and CYFRA21-1 were considered to be elevated when they exceeded 5.0 and 2.8 ng/ml, respectively, according to the manufacture's instructions (CEA: Wako, Japan, CYFRA21-1: Roche Diagnostics). Preoperative CEA and CYFRA21-1 values could not be found in the clinical records in 18 and 19 cases, respectively.

Survival curves were calculated using the Kaplan–Meier method, and comparisons among the survival curves were made using the log-rank test. Counts were compared using the chi-square test. Continuous data were compared using the unpaired T-test or the Mann-Whitney U-test. Multivariate analysis of prognostic factors was performed using the Cox proportional hazards model. Differences at p < 0.05 were considered to be significant. Statistical analysis was performed using the StatView 5.0 software package (SAS Institute Inc., NC, USA).


   3. Results
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
4. Discussion
 References
 
Sixty-six patients had an elevated preoperative CEA level (over 5.0 ng/ml) and 191 had a normal CEA level. The preoperative CYFRA21-1 level was elevated in 35 patients (over 2.8 ng/ml) and normal in 221 patients. The positive ratio of CEA and CYFRA21-1 in p-stage I NSCLC patients was 25.7% and 13.7%, respectively. The positive ratio of CEA and CYFRA21-1 differed according to histological type, being 27.7% and 7.8% in patients with adenocarcinoma, and 20.6% and 28.4% in patients with squamous cell carcinoma, respectively. Although the positive ratio of CEA did not differ between adenocarcinoma and squamous cell carcinoma, that of CYFRA21-1 was significantly higher in squamous cell carcinoma than in adenocarcinoma (p < 0.0001) (Table 2 ).


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  		Table 2 The distribution of CEA and CYFRA according to histological type
 
The overall 5-year survival rate was 79.3%. With a median follow-up of 35.5 months for surviving patients, those with initial serum CYFRA21-1 levels higher than 2.8 ng/ml had a significantly worse outcome (p = 0.0041) (Fig. 1 ). Univariate survival analysis demonstrated that sex, smoking, and the preoperative CYFRA21-1 level were associated with outcome of patients with p-stage I NSCLC (Table 1). Patients with an elevated preoperative CEA level exceeding 5.0 ng/ml tended to show shorter survival, but not to a significant degree. (Fig. 1) Otherwise, patients with a high preoperative CEA level had shorter disease-free survival period (p = 0.0003), whereas a high preoperative CYFRA21-1 level had no effect on disease-free survival (Fig. 2 ). Multivariate analysis showed that the preoperative CYFRA21-1 level was correlated to survival of patients with p-stage I NCSLC significantly (Table 3 ).


Figure 1
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  		Fig. 1. Survival curves of p-stage I NSCLC patients according to the level of CEA and CYFRA.

 

Figure 2
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  		Fig. 2. Disease free curves of p-stage I NSCLC patients according to the level of CEA and CYFRA.

 

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  		Table 3 Multivariate analysis: Cox proportional hazards model
 
To further investigate the prognostic value of CEA and CYFRA21-1, we examined the patients with p-stage I NCSLC according to histological type. In patients with adenocarcinoma, a CEA level exceeding 5.0 ng/ml was associated with shorter survival and early recurrence, whereas CYFRA21-1 was not associated with survival and recurrence. Otherwise, in patients with squamous cell carcinoma, CEA was not associated with survival and recurrence. CYFRA21-1 level exceeding 2.8 ng/ml was associated with a poor outcome, whereas high CYFRA21-1 level was not associated with cancer recurrence in patients with squamous cell carcinoma (Table 4 ).


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  		Table 4 Five-year disease free rate and 5-year survival rate according to the level of CEA and CYFRA for patients with adenocarcinoma and squamous cell carcinoma
 
Multivariate analyses showed that CEA had no significant association with outcome of patients with p-stage I adenocarcinoma (p = 0.0804). However, CEA had significant association with cancer relapse of patients with p-stage I adenocarcinoma (p = 0.0027) (Table 5 ).


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  		Table 5 Multivariate analyses for survival and cancer relapse in patients with p-stage I adenocarcinoma (Cox proportional hazard model)
 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
References
 
CEA and CYFRA21-1 have been reported to have the prognostic value for NSCLC. However, the majority of previous studies on the prognostic value of CEA and CYFRA21-1 were performed on NSCLC patients at all stages of disease, including both early and advanced. Therefore, to investigate the prognostic value of CEA and CYFRA21-1 without the influence of pathological stage, we included only patients who had undergone complete resection for p-stage I NSCLC, which is considered to represent a relatively homogeneous group in terms of prognosis.

Several studies [3–10] have reported the prognostic significance of CYFRA21-1 for NSCLC. Similar to previous reports, our univariate and multivariate analyses demonstrated that CYFRA21-1 was significantly correlated with prognosis of patients with p-stage I NCSLC. Up to now, however, the prognostic impact of the preoperative CEA level has been controversial. Some authors have reported that CEA has prognostic value for patients after resection of NCSLC [11–17]. In contrast, other studies have found that an elevated preoperative CEA level is only marginally predictive or completely lacking in prognostic value [5,8,10]. In the present study, patients with a high preoperative CEA value tended to have a worse outcome, but this failed to reach statistical significance. The differences in the prognostic value of the preoperative CEA level among the studies may have been due to the use of different patient populations. Most studies of the prognostic value of tumor markers have suffered from broad heterogeneity with respect to tumor stage, histology, and treatment. Therefore, we investigated the prognostic value of CEA and CYFRA21-1 according to tumor histology. Univariate survival analyses showed that the preoperative CEA level was associated with prognosis of patients with p-stage I adenocarcinoma, but was unrelated to survival in patients with squamous cell carcinoma. Therefore, if the number of patients with squamous cell carcinoma is high in a study population, then the prognostic power of preoperative CEA may be reduced. Indeed, Tomita et al. [18] and Nisman et al. [19] have reported that an elevated preoperative CEA level was a favorable prognostic factor for patients with adenocarcinoma, whereas it was unrelated to survival of patients with squamous cell carcinoma. Kulpa et al. [20] also demonstrated that the preoperative CEA level was unrelated to survival in patients with squamous cell carcinoma. Some studies that have demonstrated the prognostic value of the preoperative CEA level, a classical marker for adenocarcinoma, have tended to include a relatively high proportion of adenocarcinoma.

In this study, the preoperative CEA level was also correlated with early recurrence in patients with p-stage I NCSLC. Although the preoperative CYFRA21-1 level was shown to have a significant correlation with prognosis in these patients, it was not correlated with cancer recurrence. Although further investigation is needed to identify the role of CYFRA21-1 in predicting tumor relapse and prognosis, a possible explanation for these inconsistent findings is that the preoperative CYFRA21-1 level was higher in patients who were heavy smokers. Patients with a preoperative CYFRA21-1 level exceeding 2.8 ng/ml smoked significantly larger amounts of cigarettes than those with a preoperative CYFRA21-1 level below 2.8 ng/ml (59.0 ± 38.6 vs 33.0 ± 37.0 pack-years, p = 0.0002). Therefore, patients with a high CYFRA21-1 level might have poor respiratory function due to habitual heavy smoking, and thus a higher ratio of deaths that are unrelated to cancer recurrence. Moreover, the CYFRA21-1 level is reportedly higher in patients with benign lung disorders such as pneumonia and pulmonary fibrosis. [21] Thus, patients with a high preoperative CYFRA21-1 level might have various lung disorders that would predispose them to die of the pulmonary diseases other than lung cancer.

In conclusion, the prognostic value of CEA differs according to the histological type of lung cancer. Patients with p-stage I adenocarcinoma and a high preoperative CEA value showed a shorter disease-free period and a lower 5-year survival rate, whereas the CEA level was not predictive of survival or recurrence in patients with p-stage I squamous cell carcinoma. Although the preoperative CYFR21-1 level was significantly related to the survival of patients with NSCLC, it was not related to cancer recurrence even in patients with squamous cell carcinoma. Although several studies have claimed that CYFRA21-1 is a valuable prognostic determinant in patients with NSCLC, the present retrospective study failed to demonstrate that it had any prognostic value in patients with stage I NSCLC. Therefore, patients with p-stage I adenocarcinoma who have a high preoperative CEA level might be considered good candidates for adjuvant chemotherapy. The preoperative CYFRA21-1 level did not appear useful for selecting candidates for adjuvant chemotherapy.


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

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