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Ann Thorac Surg 2004;78:216-221
© 2004 The Society of Thoracic Surgeons

Original article: general thoracic

Prognostic significance of perioperative serum carcinoembryonic antigen in non-small cell lung cancer: analysis of 1,000 consecutive resections for clinical stage I disease

Morihito Okada, MD, PhDa*, Wataru Nishio, MD, PhDa, Toshihiko Sakamoto, MD, PhDa, Kazuya Uchino, MDa, Tsuyoshi Yuki, MDa, Akio Nakagawa, MDa, Noriaki Tsubota, MD, PhDa

a Department of Thoracic Surgery, Hyogo Medical Center for Adults, Akashi City, Hyogo, Japan

Accepted for publication February 3, 2004.

* Address reprint requests to Dr Okada, Department of Thoracic Surgery, Hyogo Medical Center for Adults, Kitaohji-cho13-70, Akashi City 673-8558, Hyogo, Japan
e-mail: morihito1217jp{at}aol.com


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 References
 
BACKGROUND: The prognostic implication of serum carcinoembryonic antigen (CEA) has yet to be comprehensively analyzed since the reports available so far have comprised small patient populations. We evaluated perioperative CEA values with regard to surgical results in a large number of patients to clarify its merit.

METHODS: We measured serum CEA levels before and after surgery in 1,000 consecutive patients with clinical stage I non-small cell lung cancer who underwent resection of tumor. High CEA value was greater than 5.0 ng/mL.

RESULTS: Three hundred and sixty-eight patients (36.8%) had high preoperative CEA levels. The CEA levels after surgery were normalized in 242 patients (24.2%) and persistently elevated in 126 patients (12.6%). High CEA levels were seen more frequently in patients with older age, male gender, larger size of tumor, incomplete resection, and advanced pathologic stage. Patients with a high preoperative CEA level had a poor survival. Among these patients, even worse survival was seen for those with a high postoperative CEA level. These prognostic trends were still observed for patients with pathologic stage I disease. Multivariate analysis demonstrated that both preoperative and postoperative CEA levels were independent prognostic determinants (p = 0.0243 and p < 0.0001, respectively).

CONCLUSIONS: Perioperative measurement of serum CEA concentrations yields information valuable for detecting patients at high risk of poor survival. Normalization of CEA levels after surgery was a significant favorable prognostic sign in patients with an elevated CEA level before surgery. Even after apparently successful surgical therapy, patients with a high CEA level should be carefully followed up, and might represent a suitable target for neoadjuvant clinical trials.


   Introduction
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 Abstract
 Introduction
Material and methods
 Results
 Comment
 References
 
Although the international TNM classification system is the key to planning therapy options in patients with non-small cell lung cancer and is considered the best available prognostic predictor, its power is limited. Among patients within the same TNM group of risk, we have often encountered differences between expected and real surgical results following curative resection. Owing to the possible concept that response to treatment or prognosis may be based on inherent biological characteristics of cancer cells, we should rapidly expand methods for the description of biological tumor aggressiveness.

Presently, the idea that serum biomarkers are helpful in the management of lung cancer is not uniformly accepted. In 1997, the American Thoracic Society and The European Respiratory Society jointly published guidelines [1] for assessment of non-small cell lung cancer, indicating that no serum tumor markers had sensitivity and specificity sufficient to reliably detect occult disease or influence treatment. Finally, they did not recommend routine measurement of any biomarkers in the screening, staging, or evaluation of disease progression.

Carcinoembryonic antigen (CEA) represents a heterogeneous group of oncofetal glycoprotein antigens, which circulate in high concentrations in patients with certain malignancies. Because of reports of its low sensitivity and specificity as a tumor marker, CEAs have played a less valuable role in the diagnosis, management, and prognosis of non-small cell lung cancer than has been the case with most other common cancers [2]. Routine measurement of serum CEA levels is not widely performed before or after resection for non-small cell lung cancer, particularly in the United States. However, several reports suggested that increased preoperative serum CEA levels were associated with more advanced disease and with poor survival after presumptively curative resection [3–7]. Carcinoembryonic antigen assay may be a useful serum test that could correlate with aspects of tumor biological aggressiveness not measured by conventional modalities. This capacity has yet to be intensively investigated since reports published thus far have dealt with small patient populations. The present study, which consisted of consecutive series of numerous patients, was undertaken to analyze the biology plausibility of CEA as a predictive method by associating increase in its levels with clinical characteristics of patients and pathologic findings, and to evaluate the independent prognostic significance of perioperative CEA values. In addition, some reports indicated that non-small cell lung cancer patients, with a serum CEA level higher than 50 ng/mL, all died within a few years, even if apparently curative surgery was performed [3, 7, 8]; we examined follow-up data for such patients in our series.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 References
 
From January 1985 to December 2002, we measured serum CEA levels before and after surgery in 1,000 consecutive clinical stage I patients who underwent resection for primary non-small cell lung cancer. Institutional review board approval was obtained for collecting the data in a secure database and reporting on its analyses. Patients who had preoperative chemotherapy or radiotherapy were excluded. For preoperative evaluation or clinical staging, we used a detailed history and physical examination, biochemical profile, chest roentgenogram examination, bronchoscopy, computed tomography of the chest, brain, and upper portion of the abdomen, and bone scintigraphy. Staging was determined according to the international TNM staging system [9]. Intraoperative staging was performed by dissecting intrapulmonary, hilar, and mediastinal lymph nodes, and careful postoperative examination was carried out by pathologists. The histologic type of the tumor was determined using the World Health Organization classification. There were 644 males and 356 females, ranging in age from 15 to 88 years (mean, 64.5 ± 10.1 years). The average size of tumor was 28.4 ± 15.1 mm. Histologic diagnosis was adenocarcinoma in 694 patients, squamous cell carcinoma in 260, large cell carcinoma in 18, carcinoid in 15 and adenosquamous carcinoma in 13. The surgical procedure was lobectomy in 660 patients, segmentectomy in 261, wedge resection in 75, and pneumonectomy in 4, and the rate of curative resection reached 93.3%. Pathologic stage was I in 695 patients, II in 119, III in 167, and IV in 19. Patient characteristics and pathologic stage are summarized in Tables 1 and 2, respectively.


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  		Table 1. Characteristics of Patients With Clinical Stage I Non-Small Cell Lung Cancer (n = 1,000)

 

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  		Table 2. Pathologic TNM Stage of Patients With Clinical Stage I Non-Small Cell Lung Cancer (n = 1,000)

 
Blood sampling was performed within the 1-month period preceding surgery and 1 month after surgery. The serum CEA level of all blood samples was measured by the enzyme immunoassay method (Fuji Rebio, Tokyo, Japan). According to the manufacturer, the average for this assay in healthy individuals is 1.93 ng/mL and the upper limit of normal is 5.0 ng/mL. Patients were categorized according to shift of CEA levels by surgery as follows: continuously normal (N group), continuously high (HH group), or returned to normal range (HN group).

After surgery, the patients were in general examined at 3-month intervals for 5 years and thereafter at 1-year intervals. The evaluations included physical examination, chest roentgenography, and tumor markers. Moreover, chest, abdominal, and brain computed tomographic scans and a bone scintiscan were carried out each year. Whenever any symptoms or signs of recurrence appeared in these examinations, further evaluations to detect disease were performed.

The statistical significance of differences between the classified groups and several clinical-pathologic factors was assessed by the Kruskal-Wallis test. Survival was calculated by the Kaplan-Meier method, and differences in survival were determined by log-rank analysis. A multivariate analysis of several prognostic factors was carried out using Cox's proportional hazards regression model. Zero time was the date of pulmonary resection, and the terminal event was death attributable to cancer, noncancer, or unknown cause. Significance was defined as p less than 0.05.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 References
 
Among 1,000 patients with clinical stage I non-small cell lung cancer, 632 (63.2%) had a normal preoperative CEA level (N group) and 368 (36.8%) had a high one. Of the latter 368 patients, postoperative evaluations of CEA revealed a return to normal range in 242 patients (HL group) and unchanged at a high level in 126 (HH group). The distributions of the previously mentioned groups according to age, gender, size of tumor, histologic type, surgical procedure, and resectability are shown in Table 1. Older age, male gender, larger size of tumor, and incomplete resection were frequently observed in patients with a high postoperative CEA level, particularly in the HH group. Moreover, the HH group exhibited more advanced disease than not only the N group but also the HN group (Table 2).

Next, we analyzed the affect of serum CEA level on survival. Overall follow-up ranged from 8 to 224 months, with a median of 61 months for surviving patients. The 5-year survival rates were 75.2% and 53.8% for patients with normal and high preoperative CEA levels, respectively (Fig 1A). The survival rate was significantly poorer for patients with a high preoperative CEA level (p < 0.0001). In addition, we investigated the survival rates for groups subdivided by preoperative CEA levels (Fig 1B). The higher the preoperative CEA level, the poorer survival was, even within the normal range. When we also considered postoperative CEA levels, the survival rates for 5 years in the HH group and HN group were 35.2% and 62.6%, respectively (p < 0.0001, Fig 2A). In general, patients with pathologic stage I disease are assumed to have been cured following complete resection of the tumor because lymph nodes are not involved. However, we found that a considerable number of patients with still elevated CEA levels had poor survival despite being postoperatively diagnosed as having pathologic stage I disease. The 5-year survival rates of pathologic stage I patients of the N group, the HL group, and the HH group were 84.2%, 74.2%, and 48.6%, respectively (Fig 2B). These data suggested that failure to normalize CEA levels after surgery was associated with a significantly worse prognosis, and that the survival, even of patients with pathologic stage I disease for 5 years, was less than 50%.



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  		Fig 1. Cumulative survival curves for patients with clinical stage I non-small cell lung cancer according to preoperative serum CEA values (A) (— = CEA ≤ 5.0 ng/mL [n = 632]; · · · = CEA ≥ 5.1 ng/mL [n = 368]). In addition, the study groups were subdivided by serum CEA levels (B) (— = CEA; ≤ 2.5 ng/mL [n = 269]; – – = CEA; 2.6 to 5.0 ng/mL [n = 363]; – · = CEA; 5.1 to 10.0 ng/mL [n = 244]; · · · = CEA; ≥ 10.1 ng/mL [n = 124]). (CEA = carcinoembryonic antigen.)

 


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  		Fig 2. Cumulative survival curves for patients with clinical stage I non-small cell lung cancer (A) (— = N group [n = 632]; – – = HN group [n = 242]; · · · = HH group [n = 126]), and of patients with pathologic stage I non-small cell lung cancer (B) (— = N group [n = 472]; – – = HN group [n = 154]; · · · = HH group [n = 69]). According to change in serum CEA values before and after surgery, patients were classified into three groups; continuously normal (N group), returned to normal range (HN group), and continuously high (HH group). (CEA = carcinoembryonic antigen.)

 
Univariate analyses demonstrated that not only male gender (p < 0.0001), age older than 65 years (p = 0.0001), tumor size larger than 30 mm (p < 0.0001), advanced pathologic stage (p < 0.0001), and incomplete resectability of the tumor (p < 0.0001), but also a high CEA level before (p < 0.0001) and after surgery (p = 0.0001) significantly and negatively affected survival. Using these variables we performed multivariate analyses for the prognostic significance of CEA values to be strongly emphasized. Multivariate Cox analysis for preoperative determined factors demonstrated that CEA level (p = 0.0243) as well as gender (p = 0.0003), age (p < 0.0001), and size of tumor (p < 0.0001) were independent, significant prognostic determinants (Table 3). Furthermore, analysis for postoperative determined factors revealed that CEA level (p < 0.0001) as well as pathologic stage (p < 0.0001), and resectability of the tumor (p = 0.0097) were independent, significant prognostic variables (Table 4).


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  		Table 3. Multivariate Analysis of Prognostic Factors With Preoperative Determined Variables (n = 1,000)

 

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  		Table 4. Multivariate Analysis of Prognostic Factors With Postoperative Determined Variables in Patients With a High Preoperative CEA Value (n = 368)

 
Last, we examined the follow-up data for patients with preoperative CEA level greater than 50 ng/mL (Table 5). There were 13 patients (1.3%) belonging to this category among 1,000 patients diagnosed as having clinical stage I disease. Of them, 9 (69%) had distant metastasis as initial recurrence, and had already died of cancer. Interestingly, 3 patients (23%) in this category are alive more than 5 years without recurrence.


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  		Table 5. Characteristics and Surgical Results of C-stage I Patients with Preoperative CEA Values Greater than 50 ng/mL (n = 13)

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
References
 
The genuine question examined in this study was whether patients who otherwise appeared to have curable tumors would have a worse prognosis if serum CEA value was high. In our series, the results yielded by univariate and multivariable analyses demonstrated that both preoperative and postoperative serum CEA values had a strong impact on survival. In addition, multivariate analysis for postoperative factors showed that CEA values as well as pathologic TNM stage and resectability of tumor were significant, important predictive variables affecting survival. Results suggested that CEA values did not simply reflect tumor load but were independent prognostic factors per se and might serve to stratify patients within the same TNM stage after complete resection. One of the most interesting issues is to the prognosis of patients with only a serum high CEA value, particularly of those who otherwise underwent curative surgery for proven early-stage cancer. It was surprising that 5-year survival rate was less than 50% for patients with a still elevated postoperative CEA level diagnosed as having pathologic stage I disease after apparently complete resection of tumor.

We have provided powerful evidence that completeness of removal of the tumor is essential. It would be of concern if patients whose disease was judged to be incompletely resected actually had similar survival to those with completely resected disease. As well as the prognostic advantage seen in completely resected patients, a higher proportion of patients with elevated CEA levels before surgery had a return to normal range in CEA level. In our series, CEA levels returned to normal range in approximately 66% of patients, which we believe will get better with further experience and practice. We suspect that failure to achieve normal levels of CEA is caused either by unrecognized extrapulmonary disease or failure to eradicate all pulmonary disease.

Icard and colleagues [7] reported that all patients with preoperative CEA levels higher than 50 ng/mL who underwent seemingly curative resection for non-small cell lung cancer died within 2 years. Earlier, Concannon and colleagues [3] demonstrated that all 47 patients who had resected lung cancer and high CEA levels failed to survive longer than 3 years. The most interesting inquiry was whether a preoperative CEA level higher than 50 ng/mL always indicated metastatic carcinoma, or whether thoracic surgeons would accept the validity of CEA testing to exclude patients who have such an abnormally elevated level from undergoing lung resections. In our analysis, it should be emphasized that 69% (9 of 13) of clinical stage I patients with preoperative CEA greater than 50 ng/mL developed distant metastasis and died of cancer. Despite these poor survival data, we still have concern about giving up surgical therapy in clinical stage I lesions even if they have an excessively high CEA level. To our surprise, among patients with preoperative CEA higher than 50 ng/mL, 3 (23%) were long-term survivors with no recurrence. One patient had a 427.8 ng/mL CEA level before surgery but a remarkable drop after surgery. The CEA levels of the other 2 patients normalized postoperatively. It is of great interest to note that normalization of serum CEA level after surgery was an important prognostic sign even in patients with an abnormally elevated CEA level before surgery.

A point will be reached when the risk signaled by serum CEA value may be greater than the risk indicated by a more advanced TNM stage. In other words, when a patient has had extremely high CEA levels, the influence of CEA on prognosis might be more crucial than the influence of TNM stage. This emphasizes the need to avoid dichotomous results (positive vs negative) at least in cases in which CEA is employed to estimate prognosis. It seems more satisfactory to use CEA as a continuous variable since this would enable any predictive information to be more effectively utilized. Although a cutoff point is usually used to define a high or low risk group of patients, this method tends to oversimplify and even distort the associations between variables and results.

At present, perioperative measurement of serum CEA is not commonly performed during the staging or resection of tumors in patients with non-small cell lung cancer. This study describes the significant independent value of serum CEA in patients undergoing stage determination, undergoing resection, or considering adjuvant therapy for non-small cell lung cancer. Unfortunately, this has not gained universal acceptance with physicians or surgeons, particularly in the United States.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 References
 

  1. Pretreatment evaluation of non-small-cell lung cancer. Official statement of The American Thoracic Society and The European Respiratory Society. Am J Respir Crit Care Med 1997;156:320–2
  2. Carcinoembryonic antigen: its role as a marker in the management of cancer. Br Med J 1981;282:373–5
  3. Concannon J.P., Dalbow M.H., Hodgson S.E., et al. Prognostic value of preoperative carcinoembryonic antigen (CEA) plasma levels in patients with bronchogenic carcinoma. Cancer 1978;42:1477-1483.[Medline]
  4. Ford C.H., Stokes H.J., Newman C.E. Carcinoembryonic antigen and prognosis after radical surgery for lung cancer: immunocytochemical localization and serum levels. Br J Cancer 1981;44:145-153.[Medline]
  5. Dent P.B., McCulloch P.B., Wesley-James O., et al. Measurement of carcinoembryonic antigen in patients with bronchogenic carcinoma. Cancer 1978;42:1484-1491.[Medline]
  6. 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 2003;74:174-179.
  7. Icard P., Regnard J.F., Essomba A., et al. Preoperative carcinoembryonic antigen level as a prognostic indicator in resected primary lung cancer. Ann Thorac Surg 1994;58:811-814.[Abstract]
  8. Sadoff L. The usefulness of carcinoembryonic antigen testing in the overall management of patients with non-small-cell lung cancer. Am J Clin Oncol 1998;21:284-286.[Medline]
  9. Mountain C.F. Revisions in the International System for Staging Lung Cancer. Chest 1997;111:1710-1717.[Abstract/Free Full Text]



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