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Ann Thorac Surg 2002;74:174-179
© 2002 The Society of Thoracic Surgeons

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Original article: general thoracic

Serum carcinoembryonic antigen level in surgically resected clinical stage i patients with non-small cell lung cancer

^a Division of Surgery, Toneyama National Hospital, Toyonaka, Osaka, Japan
^c Division of Clinical Pathology, Toneyama National Hospital, Toyonaka, Osaka, Japan
^b Division of General Thoracic Surgery, Department of Surgery (E-1), Osaka University Graduate School of Medicine, Osaka, Japan

* Address reprint requests to Dr Sawabata, Division of Surgery, Toneyama National Hospital, 5-1-1 Toneyama, Toyonaka, Osaka 560-8552, Japan
e-mail: nori{at}toneyama.hosp.go.jp

Presented at the Poster Session of the Thirty-eighth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 28–30, 2002.

	Abstract

Top Abstract Introduction Patients and methods Results Comment References

 
Background. There is little general agreement concerning the effectiveness of serum carcinoembryonic antigen (CEA) as a prognostic indicator for non-small cell lung cancer (NSCLC) in clinical stage I patients. We conducted a retrospective study to investigate the relationship between serum CEA level and survival.

Methods. We assessed 297 consecutive patients with clinical stage I NSCLC who underwent surgical resection at Toneyama National Hospital from 1985 to 1998. Serum CEA levels were measured with an enzyme-linked immunosorbent assay kit with the upper limit of normal defined as 7.0 ng/mL based on the 95% specificity level for benign lung disease, in our hospital.

Results. There were 56 (19%) patients with serum CEA greater than 7.0 ng/mL. The high CEA group had a median survival time of 50 months and a 5-year survival rate of 49% compared with a 5-year survival rate of 72% (p < 0.0001) for the normal CEA group (n = 241). Patients with postoperatively high CEA levels (n = 15) had the worse prognosis (median survival time 35 months, and 5-year survival 18%) compared with patients whose levels returned to normal (n = 41, median survival time 8 8 months, and 5-year survival 68%; p = 0.01). These differences were also observed in patients with pathologic stage I or II tumors but not in those with pathologic stage III or IV tumors.

Conclusions. Serum CEA level is a useful predictor of survival for patients with clinical stage I NSCLC, and a persistently high CEA level after surgery is an especially strong indicator of a very poor prognosis.

	Introduction

Top Abstract Introduction Patients and methods Results Comment References

 
Carcinoembrionic antigen (CEA) is a tumor marker for substantial malignant tumors, including nonsmall cell lung cancer (NSCLC). Serum CEA is significantly elevated in 40% to 60% of patients with advanced NSCLC [1–3]. Evaluating serum CEA level is useful for monitoring response to chemotherapy and predicting relapse of advanced NSCLC [2].

Studies have investigated the relationship between preoperative serum CEA levels and prognosis among patients with operable NSCLC [1, 4–11]. These investigations reveal that a high preoperative serum CEA level is a significant poor prognostic factor. However, very few studies have looked into the relationship between postoperative serum CEA levels and prognosis.

In this study, we conducted a retrospective investigation to assess the relationship between perioperative serum CEA levels and surgical treatment outcomes for patients with clinical stage I NSCLC.

	Patients and methods

Top Abstract Introduction Patients and methods Results Comment References

 
We undertook a retrospective study using consecutive patients with clinical stage I NSCLC who underwent surgery at Toneyama National Hospital during the period 1985 to 1998. The data for this study were collected from medical records in which clinical stage had been diagnosed for all patients using the following: chest roentgenography, chest computed tomography (CT), abdominal CT scan, brain CT scan or magnetic resonance imaging, and general bone scintigraphy. Serum CEA level was measured as a part of the routine preoperative and postoperative evaluation. Postoperative serum CEA level was measured 3 months after surgery. The serum CEA level was calculated using an enzyme-linked immunosorbent assay (ELISA) kit with the upper limit of normal in our hospital defined as 7.0 ng/mL based on the 95% specificity level for benign lung disease.

Survival data were obtained by reviewing hospital records and by contacting patients or their families. All surviving patients were contacted by August 2001. Because clinical symptoms and radiographic studies are not sensitive enough to accurately diagnose early recurrence, the disease-free interval is difficult to calculate and thus survival is the major endpoint of this study. The survival duration was measured from the date of operation to the date of follow-up contact or death.

Sex, serum CEA levels, clinical stages, and tumor histology were chosen as preoperatively determined variables. We selected pathologic (p) stage and change in serum CEA level between preoperative time and 3 months after surgery as the postoperatively determined variables. P stage I or II was categorized as early stage and p stage III or IV as advanced stage. Alterations of serum CEA were defined as follows: normal—both preoperatively and postoperatively normal (N-N); returned to normal—preoperatively high but postoperatively normal (H-N); and persistently high—both preoperatively and postoperatively high (H-H).

Characteristics of the patients, surgery, and pathologic variables were compared using the t test, the ² test, or Fisher’s exact test as appropriate. Survival curves were obtained according to the Kaplan-Meier method. Comparison of survival curves was carried out using the log rank test. For multivariate analysis of Cox regression hazards model, sex, age, preoperative serum CEA level, clinical stage, and adenocarcinoma were used as preoperatively determined variables and p stage and alterations of serum CEA were used as postoperatively determined variables. Statistical calculations were conducted with Stat View (Abacus Comp. Inc. Berkley, CA) and values of p less than 0.05 were accepted as significant.

	Results

Top Abstract Introduction Patients and methods Results Comment References

 
Patient characteristics
Table 1 shows patients’ demographics, preoperative serum CEA level, clinical stage, tumor histology, location of tumor, and pattern of resection. In a comparison of patients with preoperative normal serum CEA level and patients with preoperative high serum CEA level, there were statistically significant differences in age and serum CEA level but not in other variables.

Analysis using preoperatively determined variables
Figure 1 shows survival curves for patients with preoperatively normal serum CEA level and patients with preoperatively high (> 7.0 ng/mL) serum CEA level. The normal CEA patients (n = 241) achieved a 72% 5-year survival rate and the high CEA patients (n = 56) achieved a 49% 5-year survival rate (p < 0.0001). Using multivariate analysis preoperatively high CEA level was shown to be an independently significant prognostic factor (hazard ratio = 1.4, 95% confidence interval [CI]: 1.2 to 1.8, p < 0.0001; Table 3).

View larger version (16K): [in this window] [in a new window]   Fig 1. Actuarial survival by preoperative serum carcinoembryonic antigen (CEA) level. Patients with normal (n = 241) preoperative serum CEA levels (<7.0 ng/mL) achieved a 72% 5-year survival rate and patients with high (n = 56) preoperative CEA levels (7.0 ng/mL) had a 49% 5-year survival rate (p < 0.0001).

View larger version (19K): [in this window] [in a new window]   Fig 2. Actuarial survival by postoperative serum carcinoembryonic antigen (CEA) level. Patients with persistently high serum CEA levels after surgery (Group H-H, n = 15) have an 18% 5-year survival rate (p < 0.0001) compared with a 68% 5-year survival rate for patients whose levels return to normal after surgery (Group H-N, n = 41) and a 72% 5-year survival rate for patients with normal levels before and after surgery (Group N-N, n = 241).

In an analysis of early stage patients, persistently high (H-H) serum CEA level was a statistically significant poor prognostic factor in univariate analysis. Patients with preoperatively high serum CEA levels (n = 44) had a 5-year survival rate of 58%, and patients with preoperatively normal serum CEA levels (n = 212) had a 5-year survival rate of 79% (p = 0.002; Fig 3). Figure 4 shows that patients with normal (N-N) serum CEA levels had a 5-year survival rate of 79%, patients whose high levels returned to normal (H-N) had a 5-year survival rate of 78%, and patients with persistently high (H-H) serum CEA levels had a median survival time of 29 months and a 5-year survival rate of 18% (p < 0.0001). Using multivariate analysis by these two variables, only H-H serum CEA level was an independently statistically significant prognostic factor (Table 6).

View larger version (16K): [in this window] [in a new window]   Fig 3. Actuarial survival by preoperative serum carcinoembryonic antigen (CEA) level for pathologic stage I or II disease. Patients with normal (n = 212) preoperative serum CEA levels (<7.0 ng/mL) achieved a 79% 5-year survival rate and patients with high (n = 44) preoperative levels ( 7.0 ng/mL) had a 41% 5-year survival rate (p = 0.002).

View larger version (19K): [in this window] [in a new window]   Fig 4. Actuarial survival by postoperative serum carcinoembryonic antigen (CEA) level for pathologic stage I or II disease. Patients with persistently high serum CEA levels after surgery (Group H-H, n = 10) had a 5-year survival rate of 18%, patients whose levels returned to normal after surgery (Group H-N, n = 34) had a 78% 5-year survival rate, and patients with normal levels before and after surgery (Group N-N, n = 212) had a 79% 5-year survival rate (p < 0.0001).

View larger version (16K): [in this window] [in a new window]   Fig 5. Actuarial survival by preoperative serum carcinoembryonic antigen (CEA) level for pathologic stage III or IV disease. Patients with normal (n = 29) preoperative serum CEA levels (<7.0 ng/mL) had a 29% 5-year survival rate, and patients with high (n = 12) preoperative levels (7.0 ng/mL) had a 28% 5-year survival rate (p = 0.6).

View larger version (18K): [in this window] [in a new window]   Fig 6. Actuarial survival by postoperative serum carcinoembryonic antigen (CEA) level for pathologic stage III or IV disease. Patients with persistently high serum CEA levels after surgery (Group H-H, n = 5) have a 5-year survival rate of 20%, patients whose levels returned to normal after surgery (Group H-N, n = 7) had a 36% 5-year survival rate, and patients with normal levels before and after surgery (Group N-N, n = 29) had a 29% 5-year survival rate (p = 0.9).

	Comment

Top Abstract Introduction Patients and methods Results Comment References

Several studies have found that the prognosis was poor for patients with preoperatively high serum CEA levels [1, 4, 7, 9, 10]. In the cases of clinical stage I disease, Icard and associates [9] reported that 7 patients with preoperatively high serum CEA levels had a 0% 5-year survival rate compared with a 49% 5-year survival rate for 35 patients with normal levels; and Hotta and associates [7] reported an approximately 50% 5-year survival rate for 9 patients with high serum CEA levels and an approximately 80% 5-year survival rate for 30 patients with normal levels. Our study showed that the 56 patients with preoperatively high serum CEA levels had a 49% 5-year survival rate compared with a 72% 5-year survival rate for the 241 patients with preoperatively normal levels. This finding suggests that even if a patient has clinical stage I NSCLC the prognosis is poor when the preoperative serum CEA level is high. This disadvantage might depend on the greater prevalence of advanced disease. In an analysis using postoperatively determined variables, however, persistently high serum CEA level after surgery was an independent prognostic factor as well as p-stage.

There is little information about the relationship between postoperative serum CEA level and prognosis. Dent and colleagues [13] whose subjects’ clinical disease stages ranged from I to III showed that patients with postoperatively high serum CEA levels had poor survival rates compared with those of patients with postoperatively normal levels. Yoshimatsu and associates [14] reported that CEA half-time after surgery reflected disease-free survival. Our study, which has patients with clinical stage I NSCLC only, shows that the patients with persistently high serum CEA levels had an 18% 5-year survival rate compared with a 68% 5-year survival rate for the patients whose high levels returned to normal, similar to that of the patients with preoperatively normal serum CEA levels. Additionally, a persistently high serum CEA level after surgery was an independent factor for poor prognosis in an analysis using patients with early stage disease only. Therefore a persistently high serum CEA level after surgery is an indicator of a very poor prognosis.

Patients with early stage NSCLC do not usually undergo induction therapy before surgery, although there are ongoing studies—BLOT study (phase II) [14] and S9900: Intergroup Lung Cancer Trial (phase III)—in which patients with early stage NSCLC are administered preoperative chemotherapy. Induction therapy is undertaken to improve survival for patients with NSCLC. If patients with stage I NSCLC having a preoperative high serum CEA level have a poor prognosis, it would be also reasonable for them to undergo induction therapy. Only postoperative persistently high serum CEA level was an independent factor in a multivariate analysis of patients with pathologically early stage disease. And so induction therapy for patients with a persistently high serum CEA level might be warranted even though predicting postoperative CEA level is not possible yet. Therefore it is important to find characteristics that can distinguish patients who will have persistently high serum CEA levels from patients whose levels will return to normal.

In conclusion, serum CEA level is useful for predicting survival of patients with clinical stage I NSCLC. And a persistently high serum CEA level after surgery is an especially strong indicator of a very poor prognosis. Further study into what characteristics can predict a persistently high serum CEA level after surgery is needed to identify these patients who have a poor prognosis.15

	References

Top Abstract Introduction Patients and methods Results Comment References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Noriyoshi Sawabata Shin-ichi Takeda Hajime Maeda Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sawabata, N. Articles by Maeda, H. Search for Related Content PubMed PubMed Citation Articles by Sawabata, N. Articles by Maeda, H. Related Collections Lung - cancer