ANTICANCER RESEARCH 25: 3601-3606 (2005)
Serum Carcinoembryonic Antigen Level in pN1 Non-small Cell Lung Cancer Patients MASAKI TOMITA, YASUNORI MATSUZAKI, TETSUYA SHIMIZU, MASAKI HARA, TAKANORI AYABE and TOSHIO ONITSUKA
Department of Surgery II, Faculty of Medicine, University of Miyazaki, Japan
Abstract.
Background: Although the prognostic significance of the serum carcinoembryonic antigen (CEA) level in non-small cell lung cancer has been reported in several studies, it is unknown whether the serum CEA level is a prognostic determinant for pN1 disease or not. Materials and Methods: Seventy patients with pN1 nonsmall cell lung cancer who received complete resection were reviewed. The preoperative serum CEA level was measured in all patients. Results: The pN1 patients with pT2-4 disease, hilar node involvement, multiple N1 station and elevated serum CEA level (>5 ng/mL) had a significantly unfavorable prognosis. Although a serum CEA level higher than 5 ng/mL was not an independent prognostic determinant, more than 10 ng/mL was an independent factor by multivariate analysis. In patients with pT1-2N1 disease, a serum CEA level more than 10 ng/mL was also a prognostic determinant. Conclusion: An elevated serum CEA level, especially higher than 10 ng/mL, is a significant prognostic determinant for pN1 lung cancer patients. The existence of regional lymph node metastasis is the most important prognostic factor for resectable non-small cell lung cancer (NSCLC). According to the accepted pathological Tumor-Node-Metastasis (pTNM) staging (1), the 5-year survival rate of pN1 disease was 47%, an intermediate value between those of pN0 (56%) and pN2 (20%) (1). The number of studies regarding the postoperative prognosis of pN1 NSCLC is small, probably because of the relatively small number of patients. In recent years, however, many studies about pN1 NSCLC have appeared (2-9), indicating that pN1 disease has become cynosure.
Correspondence to: M. Tomita, Department of Surgery II, Faculty of Medicine, University of Miyazaki, Kihara 5200, Kiyotake, Miyazaki, 889-1692, Japan. Tel: 81-985-85-2291, Fax: 81-985-855563, e-mail:
[email protected] Key Words: Lung cancer, pN1, carcinoembryonic antigen.
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The carcinoembryonic antigen (CEA) is one of the most commonly used serum markers to date for NSCLC patients. Several reports have indicated that elevated preoperative serum CEA levels are associated with more advanced disease and with very poor survival after surgical resection (10-16). Although measurement of the serum CEA level is a classic examination, many recent studies have re-evaluated the prognostic significance of serum CEA level (17-23). Despite several studies on the prognostic significance of the serum CEA level, to our knowledge, there have been no studies that focused on the serum CEA level in pN1 disease. The purpose of this study was to evaluate the significance of the serum CEA level in pN1 NSCLC patients.
Materials and Methods The present study was conducted from 1990 through 2003, including all patients with lung cancer who had received complete resection, which consisted of either a lobectomy or a pneumonectomy, together with regional lymph node dissection. The pN1 was present when any hilar or lober node was histologically involved. Patients who did not receive complete resection, who died of other diseases within 5 years after surgery or who were lost to follow-up were excluded. A total of 70 lung cancer patients with pN1 disease, who fulfilled the inclusion criteria, were included in this study. There were 52 men and 28 women, whose ages ranged from 41 to 77 years, with an average of 65 years. The baseline characteristics and stage are summarized in Table I. The overall follow-up ranged from 12 to 168 months (mean 82.3 months). Clinical TNM (cTNM) staging was recorded for all patients, and was diagnosed using the following: chest roentgenography, chest computed tomography (CT), upper abdominal CT scan, brain magnetic resonance imaging and general bone scintigraphy. The 10-mm-thick contiguous sections were used to evaluate cN1 status. The clinical investigation section of our hospital measured the serum CEA levels using the two-site immunoenzymometric assay; with a normal upper limit of 5 ng/mL. The time-interval between serum CEA examination and staging or surgical resection was less than a month in all the patients. All surgically-resected tumors and lymph nodes were formalin-fixed and paraffin-embedded and routine pathological studies were performed.
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ANTICANCER RESEARCH 25: 3601-3606 (2005) Table I. Patient characteristics. No. of patients Age
65 > 65
10. 1 ng/mL). CEA; carcinoembryonic antigen.
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Age Gender Histology cN status pT status Side Location Serum CEA level N1 station Hilar node involvement Adjuvant therapy
Hazard Ratio 1.1659 0.9958 1.0527 1.1264 1.6307 1.3382 1.1515 1.6133 1.5324 1.8445 1.2480
95% CI 0.5949-1.2175 0.6990-1.4114 0.7415-1.4945 0.6252-1.2606 0.107-2.336 0.9425-1.9301 0.8086-1.6533 1.115-2.439 1.0544-2.1800 1.2958-2.6526 0.8534-1.9261
CI: confidence interval, CEA: carcinoembryonic antigen
p Value 0.3925 0.9810 0.7717 0.5021 0.0147 0.1035 0.4334 0.0105 0.0263 0.0007 0.2631
Tomita et al: CEA in pN1 Lung Cancer
Table III. Multivariate analysis. A Unfavorable
Favorable
Hazard Ratio
95% CI
p value
pT2-4 Multiple Involved 5ng/mL >
pT1 Single Not involved < 5ng/mL
1.2326 1.0970 1.4883 1.4059
0.5396-1.2358 0.7183-1.6702 0.9643-2.3010 0.9618-2.195
0.3226 0.6647 0.0725 0.0933
Factors
Unfavorable
Favorable
Hazard Ratio
95% CI
p value
pT status N1 station Hilar node Serum CEA level
pT2-4 Multiple Involved 10ng/mL >
pT1 Single Not involved < 10ng/mL
1.3006 1.2343 1.3917 1.5921
0.5139-1.1683 0.8027-1.8926 0.9043-2.1578 1.036-2.484
0.2125 0.3339 0.1329 0.0390
Factors pT status N1 station Hilar node Serum CEA level B
CI: confidence interval, CEA: carcinoembryonic antigen
No pre- or intra-operative chemotherapy was performed on any patient. Forty-nine patients received postoperative adjuvant therapies, as follows: radiation therapy in 5 patients, intravenous chemotherapy in 8 patients and oral administration of tegafur and uracil (UFT) in 36 patients. The follow-up information, including cause of death, was acquired through clinic follow-up notes and direct or family contact. Survival curves were obtained according to the KaplanMeier method. Comparison of survival curves was carried out using the log rank test. Factors related to prognosis were analyzed by multivariate analyses according to the Cox proportional hazards model. Statistical calculations were conducted with StatView (Abacus Comp. Inc., Berkley, CA, USA) and values of p less than 0.05 were accepted as significant.
Results The overall 5-year survival was 56.5%, and the 5-year survival rates of patients with normal and elevated serum CEA level were 75.10% and 41.90%, respectively (p=0.012). Patients were subdivided into 3 groups according to serum CEA level: (i) Normal group (group N): patients with serum CEA level less than 5 ng/mL; (ii) moderately-elevated group (group M): those 5.1 to 10 ng/mL; and (iii) highly-elevated group (group H): those more than 10.1 ng/mL. As shown in Figure 1, the 5-year survival rates of groups N, M and H were 75.10%, 49.43% and 30.77%, respectively (p=0.003). No significant differences in overall survival were found with regard to age (65> vs. 655 ng/mL) was not an independent prognostic factor by multivariate analysis. Furthermore, the relationship between elevated serum CEA level and patients’ survival did not reach statistical significance in patients with pT1-2N1M0 NSCLC. These results indicate that a serum CEA level of more than 5 ng/mL was not a strong prognostic determinant for pN1 NSCLC. In other words, there are some patient groups of pN1 NSCLC with favorable prognosis, in spite of elevated serum CEA levels. There is also a possibility that there are some patient groups whose elevated serum CEA levels are primarily attributable to other factors such as smoking status. In fact, a correlation between smoking and serum CEA level has been reported previously (26). Our results do, however, indicate that a serum CEA level higher than 10 ng/mL was an independent prognostic determinant for overall pN1 NSCLC patients. Furthermore, a serum CEA level of more than 10 ng/mL was also significantly related to patients’ survival in pT1-2N1M0 NSCLC. Therefore, it is suggested that the influence of smoking might be weaker in patients with serum CEA levels >10 ng/mL than those
