Carcinoembryonic Antigen Level in Serum and ...

Original Thoracic

Carcinoembryonic Antigen Level in Serum and Pleural Lavage Fluid in Non-Small Cell Lung Cancer

Authors

M. Tomita, T. Shimizu, T. Ayabe, A. Yonei, T. Onitsuka

Affiliation

Surgery II, University of Miyazaki, Miyazaki, Japan

Key words " thoracic surgery l " lung cancer l " CEA l " survival l " non‑small cell lung cancer l

Abstract

received

January 5, 2010

Bibliography DOI http://dx.doi.org/ 10.1055/s-0030-1250025 Thorac Cardiov Surg 2010; 58: 350–353 © Georg Thieme Verlag KG Stuttgart · New York · ISSN 0171‑6425 Correspondence Dr. Masaki Tomita Surgery II University of Miyazaki Kihara 5200, Kiyotake 889-1692 Miyazaki Japan Phone: + 81 9 85 85 22 91 Fax: + 81 9 85 85 55 63 [email protected]

Background: This study evaluates the tumor marker index (TMI) based on carcinoembryonic antigen (CEA) levels in serum and pleural lavage fluid as a potential prognostic determinant for patients with non-small cell lung cancer (NSCLC). Materials and Methods: Three hundred and eighty-three consecutive NSCLC patients were reviewed retrospectively. Results: The 5-year survival of patients with normal and high serum CEA levels was 71.78 % and 51.38 %, respectively (p < 0.0001). The 5-year sur-

vival of patients with high CEA levels in pleural lavage fluid was 25.0 %, which was significantly poorer compared with that of patients with normal lavage CEA levels (78.23 %, p < 0.0001). There was a 5-year survival rate of 73.75 % in patients with a TMI less than or equal to 1.0 compared to a rate of only 55.12 % in patients with a TMI greater than 1.0 (p < 0.001). Both univariate and multivariate analyses indicated the independent prognostic impact of the TMI. Conclusions: The TMI based on serum and lavage CEA levels might be useful for predicting the prognosis of NSCLC patients.

Introduction

Patients and Methods

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Prognostic indicators for non-small cell lung cancer (NSCLC) patients traditionally include TNM staging, pleural lavage cytology [1–4], and serum carcinoembryonic antigen (CEA) levels [5–8]. In addition, we previously reported on the prognostic significance of CEA levels in pleural lavage fluid (lavage CEA) for patients with lung adenocarcinoma [9]. Both serum and lavage CEA levels have been shown to be of prognostic value. However the combined evaluation of these is often difficult. Previously, Muley et al. introduced an algorithm using serum CYFRA 21–1 and CEA levels [10]. This variable was called the tumor marker index (TMI) and corresponds to the geometric mean of normalized CYFRA21-1 and CEA levels (marker value divided by diagnostic cutoff). The TMI can evaluate not only the degree of marker elevation but also the combined use of two markers. In the present study, therefore, the prognostic impact of the TMI based on serum and lavage CEA levels was retrospectively investigated for NSCLC patients.

Three hundred and eighty-three consecutive NSCLC patients who had undergone surgical resection and pleural lavage cytology from 1998 through 2004 were included in this study. There were 244 men and 139 women, with ages ranging from 26 to 90 years, and an average age of 67 years. The overall follow-up periods ranged from 33 to 132 months. The baseline characteristics " Table 1. are summarized in l All patients underwent thoracotomy and were examined using pleural lavage cytology (PLC) as described previously [9]. The CEA level in the pleural lavage fluid was also measured using the same procedure as for serum CEA levels, as described before [9]. The normal upper limit for lavage CEA levels that we had previously decided on was 0.5 ng/ml [9]. The TMI [10, 11] was defined by taking the geometric mean of normalized values of serum and lavage CEA levels, where normalization was performed by dividing individual marker values by corresponding diagnostic cutoff points, i.e., 5.0 ng/ml for serum CEA and 0.5 ng/ml for lavage CEA: the square root of (serum CEA level/5.0 ng/ ml) × (lavage CEA level/0.5 ng/ml).

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Tomita M et al. Carcinoembryonic Antigen Level …

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Table 1 Baseline clinicopathological factors.

Age Gender Histology pStage pT status pN status PLC Serum CEA

< 65 > 65 male female adenocarcinoma other I II–III pT1 pT2–4 pN0 pN1–2 negative positive normal high

Normal

High

lavage CEA

lavage CEA

108 174 172 110 202 80 212 70 171 111 226 56 273 9 208 74

32 69 72 29 77 24 44 57 33 68 56 45 80 21 30 71

p Value 0.2873 0.0844 0.4456 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001

Pathologic (p) TNM staging was recorded for all patients. Followup information, including the cause of death, was ascertained through a review of the clinical notes and direct or family contact. Comparisons of data between the 2 groups were made using Fisherʼs exact test. Survival curves were obtained according to the Kaplan-Meier method. A comparison of survival curves was carried out using the log-rank test. Statistical calculations were conducted with JMP (SAS Institute, Inc., Cary, NC, USA) and values of p less than 0.05 were accepted as significant.

Fig. 1 a and b Survival of patients based on their preoperative serum CEA (a) and lavage CEA levels (b).

Results !

Positive PLC findings were present in 30 (7.83%) patients. There were 101/383 patients with high lavage CEA levels. As shown in " Table 1, high lavage CEA levels were related to pStage, pT status, l pN status, PLC findings and serum CEA levels. " Fig. 1 a, the 5-year survival of patients with normal As shown in l and high serum CEA levels was 71.78 % and 51.38 %, respectively (p < 0.0001). Patients with high lavage CEA levels also had a significantly poorer prognosis compared with patients with normal " Fig. 1 b). lavage CEA levels (45.59 % vs. 71.88 %, p < 0.0001; l When both tumor marker levels are within normal upper limits, the TMI cannot be greater than 1.0. Therefore, in the present study, we determined the discriminatory value of the TMI as 1.0. Using this discriminatory value, we subdivided the patients into 2 groups: those with TMI less than or equal to 1.0, and those with TMI greater than 1.0. There were 216 patients with a TMI less than or equal to 1.0, and 167 patients with a TMI greater than " Fig. 2. 1.0. The survival curve based on the TMI is shown in l The 5-year survival rate for patients with a TMI less than or equal to 1.0 was 73.75 % compared to a survival rate of only 55.12 % for patients with a TMI greater than 1.0 (p < 0.001). " Table 2. The results of univariate analysis are summarized in l Gender, histology, pT status, pN status, PLC and TMI were related to the patientʼs prognosis. The results of multivariate analysis including all variables for which p was less than 0.05 on univariate " Table 3. The variables “gender”, analysis are summarized in l “histology”, “pT status”, ”pN status”, “PLC” and “TMI” were included in the multivariate analysis.

Discussion !

In our study, 7.83 % (30/383) of patients had positive PLC, and positive PLC was an independent prognostic factor in both univariate and multivariate analysis. Most previous studies also conclude that patients with a positive PLC, a possible indicator of the initial stage of carcinomatous pleuritis, have a poor survival rate [1–4]. Our data supports these findings. In addition to positive PLC findings, we also showed that high lavage CEA levels were a prognostic determinant. Our data demonstrated a significant correlation between high lavage CEA levels and clinicopathological factors, suggesting that high lavage CEA levels may be a useful prognostic determinant. Although the extraction mechanisms of CEA in pleural lavage fluid are unknown in detail, the source of lavage CEA might be microdisseminated tumor cells. Despite the statistically significant correlation between the results of PLC and lavage CEA, 80 of 353 patients with negative PLC showed high lavage CEA. There is a possibility that high lavage CEA levels may reflect subclinical microdissemination that is not always detected by PLC. On the other hand, 9 of 30 patients with positive PLC showed normal lavage CEA levels. Therefore, the results of PLC and lavage CEA level do not always correspond. The mechanism of a high lavage CEA level might be different from that of positive PLC. The results of serum and lavage CEA levels were also not consistent despite the statistical correlation. Out of 238 patients with normal serum CEA levels, 30 patients had a poorer prognosis




CEA: carcinoembryonic antigen, PLC: pleural lavage cytology

Original Thoracic

Table 2 Univariate analysis. Factors

Risk ratio

95 % CI

p Value

Age Gender Histology pT pN PLC TMI

1.0821 1.5610 1.5285 1.7599 1.9700 1.7331 1.4101

0.9061–1.3012 1.2732–1.9480 1.2799–1.8184 1.4709–2.1217 1.6538–2.3429 1.3453–2.1751 1.1865–1.68813

0.3875 < 0.0001 < 0.0001 < 0.0001 < 0.0001 0.0001 0.0001

CI: confidence interval, PLC: pleural lavage cytology, TMI: tumor marker index

Table 3 Multivariate analysis. Factors

Risk ratio

95 % CI

p Value

Gender Histology pT pN PLC TMI

1.2984 1.3577 1.3830 1.7231 1.3446 1.2295

1.0509–1.6306 1.1286–1.6283 1.1459–1.6809 1.4379–2.0616 1.0351–1.7057 1.0298–1.4724

0.0148 0.0013 0.0006 < 0.0001 0.0276 0.0222

CI: confidence interval, PLC: pleural lavage cytology, TMI: tumor marker index

based on their high lavage CEA levels. In contrast, 74 patients had a high serum CEA but a normal lavage CEA. Although the reason for these discrepancies is not known, there is a possibility that the extraction mechanisms of CEA in serum and pleural lavage fluid may differ. The combined use of serum and lavage CEA levels, therefore, may prove a useful prognostic determinant, because both serum and lavage CEA levels are useful prognostic factors. However, it is sometimes difficult to evaluate patients in whom only one marker is positive, as described above. In the present study, we therefore selected the TMI as introduced by Muley and coworkers [10, 11]. The TMI can evaluate two markers collectively. Our result showed that TMI based on serum and lavage CEA is an independent negative prognostic determinant for NSCLC patients. The TMI can evaluate the degree of marker elevation. In the present study, patients were subdivided into 2 groups: patients with TMI ≤ 1.0 and patients with TMI > 1.0. Using this discriminatory value, we could clearly differentiate between the two prognostic groups. However, there remains a possibility that other useful discriminatory values exist and we will try to find other values in the near future. Muley et al. introduced the TMI based on serum CEA and CYFRA 21–1 levels, and they reported two discriminatory values: 0.48 and 0.83 [10]. However, they did not describe the method by which they determined these discriminatory values [11]. Measurement of serum and lavage CEA levels is inexpensive and routinely available. Although some studies have investigated the use of the more sensitive CEA mRNA to detect microdissemination or micrometastasis [12–14], these molecular detections of tumor cells are expensive and available only as research tools. Despite current advanced diagnostic procedures for preoperative staging, the present results showed a role for the use of the TMI based on serum and lavage CEA levels as an adjunct to conventional staging for NSCLC patients. Based on our results, there is a possibility that adjuvant chemotherapies might be useful for patients with a high TMI. The subgroup of patients with a high TMI could represent a reasonable study population for an adjuvant


Fig. 2 Survival of patients based on the tumor marker index (TMI) based on serum and lavage CEA levels.

therapy trial. Further prospective studies in this area are warranted. In conclusion, the TMI based on serum and lavage CEA levels appears to be an independent prognostic determinant in patients with NSCLC. When planning postoperative adjuvant therapies, we believe that the TMI based on serum and lavage CEA levels should be considered. Unfortunately, there is no evidence that adjuvant therapy would be useful in patients with a TMI greater than 1.0, but this may be a question for future studies.

Conflict of interest None declared.

References 1 Buhr J, Berghauser KH, Gonner S, Kelm C, Burkhardt EA, Padberg WM. The prognostic significance of tumor cell detection in intraoperative pleural lavage and lung tissue cultures for patients with lung cancer. J Thorac Cardiovasc Surg 1997; 113: 683–690 2 Riquet M, Badoual C, Le Pimpec Barthes F et al. Visceral pleura invasion and pleural lavage tumor cytology by lung cancer: a prospective appraisal. Ann Thorac Surg 2003; 75: 353–355 3 Okada M, Sakamoto T, Nishio W, Uchino K, Tsuboshima K, Tsubota N. Pleural lavage cytology in non-small cell lung cancer: lessons from 1000 consecutive resections. J Thorac Cardiovasc Surg 2003; 26: 1911–1915 4 Lim E, Ali A, Theodorou P, Nicholson AG, Ladas G, Goldstraw P. Intraoperative pleural lavage cytology is an independent prognostic indicator for staging non-small cell lung cancer. J Thorac Cardiovasc Surg 2004; 127: 1113–1118 5 Icard P, Regnard JF, Essomba A, Panebianco V, Magdeleinat P, Levasseur P. Preoperative carcinoembryonic antigen level as a prognostic indicator in resected primary lung cancer. Ann Thorac Surg 2004; 58: 811–814 6 Rubins JB, Dunitz J, Rubins HB, Maddaus MA, Niewoehner DE. Serum carcinoembryonic antigen as an adjunct to preoperative staging of lung cancer. J Thorac Cardiovasc Surg 1998; 116: 412–416 7 Tomita M, Matsuzaki Y, Edagawa M, Shimizu T, Hara M, Onitsuka T. Prognostic significance of preoperative serum carcinoembryonic antigen level in lung adenocarcinoma but not squamous cell carcinoma. Ann Thorac Cardiovasc Surg 2004; 10: 76–80 8 Okada M, Nishio W, Sakamoto T et al. Prognostic significance of perioperative serum carcinoembryonic antigen in non-small cell lung cancer: analysis of 1,000 consecutive resections for clinical stage I disease. Ann Thorac Surg 2004; 78: 216–221 9 Tomita M, Shimizu T, Matsuzaki Y, Hara M, Ayabe T, Onitsuka T. Prognostic significance of carcinoembryonic antigen level in pleural lavage fluid for patients with lung adenocarcinoma. Ann Thorac Surg 2005; 80: 276–281



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13 Kurusu Y, Yamashita J, Ogawa M. Detection of circulating tumor cells by reverse transcriptase-polymerase chain reaction in patients with resectable non-small-cell lung cancer. Surgery 1999; 126: 820–826 14 DʼCunha J, Corfits AL, Herndon 2nd JE et al. Molecular staging of lung cancer: real-time polymerase chain reaction estimation of lymph node micrometastatic tumor cell burden in stage I non-small cell lung cancer – preliminary results of Cancer and Leukemia Group B Trial 9761. J Thorac Cardiovasc Surg 2002; 123: 484–491


10 Muley T, Dienemann H, Ebert W. CYFRA 21-1 and CEA are independent prognostic factors in 153 operated stage I NSCLC patients. Anticancer Res 2004; 24: 1953–1956 11 Muley T, Fetz TH, Dienemann H et al. Tumor volume and tumor marker index based on CYFRA 21-1 and CEA are strong prognostic factors in operated early stage NSCLC. Lung Cancer 2008; 60: 408–415 12 Castaldo G, Tomaiuolo R, Sanduzzi A, Ponticiello A, Marchetiello I, Salvatore F. Carcinoembryonic antigen mRNA analysis detects micrometastatic cells in blood from lung cancer patients. Eur Respir J 2003; 22: 418–421

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