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ORIGINAL ARTICLE
Year : 2015  |  Volume : 52  |  Issue : 7  |  Page : 158-163
 

High preoperative and postoperative levels of carcinoembryonic antigen and CYFRA 21-1 indicate poor prognosis in patients with pathological Stage I nonsmall cell lung cancer


Department of Thoracic Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China

Date of Web Publication20-Jul-2016

Correspondence Address:
Y Cui
Department of Thoracic Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.186564

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 » Abstract 

BACKGROUND: Serum carcinoembryonic antigen (CEA) and the soluble fragment of cytokeratin 19 (CYFRA 21-1) are supposed to have a prognostic role in patients with nonsmall cell lung cancer (NSCLC) after surgery, but it has not been used as an adjunct to the tumor-node-metastasis (TNM) staging system to provide therapy options for patients with pathological Stage I NSCLC. This study was designed to investigate the effect of serum levels of CEA and CYFRA 21-1 before and after surgery on the prognosis of patients with Stage I NSCLC. MATERIALS AND METHODS: A retrospective review was performed regarding the medical records and follow-ups of 169 patients with Stage I NSCLC before and after surgery. The patients were divided into three groups based on levels of serum CEA and CYFRA 21-1 before and after surgery: (1) continuously normal-level groups (CEA [NN] and CYFRA 21-1 [NN] groups); (2) declined to normal-level groups (CEA [HN] and CYFRA 21-1 [HN] groups); and (3) continuously high-level groups (CEA [HH] and CYFRA 21-1 [HH] groups). Survival analysis was conducted using the Kaplan-Meier method for each group. The Chi-square or Fisher exact test was employed to compare clinical and pathologic factors at the level of P < 0.05. The prognostic factor was evaluated by the Cox proportional hazards model. RESULTS: Compared with the continuously normal-level groups, the CEA [HN] group was significantly correlated to tumor size (P = 0.011), and the CYFRA 21-1 [HN] group was significantly correlated to tumor type and pathological TNM in addition to tumor size. Five-year survivals were significantly lower (P = 0.004) in the CEA [HH] group (67.3%) and the CEA [HN] group (86.5%) than in the CEA [NN] group (85.7%) and were significantly lower (P < 0.001) in the CYFRA 21-1 [HH] group (47.2%) and the CYFRA 21-1 [HN] group (70.1%) than in the CYFRA 21-1 [NN] group (90.1%). Multivariate analysis demonstrated that tumor size (21-50 mm), CEA [HH], and CYFRA 21-1 [HH] were independent unfavorable prognostic factors for overall survival (OS), whereas tumor size (21-50 mm), CEA [HH], CYFRA 21-1 [HN], and CYFRA 21-1 [HH] were independent significant prognostic factors for progression-free survival (PFS). CONCLUSION: Patients with a persistently high serum CEA or CYFRA 21-1 before and after surgery had shortest OS and PFS. These patients had worst prognosis. Adjuvant chemotherapy was likely to improve survival for these patients.


Keywords: Carcinoembryonic antigen, CYFRA 21-1, nonsmall cell lung cancer, prognosis, tumor marker


How to cite this article:
Duan X, Cui Y, Li H, Shi G, Wu B, Liu M, Chang D, Wang T, Kong Y. High preoperative and postoperative levels of carcinoembryonic antigen and CYFRA 21-1 indicate poor prognosis in patients with pathological Stage I nonsmall cell lung cancer. Indian J Cancer 2015;52, Suppl S3:158-63

How to cite this URL:
Duan X, Cui Y, Li H, Shi G, Wu B, Liu M, Chang D, Wang T, Kong Y. High preoperative and postoperative levels of carcinoembryonic antigen and CYFRA 21-1 indicate poor prognosis in patients with pathological Stage I nonsmall cell lung cancer. Indian J Cancer [serial online] 2015 [cited 2019 Aug 24];52, Suppl S3:158-63. Available from: http://www.indianjcancer.com/text.asp?2015/52/7/158/186564



 » Introduction Top


In many countries, lung cancer has become one of the cancers with highest rate of incidence and mortality. Moreover, 85% of lung cancer is nonsmall cell lung cancer (NSCLC). [1] Surgical resection is the main method of treatment, and early lung cancer after surgical treatment is usually considered to achieve the effect of cure. However, it is reported that the 5-year survival rate is about 71-77% for patients with Stage Ia of NSCLC and 58% for patients with Stage Ib of NSCLC. [2]

Serum carcinoembryonic antigen (CEA) and CYFRA 21-1 are two important tumor markers for diagnosis and disease monitoring of patients with lung cancer. Many studies show that either of both tumor markers plays a significant prognostic role for overall survival (OS) of the patients with early lung cancers after surgery. [1],[3],[4],[5],[6],[7],[8],[9],[10] However, there was little information available on the prognostic value for progression-free survival (PFS). The objective of this study was to analyze the clinical value of serum CEA and CYFRA 21-1 before and after operation and to investigate their clinical value in prognosis for the patients with Stage I NSCLC.


 » Materials and Methods Top


Patients' characteristics

This retrospective study covered 185 patients with Stage I NSCLC, who accepted exclusively surgical treatment at Beijing Friendship Hospital between March 2004 and November 2014. All patients met the inclusion criteria: (1) Clinical records were complete; (2) the 7 th edition of the international lung cancer tumor-node-metastasis (TNM) staging criteria; [11] (3) postoperative pathologic type was adenocarcinoma and squamous cell carcinoma (SCC); [12] and (4) CEA and CYFRA 21-1 were measured within 1 week before operation and were checked and reviewed within 3 months after surgery. OS refers to the time from the 1 st day immediately after surgery of a patient to the day of death or the day of last follow-up. PFS is the time from the 1 st day right after clinical surgery to the day when disease progression was first diagnosed and confirmed or to the death day with any medical cause. By 20 April, 2015, 169 patients received follow-ups and 16 patients lost communications. The median of follow-up time was 46.2 months with the range of 5-131 months. Among 169 patients, 137 patients were alive, and the others passed away. Ten patients had lung cancer recurrence or metastasis that was confirmed by computed tomography (CT), magnetic resonance imaging, bone scintigraphy, and positron emission tomography-CT. These 169 patients were finally selected, and their medical records were carefully reviewed including age, gender, smoking history, tumor type, tumor differentiation, tumor size, tumor location, clinical surgery type, visceral pleural invasion (VPI), pathological TNM (pTNM), preoperative and postoperative serum CEA and CYFRA 21-1 levels, and survival situation.

Groups of patients and tumor marker assay

The 169 patients were divided into three groups according to the serum CEA levels before and after surgery: Continuously normal-level group (CEA [NN] group, 135 cases, 79.88%); declined to normal-level group (CEA [HN] group, 20 cases, 11.84%); and continuously high-level groups (CEA [HH] group, 14 cases, 8.28%). Similarly, based on the levels of CYFRA 21-1 before and after operation, the patients were grouped into CYFRA 21-1 [NN] group (125 cases, 73.97%), CYFRA 21-1 [HN] group (30 cases, 17.45%), and CYFRA 21-1 [HH] group (14 case, 8.28%). Due to minor statistical analysis efficiency, two patients with normal preoperative and high postoperative CEA levels were merged into the group of CEA [HH]. Similarly, four patients with normal preoperative and high postoperative CYFRA 21-1 levels were included in the group of CYFRA 21-1 [HH].

The serum CEA was measured by chemiluminescent immunoassay method, and the reagent kit was manufactured by Abbott (Abbott Park, IL, USA). The serum CYFRA 21-1 was analyzed by electrochemiluminescence method using Roche Elecsys (Roche Diagnostics Limited, Shanghai, China). The normal upper limit was set as 5.0 and 3.3 ng/mL for CEA and CYFRA 21-1 in this study, respectively.

Statistics

Serum CEA, CYFRA 21-1, and other clinical variables were compared using Chi-square or Fisher exact test. Kaplan-Meier method was used to generate survival curves, and survival differences were analyzed using the log-rank test. A multivariate analysis of several prognostic factors was carried out using Cox's proportional hazards regression model. The software used in the study was SPSS 23.0 (IBM, Armonk, NY, USA). The significant difference was concluded if the P value was < 0.05.


 » Results Top


The relationship between the clinical and pathological characteristics of the patients is summarized in [Table 1] according to the levels of serum CEA and CYFRA 21-1 before and after operation. Compared with CEA [NN], the CEA [HN] group was significantly correlated to tumor size (P = 0.011). In the meanwhile, compared with group CYFRA 21-1 [NN], the CYFRA 21-1 [HN] group was not only significantly correlated with tumor size but also significantly correlated with tumor type and pTNM (all P values were < 0.05).
Table 1: Statistics of the 169 patients with Stage I nonsmall cell lung cancer


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The 5-year OS of the CEA [HH] group (67.3%) and the CEA [HN] group (86.5%) was significantly lower (P = 0.004) than that of the CEA [NN] group (87.5%). Further paired test found that there existed significantly statistical difference (P = 0.002) of the 5-year OS between the CEA [HH] group and the CEA [NN] group, but no significant difference (P = 0.686) between the CEA [HN] group and the CEA [NN] group was found [Figure 1]a. The 5-year PFS of the CEA [HH] group (60.6%) and the CEA [HN] group (80.8%) was significantly lower (P = 0.004) than that of the CEA [NN] group (80.9%). Further paired test showed that the 5-year PFS of the CEA [HH] group was significantly different (P = 0.001) from that of the CEA [NN], and the CEA [HN] group had no significant difference (P = 0.950) from the CEA [NN] with respect to the 5-year PFS [Figure 1]b. The 5-year OS of the CYFRA 21-1 [HH] group (47.2%) and the CYFRA 21-1 [HN] group (70.1%) was significantly lower (P < 0.001) than that of the CYFRA 21-1 [NN] group (90.1%) [Figure 2]a. There was a significant difference of the 5-year OS between the CYFRA 21-1 [HH] group and the CYFRA 21-1 [NN] group (P < 0.001) and between the CYFRA 21-1 [HN] group and the CYFRA 21-1 [NN] group (P = 0.015). The 5-year PFS of the CYFRA 21-1 [HH] group (47.2%) and the CYFRA 21-1 [HN] group (54.9%) was significantly lower (P < 0.001) than that of the CYFRA 21-1 [NN] group (86.8%); there existed significant difference of the 5-year PFS between the CYFRA 21-1 [HH] group and the CYFRA 21-1 [NN] group (P < 0.001) and between the CYFRA 21-1 [HN] group and the CYFRA 21-1 [NN] group (P = 0.001) [Figure 2]b.
Figure 1: Curves of the overall survival and the progression - free survival of the carcinoembryonic antigen group (a and b). aThe log - rank test

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Figure 2: Curves of the overall survival and the progression - free survival of the CYFRA 21 - 1 group (a and b). aThe log - rank test

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The analysis results of the univariate analysis indicated that tumor differentiation degree, VPI, tumor size, pTNM, CEA levels, and CYFRA 21-1 levels were significant prognostic factors for OS [Table 2]. The significant prognostic factors for the PFS included tumor differentiation degree, tumor size, pTNM, CEA levels, and CYFRA 21-1 levels.
Table 2: The analysis results of univariate Cox proportional hazards model: Predictors of the overall survival and the progression-free survival


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Multivariate analyses included age, sex, and the significant factors identified by univariate analysis. The results showed that the significant independent unfavorable prognostic factors for the OS were tumor size (21-50 mm) with hazard ratio (HR) of 7.233 and confidence interval (CI) of 95% (1.952-26.791), CEA [HH] with HR of 7.042 and CI of 95% (2.178-22.772), and CYFRA 21-1 [HH] with HR of 8.333 and CI of 95% (2.173-31.956). The significant independent unfavorable prognostic factors for the PFS were tumor size (21-50 mm) with HR of 3.780 and 95% CI (1.442-2.753), CEA [HH] with HR of 5.964 and 95% CI (2.168-16.409), CYFRA 21-1 [HN] with HR of 2.931 and 95% CI (1.236-6.952), and CYFRA 21-1 [HH] with HR of 5.409 and 95% CI (1.674-17.480) [Table 3].
Table 3: The analysis results of multivariate Cox proportional hazards model: The overall survival and the progression-free survival


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 » Discussion Top


Some reports [7],[8],[9],[10] based on pre- and post-operative levels of CEA revealed that continuously high level of CEA was an independent unfavorable prognostic factor for Pathological-Stage I NSCLC patients. Those studies were similar to this study with respect to CEA levels grouping including NN, HN, and HH groups. [7],[8],[9],[10] The difference of this study from those studies lies in that this study analyzed two tumor markers of CEA and CYFRA 21-1 in the same time. With consideration of CEA, the findings of this study were consistent with the research results conducted by Matsuguma et al. [7],[8],[9],[10] Multivariate analysis in this study revealed that CEA [HH] was an independent risk factor for the prognosis of patients with Stage I NSCFC, in the meanwhile, CYFRA 21-1 [HH] was also an independent risk factor for the prognosis of patients with Stage I NSCLC.

Moreover, the findings in this study were consistent with those reported by Kozu et al. [10] that serum CEA and CYFRA 21-1 levels before and after surgery were significantly correlated with the 5-year survival rate of patients with Stage I NSCLC after surgery, and the 5-year survival rate of patients was lowest for the patients with Stage I NSCLC with elevated levels of pre- and post-operative CEA and CYFRA 21-1.

The study conducted by Wang et al. [8] revealed that CEA [HN] was significantly associated with tumor type, which was mainly lung adenocarcinoma, but not with age, gender, smoking history, VPI, and other factors. However, this study demonstrated that CEA [HN] was significantly correlated with tumor size (P = 0.011), and was not significantly correlated to age, sex, smoking history, VPI, and tumor type. Kozu et al. [10] also confirmed that the elevated level of CEA before surgery was not related to tumor type. In addition, this study showed that CYFRA 21-1 [HN] was not only significantly correlated to tumor type (P = 0.001), but also to tumor size (P = 0.005) and pTNM (P = 0.003). This study illustrated that 43.5% of patients with lung SCC have high CYFRA 21-1 level. Reinmuth et al. [6] also found that the sensitivity of CYFRA 21-1 to lung SCC was significantly high. In summary, the relationship between high preoperative CEA level and tumor type was controversial and not clarified till date; high preoperative CYFRA 21-1 level is often found in patients with lung SCC; and high levels of CYFRA 21-1 and CEA are closely related to tumor size.

In this study, the PFS analysis showed that the 5-year PFS in patients with Stage I NSCLC had the trend of becoming worse when the level change pattern of CEA and CYFRA 21-1 was from the pattern of continuously normal before and after surgery, to the pattern of high level before surgery and normal level after surgery, and to the pattern of high level before and after surgery. Multivariate analysis demonstrated that tumor size (21-50 mm), CEA [HH], CYFRA 21-1 [HN], and CYFRA 21-1 [HH] were independent significant prognostic factors for PFS. Thus, it can be speculated that there may exist residual cancer cells, micrometastases, or latent lymph node metastases in CEA [HH] group and CYFRA 21-1 [HH] group. These residuals may be the cause of postoperative metastasis, recurrence, and low survival rate for the patients with Stage I NSCLC.

In reality, serum CEA and CYFRA 21-1 have unique advantages and potential clinical value. First of all, compared with erbB-2, VPI, blood vessel invasion, pT, p-53 and other biological markers, both of them have the advantages of simple sampling, reproducibility, and low cost. [13],[14],[15] Second, this study confirmed that continuously high-level groups of CEA and CYFRA 21-1 (CEA [HH] and CYFRA 21-1 [HH]) could be used as a reasonable model for biological staging. [16],[17] This model has the potential to well predict the prognosis of patients with Stage I NSCLC, and it may also be used as an adjunct to the TNM staging system by being integrated into pTNM staging. Finally, it has been proved by randomized controlled trials [18],[19],[20] that chemotherapy can improve the survival of patients with lung cancer in Stage II and even more advanced stage. According to the grouping in this study, patients in the CEA [HH] group and the CYFRA 21-1 [HH] group had worst prognosis in respective grouping based on levels of CEA or CYFRA 21-1 before and after surgery. This suggests that both groups of patients are probably suitable for postoperative adjuvant chemotherapy that possibly yields information valuable for prospective clinical study.


 » Conclusion Top


Patients with a persistently high serum CEA or CYFRA 21-1 before and after surgery had shortest OS and PFS. These patients had worst prognosis. Adjuvant chemotherapy was likely to improve survival for these patients.

Acknowledgment

We would like to express our sincere thanks to the Beijing Natural Science Foundation for the financial support (Grant no. 7102042) provided to this research project. Other warm thanks also goes to those staff who provided contribution to the completion of this project.

Financial support and sponsorship

This study was supported by the grant from the Beijing Natural Science Foundation (to Yong CUI) (No. 7102042).

Conflicts of interest

There are no conflicts of interest.

 
 » References Top

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