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Abstract

BACKGROUND:

Serum carcinoembryonic antigen (CEA) and cytokeratin 19 fragment (CYFRA 21-1) levels are prognostic predictors in non-small cell lung cancer (NSCLC). However, even in patients with the same stage of cancer, the serum levels of those markers often vary.

OBJECTIVE:

We investigated the association between the initial biomarker levels and prognosis.

METHODS:

We retrospectively reviewed 445 patients with advanced NSCLC and their baseline serum CEA and CYFRA 21-1 levels. Patients were divided into four groups according to the initial levels of those markers: the NN, HN, NH, and HH group. Kaplan-Meier survival analysis with Log-rank test and Cox proportional hazards regression analysis were performed.

RESULTS:

The 5-year overall survival (OS) rate in the HN group was the highest (32.2%). Multivariate analyses indicated that the HN group (HR 0.520, 95% CI 0.309–0.878, $P=$ 0.014), female sex (HR 0.685, 95% CI 0.498–0.944, $P=$ 0.021), serum CRP level (HR 1.057, 95% CI 1.034–1.080, $P<$ 0.001), chemotherapy (HR 0.324, 95% CI 0.228–0.460, $P<$ 0.001), and chemotherapy/radiotherapy (HR 0.266, 95% CI 0.171–0.414, $P<$ 0.001) were independent prognostic factors for overall survival.

CONCLUSIONS:

In advanced NSCLC, patients with baseline high serum CEA but low CYFRA 21-1 level have a significant longer overall survival regardless of clinical stage.

Keywords

CEA CYFRA 21-1 tumor marker prognostic factor NSCLC

1. Introduction

Tumor markers have been used to screen, diag- nose and monitor the treatment response in cancer. Serum carcinoembryonic antigen (CEA) and cytokeratin 19 fragment (CYFRA 21-1) are important markers in the diagnosis of non-small cell lung cancer (NSCLC) [1, 2].

CEA is a glycoprotein involved in cell adhesion and is normally produced during fetal development [3]. CEA is one of the most widely used tumor markers due to its limited expression in normal tissues and high expression in tumors. CEA is expressed in several tumors of epithelial origin, including colorectal carcinoma, mucinous ovarian carcinoma and lung adenocarcinoma [4]. Elevated serum CEA levels can occur when the antigen is produced by carcinoma cells, and CEA can enhance the metastatic potential of weak metastatic cells [5, 6].

CYFRA 21-1 is a soluble fragment of cytokeratin 19 that is recognized by two monoclonal antibodies, BM 19-21 and KS 19-1 [7]. All epithelial tissues, both normal epithelium and their malignant counterparts, contain cytokeratins that form the intermediate filament cytoskeleton within epithelial cells [8]. Cytokeratin 19 is an acidic (type I) subunit expressed in all simple epithelium and in carcinomas that arise from them [9]. It is widely expressed in both adenocarcinomas and squamous cell carcinomas. The detection of soluble cytokeratin 19 fragments in the serum released by carcinoma cells by the CYFRA 21-1 assay has identified its clinical application as a marker to detect particular squamous cell carcinomas of the lung [10]. In several studies, it has been suggested that CYFRA 21-1 is released from injured bronchial epithelium [11] and is a marker of apoptosis in lung cancer [12].

Rapidly progressing lung cancer is associated with a poor prognosis and a high mortality rate. Radiologic examinations and serologic tests have been used to diagnose lung cancer and evaluate the treatment response. CEA and CYFRA 21-1 have often been used as serologic markers; they are associated with a poor prognosis and treatment response, as reported in previous studies [13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25]. However, even in patients with the same stage of lung cancer, the levels of serum CEA and CYFRA 21-1 often vary. There is heterogeneity in the prognostic role of these markers in NSCLC by the published literature, and the authors would like to clarify the role in a large patient cohort. Therefore, the aim of this study was to evaluate the impact of CEA and CYFRA 21-1 according to serum level in advanced NSCLC. We divided patients with stage III-IV NSCLC into subgroups according to initial levels of serum CEA and CYFRA 21-1. We focused on the association between initial serum CEA and CYFRA 21-1 levels and clinical parameters and prognosis.

2. Materials and methods

2.1 Patients and materials

Between February 2001 and March 2015, 1,060 patients were diagnosed with stage III or IV NSCLC at Soonchunhyang University Hospital, Bucheon, Korea. Of these, 445 patients who met all of the following criteria were included and retrospectively reviewed in the present study. Inclusion criteria were as follows: (1) age more than 18 years and (2) measurement of serum CEA and CYFRA 21-1 concentrations within the 1-month period before pathologic diagnosis. Exclusion criteria were as follows: (1) history of previous or current malignant neoplasm, (2) patients who underwent surgery with adjuvant chemotherapy in 3A stage, (3) patients who were transferred to other hospital immediately after diagnosis. This study was approved by the Institutional Review Board (IRB) of the Soonchunhyang University College of Medicine.

Serum CEA and CYFRA 21-1 levels were measured using a chemiluminescence enzyme immunoassay kit and an electrochemiluminescence immunoassay in an automatic analyzer (Extension E170 Module; Roche Diagnostics GmbH, Mannheim, Germany), respectively. A serum concentration $<$ 4.7 ng/mL was defined as normal for CEA, and $<$ 3.3 ng/mL was defined as normal for CYFRA 21-1. Patients were divided into four groups according to the initial levels of serum CEA and CYFRA 21-1: the NN group (normal CEA and normal CYFRA 21-1 level), the HN group (high CEA and normal CYFRA 21-1 level), the NH group (normal CEA and high CYFRA 21-1 level), and the HH group (high CEA and high CYFRA 21-1 level).

The medical records of each patient were examined for age, sex, smoking status with pack-years, serum CEA and CYFRA 21-1 levels, serum CRP levels, tumor diameter, histologic type, stage, treatment modalities, and survival period. Inflammatory marker such as CRP was fluctuated dynamically, and pre-treatment levels were chosen after stabilization. Despite the fact that staging system changed from 6 ${}^{\text{th}}$ to 7 ${}^{\text{th}}$ edition during the study period, all patients underwent re-staging according to the AJCC (7 ${}^{\text{th}}$ edition) staging system [26]. N staging was almost determined complementarily using chest computed tomography (CT) and position emission tomography (PET)-CT. Lymph node which is longer than 1 cm in the smallest diameter was suspected as malignant node in chest CT, and further hypermetabolic lymph nodes were detected in PET-CT. Among 114 patients in stage 3, all patients

Table 1
Baseline characteristics according to NN, HN, NH, and HH groups

	Total		NN group		HN group		NH group		HH group		p-value
	( $n=$ 445)		( $n=$ 53)		( $n=$ 69)		( $n=$ 132)		( $n=$ 191)
CEA (ng/mL)	5.98	(0.00, 7373.00)	2.38	(0.07, 4.60)	19.42	(4.71, 1456.00)	2.77	(0.00, 5.17)	22.22	(3.05, 7373.00)	$<$ 0.001
CYFRA 21-1 (ng/mL)	5.30	(1.10, 289.20)	2.40	(1.20, 3.30)	2.60	(1.10, 3.30)	8.15	(3.40, 289.20)	7.80	(3.40, 192.00)	$<$ 0.001
Age (year)	68.00 $\pm$ 0.53		64.25 $\pm$ 1.42		64.55 $\pm$ 1.30		70.48 $\pm$ 0.84		69.00 $\pm$ 0.78		$<$ 0.001
Sex											0.137
Male	319	(71.7%)	41	(77.4%)	42	(60.9%)	99	(75.0%)	137	(71.7%)
Female	126	(28.3%)	12	(22.6%)	27	(39.1%)	33	(25.0%)	54	(28.3%)
Stage											$<$ 0.001
3A	35	(7.9%)	10	(18.9%)	1	(1.4%)	16	(12.1%)	8	(4.2%)
3B	79	(17.8%)	14	(26.4%)	11	(15.9%)	34	(25.8%)	20	(10.5%)
4	331	(74.4%)	29	(54.7%)	57	(82.6%)	82	(62.1%)	163	(85.3%)
Tumor diameter (cm)	4.17	(1.00, 51.00)	4.00	(1.30, 14.00)	3.65	(1.60, 10.00)	5.85	(1.50, 40.00)	4.80	(1.00, 51.00)	$<$ 0.001
Histologic type											$<$ 0.001
Adenocarcinoma	266	(59.8%)	31	(58.5%)	55	(79.7%)	52	(39.4%)	128	(67.0%)
Squamous cell carcinoma	140	(31.5%)	19	(35.8%)	9	(13.0%)	63	(47.7%)	49	(25.7%)
Others	39	(8.8%)¶	3	(5.7%)	5	(7.2%)	17	(12.9%)	14	(7.3%)
CRP (mg/dL)	1.66	(0.00, 34.30)	0.66	(0.00, 23.90)	0.79	(0.00, 21.90)	2.19	(0.00, 16.20)	1.90	(0.00, 34.30)	$<$ 0.001
Smoking status											0.054
Never smoker	159	(35.7%)	15	(28.3%)	35	(50.7%)	46	(34. 8%)	63	(33.3%)
Ex-smoker	130	(29.2%)	14	(26.4%)	12	(17.4%)	40	(30.3%)	64	(33.9%)
Current smoker	154	(34.6%)	24	(45.3%)	22	(31.9%)	46	(34.8%)	62	(32.8%)
Pack years (year)	26.50	(0.00, 150.00)	35.00	(0.00, 70.00)	0.00	(0.00, 150.00))	25.00	(0.00, 150.00)	30.00	(0.00, 125.00)	0.045
Treatment modalities											0.001
Supportive care without anti-cancer therapy	97	(21.8%)	4	(7.5%)	12	(17.4%)	34	(25.8%)	47	(24.6%)
Chemotherapy	261	(58.7%)	31	(58.5%)	52	(75.4%)	78	(59.1%)	100	(52.4%)
Radiotherapy	15	(3.4%)	2	(3.8%)	2	(2.9%)	3	(2.3%)	8	(4.2%)
Chemotherapy/Radiotherapy	72	(16.2%)	16	(30.2%)	3	(4.3%)	17	(12.9%)	36	(18.8%)

CEA $=$ carcinoembryonic antigen; CYFRA 21-1 $=$ cytokeratin 19 fragment; NN group $=$ normal CEA and normal CYFRA 21-1 level; HN group $=$ high CEA and normal CYFRA 21-1 level; NH group $=$ normal CEA and high CYFRA 21-1 level; HH group $=$ high CEA and high CYFRA 21-1 level; ESR $=$ erythrocyte sedimentation rate; CRP $=$ C-reactive protein. ¶Others: Large cell carcinoma (10), Basaloid carcinoma (2), Adenosquamous cell carcinoma (1), Mucoepidermoid carcinoma (1), Pleomorphic carcinoma (1), Not otherwise specified types (23).

underwent chest CT and 100 patients (88%) underwent PET-CT; of these, SUV values were reported in 33 patients (median 5.00) and the results were reported as hypermetabolic in the remaining patients. Mediastinoscopic lymph node biopsy was performed in only 3 patients.

2.2 Statistical analysis

Data were reported as median (min, max) or mean $\pm$ standard deviation for continuous variables and n (%) for categorical variables. Baseline characteristics of the groups were compared using Kruskal-Wallis test and Chi-square test. The Kaplan-Meier method was used to generate survival curves. The log-rank test was used to compare the differences of overall survival between the groups. Univariate and multivariate analyses of prognostic factors were performed using the Cox proportional hazards model. A p-value less than 0.05 was considered to indicate statistical significance. Statistical analysis was performed using SPSS Statistics version 14.0 (IBM Corp., Armonk, NY, USA).

3. Results

3.1 Baseline characteristics of 4 groups according to CEA and CYFRA 21-1 levels

The clinicopathological factors of the 445 patients are summarized in Table 1. There were 53, 69, 132, and 191 patients in the NN, HN, NH and HH group, respectively. The median serum CEA levels of total patients and each groups (NN, HN, NH, and HH group) were 5.98, 2.38, 19.42, 2.77, and 22.22 ng/mL, respectively. The median serum CYFRA 21-1 levels of total patients and each groups (NN, HN, NH, and HH group) were 5.30, 2.40, 2.60, 8.15, and 7.80 ng/mL, respectively. There was no sex difference between the groups. The NH and HH groups were associated with older age, larger tumor diameter, higher CRP levels than the NN and HN groups. There were more stage 4 patients in the HN and HH groups. Never-smokers were included most in the HN group (50.7%), and the documented median pack-year in the group was 0. Chemotherapy was the most commonly performed treatment (74.9%), and 16.2% of patients underwent radiotherapy besides chemotherapy on the treatment course. There were more patients in the NH and HH group (25.8% and 24.6%), who received supportive care without anti-cancer therapy.

Pathological examinations revealed 266 (59.8%) adenocarcinomas, 140 (31.5%) squamous cell carcinomas, and 39 (31.5%) other subtypes: 10 large cell carcinomas, 2 basaloid carcinomas, 1 adenosquamous cell carcinoma, 1 mucoepidermoid carcinoma, 1 pleomorphic carcinoma, and 23 not otherwise specified types. Adenocarcinoma was the most common histologic type in most groups (NN 58.5%, HN 79.7%, and HH group 67.0%), whereas squamous cell carcinoma was the most common histologic type in the NH group (47.7%).

Figure 1.

Overall survival probability according to NN, HN, NH, and HH groups. NN group $=$ normal CEA and normal CYFRA 21-1 level; HN group $=$ high CEA and normal CYFRA 21-1 level; NH group $=$ normal CEA and high CYFRA 21-1 level; HH group $=$ high CEA and high CYFRA 21-1 level. The Kaplan-Meier survival curve shows a significant survival difference in 4 different groups according to CEA and CYFRA 21-1 level (log ran test $<$ 00.001). A significant difference in overall survival(OS) was observed between the NN and HN group ( $P=$ 0.046), between the NN and HH group ( $P=$ 0.011), between the HN and NH group ( $P=$ 0.008), between the HN and HH group ( $P<$ 0.001), and between the NH and HH group ( $P=$ 0.033). There was no significant survival difference only between the NN and NH group ( $P=$ 0.538). The 5-year OS rate in the HN group was 32.2 $\pm$ 8.9%, the highest compared with those in the other groups (NN group: 7.4 $\pm$ 6.4%; NH group: 11.6 $\pm$ 6.0%; HH group: 6.4 $\pm$ 3.3%). Median survival time of NN, HN, NH, and HH group was 15.50 $\pm$ 2.54 (10.52–20.48), 41.47 $\pm$ 12.19 (17.57–65.37), 17.10 $\pm$ 2.46 (12.28–21.92), and 11.00 $\pm$ 1.68 (12.81–17.06) months, respectively.

Table 2

Univariate and multivariate Cox regression analysis for overall survival in patients with advanced NSCLC

	Univariate analysis		Multivariate analysis
Variables	HR [95% CI]	p-value	HR [95% CI]	p-value
Tumor markers
CEA	1.000 [0.999–1.000]	0.502
CYFRA 21-1	1.013 [1.009–1.018]	$<$ 0.001
4 Groups by tumor markers
NN	1	–	1	–
HN	0.611 [0.370–1.009]	0.054	0.520 [0.309–0.878]	0.014
NH	1.138 [0.752–1.723]	0.542	0.989 [0.647–1.511]	0.958
HH	1.620 [1.099–2.388]	0.015	1.454 [0.974–2.172]	0.067
Age	1.010 [0.997–1.023]	0.127
Sex (female)	0.589 [0.432–0.803]	0.001	0.685 [0.498–0.944]	0.021
Stage
3A	1	–
3B	1.289 [0.763–2.178]	0.343
4	1.265 [0.795–2.013[	0.321
Tumor diameter	1.033 [1.011–1.056]	0.003	1.019 [0.993–1.045]	0.156
Histologic type
Adenocarcinoma	1	–
Squamous cell carcinoma	1.141 [0.861–1.512]	0.359
Others	1.298 [0.819–2.057]	0.267
CRP	1.068 [1.046–1.090]	$<$ 0.001	1.057 [1.034–1.080]	$<$ 0.001
Smoking status
Never-smoker	1	–	1	–
Ex-smoker	1.590 [1.144–2.209]	0.006	1.058 [0.706–1.587]	0.784
Current smoker	1.403 [1.027–1.916]	0.033	1.168 [0.794–1.720]	0.430
Treatment modalities
Supportive care without anti-cancer therapy	1	–	1	–
Chemotherapy	0.314 [0.222–0.444]	$<$ 0.001	0.324 [0.228–0.460]	$<$ 0.001
Radiotherapy	0.911 [0.472–1.756]	0.780	0.858 [0.439–1.675]	0.654
Chemotherapy/Radiotherapy	0.303 [0.198–0.464]	$<$ 0.001	0.266 [0.171–0.414]	$<$ 0.001

HR (Hazard ratio) $>$ 1 means shorter survival. NN group $=$ normal CEA and normal CYFRA 21-1 level; HN group $=$ high CEA and normal CYFRA 21-1 level; NH group $=$ normal CEA and high CYFRA 21-1 level; HH group $=$ high CEA and high CYFRA 21-1 level; ESR $=$ erythrocyte sedimentation rate; CRP $=$ C-reactive protein.

3.2 Overall survival (OS) of 4 groups according to CEA and CYFRA 21-1 levels

The 5-year OS rate in the HN group was 32.2 $\pm$ 8.9%, the highest compared with those in the other groups (NN group: 7.4 $\pm$ 6.4%; NH group: 11.6 $\pm$ 6.0%; HH group: 6.4 $\pm$ 3.3%) (Fig. 1). Median survival time of NN, HN, NH, and HH group was 15.50 $\pm$ 2.54 (10.52–20.48), 41.47 $\pm$ 12.19 (17.57–65.37), 17.10 $\pm$ 2.46 (12.28–21.92), and 11.00 $\pm$ 1.68 (12.81–17.06) months, respectively. The Log-rank test suggested a significant difference in survival among the 4 groups ( $P<$ 0.001). A significant difference in OS was observed between the NN and HN group ( $P=$ 0.046), between the NN and HH group ( $P=$ 0.011), between the HN and NH group ( $P=$ 0.008), between the HN and HH group ( $P<$ 0.001), and between the NH and HH group ( $P=$ 0.033). There was no significant survival difference only between the NN and NH group ( $P=$ 0.538).

3.3 Predictors of overall survival in patients with advanced NSCLC

The results of univariate and multivariate cox regression analysis for overall survival are summarized in Table 2. Univariate analyses indicated that the clinical factors of CYFRA 21-1 rather than CEA, group according to CEA and CYFRA 21-1 levels (NN, HN, NH, and HH), sex, tumor diameter, serum CRP level, smoking status, treatment modalities were significant prognostic factors.

Multivariate analysis was performed using the factors proven significant in the univariate analysis. A backward elimination (Likelihood Ratio) algorithm was used to produce the most parsimonious model by removing nonsignificant variables and re-estimating the hazard ratio, 95% CI, and p-value at each step. In multivariate analyses, the HN group (HR 0.520, 95% CI 0.309–0.878, $P=$ 0.014), female sex (HR, 0.685, 95% CI 0.498–0.944, $P=$ 0.021), serum CRP level (HR 1.057, 95% CI 1.034–1.080, $P<$ 0.001), chemotherapy (HR 0.324, 95% CI 0.228–0.460, $P<$ 0.001), and chemotherapy/radiotherapy (HR 0.266, 95% CI 0.171–0.414, $P<$ 0.001) were found to be independent prognostic factors for overall survival (Table 2). The HH group (HR 1.454, 95% CI 0.974–2.172, $P=$ 0.067) showed a trend to decreased overall survival.

4. Discussion

In this study, we found that the clinical stage did not directly affect survival in advanced NSCLC. Patients in the HN group had significantly higher 5-year survival rate (32.2 $\pm$ 8.9%) than those in the NN (7.4 $\pm$ 6.4%), NH (11.6 $\pm$ 6.0%), and HH group (6.4 $\pm$ 3.3%) (Fig. 1). The fact that the survival rate is highest in the HN group (stage 4, 82.6%) with high CEA but normal CYFRA 21-1 level compared to the HH group (stage 4, 85.3%) with high CEA and CYFRA 21-1 level is very attractive. It suggests that there are other factors that affect patient survival besides the initial extent of cancer metastasis.

Several studies have reported that serum CEA levels were significantly higher in patients with M1 stage than in patients with M0 stage [6, 15, 27, 28]. Tomita et al. [27] found that the serum CEA level was not always related to TNM stage, but there were significant differences in the serum CEA level between M0 and M1 NSCLC patients. Ursavaş et al. [6] reported that a high level of serum CEA may be an indication to perform routine investigation of distant metastases, even in the absence of symptoms and signs. Lee et al. [15] found that abnormal serum CEA levels were strongly correlated with increased whole-body metastatic potential in treatment-naïve stage IV NSCLC. However, patient survival was not investigated in the reports by Ursavaş et al. [6] and Lee et al. [15]. Our data are in partial agreement with previous results; the clinical stage of 4 was found more frequently in patients with elevated serum CEA levels. The HN and HH groups which have high serum CEA levels showed a higher percentage of stage 4 than the NN and NH group. The metastatic potential and recurrence may be important in relation to the survival of patients with non-advanced-stage disease, but not to patients who already have advanced-stage disease. Tumor mass and progression rate may be more important in relation to patient prognosis in advanced disease. Only patients with stage III–IV NSCLC were included in the present study, and we conclude that the serum CEA level itself is not an independent prognostic factor. Even if the CEA level is high, certain factors that reduces CYFRA 21-1 in advanced NSCLC have led to improved survival.

CYFRA 21-1 is released from apoptotic cells during tumor necrosis [12]. Doweck et al. [29] reported that CYFRA 21-1 reflects the tumor mass more accurately than the disease stage, as expressed by the TNM in patients with head and neck cancer. The prognostic value of CYFRA 21-1 in NSCLC was reported previously [29]. A meta-analysis of 2,063 patients with NSCLC of any stage showed that a high pre-treatment CYFRA 21-1 level was an unfavorable prognostic factor regardless of the planned treatment [30]. Our results are consistent with these previous reports. In the univariate analysis, CYFRA 21-1 was proven as more significant prognostic factor rather than CEA. Among the patients with high level of CEA, patients in the HN group with normal CYFRA 21-1 had the best overall survival rate, while HH group with high CYFRA 21-1 had the worst overall survival.

Kim et al. [31] demonstrated that patients with a high pre-treatment CEA level showed better responses and a longer progression-free survival (PFS) in NSCLC patients treated with gefitinib or erlotinib. They also demonstrated that patients with a low pre-treatment CYFRA 21-1 level showed a longer PFS and OS, a finding similar to that in the present study. In contrast to this study, we extended our analysis regardless of the treatment. Moreover, we found that patients with an elevated level of CEA with a normal level of CYFRA 21-1 showed the best prognosis by measuring CEA and CYFRA 21-1 simultaneously.

In a recent meta-analysis, pretreatment levels of both CEA and CYFRA 21-1 were found to predict therapeutic response [32]. Although it seems to be contrary to our findings, the authors emphasized the usefulness of the markers in monitoring therapeutic response, rather than predicting prognosis at baseline.

Serum inflammatory marker such as CRP was evaluated as a prognostic factor in this study. Previously, elevated CRP level was correlated with the tumor size, staging, and poor prognosis [33]. CRP was reported as prognostic marker for tumor invasion and metastasis [34, 35]. In the multivariate analysis for predictors of overall survival (OS) of our study, CRP was found as one of the final risk factors for overall survival.

There are several limitations of this study. First, it was a retrospective study based on patients at one center, and a selection bias could not be completely avoided. Second, we considered only whether or not tumor markers were elevated, data that did not reflect the differences according to the degree of elevation. Third, we did not review the detailed treatment regimens given to the patients. Fourth, we have to consider the fact that there were advances in anti-cancer therapy including the development of targeted therapy during the long time interval of this cohort.

In conclusion, patients with baseline high serum CEA but low CYFRA 21-1 level have a significant longer overall survival regardless of clinical stage in advanced NSCLC. Further study is needed to elucidate the biologic basis that how the tumor markers affect survival and the differences according to the histologic type in advanced NSCLC.

Footnotes

Conflict of interest

All authors declare that they have no conflict of interest.

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Prognostic value of baseline carcinoembryonic antigen and cytokeratin 19 fragment levels in advanced non-small cell lung cancer

Abstract

BACKGROUND:

OBJECTIVE:

METHODS:

RESULTS:

CONCLUSIONS:

Keywords

1. Introduction

2. Materials and methods

2.1 Patients and materials

Table 1 Baseline characteristics according to NN, HN, NH, and HH groups

3. Results

3.1 Baseline characteristics of 4 groups according to CEA and CYFRA 21-1 levels

3.3 Predictors of overall survival in patients with advanced NSCLC

4. Discussion

Footnotes

Conflict of interest

References

Table 1
Baseline characteristics according to NN, HN, NH, and HH groups