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Abstract

BACKGROUND:

Epithelial ovarian cancer is a highly lethal gynecological malignancy. Accurate and cost-effective predictive tools to estimate the prognosis of patients with epithelial ovarian cancer before treatment are currently lacking.

OBJECTIVE:

The purpose of this study was to evaluate the prognostic significance of pretreatment serum levels of carcinoembryonic antigen (CEA) and carbohydrate antigen-125 (CA-125) in primary epithelial ovarian cancer.

METHODS:

Between 2008 and 2016, 326 patients with a diagnosis of primary epithelial ovarian cancer were retrospectively reviewed. We attempted to identify an optimal cut-off value of CEA to predict survival using ROC curve analysis. Cox regression univariate and multivariate analyses were used to evaluate prognostic factors.

RESULTS:

The optimal cut-off value of CEA was 2.6 ng/mL. In univariate and multivariate analyses, FIGO stage and pretreatment CA-125 and CEA levels significantly predicted progression-free and overall survival. The 5-year progression-free survival rate for patients with both a CEA level $<$ 2.6 ng/mL and CA-125 level $<$ 35 U/mL was 84%, compared to only 33% for the patients with higher levels of both markers ( $p<$ 0.001). The 5-year cancer specific survival rate was 94% in those with a CEA level $<$ 2.6 ng/mL and CA-125 level $<$ 35 U/mL, and only 39% for those with higher levels of both markers ( $p<$ 0.001).

CONCLUSIONS:

In addition to traditional prognostic factors, a pretreatment serum CEA level $\geqslant$ 2.6 ng/mL and CA-125 level $\geqslant$ 35 U/mL were also independent prognostic factors for epithelial ovarian cancer. Patients with an elevated CEA and/or CA-125 level before treatment should be considered to be at high-risk of recurrence and death.

Keywords

Epithelial ovarian cancer carcinoembryonic antigen carbohydrate antigen 125

1. Introduction

Epithelial ovarian cancer is a common gynecological malignancy in developed countries, and is one of the leading causes of death from female malignancy due to difficulty in making an early diagnosis, a high recurrence rate, and because it has usually spread beyond the ovaries at the time of diagnosis [1]. Past studies have reported that changes in perioperative serum carbohydrate antigen-125 (CA-125) level are strongly associated with relapse in patients with advanced ovarian cancer who received optimal debulking surgery [2]. Currently, accurate and cost-effective predictive tools for the prognosis of epithelial ovarian cancer before any treatment are lacking, which may lead to a delay in diagnosis and worse outcomes.

The carcinoembryonic antigen (CEA) family is a superfamily of glycoproteins with a carboxyl terminal providing linkage to cell membranes [3]. Most CEAs in healthy people are located in colon and play a role in cell adhesion, signal transduction and regulation [4]. It is thought that tumor cells produce this protein more and altered in posttranscriptional regulation [5]. Previous studies have shown that the level of CEA can be used to assess the prognosis and monitor recurrence in patients with colorectal cancer, and also that it can predict the response to surgical and chemotherapy treatment [6, 7]. Moreover, pretreatment CEA level has been shown to be an independent factor for prognosis and survival in breast cancer, colorectal cancer, gastric cancer, and non-small cell lung cancer [8, 9].

Nevertheless, few studies have investigated the prognostic significance of CEA level in patients with epithelial ovarian cancer, and the results have been controversial. In one meta-analysis, Guo and colleagues [10] reported that the combination of serum CA-125, CA-199 and CEA had a relatively high sensitivity and specificity for the diagnosis of epithelial ovarian cancer. In 2015, Sagi-Dain and colleagues found that a higher CEA level could be a promising tool to differentiate metastatic tumors from primary ovarian malignancy, and in the diagnosis of a mucinous histology [11]. In 2018, Lin and colleagues [12] investigated the prognostic significance of preoperative serum CEA level in small sample of patients with a primary mucinous histology of ovarian cancer, and they found that elevated preoperative serum CEA level may indicate a poorer prognosis.

To date, powerful evidence about the prognostic significance of pretreatment serum CEA level in patients with epithelial ovarian cancer is lacking. Therefore, in this study, we aimed to evaluate the prognostic value of pretreatment levels of CEA and CA-125 in patients with primary epithelial ovarian cancer.

2. Material and methods

2.1 Study population

This retrospective cohort study included patients with primary epithelial ovarian cancer treated at Kaohsiung Chang Gung Memorial Hospital between 2008 and 2016. All patients had a histopathologically confirmed diagnosis of epithelial ovarian cancer and pretreatment measurements of serum CEA and CA-125. Data acquired from medical records included age, FIGO (International Federation of Gynecology and Obstetrics) stage, histologic type, tumor size, and surgical debulking status. Optimal debulking status was defined as a residual tumor $<$ 1 cm in size. The largest tumor size was determined from surgical notes recorded by gynecologic oncologists. Postoperative adjuvant chemotherapy was delivered according to our institutional guidelines. Patients who received neoadjuvant chemotherapy followed by interval debulking surgery were also included. The Institutional Review Board of Chang Gung Memorial Hospital approved this study (201901805BO).

All patients were followed up every 3 months in the first 2 years after completing primary treatment, and the interval was extended to every 3–6 months in the following 3 years and then to every 6–12 months thereafter. Details of clinical symptoms and pelvic examinations were recorded, and serial chest X-rays and computed tomography scans (if necessary) were arranged. Serum CEA level was analyzed on ADVIA Centaur XP with principle method of chemiluminescence immunoassay (CLIA). Architect CA-125 II assay, a chemiluminescent microparticle immunoassay (CMIA) was used for quantitative determination of serum CA-125. Both tumor markers were measured during every follow-up visit.

2.2 Statistical analysis

All statistical analyses were performed using IBM SPSS software (version 20). Receiver operating characteristic (ROC) curves and areas under the ROC curves (AUCs) were used to analyze CEA. We attempted to identify an optimal cut-off value of CEA to predicting survival by determining the point with a maximal Youden index value on the ROC curve. The cut-off value for an elevated CA-125 level ( $>$ 35 U/mL) was determined according to the upper reference limit [13]. Differences between proportions were evaluated using the chi-square test, and the Mann-Whitney U test was used to compare medians between groups. Univariate survival curves for progression-free survival (PFS) and cancer specific survival (CSS) were estimated using the Kaplan-Meier method. Multivariate Cox regression analysis was used to compare independent prognostic factors for PFS and CSS and to calculate hazard ratios (HRs). All significant parameters in univariate analyses were entered into a multivariate model, and those with $P$ values $>$ 0.05 were excluded. PFS was calculated from the date of diagnosis to the date of disease recurrence or progression. CSS was calculated from the date of diagnosis to the date of cancer related death. A $P$ value $<$ 0.05 was considered to be statistically significant.

Table 1
Clinical characteristics of the 326 patients with primary epithelial ovarian cancer

Characteristics	Number (%)
Median age (range), years	54 (20–89)
FIGO stage
I	126 (38.7)
II	36 (11.0)
III	125 (38.3)
IV	39 (12.0)
Histology
Serous	115 (35.3)
Mucinous	43 (13.2)
Clear cell	57 (17.5)
Endometrioid	62 (19.0)
Others	49 (15.0)
Tumor size (cm)
$<$ 10	175 (53.7)
$\geqq$ 10	151 (46.3)
Surgical debulking
Optimal	250 (76.7)
Suboptimal	76 (23.3)
Adjuvant chemotherapy
Yes	245 (75.1)
No	81 (24.9)
Pretreatment CA-125 level (U/mL)
$<$ 35	48 (14.7)
$\geqq$ 35	278 (85.3)
Pretreatment CEA level (ng/mL)
$<$ 5	279 (85.6)
$\geqq$ 5	47 (14.4)

Table 2

Clinical characteristics of the patients with respect to preoperative CEA level (ng/mL)

	CEA $<$ 2.6 (N $=$ 239) $n$ (%)	CEA $\geqq$ 2.6 (N $=$ 87) $n$ (%)	$P$ value
Age, median, years	52 (45–60)	57 (51–68)
(25 ${}^{\text{th}}$ –75 ${}^{\text{th}}$ )
FIGO stage			0.953
Early (I, II)	119 (49.8)	43 (49.4)
Advanced (III, IV)	120 (50.2)	44 (50.6)
Histology			0.001
Serous	97 (40.6)	18 (20.7)
Mucinous	26 (10.9)	17 (19.5)
Clear cell	49 (20.5)	8 (9.2)
Endometrioid	40 (16.7)	22 (25.3)
Others	27 (11.3)	22 (25.3)
Tumor size (cm)			0.152
$<$ 10	134 (56.1)	41 (47.1)
$\geqq$ 10	105 (43.9)	46 (52.9)
Surgical debulking			0.047
Optimal	190 (79.5)	60 (69.0)
Suboptimal	49 (20.5)	27 (31.0)
Pretreatment			0.178
CA-125 level (U/mL)
$<$ 35	39 (16.3)	9 (10.3)
$\geqq$ 35	200 (83.7)	78 (89.7)

3. Results

A total of 562 primary ovarian cancer patients were treated during the study period, of whom 201 with no pretreatment CEA or CA-125 data and another 35 with a histological diagnosis other than primary epithelial ovarian cancer were excluded. The remaining 326 patients were included and analyzed, and the median follow-up period was 42.5 months (range, 1–132 months). The clinicopathological characteristics of the patients including age, early (I and II) and advanced (III and IV) FIGO stage, histologic type (serous, mucinous, clear cell, endometrioid or others), tumor size ( $<$ 10 cm vs. $\geqslant$ 10 cm), surgical debulking status (optimal vs. suboptimal) and pretreatment CA-125/CEA levels are summarized in Table 1. Only 14.4% of patients had a CEA level over the upper reference limit of 5 ng/mL. ROC curve analysis showed that the optimal cut-off value of CEA to predict survival was 2.6 ng/mL, with an AUC of 0.6 (95% confidence interval (CI): 0.53–0.67, $p=$ 0.003). Of the 326 patients, 239 (73.3%) had a pretreatment CEA level $<$ 2.6 ng/ml and 87 (26.7%) had a pretreatment CEA level $\geqslant$ 2.6 ng/mL. The median age at the time of diagnosis in the pretreatment CEA $<$ 2.6 ng/mL group was significantly younger than that in the pretreatment CEA $\geqslant$ 2.6 ng/mL group. In histologic type analysis, the serous and clear cell types accounted for the majority of cases in the CEA $<$ 2.6 ng/mL group, while higher frequency of mucinous and endometrioid type tumors and lower frequency of serous and clear cell type tumors in group of CEA $>$ 2.6. Most of the patients in CEA $<$ 2.6 ng/mL group achieved optimal debulking status, however there were no statistically significant differences in terms of FIGO stage, tumor size, and pretreatment CA-125 level between the two groups. The clinicopathological characteristics of the patients with respect to preoperative CEA level are summarized in Table 2.

In univariate analysis, age, FIGO stage, histology type, surgical debulking status, pretreatment CA-125 and CEA level were significantly associated with PFS and CSS respectively. Tumor size was significantly associated with PFS ( $p=$ 0.002) but not CSS ( $p=$ 0.581). The results of multivariate Cox proportional hazard regression analysis after adjusting for age, histologic type, and debulking status for 5-year PFS and CSS are shown in Table 3. The results showed that FIGO stage, pretreatment CA-125, and CEA levels remained independent prognostic factors affecting PFS and CSS. The HRs of 5-year PFS were 5.118 (95% CI, 3.152–8.311) for advanced FIGO stage, 1.819 (95% CI, 1.249–2.651) for CEA $\geqslant$ 2.6 ng/mL, and 2.634 (95% CI, 1.262–5.496) for CA-125 $\geqslant$ 35 U/mL, while the HRs of 5-year CSS were 3.604 (95% CI, 2.019–6.434) for advanced FIGO stage, 2.845 (95% CI, 1.834–4.413) for CEA $\geqslant$ 2.6 ng/mL, and 5.437 (95% CI, 1.648–17.559) for CA-125 $\geqslant$ 35 U/mL.

Table 3
Univariate and multivariate analysis of factors related to PFS and CSS ${}^{1}$

Variable	Univariate analysis				Multivariate analysis
	PFS		CSS		PFS		CSS
	HR (95% CI)	$P$ value	HR (95% CI)	$P$ value	HR (95% CI)	$P$ value	HR (95% CI)	$P$ value
Age (ys)
$<$ 50	–	0.010	–	0.023	–	0.209	–	0.374
$\geqq$ 50	1.559 (1.110–2.190)		1.638 (1.071–2.504)		0.787 (0.541–1.143)		0.803 (0.496–1.302)
Stage
Early (I, II)	–	$<$ 0.001	–	$<$ 0.001	–	$<$ 0.001	–	$<$ 0.001
Advanced (III, IV)	5.776 (3.940–8.470)		4.088 (2.620–6.379)		5.118 (3.152–8.311)		3.604 (2.019–6.434)
Histology
Serous	–	$<$ 0.001	–	0.002	–	–	–	–
Mucinous	0.409 (0.227–0.737)	0.003	0.622 (0.314–1.234)	0.174	1.632 (0.802–3.322)	0.177	–	–
Clear cell	0.558 (0.352–0.882)	0.013	0.739 (0.424–1.290)	0.288	1.704 (1.015–2.861)	0.044	–	–
Endometrioid	0.235 (0.131–0.424)	$<$ 0.001	0.316 (0.155–0.645)	0.002	0.580 (0.305–1.104)	0.097	0.671 (0.305–1.475)	0.321
Other	1.115 (0.735–1.694)	0.608	1.387 (0.848–2.288)	0.201	–	–	–	–
Size (cm)
$<$ 10	–	0.002	–	0.581	–	0.266	–	–
$\geqq$ 10	0.594 (0.429–0.824)		0.897 (0.609–1.320)		0.802 (0.544–1.183)
Debulking
Optimal	–	$<$ 0.001	–	$<$ 0.001	–	0.001	–	0.003
Suboptimal	3.895 (2.683–5.655)		3.621 (2.299–5.705)		1.974 (1.305–2.985)		2.184 (1.301–3.666)
CEA (ng/mL)
$<$ 2.6	–	0.009	–	$<$ 0.001	–	0.002	–	0.001
$\geqq$ 2.6	1.562 (1.117–2.186)		2.460 (1.665–3.635)		1.819 (1.249–2.651)		2.845 (1.834–4.413)
CA125 (U/mL)
$<$ 35	–	0.001	–	0.001	–	0.010	–	0.005
$\geqq$ 35	4.429 (2.173–9.025)		7.505 (2.379–23.672)		2.634 (1.262–5.496)		5.437 (1.648–17.559)

${}^{1}$ After adjusting for age, histology, and surgical debulking status.

Figure 1.

Progression-free survival (PFS) curves of epithelial ovarian cancer patients related to pretreatment CEA (ng/mL) and CA-125 (U/mL) levels.

Figure 2.

Cancer specific survival (CSS) curves of epithelial ovarian cancer patients related to pretreatment CEA (ng/mL) and CA-125 (U/mL) levels.

As shown in Fig. 1, the PFS was correlated to pretreatment CEA and CA-125 levels. The 5-year PFS rate for patients with both a CEA level $<$ 2.6 ng/mL and CA-125 level $<$ 35 U/mL was 84%, compared to 45% for patients with an elevation in either CEA or CA-125 level, and only 33% for those with higher levels of both markers. The CSS was also correlated with pretreatment CEA and CA-125 levels, with 5-year CSS rates of 94% in those with a CEA level $<$ 2.6 ng/mL and CA-125 level $<$ 35 U/mL, 65% for patients with an elevation in either CEA or CA-125 level, and only 39% for those with higher levels of both markers (Fig. 2). This difference was statistically significant ( $p<$ 0.001) and clearly shown in the figures.

4. Discussion

Prior to this study, there was lack of powerful evidence about the prognostic significance of pretreatment serum CEA level in patients with epithelial ovarian cancer. Our data showed that a pretreatment serum CEA value $\geqslant$ 2.6 ng/ml was an independent prognostic factor in these patients, and that they had a lower PFS and CSS compared to the patients with a CEA level $<$ 2.6 ng/ml. In multivariate analysis, FIGO stage, debulking status, and pretreatment CEA and CA-125 levels were independent prognostic factors. The prognostic roles of FIGO stage and debulking status are consistent with previous studies [14, 15], while to the best of our knowledge, this is the first study to report that CEA level was an independent prognostic factor for epithelial ovarian cancer.

The prognostic value of CEA has been investigated in some studies, however the results have been controversial. In 2017, Nomelini et al. reported that the CEA level was significantly higher in patients with non-serous neoplasm, but that it was not statistically a prognostic factor for ovarian cancer [16]. A recent study from Beijing demonstrated the prognostic significance of preoperative serum CEA level in patients with primary mucinous ovarian carcinoma in univariate analysis but not in multivariate analysis [12]. In other previous small group studies, serum CEA level has been reported to be higher in patients with the mucinous type of ovarian cancer, and then to characteristically return to a normal level within 8 weeks after optimal debulking surgery. In these studies, the disappearance or a persistently low level of serum CEA during treatment course was associated with a good prognosis [17, 18, 19]. In addition to the serum level of CEA, the Danish ‘MALOVA’ ovarian cancer study found that the protein expression level of CEA was an independent prognostic factor for epithelial ovarian cancer, and that a higher proportion of mucinous tumors were CEA-positive compared with other histologic types [20].

Although past studies have revealed a more specific role of elevated CEA value in patients with the mucinous type of ovarian cancer, our data showed a similar percentage of patients with the serous, endometrioid, and mucinous types of ovarian cancer (20.7%, 19.5% and 25.3%, respectively) had a CEA level elevation when a more precise cut-off value of 2.6 ng/mL was used according to ROC curve analysis. To redefine a cut-off value for CEA levels is necessary since the median value of CEA in our study cohort is very low (median $=$ 1.47 ng/mL), it might be proper to revise the cut-off value downwardly. The similar situation was also found in other types of cancers. In non-small cell lung cancer and colon cancer, CEA has been a useful tumor marker in past studies and plays a potential prognostic role. Even though, the cut-off value varied between 2.5 and 40 ng/ml among the varies studies [8, 21]. In multivariate analysis of PFS and CSS in our study, pretreatment CEA level was still an independent prognostic factor after adjusting for other variables including histologic type. These findings indicate that CEA level plays a role not only in mucinous but also in serous, clear cell, and endometrioid types ovarian cancer, which account for a large proportion of all epithelial ovarian cancers. Furthermore, measuring the serum level of CEA is easier in clinical practice than measuring the CEA level in tissue protein.

Serial measurements of CA-125 are routinely used in clinical practice to monitor treatment response during chemotherapy and recurrence during surveillance. However, the prognostic role of CA-125 in epithelial ovarian cancer has also been extensively surveyed. Many investigators have found that a high postoperative decline in serum CA-125 level was associated with an increased likelihood of achieving optimal primary cytoreduction [2, 22]. Thus, a perioperative decline in serum CA-125 could be used as an early biomarker to predict disease-specific survival in patients who undergo primary cytoreductive surgery for advanced stage disease. In our study cohort, we did not focus on changes in perioperative CA-125 level since the baseline characteristics of our patients were different to those of previous studies. As many as 40% of our patients had FIGO stage I disease, and only about half had a CA-125 level $\geqslant$ 35 U/mL, which is consistent with a previous report [23]. Therefore, it would not make sense to assess the association between perioperative changes in CA-125 level and surgical debulking status if we did not exclude patients with stage I and II disease. Other investigators have reported that single pretreatment CA-125 level was an independent prognostic factor but with different cut-off levels from 30 to 65 U/mL [24, 25]. In addition, Menczer et al. investigated all stages of disease and found that patients with a CA-125 level $<$ 35 U/mL had better PFS and OS, which is similar to our results [26]. The previous studies were consistent in showing elevated CA-125 level with poor prognosis and our study also verified this association.

There are several limitations to this study. First, this was a retrospective cohort study, and patients were excluded if data on pretreatment serum CEA level was not available. This may have caused selection bias. Second, the limited number of articles discussing the prognostic role of CEA in epithelial ovarian cancer may increase the difficulty in describing a clear pathogenesis. Pretreatment CEA level may carry prognostic information in different types of epithelial ovarian cancer, but itself is not strong enough to guide the treatment. Third, the predictive role of CEA value in different histological subtypes was unable to be analyzed due to the limited number of cases. Further multi-center validation studies with more cases may be needed to minimize selection bias and potential confounding factors such as difference in geographic distribution or other benign physiological status that would influence CEA level.

In conclusion, our results provide evidence that an elevated pretreatment serum CEA level $\geqslant$ 2.6 ng/mL may be an independent prognostic factor for epithelial ovarian cancer, not only in the mucinous type but also in serous, clear cell, and endometrioid types of ovarian cancer. The detection of serum CEA and CA-125 has the benefits of being cheap and easy in clinical practice which may act as a good and straightforward communication tool between clinicians and patients before medical treatment or staging surgery. Our study may alert clinicians that after standard treatment, patients with an elevated CEA and/or CA-125 levels before treatment may need more close follow-up. Further validation studies with a larger sample size may be needed to validate our findings.

Footnotes

Acknowledgments

This work was supported by the research grant of Chang Gung Memorial Hospital [CMRPG8G0111-3]. We also thank the Biostatistics Center of Kaohsiung Chang Gung Memorial Hospital for assistance with the statistical analysis.

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Prognostic significance of elevated pretreatment serum levels of CEA and CA-125 in epithelial ovarian cancer