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Original Article

Value of pre-operative serum CA125 level for prediction of prognosis in

patients with endometrial cancer

Yu-Li CHEN,1 Chia-Yen HUANG,1 Tsai-Yen CHIEN,1 Shih-Hung HUANG,2 Ching-Jung WU3

and Chih-Ming HO1,4,5

1Gynecologic Cancer Center, Department of Obstetrics and Gynecology, Cathay General Hospital, Departments of

2Pathology,

3Radiation Oncology, Cathay General Hospital,

4School of Medicine, Fu Jen Catholic University, Hsinchuang, and

5School of

Medicine, Taipei Medical University, Taipei, Taiwan

Background:High pre-operative CA125 levels in women with endometrial cancer may be related to lymph node

metastases and poor prognosis.

Aim: To evaluate whether pre-operative cancer antigen 125 (CA125) levels are associated with lymph node metastases

and prognosis in endometrial cancer.

Methods: One hundred and twenty women with endometrial cancer were retrospectively reviewed for pre-operative

CA125 levels. The results were then correlated with the clinicopathological outcome.Results: An elevated CA125 (>40 UmL) was significantly correlated with higher stage, higher grade, increased depth of

myometrial invasion, lymph node metastases and the presence of lympho-vascular space involvement in endometrial

cancer. Five-year overall survival (OS) and recurrence-free survival (RFS) rates were significantly higher in women with

endometrial cancer with CA125 40 UmL than those with CA125 > 40 UmL (P< 0.001). When women

were further stratified according to CA125 levels and lymph node status, OS and RFS were highest for those with

CA125 40 UmL and without lymph node metastases, and lowest for those with lymph node metastases and

CA125 > 40 UmL (P< 0.001).

Conclusion:The testing of pre-operative CA125 levels may a useful prognostic tool in endometrial cancer management.

Key words: lymphadenectomy, overall survival, pre-operative CA125, recurrence-free survival, stage I endometrial cancer.

IntroductionUterine cancer is the seventh most common cause of

malignancy in Asian women, with approximately 131,178

newly diagnosed cases in 2008.1 In Australia and New

Zealand, uterine cancer is the fifth most common female

cancer.1

Since 1988, surgical staging methods, including

simple total hysterectomy, bilateral salpingo-oophorectomy,

pelvic andor para-aortic lymph node dissection and washing

cytology, were the standard treatments for endometrial

cancer.2

However, the benefits of routine pelvic andor

para-aortic lymphadenectomy in endometrial cancer are

questioned as systematic pelvic lymphadenectomy does not

improve recurrence-free survival (RFS) or overall survival

(OS).

35

Postoperative complications after lymphadenectomymay also restrict surgical staging in women with endometrial

cancer.6

The pre-operative evaluation of women with endometrial

cancer, who may benefit from complete surgical staging or

less invasive surgery, is important. Women with high

probabilities of metastatic disease usually require complete

surgical staging. Women with a minimal likelihood of extra-

uterine disease may be successfully treated using less invasive

surgery. However, pre-operative factors, such as age,

histology type, tumour grade and lympho-vascular space

involvement (LVSI), cannot accurately predict lymph node

metastases,7,8

and frozen section correlates poorly with the

final pathologic diagnosis in terms of the depth of

myometrial invasion and tumour grade.9 The groups ofSood and Hsieh10,11 proposed that pre-operative serum

CA125 might be a useful marker in the prediction of extra-

uterine spread, lymph node metastases and prognosis.

CA125 was first reported by Bast et al.12 as a circulating

antigen in women with epithelial ovarian cancer. CA125

levels reflect residual tumour volume and are currently

routinely used to monitor response to chemotherapy and the

detection of disease recurrence.12,13

However, the assessment

Correspondence: Chih-Ming Ho, M.D., Ph.D., Gynecologic

Cancer Center, Cathay General Hospital, 280 Section 4,

Jan-Ai Road, Taipei 110, Taiwan. Email: cmho@cgh.org.tw

The order of authorship is related to the relative individualcontributions to the paper.

Received 19 November 2010; accepted 11 April 2011.

2011 The Authors 397

Australian and New Zealand Journal of Obstetrics and Gynaecology 2011 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists

Australian and New Zealand Journal of Obstetrics and Gynaecology2011; 51: 397402 DOI: 10.1111/j.1479-828X.2011.01325.x

Te Australian and

New Zealand Journalof Obstetrics andGynaecology

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of pre-operative serum CA125 levels in endometrial cancer

is not widely used in clinical practice. In previous studies, an

appropriate cut-off pre-operative CA125 value for predicting

lymph node metastases and prognosis was not

consistent.10,11,14

We hypothesised that elevated pre-operative CA125 levels

might indicate micrometastasis as well as gross extra-uterine

spread. To test this hypothesis, we retrospectively reviewed

pre-operative CA125 levels in 120 women with endometrialcancer and evaluated the association of these values with

various clinicopathologic factors.

Materials and methods

Between January 1998 and December 2006, a total of 184

women were diagnosed with endometrial cancer in a search

of the tumour registry of Cathay General Hospital (CGH).

One hundred and twenty of the 184 cases had been assessed

for pre-operative CA125 and were included in this study. All

of the 120 women underwent surgical treatment in CGH.

Staging surgery included simple or radical hysterectomy,

bilateral salpingo-oophorectomy, lymph node dissection and

washing cytology. Detailed records were retrospectivelyobtained until June 2010. The institutional review board

approved this study.

Disease staging was based on the 1988 International

Federation of Gynecology and Obstetrics (FIGO) guidelines.

The reasons for the 32 women (32120, 26.7%) without

lymphadenectomy were as follows: no or minimal

myometrial invasion from the confirmation of frozen

sections during operation in cases (younger than 60 years

old) with pre-operative curettage diagnosis of grade 1 or 2

tumour, or major comorbidities for surgery, including

morbid obesity and poor cardiac or pulmonary function. For

these women, the FIGO clinical staging system was used. A

retrospective review of medical records was performed,including pre-operative and postoperative clinicopathologic

variables that would affect the prognosis. These parameters

included: age, body mass index, menopause status, histologic

type, stage, grade, tumour size, depth of myometrial

invasion, LVSI, lymph node status and pre-operative CA125

serum levels. The association between pre-operative CA125

levels and 5-year OS or RFS was also investigated.

After surgery and pathologic examinations, the

recommendations for postoperative treatments, including

adjuvant radiotherapy (RTx), chemotherapy (CTx), and

RTx and CTx, were primarily based on National

Comprehensive Cancer Network (NCCN) guideline of

endometrial carcinoma http://www.nccn.org/professionals/

physician_gls/f_guidelines.asp. However, if sexual life wasemphasised by those who needed adjuvant treatment, six

cycles at 21-day intervals of cisplatin-based CTx would be

suggested instead of RTx or observation would be

considered for stage I cases. In our study, we divided the

women receiving adjuvant treatment into CA125 > 40

group and CA125 40 group. The association between

disease recurrence and adjuvant treatment was evaluated

within each group.

The follow-up schedules for women with endometrial

cancer in CGH were as follows: a pelvic examination and

vault smear every 3 months for the first 3 years, and every

6 months thereafter. A chest X-ray was performed annually.

On each visit, tumour markers, such as cancer antigen 125

(CA125) and carcinoembryonic antigen, were tested.

Computed tomography (CT) or magnetic resonance

imaging was performed in cases of suspected recurrence.

Abnormal findings of imaging studies, elevated tumourmarker (2 fold upper normal limits) in two consecutive

tests in a 2-week interval, positive aspiration cytology from

ascites or pleural effusion or biopsy-proven tissue, if

possible, was defined as disease recurrence.

Statistical analyses were performed using the Statistical

Package of Social Studies (SPSS) version 15.0 (SPSS Inc.,

Chicago, IL, USA) for Windows. The values of pre-

operative CA125 were presented by receiver operating

characteristic (ROC) curve. The chi-square was employed to

determine the association of CA125 levels with

clinicopathologic variables, and the logistic regression model

was used to evaluate the clinicopathological variables

predicting lymph node metastases. Time of follow-up was

measured from the date of diagnosis to the date of the lastvisit or death. OS was calculated from the date of diagnosis

to the date of death caused by the disease or, for surviving

patients, to the date of the last follow-up. RFS was defined as

the length of time, after completing the primary treatment,

during which women survived without any clinical sign of

disease relapse. The survival rate was evaluated using the

KaplanMeier method, and Cox regression analysis was used

to evaluate prognostic factors for RFS and OS. The

Binomial test was used to analyse the association between

disease recurrence and adjuvant treatment. A P value

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versus >40 UmL) was significantly associated withadvanced stage disease (P < 0.001), higher tumour grade

(P< 0.001), deep myometrial invasion (P < 0.001), LVSI

(P= 0.002) and lymph node metastasis (P = 0.004). In

addition to CA125, our results also revealed LVSI (presence

versus absence, P < 0.001), stage (III and IV versus I and

II,P< 0.001), tumour grade (1 and 2 versus 3, P= 0.004)

and myometrial invasion (12 versus >12, P= 0.024)

were related to lymph node metastasis.

As exhibited in Table 2, women with advanced disease

(P< 0.001 for OS, P< 0.001 for RFS), lymph nodal

involvement (P< 0.001 for OS, P < 0.001 for RFS), pre-

operative CA125 levels more than 40 UmL (P< 0.001 for

OS, P< 0.001 for RFS) and higher tumour grade

(P < 0.001 for OS, P< 0.001 for RFS) had significantly

lower 5-year OS and RFS. Elevated pre-operative CA125

was the only independent factor for predicting poor RFS

(P= 0.01), but not OS, by Cox multivariate analysis(Table 3A).

When focusing on the 88 stage I cases with endometrial

cancer, our results demonstrated that stage (P= 0.03), age

(P= 0.03), CA125 (P = 0.01) and grade (P < 0.001) were

significant prognostic factors for RFS in stage I patients.

However, lymph node dissection was not a significant

prognostic factor for RFS and OS in stage I patients.

Multivariate analysis by Cox regression model also exhibited

that elevated CA125 (P= 0.02), age (P= 0.03) and grade

(P = 0.008) were independent predictors of poor RFS in

stage I endometrial cancer (Table 3b). When the stage I

cases were divided into CA125 40 UmL (75 cases) and

CA125 > 40 UmL (13 cases) groups, the 5-year RFS wasFigure 1 The receiver operating characteristic (ROC) curve of

values of pre-operative CA125.

Table 1 The associations between CA125 and various variables

in 120 women with endometrial carcinoma

Variables

CA125 40

(UmL)

CA125 > 40

(UmL) P*

Stage

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significantly higher in women with CA125 40 UmL than

those with CA125 > 40 UmL (96.1% versus 70.0%,

P= 0.001, by Log rank test) (Fig. 2).

After stratifying the 120 women according to pre-

operative serum CA125 levels, with a cut-off point of

40 UmL, and postoperative lymph node status, those with

CA125 40 UmL and without lymph node involvement

had the highest OS and RFS when compared with the

normal population, followed by those with CA125 >

40 UmL and without lymph node metastases, and those

with CA125 40 UmL and lymph node metastases. The

women with CA125 > 40 UmL and lymph node

involvement had the lowest life expectancy when referenced

against the 5-year survival of normal population (P< 0.001,

by Log rank test) (Table 4).

As shown in Table 5, there were 48 women undergoing

adjuvant treatment in this study. Twenty-one women had pre-

operative CA125 > 40 U

mL, and 27 cases had pre-operative CA125 40 UmL. In the CA125 > 40 group, the

disease recurrence rate of patients with adjuvant RTx (20.0%)

was lower than that of cases with adjuvant CTx (28.6%) or

RTx and CTx (33.3%), although the differences were not

significant (P= 0.08). However, the adjuvant RTx had

significantly better controlling of recurrence than the other

two adjuvant methods in the CA125 40 group (P= 0.002).

In addition, the impact of disease stage, tumour grade or

lymph nodal status on each adjuvant treatment group could

not be analysed because of small studied population.

Discussion

The tumour marker CA125 is reportedly useful inidentifying a poor prognosis for women with endometrial

cancer.10,14 Elevated CA125 can also guide therapy by

identifying women failing to respond to treatment. In this

study, the cut-off value of CA125 (40 UmL, Fig. 1) was

the same as that in from a previous study.11

However, Sood

et al.10 reported more meaningful statistical findings when

using a cut-off value of CA125 (20 UmL) in comparison

with a cut-off value of CA125 (35 UmL).

Retroperitoneal lymph node metastasis is one of the

important prognostic factors in endometrial cancer.

Reported risk factors associated with retroperitoneal lymph

node metastasis include histologic grade, myometrial

invasion, LVSI and CA125.

1517

In accordance with ourfindings (Table 1), many previous reports1821

have

demonstrated that elevated pre-operative serum CA125

levels correlate significantly with higher stage, higher grade,

deeper myometrial invasion, lymph node metastasis and

presence of LVSI in endometrial cancer.

Although FIGO recommended, in 1988, that adequate

surgical staging requires a total abdominal hysterectomy,

bilateral salpingo-oophorectomy and pelvic and para-aortic

lymphadenectomies,2

there is no consensus on whether

routine pelvic and para-aortic lymphadenectomies are

essential for women with endometrial cancer.35

Sood et al.10

suggested that lymphadenectomy may be omitted when the

CA125 20 UmL. Furthermore, the findings of Hsieh

et al.11 indicated that lymphadenectomy should beperformed when CA125 > 40 UmL in women with

endometrial cancer due to an increased risk of poor

prognosis.

The ability of CA125 to predict RFS or OS in women

with stage I endometrial cancer is not widely reported. This

is the first study to observe that surgical stage I cases with

CA125 > 40 UmL have a significantly lower RFS rate than

those with CA125 40 UmL (Fig. 2). Elevated CA125

Table 3 Significant prognostic factors for 5-year recurrence-free

survival using Cox regression analysis in (a) 120 women with endo-

metrial carcinoma (b) 88 stage I women with endometrial cancer

Hazard

ratio

95% confidence

interval P

(a)

Age 1.97 (0.37910.188) 0.42

CA125 (cut-off

point: 40 UmL)

12.07 (1.62699.64) 0.01

Stage 0.14 (0.0161.228) 0.08

Tumour grade 2.33 (0.8996.041) 0.08Lymphovascular invasion 0 0 1.0

Lymph nodal involvement 40 UmL group (13 cases).

Y-L. Chen et al.

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may represent extra-uterine or deeper myometrial spreading

via micrometastasis, which is not easily detected by

pathologic examination of surgical specimens (Table 1).

Risk assessment of women with endometrial cancer can be

conducted postoperatively. As certain pathologic factors are

not available, or accurate, pre-operatively or intra-operatively,it may be difficult to select which cases should receive a

lymphadenectomy. Pre-operative histology, obtained from

endometrial biopsy or dilatation and curettage, often differs

from final pathology.7,22

Therefore, when selecting optimal

care for women with endometrial cancer, the aim is to avoid

both overtreatment and undertreatment.

Our results suggest that comprehensive surgical staging

combined with CA125 levels might allow women to be

classified into risk categories (Table 4). Five-year OS and

RFS were highest for those with CA12540 UmL and

without lymph node metastases, and lowest for those with

lymph node metastases and CA125 > 40 UmL, when

compared with normal population. Disease stagingcombined with CA125 testing in women with endometrial

cancer might, therefore, provide an alternative method to

evaluate which cases need adjuvant treatment or observation.

The major limitation of this study was the small sample size

of cases with pre-operative evaluation of CA125. Only four

cases of clear cell carcinoma and three cases of papillary

serous carcinoma were noted in this study. To assess the

association between CA125 and prognosis in histologic

subtypes would be difficult. In addition, the number of cases

with elevated CA125 (>40 UmL) was small (30 women),

which restricted the study population from further subgroup

analysis. However, 21 of the 30 women (70.0%) needed

adjuvant chemotherapy (Table 5). Although the differences

were not significant, the disease recurrence rate of patients

with adjuvant RTx was lower. In our analysis, our results also

might imply that adjuvant treatment could be considered for

cases without comprehensive surgical staging, when elevatedpre-operative CA125 was noted. Therefore, a large

randomized trial such as PORTEC-3 (http://clinicaltrials.

gov/ct/show/NCT004 111 38;jsessionid=2309E60C1051E921

B4E2614F2BE708A4?order=9) is needed to further

investigate the impact of CA125 on the prognosis and

appropriate postoperative therapeutic modalities for

women with endometrial cancer.

In conclusion, pre-operative CA125 levels may be

included in the management of endometrial cancer. Women

with lymph node metastases and CA125 > 40 UmL might

require more aggressive postoperative treatment. Stage I

cases with CA125 > 40 UmL had a significantly lower

survival rate than those with CA125 40 UmL, and this

warrants further investigation.

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Table 4 The studied women were stratified by CA125 and lymph node metastasis (LNM) (yes versus no) for 2-year and 5-year overall

survival (OS) and recurrence-free survival (RFS)

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NA, non-available.

*One patient was lost of follow-up.

Because 2-year RFS could not be analysed, we presented the 1-year RFS.

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(21 cases)

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RTx 1 4 0 11

CTx 2 5 1 1

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*By Binomial test.

Value of pre-operative serum CA125 level

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