Prognostic Impact of Carcinoembryonic Angtigen (CEA) in Locally Advanced Cervical Cancer Treated with Concurrent Chemoradiotherapy

doi:10.4236/ss.2012.310092

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Surgical Science, 2012, 3, 463-468

http://dx.doi.org/10.4236/ss.2012.310092 Published Online October 2012 (http://www.SciRP.org/journal/ss)

Prognostic Impact of Carcinoembryonic Angtigen (CEA)

in Locally Advanced Cervical Cancer Treated with

Concurrent Chemoradiotherap y

Kiyosumi Shibata*, Hiroaki Kajiyama, Mik Mizuno, Eiko Yamamoto, Fumitaka Kikkawa

Department of Obstetrics and Gynecology, Graduate School of Medicine, Nagoya University, Nagoya, Japan

Email: *[email protected]

Received August 24, 2012; revised September 27, 2012; accepted October 8, 2012

ABSTRACT

Objective: To identify prognostic factors in patients with locally advanced cervical cancer treated with concurrent

chemoradiotherapy (CCRT). Methods and Materials: We analyzed 76 patients with FIGO stage IB2-IVb cervical

cancer treated with CCRT between 2001 and 2006 at the Nagoya University Hospital. Patients with an advanced cervi-

cal cancer treated with CCRT. Overall survival (OS) and Progression-free survival (PFS) rates were estimated using the

Kaplan-Meier method. The log-rank test was used to test differences in survival. Fisher’s exact test was employed for

univariate analysis. The Cox proportional hazard model was used for multivariate analysis. Results: The median age

was 52, and the median follow-up period was 36 months. The 5-year OS and PFS rates of all patients were 88.2% and

72.4%, respectively. Twenty-one of the 76 patients were diagnosed with recurrence. A higher serum CEA before CCRT

was an independent predictive factor for a poor prognosis on multivariate analysis. Conclusions: A high level of serum

CEA was a predictive factor for a poor prognosis. New strategies should be considered to control disease in this group

of patients.

Keywords: Cervical Cancer; Chemoradiotherapy; Recurrence; Prognostic Factor; Carcinoembryonic Angtigen (CEA)

1. Introduction

Cervical cancer is a significant cause of death from ma-

lignant disease in women in developing countries, and

most of these cases have locally advanced at the time of

diagnosis [1]. Both radical hysterectomy with lym-

phadenectomy and radiation therapy are used for ad-

vanced cervical cancer. However, the survival rate in

women with advanced cervical cancer has remained rela-

tively unchanged over the last two decades. Most inves-

tigators agree that the cervical tumor size is a significant

negative prognostic factor, since bulky tumors are asso-

ciated with a high incidence of lymph node metastases as

well as recurrence as compared with smaller tumors [2,3].

Recurrence is more frequent in patients with the in-

volvement of lymph nodes, parametrium, and surgical

margins, and in patients with large or deeply invasive

lesions. Recently, four randomized studies, including

almost 2000 patients, showed that the concomitant ad-

ministration of cisplatin-based chemotherapy and radia-

tion could significantly improve survival as compared

with the conventional use of radiotherapy as exclusive

therapy [4-7]. It is therefore important to determine fac-

tors that indicating a poor prognosis. Various predictive

factors for recurrence in advanced cervical cancer have

been reported, such as lymph node metastasis, the tumor

size, and hemoglobin level. Here in, we retrospectively

analyzed 76 patients with locally advanced cervical can-

cer treated with CCRT in our institution, and investigated

factors indicating a poor prognosis.

2. Patients and Methods

We retrospectively analyzed 76 patients with squamous

cell carcinoma and adenocarcinoma of the uterine cervix

who were treated with CCRT between 2001 and 2006 at

the University of the Nagoya Hospital. The clinical stag-

ing was based on FIGO stage classifications. The proce-

dure for staging included a detailed history and a physi-

cal examination, as well as common laboratory tests and

standard chest radiographs, intravenous pyelograms, X-

rays, cystoscopies, and sigmoidoscopies. In the evalua-

tion of lymph node involvement, computed tomography

(CT) scans or magnetic resonance imaging (MRI) were

performed in all patients. The principal criterion for posi-

tive node involvement was based on the axial diameter of

the lymph node. Lymph nodes larger than 1 cm in the

short-axis dimension were considered abnormal. All

*Corresponding author.

K. SHIBATA ET AL.

464

patients gave written informed consent for the treatment.

The study design was described in our previous report [8].

The schedule of concomitant chemotherapy was as fol-

lows: intraarterial or intravenous infusion of 70 mg·m2

cisplatin, days 1 and 22; 24-hour continuous intravenous

infusion of 700 mg·m2 5-FU, days 1 - 4 and 22 - 25. The

intravenous infusion of cisplatin was performed only in

patients suspected of having lymph node metastasis by

computed tomography (CT) or MRI. For intraarterial

infusion, a catheter was introduced via the femoral artery

using Seldinger’s technique and the tip was advanced to

a level beyond the superior gluteal artery, a branch of the

internal iliac artery, or as far as the uterine artery. After

confirming the blood supply to the uterus by angiogra-

phy, 70 mg·m2 cisplatin (35 mg·m2 each into the left

and right uterine arteries) was infused over five min-

utes.

Two weeks after the end of concurrent chemoradiation,

patients were restaged and evaluated regarding the objec-

tive response and operability, based on a second MRI

and clinical examination. The response to CCRT was

defined as follows: a complete response (CR) indicated

the disappearance of all measurable disease; a partial

response (PR) was a 50% or greater reduction in the

product of the transverse diameters of the cervical lesions;

stable disease (SD) was a reduction <50% or an increase

<25% in the product of the transverse diameters of the

cervical lesions; progressive disease (PD) was a 25% or

greater increase in the product of the transverse diame-

ters of the cervical lesions. Toxicity assessment was per-

formed according to the World Health Organization cri-

teria.

Four weeks after the end of CCRT, the patients un-

derwent surgery. Regarding the surgery types, radical

hysterectomy and pelvic lymphadenectomy were per-

formed when applicable. When the surgeon judged that

radical hysterectomy was not applicable because of the

state of residual tumors and complications, modified

radical hysterectomy or simple total hysterectomy was

selected. The surgical specimen was carefully examined

to assess the following parameters: macroscopic residual

disease, microscopic residual disease, parametrial in-

volvement, vaginal involvement, lymph node involve-

ment, and lymph vascular space involvement. Patients

with tumors involving the surgical margins were referred

for additional chemotherapy. Patients were followed-up

every 3 months with complete pelvic examinations, as

well as blood counts, clinical chemistry, and chest X-

rays. CT, ultrasound, and other studies were carried out

when appropriate. Postoperative complications were also

evaluated. Overall survival (OS) was defined as the time

from the start of CCRT until death. Disease-free survival

(DFS) was measured from the start of CCRT to the time

of relapse. Survival was calculated according to the

method of Kaplan and Meier, and a log-rank test was

used to determine the significance of differences in the

survival distribution.

The prognostic significance of several clinical and

pathological variables was assessed using the multivari-

ate Cox’s proportional hazard’s analysis. Stat View

software ver.5.0 (SAS, Institution Inc., Cary, NC, USA)

was used for all statistical analyses, and a p-value of <

0.05 was considered significant.

3. Results

Patient characteristics are shown in Table 1. The median

follow-up period was 36 months (range: 14 - 57 months).

Staging of the disease was determined according to the

International Federation of Gynecology and Obstetrics

(FIGO) classification. Stages were distributed as follows:

11 patients in IB2, 3 patients in IIA, 38 patients in IIB, 2

patient in IIIA, 9 patients in IIIB, 6 patients in IVA, and

7 patients in IVB. All patients were available for the

measurement of the response to treatment. A complete

response was defined as no viable cancer cells clinically

or pathologically at 3 months after the completion of

CCRT. Complete responses were achieved in 55 of 76

patients (72.4%) clinically. Fifty-five of the 76 (72.4%)

treated cases underwent surgery. Radical hysterectomy

was performed in 26 patients, whereas 17 and 8 patients

underwent modified radical and simple hysterectomy,

respectively. Pelvic lymphadenectomy was performed in

52 patients. Twenty-one patients were positive for lymph

node metastasis. The 5-year OS and PFS rates of all pa-

tients were 88.2% and 72.4%, respectively (Figure 1).

Relapse of disease was observed in 21 patients, distrib-

uted as follows: 6 central pelvic, 5 lymph nodal (1 com-

mon iliac and 4 aortic), 4 abdominal, 2 vaginal wall, and

4 lung metastases. The prognostic model for OS is based

on 11 factors: age 50< years (vs. age < 50 years), stage I-

II disease (vs. stage III-IV disease), procedure to use

CDDP (IA vs. IV), the tumor size (<4 cm vs. 4 cm<),

pathological group (squamous cell carcinoma vs. adeno-

carcinoma), lymph node swelling (positive vs. negative),

Hb (<8 g/dl vs. 8 g/dl), serum CA125 level (<35 U/ml vs.

35 U/ml<), serum SCC level (<7 U/ml vs. 7 U/ml<), and

serum CEA level (<7 U/ml vs. 7 U/ml<). On univariate

analysis of OS, an advanced stage, positive for lymph

node swelling, and a higher serum CA125 level were

independent predictors for a poorer survival (Table 2).

On multivariate analysis of OS, no factor was an inde-

pendent predictor for a poorer survival (Table 3). On

univariate analysis of PFS, an advanced stage, squamous

cell carcinoma, positive for lymph node swelling, a

higher serum CA125 level, and higher serum CEA level

were independent predictors for a poorer survival (Table

4). On multivariate analysis of PFS, only a higher serum

CEA level (p < 0.05) was an independent predictor for a

oorer survival (Table 5). The hazard ratio of a poor p

K. SHIBATA ET AL.

465

Table 1. Patient characteristics.

No. of patients

(n = 76)

Age 50 y≥ 42

51 y≤ 34

FIGO stage Ib2 11

II 41 (IIa 3, IIb 38)

III 11 (IIIa 2, IIIb 9)

IV 13 (IVa 6, IVb 7)

Histological type Squamous 63

Adenocarcinoma 13

Tumor size 4 cm> 54

4 cm≤ 22

Lymph node Negative 41

Positive 35

Chemotherapy Cisplatin IV 40

Cisplatin IA 36

Surgery No surgery 34

Do surgery 42

Hb 8 g/ml> 35

8 g/ml≤ 41

Serum SCC 7 U/ml> 55

7 U/ml≤ 21

Serum CEA 10 U/ml> 68

10 U/ml≤ 8

Serum CA125 35 U/ml> 56

35 U/ml≤ 20

Table 2. Univariate analysis of overall survival.

Hazard ratio 95% Confidence interval p-value

Age (50 y≥ vs. 51 y≤) 6.619 0.756 - 50.323 0.0893

Surgery (Do surgery vs. no surgery) 0.749 0.187 - 3.001 0.6828

Chemotherapy (cisplatin IV vs. IA) 6.401 0.781 - 52.458 0.0837

FIGO stage (III-IV vs. I-II) 6.141 1.232 - 30.615 0.0268

Tumor size（4 cm> vs. 4 cm≤） 2.828 0.347 - 23.041 0.3315

Histological type（squamous vs. adenocarcinoma） 0.386 0.092 - 1.626 0.1945

Lymph node（positive vs. negative） 9.307 1.142 - 75.841 0.0372

Hb（8 g/ml> vs. 8 g/ml≤） 0.35 0.070 - 1.753 0.2017

Serum CA125（35 U/ml> vs. 35U/ml≤） 8.913 1.793 - 4.299 0.0075

Serum SCC（7 U/ml> vs. 7 U/ml≤） 2.688 0.669 - 10.800 0.1636

Serum CEA（10 U/ml> vs. 10 U/ml≤） 5.612 1.321 - 23.836 0.0941

K. SHIBATA ET AL.

466

Table 3. Univariate analysis of progression-free survival.

Hazard ratio 95% Confidence interval p-value

Age (50 y ≥ vs. 51 y ≤) 1.701 0.686 - 4.216 0.2514

Surgery (Do surgery vs. no surgery) 0.684 0.289 - 1.615 0.3858

Chemotherapy (cisplatin IV vs. IA) 2.144 0.864 - 5.320 0.0988

FIGO stage (III-IV vs. I-II) 2.665 1.128 - 6.298 0.0255

Tumor size (4 cm> vs. 4 cm≤) 2.783 0.819 - 9.458 0.1011

Histological type (squamous vs. adenocarcinoma) 0.371 0.149 - 0.922 0.0328

Lymph node (positive vs. negative) 2.438 1.007 - 5.904 0.0438

Hb (8 g/ml> vs. 8 g/ml≤) 0.566 0.238 - 1.347 0.1986

Serum CA125 (35 U/ml> vs. 35 U/ml≤) 2.535 1.064 - 6.044 0.0358

Serum SCC (7 U/ml> vs. 7 U/ml≤) 1.792 0.742 - 4.326 0.1945

Serum CEA (10 U/ml> vs. 10 U/ml≤) 4.307 1.653 - 11.221 0.0028

Table 4. Multivariate analysis of overall survival.

Hazard ratio 95% Confidence interval p-value

Age (50 y ≥ vs. 51 y ≤) 4.152 0.306 - 56.240 0.2844

Chemotherapy (cisplatin IV vs. IA) 2.893 0.163 - 51.443 0.4625

FIGO stage (III-IV vs. I-II) 3.27 0.353 - 30.250 0.2699

Histological type (adenocarcinoma vs. squamous) 3.081 0.294 - 32.320 0.348

Lymph node (positive vs. negative) 6.64 0.587 - 75.084 0.1261

Serum CA125 (35 U/ml> vs. 35 U/ml≤) 7.142 0.951 - 53.643 0.056

Serum SCC (7 U/ml> vs. 7 U/ml≤) 1.993 0.277 - 14.345 0.4934

Serum CEA (10 U/ml> vs. 10 U/ml≤) 2.583 0.276 - 24.130 0.5042

Table 5. Multivariate analysis of progression-free survival.

Hazard ratio 95% Confidence interval p-value

Chemotherapy (cisplatin IV vs. IA) 1.385 0.418 - 4.587 0.5938

FIGO stage (III-IV vs. I-II) 2.077 0.713 - 6.050 0.1801

Tumor size (4 cm> vs. 4 cm≤) 1.611 0.374 - 6.949 0.5224

Histological type (squamous vs. adenocarcinoma) 0.328 0.090 - 1.190 0.09

Lymph node（positive vs. negative) 1.148 0.354 - 3.724 0.8182

Hb (8 g/ml> vs. 8 g/ml≤) 1.243 0.394 - 3.923 0.7108

Serum CA125 (35 U/ml> vs. 35 U/ml≤) 1.389 0.467 - 4.135 0.5544

Serum SCC (7 U/ml> vs. 7 U/ml≤) 1.83 0.612 - 5.476 0.2798

Serum CEA (10 U/ml> vs. 10 U/ml≤) 3.349 1.185 - 9.468 0.0226

K. SHIBATA ET AL.

467

(a) (b)

Figure 1. Overall survival (OS) and progression-free survival (PFS) curve drawn using Kaplan-Meier methods in 76 patients

with locally advanced cervical cancer treated with CCRT. OS (a) and PFS (b) in all patients.

patients, including 3 in whom solitary paraaortic lymph

node metastasis occurred. The prevention of distant re-

lapse, mainly relapse in the paraaortic lymph node, is a

future area of study. A previous report showed that

paraaortic nodal metastasis is the most significant prog-

nostic factor in patients with locally advanced cervical

cancer [12]. For prevention measures, additional irradia-

tion of the paraaortic lymph node region, and modifica-

tion of the chemotherapy regimen and administration

method, should be considered.

prognosis for patients with a higher serum CEA level

was 3.49 (95% confidence interval [CI], 1.185 - 9.468).

4. Discussion

We reported the effects of CCRT in our previous study.

In this study, we increased the number of patients, and

noted an increase in the response rate. We also investi-

gated OS and PFS in this study, and the 5-year OS and

PFS rates were 88.8% and 75%, respectively. Consider-

ing that 10 patients in stages III and IV were included

(28%), the outcomes were better than those in the re-

cently reported therapeutic results of advanced cervical

carcinoma [9-11]. Furthermore, we performed surgery

after CCRT in patients for whom it was applicable, and

investigated the outcome after each surgical procedure.

The 5-year PFS rates were 83.3%, 75%, 75%, and 66.6%

in the radical hysterectomy, modified radical hysterec-

tomy, simple total hysterectomy, and non-surgical groups,

respectively, showing no significant difference among

the groups, although the result was slightly better in the

radical hysterectomy group. Of 13 patients who were

judged to show a CR and underwent surgery, a residual

tumor was found in the surgical specimen after patho-

logical examination in 4 patients (31%). Of the 24 pa-

tients who underwent surgery, cancer infiltration in the

parametrium was noted in 1 patient, and pelvic lymph

node metastasis was noted in 7 patients (29%). No severe

postoperative complication occurred because surgery was

performed after CCRT, but the incidence of complica-

tions was high in the radical hysterectomy group, and the

incidences of bladder atony and lymphocyst were par-

ticularly high. The above findings suggested that, in our

study, it was better to perform surgery after CCRT when

it was applicable. Regarding the site of relapse, local and

intrapelvic relapses were well controlled, but the control

of relapse at distant sites was poor. Relapse occurred in 5

In this study, we found that high serum CA125 and

CEA levels were useful factors to predict recurrence after

preoperative CCRT. CEA levels were reported to be ele-

vated at the time of recurrence, particularly in paraaortic

lymph node metastasis [13]. A recent study reported the

association of the CEA level with the response rate of

preoperative CCRT [14]; however, this paper is the first

to report an association between the CEA level and

prognosis. In addition, a previous study reported that the

serum CA125 level was a prognostic factor for cervical

adenocarcinoma [15], which was the case in this study, in

which the majority of patients had cervical squamous cell

carcinoma. An association between CEA expression and

5-FU sensitivity has been reported, and our results also

suggest an association between CEA and chemoradiation

sensitivity, which requires further study. Although a pre-

vious study reported that SCC was a prognostic factor

after CCRT [16], this was not the case in the present

study. The difference in the results appears to be due to

the fact that we used a combination of 5-FU-based CCRT

and surgery.

Although several methods of chemotherapy for CCRT

have been reported, the optimum combination and ad-

ministration method have not been established. Preopera-

tive CCRT improved the short-term prognosis of ad-

vanced cervical carcinoma. Additional investigations

K. SHIBATA ET AL.

468

including long-term outcomes and new strategies should

be considered to control disease in which serum CEA

and CA125 are at high levels.

5. Conclusion

Our results suggest that a high level of serum CEA was a

predictive factor for a poor prognosis. Thus, further pro-

spective studies that include many cases are needed, and

strategies should be considered to control disease in this

group of patients.

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