Surgical Science, 2012, 3, 463-468 Published Online October 2012 (
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: *
Received August 24, 2012; revised September 27, 2012; accepted October 8, 2012
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.
opyright © 2012 SciRes. SS
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-
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-
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
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Copyright © 2012 SciRes. SS
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 size4 cm> vs. 4 cm 2.828 0.347 - 23.041 0.3315
Histological typesquamous vs. adenocarcinoma 0.386 0.092 - 1.626 0.1945
Lymph nodepositive vs. negative 9.307 1.142 - 75.841 0.0372
Hb8 g/ml> vs. 8 g/ml 0.35 0.070 - 1.753 0.2017
Serum CA12535 U/ml> vs. 35U/ml 8.913 1.793 - 4.299 0.0075
Serum SCC7 U/ml> vs. 7 U/ml 2.688 0.669 - 10.800 0.1636
Serum CEA10 U/ml> vs. 10 U/ml 5.612 1.321 - 23.836 0.0941
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 nodepositive 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
Copyright © 2012 SciRes. SS
Copyright © 2012 SciRes. SS
(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
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.
[1] M. Parkin, F. Bray, J. Ferlay and P. Pisani, “Global Can-
cer Statistics,” CA: A Cancer Journal for Clinicians, Vol.
55, No. 2, 2005, pp. 74-108.
[2] L.-C. Horn, U. Fischer, G. Raptis, K. Bilek and B. Hent-
schel, “Tumor Size Is of Prognostic Value in Surgically
Treated FIGO Stage II Cervical Cancer,” Gynecologic
Oncology, Vol. 107, No. 2, 2007, pp. 310-315.
[3] C. A. Perez, P. W. Grigsby, K. S. Chao, D. G. Mutch and
M. A. Lockett, “Tumor Size, Irradiation Dose, and Long-
Term Outcome of Carcinoma of Uterine Cervix,” Inter-
national Journal of Radiation Oncology, Biology, Physics,
Vol. 41, No. 2, 1998, pp. 307-317.
[4] M. Morris, P. J. Eifel, J. Lu, et al., “Pelvic Radiation with
Concurrent Chemotherapy Compared with Pelvic and
Para-Aortic Radiation for High-Risk Cervical Cancer,”
The New England Journal of Medicine, Vol. 340, No. 15,
1999, pp. 1137-1143.
[5] H. M. Keys, B. N. Bundy, F. B. Stehman, et al., “Cis-
platin, Radiation, and Adjuvant Hysterectomy Compared
with Radiation and Adjuvant Hysterectomy for Bulky
Stage IB Cervical Carcinoma,” The New England Journal
of Medicine, Vol. 340, No. 15, 1999, pp. 1154-1161.
[6] P. G. Rose, B. N. Bundy, E. B. Watkins, et al., “Concur-
rent Cisplatin-Based Radiotherapy and Chemotherapy for
Locally Advanced Cervical Cancer,” The New England
Journal of Medicine, Vol. 340, No. 15, 1999, pp. 1144-
1153. doi:10.1056/NEJM199904153401502
[7] W. A. Peters III, P. Y. Liu, R. Barrett, et al ., “Concurrent
Chemotherapy and Pelvic Radiation Therapy Compared
with Pelvic Radiation Therapy Alone as Adjuvant Ther-
apy after Radical Surgery in High-Risk Early-Stage Can-
cer of the Cervix,” Journal of Clinical Oncology, Vol. 18,
No. 8, 2000, pp. 1606-1613.
[8] K. Shibata, F. Kikkawa, Y. Suzuki, et al., “Usefulness of
Preoperative Chemoradiation in Locally Advanced Cer-
vical Carcinoma,” Gynecologic and Obstetric Investiga-
tion, Vol. 57, No. 2, 2004, pp. 93-99.
[9] C. W. Whitney, W. Sause, B. N. Bundy, et al., “A Ran-
domized Comparison of Fluorouracil Plus Cisplatin ver-
sus Hydroxyurea as an Adjunct to Radiation Therapy in
Stage IIB-IVA Carcinoma of the Cervix with Negative
Para-Aortic Lymph Nodes: A Gynecologic Oncology
Group and Southwest Oncology Group Study,” Journal of
Clinical Oncology, Vol. 17, No. 5, 1999, pp. 1339-1348.
[10] R. Pearcey, M. Brundage, P. Drouin, et al., “Phase III
Trial Comparing Radical Radiotherapy with and without
Cisplatin Chemotherapy in Patients with Advanced Squa-
mous Cell Cancer of the Cervix,” Journal of Clinical
Oncology, Vol. 20, No. 4, 2002, pp. 966-972.
[11] R. S. Lavey, P. Y. Liu, B. E. Greer, et al., “Recombinant
Human Erythropoietin as an Adjunct to Radiation Ther-
apy and Cisplatin for Stage IIB-IVA Carcinoma of the
Cervix: A Southwest Oncology Group Study,” Gyneco-
logic Oncology, Vol. 95, No. 1, 2004, pp. 145-151.
[12] P. W. Grigsby, M. L. Vest and C. A. Perez, “Recurrent
Carcinoma of the Cervix Exclusively in the Paraaortic
Nodes Following Radiation Therapy,” International Jour-
nal of Radiation Oncology, Biology, Physics, Vol. 28, No.
2, 1994, pp. 451-455. doi:10.1016/0360-3016(94)90070-1
[13] H.-H. Chou, C.-C. Wang, C.-H. Lai, et al., “Isolated
Paraaortic Lymph Node Recurrence after Definitive Irra-
diation for Cervical Carcinoma,” International Journal of
Radiation Oncology, Biology, Physics, Vol. 51, No. 2, 2001,
pp. 442-448. doi:10.1016/S0360-3016(01)01628-5
[14] S. M. Yoon, K. H. Shin, J.-Y. Kim, et al., “The Clinical
Values of Squamous Cell Carcinoma Antigen and Carci-
noembryonic Antigen in Patients with Cervical Cancer
Treated with Concurrent Chemoradiotherapy,” Interna-
tional Journal of Gynecological Cancer, Vol. 17, No. 4,
2007, pp. 872-878.
[15] A. Gadducci, R. Tana, A. Fanucchi and A. R. Genazzani,
“Biochemical Prognostic Factors and Risk of Relapses in
Patients with Cervical Cancer,” Gynecologic Oncology,
Vol. 107, No. 1, 2007, pp. S23-S26.
[16] M. Hirakawa, Y. Nagai, M. Inamine, et al., “Predictive
Factor of Distant Recurrence in Locally Advanced Squa-
mous Cell Carcinoma of the Cervix Treated with Con-
current Chemoradiotherapy,” Gynecologic Oncology, Vol.
108, No. 1, 2008, pp. 126-129.
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