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doi:10.1111/j.1447-0756.2012.01871.x

J. Obstet. Gynaecol. Res. Vol. 38, No. 11: 13151320, November 2012

Outcomes and prognostic factors of cervical cancer after

concurrent chemoradiation
jog_1871

1315..1320

Tae-Eung Kim1, Byung-Joon Park4, Hyun-Sung Kwack5, Ji-Young Kwon1,

Jang-Heub Kim2 and Sei-Chul Yoon3
1
Department of Obstetrics and Gynecology, St. Pauls Hospital, Departments of 2Obstetrics and Gynecology and 3Radiation
Therapy, Seoul St. Marys Hospital, College of Medicine, Catholic University of Korea, Seoul, 4Department of Obstetrics and
Gynecology, Incheon St. Marys Hospital, Incheon, and 5Department of Obstetrics and Gynecology, St. Vincents Hospital,
Suwon, Korea

Abstract
Aim: Concurrent chemoradiation (CCRT) is the standard treatment for locally advanced cervical cancer. This
study was undertaken to evaluate the outcomes and the prognostic factors for cervical cancer after CCRT.
Material and Methods: The medical records of 174 patients with International Federation of Gynecology and
Obstetrics stage IB1IVA who were treated at three affiliated hospitals of the Catholic University of Korea
between January 1999 and December 2008 were reviewed and analyzed. Patients received pelvic radiotherapy
with one of three regimens of cisplatin-based chemotherapy concurrently and high-dose rate brachytherapy.
The radiation field was extended to include para-aortic lymph nodes, if necessary.
Results: The median follow-up period was 29.5 months (range, 596 months). Using multivariate analysis,
stage (P = 0.014), tumor size (P = 0.043), and clinical response (P = 0.001) had a significant effect on overall
survival. Similarly, progression-free survival (PFS) was influenced by stage (P = 0.004), tumor size (P = 0.02),
clinical response (P = 0.011), and normalized squamous cell carcinoma antigen level after CCRT (P = 0.007).
The 5-year survival rates were 91.7% (standard error, 5.8%) for stages IB1IIA, 71.5% (standard error, 7.8%) for
stage IIB, 44.9% (standard error, 7.8%) for stage III, and 20.9% (standard error, 12.0%) for stage IVA. A total of
151 out of 174 patients (86.8%) completed the planned treatment. Toxicities were manageable with supportive
therapy.
Conclusions: Cisplatin-based CCRT is well-tolerated. Good clinical response revealed a favorable correlation
to survival. A maximal effort to achieve this goal might prolong survival in patients with cervical cancer.
Key words: cervical cancer, concurrent chemoradiation, prognostic factor.

Introduction
Significant improvements in screening techniques,
diagnostic procedures, and treatment modalities have
continued to decrease the incidence and mortality of
cervical cancer in recent decades. In 1999, after publication of five randomized trials,15 the National Cancer
Institute (NCI) issued a clinical announcement that
improved survival resulted when platinum-based che-

motherapy was added to radiation therapy in patients

with locally advanced cervical cancer.
In South Korea, cervical cancer was ranked as the
6th most common gynecologic neoplasm in 2008,
with 3888 new cases and a crude incidence rate of
15.8 women per 100 000.6 This study was conducted
to evaluate the outcomes and the prognostic factors
for cervical cancer after concurrent chemoradiation
(CCRT).

Received: July 12 2011.

Accepted: January 22 2012.
Reprint request to: Professor Jang-Heub Kim, Department of Obstetrics & Gynecology, Seoul St. Marys Hospital, College of
Medicine, Catholic University of Korea, 505 Banpo-dong, Seocho-ku, 137-701 Seoul, Korea. Email: janghkim@catholic.ac.kr

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1315

T-E. Kim et al.

Methods
Patients
A total of 174 patients with untreated stage IB1IVA
cervical cancer were entered into this retrospective
study. After approval from the Institutional Review
Board of the Catholic University of Korea, all patients
were evaluated for eligibility. The criteria included an
Eastern Cooperative Oncology Group performance
status of 02, and normal hematologic, renal, and liver
function. Patients were excluded if they met any of the
following criteria: history of other cancer; prior pelvic
radiation or systemic chemotherapy; medical contraindications to chemotherapy; and para-aortic lymphadenopathy (>1 cm in the short axis dimension) above the
first lumbar vertebra on imaging study.
Treatment
External whole pelvis irradiation using 1015 MV
photon was performed with a dose of 1.8 Gy per fraction 5 times per week for a total dose of 50.4 Gy (range;
50.456.0 Gy). External whole pelvis irradiation was
followed by high-dose rate intracavitary radiation with
six insertions (twice per week) with a fractional dose of
5.0 Gy to a total dose of 30.0 Gy at point A. When
brachytherapy could not be done due to closed cervical
os or patient refusal, external-beam boost was added.
Those patients were excluded in this study. Central
shielding was added after receiving 45 Gy radiotherapy. Typical field borders (four fields) for the
anteroposteriorposteroanterior (AP-PA) field were as
follows: the superior border (50% isodose line) was at
the L4L5 interspace; inferior border was at the lower
obturator foramen; and lateral borders were 1.5 cm
lateral to the bony pelvis. For the lateral fields, the
superior and inferior borders were the same, the anterior field border was at the anterior symphysis pubis,
and the posterior border included the anterior sacral
silhouette. In cases of pelvic lymph node involvement
on imaging study, external beam irradiation with 3-D
conformal technique to avoid rectum and bladder from
radiation field was performed with a dose up to 56 Gy.
In case of para-aortic lymph node enlargement,
extended-field irradiation was administered. The
overall treatment time was on average 60.4 days (range,
5869 days).
Concurrent chemotherapy was given with one of the
three regimens of cisplatin-based chemotherapy: (i)
weekly cisplatin (40 mg/m2) in 140 patients; (ii) cisplatin (60 mg/m2 on day 1) and 5-FU (1000 mg/m2 per
day on days 14) every 3 weeks in 13 patients; and (iii)

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cisplatin (60 mg/m2) plus paclitaxel (135 mg/m2) every

3 weeks in 21 patients.

Follow-up evaluation and statistical analysis

After completion of the whole treatment, the patients
were followed up at 1 month, then every 3 months for
the first 2 years and every 6 months thereafter with
physical examination, tumor marker and pelvic
imaging study.
Response to treatment was evaluated based on both
pelvic imaging study and physical examination
3 months after the completion of treatment. Complete
response was defined as the disappearance of gross
tumor clinically or radiologically, whereas the partial
response was defined as a greater than 50% reduction
of initial tumor volume.
We conducted immunoradiometric assay for measuring squamous cell carcinoma antigen (SCC-Ag)
level using an SCC kit (normal range <2.0 ng/mL).
Among the patients with elevated SCC-Ag before
receiving CCRT, normalized SCC-Ag levels were
judged 3 month after completing treatment.
Overall survival (OS) was assessed from the date of
CCRT to death from any cause or the date of last
contact. Progression-free survival (PFS) was measured
from the treatment start to either the date of progression or the date of last contact.
The OS and PFS curves were calculated according to
the KaplanMeier method. Differences in survival
were compared using a logrank statistical test. Prognostic factor analyses for OS and PFS were performed
using a Cox regression method. Hazard ratio is given
with 95% confidence intervals (95%CI). spss 12.0 was
used for a statistical analysis. A P-value <0.05 was
considered to be statistically significant.

Results
Patient characteristics
The patients and tumor-associated characteristics are
summarized in Table 1. Thirty-four patients (19.5%)
were >71 years of age. The major histologic subtype of
tumor was SCC (93.1%). The International Federation
of Gynecology and Obstetrics (FIGO) stages were as
follows: IB1IIA, 17.8%; IIB, 50.5%; IIIB, 19.0%; and
IVA, 12.6%. Of the tumors, 63.2% showed bulky tumor
(>4 cm) and 40.2% were lymph-node-negative. Complete and partial remissions were achieved in 110
patients (63.2%) and 37 patients (22.3%), respectively.

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CCRT of cervical cancer

Among the 116 patients with elevated SCC-Ag before

CCRT, the level normalized in 77.6% of the patients
after treatment.

Survival
A total of 151 out of 174 patients (86.8%) completed the
planned treatment. More than three cycles of weekly
Table 1 Patients characteristics (n = 174)
n (%)
Age (years)
<30
3140
4150
5160
6170
7180
>80
Histology
Squamous
Adenosquamous
Other type
Stage
IB1IIa
IIB
III
IVA
Tumor size
<4 cm
>4 cm
Lymph node status
Negative
Pelvic node positive
Para-aortic node positive
Clinical response
Complete remission
Partially remission
Stable or progressive
Tumor marker (SCC-Ag)
Not elevated before CCRT
Elevated before CCRT
Normalized after CCRT
Sustained after CCRT

1
13
26
46
54
31
3

(0.6)
(7.4)
(14.9)
(26.4)
(31.0)
(17.8)
(1.7)

162 (93.1)
6 (3.4)
6 (3.4)
31
88
33
22

(17.8)
(50.5)
(19.0)
(12.6)

64 (36.8)
110 (63.2)
70 (40.2)
74 (42.5)
30 (17.2)

Toxicity
Toxicities were assessed weekly during the treatment
and at the time of each visit and adjusted based on the
NCI Common Terminology Criteria for Adverse Effect
v 3.0.
The acute common toxicities were hematologic (65/
174 [37.4%]), gastrointestinal (48/174 [29.9%]), and
renal (7/174 [4.0%]). Among these patients, four had
grade 4 hematologic toxicity and the other cases were

110 (63.2)
37 (22.3)
27 (15.5)
58
116
90/116
26/116

cisplatin and more than two cycles of tri-weekly combined chemotherapeutic agents were administered to
the remaining 14 patients and nine patients, respectively. If there were myelosuppression, we delayed
whole treatment while maintaining supportive care. In
case of hepatic or renal toxicity, we omitted chemotherapy. We did not reduce the dosage of chemotherapeutic agent due to toxicity. Forty patients (23.0%) had
recurrences and 41 patients (23.6%) died.
Prognostic factors, such as stage, pelvic or para-aortic
lymph node involvement, tumor size, clinical response
and SCC-Ag levels after CCRT were analyzed. Based on
univariate and multivariate analyses of PFS according to
these factors, stage (P = 0.004), tumor size (P = 0.02),
clinical response (P = 0.011), and normalized SCC-Ag
level after CCRT (P = 0.007) were statistically significant
(Table 2). Based on univariate and multivariate analysis
on OS, stage (P = 0.014), tumor size (P = 0.043), and
clinical response (P = 0.001) showed a significant
outcome (Table 3).
The estimated 5-year survival rates according to
patient subgroups are described in Table 4. The 5-year
survival rates were 91.7% (standard error, 5.8%) for
stages IB1IIA, 71.5% (standard error, 7.8%) for stage
IIB, 44.9% (standard error, 7.8%) for stage III, and 20.9%
(standard error, 12.0%) for stage IVA. Tumor size
(<4 cm) and good clinical response also had significantly favorable outcome rates with respect to the
5-year OS. The OS curves for stage, tumor size, and
clinical response are shown in Figure 1.

(33.3)
(66.7)
(77.6)
(22.4)

CCRT, concurrent chemoradiation; SCC-Ag, squamous cell carcinoma antigen.

Table 2 Univariate and multivariate analysis of prognostic factor for progression free survival (Cox proportional hazard)
Variables

Univariate analysis
P-value
Hazard ratio
(95%CI)

Multivariate analysis
P-value
Hazard ratio
(95%CI)

Stage
Pelvic or para-aortic lymph node involvement
Tumor size (> or <4 cm)
Clinical response
Tumor maker (normalized or sustained after CCRT)

<0.01
<0.01
<0.01
<0.01
<0.01

<0.01
0.64
0.02
0.01
0.01

2.79 (2.003.90)
2.21 (1.463.56)
8.51 (2.6327.58)
3.89 (2.625.77)
9.05 (4.3019.07)

1.87 (1.222.86)
1.17 (0.612.21)
5.56 (1.3223.49)
2.06 (1.183.16)
3.76 (1.459.79)

Complete remission or partial remission or stable and progressive. CCRT, concurrent chemoradiation; CI, confidence interval.

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T-E. Kim et al.

Figure 1 Overall survival curves for stage (left, P = 0.01); tumor size (middle, P = 0.04); and clinical response (right, P < 0.01).
CR, complete remission; PR, partial remission.

Table 3 Univariate and multivariate analysis of prognostic factor for overall survival (Cox proportional hazard)
Variables

Univariate analysis
P-value
Hazard ratio
(95%CI)

Multivariate analysis
P-value
Hazard ratio
(95%CI)

Stage
Pelvic or para-aortic lymph node involvement
Tumor size (> or <4 cm)
Clinical response
Tumor maker (normalized or sustained after CCRT)

<0.01
<0.01
<0.01
<0.01
<0.01

0.01
0.92
0.04
<0.01
0.08

2.74 (1.973.81)
2.32 (1.523.54)
8.17 (2.5226.47)
4.52 (3.046.73)
9.24 (4.5218.92)

1.66 (1.112.48)
0.97 (0.472.00)
4.52 (1.0519.55)
3.25 (1.726.12)
2.24 (0.915.51)

Complete remission or partial remission or stable and progressive. CCRT, concurrent chemoradiation; CI, confidence interval.

Discussion

Table 4 Five-year OS rate for patients subgroup

No. (%)
of patients
Stage
IB1IIA
IIB
III
IVA
Tumor size
<4 cm
>4 cm
Clinical response
Complete remission
Partial remission
Stable or progressive

5-year
OS (%)

%SE

91.7
71.5
44.9
20.9

5.8
7.8
7.8
12.0

64 (36.8)
110 (63.2)

93.85
49.87

3.4
6.6

110 (63.2)
37 (22.3)
27 (15.5)

78.1
55.0
0.0

5.5
13.1
0.0

31
88
33
22

(17.8)
(50.5)
(19.0)
(12.6)

OS, overall survival; SE, standard error.

<grade 4. Late toxicity was defined as that occurring

>90 days after the 1st day of radiotherapy. The incidence of colorectal toxicity was 18.4% (32/174) and the
incidence of genitourinary toxicity was 15.5% (29/174),
including three fistulas, which required surgical intervention. All six cases of lymphedema were grade 2.

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Despite a few contradictory reports,79 recent reviews

strongly suggest that CCRT improves OS and PFS of
cervical cancer patients, whether or not platinum
is used, with absolute benefits of 10% and 13%,
respectively.1012 Like previous studies,15,8,13 we used
cisplatin alone in most patients and administered cisplatin combination regimens in some cases later in this
study.
The 5-year survival rates were 91.7% (standard error,
5.8%) for stages IB1IIA, 71.5% (standard error, 7.8%)
for stage IIB, 44.9% (standard error, 7.8%) for stage III,
and 20.9% (standard error 12.0%) for stage IVA. As our
study is retrospective, we have some disadvantages; 23
of 174 patients (14.2%) did not complete the planned
chemotherapy and 34 patients (19.5%) were administered cisplatin combination regimens; there was variation for dose of external pelvic irradiation according to
pelvic lymph node status. Despite the obvious limitations of comparing our results from other reports,2,9,1416
the 5-year survival rates of stages IBIIB were comparable to other results; however, the 5-year survival rates

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Journal of Obstetrics and Gynaecology Research 2012 Japan Society of Obstetrics and Gynecology

CCRT of cervical cancer

of stages III and IV were lower than other results. This

discrepancy might be due to the fact that patients with
para-aortic lymph node involvement were excluded in
other studies. In our study, there were 31 cases with
stages IB1IIA. Those patients were older than 65 years
old or medically unfit for radical surgery. After the
explanation that radiotherapy has almost equal therapeutic benefit compared to surgery in this stage, we
performed CCRT to those patients.
Anemia, FIGO stage, tumor size, grade, and nodal
status were reported as prognostic factors of cervical
cancer treated with CCRT.1619 Our study showed that
stage, tumor size and clinical response were prognostic
factors on OS. Lymph node status was not a prognostic
factor because lymph node status was judged according
to lymph node size on imaging rather than lymph node
sampling.
Pretreatment SCC-Ag level was reported as a prognostic factor on PFS and OS.20,21 In our study, we analyzed normalized level of SCC-Ag after CCRT.
Although this factor was shown to be associated with
PFS, we failed to demonstrate that this factor prolonged the OS.
Anemia may decrease tumor sensitivity to chemotherapy and radiotherapy. Pretreatment hypoxia has
been known to be associated with lower overall and
disease-free survival, greater recurrence and less local
control in cervical cancer.22 A retrospective study also
showed that the mean hemoglobin level during treatment was one of the predictors of disease progression.23 Considering these outcomes, we tried to correct
anemia with frequent transfusions in the present
study.
In this study there were three genitourinary fistulas,
which required surgical intervention. Other toxicities
were acceptable with supportive care. There was no
treatment-related death.
It was recently reported that surgery after CCRT is
feasible.2426 Pathologic residual cervical tumor is the
single independent factor which has been shown to
decrease the probability of disease-free survival,27 and
best survival was observed for patients with a pathologic complete response or microscopic residual
disease compared to patients with macroscopic residues.28,29 Hence, maximal efforts to achieve this goal,
such as new drug administration, consolidation chemotherapy,30 and surgery after CCRT, might prolong
survival in patients with cervical cancer.
We conclude that cisplatin-based CCRT is welltolerated, and additional modality will be needed to
prolong survival of patients with poor prognostic factors.

Disclosure
The authors have no potential conflicts of interest to
disclose.

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