Int J Gynecol Cancer 2007, 17, 833842

Long-term outcome and prognostic factors

in patients with cervical carcinoma:
a retrospective study
I.L. ATAHAN*, C. ONAL*, E. OZYAR*, F. YILIZ*, U. SELEK* & F. KOSEy
*Department of Radiation Oncology, Hacettepe University School of Medicine, Sihhiye, Ankara,
Turkey; and yDepartment of Gynecologic Oncology, Social Insurance Institution, Ankara Maternity
Hospital, Etlik, Ankara, Turkey

Abstract.

Atahan IL, Onal C, Ozyar E, Yiliz F, Selek U, Kose F. Long-term outcome and prognostic factors
in patients with cervical carcinoma: a retrospective study. Int J Gynecol Cancer 2007;17:833842.

This study evaluates treatment outcomes and possible prognostic factors of inoperable cervical cancer
patients treated with external beam radiotherapy (EBRT) and highdose rate brachytherapy (HDR BRT).
Between 1993 and 2000, 183 patients with cervical cancer were treated at our institute. Radiotherapy was
the sole treatment modality until January 1997; after the announcement of National Cancer Institute in
1999, 40 mg/m2 of cisplatin (49%) was routinely applied every week. Median age was 54 years (3292
years). Most patients (88%) had advanced-stage disease (IIBIIIB). With a median follow-up time of 45
months (6121 months), the 5-year overall survival (OS), local recurrencefree survival, disease-free survival
(DFS), and distant metastasisfree survival (DMFS) rates were 55%, 71%, 51%, and 77%, respectively. Univariate analysis revealed that age, tumor size, lymph node status, and concomitant cisplatin were prognostic factors for OS. The DFS rates were lower in young age group. Patients with tumor greater than 4 cm
and age greater than 40 were at greater risk for local recurrence. Distant metastases were more frequent in
patients with adenocarcinoma. Concurrent cisplatin use increases DMFS rates (91% vs 78%; P 0.05). In
multivariate analysis, extensive stage, parametrial infiltration, young age, adenocarcinoma histopathology,
and lymph node metastasis were negative prognostic factors for OS while concomitant cisplatin increases
OS. Likewise, patients with extensive stage, adenocarcinoma, and without concurrent cisplatin administration had more risk for distant metastasis. There was no treatment-related mortality. Grade 34 morbidity
rates were seen only in eight patients (4%). The combination of EBRT and HDR BRT together with concomitant chemotherapy in the treatment of locally advanced carcinoma of cervix is safe and well tolerated with
acceptable morbidity.
KEYWORDS:

brachytherapy, cervical cancer, chemoradiotherapy, prognostic factors, radiotherapy.

Cervical cancer is the seventh most common cancer

worldwide and is the second most common cancer
after breast cancer among women(1). Over the past two
decades, the most important change in the treatment of
patients with cervical cancer to improve survival and
local control was the utility of combined chemoradiotherapy. The addition of cisplatin-based chemotherapy to pelvic radiation for patients with high-risk
Address correspondence and reprint requests to: Cem Onal, MD,
Department of Radiation Oncology, Hacettepe University School of
Medicine, Sihhiye, Ankara 06100, Turkey. Email: hcemonal@hotmail.
com
doi:10.1111/j.1525-1438.2007.00895.x
2007, Copyright the Authors
Journal compilation # 2007, IGCS and ESGO

cervical cancer conferred significant benefits in both

local and distant controls, as well as in survival(26).
In current practice, early-stage cervical cancers
(FIGO IAIIA) are generally treated by either surgery
or combined external beam radiotherapy (EBRT) and
brachytherapy (BRT)(7), meanwhile, the standard treatment for locally advanced FIGO stage IIBIVA cervical
cancer is widely accepted to be chemoradiotherapy
jointly with BRT(26). BRT, an essential component in
the treatment of cervical carcinoma, has stimulated
enthusiasm for highdose rate (HDR) delivery in
recent years offering outpatient treatment, easy radiation protection, low cost, and improved tumordose distribution(810). Recent recommendations of the

834 I.L. Atahan et al.

American Brachytherapy Society (ABS) also purified

the ongoing controversies in the optimum dose and
fractionation schema of HDR(11).
The policy at The Hacettepe University Oncology Institute has been to treat patients with locally advanced
cervix cancer with radiotherapy-based schema; however,
modifications in treatment approach have been performed throughout the years with updated evidencebased literature. We have undertaken this retrospective
study to analyze the long-term outcomes of these patients
and to identify any unfavorable clinical or pathologic
prognostic factors of the disease in our cohort.

Materials and methods

Patients
We performed a database search maintained by the
Department of Radiation Oncology of Hacettepe
University School of Medicine for patients with
histologically proven carcinoma of the uterine cervix
who were treated with radiotherapy-based management. This search identified 183 patients treated
between December 1993 and January 2002. The latter
date was chosen to allow a minimum follow-up of
4 years at the time of our analysis. The data were
completed by reviewing the medical records, by telephone or written correspondence, and by the review
of the death reports.
Patient and tumor characteristics are summarized in
Table 1. The median age was 54 years (range 3292
years). Most patients (88%) had advanced-stage
disease (IIBIIIB). The distribution of 183 patients acTable 1.

Patient and tumor characteristics

Variable

Stratification

40
.40
Tumor size (cm)

4
.4
Parametrial infiltration Unilateral
Bilateral
None
Vaginal infiltration
Upper 2/3
Lower 1/3
None
Hemoglobin (g/dL)

10
1012
.12
Chemotherapy
Cisplatin
Hydroxyurea
None
Treatment time

6 weeks
.6 weeks
Age (years)

Number of Percentage
patients
(%)
18
165
118
65
117
36
30
44
10
129
34
67
82
89
68
26
60
123

10
90
64
36
64
20
16
24
6
70
19
36
45
49
37
14
33
67

cording to FIGO system was as follows: stage IB1 6%

(n 11), IB2 4% (n 8), IIA 4% (n 7), IIB 60% (n
109), IIIA 4% (n 8), and IIIB 22% (n 40). Of the 183
patients, 166 (91%) had squamous cell carcinoma
(SCC) and 17 (9%) had adenocarcinoma. Patients with
small-cell carcinoma were not included in this study,
due to the different tumor biology.
Staging and surveillance
The routine staging evaluation included medical history, systemic and detailed gynecological examination,
biopsy of the tumor, hematology and biochemistry
screens, urine analysis, chest x-ray, intravenous pyelography, rectoscopy (biopsy if required), and cystoscopy (biopsy if required). Biopsy, gynecological
examination, and cystoscopy were performed under
general anesthesia. Seventy patients (26%) were also
evaluated with magnetic resonance imaging (MRI) (55
patients) and/or computed tomography (CT) (15
patients). All patients were staged according to the
guidelines of the FIGO.
All patients were followed by a radiation oncologist
during radiotherapy (RT) course and a radiation
oncologist and a gynecological oncologist every 3
months during the first 2 years, and every 6 months
up to fifth year, and annually after the fifth year. Patients were evaluated for acute toxicity, and complete
blood counts were taken once a week during treatment. After therapy, a complete physical and gynecological examination in addition to routine complete
blood counts, serum biochemical analyses, chest x-ray,
and Papanicolaou smear were performed in every follow-up visit, and if clinically indicated, CT or MRI of
the primary site was taken. Acute and late toxicity was
graded according to Radiation Therapy Oncology
Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) common toxicity criteria(7). Acute toxicities were scored prospectively during
the treatment period. Late toxicity was recorded retrospectively by a thorough review of the patients hospital charts.
Nodal evaluation
Of the 183 patients, 144 (79%) had their pelvic and
para-aortic lymph node status evaluated. Ninety-six
of 144 patients (53%) underwent staging laparatomies; of them, extraperitoneal lymph node dissection was performed in 84 patients and 12 patients
were evaluated for lymph node metastasis by transperitoneal route. Fifty-two (36%) of 144 patients had
pelvic and/or para-aortic lymph node involvement,
proven with exploratory laparatomies (40 patients;

2007 IGCS and ESGO, International Journal of Gynecological Cancer 17, 833842

Radiotherapy in locally advanced cervical carcinoma

28%) or CT/MRI examination (12 patients; 8%). The

mean number of pelvic lymph nodes dissected was
15  9 (range 257), and mean number of metastatic
lymph nodes was 2.5  1.5 (range 115). Likewise,
para-aortic dissection was performed in 96 patients
(53%). The number of resected para-aortic lymph
nodes ranged between 1 and 32 (mean 11.5  7);
and metastatic lymph nodes were in the range of
1 to 15 (mean 2.5  1).
External beam radiotherapy
All patients were treated by megavoltage EBRT to the
pelvis with a median dose of 50.4 Gy with a daily fraction of 1.82.0 Gy with either Co-60 or 6-MV or 25-MV
photon beams using anteriorposterior fields or fourfield box technique depending on anteroposterior thickness of patients. A midline block was used in all
patients at 45 Gy to shield the rectum and bladder.
Para-aortic EBRT dose was 45 Gy with 1.5 Gy daily
fraction size. Treatment fields were arranged according
to the stage and lymph node status. In case of paraaortic lymph node metastasis, an additional para-aortic
field was added to pelvic fields. Prophylactic paraaortic irradiation was not performed. The upper border
of pelvic field was at the L4 and L5 interspace and the
lower border was at the mid-obturator line. The lower
border of the pelvic field was placed at least 3 cm
below the lowest involvement of the tumor in case of
vaginal involvement. The lateral borders were 1.52 cm
lateral to the pelvic inlet. Anteroposterior fields were
used in para-aortic irradiation. The lower border was
placed at the L4 and L5 junction. The upper border
was at the T12-L1 junction and the lateral borders were
the transverse processes of the vertebrae.
Brachytherapy
BRT was performed with remote afterloading HDR
unit with radioactive iridium-192 source. Fletcher-Suit
applicators consisting of uterine tandem and pair
ovoids or ring applicators were used. The intracavitary BRT procedure was ideally initiated at third week
of EBRT; however, postponed to further weeks in case
of inadequate tumor shrinkage. Point A dose was prescribed as 21 Gy in three fractions between 1995 and
2000 and was escalated to 28 Gy for four fractions in
stage IIBIVA disease after year 2000. Three quarters
of patients (139 cases; 75%) were treated with three
fractions of HDR BRT, whereas 46 patients (25%) were
treated with four fractions. Concomitant chemotherapy and EBRT were avoided during BRT days. Tumor
response was evaluated by a thorough gynecological
examination before each BRT application. The bladder
#

835

and rectal dose was tried to be kept less than 80% of

the point A dose, respectively.
Concomitant chemotherapy
Radiotherapy was the sole treatment modality in the
management of locally advanced cervical carcinoma
until January 1997. Between January 1997 and June
1999, hydroxyurea (per oral, 0.5 g tid) was given concomitantly in 68 patients (37%). After July 1999, cisplatin (intravenously over a 4-h period, 40 mg/m2/
week) was used concomitantly in 89 patients (49%); as
announced by National Cancer Institute. Overall, 26
patients (14%) were treated with RT alone. Cisplatin
dose was reduced to 25 mg/m2/week in patients treated with pelvic and para-aortic fields. Only 57% of patients could complete the planned six weekly cycles of
cisplatin. Patients treated with neoadjuvant chemotherapy were not included in this study cohort.
Clinical end points
This retrospective study was undertaken to analyze
the long-term outcomes of our cohort and overall survival (OS) as the primary end point and to identify
any unfavorable clinical or pathologic prognostic factors of the disease along with its impact on local recurrencefree survival (LRFS), distant metastasisfree
survival (DMFS), and disease-free survival (DFS); besides the safety of chemoradiotherapy and complications as secondary end points. The sites of recurrence
were categorized as local including the central pelvic
region, including vagina, bladder, rectum, as well as
those involving the pelvic sidewall, and as distant for
events outside the pelvis. Recurrences were documented by surgical exploration, biopsy, or by imaging
studies.
All intervals were calculated from the date of cervical
biopsy before radiotherapy until the date of treatment
failure or last date of follow-up. Patients were classified
as no evidence of disease if they were without any
suspicion of tumor recurrence or persistence; alive
with disease if any signs of relapse were detected; died
of disease if cancer-related death occurred; and died of
other causes if death occurred due to other causes. For
calculation of DFS, treatment failure was defined as
locoregional recurrence, para-aortic recurrence, distant
progression, or death as a result of any cause.
Statistical analysis
Statistical analyses were performed using Statistical
Package for Social Sciences for Windows version 11.0

2007 IGCS and ESGO, International Journal of Gynecological Cancer 17, 833842

836 I.L. Atahan et al.

(SPSS Inc., Chicago, IL). Survival was measured from

last visit or time of death to the start of treatment.
Survival rates were calculated using the KaplanMeier
method(12) and possible prognostic factors were evaluated
by log-rank test. Multivariate analysis was performed
using the Cox proportional hazards regression
model(13). Fisher exact test was used for comparison
of the groups in terms of the rate of late complications.
A P value of 0.05 or less was considered statistically
significant.

Results
The median follow-up is 45 months (range 6121
months) for the cohort, and the survivors have been
followed for a median of 59 months (range 25121
months). At last follow-up, 49% of patients (89/183)
were alive without evidence of disease. Seven patients
(4%) had both synchronous distant metastasis and
locoregional failure. Fourteen patients (7%) died of
other causes than cancer. The 2- and 5-year actuarial

Table 2.
Variable

Local control
Crude local recurrence rate was 26% (48/183, 41 died
of disease). Local control rates were 79% for 2 years
and 71% for 5 years. The highest incidence of locoregional failure was observed in patients with stage IIIB
disease (18 [43%] of 40), whereas only 1 of 19 patients
with stage IB disease had local relapse. In univariate
analysis, tumor size (
4 vs .4 cm), lymph node status,
age (
40 vs .40 years), and concurrent chemotherapy
(RT alone vs hydroxyurea vs cisplatin) were all significant factors effecting local control (Table 2). The concurrent chemotherapy with cisplatin improves 5-year
LRFS rates compared to patients treated with either
hydroxyurea or RT alone (77% vs 69% vs 55%, P
0.03). Of the 164 patients with stage IIIII diseases, 120
patients (73%) were treated with three fractions of BRT,
whereas 40 patients (27%) had four fractions. There

The prognostic factors for survival

5-year LRFS (%)

Age (years)

40
32
.40
75
Parametrial infiltration
None
83
Unilateral
70
Bilateral
64
Vaginal infiltration
Yes
73
No
64
Stage
IB
95
IIA
71
IIB
75
IIIA
75
IIIB
49
Tumor size (cm)

4
75
.4
63
Pathology
SCC
72
Adenocarcinoma
53
Lymph node metastasis
Yes
47
No
78
Chemotherapy
None
55
Hydroxyurea
69
Cisplatin
77
Overall treatment time (weeks)

6
75
.6
65
#

DFS and OS rates were found to be 64% and 51%, and

67% and 55%, respectively.

5-year OS (%)

5-year DFS

,0.001

13
60

,0.001

13
58

,0.001

0.2

60
57
41

0.2

73
51
44

0.1

0.2

59
42

0.1

58
45

0.2

0.002

73
43
64
63
23

,0.001

90
43
58
57
27

0.01

0.05

60
44

0.01

56
49

0.2

0.4

57
35

0.008

55
35

0.04

0.01

29
62

,0.001

16
66

,0.001

0.03

36
44
69

,0.001

43
45
63

0.009

0.1

66
49

0.03

62
44

0.03

2007 IGCS and ESGO, International Journal of Gynecological Cancer 17, 833842

Radiotherapy in locally advanced cervical carcinoma

was no significant difference in local control between

patients treated with either three fractions of BRT or
four fractions of BRT. No major difference was found
in local control between patients with parametrial and/
or vaginal involvement and patients without infiltration. On multivariate analysis, age (P , 0.001), stage
(P , 0.001), lymph node status (P , 0.001), and concurrent chemotherapy (P 0.01) were found to be significant prognostic factors for local control (Table 3).
Distant metastasis
Crude distant metastasis was 18% (32 patients, only
4 patients were alive with distant metastasis). The 2and 5-year DMFS rates were 87% and 77%, respectively. Patients with metastatic lymph nodes had a worse
5-year DMFS rates compared to patients without
lymph node metastasis (42% vs 85%; P , 0.001). In
regard to histopathologic findings, patients with SCC
histology had significantly better DMFS rates compared to patients with adenocarcinoma (79% vs 51%;
P 0.03). The prolongation of treatment time over
6 weeks did not alter the distant metastasis rates. The
use of concomitant cisplatin increased the DMFS rates
compared to patients treated with hydrea and without chemotherapy (84% vs 66% and 79%; P 0.04).
On multivariate analysis, age of less than or equal to
40 (P 0.03), adenocarcinoma histopathology (P
0.02), advanced stage (P 0.02), lymph node metastasis (P , 0.001), and without concomitant chemotherapy (P 0.02) remained negative prognostic
factors for DMFS.

837

Disease free survival

The 2- and 5-year actuarial DFS rates were found to be
64% and 51%, respectively. The 5-year DFS rates according to stages were 90% for stage I, 43% for stage IIA,
58% for stage IIB, 57% for stage IIIA, and 27% for stage
IIIB. The lower DFS rates for patients with FIGO stage
IIA may be attributed to the small number of patients
and presence of lymph node metastasis (2/7 patients).
On univariate analysis, the prognostic factors effecting
DFS are summarized in Table 2. Presence of lymph
node metastasis was a significant factor decreasing the
DFS rates (16% vs 66%; P , 0.001). For patients with
FIGO stages IIIA and IIIB, the 5-year DFS rates for
patients with lymph node metastasis was 13%, and
45% for those without lymph node metastasis (P
0.003). Likewise, the presence of lymph node metastasis
was found to be a negative predictor for patients with
stage IIB disease (19% vs 72%; P , 0.001). The 5-year
DFS rates for patients treated with RT alone was found
to be 43%; with concurrent hydroxyurea, 45%; and for
those treated with concurrent cisplatin, 63% (P 0.009).
The use of concomitant cisplatin did also improve DFS
rates compared to those treated with RT alone or concurrent hydroxyurea (63% vs 44%; P 0.002) (Fig. 1).
There was no significant difference between patients
treated with three fractions of BRT and those treated
with four fractions regarding DFS. On multivariate
analysis, age (P , 0.001), stage (P , 0.001), lymph node
status (P , 0.001), treatment time (P 0.02), and concurrent chemotherapy (P 0.01) were found to be significant prognostic factors for local control.

Table 3. Multivariate analysis (Cox model)

Factor
Age (,40 vs 40 years)
Parametrial infiltration
(positive vs negative)
Vaginal infiltration
(positive vs negative)
Stage (limited vs
extensive)
Tumor size (
4 vs . 4 cm)
Pathology (SCC vs
adenocarcinoma)
Overall treatment time
(
6 vs . 6 weeks)
Nodal status (N0 vs N1)
Treatment mode (RT alone
vs RT 1 CT)
Treatment mode (RT alone
vs RT 1 hydroxyurea
vs RT 1 P)

LRFS exp(B)
(95% CI for exp[B])

DMFS exp(B)
(95% CI for exp[B])

DFS exp(B)
(95% CI for exp[B])

OS exp(B)
(95% CI for exp[B])

3.2 (1.57.0), P , 0.001

2.7 (0.62.8), P 0.2

2.7 (1.08.1), P 0.03

1.2 (0.82.6), P 0.2

3.4 (1.86.4), P , 0.001

1.2 (0.72.2), P 0.4

2.9 (1.55.4), P , 0.001

2.2 (0.84.4), P 0.01

3.2 (0.513.8), P 0.1

0.9 (0.62.1), P 0.09

1.1 (0.81.6), P 0.5

4.0 (2.015.6), P 0.1

0.7 (0.11.2), P , 0.001

0.4 (0.10.9), P , 0.001

0.4 (0.21.2), P , 0.001

0.3 (0.10.8), P , 0.001

1.6 (0.93.2), P 0.1

0.6 (0.21.2), P 0.1

1.1 (0.52.6), P 0.3

0.3 (0.10.8), P 0.02

1.5 (0.92.5), P 0.1

0.4 (0.30.7), P 0.09

0.6 (0.41.1), P 0.07

0.2 (0.10.7) P 0.002

0.7 (0.21.9), P 0.4

0.6 (0.21.4), P 0.2

0.6 (0.31.0), P 0.07

0.5 (0.30.8), P 0.08

3.7 (1.97.0), P , 0.001

3.8 (1.212.7), P 0.01

4.9 (2.210.7), P , 0.001

3.9 (1.017.2), P 0.02

4.3 (2.67.0), P , 0.001

4.2 (1.710.7), P 0.01

3.2 (2.05.4), P , 0.001

2.5 (1.54.7), P , 0.001

1.7 (0.83.9), P 0.02

1.6 (0.55.5), P 0.03

1.7 (0.62.3), P 0.01

1.4 (0.72.5), P 0.01

RT, radiotherapy; P, cisplatin.

#

2007 IGCS and ESGO, International Journal of Gynecological Cancer 17, 833842

838 I.L. Atahan et al.

Figure 1. DFS according to concurrent treatment.

Overall survival
The 2- and 5-year actuarial OS rates were found to be
67% and 55%, respectively. On univariate analysis, the
prognostic factors for OS are summarized in Table 2.
Lymph node dissection had no impact on DFS for
cohort and also for subgroups. Lymph node metastasis
was found to be an important factor for survival. The
concurrent chemotherapy with cisplatin improves OS
compared to patients treated with either hydroxyurea
or RT alone (63% vs 43%; P 0.03) (Fig. 2). Increasing
the number of BRT fractions did not improve survival.
On multivariate analysis, age (P , 0.001), stage (P ,
0.001), parametrial infiltration (P 0.01), histopathology (P 0.002), lymph node status (P , 0.001), and
concurrent chemotherapy (P , 0.001) were all found to
be significant prognostic factors for survival.
Complications
Acute reactions
Most patients experienced transient symptoms of
acute cystourethritis and/or proctitis (grade 1) according

to the RTOG/EORTC scale. No treatment-related

mortality occurred. Fifty patients (27%) finished the
treatment without any evidence of gastrointestinal
system (GIS) toxicity and 114 patients (62%) had no
genitourinary system (GUS) toxicity. The incidence of
grade 2 GIS and GUS toxicities were 48% and 15%.
Grade 3 acute GIS toxicity was seen only in six
patients (3%), whereas only two patients (1%) had grade
3 GUS toxicity. There was no difference in GIS toxicities between patients with lymph node dissection and
without lymph node dissection; likewise, no difference
was observed in patients with lymph node dissection
either transperitoneally or retroperitoneally. These
symptoms resolved in all patients within 46 weeks
after completion of the treatment with conservative
managements.
Late reactions
According to RTOG/EORTC late toxicity criteria, 24
of 183 patients (13%) developed grade 2 chronic rectal
toxicity, including diarrhea, tenesmus, nausea, and
vomiting, whereas only 4 patients (2%) developed
grade 2 chronic bladder and urethra toxicity (dysuria,
polyuria, and incontinence). All of these patients
responded to conservative management. Fourteen
patients (8%) developed grade 3 bladder toxicity with
severe hematuria and frequency; and vesicovaginal
fistula developed in four patients (2%). Eight patients
(4%) developed grade 3 and 4 GIS toxicity (three patients with bowel obstruction and five with fistula formation). Among patients who developed bowel
obstruction, only one patient had prior surgery and
one had para-aortic irradiation. Statistically significant
correlation between rectovaginal fistula and high rectum dose (. 80% of the point A dose) during BRT procedure (Chi square; P , 0.001) was achieved (4/32
patients with rectum dose .80% of the point A and
1/151 patients with rectum dose
80%), whereas no
correlation between high bladder dose (2/41 patients
with bladder dose .80% of the point A and 2/142
patients with bladder dose
80%) and vesicovaginal
fistula occurrence was found. Four of nine patients
had fistulas as a result of either persistent or recurrent
disease; five of these nine patients had stage IIIB disease. No correlation is found between the surgical
intervention and the rate of complications.

Discussion

Figure 2. OS according to concurrent treatment.

#

The current study evaluated the efficacy of definitive

radiotherapy with or without chemotherapy, and prognostic factors in 183 patients with locally advanced

2007 IGCS and ESGO, International Journal of Gynecological Cancer 17, 833842

Radiotherapy in locally advanced cervical carcinoma

and/or inoperable cervical carcinoma, and importance

of lymph node metastasis detected with either radiographic or surgical procedures. We demonstrated the
significant negative impact of younger age (,40
years), advanced local stage, positive nodal metastasis,
and radiotherapy lacking concurrent cisplatin on OS
in our single institution cohort, in justification with
former reports(1417).
Surgery is not the optimal treatment of choice in
advanced cervical cancer; though RT for locally
advanced cancer is curative in approximately 65
75% of patients with stage IIB, in 3050% with stage
IIIB, and in 1015% of patients with stage IVA(7).
Local control rates with EBRT and BRT ranged from
88% to 93% for stage I, 6688% for stage II, and 48
63% for stage III disease (14,1720). This variation
may be due to the lymph node status, which is not
considered in the clinical FIGO staging system, also
unfavorable tumor biology may take a part in these
results. Unfavorable factors including tumor size of
greater than 4 cm and lymph node metastasis or
comorbid diseases play an important role in the
prognosis of early-stage diseases. Landoni et al.(7)
reported a survival rate of 72% for patients with
bulky stage IB disease treated with radiotherapy. In
this study, although local control rates were found
to be 95% for patients with stage IB disease, OS
rate was found to be lower than for those with
stage IIB (55% vs 67%). This is because 73% of patients with stage IB had tumors greater than 4 cm
and 25% had pelvic and para-aortic lymph node
metastasis. Likewise, in our series, the survival rates
were found to be 67% in patients with stage IB.
This is because, of the 19 patients with stage IB,
4 patients (21%) had lymph node metastasis and
8 patients (42%) had bulky tumor (.4 cm). Also,
patients with early stage having comorbid diseases
unsuitable for surgery were treated with RT, which
contributed to lower survival rates. Although
lymph node status does not contribute to FIGO
staging system of cervical carcinoma, it is well demonstrated that lymph node metastasis decreases 5year OS rates by 3540% compared to patients
without lymph node metastasis(2123). The 5-year OS
rates for patients with pelvic and para-aortic lymph
node metastasis for all stages were 2060%(2426).
In a large series of 3760 patients, Plentl and
Friedman(27) reported pelvic lymph node metastasis
in 15.4% for patients with stage I, 28.6% for patients
with stage II, and 47% for patients with stage III.
We evaluated the lymph node status of 144 patients; of them, 52 patients (36%) had lymph node
metastasis. Four patients (21%) with stage I, 34 pa#

839

tients (39%) with stage II, and 14 patients with stage

III disease (36%) had lymph node metastasis. The
most important prognostic factor decreasing OS rates
in our series was found to be the presence of lymph
node metastasis. The relative risk of death for lymph
node metastasis was found to be 3.2 (2.05.4; 95% CI).
The 5-year OS rates for patients with lymph node
metastasis were found to be 16% for all stages. Lymph
node metastasis was also found to be an important
predictor for distant metastasis and local control.
Although RT plays an important role in the treatment of locally advanced or inoperable cervical carcinoma, the treatment results of locally advanced
cervical carcinoma remain poor with EBRT and BRT
alone(15,2830). However, good local control is achieved
with aggressive pelvic irradiation, high rate of distant
metastasis in these patients encouraged us to use systemic chemotherapy. Many randomized and nonrandomized trials demonstrated an improvement in
LRFS and DFS. Cisplatin-based chemotherapy with
radiation yielded a complete clinical response rate of
6085% in patients with advanced disease(15,31). After
survival benefit for cisplatin-based chemotherapy given
concurrent with radiotherapy was demonstrated in
five prospective randomized trials, concomitant cisplatin-based chemoradiotherapy has become the standard treatment modality for locally advanced
carcinoma of the cervix(14,3234). These studies have
demonstrated a significant survival benefit for this
combined modality up to 3050%, in patients with
stage IB2-IV. In Gynecologic Oncology Group (GOG)
85 study, 368 patients with FIGO stage IIBIVA were
randomized to either concurrent cisplatin (50 mg/m2)
and 5-fluorouracil(FU) (1000 mg/m2) or concurrent hydroxyurea (oral 80 mg/kg bid)(6). The 5-year
OS rates were 60% for concurrent cisplatin and 5-FU
and 46% for concurrent hydroxyurea. In another randomized trial (GOG 120), patients were randomized
to RT and concomitant hydroxyurea, or RT and concomitant cisplatin, or RT and hydroxyurea, cisplatin
and 5-FU(5). The schema containing only hydroxyurea had the lower 4-year OS rates compared to multiagent regimen (37% vs 69%; P , 0.001). Also, the
OS rate was significantly higher in patients treated
with RT and concurrent cisplatin than in patients
treated with RT and concurrent hydroxyurea, with
relative risks of death of 0.61 (95% CI 0.440.85).
Although our study was not randomized, a significant improvement in survival rates was achieved by
treating patients with concomitant cisplatin compared
to patients treated with concomitant hydroxyurea (69%
vs 44%; P , 0.001), which is consistent with the findings demonstrated in the GOG studies(5,6). Also, we

2007 IGCS and ESGO, International Journal of Gynecological Cancer 17, 833842

840 I.L. Atahan et al.

found that concurrent chemotherapy with cisplatin improves OS compared to patients treated with either
hydroxyurea or RT alone (63% vs 43%; P 0.03). Concomitant cisplatin did also improve DFS rates (63% vs
43%; P 0.009) and local control (77% vs 55%; P
0.03), while it reduces the rate of distant metastasis.
Our patients with adenocarcinoma histopathology
tend to have worse prognosis than SCC; and distant
metastasis were frequent in patients with adenocarcinoma(3540). Baalbergen et al.(41) found 5-year OS
rates as 60% in 305 patients with adenocarcinoma
(79% and 37% for stage I and II, ,9% for stage III
and IV). Sahraoui et al.(42) found that 5-year local
control rate was 83% in 83 cervical adenocarcinoma patients treated with surgery and RT. Fiveyear DFS and local control rates were 47% and 71%,
respectively. Although patients with adenocarcinoma group are small, a statistically significant
higher distant metastasis rate was observed in patients with this histopathology compared to patients
with SCC; consistent with the literature (83% vs
45%; P 0.01)(3639).
The optimum dose and fractionation schema of
HDR was not agreed on, until the ABS recommendation for EBRT and BRT was made in the year 2000(11).
In this current study, the BRT doses were lower than
these recommended levels (BRT dose 21 Gy per three
fractions); however, after the ABS recommendation,
the feasibility of BRT dose fractionation was assessed,
and 28 Gy in four fractions was delivered for patients
with advanced-stage diseases. Although we could not
show any significant local control difference in our
cohort receiving three or four fractions of HDR BRT,
the unbalanced number of patients in both arms
(122 vs 35 patients) and different follow-up times may
have overshaded the difference.
It is well recognized that overall treatment time is
one of the important prognostic factors in patients
with cervical cancer treated with radiotherapy. Several
studies have demonstrated a significant decrease in
survival when overall treatment time extends beyond
6 weeks(43,44). A Patterns of Care Study demonstrated
a highly significant decrease in survival (P 0.0001)
and pelvic control (P 0.0001) as the total treatment
time was increased from ,6, 67.9, 89.9, and 101
weeks(43). In some series, the overall treatment time
was more than 8 weeks because four to five fractions
of HDR BRT were performed only after the completion of EBRT(45,46). Our series demonstrated that prolongation of total treatment time to over 6 weeks has
a statistically significant negative impact on OS rates
(66% vs 49%; P 0.03) and DFS rates (62% vs 44%;
P 0.03).
#

It has been asserted that late rectal radiation complications generally occur within the first 24 years after
the completion of treatment, but further follow-up is
needed to diagnose late urinary complications(47,48).
According to RTOG/EORTC criteria, serious late GIS
or GUS complications (grade 3 and 4) occurred in 8%
and 18% of our patients, which is comparable with
other data ranging from 4% to 24%. The only significant factor increasing late rectal complications was
found to be high dose in the rectum reference point. In
the literature, it was demonstrated that small bowel
complications highly increased in patients with transperitoneal lymph node dissection leading to severe
adhesions(22,49,50). The negative effect of surgical evaluation of lymph node status can be avoided by
extraperitoneal lymph node dissection or laparoscopic
surgery(5153). In our current series, 84 of 98 patients
(84%) had extraperitoneal lymph node dissection,
whereas only 14 patients (14%) were transperitoneally
evaluated, which made our evaluation of the impact
of surgical approach on late effects unreliable. These
results suggest that a long-term follow-up period is of
great importance for the diagnosis and management
of late complication.

Conclusions
The combination of EBRT and HDR BRT together with
concomitant chemotherapy in the treatment of locally
advanced carcinoma of cervix is safe and well tolerated with acceptable morbidity. While local and distant failure are yet to be solved in this group of
patients, ongoing research and advances in imageguided and intensity-modulated radiotherapy, as well
as progress in systemic therapy, seem to be a promise
for future improvements. Our retrospective study
with its inherent biases displays the efficacy of concurrent cisplatin-based chemoradiotherapy (with HDR
BRT), and relevant important prognostic factors for
local control and survival in accordance with the current literature.

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Accepted for publication November 5, 2006

2007 IGCS and ESGO, International Journal of Gynecological Cancer 17, 833842