original article
Annals of Oncology 22: 59–67, 2011
doi:10.1093/annonc/mdq321
Published online 1 July 2010
Outcomes after radical hysterectomy according
to tumor size divided by 2-cm interval in patients
with early cervical cancer
J.-Y. Park, D.-Y. Kim, J.-H. Kim, Y.-M. Kim, Y.-T. Kim & J.-H. Nam*
Department of Obstetrics and Gynecology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
Received 27 December 2009; revised 28 April 2010; accepted 30 April 2010
Background: This study investigated the outcomes after radical hysterectomy according to tumor size divided by
2-cm interval in patients with International Federation of Obstetrics and Gynecology stage IA2–IIA cervical cancer.
analyzed. Patients were divided into four groups according to tumor size (i.e. £2, 2–4, 4–6 and >6 cm). The
relationships between tumor size and other clinicopathologic risk factors, the probability of adjuvant therapy, survival
parameters, recurrence-free survival (RFS) and overall survival (OS) were analyzed.
Results: The incidence of intermediate- and high-risk factors gradually increased with increasing tumor size. Adjuvant
therapy was required in 13.6%, 34.0%, 56.7% and 92.9% of patients with tumor sizes of £2, 2–4, 4–6 and >6 cm,
respectively (P < 0.001). The risks of recurrence and death gradually increased with increasing tumor size, after
adjusting for other significant prognostic factors in multivariate analysis (P < 0.001 and < 0.001, respectively). Even in
patients with no intermediate- or high-risk factors, tumor size was a significant predictor of RFS and OS (P < 0.001 and
< 0.001, respectively). Immediate surgical parameters did not significantly differ according to tumor size.
Conclusions: Tumor size divided by a 2-cm interval was an independent prognostic factor and correlated well with
other risk factors and with the need for adjuvant therapy.
Key words: early cervical cancer, radical hysterectomy, risk factor, surgical outcome, survival outcome, tumor size
introduction
Cervical cancer is the second most common female cancer and
the third most fatal female cancer worldwide [1]. In addition,
cervical cancer is the only gynecologic cancer clinically staged
according to the International Federation of Obstetrics and
Gynecology (FIGO) staging system [2]. In early-stage cervical
cancer, which is amenable to radical hysterectomy, tumor size
is the main criteria for determining the stage of disease [2]. The
tumor size cut-off points of 7 mm and 4 cm have been adopted
for the FIGO staging system. However, the importance and
correlation of tumor size with survival, other clinicopathologic
factors and surgical outcomes have been reported only in
a small group of studies. Thus, the rationale for the use of these
cut-off points is arbitrary and ambiguous. In addition, it
remains unclear whether tumor size is an indicator of other risk
factors associated with poor prognosis or whether it is a true
independent predictor of poor outcome after radical
hysterectomy, even in patients lacking other risk factors. The
relationships between tumor size and immediate postoperative
*Correspondence to: Dr J.-H. Nam, Department of Obstetrics and Gynecology,
University of Ulsan College of Medicine, Asan Medical Center, #388-1 Poongnap-2
dong, Songpa-gu, Seoul, 138-736, Korea. Tel: +82-2-3010-3633; Fax: +82-2-4767331; E-mail: [email protected]
parameters and the probability of adjuvant therapy after
surgery have not yet been fully evaluated.
The aim of this study was to investigate the association of
tumor size with other clinicopathologic factors, the probability
of postoperative adjuvant therapy, survival outcomes and
radical hysterectomy outcomes in patients with early-stage
cervical cancer.
materials and methods
study population
This retrospective study included consecutive patients of a single institution
who were diagnosed with FIGO stage IA2–IIA cervical cancer and underwent
radical hysterectomy with pelvic and/or para-aortic lymphadenectomy. The
study protocol was approved by the Institutional Review Board at Asan
Medical Center (AMC, Seoul, Korea). Patients who satisfied the above criteria
were identified from the institutional cancer registry and computerized
database. The medical records of each patient were retrospectively reviewed.
Patients who received chemotherapy, radiation therapy (RT) or concurrent
chemoradiation therapy (CCRT) before radical surgery as well as patients
with unusual histologic types (e.g., neuroendocrine carcinoma, lymphoma
and sarcoma) were excluded from the study. Patients with occult cervical
cancer found after simple hysterectomy were also excluded from the
analysis. The following data were gathered from the medical records of each
ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: [email protected]
original
article
Patients and methods: A total of 1415 patients were eligible for participation in the study and were retrospectively
original article
Annals of Oncology
patient: age at diagnosis, parity, body mass index, operative procedures,
operating time, estimated blood loss (EBL), transfusion requirement,
transfusion amount, perioperative hemoglobin (Hb) level, time to return of
bowel movement after surgery, bladder dysfunction after surgery,
postoperative hospital stay, perioperative complications, FIGO stage,
histology, grade of differentiation, lymph–vascular space invasion (LVSI),
depth of cervical stromal invasion (DSI), parametrial involvement, resection
margin status, lymph node (LN) metastasis, adjuvant therapy, date of
recurrence, site of recurrent disease, treatment at recurrence, date of death or
last follow-up and status at last follow-up exam.
statistical analysis
Patients were divided into four groups according to the largest pathologic
tumor size (i.e. £2, 2–4, 4–6 and >6 cm). Tumor size was correlated with
several clinicopathologic factors, including age, parity, body mass index,
FIGO stage, histology, grade of differentiation, LVSI, DSI, vaginal
involvement, resection margin involvement, LN metastasis and
requirement for adjuvant therapy. Tumor size was also correlated with the
need for adjuvant therapy when Gynecologic Oncology Group (GOG)
92 [3] and GOG 109 [4] criteria were adopted. Relationships were
expressed in terms of odds ratios and 95% confidence intervals determined
via logistic regression analysis. Recurrence-free survival (RFS) times were
calculated, in months, from the date of surgery to the date of recurrence,
censoring or last follow-up exam. Overall survival (OS) time was calculated,
in months, from the date of surgery to the date of cancer death, censoring
or last follow-up exam. Survival curves and rates were calculated using the
Kaplan–Meier method and differences in survival times between groups
were compared via a log-rank test during the univariate analysis. All
variables determined to be significant in the univariate analysis were
included in a multivariate analysis using the Cox’s regression model. The
analysis of variance (ANOVA) test was used to evaluate differences in the
mean and median values between groups and the Tukey test was used as
post hoc test. The chi-squared and Fisher’s exact tests were used to evaluate
differences in the proportions. Differences were considered statistically
significant when P values were <0.05 on the two-sided test. Data were
analyzed using SPSS software for Windows (version 11.0; SPSS Inc.,
Chicago, IL).
results
From 1989 to 2009, 1415 patients were diagnosed with FIGO
stage IA2–IIA cervical cancer at AMC and met the eligibility
criteria for our study. Patient characteristics are shown in
Table 1. The mean age of patients was 48 years (range
24–86 years). Ninety-six (6.8%) patients with FIGO stage IA2
disease underwent type II hysterectomy with pelvic and/or
para-aortic LN dissection and 1319 (83.9%) patients with FIGO
stage IB–IIA disease underwent type III hysterectomy with
pelvic and/or para-aortic LN dissection. The largest pathologic
tumor size was £2 cm in 638 (45.1%) patients, 2–4 cm in 615
(43.5%) patients, 4–6 cm in 134 (9.5%) patients and >6 cm in
28 (1.9%) patients. After surgery, 398 (28.1%) patients received
adjuvant therapy, with 103 (7.3%) patients receiving
chemotherapy, 137 (9.7%) patients receiving RT and 158
(11.2%) patients receiving CCRT. In the adjuvant
chemotherapy group, all patients received platinum-based
drugs, and the chemotherapeutic regimen was paclitaxel/
cisplatin in 36 patients, paclitaxel/carboplatin in 5, 5fluorouracil/cisplatin in 27, others/cisplatin in 20 and cisplatin
Table 1. The relationship between tumor size and clinicopathologic factors (n = 1415)
Characteristics
Age
£48 years
>48 years
Parity
£2
>2
Body mass index
£24 kg/m2
>24 kg/m2
FIGO stage
IA2
IB1–IB2
IIA
Histology
SCCa
AdCa
AdSCCa
Differentiationa
Well
Moderate
Poor
Total (n = 1415),
n (%)
Tumor size
£2 cm (n = 638),
n (%)
2–4 cm (n = 615),
n (%)
P value
824 (58.2)
591 (41.8)
395 (61.9)
243 (38.1)
331 (53.8)
284 (46.2)
83 (61.9)
51 (38.1)
15 (53.6)
13 (46.4)
0.024
941 (66.5)
474 (33.5)
437 (68.5)
201 (31.5)
402 (65.4)
213 (34.6)
83 (61.9)
51 (38.1)
19 (67.9)
9 (32.1)
0.429
984 (69.5)
431 (30.5)
462 (72.4)
176 (27.6)
416 (67.6)
199 (32.4)
88 (65.7)
46 (34.3)
18 (64.3)
10 (35.7)
96 (6.8)
1187 (83.9)
132 (9.3)
96 (15.0)
514 (80.1)
32 (4.9)
0 (0.0)
544 (89.0)
67 (11.0)
0 (0.0)
110 (82.1)
24 (17.9)
0 (0.0)
19 (67.9)
9 (32.1)
<0.001
1085 (76.7)
245 (17.3)
85 (6.0)
488 (76.5)
116 (18.2)
34 (5.3)
467 (75.9)
107 (17.4)
41 (6.7)
104 (77.6)
22 (16.4)
8 (6.0)
26 (92.9)
0 (0.0)
2 (7.1)
0.303
372 (27.0)
674 (48.9)
332 (24.1)
213 (34.2)
251 (40.3)
159 (25.5)
124 (20.9)
343 (57.7)
127 (21.4)
30 (22.6)
66 (49.6)
37 (27.8)
5 (17.9)
14 (50.0)
9 (32.1)
<0.001
4–6 cm (n = 134),
n (%)
>6 cm (n = 28),
n (%)
a
Grade of differentiation was undetermined in 37 patients.
FIGO, International Federation of Obstetrics and Gynecology; SCCa, squamous cell carcinoma; AdCa, adenocarcinoma; AdSCCa,
adenosquamous carcinoma.
60 | Park et al.
Volume 22 | No. 1 | January 2011
original article
Annals of Oncology
alone in 15. The mean number of chemotherapy cycles was
5 (range 1–6 cycles).
the relationship between tumor size and
clinicopathologic factors
Table 1 shows the characteristics of patients and Table 2 shows
the relationship between tumor size and clinicopathologic risk
factors. As the size increased from £2 to >6 cm, the probability
of having intermediate-risk factors (e.g. LVSI and DSI) and
high-risk factors (e.g. parametrial involvement and LN
metastasis) gradually increased. The probability of vaginal
involvement also increased with increased tumor size. The
proportion of patients with moderately or poorly differentiated
tumors was also higher in the larger tumor group. Resection
margin involvement was more frequent in patients with
tumors >2 cm, but there were no differences in margin
involvement among patients with tumors 2–4, 4–6 and >6 cm.
the relationship between tumor size and
requirement for adjuvant therapy
Adjuvant therapy was required in 13.6%, 34.0%, 56.7% and
92.9% of patients with tumor sizes £2, 2–4, 4–6 and >6 cm,
respectively (Table 2). In patients with tumors £2 cm in
diameter, 5.2%, 6.0% and 2.5% received adjuvant
chemotherapy, RT or CCRT, respectively. In patients with
tumor diameters of 2–4 cm, 12.0%, 6.7% and 15.3%
received adjuvant chemotherapy, RT or CCRT, respectively.
In patients with tumor diameters of 4–6 cm, 16.4%, 12.7%
and 27.6% received adjuvant chemotherapy, RT or CCRT,
respectively. In patients with tumor diameters of >6 cm,
28.6%, 25.0% and 39.3% received adjuvant chemotherapy,
RT or CCRT, respectively. According to GOG 92 and GOG
109 criteria, adjuvant therapy was indicated in a total of
431 patients, including 11.1%, 38.2%, 72.4% and 100%
of patients with tumor sizes £2, 2–4, 4–6 and >6 cm,
respectively.
the relationship between tumor size and survival
outcome
The mean and median follow-up times were 84 and 76 months
(range 3 –236 months), respectively. At the time of analysis, 147
(10.4%) patients had recurrent disease and 116 (8.2%) patients
had died of disease. The 5- and 10-year RFS rates were 90% and
87%, respectively, and the 5- and 10-year OS rates were 93%
Table 2. The relationship between tumor size and clinicopathologic factors (n = 1415)
Characteristics
LVSI
No
Yes
OR (95% CI)
DSI
£2/3
>2.3
OR (95% CI)
Vaginal involvement
No
Yes
OR (95% CI)
PM involvement
No
Yes
OR (95% CI)
RM involvement
No
Yes
OR (95% CI)
LN metastasis
No
Yes
OR (95% CI)
Adjuvant therapy
No
Yes
OR (95% CI)
Total (n = 1415),
n (%)
Tumor size
£2 cm (n = 638),
n (%)
2–4 cm (n = 615),
n (%)
1115 (78.8)
300 (21.2)
565 (88.6)
73 (11.4)
Reference
457 (74.3)
158 (25.7)
2.7 (2.0–3.6)
80 (59.7)
54 (40.3)
5.2 (3.4–8.0)
13 (46.4)
15 (53.6)
8.9 (4.1–19.5)
<0.001
978 (69.1)
437 (30.9)
538 (84.3)
100 (15.7)
Reference
368 (59.8)
247 (40.2)
3.6 (2.8–4.7)
63 (47.0)
71 (53.0)
6.1 (4.1–9.1)
9 (32.1)
19 (67.9)
11.4 (5.0–25.8)
<0.001
1282 (90.6)
133 (9.4)
605 (94.8)
33 (5.2)
Reference
546 (88.8)
69 (11.2)
2.3 (1.5–3.6)
113 (84.3)
21 (15.7)
3.4 (1.9–6.1)
18 (64.3)
10 (35.7)
10.2 (4.4–23.8)
<0.001
1278 (90.3)
137 (9.7)
620 (97.2)
18 (2.8)
Reference
540 (87.8)
75 (12.2)
4.8 (2.8–8.1)
101 (75.4)
33 (24.6)
11.3 (6.1–20.7)
17 (60.7)
11 (39.3)
22.3 (9.1–54.4)
<0.001
1382 (97.7)
33 (2.3)
632 (99.1)
6 (0.9)
Reference
594 (96.6)
21 (3.4)
3.7 (1.5–9.3)
129 (96.3)
5 (3.7)
4.1 (1.2–13.6)
27 996.4)
1 (3.6)
3.9 (0.5–33.6)
0.019
1205 (85.2)
210 (14.8)
600 (94.0)
38 (6.0)
Reference
502 (81.6)
113 (18.4)
3.6 (2.4–5.2)
85 (63.4)
49 (36.6)
9.1 (5.6–14.7)
18 (64.3)
10 (35.7)
8.8 (3.8–20.3)
<0.001
1017 (71.9)
398 (28.1)
551 (86.4)
87 (13.6)
Reference
406 (66.0)
209 (34.0)
3.3 (2.5–4.3)
58 (43.3)
76 (56.7)
8.3 (5.5–12.5)
2 (7.1)
26 (92.9)
82.3 (19.2–353.1)
<0.001
P value
4–6 cm (n = 134),
n (%)
>6 cm (n = 28),
n (%)
LVSI, lymph–vascular space invasion; OR, odds ratio; CI confidence interval; DSI, depth of cervical stromal invasion; PM, parametrium; RM, resection
margin; LN, lymph node.
Volume 22 | No. 1 | January 2011
doi:10.1093/annonc/mdq321 | 61
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Annals of Oncology
and 89%, respectively. Univariate analysis revealed that age,
FIGO stage, histology, LVSI, DSI, vaginal involvement,
parametrial involvement, LN metastasis and tumor size were
significantly associated with both RFS and OS (Table 3).
Multivariate analysis revealed that age (>48 years of age),
histology, LN metastasis and tumor size were significantly
associated with RFS and that age (>48 years of age), histology,
LN metastasis, parametrial involvement and tumor size were
significantly associated with OS (Table 4). As shown in
Figure 1, the risk of recurrence and death gradually increased
with increasing tumor size, after adjusting for age, FIGO stage,
histology, LVSI, DSI, vaginal involvement, parametrial
involvement and LN metastasis.
In 1187 patients with FIGO stage IB disease, 1053 (88.7%)
were of FIGO stage IB1 and 134 (11.3%) of FIGO stage IB2.
The 5-year RFS rates were 92% and 74% for FIGO stage IB1
and IB2 patients, respectively (P < 0.001) (Figure 2). The 5-year
OS rates were 94% and 82% for patients with FIGO stage IB1
and IB2 disease, respectively (P < 0.001) (Figure 2).
To evaluate the impacts of tumor size on RFS and OS in the
absence of intermediate- and high-risk factors, we excluded 626
patients who demonstrated one or more risk factors (e.g. LVSI,
DSI, parametrial involvement or LN metastasis). Of the
resulting 789 patients without intermediate- or high-risk
factors, 470 patients had tumor sizes £2 cm, 284 patients had
tumor sizes of 2–4 cm, 35 patients had tumor sizes of 4–6 cm
Table 3. Clinicopathologic factors associated with RFS and OS, according to a univariate analysis (n = 1415)
Variables
Age, years
£48
>48
FIGO stage
IA2
IB1–IB2
IIA
Histology
SCCa
AdCa
AdSCCa
Differentiationa
Well
Moderate
Poor
LVSI
No
Yes
Depth of stromal invasion
£2/3
>2/3
Vaginal involvement
No
Yes
Parametrial involvement
No
Yes
Resection margin
Negative
Positive
Lymph node metastasis
No
Yes
Tumor size, cm
£2
2–4
4–6
>6
No. of patients,
n (%)
RFS
5-Year rate (%)
P value
OS
5-Year rate (%)
P value
824 (58.2)
591 (41.8)
92
87
<0.001
95
90
<0.001
96 (6.8)
1187 (83.9)
132 (9.3)
100
91
77
<0.001
100
93
88
<0.001
1085 (76.7)
245 (17.3)
85 (6.0)
91
86
79
<0.001
94
90
87
<0.001
372 (27.0)
674 (48.9)
332 (24.1)
90
90
87
0.624
92
94
92
1115 (78.8)
300 (21.2)
92
82
<0.001
94
88
<0.001
978 (69.1)
437 (30.9)
93
82
<0.001
95
88
<0.001
1282 (90.6)
133 (9.4)
91
77
<0.001
93
87
0.001
1278 (90.3)
137 (9.7)
91
73
<0.001
94
79
<0.001
1382 (97.7)
33 (2.3)
90
90
0.869
93
92
0.687
1205 (85.2)
210 (14.8)
92
76
<0.001
95
80
<0.001
95
87
76
69
<0.001
97
91
83
80
<0.001
638
615
134
28
(45.1)
(43.5)
(9.5)
(2.0)
0.6293
a
Grade of differentiation was undetermined in 37 patients.
RFS, recurrence-free survival; OS, overall survival; FIGO, International Federation of Obstetrics and Gynecology; SCCa, squamous cell carcinoma; AdCa,
adenocarcinoma; AdSCCa, adenosquamous carcinoma; LVSI, lymph–vascular space invasion.
62 | Park et al.
Volume 22 | No. 1 | January 2011
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Annals of Oncology
and no patient had tumor sizes >6 cm. The 5-year RFS rates
were 97%, 94% and 83% in patients with tumor sizes £2, 2–4
and 4–6 cm, respectively. The RFS was significantly different
between the two groups (Figure 3). The 5-year OS rates were
98%, 95% and 92% in patients with tumor sizes £2, 2–4 and
4–6 cm, respectively. The differences in OS were significant
between the £2-cm group and 2- to 4-cm group and between
the £2-cm group and the 4- to 6-cm group; however, there
were no significant differences between the 2- to 4-cm group
and the 4- to 6-cm group (Figure 3).
Figure 1. Recurrence-free survival (left) and overall survival (right) by tumor size after adjusting for age, International Federation of Obstetrics and
Gynecology stage, histology, lymph-vascular space invasion, depth of cervical stromal invasion, vaginal involvement, parametrial involvement and lymph
metastasis (Cox’s regression model).
Figure 2. Recurrence-free survival (left) and overall survival (right) in patients with International Federation of Obstetrics and Gynecology stage IB disease,
with reference to substage.
Figure 3. Recurrence-free survival (left) and overall survival (right) by tumor size.
Volume 22 | No. 1 | January 2011
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Annals of Oncology
the relationship between tumor size and surgical
outcome
The immediate operative parameters are shown in Table 5. The
mean operating time was 259 min (range 65–509 min).
This time was significantly shorter in patients with tumor
sizes £2 cm; however, there were no significant differences in
the mean operating times of patients whose tumors were 2–4,
4–6 and >6 cm. The mean EBL was 607 ml (range 20–8000 ml),
with higher values noted in patients with tumor sizes >2 cm;
however, there were no significant between-group differences
in mean EBL. The mean preoperative Hb level was 12.1 gm/dl
(range 5.8–15.7 gm/dl). Hb levels were significantly lower in the
4- to 6-cm group and the >6-cm group than in the £2-cm
group and the 2- to 4-cm group. The mean postoperative Hb
level was 10.1 gm/dl (range 5.5–14.6 gm/dl) and there were no
between-group differences in the mean postoperative Hb level.
The mean change in postoperative Hb levels was 1.8 6 1.8 gm/
dl (mean 6 standard deviation). There were no between-group
differences with regard to the mean change in perioperative Hb
level. Transfusion was required in 383 (27.1%) patients.
Transfusion requirements were higher among patients in the
4- to 6-cm group and the >6-cm group than in the £2-cm
group and the 2- to 4-cm group. The mean transfusion amount
was 2.6 pints (range 1–11 pints). There were no between-group
differences in the mean transfusion amount. The mean time
interval to return of bowel movement, defined as the initiation
of oral feeding, was 2.7 days (range 1–22 days). This time
interval was significantly longer among patients in the >6-cm
group. Interoperative and postoperative complications,
excluding bladder dysfunction, occurred in 18 (1.3%) patients
and 138 (9.8%) patients, respectively. There were no significant
between-group differences with regard to intraoperative and
postoperative complications. Bladder dysfunction, defined as
the need to reinsert a urinary catheter or undergo continuous
intermittent catheterization, occurred in 290 (20.5%) patients
and was most frequent among patients in the >6-cm group.
discussion
Our findings demonstrate that the incidence of intermediateand high-risk factors after radical hysterectomy (RH), as well as
Table 4. Clinicopathologic factors associated with RFS and OS, according to a multivariate analysis
Variables
Age, years
£48
>48
FIGO stage
IA2
IB1–IB2
IIA
Histology
SCCa
AdCa
AdSCCa
LVSI
No
Yes
Depth of stromal invasion
£2/3
>2/3
Vaginal involvement
No
Yes
Parametrial involvement
No
Yes
Lymph node metastasis
No
Yes
Tumor size, cm
£2
2–4
4–6
>6
No. of patients,
n (%)
824 (58.2)
591 (41.8)
RFS
OR (95% CI)
Reference
1.9 (1.4–2.7)
P value
<0.001
OS
OR (95% CI)
P value
Reference
2.2 (1.5–3.3)
<0.001
96 (6.8)
1187 (83.9)
132 (9.3)
Reference
3.8 (0.5–28.0)
9.1 (0.6–128.7)
0.189
0.101
Reference
3.0 (0.4–22.1)
2.6 (0.1–413.6)
1085 (76.7)
245 (17.3)
85 (6.0)
Reference
2.0 (1.3–3.0)
2.2 (1.3–3.6)
0.001
0.002
Reference
2.5 (1.6–3.9)
2.1 (1.2–3.6)
<0.001
0.014
1115 (78.8)
300 (21.2)
Reference
1.3 (0.9–1.9)
0.235
Reference
1.1 (0.7–1.8)
0.573
978 (69.1)
437 (30.9)
Reference
1.4 (0.9–2.0)
0.065
Reference
1.3 (0.8–1.9)
0.274
1282 (90.6)
133 (9.4)
Reference
0.5 (0.1–2.9)
0.425
Reference
1.3 (0.1–135.4)
0.921
1278 (90.3)
137 (9.7)
Reference
1.6 (0.9–2.5)
0.053
Reference
1.9 (1.1–3.2)
0.015
1205 (85.2)
210 (14.8)
Reference
1.6 (1.1–2.4)
0.017
Reference
2.1 (1.3–3.3)
0.001
Reference
1.9 (1.2–2.9)
3.5 (2.1–6.0)
5.2 (2.3–11.5)
0.004
<0.001
<0.001
Reference
1.9 (1.1–3.0)
3.2 (1.7–5.9)
4.4 (1.8–10.8)
0.012
<0.001
0.001
638
615
134
28
(45.1)
(43.5)
(9.5)
(2.0)
0.286
0.715
RFS, recurrence-free survival; OS, overall survival; OR, odds ratio; CR, confidence interval; FIGO, International Federation of Obstetrics and Gynecology;
SCCa, squamous cell carcinoma; AdCa, adenocarcinoma; AdSCCa, adenosquamous carcinoma; LVSI, lymph–vascular space invasion.
64 | Park et al.
Volume 22 | No. 1 | January 2011
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Annals of Oncology
the requirement for adjuvant therapy, gradually increased as
the tumor size increased by 2-cm intervals. After adjusting for
all other significant factors, multivariate analysis revealed that
tumor size was an independent risk factor associated with
decreased RFS and OS. The risks of recurrence and death
gradually increased as the tumor size increased by 2-cm
intervals. Even in patients with no intermediate- or high-risk
factors, tumor size divided by a 2-cm interval was a significant
predictor of RFS and OS. Immediate postoperative parameters
were somewhat unfavorable in patients with larger tumors, but
these differences were not significant. Surgery-related
complications were similar, regardless of tumor size.
The correlation between tumor size and prognosis in patients
with early-stage cervical cancer has been reported in a small
number of studies [5–12]. The critical point of tumor size
varied, depending on the studies. The FIGO staging system
defines stage IB cancer as tumors larger than 7 mm. In 1994,
stage IB cancer was divided into two subgroups (i.e. IB1 and
IB2) based on a tumor diameter of 4 cm [13]. Recently,
stage IIA cancer was also divided into two separate subgroups
(i.e. IIA1 and IIA2) based on a tumor diameter of 4 cm [2].
However, it remains unclear why the critical point of tumor
size was defined as a diameter of 4 cm. To our knowledge, this
is the largest study to demonstrate that prognosis after RH
differs significantly by tumor size, regardless of other risk
factors, when tumor size is divided by a 2-cm interval.
Whether the differences in prognosis reflect tumor size or
whether they stem from risk factors associated with larger
tumors remains unclear [14, 15]. Several studies have
reported that tumor size is an independent risk factor,
regardless of critical tumor size [5–12]. After adjusting for all
other significant factors, our multivariate analysis
demonstrated that tumor size divided by a 2-cm interval was
an independent prognostic factor. To our knowledge, no
studies have evaluated the role of tumor size in patients without
any other intermediate- or high-risk factors. Our results
showed that tumor size divided by a 2-cm interval was
a significant predictor of RFS and OS, even in such patients.
Therefore, tumor size itself may play a significant prognostic
role in patients with early-stage cervical cancer who
undergo RH.
Consistent with other studies, our results show that increased
tumor size was linked to higher incidence of other
intermediate- or high-risk factors that, if present, mandate the
use of adjuvant therapy [14–18]. Therefore, the probability of
adjuvant therapy after RH also increased with increasing tumor
size [10]. In our study, >50% of patients with tumor sizes
between 4–6 cm and >98% of patients with tumor sizes >6 cm
received adjuvant therapy. When GOG 92 [3] and GOG 109 [4]
criteria were adopted, adjuvant therapy was indicated in >70%
of patients with tumor sizes between 4–6 cm and 100% of
patients with tumor sizes >6 cm. Considering that the
combination of radical surgery and RT is associated with
a particularly high morbidity rate with no further survival
benefits [19], it is of paramount importance to predict the
probability of adjuvant RT after RH in patients with tumor
sizes between 4–6 cm. However, patients with tumors >6 cm
have a 10% to 17.5% central failure rate when treated with RT
Table 5. Surgical outcomes among groups with different tumor sizes (n = 1415)
Characteristics
Operating time (min), mean
(range)
EBL (ml), mean (range)
Preoperative Hb level
(gm/dl), mean (range)
Postoperative Hb level
(gm/dl), mean (range)
Perioperative Hb level change
(gm/dl), mean 6 SD
Transfusion requirement,
n (%)
Transfusion amount (pints),
mean (range)
Time interval to return of
bowel movement (days),
mean (range)
Postoperative hospital stay
(days), mean (range)
Intraoperative complications,
n (%)
Postoperative complications,
n (%)
Bladder dysfunction, n (%)
Total (n = 1415)
Tumor size
£2 cm (n = 638)
2–4 cm (n = 615)
4–6 cm (n = 134)
>6 cm (n = 28)
P value
259 (65–509)
243 (65–482)
271 (75–509)
267 (80–505)
298 (193–505)
<0.001
607 (20–8000)
12.1 (5.8–15.7)
579 (20–5000)
12.3 (6.6–15.7)
633 (20–8000)
12.2 (5.8–15.3)
624 (50–2500)
11.7 (8.6–14.8)
623 (50–1700)
11.2 (8.7–14.0)
0.475
<0.001
10.1 (5.5–14.6)
10.0 (5.5–14.6)
10.0 (5.5–14.3)
9.9 (7.1–12.7)
9.9 (7.4–13.7)
0.526
1.8 6 1.8
2.0 6 1.8
1.7 6 2.1
383 (27.1)
153 (24.0)
153 (24.9)
60 (44.8)
17 (60.7)
<0.001
2.6 (1–11)
2.6 (1–11)
2.5 (1–9)
2.5 (1–6)
3.2 (1–11)
0.040
2.7 (1–22)
2.4 (1–13)
2.5 (1–8)
2.7 (1–7)
4.2 (2–22)
<0.001
18.3 (4–140)
18.1 (4–140)
16.7 (5–100)
18.6 (4–69)
19.6 (8–40)
0.160
18 (1.3)
5 (0.8)
12 (2.0)
1 (0.7)
0 (0)
0.248
138 (9.8)
69 (10.8)
50 (8.1)
14 (10.4)
5 (17.9)
0.185
290 (20.5)
105 (16.5)
137 (22.3)
37 (27.6)
11 (39.3)
0.001
1.6 6 2.0
1.6 6 1.9
0.045
EBL, estimated blood loss; Hb, hemoglobin; SD, standard deviation.
Volume 22 | No. 1 | January 2011
doi:10.1093/annonc/mdq321 | 65
original article
alone [20]. Adjuvant hysterectomy is thought to decrease the
RT failure rate [21–23]; however, the role of this surgery
remains controversial [24–26] and the complications that can
arise from this procedure, including fistula formation, are
sometimes problematic [22, 24, 25]. Therefore, RH followed by
tailored adjuvant therapy remains a viable treatment option for
patients with tumors >6 cm.
Although immediate surgical parameters were somewhat
unfavorable in patients with larger tumors, these differences
were not significant and complication rates were similar among
the groups. Resection margin positivity was also similar in
patients with tumors >2 cm. These results suggest that RH is
feasible in all patients with early-stage cervical cancer,
regardless of tumor size.
Of the several parameters analyzed in the present study, only
disease stage was based on the clinical FIGO staging system,
whereas other parameters (including tumor size, vaginal
involvement and parametrial involvement) were evaluated
using the pTNM system. Methods of measuring tumor size
differ in previously published studies. The current FIGO
staging system measures the size of a clinically visible lesion via
pelvic or speculum examination [2]. However, the accuracy of
this measurement is 50% with a difference of <1.0 cm from the
pathologic tumor size and 52% with a 25% difference between
clinical and pathologic measurements of tumor size [11, 27].
Clinical staging systems may be intrinsically inaccurate [28, 29].
Some studies have suggested that tumor sizes differ when
measured via tumor length (vertical extension) and tumor
width (horizontal extension) [16, 17]. However, this system
remains controversial. Although imaging modalities, including
computed tomogram (CT) and magnetic resonance imaging
(MRI), can overcome the limitations of clinical tumor
measurements, the accuracy of these modalities ranges widely
from 30% to 85% [30–33]. Furthermore, in a large-scale
prospective study, the accuracy of CT and MRI were 42% and
53%, respectively [34]. Another technique involves calculating
tumor volume instead of tumor size [6, 16, 35]; however,
tumor volume is not a widely accepted measurement in the
literature. In our series, pathologic tumor sizes were measured
and the longest diameter was selected. These measurements
correlated well with patient prognoses. However, the main
limitation of this measurement is that it cannot be
preoperatively determined. Thus, it is important to develop an
accurate preoperative measurement tool that correlates well
with pathologic tumor size.
In our patient series, the surgical technique employed for
radical hysterectomy was based on Okabayashi’ s procedure
[36, 37] rather than the Wertheim operation [38, 39] or Piver–
Rutledge type III hysterectomy [40]. Radical hysterectomy was
initially established by Ernst Wertheim in 1911 as a surgical
technique for treatment of invasive cervical cancer. However,
the method has been modified many times to improve both
anatomic detail and radicality. Of surgeons who have been
active in this area, Hidekazu Okabayashi at Kyoto University in
Japan sought to improve the technique by developing a more
radical removal of tissue than advocated by Wertheim [37]. The
techniques employed, and the results of Okabayashi’s radical
hysterectomy, were first reported in 1921 [36]. Okabayashi’s
method is characterized by wide extirpation of parametrial
66 | Park et al.
Annals of Oncology
tissue and a rather novel separation of the posterior leaf of the
vesicouterine ligament [36, 37]. This method became standard
for radical hysterectomy in Japan, and our surgical technique is
also based on this approach. We are of the view that the
excellent survival outcomes seen after surgery in the present
study are attributable to the use of the more radical surgical
techniques incorporated in Okabayashi’s radical hysterectomy.
In conclusion, tumor size divided by a 2-cm interval was an
independent prognostic factor in patients with early-stage
cervical cancer undergoing RH, as well as in patients who lack
other risk factors. As tumor size increased, the incidence of
other risk factors, the probability of adjuvant therapy and the
risks of recurrence and death gradually increased. However,
immediate surgical parameters and resection margin positivity
did not differ by tumor size; thus, RH is feasible in patients
with early cervical cancer, regardless of tumor size.
disclosure
None of the authors declare conflicts of interest.
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