Available online at www.sciencedirect.

com

EJSO 39 (2013) 115e124 www.ejso.com

Review
Efficacy of neoadjuvant chemotherapy in patients with FIGO stage IB1 to IIA
cervical cancer: An international collaborative meta-analysis
H.S. Kim a, J.E. Sardi b, N. Katsumata c, H.S. Ryu d, J.H. Nam e, H.H. Chung a, N.H. Park a,
Y.S. Song a,f,g, N. Behtash h, T. Kamura i, H.B. Cai j, J.W. Kim a,*
a
Department of Obstetrics and Gynecology, Seoul National University College of Medicine, 28 Yeongeon-Dong, Jongno-Gu,
Seoul 110-744, Republic of Korea
b
Gynecologic Oncology Unit, Buenos Aires University, Buenos Aires, Argentina
c
Department of Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
d
Department of Obstetrics and Gynecology, Ajou University School of Medicine, Suwon, Republic of Korea
e
Department of Obstetrics and Gynecology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
f
Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
g
Major in Biomodulation, World Class University, Seoul National University, Seoul, Republic of Korea
h
Department of Gynecologic Oncology, Vali-e-asr Hospital, Tehran University of Medical Sciences, Tehran, Iran
i
Department of Obstetrics and Gynecology, Kurume University School of Medicine, Kurume, Japan
j
Department of Gynecologic Oncology, Zhongnan Hospital, Wuhan University, Wuhan, China

Accepted 26 September 2012

Available online 18 October 2012

Abstract
Background: The efficacy of neoadjuvant chemotherapy before surgery (NCS) has not been well-established in FIGO stage IB1 to IIA cer-
vical cancer when compared with primary surgical treatment (PST). Thus, we performed a meta-analysis to determine the efficacy of NCS
in patients with FIGO stage IB1 to IIA cervical cancer when compared with PST.
Methods: We searched Pubmed, Embase and the Cochrane Library between January 1987 and September 2010. Since there was a relative
lack of relevant randomized controlled trials (RCTs), we included 5 RCTs and 4 observational studies involving 1784 patients among 523
potentially relevant studies.
Results: NCS was related with lower rates of large tumor size (
4 cm) (ORs, 0.22 and 0.10; 95% CI, 0.13e0.39 and 0.02e0.37) and lymph
node metastasis (ORs, 0.61 and 0.38; 95% CI, 0.37e0.99 and 0.20e0.73) than PST in all studies and RCTs. Furthermore, NCS reduced the
need of adjuvant radiotherapy (RT) in all studies (OR, 0.57; 95% CI, 0.33e0.98), and distant metastasis in all studies and RCTs (ORs, 0.61
and 0.61; 95% CI, 0.42e0.89 and 0.38e0.97). However, overall and loco-regional recurrences and progression-free survival were not dif-
ferent between the 2 treatments. On the other hand, NCS was associated with poorer overall survival in observational studies when com-
pared with PST (HR, 1.68; 95% CI, 1.12e2.53).
Conclusions: Although NCS reduced the need of adjuvant RT by decreasing tumor size and lymph node metastasis, and distant metastasis,
it failed to improve survival when compared with PST in patients with FIGO stage IB1 to IIA cervical cancer.
Ó 2012 Elsevier Ltd. All rights reserved.

Keywords: Neoadjuvant; Chemotherapy; Surgery; Cervical cancer

Abbreviations: CCR, concurrent chemoradiation; CENTRAL, Co-

chrane Central Register of Controlled Trials; CI, confidence interval;
FIGO, International Federation of Gynaecology and Obstetrics; HR, haz-
ard ratio; NCS, neoadjuvant chemotherapy before surgery; OR, odds ratio;
PST, primary surgical treatment; RT, radiotherapy; RCT, randomized con-
trolled trial.
* Corresponding author. Tel.: þ82 02 2072 3511; fax: þ82 02 762 3599.
E-mail address: kjwksh@snu.ac.kr (J.W. Kim).
Introduction
The treatment modality for cervical cancer depends on
disease status at the time of diagnosis. The treatment for pa-
tients with International Federation of Gynaecology and
Obstetrics (FIGO) stage IA1 cervical cancer has focused
on type I or II hysterectomy or conization for fertility

0748-7983/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.ejso.2012.09.003
116 H.S. Kim et al. / EJSO 39 (2013) 115e124
Potentially relevant
Identification citations/abstracts
indentified and screened
for retrieval (n=523)
Studies retrieved for more
Screening detailed information (n=254)
Potentially appropriate
Eligibility studies to be included in
the meta-analysis (n=123)
Final studies in the meta-
Included analysis (n=9)
Figure 1. Preferred reporting items for systematic reviews and meta-analyses flow diagram. PST, primary surgical treatment; NCS, neoadjuvant chemotherapy
before surgery.
preservation, whereas primary concurrent chemoradiation
(CCR) is effective to treat locally advanced cervical cancer
(IIB to IVA).1,2 Although primary radiotherapy (RT) or
CCR is considered, primary surgical treatment (PST) with
or without adjuvant RT or CCR is also an alternative
method to treat stage IA2 to IIA disease.3,4
The advantage of PST is that patients can avoid RT-related
complications including menopause, and preserve fertility, if
desired. However, adjuvant RT or CCR should also be consid-
ered according to the final pathologic reports, including inter-
mediate- or high-risk factors after PST for improving clinical
outcomes in patients with stage IB1 to IIA cervical cancer.1 To
overcome the limitations of PST, the efficacy of neoadjuvant
chemotherapy before surgery (NCS) has been investigated
in patients with cervical cancer over the past two decades.5,6
The potential advantage of NCS has been suggested to de-
crease tumor volume, and to increase the possibility of obtain-
ing a wider uninvolved resection margin, thereby avoiding
adjuvant RT, whereas the delay in surgery, prolonged duration
of treatment, and accelerated repopulation of resistant cancer
cells should be considered as disadvantages of NCS.
Nevertheless, the efficacy of NCS has not been deter-
mined when compared with PST in previous randomized
controlled trials (RCTs),7e11 and observational stud-
ies.5,12e14 In contrast, two relevant meta-analyses have
shown the efficacy of neoadjuvant chemotherapy in cervi-
cal cancer.15,16 However, there were some limitations in
the meta-analyses, including a lack of the evaluation of sur-
gical efficacy due to RT as the main treatment, heterogene-
ity among relevant studies by including patients with
locally advanced cervical cancer, no investigation for the
efficacy of NCS affecting intermediate- or high-risk factors,
and the need for adjuvant RT when compared with PST.
Citations excluded (n=269)
Review articles (n=148)
Preclinical studies (n=48)
Other cancers (n=41)
Case reports (n=32)
Articles excluded (n=131)
Prognostic factors (n=37)
Drug-related (n=37)
Diagnostic tools (n=22)
Surgical skills (n=22)
Radiation therapy (n=13)
Article excluded (n=114)
Lack of the comparison of
clinical outcomes between PST
and NCS (n=113)
Insufficient data (n=1)
Although the efficacy of NCS should be confirmed by
more RCTs, it will take a long time to obtain relevant results.
Thus, we designed an international collaborative meta-
analysis using most of the relevant studies to better understand
the impact of NCS on clinical outcomes, including intermedi-
ate- or high-risk factors, the need for adjuvant RT, pattern of
disease recurrence, and survival in patients with FIGO stage
IB1 to IIA cervical cancer when compared with PST.
Methods
Search strategy
For this meta-analysis, we searched PubMed, Scopus,
Embase, and Cochrane Central Register of Controlled Tri-
als (CENTRAL) in the Cochrane Library between January
1987 and September 2010. For this search, we used com-
mon keywords for this meta-analysis as follows: cervical
cancer; cervical carcinoma; and neoadjuvant chemotherapy.
We also reviewed the bibliographies of the relevant articles
to locate additional publications.
Selection criteria
We included previous relevant studies which met all of
the following criteria: cervical cancer; stage IB1 to IIA dis-
ease by 1994 FIGO criteria17; and a comparison of clinical
outcomes, including intermediate- or high-risk factors, the
need of adjuvant RT, pattern of disease recurrence, and sur-
vival between PST and NCS. The exclusion criteria were
FIGO stage IA or locally advanced cervical cancer (stage
IIB to IVA), no comparison of the clinical outcomes be-
tween PST and NCS, and due to a lack of accessibility
Table 1
Demographic characteristics of 9 included studies.
Author Design Duration Follow-up (months) FIGO stage Histology No. of patients Regimen of NCS Cycles of NCS Indication of radiotherapy
NCS PST
Sardi7 RCT 1987e1993 67 IB SCC 102 103 $V: 1 mg/m2 (D1) Every 10 days $All cases
$B: 25 mg/m2 for 3 cycles
IB1: 41 IB1: 74 (D1eD3)
IB2: 61 IB2: 56 $P: 50 mg/m2 (D1)
Napolitano8 RCT 1986e1995 49 IB-IIA SCC 70 56 $V: 1 mg/m2 (D1) Every 21 days $Parametrial invasion
$B: 25 mg/m2 for 3 cycles $Lymph node metastasis
IB1: 24 IB1: 22 (D1eD3)
IB2: 36 IB2: 29 $P: 50 mg/m2 (D1)
IIA: 10 IIA: 5
Cai9 RCT 1999e2002 62 IB SCC, AC 52 54 $F: 24 mg/kg Every 21 days $Deep stromal invasion
(D1eD5) for 2 cycles $Parametrial invasion
IB1: 14 IB1: 24 $P: 75 mg/m2 (D1) $Lymph node metastasis
IB2: 38 IB2: 30
Eddy10 $V: 1 mg/ $Parametrial invasion

H.S. Kim et al. / EJSO 39 (2013) 115e124

RCT 1996e2001 62 IB2 SCC, 145 143 Every 10 days
AC, ASC m2 (D1) for 3 cycles $Lymph node metastasis
$P: 50 mg/
m2 (D1)
Katsumata11 RCT 2001e2005 38.3 IB2-IIA SCC, ASC 29 33 $B: 7 mg/m2 Every 21 days $Deep stromal invasion >2/3
(D1eD5) for 2 cycles $Parametrial invasion
IB2: 24 IB2: 29 $V: 0.7 mg/ $Lymph node metastasis
IIA: 5 IIA: 4 m2 (D5)
$M: 7 mg/m2 (D5)
$P: 14 mg/m2
(D1eD5)
Behtash12 O 1996e2004 450 IB-IIA SCC, AC 22 160 $V: 1 mg/m2 (D1) Every 10 days $Deep stromal invasion
$P: 50 mg/ for 2 cycles $Close or involved margin
IB1: 1 IB1: 1 m2 (D1) $Lymph node metastasis
IB2: 1 IB2: 148 $Lymphovascular invasion
IIA: 20 IIA: 11
Ryu13 O 1995e2005 67.9 IB2 Various 181 304 $Various Various $
2 intermediate-risk factors
-Tumor size (
4 cm)
-Deep stromal invasion
1/2
-Lymphovascular invasion
$
1 high-risk factors
-Positive resection margin
-Parametrial invasion
-Lymph node metastasis
Cho14 O 1999e2007 48.5 IB2-IIA SCC, 51 35 $T: 135 Every 21 days $
2 intermediate-risk factors
AC ASC mg/m2 (D1) for 2 cycles -Tumor size (
4 cm)
IB2: 29 IB2: 19 $P: 75 -Deep stromal invasion
1/2
IIA: 22 IIA: 16 mg/m2 (D1) -Lymphovascular invasion
or -
1 high-risk factors
$T: 135 -Positive resection margin
mg/m2 (D1) -Parametrial invasion
$C: AUC -Lymph node metastasis
5.0 (D1)

117
(continued on next page)
118 H.S. Kim et al. / EJSO 39 (2013) 115e124

-Deep stromal invasion
1/2

AC, adenocarcinoma; ASC, adenosquamous carcinoma; B, bleomycin; C, carboplatin; F, 5-fluorouracil; FIGO, International Federation of Gynecology and Obstetrics; NCS, neoadjuvant chemotherapy before
and difficulty with critical reading, non-English literature.

$
2 intermediate-risk factors

-Lymphovascular invasion

-Positive resection margin

All of the resulting abstracts were reviewed for potential el-

-Lymph node metastasis

igibility, and the full article texts were obtained for further

-Tumor size (
4 cm)

-Parametrial invasion
Indication of radiotherapy

$
1 high-risk factors

evaluation when the abstracts did not provide sufficient de-
tails to determine eligibility.

Studies identified

Five hundred twenty-three potentially relevant studies

were identified based on the above search terms. All of the
studies retrieved from the databases were independently

surgery; O, observational; P, cisplatin; PST, primary surgical treatment; RCT, randomized controlled trial; SCC, squamous cell carcinoma; T, paclitaxel; V, vincristine.
for 2 or 3 cycles
Cycles of NCS

Every 21 days

evaluated. After screening the potential abstracts, 269 studies

were excluded due to review articles (n ¼ 148), preclinical
studies (n ¼ 48), other cancers (n ¼ 41), and case reports
(n ¼ 32). Further assessment for more detailed information
indentified 254 ineligible studies associated with prognostic
factors (n ¼ 37), drug-related effects (n ¼ 37), diagnostic
$T: 175 mg/m2 (D1)

$P: 60 mg/m2 (D1)

$C: AUC 5.0 (D1)

$C: AUC 5.0 (D1)

tools (n ¼ 22), surgical skills (n ¼ 22), and RT (n ¼ 13). After

$F: 1000 mg/m2

$F: 100 mg/m2

Regimen of NCS

we reviewed the full articles of the remaining studies, 114

(D1eD5)

studies were excluded because of a lack of comparison of

(D1-D5)

the clinical outcomes between PTS and NCS (n ¼ 113) and

insufficient data (n ¼ 1). Finally, 5 RCTs and 4 observational
or

or

studies were scrutinized by the collaboration of relevant au-

thors,5,7e14 and we performed this international collaborative
IB1: 72
IB2: 27
IIA: 84

meta-analysis after we completed the collection of relevant

PST
183
No. of patients

data (Fig. 1).

IB1: 24

IIA: 28
IB2: 9

Statistical analysis
NCS
61

The aim of this meta-analysis was to evaluate the effi-

cacy of NCS for decreasing intermediate- or high-risk fac-
Histology

SCC, AC

tors and the need for adjuvant RT, and for improving
disease recurrence and survival when compared with PST.
This meta-analysis was performed in line with the recom-
IB1, IB2, IIA

mendations from the PRISMA guidelines.18 The following

FIGO stage

data were independently extracted for this meta-analysis:

the first author; design of study; duration of study; duration
of follow-up; FIGO stage; histology; numbers of patients
who underwent PST or NCS; regimens and cycles of neo-
Follow-up (months)

adjuvant chemotherapy; and indications of adjuvant RT.

For survival analysis, we used a previous method19; the
brief procedures were as follows. After we calculated the ob-
served number of events on the experimental intervention
44

(O), the log-rank expected number of events on the experi-

mental intervention (E ), and the variance of the log-rank sta-
tistic (V), we estimated the hazard ratio (HR) and 95%
2000e2008
Duration

confidence interval (CI). Furthermore, other dichotomous

data eligible for this meta-analysis in each study were shown
as an odds ratio (OR) with the 95% confidence interval (CI).
Heterogeneity was assessed using Higgins I2, which mea-
Design

sures the percentage of the total variation across studies that

Table 1 (continued )

is due to heterogeneity rather than chance.20 I2 is evaluated as

follows: I2 ¼ (Q  df )/Q  100%, where Q is the Cochran
heterogeneity statistic and df is the degrees of freedom. The
Author

value of I2 ranges from 0% (no observed heterogeneity) to

Kim5

100% (maximal heterogeneity). An I2 >50% was considered

 H.S. Kim et al. / EJSO 39 (2013) 115e124 119

Figure 2. Comparison of intermediate-risk factors between primary surgical treatment (PST) and neoadjuvant chemotherapy before surgery (NCS) in patients
with FIGO stage IB1 to IIA cervical cancer; (A) large tumor size (
4 cm): (B) lymphovascular invasion: (C) deep stromal invasion (
1/2).

to represent substantial heterogeneity, and we used the ran-
dom effects model using the DerSimonian and Laird method.
However, the fixed effect model using the ManteleHaenszel
method was used in this meta-analysis when the I2 was 50%
because it indicated no heterogeneity.
For identifying publication bias, funnel plots were repre-
sented, which were scatter plots of HRs or ORs of individ-
uals studies on the X axis against the SE of the log HR or
log OR of each study on the Y axis. HRs or ORs of small
scale studies scattered widely at the bottom of the graph
with the spread narrowing among large-scale studies, which
resembled symmetric inverter funnels, suggesting that there
was no publication bias in this meta-analysis. This meta-
analysis was performed using Review Manager Version
5.0 (the Nordic Cochrane Centre, Copenhagen, Denmark),
and a p <0.05 was considered statistically significant.
Results
Characteristics of relevant studies
After the final screening of 9 relevant studies, 1784 patients
were enrolled for this meta-analysis. Among them, 787 and
997 patients were included in 5 RCTs,7e11 and 4 observational
studies, respectively.5,12e14 Clinical characteristics of the 9 in-
cluded studies are depicted in Table 1. For surgical treatment,
type II or III hysterectomy with pelvic lymphadenectomy
was performed in all studies, whereas para-aortic lymphade-
nectomy was performed if indicated except 2 studies.9,10 As
chemotherapeutic regimens, vincristine/bleomycin/mitomy-
cin/cisplatin,11 vincristine/bleomycin/cisplatin,7,8 vincristine/
cisplatin,10,12 5-fluorouracil/cisplatin,5,9 5-fluorouracil/carbo-
platin,5 paclitaxel/cisplatin,14 and paclitaxel/carboplatin were
administered.5,14
Furthermore, the indications for adjuvant RT after sur-
gery were different among all studies, which included lym-
phovascular invasion,12 deep stromal invasion,9,11,12
parametrial invasion,5,8e14 lymph node metastasis,5,8e14
and positive resection margins.5,12e14 Patients with
2
intermediate-risk factors (large tumor size
4 cm, lympho-
vascular invasion, and deep stromal invasion
1/2) or
1
high-risk factor (positive resection margins, parametrial in-
vasion, and lymph node metastasis) received adjuvant RT
after surgery in 3 observational studies,5,13,14 and all pa-
tients in 1 RCT received adjuvant RT regardless of interme-
diate- or high-risk factors.7 In all of the studies, 2 or 3
120 H.S. Kim et al. / EJSO 39 (2013) 115e124

Figure 3. Comparison of high-risk factors between primary surgical treatment (PST) and neoadjuvant chemotherapy before surgery (NCS) in patients with
FIGO stage IB1 to IIA cervical cancer; (A) positive resection margin: (B) parametrial invasion: (C) lymph node metastasis.

cycles of chemotherapy were administered every 10 or 21
days in patients who received NCS.
Intermediate- or high-risk factors
For the reasonable concordance of intermediate- or high-
risk factors among the 9 included studies, we defined inter-
mediate- or high-risk factors as in 3 previous studies.5,13,14
As a result, NCS was associated with lower rates of large
tumor size (
4 cm) [total, 134/450 (29.8%) vs. 407/673
(60.5%); OR, 0.22; 95% CI, 0.13e0.39], lymphovascular
invasion [185/576 (32.5%) vs. 354/779 (45.4%); OR,
0.49; 95% CI, 0.29e0.84], and deep stromal invasion
(
1/2) [237/558 (42.5%) vs. 506/790 (64.1%); OR, 0.45;
95% CI, 0.23e0.89] than PST in all studies. These finding
were similar in the observational studies, whereas NCS was
only related to a lower rate of large tumor size (
4 cm)
compared to PST in RCTs [23/132 (17.4%) vs. 119/190
(62.6%); OR, 0.10; 95% CI, 0.02e0.37] (Fig. 2). Further-
more, NCS decreased parametrial invasion [79/630
(12.5%) vs. 145/858 (16.9%); OR, 0.63; 95% CI,
0.43e0.86] and lymph node metastasis [158/570 (27.7%)
vs. 288/825 (34.9%); OR, 0.61; 95% CI, 0.37e0.99]
when compared with PST in all studies, whereas NCS
showed only a reduction of lymph node metastasis in
RCTs [82/324 (25.3%) vs. 137/333 (41.1%); OR, 0.38;
95% CI, 0.20e0.73] without a decrease in the observation
studies (Fig. 3).
Disease recurrence and adjuvant radiotherapy
There were no differences in overall and loco-regional
recurrences between the two treatments in all studies,
RCTs, and observational studies. However, NCS was asso-
ciated with a lower rate of distant metastasis in all studies
[49/630 (7.8%) vs. 86/793 (10.8%); OR, 0.61; 95% CI,
0.42e0.89] and RCTs [33/321 (10.3%) vs. 51/323
(15.8%); OR, 0.61; 95% CI, 0.38e0.97], whereas there
was no difference in distant metastasis in the observational
studies (Fig. 4). Furthermore, NCS decreased the need for
adjuvant RT when compared with PST in all studies [214/
620 (34.5%) vs. 483/912 (53%); OR, 0.57; 95% CI,
0.33e0.98]. Nevertheless, when we performed sub-
analyses according to the design of the study, there was
no difference in the need for adjuvant RT in RCTs and ob-
servational studies (Fig. 5A).
 H.S. Kim et al. / EJSO 39 (2013) 115e124 121

Figure 4. Comparison of disease recurrence between primary surgical treatment (PST) and neoadjuvant chemotherapy before surgery (NCS) in patients with
FIGO stage IB1 to IIA cervical cancer; (A) overall recurrence: (B) loco-regional recurrence: (C) distant metastasis.

Survival observational studies, which were used to support those

Progression-free survival (PFS) was not different be-
tween the two treatments in all studies, RCTs, and observa-
tional studies (Fig. 5B). Furthermore, there was also no
difference in overall survival (OS) between the two treat-
ments in all studies, and RCTs, whereas NCS was associ-
ated with poor OS when compared with PST in
observational studies (HR, 1.68; 95% CI, 1.12e2.53)
(Fig. 5C).
Discussion
Background
For this meta-analysis, we included 4 observational stud-
ies and 5 RCTs because there was a relative lack of relevant
RCTs for identifying the role of NCS and the 4 observa-
tional studies included more patients for comparing clinical
outcomes between the two treatments in patients with
FIGO stage IB1 to IIA cervical cancer. Since RCTs are
known to suggest a higher level of evidence than observa-
tional studies,21 we reasoned that meta-analytic results
from RCTs were superior to results from all studies and
from RCTs. As a result, we obtained four clinically mean-
ingful results in this meta-analysis.
Risk factors
NCS was only efficient in decreasing large tumor size
(
4 cm) and lymph node metastasis, which was demon-
strated in RCTs (ORs, 0.10 and 0.38; 95% CIs,
0.02e0.37 and 0.20e0.73, respectively). Although NCS re-
duced all three intermediate-risk factors without an effect
on high-risk factors in observational studies, we concluded
that the meta-analytic results from RCTs were more reli-
able than the results from observational studies. These find-
ings led to the decrease in adjuvant RT. In all studies, NCS
was shown to reduce the need for adjuvant RT (OR, 0.57;
95% CI, 0.33e0.98), whereas NCS was not different be-
tween the 2 treatments based on the design of the study.
The reason for this finding is unclear, but the various crite-
ria for adjuvant RT among all included studies appeared to
be one of the main causes. However, this finding is worthy
of further evaluation through more relevant RCTs because
previous studies have also recommended reducing the
need for adjuvant RT by neoadjuvant chemotherapy,
122 H.S. Kim et al. / EJSO 39 (2013) 115e124

Figure 5. Comparison of the need of adjuvant radiotherapy and survival between primary surgical treatment (PST) and neoadjuvant chemotherapy before
surgery (NCS) in patients with FIGO stage IB1 to IIA cervical cancer; (A) the need of adjuvant radiotherapy: (B) progression-free survival: (C) overall
survival.

suggesting that NCS might help in avoiding complications
by adjuvant RT.5,11,13,14
Survival
NCS did not improve PFS and OS when compared with
PST in patients with FIGO stage IB1 to IIA cervical cancer.
In particular, these findings were not consistent with the
previous meta-analysis where PFS was significantly im-
proved with NCS (HR ¼ 0.76; 95% CI, 0.62e0.94).16
However, only early-stage disease (FIGO stage IB1 to
IIA) was included in this meta-analysis, while locally ad-
vanced disease (FIGO stage IIB to IIIB) was also included
in the previous study.16 Because tumor vascularity and per-
fusion have been demonstrated to increase in advanced cer-
vical cancer,22,23 chemotherapeutic drugs are expected to
have better delivery in advanced-stage disease, which re-
sults in greater efficacy of NCS. Conversely, it would be
less effective to treat FIGO stage IB1 disease which shows
lymphovascular tumor emboli or deep stromal invasion less
frequently. This hypothesis can be also supported by
a previous result where the efficacy of NCS was observed
less frequently in early-stage disease.5
Furthermore, the paradoxical finding that NCS failed to im-
prove survival in spite of the decrease of intermediate- or high-
risk factors when compared with PST can be explained by
“Concealing effect”.24 It means that neoadjuvant chemotherapy
could make a small metastasis hard to detect at histological ex-
amination by making a tumor smaller. Since tumor detection on
histological examination depends on the thickness of tissue sec-
tion, small tumors could be undetected if they were located be-
tween tissue sections. In particular, this effect could be observed
more definitely in FIGO stage IIA than IB disease.5
Adjuvant treatment
This meta-analysis demonstrated that NCS may have the
possibility to reduce the need of adjuvant RT by decreasing
risk factors, in spite of no difference in survival between
the two treatments. However, NCS showed the possibility
of poor OS when compared with PST in observational studies
(HR, 1.68; 95% CI, 1.12e2.53), suggesting that post-
 H.S. Kim et al. / EJSO 39 (2013) 115e124
operative chemotherapy may be required in patients treated
with NCS to improve survival. It can be supported by a previ-
ous study in which post-operative chemotherapy after neoad-
juvant chemotherapy, followed by surgery but no RT, is
a viable option in the treatment of patients with FIGO stage
IB2 to IIB cervical cancer, suggesting that this treatment
may allow the avoidance of RT-related toxicities.25
Disease recurrence
NCS contributed to reduce distant metastasis in spite of no
change in the overall and loco-regional recurrence rates be-
tween the 2 treatments (OR, 0.61; 95% CI, 0.38e0.97). The
finding should be re-evaluated through further trials because
the current study showed no improvement of survival in spite
of the reduction of distant metastasis. We thought that various
types and schedules of neoadjuvant chemotherapy, and differ-
ent indications for adjuvant RT influenced the risk of distant me-
tastasis between the 2 treatments. Furthermore, a previous study
had shown no association between the number of metastatic
lymph node and the risk of distant metastasis in patients treated
with NCS when compared with those treated with PST,26 sug-
gesting the association between neoadjuvant chemotherapy and
“Concealing effect” on lymph node metastasis.26
Limitations
However, the current study has some limitations as fol-
lows. First, primary CCR show the efficacy to treat bulky
cervical cancer (tumor size >4 cm) with high-level evi-
dence when compared with PST.1 Thus, sub-analyses based
on tumor size (4 vs. >4 cm) at diagnosis should be per-
formed to clarity the efficacy of neoadjuvant chemotherapy
in early-stage cervical cancer. In particular, the comparison
between PST and NCS should be investigated in stage IB2
to IIA cervical cancer because the efficacy of primary CCR
is more definite than that of surgery. Nevertheless, we could
not perform sub-analyses according to tumor size (4 vs.
>4 cm) and the type of RT (CCR vs. RT alone) due to dif-
ferent proportion of enrolled patients in each study. Second,
various types and schedules of neoadjuvant chemotherapy,
different indications for adjuvant RT could affect the need
of adjuvant RT and survival. Third, relative lack of RCTs
and inclusion of observational studies could be biases in in-
terpreting the results from this meta-analysis.
Conclusions
In spite of these limitations, the efficacy of NAC is still
expected because it can reduce intermediate- or high-risk
factors, thereby avoiding adjuvant RT. Nonetheless, “Con-
cealing effect” of neoadjuvant chemotherapy can leave hid-
den cancer cells untreated by adjuvant RT. Thus, the role of
post-operative chemotherapy should be investigated in pa-
tients treated with NCS to improve clinical outcomes
through further RCTs.
123
Acknowledgments
This research was supported by grant (No. 03-2012-0170)
from SNUH (Seoul National University Hospital) research
fund, the Priority Research Centers Program through the Na-
tional Research Foundation of Korea (NRF, No. 2009-
0093820), and World Class University Program through the
Korea Science and Engineering Foundation (No. R31-
2008-000-10056-0) funded by the Ministry of Education,
Science and Technology. Furthermore, we also thank the
Cervical Cancer Committee of the Korean Gynecologic On-
cologic Group (KGOG) and the Japan Clinical Oncology
Group (JCOG) for giving us relevant meta-analysis data.
Conflict of interest statement
The authors declare that there are no conflicts of interest.
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