Taiwanese Journal of Obstetrics & Gynecology 60 (2021) 433e441

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Taiwanese Journal of Obstetrics & Gynecology

journal homepage: www.tjog-online.com

Review Article

Neoadjuvant chemotherapy increases the 5-year overall survival of

patients with resectable cervical cancer: A systematic review and
meta-analysis
Yunbao Xu a, b, 1, Mengting Zhang c, 1, Jiaying Zhang c, Derry Minyao Ng d, Xiaoxiao Chen e,
Yuexiu Si f, Yetan Shi c, Xiangyuan Li c, Danyi Mao f, Lu Yang a, *
a
Department of Radiotherapy and Chemotherapy, Hwamei Hospital, University of Chinese Academy of Sciences, Ningbo, Zhejiang, China
b
Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, Zhejiang, China
c
The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
d
Medical College of Ningbo University, Ningbo, Zhejiang, China
e
Intensive Care Unit, Ningbo First Hospital, Ningbo, Zhejiang, China
f
Basic Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China

a r t i c l e i n f o a b s t r a c t

Article history: Cervical cancer is a global health challenge in women. Neoadjuvant chemotherapy (NACT) is a recent
Accepted 23 February 2021 prospect for alternative cervical cancer treatments. This study investigated the efficacy of NACT against
resectable cervical cancer based on the medium and long-term survival of patients with the disease. We
Keywords: searched through PubMed, Web of Science, EBSCO and Cochrane Library for relevant reports published
Neoadjuvant chemotherapy by June 2020. The primary outcomes were 3-year and 5-year progression-free survival (PFS) and overall
Resectable cervical cancer
survival (OS) of patients with resectable cervical cancer. Overall, 22 publications encompassing 5627
Prognosis
patients fulfilled the inclusion criteria. We found NACT not to affect both 3-year PFS and OS as well as 5-
Meta-analysis
year PFS of patients with resectable cervical cancer. However, NACT significantly improves the 5-year OS
of patients with resectable cervical cancer (HR ¼ 0.83, 95% CI: 0.73e0.94, p ¼ 0.013). Subgroup analysis
(RCTs, non-RCTs, NACT þ surgery þ AT vs. surgery þ AT, NACT þ surgery þ AT vs. CCRT/RT/CRT) further
revealed NACT had no significant effect on 5-year PFS of patients with resectable cervical cancer,
converse to the 5-year OS subgroup analysis, which validated the beneficial effect of NACT in patients
with resectable cervical cancer. In addition, the effect of NACT was most significant in the non-RCTs
subgroup (p ¼ 0.012). NACT may improve the long-term prognosis of patients with resectable cervical
cancer. However, further large-scale multicenter studies are needed to validate this finding.
© 2021 Taiwan Association of Obstetrics & Gynecology. Publishing services by Elsevier B.V. This is an
open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Introduction
Cervical cancer is not only the fourth most common gyneco-
logical malignancy, but also one of the major causes of cancer death
worldwide. Globally, approximately 85% of deaths from cervical
cancer occur in underdeveloped or developing countries, with
Central and South America, the Caribbean, Sub-Saharan Africa, and
Southern Asia bearing the greatest brunt [1]. Currently, typical
* Corresponding author. Department of Radiotherapy and Chemotherapy, Hwa-
mei Hospital, University of Chinese Academy Of Sciences, Northwest Street 41,
Haishu District, Ningbo, 315010, Zhejiang, China.
E-mail address: lihugucc@163.com (L. Yang).
1
Yunbao Xu and Mengting Zhang contributed equally to this work.
treatment for uterine cervical cancer is based on the 2018 guide-
lines by the International Federation of Gynecology and Obstetrics
(FIGO) staging system [2]. Surgery or radiotherapy (RT) are the
most preferred treatment options for patients with FIGO stage IB1
to IIA1 cervical cancer. Concurrent chemoradiotherapy (CCRT) is
recommended for local advanced cervical cancer (FIGO IB3 and
IIA2), whereas chemoradiotherapy (CRT) is preferred for patients
who cannot undergo hysterectomy [2,3]. Postoperative adjuvant
therapy (AT) can inhibit distant metastases as well as decrease
pathological density rate [4]. Even though these therapeutic mo-
dalities are effective in patients with local advanced cervical cancer,
the survival benefits remain sub-optimal. They are also associated
with high incidences of local and distant recurrence [5,6]. Accord-
ingly, there is a continuous endeavor to develop new therapeutic

https://doi.org/10.1016/j.tjog.2021.03.008
1028-4559/© 2021 Taiwan Association of Obstetrics & Gynecology. Publishing services by Elsevier B.V. This is an open access article under the CC BY license (http://
creativecommons.org/licenses/by/4.0/).
Y. Xu, M. Zhang, J. Zhang et al.
techniques that can further improve the prognosis of patients with
rescetable cervical cancer.
Neoadjuvant chemotherapy (NACT) is preferred against cancers
because it reduces the primary tumor, which improves operability
and subsequent treatment. It also improves radiosensitivity and
reduces the number of hypoxic cells. Moreover, NACT clears
micrometastatic tumors, reducing the risk of recurrence [7]. The
effect of NACT prior surgery or RT on cancer prognosis has been
extensively investigated [8]. However, to date, long-term prognosis
of resectable cervical cancer after NACT remains controversial.
In some clinical trials, surgery or RT following NACT [9e11] did
not improve survival outcomes for local advanced cervical cancers.
Conversely, Shoji et al. reported that NACT improved the overall
survival (OS) and progression-free survival (PFS) of patients with
cervical cancer [12]. Additionally, one study in China reported that
NACT significantly reduces the risk of surgery and the rate of
lymph-vascular space involvement [13]. Consequently, this meta-
analysis evaluated the effect of NACT on medium or long-term
prognosis of resectable cervical cancer patients.
Methods
Search strategy
Relevant reports published by June 2020 were retrieved from
PubMed, Web of Science, EBSCO and Cochrane Library electronic
dart abases. The search combined free text and Medical Subject
Headings (MeSH) terms. Search terms included “uterine cervical
neoplasms or cervical cancer or cervix cancer or cervical carci-
noma,” “neoadjuvant or preoperative” and “chemoradiotherapy or
chemotherapy or therapy.” Manual search was also performed for
potential studies identified from references of the included articles.
Eligible criteria
Relevant articles included in this meta-analysis fulfilled the
following: (1) were full-length observational study or randomized
controlled trial (RCT) related to preoperative or neoadjuvant
chemotherapy for cervical cancer; (2) evaluated the additional
benefits of NACT; (3) contained detailed data on PFS and/or OS for
patients with rescetable cervical cancer; (4) included at least 3-year
or 5-year survival outcomes; (5) were published in English.
Studies (1) without retrievable data, (2) on non-resectable tu-
mor or with majority of patients at stage IV cervical cancer, (3)
reviews and meta-analyses as well as (4) duplicates were all
excluded from this study.
Outcome measures
In this meta-analysis, the endpoints were 3-year and 5-year PFS
and OS. PFS was defined as the time between randomization and
disease progression or death. OS was defined as the time from date
of random selection until death from any cause or to the last follow-
up [6]. The effect of NACT on medium and long-term survival rates
in patients with resectable cervical cancer were evaluated by
comparing 3-year and 5-year PFS and OS.
Quality assessment and data extraction
Relevant articles were evaluated for eligibility by two inde-
pendent reviewers. Disagreements were arbitrated by a third
researcher. Thereafter, the included RCTs and observational studies
434
Taiwanese Journal of Obstetrics & Gynecology 60 (2021) 433e441
were assessed for risk of publication bias using the Cochrane Col-
laboration's tool and NewcastleeOttawa Quality Assessment Scale
and classified under three levels of “low risk”, “high risk” and
“uncertain risk”. Information on the author, year of publication,
country, primary FIGO tumor stage, number of participants, treat-
ment regimen, study design, age of the patients, follow-up dura-
tion, tumor differentiation, lymph node metastasis, pathologic type
and survival data were all captured.
Statistic analysis
The 3-year and 5-year PFS and OS in the NACT and control
groups were compared using the hazard ratio (HR) at 95% confi-
dence interval (95% Cl). Heterogeneity of HR was assessed based on
the I2. Random effects model was used to increase data credibility
due to differences in treatment regimens and tumor stages. Risk of
publication bias was analyzed using the Begg's and Egger's tests,
with p < 0.05 considered statistically significant. Sensitivity anal-
ysis for the suitability of the data was performed using Stata soft-
ware, V 12.0.
Results
Characteristics of eligible research
The search yielded 5169 studies. After screening, 22 studies
encompassing 5627 patients fulfilled the inclusion criteria [14e35].
The detailed screening process of the articles is summarized in
Fig. 1.
The characteristics of the included studies are listed in Table 1.
Most of the reports were retrospective observational studies
(n ¼ 14), whereas the rest (n ¼ 8) were RCTs. We compared three
treatment modalities; NACT followed by surgery and adjuvant
therapy (NACT þ surgery þ AT), versus surgery plus adjuvant
therapy (surgery þ AT) (n ¼ 14), NACT followed by surgery and
adjuvant therapy (NACT þ surgery þ AT) versus concurrent che-
moradiotherapy or radiotherapy or chemoradiotherapy (CCRT/RT/
CRT) (n ¼ 8) and NACT followed by chemoradiotherapy
(NACT þ CRT) versus chemoradiotherapy (CRT) (n ¼ 1). Of the 22
studies, 14 were performed in China, 3 in Japan, 1 in Korea, 1 in Iran,
1 in Brazil and 2 in Italy, all published between 2000 and 2020. The
majority of NACT treatment regimens were platinum and/or
taxane-based chemotherapy. The number of patients in each study
ranged from 42 to 800, with the majority of the patients diagnosed
with stage FIGO IB-IIB cervical cancer. Additional details of included
studies are shown in Supplementary Table 1.
Quality assessment
The quality of the 8 RCTs included in this study was assessed
using Cochrane collaboration tool. For the retrospective studies,
quality assessment was performed based on the NewcastleeOttawa
Quality Assessment Scale, along 8 parameters, each with a
maximum of 9 points. Only studies with overall score 6 were
included in the final analysis. Details on the quality assessment are
shown in Supplementary Table 2.
Prognostic analysis
Three articles reported on 3-year PFS of 391 patients, with 199
patients on NACT and 192 controls. Overall NACT treatment did not
significantly improve the 3-year PFS of the rescetable cervical
Y. Xu, M. Zhang, J. Zhang et al.
Fig. 1. A schematic flow for the selection of articles included in this meta-analysis.
cancer patients (HR ¼ 0.97, 95% CI: 0.69e1.24, p ¼ 0.841; Fig. 2a).
Random effect analysis revealed high heterogeneity in the three
studies (I2 ¼ 78.4%). Also, random effect analysis of four of the 22
reports on 3-year OS encompassing 562 patients found no statis-
tical difference between the NACT and the control groups, implying
that NACT did not significantly improve the 3-year OS of patients
with resectable cervical cancer (HR ¼ 0.99, 95% CI: 0.90e1.08,
p ¼ 0.931; Fig. 2b).
Of the 22 articles, 15 reports with high heterogeneity
(I2 ¼ 88.2%) and encompassing 4502 patients assessed 5-year PFS.
We found NACT treatment did not significantly increase the 5-year
PFS of patients with resectable cervical cancer (HR ¼ 0.89, 95% CI:
0.71e1.08, p ¼ 0.268; Fig. 3). Also, 20 highly heterogenous articles
(I2 ¼ 80.4%) with combined 5343 patients evaluated 5-year OS.
Converse to previous findings, NACT conferred significantly higher
5-year OS (HR ¼ 0.83, 95% CI: 0.73e0.94, p ¼ 0.013; Fig. 4).
Subgroup analysis of the long-term (5-year) survival
Because NACT treatment offered favorable 5-year OS, we per-
formed a further subgroup 5-year survival analyses along treat-
ment strategies and study types.
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Taiwanese Journal of Obstetrics & Gynecology 60 (2021) 433e441
Of the fifteen studies on 5-year PFS, 8 reported on
NACT þ surgery þ AT vs. surgery þ AT (HR ¼ 0.97, 95% CI: 0.77e1.17,
p ¼ 0.325), whereas 7 compared NACT þ surgery þ AT with CCRT/
RT/CRT (HR ¼ 0.81, 95% CI: 0.52e1.10, p ¼ 0.209). In addition, 4 of
the 15 studies were RCTs (HR ¼ 0.91, 95% CI: 0.65e1.16, p ¼ 0.451),
whereas the rest (n ¼ 11) were non-RCTs (HR ¼ 0.88, 95% CI:
0.63e1.13, p ¼ 0.348). Subgroup analysis revealed NACT had no
significant effect on the 5-year PFS among the 4 subgroups
(Table 2).
Of the 20 studies on 5-year OS, 12 reported on
NACT þ surgery þ AT vs. surgery þ AT (HR ¼ 0.90, 95% CI:
0.79e1.00, p ¼ 0.05) whereas 8 analyzed the efficacy of
NACT þ surgery þ AT vs. CCRT/RT/CRT (HR ¼ 0.76, 95% CI:
0.56e0.96, p ¼ 0.013). The subgroup analysis revealed that NACT
significantly increased the 5-year OS. Also, the statistical differ-
ences between NACT þ surgery þ AT vs. CCRT/RT/CRT was greater
than that of NACT þ surgery þ AT vs. surgery þ AT studies (Table 2).
Furthermore, of the 20, 6 studies were RCTs, whereas the rest
(n ¼ 14) were non-RCTs. Subgroup analysis of RCTs revealed that
although NACT could increase 5-year OS (HR ¼ 0.78, 95% CI:
0.55e1.01, p ¼ 0.062), the improvement was insignificant. On the
other hand, subgroup analysis of non-RCTs demonstrated that
 Table 1

Y. Xu, M. Zhang, J. Zhang et al.

Characteristics of all the studies included in the meta-analysis.

Group Author Year Country Patients number Tumor Regimen Study

NACT Control

NACT Control FIGO preoperative intraoperative postoperative intraoperative postoperative

a
NACT þ S vs.S Ouyang 2020 China 24 38 29 IB2/IIA2 platinum RH III EBRT ± BCT þ CT RH III EBRT þ BCT þ CT ROBSs
TP/TC/TNa
NACT þ S vs.S Yan 2019 China 60 84 IB2/IIA2 TP/TN/TL type C CT/RT/CT þ RT type C CT/RT/CT þ RT ROBSs
RS þ BPLT RS þ BPLT
NACT þ S vs.S Zhao 2019 China 178 125 IB2/IIA2 TP/BIP/BMP/ type III CRT type III CRT ROBSs
BCP RH þ BPLT RH þ BPLT
NACT þ S vs.S Li 2019 China 279 149 IB2-IIB TC/TP/PF type C/III CT/RT/CCRT/ type C/III CT/RT/CCRT/ ROBSs
RH þ LT combination RH þ LT combination
NACT þ S vs.S Yang 2016 China 109 110 IB2-IIB IP/TP type III d/RT/CT/ type III d/RT/CT/RT þ CT/ RCT
RH þ PALT RT þ CT/CCRT RH þ PALT CCRT
NACT þ S vs.S Qin 2016 China 35 30 II TP RS þ PLT d/RT/CT/CCRT RS þ PLT d/RT/CT/CCRT ROBSs
NACT þ S vs.S Gong 2016 China 411 389 IB2-IIB BP/BVP、 type III CT/RT/CRT type III CT/RT/CRT ROBSs
FBP/FIP、TP/ RH þ LT RH þ LT
TC
NACT þ S vs.S Zhang 2016 China 80 91 IB2/IIA2 ICR RH þ LT ETRT þ CT/ RH þ LT ETRT þ CT/ ROBSs
NRT þ PRT NRT þ PRT
NACT þ S vs.S Katsumata 2013 Japan 67 67 IB2-IIB BOMP RH RT (EBRT/BCT) RH RT (EBRT/BCT) RCT
NACT þ S vs.S Yinb 2011 China 187 195 IB2-IIB PVB/TP RS þ LT RT/CCRT RS þ LT RT/CCRT ROBSs
NACT þ S vs.S Mossa 2010 Italy 159 129 IB-IIIB PVB type III/Ⅳ RT (EBRT/BCT) type III/Ⅳ RT (EBRT/BCT) RCT
RH þ LT RH þ LT
NACT þ S vs.S Cai 2006 China 53 54 IB PF type III CT type III CT RCT
RH þ LT RH þ LT
NACT þ S vs.S Behtash 2006 Iran 22 160 IB-IIA PV type III RT type III RT ROBSs
436

RH þ PALT RH þ PALT
NACT þ S vs.S Aoki 2001 Japan 21 21 IB-IIB PVP RH þ LT RT RH þ LT RT ROBSs
NACT þ S Hsieh 2019 China 44 49 IB2 PVB RH þ LT CRT/CT/RT/LT NA IMRT þ CT þ ICR/ ROBSs
vs.CCRT RS
NACT þ S Yoshida 2019 Japan 50 76 IB2-IIB EBRT þ PF RH þ LT CT NA EBRT þ ICR þ CT ROBSs
vs.CCRT
NACT þ S Gupta 2018 India 317 318 IB2-IIB TP type III RT/CT þ RT、 NA CCRT þ EBRT þ BCT RCT
vs.CCRT RH þ BPLT EBRT þ BCT
NACT þ S Lee 2016 Korea 85 358 IB-IIB Platinum/ RS þ LT RT/CT NA CCRT (EBRT/ ROBSs

Taiwanese Journal of Obstetrics & Gynecology 60 (2021) 433e441

vs.CCRT VC/FU/EP EBRT þ ICR/ICR)
NACT þ S Yang 2015 China 103 141 IIB TP/TC/TN type III RT NA EBRT þ IAT þ CCRT ROBSs
vs.CCRT RH þ LT
NACT þ S Yinb 2011 China 187 94 IB2-IIB PVB/TP RS þ LT RT/CCRT NA CCRT þ PRT þ IAT ROBSs
vs.CCRT
NACT þ S vs.RT Benedetti-Panici 2002 Italy 210 199 IB2-III PB/PVB/IP/ type III-Ⅳ RT NA ERT þ BCT RCT
Platinum RH þ LT
NACT þ S vs.RT Chang 2000 China 68 52 IB-IIA PVB type III RT/CT NA ERT þ BCT RCT
RH þ LT
NACT þ CRT da Costa 2019 Brazil 55 52 IIB-IVA NAC (PG)þCRT CRT þ EBRT ± BCT RCT
vs.CRT

NACT, Neoadjuvant chemotherapy; RCT, Randomized controlled trial; ROBSs, Retrospective observational studies; FIGO, International Federation of Gynecology and Obstetrics.
TP, Paclitaxel þ cisplatin; TC, Paclitaxel þ carboplatin; TN, Paclitaxel þ nedaplatin; TL, Paclitaxel þ lobaplatin; BIP, Bleomycin with ifosfamide and cisplatin; BMP, Bleomycin with mitomycin and cisplatin; BCP,
Bleomycin þ carboplatin; PF, Flurouracil þ cisplatin; IP, Irinotecan þ cisplatin; BP, Cisplatin þ bleomycin/pingyangmycin; BVP/PVB, BP þ vincristine.
FBP, 5-fluorouracil þ cisplatin þ bleomycin/pingyangmycin; FIP, 5fluorouracil þ cisplatin þ ifosfamide and mesna; BOMP, Bleomycin þ vincristine þ mitomycin þ cisplatin.
PVP, Cisplatin þ vincristine þ peplomycin; VC, Vincristine; FU, 5-fluorouracil; EP,etoposide; PG, Cisplatin þ gemcitabine; RH, Radical hysterectomy; RS, Radical surgery; RT, Radiation therapy.
CRT, Chemoradiotherapy; CCRT, Concurrent chemoradiotherapy; EBRT, External beam radiation therapy; ICR, Intracavitary brachytherapy; LT, Lymphadenectomy; BPLT, Bilateral pelvic lymphadenectomy; PALT, Pevlic/para-
aortic lymphadenectomy; ETRT, External radiotherapy; NRT, Nodal radiotherapy; PRT, Plevic radiation; BCT, Brachytherapy; IMRT, Intensity-modulated radiotherapy; IAT, Intracavitary afterloading therapy; NA, Not available;
d, No postoperative therapy.
a
Neoadjuvant chemoradiotherapy.
b
Both were from the same study.
Y. Xu, M. Zhang, J. Zhang et al.
Fig. 2. Forest plot of the 3-year PFS and OS of patients with resectable cervical cancer on neoadjuvant chemotherapy (NACT) (a, progression-free survival, p ¼ 0.841; b, overall
survival, p ¼ 0.931).
NACT could significantly improve 5-year OS of patients with
resectable cervical cancer (HR ¼ 0.86, 95% CI: 0.73e0.98, p ¼ 0.012)
(Table 2).
Publication bias and sensitivity analysis of 5-year OS
The Begg's plot and Egger's plot analyses revealed there was no
significant publication bias in this meta-analysis (p > 0.05). On the
other hand, sensitivity analysis on the stability of 5-year OS for this
study revealed the results were robust and reliable (Supplementary
Fig. 1 and Supplementary Fig. 2).
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Taiwanese Journal of Obstetrics & Gynecology 60 (2021) 433e441
Discussion
In the 1980s, preoperative chemotherapy was shown to improve
PFS of malignant tumors such as breast cancer [36]. Sardi et al.
found that preoperative chemotherapy could shrink inoperable
cervical tumors to radical surgical treatment levels [37]. These early
positive outcomes suggested preoperative chemotherapy was
potentially a new prospect in cervical cancer treatment. Preoper-
ative chemotherapy may also significantly improve the survival of
patients with less advanced tumors. Since its inception, NACT has
gradually been adopted in the treatment of cervical cancer to either
Y. Xu, M. Zhang, J. Zhang et al.
Fig. 3. Forest plot of the 5-year progression-free survival (PFS) of resectable cervical cancer patients on neoadjuvant chemotherapy (NACT) (p ¼ 0.268).
allow resection or to improve the prognosis of the cancer [38].
However, the effect of NACT on increasing PFS or OS of cancer pa-
tients remains controversial.
Indeed previous meta-analyses and reviews give conflicting
findings on the effect of NACT on survival outcomes of cancer
patients. For instance, Rydzewska et al. found that NACT signifi-
cantly improved PFS (HR ¼ 0.76, 95% CI: 0.62e0.94, p ¼ 0.01), but
not OS (HR ¼ 0.85, 95% CI: 0.67e1.07, p ¼ 0.17) [39]. However, the
difference between PFS and OS in the study may be attributed to
missing data on OS in one of the included articles. A separate
meta-analysis by Kim et al. revealed that compared with primary
surgical treatment, NACT does not improve the survival of patients
with resectable cervical cancer [40]. In fact, the OS of cancer pa-
tients in observational studies was worse than in RCTs, attributed
to. However, Zhao et al. suggested that surgery after NACT can
significantly improve the OS and decrease local recurrence rate
[41]. However, there was no specific distinction on short-term or
long-term survival rates in the study. In a recent meta-analysis, Ye
et al. reported that NACT þ surgery may confer longer OS and PFS
than RT or CCRT alone [42]. However, the sample size for their
study (1000 patients) casts doubt on the credibility of the findings.
Thus, there is need to evaluate current trend on the medium and
long-term prognosis of NACT in resectable cervical cancer
patients.
This meta-analysis analyzed 22 reports, encompassing more
than 5000 patients, to assess the impact of NACT on the 3-year and
5-year survival of patients with resectable cervical cancer. Com-
parisons were made among NACT þ surgery þ AT versus
surgery þ AT, NACT þ surgery þ AT versus CCRT/RT/CRT and
NACT þ CRT versus CRT. Most patients included in the study
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Taiwanese Journal of Obstetrics & Gynecology 60 (2021) 433e441
presented with squamous cell carcinoma, with only a few diag-
nosed with non-squamous cell carcinoma.
In this meta-analysis we found NACT does not significantly
increase the 3-year PFS and OS of patients with resectable cer-
vical cancer. In a separate but related study, Marchetti and col-
leagues reported that NACT negatively affect the PFS (HR ¼ 1.32,
95% CI: 1.07e1.62). However, their findings may have been
influenced by relatively short follow-up time [43]. Meanwhile, in
their randomized trial, Da Kasta et al. found the 3-year PFS (40.9%
vs. 60.9%) was lower for patients on NACT compared with pa-
tients on standard treatment [20]. Apart from differences in
participants’ baseline information, they suggested the results
may have been influenced by the distant metastases in the ma-
jority of the patients. Additionally, the poor 3-year OS after NACT
may have been influenced by cancer stage, most of which were
agate III-IVA [20]. In the current meta-analysis, the insignificance
of NACT on 3-year PFS and OS may be attributed to the small
sample size, which included only 3 studies and 4 studies pa-
tients, respectively. The short follow-up time of 3 years may have
also impacted on the findings. We also believe postoperative AT
affected the survival of patients (3-year PFS and OS) included in
this study, because AT may have masked the advantages of NACT.
Indeed, we also cannot rule out the possibility that NACT did not
have a medium survival advantage for patients with resectable
cervical cancer.
This meta-analysis also revealed that NACT did not improve 5-
year PFS of patients with resectable cervical cancer. A previous
meta-analysis including 739 cervical cancer patients demonstrated
that although NACT significantly reduced the number of positive
lymph nodes and the degree of parametrial infiltration, there were
Y. Xu, M. Zhang, J. Zhang et al. Taiwanese Journal of Obstetrics & Gynecology 60 (2021) 433e441

Fig. 4. Forest plot for the 5-year overall survival (OS) of resectable cervical cancer patients on neoadjuvant chemotherapy (NACT) (p ¼ 0.013).

Table 2
Subgroup analysis of the 5-year long-term survival of resectable cervical cancer patients.

No. of studies HR 95%CI p Heterogeneity (I2) (%)

5-year progression-free survival

NACT þ surgery vs. surgery 8 0.97 0.77e1.17 0.325 71.8
NACT þ surgery vs. CCRT/RT/CRT 7 0.81 0.52e1.10 0.209 90.5
RCTs 4 0.91 0.65e1.16 0.451 67.6
Non-RCTs 11 0.88 0.63e1.13 0.348 90.8
5-year overall survival
NACT þ surgery vs. surgery 12 0.90 0.79e1.00 0.05 71.3
NACT þ surgery vs. CCRT/RT/CRT 8 0.76 0.56e0.96 0.013 82.3
RCTs 6 0.78 0.55e1.01 0.062 75.2
Non-RCTs 14 0.86 0.73e0.98 0.012 82.6

NACT, Neoadjuvant chemotherapy; CCRT, concurrent radiotherapy; RT, radiotherapy; CRT, chemoradiotherapy; RCTs, Randomized controlled trials.

no significant differences in 5-year survival (OS, PFS and recurrence
rates) between NACT followed by radical surgery patients and those
on radical surgery alone [44]. Meanwhile, compared with non-
squamous cell carcinoma patients, squamous cell carcinoma pa-
tients showed a favorable 5-year PFS and OS after NACT [45]. For
this meta-analysis, some patients in the included literature pre-
sented with non-squamous cell carcinoma. Additionally, we believe
the 5-year PFS of patients included in this study may have been
influenced by the pathologic types. This conjecture is supported by
the aforementioned studies. Unfortunately, due to the lack of
relevant data in the included literature, we were unable to conduct
further subgroup analysis.
Further subgroup analyses (RCTs, non-RCTs, NACT þ surgery
þ AT vs. surgery þ AT, NACT þ surgery þ AT vs. CCRT/RT/CRT) also
revealed no difference in 5-year PFS between NACT patients and
controls. Li et al. [18] and Liu et al. [46] reported that preoperative
NACT did not improve long-term PFS of patients with local
advanced cervical cancer. Also, Fu et al. demonstrated that there
was no significance difference in 5-year PFS between RT and NACT
patients [47], all consistent with our findings.
Strikingly, in this research, analysis of the pooled data revealed
that NACT significantly improves 5-year OS of resectable cervical
cancer patients. Further subgroup analysis on 5-year OS revealed
comparable findings, albeit statistically insignificant (p ¼ 0.062).
This difference may however be attributed to the limited sample
size. Even so, the effect of NACT on the prognosis of patients with
resectable cervical cancer is worth recognizing. Indeed increasing
evidence suggests NACT could prolong the long-term prognosis of

439
Y. Xu, M. Zhang, J. Zhang et al.
cervical cancer patients, consistent with our finds. For instance,
Rydzewska et al. notes that NACT (HR ¼ 0.77, 95% CI: 0.62e0.96,
p ¼ 0.02) improved OS [48]. Also, their exploratory analysis of
pathologic responses revealed that NACT significantly reduced
adverse pathological events including lymph node metastasis and
parametrial infiltration. Moreover, a recent subgroup retrospective
study revealed that preoperative NACT conferred superior OS than
CCRT [49]. Lymph node metastasis strongly affects the prognosis of
cervical cancer. Interestingly, Benedetti-Panici et al. [50] and Zhang
et al. [51] reported that patients receiving NACT had significantly
lower rate of lymph node metastasis, which may be attributed to
better OS of patients with resectable cervical cancer.
In our 5-year OS subgroup analysis, the difference between
NACT þ surgery þ AT vs. CCRT/RT/CRT was greater than that of
NACT þ surgery þ AT vs. surgery þ AT. This suggest that under the
same conditions, perhaps radical surgery is superior to CCRT/RT/
CRT. Indeed Heish et al. reported that patients who underwent
radical hysterectomy exhibited better 5-year OS (93.8% vs. 80.1%)
and PFS (91.0% vs. 79.5%) than those who underwent CCRT [19].
Nonetheless, this conjecture remains to be further validated.
Unfortunately, this meta-analysis was unavailable to compare 3-
year OS with 5-year OS in the same study data. The reasons were as
follows: in the included studies, the 3-year OS sample size was
small, while the 5-year OS sample size was large, which had led to
significant differences. Furthermore, except that the 3-year OS data
and 5-year OS data could be extracted simultaneously in Zhang's
and Behtash's studies, the rest of the data were extracted from
different studies. Therefore, more studies are needed to provide
relevant data on this issue.
Compared with other reports, this study analyzed a relatively
larger sample, which offers more credible findings on the impact of
NACT on resectable cervical cancer. In addition, assessment of both
3-year and 5-year survival rates (OS, PFS) gives a better insight on
the effect of NACT to both long and short term prognosis of patients
with resectable cervical cancer. Our findings notwithstanding, this
meta-analysis suffered several limitations. First, the inherent
shortcoming of retrospective data may impact on the credibility of
the findings. Second, exclusion based on publication language
limited our sample size. Finally, there were numerous NACT mo-
dalities, and the basic treatment was also different. These differ-
ences may have impacted on the outcome of our findings.
In conclusion, despite the insignificant impact of NACT on 3-year
OS, PFS and 5-year PFS, this meta-analysis found NACT improves
the 5-year OS of patients with resectable cervical cancer. None-
theless, this finding should be validated by large-scale multicenter
clinical trials.
Ethics approval and consent to participate
Not applicable.
Consent to publish
Not applicable.
Availability of data and materials
Data supporting findings reported in this study are available in
the supplementary materials.
Funding
The authors received no financial support in conducting this
meta-analysis.
440
Taiwanese Journal of Obstetrics & Gynecology 60 (2021) 433e441
Declaration of competing interest
The authors declare there was no conflict of interest.
Acknowledgements
Not applicable.
Abbreviations
NACT neoadjuvant chemotherapy
CCRT concurrent chemoradiotherapy
RT radiotherapy
CRT chemoradiotherapy
AT adjuvant therapy
OS overall survival
PFS progression-free survival
HR hazard ratio
CI confidence interval
FIGO International Federation of Gynecology and Obstetrics
RCTs randomized controlled trials.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tjog.2021.03.008.
References
[1] Small W, Bacon M, Bajaj A, Chuang L, Fisher B, Harkenrider M, et al. Cervical
cancer: a global health crisis. Cancer 2017;123(13):2404e12.
[2] Salib M, Russell J, Stewart V, Sudderuddin S, Barwick T, Rockall A, et al. 2018
FIGO staging classification for cervical cancer: added benefits of imaging.
Radiographics : a review publication of the Radiological Society of North
America, Inc; 2020. p. 200013.
[3] Koh W-J, Abu-Rustum NR, Bean S, Bradley K, Campos SM, Cho KR, et al. Cer-
vical cancer, version 3.2019, NCCN clinical practice guidelines in oncology.
J Natl Compr Canc Netw 2019;17(1):64e84.
[4] Matoda M, Takeshima N, Michimae H, Iwata T, Yokota H, Torii Y, et al. Post-
operative chemotherapy for node-positive cervical cancer: results of a
multicenter phase II trial (JGOG1067). Gynecol Oncol 2018;149(3):513e9.
[5] Waggoner SE. Cervical cancer. Lancet 2003;361(9376):2217e25.
[6] Zou W, Han Y, Zhang Y, Hu C, Feng Y, Zhang H, et al. Neoadjuvant chemo-
therapy plus surgery versus concurrent chemoradiotherapy in stage IB2-IIB
cervical cancer: a systematic review and meta-analysis. PloS One
2019;14(11):e0225264.
[7] Gonzalez-Martin A, Gonzalez-Cortijo L, Carballo N, Garcia JF, Lapuente F,
Rojo A, et al. The current role of neoadjuvant chemotherapy in the manage-
ment of cervical carcinoma. Gynecol Oncol 2008;110(3 Suppl 2):S36e40.
[8] Lapresa M, Parma G, Portuesi R, Colombo N. Neoadjuvant chemotherapy in
cervical cancer: an update. Expet Rev Anticancer Ther 2015;15(10):1171e81.
[9] Gong L, Lou J-Y, Wang P, Zhang J-W, Liu H, Peng Z-L. Clinical evaluation of
neoadjuvant chemotherapy followed by radical surgery in the management of
stage IB2-IIB cervical cancer. Int J Gynecol Obstet 2012;117(1):23e6.
[10] Lee J, Kim TH. Neoadjuvant chemotherapy followed by surgery has no ther-
apeutic advantages over concurrent chemoradiotherapy in International
Federation of Gynecology and Obstetrics stage IB-IIB cervical cancer
2016;27(5):e52.
[11] Mocellin S, Goldin E, Marchet A, Nitti D. Sentinel node biopsy performance
after neoadjuvant chemotherapy in locally advanced breast cancer: a sys-
tematic review and meta-analysis. Int J Canc 2016;138(2):472e80.
[12] Shoji T, Kumagai S, Yoshizaki A, Yokoyama Y, Fujimoto T, Takano T, et al.
Efficacy of neoadjuvant chemotherapy followed by radical hysterectomy in
locally advanced non-squamous carcinoma of the uterine cervix: a retro-
spective multicenter study of Tohoku Gynecologic Cancer Unit. Eur J Gynaecol
Oncol 2012;33(4):353e7.
[13] Wang Y, Wang G, Wei LH, Huang LH, Wang JL, Wang SJ, et al. Neoadjuvant
chemotherapy for locally advanced cervical cancer reduces surgical risks and
lymph-vascular space involvement. Chin J Canc 2011;30(9):645e54.
[14] Ouyang P, Cai J, Gui L, Liu S, Wu NY, Wang J. Comparison of survival outcomes
of neoadjuvant therapy and direct surgery in IB2/IIA2 cervical adenocarci-
noma: a retrospective study. Arch Gynecol Obstet 2020;301(5):1247e55.
[15] Zhao H, He Y, Zhu LR, Wang JL, Guo HY, Xu T, et al. Effect of neoadjuvant
chemotherapy followed by radical surgery for FIGO stage IB2/IIA2 cervical
cancer: a multi-center retrospective clinical study. Medicine 2019;98(21):
e15604.
Y. Xu, M. Zhang, J. Zhang et al.
[16] Yoshida K, Kajiyama H, Yoshihara M, Tamauchi S, Ikeda Y, Yoshikawa N, et al.
The role of additional hysterectomy after concurrent chemoradiation for pa-
tients with locally advanced cervical cancer. Int J Clin Oncol 2019;25(2):
384e90.
[17] Yan W, Si L, Ding Y, Qiu S, Zhang Q, Liu L. Neoadjuvant chemotherapy does not
improve the prognosis and lymph node metastasis rate of locally advanced
cervical squamous cell carcinoma: a retrospective cohort study in China.
Medicine 2019;98(39):e17234.
[18] Li L, Wu M, Ma S, Tan X, Zhong S. Neoadjuvant chemotherapy followed by
radical hysterectomy for stage IB2-to-IIB cervical cancer: a retrospective
cohort study. Int J Clin Oncol 2019;24(11):1440e8.
[19] Hsieh H-Y, Huang J-W, Lu C-H, Lin J-C, Wang L. Definite chemoradiotherapy is
a competent treatment option in FIGO stage IB2 cervical cancer compared
with radical surgery þ/ neoadjuvant chemotherapy. J Formos Med Assoc
2019;118(1):99e108.
[20] da Costa SCS, Bonadio RC, Gabrielli FCG, Aranha AS, Dias Genta MLN,
Miranda VC, et al. Neoadjuvant chemotherapy with cisplatin and gemcitabine
followed by chemoradiation versus chemoradiation for locally advanced
cervical cancer: a randomized phase II trial. J Clin Oncol : official journal of the
American Society of Clinical Oncology 2019;37(33):3124e31.
[21] Gupta S, Maheshwari A, Parab P, Mahantshetty U, Hawaldar R, Sastri Chopra S,
et al. Neoadjuvant chemotherapy followed by radical surgery versus
concomitant chemotherapy and radiotherapy in patients with stage IB2, IIA,
or IIB squamous cervical cancer: a randomized controlled trial. J Clin Oncol :
official journal of the American Society of Clinical Oncology 2018;36(16):
1548e55.
[22] Zhang T, Kong W, Li F, Song D, Liu T, Han C, et al. Effect of preoperative
radiotherapy on stage IB2 and IIA2 cervical cancer: a retrospective cohort
study. Int J Surg 2016;30:63e7.
[23] Yang Z, Chen D, Zhang J, Yao D, Gao K, Wang H, et al. The efficacy and safety of
neoadjuvant chemotherapy in the treatment of locally advanced cervical
cancer: a randomized multicenter study. Gynecol Oncol 2016;141(2):231e9.
[24] Qin T, Zhen J, Zhou M, Wu H, Ren R, Qu B, et al. Efficacy of neoadjuvant
chemotherapy plus radical surgery in patients with bulky stage II cervical
squamous cell carcinoma: a retrospective cohort study. Int J Surg 2016;30:
121e5.
[25] Lee J, Kim TH, Kim GE, Keum KC, Kim YB. Neoadjuvant chemotherapy fol-
lowed by surgery has no therapeutic advantages over concurrent chemo-
radiotherapy in International Federation of Gynecology and Obstetrics stage
IB-IIB cervical cancer. Journal of gynecologic oncology 2016;27(5).
[26] Gong L, Zhang J-W, Yin R-T, Wang P, Liu H, Zheng Y, et al. Safety and efficacy
of neoadjuvant chemotherapy followed by radical surgery versus radical
surgery alone in locally advanced cervical cancer patients. Int J Gynecol Canc
2016;26(4):722e8.
[27] Yang S, Gao Y, Sun J, Xia B, Liu T, Zhang H, et al. Neoadjuvant chemotherapy
followed by radical surgery as an alternative treatment to concurrent chemo-
radiotherapy for young premenopausal patients with FIGO stage IIB squamous
cervical carcinoma. Tumour biology : the journal of the International Society for
Oncodevelopmental Biology and Medicine 2015;36(6):4349e56.
[28] Katsumata N, Yoshikawa H, Kobayashi H, Saito T, Kuzuya K, Nakanishi T, et al.
Phase III randomised controlled trial of neoadjuvant chemotherapy plus
radical surgery vs radical surgery alone for stages IB2, IIA2, and IIB cervical
cancer: a Japan Clinical Oncology Group trial (JCOG 0102). Br J Canc
2013;108(10):1957e63.
[29] Yin M, Zhao F, Lou G, Zhang H, Sun M, Li C, et al. The long-term efficacy of
neoadjuvant chemotherapy followed by radical hysterectomy compared with
radical surgery alone or concurrent chemoradiotherapy on locally advanced-
stage cervical cancer. Int J Gynecol Canc : official journal of the International
Gynecological Cancer Society 2011;21(1):92e9.
[30] Mossa B, Mossa S, Corosu L, Marziani R. Follow-up in a long-term randomized
trial with neoadjuvant chemotherapy for squamous cell cervical carcinoma.
Eur J Gynaecol Oncol 2010;31(5):497e503.
[31] Cai H-B, Chen H-Z, Yin H-H. Randomized study of preoperative chemotherapy
versus primary surgery for stage IB cervical cancer. J Obstet Gynaecol Res
2006;32(3):315e23.
[32] Behtash N, Nazari Z, Ayatollahi H, Modarres M, Ghaemmaghami F, Mousavi A.
Neoadjuvant chemotherapy and radical surgery compared to radical surgery
alone in bulky stage IB-IIA cervical cancer. Eur J Surg Oncol 2006;32(10):
1226e30.
441
Taiwanese Journal of Obstetrics & Gynecology 60 (2021) 433e441
[33] Benedetti-Panici P, Greggi S, Colombo A, Amoroso M, Smaniotto D,
Giannarelli D, et al. Neoadjuvant chemotherapy and radical surgery versus
exclusive radiotherapy in locally advanced squamous cell cervical cancer:
results from the Italian multicenter randomized study. J Clin Oncol : official
journal of the American Society of Clinical Oncology 2002;20(1):179e88.
[34] Aoki Y, Tomita M, Sato T, Watanabe M, Kase H, Fujita K, et al. Neoadjuvant
chemotherapy for patients younger than 50 years with high-risk squamous
cell carcinoma of the cervix. Gynecol Oncol 2001;83(2):263e7.
[35] Chang TC, Lai CH, Hong JH, Hsueh S, Huang KG, Chou HH, et al. Randomized
trial of neoadjuvant cisplatin, vincristine, bleomycin, and radical hysterec-
tomy versus radiation therapy for bulky stage IB and IIA cervical cancer. J Clin
Oncol : official journal of the American Society of Clinical Oncology
2000;18(8):1740e7.
[36] Gasparini G, Toffoli G, Berlanda G, Rossi C. A pharmacological rationale for
neoadjuvant chemotherapy with adriamycin in locally advanced breast can-
cer. Anticancer Res 1990;10(1):193e6.
[37] Sardi J, di Paola G, Cachau A, Ortiz O, Sananes C, Giaroli A, et al. A possible new
trend in the management of the carcinoma of the cervix uteri. Gynecol Oncol
1986;25(2):139e49.
[38] Sardi J, Sananes C, Giaroli A, Maya G, di Paola G. Neoadjuvant chemotherapy in
locally advanced carcinoma of the cervix uteri. Gynecol Oncol 1990;38(3):
486e93.
[39] Rydzewska L, Tierney J, Vale C, Symonds P. Neoadjuvant chemotherapy plus
surgery versus surgery for cervical cancer. Cochrane Database Syst Rev
2010;20(1):CD007406.
[40] Kim H, Sardi J, Katsumata N, Ryu H, Nam J, Chung H, et al. Efficacy of neo-
adjuvant chemotherapy in patients with FIGO stage IB1 to IIA cervical cancer:
an international collaborative meta-analysis. Eur J Surg Oncol : the journal of
the European Society of Surgical Oncology and the British Association of
Surgical Oncology 2013;39(2):115e24.
[41] Zhao H, He Y, Yang S, Zhao Q, Wu Y. Neoadjuvant chemotherapy with radical
surgery vs radical surgery alone for cervical cancer: a systematic review and
meta-analysis. OncoTargets Ther 2019;12:1881e91.
[42] Ye Q, Yang Y, Tang X, Li J, Li X, Zhang Y. Neoadjuvant chemotherapy followed
by radical surgery versus radiotherapy (with or without chemotherapy) in
patients with stage IB2, IIA, or IIB cervical cancer: a systematic review and
meta-analysis. Dis Markers 2020;2020:7415056.
[43] Marchetti C, Fagotti A, Tombolini V, Scambia G, De Felice F. Survival and
toxicity in neoadjuvant chemotherapy plus surgery versus definitive che-
moradiotherapy for cervical cancer: a systematic review and meta-analysis.
Canc Treat Rev 2020;83:101945.
[44] Peng YH, Wang XX, Zhu JS, Gao L. Neo-adjuvant chemotherapy plus surgery
versus surgery alone for cervical cancer: meta-analysis of randomized
controlled trials. J Obstet Gynaecol Res 2016;42(2):128e35.
[45] He L, Wu L, Su G, Wei W, Liang L, Han L, et al. The efficacy of neoadjuvant
chemotherapy in different histological types of cervical cancer. Gynecol Oncol
2014;134(2):419e25.
[46] Liu S, Yang J, Cao D, Shen K, Xiang Y, Lang J. Efficacy of neoadjuvant cisplatin
and 5-flourouracil prior to surgery in FIGO stage IB2/IIA2 cervical cancer.
Molecular and clinical oncology 2014;2(2):240e4.
[47] Fu J, Gao Z, Ren C, Shi Y. Comparison of clinical efficacy of three different
neoadjuvant approaches (chemotherapy combined vaginal intracavitary
irradiation, neoadjuvant chemotherapy alone or radiotherapy) combined with
surgery for patients with stage Ib2 and IIa2 cervical cancer. Asian Pac J Cancer
Prev APJCP : Asian Pac J Cancer Prev APJCP 2013;14(4):2377e81.
[48] Rydzewska L, Tierney J, Vale C, Symonds P. Neoadjuvant chemotherapy plus
surgery versus surgery for cervical cancer. Cochrane Database Syst Rev
2012;12:CD007406.
[49] Tian T, Gao X, Ju Y, Ding X, Ai Y. Comparison of the survival outcome of
neoadjuvant therapy followed by radical surgery with that of concomitant
chemoradiotherapy in patients with stage IB2-IIIB cervical adenocarcinoma.
Archives of gynecology and obstetrics; 2020.
[50] Benedetti-Panici P, Greggi S, Scambia G, Amoroso M, Salerno M, Maneschi F,
et al. Long-term survival following neoadjuvant chemotherapy and radical
surgery in locally advanced cervical cancer. European journal of cancer (Ox-
ford, England : 1990) 1998;34(3):341e6.
[51] Zhang H, Peng W, Zhang Y. Detection of cell apoptosis in pelvic lymph nodes
of patients with cervical cancer after neoadjuvant chemotherapy. J Int Med
Res 2014;42(3):641e50.