IJG-08288; No of Pages 5

International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx

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International Journal of Gynecology and Obstetrics

journal homepage: www.elsevier.com/locate/ijgo

CLINICAL ARTICLE

Prognostic risk factors for small cell carcinoma of the cervix and impact of
platinum-based neoadjuvant chemotherapy
Xiong Li a,b,1, Ru Yang a,c,1, Yao Jia a, Jin Zhou a, Ding Ma a, Shuang Li a,⁎
a
Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
b
Department of Gynecology and Obstetrics, The Central Hospital of Wuhan, Wuhan, China
c
Henan Tumor Hospital, Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou, China

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

Article history: Objective: To evaluate prognostic risk factors and the effects of platinum-based neoadjuvant chemotherapy
Received 20 September 2014 (NACT) among patients with small cell carcinoma of the cervix (SCCC). Methods: In a retrospective multicenter
Received in revised form 17 January 2015 study, data were analyzed from patients with SCCC diagnosed between July 2001 and October 2009 at one
Accepted 27 March 2015 of three hospitals in China. Prognostic risk factors were identified by the Cox proportional hazards model.
Results: Follow-up information was available for 22 patients, including 18 cases of early (FIGO stage IA–IIA)
Keywords:
and four cases of advanced (stage IIB–IV) SCCC. The 3-year disease-free survival (DFS) rate was 62% for patients
Neoadjuvant chemotherapy
Prognosis
with early stage disease and 0% for those at a late stage (P = 0.003). The 3-year overall survival (OS) rate was 68%
Small cell carcinoma of the cervix and 0%, respectively (P = 0.001). The 3-year OS rate was 73% for patients with no lymphovascular space invasion
and 0% for those with lymphovascular space invasion (P = 0.031). Advanced FIGO stage was the only indepen-
dent risk factor for 3-year DFS (P = 0.017) and 3-year OS (P = 0.006). Patients who received NACT plus radical
surgery had a lower rate of distant recurrence than did patients who received radical surgery as the primary
treatment (0/8 vs 5/9; P = 0.029). Conclusion: Advanced disease was an independent risk factor for SCCC
prognosis. Platinum-based NACT seemed to prevent distant recurrence.
© 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

1. Introduction
Small cell carcinoma of the cervix (SCCC) accounts for approximate-
ly 1%–3% of all cervical cancers [1–3]. This neuroendocrine tumor was
first described in 1957 by Reagan et al. [4]. Neuroendocrine tumors
have been classified by the College of American Pathologists and the Na-
tional Cancer Institute into four subtypes [5]: typical carcinoid, atypical
carcinoid, large cell neuroendocrine carcinoma, and small cell neuroen-
docrine carcinoma. SCCC is the most aggressive type of all cervical can-
cers, characterized by a high incidence of nodal and distant metastases
at an early stage, and hematogenously disseminated [1,6,7]. It has a
lower survival rate than do other subtypes of cervical cancer [8–16].
Owing to the low incidence of SCCC, it is difficult to collect data on
enough cases for analysis. Previous studies have not reached a consen-
sus with regard to the prognostic factors of SCCC. Some studies have
considered the International Federation of Gynecology and Obstetrics
(FIGO) stage as an important prognostic factor [15–17]. Chang et al.
[8] reported that lymph node metastasis was a poor prognostic factor,
⁎ Corresponding author at: Department of Obstetrics and Gynecology, Tongji Hospital,
Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang
Anv, Wuhan, Hubei, 430030, China. Tel.: +86 27 83662475; fax: +86 27 83662681.
E-mail address: lee5190008@126.com (S. Li).
1
These authors contributed equally.
but Lee [11] who noted that lymph node metastasis was not significant-
ly associated with poor survival.
At present, there is no standard effective treatment regimen for
SCCC. In previous studies, several chemotherapy regimens have been
used; the most accepted regimens are EP (platinum and etoposide)
and VAC (vincristine, adriamycin, and cyclophosphamide). Chemother-
apy has been shown to have a role in distant control, coupled with radi-
ation therapy for local control [13]. However, the role of neoadjuvant
chemotherapy (NACT) is not clear. In one study [11], patients with
stage IB–IIA disease who received NACT had a worse prognosis than
did those who did not receive NACT. Other studies have suggested
that NACT before surgery is detrimental [15,18].
The aim of the present study was therefore to evaluate prognostic
risk factors for SCCC and the effects of platinum-based NACT, including
short-term response, long-term response, and impact on recurrence.
2. Materials and methods
In the present multicenter retrospective study, data were analyzed
from the Cervical Cancer Database version 1.10 [19] for patients with
SCCC who were diagnosed between July 1, 2001, and October 31,
2009, at Tongji Hospital (Wuhan, China), Hunan Province Tumor Hospi-
tal (Changsha, China), or the Women’s Reproductive Health Laboratory
of Zhejiang Province (Zhejiang, China). The study inclusion criteria were

http://dx.doi.org/10.1016/j.ijgo.2015.02.022
0020-7292/© 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

Please cite this article as: Li X, et al, Prognostic risk factors for small cell carcinoma of the cervix and impact of platinum-based neoadjuvant
chemotherapy, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.02.022
2 X. Li et al. / International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx

a diagnosis of FIGO stage IA1–IVB SCCC, positive tests for morpholog-
ical criteria of the disease (Supplementary Material S1) and for at
least one of the neuroendocrine markers (e.g. chromogranin A and
synaptophysin) [20], and a low rate of missing information. Patients
diagnosed with SCCC for whom data on neuroendocrine markers were
unavailable or with more than 40% of information missing were exclud-
ed. The study was authorized by the Ethics Committee of the Huazhong
University of Science and Technology, and all participants gave
informed consent for the use of their data in future analyses.
The clinical and pathologic variables extracted from the database in-
cluded patient age, FIGO stage, tumor size, histologic homology, lymph
node metastasis, depth of stromal invasion, lymphovascular space invasion
(LVSI), parametrial extension, surgical margin, and treatment modality.
Patients were divided into two treatment groups: group A received
NACT plus radical surgery, whereas group B received radical surgery
as the primary treatment. For NACT, the platinum-based regimen was
used. Depending on the response and tolerance, NACT was adminis-
tered in one or two courses. The platinum-based NACT regimens includ-
ed TP (28-day cycle: 135–175 mg/m2 intravenous paclitaxel on day 1,
and 80–85 mg/m2 intravenous cisplatin on days 2–3), PF (21-day
cycle: 75 mg/m2 intravenous cisplatin on day 1, and 24 mg/kg per day
intravenous 5-fluorouracil from day 1 to day 5), CP (28-day cycle:
60 mg/m2 intravenous irinotecan on days 1, 8, and 15; and 60 mg/m2
intravenous cisplatin on day 1), and VP (28-day cycle: 60–100 mg/m2
intravenous etoposide from day 1 to day 5, and 80–85 mg/m2 intrave-
nous cisplatin on days 2 and 3).
Table 1
Clinical, pathologic, and treatment characteristics (n = 30).
Characteristic
The clinical response to NACT was evaluated by comparing the
tumor volume at the initial diagnostic procedure and before surgery
in accordance with WHO criteria. Magnetic resonance imaging, com-
puted tomography, and B-ultrasonography results were combined
with gynecologic examination to evaluate the tumor size. Complete
response was defined as complete disappearance of the tumor. Partial
response was defined as a decrease in tumor volume of 50% or more.
A less than 50% reduction in tumor volume was regarded as stable
disease, whereas progressive disease was defined as an increase of
25% or more in volume or the appearance of new lesions. NACT re-
sponders were defined as patients with complete or partial response,
whereas NACT non-responders were defined as patients with stable or
progressive disease [19].
Follow-up information was updated semiannually. Statistical analy-
ses were done in SPSS version 13.0 (SPSS Inc, Chicago, IL, USA). Disease-
free survival (DFS) and overall survival (OS) were estimated by the
Kaplan–Meier method, and the log-rank test was used to compare sur-
vival curves between treatment groups. Independent factors that were
prognostic for DFS and OS were identified via the Cox proportional haz-
ards model. A χ2 test or Fisher exact test was used to compare frequency
data as appropriate. P b 0.05 was considered significant.
3. Results
A total of 30 patients with SCCC and sufficient clinical information
were identified. The detailed clinical, pathologic, and treatment infor-
mation for the 30 patients is shown in Supplementary Material S2.
Nine (30%) patients received platinum-based NACT plus surgery
(group A), 14 (47%) patients received surgery as the primary treatment
(group B), and 7 (23%) patients received other treatment regimens
(Table 1). The median age of the patients was 40.7 years (range
28–62). Overall, 22 (73%) patients had early SCCC (FIGO stage IA–IIA),
Valuea

Age, y 40.20 (28–62)

≤40 18 (60)
Table 2
N40 12 (40)
Univariate analysis of survival by clinical and pathologic factors and treatment (n = 22).
FIGO stage
IB1 11 (37) Factor No. of Disease-free Overall
IB2 7 (23) patients survival survival
IIA 4 (13)
3-year P value 3-year P value
IIB 4 (14)
rate, % rate, %
IIIB 1 (3)
IV 3 (10) Age, y
Histologic homology ≤40 13 68 0.060 66 0.161
Pure 23 (77) N40 9 19 38
Mixed 7 (23) FIGO stage
Tumor size, cm Early (IB1–IIA) 18 62 0.003 68 0.001
≤4 14 (47) Advanced (IIB–IV) 4 0 0
N4 16 (53) Tumor size, cm
Lymph node metastasisb ≤4 13 66 0.113 63 0.223
No 14 (48) N4 9 30 44
Yes 15 (52) Histologic homology
Lymphovascular space invasionb Pure 17 42 0.173 49 0.220
No 20 (69) Mixed 5 80 67
Yes 9 (31) Lymphovascular space invasion a
Depth of cervical stromal invasionb No 15 64 0.089 73 0.031
b2/3 17 (65) Yes 6 21 0
≥2/3 9 (35) Depth of cervical stromal invasiona
Parametrial extensionb b2/3 14 64 0.176 63 0.337
No 24 (86) ≥2/3 7 0 51
Yes 4 (14) Parametrial extensiona
Treatment No 19 52 0.655 58 0.553
Neoadjuvant chemotherapy and radical surgery 9 (30) Yes 2 50 50
Radical surgery and adjuvant chemotherapy, radiotherapy, 14 (47) Lymph node metastasisa
or concurrent chemoradiation No 13 42 0.329 51 0.626
Concurrent chemoradiation followed by radical surgery 5 (17) Yes 8 73 73
Radiotherapy plus radical surgery 1 (3) Treatmentb
Radiotherapy alone 1 (3) Group A 8 45 0.670 44 0.362
Group B 8 30 50
Abbreviation: FIGO, International Federation of Gynecology and Obstetrics.
a
Values are given as mean (range) or number (percentage). Abbreviation: FIGO, International Federation of Gynecology and Obstetrics.
b a
Data available for 29 patients for lymph node metastasis and lymphovascular space Data available for 21 patients.
b
invasion, for 26 patients for cervical stromal invasion, and for 28 patients for parametrial Group A patients received NACT; group B patients received surgery as the primary
extension. treatment.

Please cite this article as: Li X, et al, Prognostic risk factors for small cell carcinoma of the cervix and impact of platinum-based neoadjuvant
chemotherapy, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.02.022
 X. Li et al. / International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx 3

and 8 (27%) had advanced SCCC (FIGO stage IIB–IV). Approximately
half of patients for whom relevant information was available had
lymph node metastasis (Table 1). There were no significant differ-
ences in clinical and pathologic variables between group A and
group B (Supplementary Material S3).
Eight (27%) of the 30 patients were lost to follow-up over the course
of the study. During a median follow-up of 24.1 months (range
2.1–57.9), 12 (55%) of the remaining 22 patients survived without dis-
ease, and 10 (45%) patients developed recurrence. The median DFS for
the 22 patients was 34.7 months (95% confidence interval [CI]
24.5–44.8). The median OS was 37.8 months (95% CI 28.2–47.3). The
3-year DFS and OS rates for all patients were 50% and 55%, respectively.
In univariate analysis (Table 2), patients with early disease (stage
IA–IIA) had a 3-year DFS rate of 62% as compared with 0% for patients
with advanced disease (stage IIB–IV) (P = 0.003) (Fig. 1A). However,
the 3-year DFS rates of patients with and without LVSI did not differ sig-
nificantly (21% vs 64%; P = 0.089) (Fig. 1B). The 3-year OS rate was 68%
for patients with early disease as compared with 0% for patients with
advanced disease (P = 0.001) (Fig. 1C). The 3-year OS rate was 0% for
patients with LVSI as compared with 73% for patients without LVSI
(P = 0.031) (Fig. 1D).
Other factors showed no significant effect on either the 3-year DFS
rate or the 3-year OS rate. However, DFS and OS were decreased slightly
among patients who were older than 40 years, had a tumor size of more
than 4 cm, a pure histologic type, a depth of stromal invasion of
two-thirds or more, or a parametrial extension (Table 2). Additionally,
although not significant, the 3-year DFS and 3-year OS rates for patients
with lymph node metastasis were higher than were those for patients
without lymph node metastasis (Table 2).
The 3-year DFS rate was 45% for group A and 30% for group B
(P = 0.670). However, the 3-year OS rate was 44% for group A as
compared with 50% for group B (P = 0.362). Thus, NACT seemed
to benefit 3-year DFS but not 3-year OS, although this observation
was not significant.
Advanced FIGO stage (IIB–IV) remained the only significant inde-
pendent prognostic factor for both the 3-year DFS rate (hazard ratio
6.33, 95% CI 1.39–28.71; P = 0.017) and 3-year OS rate (hazard ratio
9.99, 95% CI 1.97–50.79; P = 0.006) in the multivariate analysis. In the
analysis of the association between FIGO stage and clinicopathologic
variables, patients with advanced disease were more likely to have
parametrial extension (P = 0.038) and a tumor size greater than 4 cm
(P = 0.039) (Table 3).
Of the nine patients who received NACT (group A), five received TP,
two patients received PF, and two received VP and CP, respectively.
Eight of the nine patients were evaluated as NACT responders, whereas
there was one NACT non-responder (Supplementary Material S4).
Recurrence information was available for 17 patients (eight from
group A and nine from group B). Nine (53%) developed recurrent dis-
ease, and 4 (24%) developed both local and distant recurrent disease
(Supplementary Material S5).
An association was recorded between distant recurrence and NACT
(P = 0.029) (Table 4). However, overall recurrence and local recurrence
were not associated with NACT.
4. Discussion
In the present study, advanced disease (FIGO stage IIB–IV) was asso-
ciated with poor 3-year OS and poor 3-year DFS among patients with

Fig. 1. Univariate analysis of clinicopathologic factors affecting 3-year overall survival and 3-year disease-free survival. (A) Disease-free survival of patients with FIGO stage IA–IIA and stage
IIB–IV disease. (B) Disease-free survival of patients with and without LVSI. (C) Overall survival of patients with FIGO stage IA–IIA and stage IIB–IV disease. (D) Overall survival of patients
with and without LVSI. Abbreviations: FIGO, International Federation of Gynecology and Obstetrics; LVSI, lymphovascular space invasion.

Please cite this article as: Li X, et al, Prognostic risk factors for small cell carcinoma of the cervix and impact of platinum-based neoadjuvant
chemotherapy, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.02.022
4 X. Li et al. / International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx

Table 3 SCCC were positive for HPV, and 9 of the 10 patients were positive for
Association between International Federation of Gynecology and Obstetrics stage and HPV18. Deactivation of retinoblastoma protein by HPV18 E7 protein
clinicopathologic factors.
could be associated with the carcinogenesis of SCCC. However, the rela-
Clinicopathologic factors Stage I–IIA Stage IIB–IV P valuea tionship between HPV genotype and prognosis of SCCC is uncertain.
(n = 22) (n = 8) Huang et al. [23] reported that low expression of has-miR-125b and
Tumor size, cm has-miR-100—which is associated with tumor metastasis—is related to
≤4 13 1 0.039 poor survival of patients with SCCC.
N4 9 7
In the present study, nine patients received platinum-based NACT,
Lymphovascular space invasion
No 17 3 0.158 most of whom received the TP regimen. Eight of the nine patients had
Yes 5 4 a complete or partial response to NACT, whereas only one had a stable
Depth of cervical stromal invasion response. This NACT response (complete or partial) rate (~ 90%) is
b2/3 15 2 0.138 higher than that commonly observed in squamous cell or adenocarcino-
≥2/3 5 4
Lymph node metastasis
ma of the cervix (~ 80%) [19]. This difference suggests that platinum-
No 13 1 0.080 based NACT tended to show a good short-term response, although it
Yes 9 6 had no significant impact on the 3-year DFS or 3-year OS.
Parametrial extension Among the eight patients who received NACT and had recurrence in-
No 20 4 0.038
formation, four developed local recurrence only, and the remaining four
Yes 1 3
showed no recurrence. Among the nine patients of group B who had re-
a
Calculated by Fisher exact test. currence information, four developed both local and distant recurrence,
one showed distant recurrence only, and the remaining four did not
Table 4 develop recurrence. These results suggest that NACT has the ability to
Association between use of neoadjuvant chemotherapy and recurrence (n = 17). control distant recurrence. By contrast with other subtypes of cervical
Characteristic Total Group Aa Group Ba P valueb cancer, SCCC at an early FIGO stage shows distant recurrence as one of
Overall recurrence
its features, and distant disease is the main reason for treatment failure
No 8 4 4 N0.99 [1,24,25]. Thus, the role of NACT in controlling distant recurrence might
Yes 9 4 5 be beneficial to patients with SCCC. Lee et al. [11] previously reported
Local recurrence that NACT might be useful for enhancing the resectability of bulk
No 9 4 5 N0.99
tumors, but it did not improve survival. In the present study, platinum-
Yes 8 4 4
Distant recurrence based NACT had a good short-term response but no significant impact
No 12 8 4 0.029 on survival.
Yes 5 0 5 The present study was limited by its small sample size. Furthermore,
a
Group A patients received neoadjuvant chemotherapy plus surgery; group B patients because the treatment of SCCC was not standard, there was a low num-
received radical surgery as the primary treatment. ber of patients in each treatment subgroup. The follow-up rate should
b
Calculated by Fisher exact test. also be improved to evaluate the prognosis of patients with SCCC.
Owing to the rarity of this cancer, it is difficult to recruit adequate num-
bers of patients even across several institutions. Multicenter studies
SCCC. Platinum-based NACT, although it did not improve survival, performed by more institutions are needed to obtain sufficient statisti-
showed an effect of controlling distant recurrence. In previous reports, cal power for analyses.
large tumor size, lymph node metastasis, advanced FIGO stage, deep In conclusion, advanced disease (FIGO stage IIB–IV) was associated
stromal invasion, and pure histologic type have been considered as with a poor prognosis, and platinum-based NACT seemed to improve
probable indicators of poor prognosis [1,8,10,15,16,21]. distant recurrence control among patients with SCCC. Because of the
The present study found that LVSI tended to decrease the 3-year OS limitations of the study, the present conclusions should be confirmed
but not the 3-year DFS. Patients with LVSI are more likely to have other by future studies.
risk factors than are patients without LVSI, which might result in the sig-
nificant difference observed in 3-year OS between the two groups. Supplementary data to this article can be found online at http://dx.
However, many factors other than LVSI might affect disease relapse in doi.org/10.1016/j.ijgo.2015.02.022.
patients. Variables such as being aged 40 years or older, pure histologic
type, large tumor size, deep stromal invasion, and parametrial extension
tended to adversely affect survival in the present study, although the Acknowledgments
difference between the groups was not significant. Lymph node metas-
tases also seemed to favor survival, but again the difference was not sig- The study was endorsed by the Key Basic Research and Development
nificant. It is possible that the natural history of SCCC differs sufficiently Program Foundation of China (973 Program, no. 2009CB521808) and
from that of squamous cell and adenocarcinoma of the cervix, leading to was supported by grants from the National Natural Science Foundation
a higher probability of the development of lymph node metastases, as of China (nos. 81230038, 81230052, 30973472, 81001151, 81071663,
well as other pathologic conditions, such as parametrial extension, 81090414, 30973205, 30973184, 81172464, and 81101964).
deep stromal invasion, and LVSI.
As compared with patients with early disease (FIGO stage IA–IIA), Conflict of interest
patients with advanced disease (stage IIB–IV) were more likely to
have a large tumor size and parametrial extension, and tended to devel- The authors have no conflicts of interest.
op lymph node metastases, although the differences were not signifi-
cant. Patients with advanced disease might have a poorer prognosis
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chemotherapy, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.02.022
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