Perioperative Complications and Safety Evaluation of Robot-Assisted Radical Hysterectomy of Cervical Cancer After Neoadjuvant Chemotherapy

Abstract

Purpose
To evaluate the perioperative complications of patients with cervical cancer who are treated with robot-assisted radical hysterectomy (RRH) and to further evaluate the safety of patients undergoing NACT.

Methods
A total of 805 consecutive cervical cancer patients undergoing RRH were involved in this report. Their clinical characteristics were retrieved from hospital medical records. Perioperative complications were subdivided into intraoperative and postoperative complications, which were graded according to the Clavien–Dindo classification (CDC), and the complications of grade III and above were defined as severe complications. Furthermore, the two-level logistic regression model was used to estimate the risk factors of perioperative and severe complications and to further confirm the relationship between NACT and perioperative and severe complications.

Results
The perioperative complication rate and severe complications were 45.09% and 7.83%, respectively. Poorly differentiated tumor and NACT were identified as independent risk factors for perioperative complications by multifactor analysis. Furthermore, we concentrated on the relations between NACT and complications. The risk of perioperative complications of the group with NACT (OR = 11.08, 95% CI: 5.70–21.54) was significantly higher than the group without NACT, especially in postoperative complications (OR=17.65, 95% CI: 8.63–36.08), even after adjusting confounding factors. However, there was no statistically significant difference in terms of severe complications (OR=1.68, 95% CI: 0.64–4.41) and intraoperative complications (OR=0.51, 95% CI: 0.18–1.41). Moreover, as the times of NACT increase, the impact on perioperative complications is more pronounced. A similar trend was observed in postoperative complications, while this statistical difference was still not observed in intraoperative and severe complications.

Conclusion
This result demonstrates the feasibility and safety of RRH of cervical carcinoma after NACT in generally, since it only causes mild complications, not severe complications.

Full text

ORIGINAL RESEARCH
Perioperative Complications and Safety Evaluation
of Robot-Assisted Radical Hysterectomy of Cervical
Cancer After Neoadjuvant Chemotherapy
This article was published in the following Dove Press journal:
Cancer Management and Research
Wei-Fu Chan g
1–3
Ai-Jing Luo
1,3,4
Yi-Feng Yuan
5
Yan g C he n
5
Zi-Rui Xin
3,5
Shuai-Shuai Xu
1
1
Xiangya School of Public Health, Central
South University, Changsha 410008,
Hunan, People’s Republic of China;
2
The
Third Xiangya Hospital of Central South
University, Changsha 410013, Hunan,
People’s Republic of China;
3
Key
Laboratory of Medical Information
Research, Central South University,
Changsha 410013, Hunan, People’s
Republic of China;
4
The Second Xiangya
Hospital of Central South University,
Changsha 410011, Hunan, People’s
Republic of China;
5
School of Life
Sciences, Central South University,
Changsha 410013, Hunan, People’s
Republic of China
Purpose: To evaluate the perioperative complications of patients with cervical cancer who
are treated with robot-assisted radical hysterectomy (RRH) and to further evaluate the safety
of patients undergoing NACT.
Methods: A total of 805 consecutive cervical cancer patients undergoing RRH were involved in
this report. Their clinical characteristics were retrieved from hospital medical records.
Perioperative complications were subdivided into intraoperative and postoperative complica-
tions, which were graded according to the Clavien–Dindo classification (CDC), and the com-
plications of grade III and above were defined as severe complications. Furthermore, the two-
level logistic regression model was used to estimate the risk factors of perioperative and severe
complications and to further confirm the relationship between NACT and perioperative and
severe complications.
Results: The perioperative complication rate and severe complications were 45.09% and
7.83%, respectively. Poorly differentiated tumor and NACT were identified as independent
risk factors for perioperative complications by multifactor analysis. Furthermore, we concen-
trated on the relations between NACT and complications. The risk of perioperative complica-
tions of the group with NACT (OR = 11.08, 95% CI: 5.70–21.54) was significantly higher than
the group without NACT, especially in postoperative complications (OR=17.65, 95% CI: 8.-
63–36.08), even after adjusting confounding factors. However, there was no statistically sig-
nificant difference in terms of severe complications (OR=1.68, 95% CI: 0.64–4.41) and
intraoperative complications (OR=0.51, 95% CI: 0.18–1.41). Moreover, as the times of NACT
increase, the impact on perioperative complications is more pronounced. A similar trend was
observed in postoperative complications, while this statistical difference was still not observed in
intraoperative and severe complications.
Conclusion: This result demonstrates the feasibility and safety of RRH of cervical carcinoma
after NACT in generally, since it only causes mild complications, not severe complications.
Keywords: cervical carcinoma, robot-assisted radical hysterectomy, neoadjuvant
chemotherapy, Clavien–Dindo classification, perioperative complications
Introduction
Despite advances in prevention, screening, diagnosis, and treatment during the past
decade, cervical cancer remains a major issue of public health, representing the fourth
most common female malignancy worldwide.
1
Approximately 90% of the 270 000
cervical cancer deaths in 2015 occurred in low income and middle-income countries.
2
An increasing trend in incidence and mortality of cervical cancer has also been observed
in China.
3
Correspondence: Ai-Jing Luo
The Second Xiangya Hospital of Central
South University, 139 Renmin Middle
Road, Furong District, Changsha 410011,
Hunan, People’s Republic of China
Email 574224075@qq.com
Cancer Management and Research Dovepress
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With advances in the development of instrumentation and
surgical expertise, we witnessed a progressive shift from
traditional open surgery towards minimally invasive surgery
in the treatment of cervical cancer. Minimally invasive sur-
gery is now considered as a widely accepted approach for the
management of early-stage gynecological malignancies,
which is particularly beneficial in terms of blood loss, pain,
hospitalization and recovery, without detrimental effects on
the curative or survival outcomes.
4–6
Robotic surgery is the most advanced technology for
minimally invasive surgery, which was approved by the
US Food and Drug Administration for gynecology in
2005. Sert et al. were the first to report robot-assisted
radical hysterectomy (RRH) and lymph node dissection
in 2006.
7,8
In 2015, our hospital carried out the first
RRH operation. In order to ensure better surgical quality
and standardization of the entire procedure from pre-
operation to post-operation, in this study, a total of 805
cervical cancer patients received RRH. However, this
treatment method is somewhat controversial. Several stu-
dies revealed that minimally invasive surgery may be
associated with shorter overall survival than open
surgery
9
and increased rates of death and recurrence
10
in
patients with cervical cancer. This may lead to a paradigm
shift in the treatment of cervical cancer, therefore we
further evaluate the data from our institution.
In previous studies, a great deal of articles focused on
the long-term effects after RRH,
9–13
while researches on
the short-term effects were rare relatively. In order to
better evaluate this therapeutic approach, we concentrated
on the short-term perioperative impacts of RRH on
patients. Although there were a little of researches about
perioperative complications for cervical carcinoma,
14,15
most studies were based on retrospective reviews of med-
ical records or were performed without consideration of
the severity of each complication or based on their own
criteria. Therefore, it is probable that not all complications
have been fully documented, and it is difficult to compare
complication rates and identify risk factors for complica-
tions reliably.
The incidence of perioperative complication is an impor-
tant index reflecting the effect of surgery, and the principle of
classification for perioperative complications should be sim-
ple, reproducible, flexible, and applicable irrespective of the
cultural background.
16,17
Such requirements are met by the
Clavien–Dindo classification (CDC) proposed in 2004.
18
Since then, this classification has been applied to many
surgeries including gastrectomy, renal cell cancer resection,
colorectal resection, pancreaticoduodenectomy, breast can-
cer and urological resection.
17,19–22
However, the periopera-
tive complications assessed by CDC in radical hysterectomy
of cervical cancer have been described scarcely.
Therefore, the purpose of this study is to analyze the
severity of perioperative complications of cervical cancer
patients undergoing RRH by CDC, evaluate the relation-
ship between NACT and complications, and further con-
firm the feasibility and safety of RRH of cervical
carcinoma after NACT.
Materials and Methods
Patients
From January 2016 to April 2019, a total of 805 patients
receiving RRH in our hospital were asked to participate in
this retrospective observational study. 244 patients under-
went NACT, and 561 patients did not receive NACT. After
patients received NACT treatment for 3 courses, the eligible
patients wanted to receive RRH with Da Vinci Si Surgical
System. The surgery was performed by an experienced sur-
gical team proficient in gynecologic oncology, the member of
which all have extensive experience in minimally invasive
surgery. All pathological diagnosis was confirmed by two
experienced pathologists.
The study was approved by the institutional review board
(IRB) of the Third Xiangya Hospital, Central South
University. Radical hysterectomy was performed for all
patients with proper consultation and written informed con-
sent was obtained from each subject.
Data Collection
Data of patients’demographics, laboratory examination, clin-
ical manifestation and perioperative complications were
obtained from medical records, which include age, stage
according to the International Federation of Gynecology and
Obstetrics (FIGO), histopathological type, tumor grade,
American Association of Anesthesiologists (ASA) classifica-
tion, classification for HPV and NACT. Intraoperative para-
meters include mean surgical time, blood loss, number and
metastasis condition of pelvic lymph nodes and postoperative
hospital stay. According to the definition of perioperation,
perioperative complications are divided into intraoperative
complications and postoperative complications.
NACT Regimen
Patients with squamous cell carcinoma received 3 courses of
TIP (paclitaxel 175 mg/m
2
+ifosfamide5g/m
2
+ cisplatin
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75 mg/m
2
), and patients with cervical adenocarcinoma
received 3 courses of TEP (paclitaxel 175 mg/m
2
+epirubicin
80 mg/m
2
+ cisplatin 75 mg/m
2
).
23–25
The rest of the che-
motherapy regimens were performed with reference to the
clinician’s experience and the actual situation of the patients.
Within 2–3 weeks after the completion of NACT, patients
were re-evaluated through imaging and physical examination.
After the assessment was passed, Da Vinci robot-assisted
hysterectomy was performed for the patient with the patient’s
knowledge and consent.
Perioperative Complications
Perioperative complications were defined according to
previously reported references, and subdivided into
intraoperative and postoperative complications.
18,26
Intraoperative complications included transfusion within
72 h after surgery, ureter or bladder injury and bowel
injury. Postoperative complications included fever (>38°
C) for >24 h postoperatively, urinary retention, short-term
abnormal liver and renal function, severe edema of lower
extremity, lymphocytic cyst infection, postoperative infec-
tion, severe anemia, bowel obstruction, vaginal vault
dehiscence, vault bleeding, urinary tract infection, lymphe-
dema, fistula, pelvic infection, remnant drain catheter and
deep venous thrombosis. All perioperative complications
were classified into 5 grades according to CDC. Grade
I complications: no special treatment is required; Grade
II complications: medical treatment and parenteral nutri-
tion are required; Grade III complications: surgery, endo-
scopic or radiological intervention are required to be
performed under general anesthesia (Class IIIb) or local
anesthesia (Class IIIa); Grade IV complications: intensive
care is required due to single or multiple organ failure;
Grade V complications: death.
17
Statistical Analysis
Statistical analyses were performed using IBM SPSS
Statistics23.0 (IBM SPSS Inc., Chicago, IL). Descriptive
statistics were performed on the distributions of demo-
graphic characteristics and perioperative complications.
Continuous data were described as mean ± standard devia-
tion and categorical data as number (percentage).
Continuous variables were compared using the Student
T-test or Mann–Whitney U-test. Categorical variables
were compared using the Chi-square test or Fisher’s exact
test. Two-level logistic regression model was used to eval-
uate the risk factors between NACT and perioperative and
severe complications. Two-level logistic regression model
was used to estimate the odds ratio (OR) and the 95%
confidence interval (CI) of the risk of perioperative compli-
cations by analysis of multiple clinical indicators. Variables
with p<0.05 in the univariate analysis were considered in
a multivariate analysis. P<0.05 was considered statistically
significant.
Results
Patient Characteristics
The demographic characteristics of the study population
are shown in Table 1. 805 patients receiving RRH were
included in the study, among which, 244 patients (30.31%)
underwent NACT and 561 patients (69.69%) did not
receive NACT. 439 patients (54.53%) were in stage IA-
IB and 366 patients (45.47%) were in stage II or above by
FIGO staging. Medium differentiation of tumor grade and
squamous of histology cell were observed at highest fre-
quency in 489 (60.75%) and 641 (79.63%), respectively.
164 patients (20.37%) had preoperative comorbidities with
ASA score ≥3. Type 16 and 18 of HPV were regarded as
relatively high risk for cervical carcinoma and were
detected in 587 patients (79.92%). 137 patients (17.02%)
showed lymph node metastasis. The median of surgical
time, blood loss, indwelling time of drainage tube and
postoperative hospital stay were 140.00, 150.00 and 3.00,
respectively. The mean of age, number of pelvic lymph
nodes and days of postoperative hospital stay were 49.44,
12.74 and 7.40, respectively.
Perioperative Complications
Detailed information on perioperative complications in
patients are shown in Table 2. In this study, of 805 patients
receiving RRH, 363 patients (45.09%) had perioperative
complications; 64 patients (7.95%) had intraoperative com-
plications; 328 patients (40.75%) had postoperative com-
plications; and 29 patients had both intraoperative and
postoperative complications. According to the CDC, 334
(60.95%), 146 (26.64%), 66 (12.04%), 2 (0.36%) and 0
(0.00%) perioperative complications were classified as
Grade I, Grade II, Grade III, Grade IV and Grade V, respec-
tively. Severe complications are defined Grade III and
above according to CDC. Our study showed that most of
the complications of patients receiving RRH were grades I
and II, and the most common complications were Grade
I urinary retention and Grade II urinary tract infection,
however there were also 63 cases of severe complications.
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Risk Factors for Perioperative and Severe
Complications
The univariate analysis showed that perioperative complica-
tions correlated significantly with age (p=0.008), clinical
stagingbyFIGO(p<0.001), tumor grade (p<0.001), histo-
pathological type (p<0.001), lymph node metastasis
(p<0.001), NACT (p<0.001), surgical time (p=0.011), blood
loss (p<0.001), number of pelvic lymph node dissection
(p=0.001) and indwelling time of drainage tube (p<0.001)
(Table 3). Factors with pvalue<0.05 in the univariate analysis
were selected as covariables in the two-level logistic regression
analysis. It was found that NACT (OR = 9.59, 95% CI: 6.43–
14.28, p <0.001) was an independent risk factor for a higher
perioperative complication rate. Besides, compared with well-
differentiated tumor, moderately differentiated (OR=1.85,
95% CI: 1.03–3.33, p=0.041) and poorly differentiated tumor
(OR=4.63, 95% CI: 3.08–6.96, p<0.001) (Table 4 ) are another
independent risk factor for a higher perioperative complication
rate. For severe complications, the univariate analysis was only
significantly correlated with human papillomavirus typing
(P=0.008), and no furthermultivariate analysis was conducted.
Table 1 Summary of Patient Characteristics
Characteristics Total (n=805)
Age (years) 49.44±9.19
Stage (FIGO)
IA1 189 (23.49%)
IA2 8 (0.99%)
IB1 215 (26.71%)
IB2 27 (3.35%)
IIA1 150 (18.63%)
IIA2 87 (10.81%)
IIB and above 129 (16.02%)
Tumor grade
Well differentiated 99 (12.30%)
Moderately differentiated 489 (60.75%)
Poorly differentiated 217 (26.96%)
Histopathological type
Adenosquamous carcinoma 18 (2.24%)
Squamous 641 (79.63%)
Adenocarcinoma 76 (9.44%)
Other 70 (8.70%)
ASA classification
Ⅰ38 (4.72%)
Ⅱ603 (74.91%)
≥164 (20.37%)
Classification for HPV
Negative 42 (5.22%)
Low risk 7 (0.87%)
High risk 169 (20.99%)
Extremely high risk 587 (72.92%)
Lymph node metastasis
No 668 (82.98%)
Yes 137 (17.02%)
Neoadjuvant chemotherapy
No 561 (69.69%)
Yes 244 (30.31%)
Surgical time (mins) 140.00 (115.00–169.75)
Blood loss (mL) 150.00 (80.00–250.00)
Number of lymph nodes dissection 12.74±8.16
Indwelling time of drainage tube (day) 3.00 (2.00–3.00)
Postoperative hospital stay(day) 7.40±2.34
Abbreviations: FIGO, International Federation of Gynecology and Obstetrics;
ASA, American Society of Anesthesiologists; HPV, human papillomavirus.
Table 2 Perioperative Complications
CDC Number Percent
(%)
Perioperative complications 363 45.09
Intraoperative complications 64 7.95
Postoperative complications 328 40.75
Severe complications 63 7.83
CDC classification 548 100.00
Grade I 334 60.95
Fever (>38°C) 53 9.67
Urinary retention 141 25.73
Short-term abnormal liver function 51 9.31
Short-term abnormal renal function 9 1.64
Severe edema of lower extremity 4 0.73
Lymphocytic cyst 26 4.74
Intraoperative blood transfusion 50 9.12
Grade Ⅱ146 26.64
High fever with elevated white blood
cells
48 8.76
Urinary tract infection 84 15.33
Severe anemia 2 0.36
Lymphocytic cyst infection 5 0.91
Bowel obstruction 7 1.28
Grade 66 12.04
Bowel injury 6 1.09
Bladder or ureter injury 11 2.01
Ureteroscopy 1 0.18
Vaginal vault dehiscence 6 1.09
Vaginal fistula 36 6.57
Bladder vaginal fistula 4 0.73
Lymphatic fistula 2 0.36
Grade Ⅳ2 0.36
Deep vein thrombosis 2 0.36
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Associations Between NACT and
Complications
Table 5 shows the association between NACT and perio-
perative and severe complications. The rough estimate
demonstrated NACT was associated with perioperative
complications, especially postoperative complications,
but not with intraoperative or severe complications. After
the confounders of model I was adjusted, it was found that
NACT was associated with postoperative complications
(OR=17.19, 95% CI: 8.49–34.83, p<0.001) and periopera-
tive complications (OR=10.83, 95% CI: 5.62–20.86,
p<0.001). Even if all confounders were adjusted in
Table 3 Univariate Analysis of Risk Factors for Perioperative and Severe Complications After Robot-Assisted Radical Hysterectomy
Variables Perioperative Complications (%) P-value Severe Complications (%) P-value
Age(years) 50.38 ± 8.90 0.008 49.75 ± 9.85 0.783
Stage (FIGO) <0.001 0.971
IA1 17.36 (63/189) 7.41 (14/189)
IA2 0.00 (0/8) 0.00 (0/8)
IB1 32.09 (69/215) 8.84 (19/215)
IB2 48.15 (13/27) 7.41 (2/27)
IIA1 38.67 (58/150) 7.33 (11/150)
IIA2 66.67 (58/87) 9.20 (8/87)
IIB 79.07 (102/129) 6.98 (9/129)
Tumor grade <0.001 0.530
Well differentiated 26.27 (28/99) 5.05(5/99)
Moderately differentiated 56.85 (278/489) 8.38(41/489)
Poorly differentiated 28.28 (57/217) 7.83(17/217)
Histopathological type <0.001 0.941
Adenosquamous carcinoma 55.56 (10/18) 5.56 (1/18)
Squamous 47.43 (304/641) 8.11 (52/641)
Adenocarcinoma 44.74 (34/76) 6.58 (34/76)
Other 21.43 (15/70) 7.14 (5/70)
ASA classification 0.557 0.167
Ⅰ39.47 (15/38) 0.00 (0/38)
Ⅱ44.61 (269/603) 7.96 (48/603)
≥48.17 (79/164) 9.15 (15/164)
Classification for HPV 0.426 0.008
Negative 57.14 (14/42) 2.38 (1/42)
Low risk 45.56 (4/7) 42.86 (3/7)
High risk 45.66 (77/169) 8.88 (15/169)
Extremely high risk 33.33 (268/587) 7.50 (44/587)
Lymph node metastasis 0.001 0.655
No 42.37 (283/668) 7.63 (51/668)
Yes 58.39 (80/137) 8.76 (12/137)
Neoadjuvant chemotherapy <0.001 0.669
No 30.84 (173/561) 7.49 (42/561)
Yes 52.34 (190/244) 8.61 (21/244)
Surgical time (min) 143.00 (121.00–170.00) 0.011 138.00 (115.00–161.00) 0.717
Blood loss (mL) 200.00 (100.00–300.00) <0.001 200.00 (100.00–200.00) 0.566
Number of lymph nodes dissection 13.81 ± 7.66 0.001 12.21 ± 7.36 0.591
Dwelling time of drainage tube (day) 3.00 (3.00–4.00) <0.001 3.00 (2.00–4.00) 0.490
Postoperative hospital stay (day) 7.55 ± 2.16 0.095 7.57 ± 2.51 0.536
Abbreviations: FIGO, International Federation of Gynecology and Obstetrics; ASA, American Society of Anesthesiologists; HPV, Human papillomavirus.
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model II, NACT was still associated with postoperative
complications (OR=17.65, 95% CI: 8.63–36.08, p<0.001)
and perioperative complications (OR=11.08, 95% CI: 5.-
70–21.54, p<0.001). However, NACT was not associated
with intraoperative complications (OR=0.51, 95%
CI:0.18–1.41, p=0.194) and severe complications
(OR=1.68, 95% CI:0.64–4.41, p=0.294), respectively.
Therefore, this seems to indicate that NACT in cervical
cancer patients can only lead to an increase in mild com-
plications and has certain safety.
Associations Between Times of NACT
and Complications
As shown in the previous results, NACT is associated with
perioperative complications. This study is expected to
verify whether the incidence of complications increase as
the times of NACT increase. Therefore, the two-level
logistic regression model was applied to clarify the special
correlation, and results are shown in Table 6. A step-wise
algorithm was used to select factors associated with NACT
considering the multicollinearities. In the crude model, the
risk of perioperative complications in the group with 1
NACT (OR = 6.77, 95% CI: 3.80–12.06, P <0.001) and
the group with 2 or more NACTs (OR = 8.54, 95% CI:
5.70–12.79, P <0.001) was higher than the group without
NACT and the difference was statistically significant
(P<0.05). Similarly, the postoperative complications in
the group with 1 NACT (OR=7.74, 95% CI: 4.41–13.59,
p<0.001) and the group with 2 or more NACTs
(OR=10.97, 95% CI: 7.31–16.48, p<0.001) was higher
than the group without NACT.As previously depicted, no
significant correlation was found between intraoperative
complications and severe complications and the times of
NACT. After all confounding factors were adjusted; the
upward trend still existed stably. The risk of perioperative
complications in the group with 1 NACT (OR=9.39, 95%
CI: 4.61–19.14, P<0.001) and the group with 2 or more
NACTs (OR=10.90, 95% CI: 5.12–23.20, P<0.001) was
higher than the group without NACT; the risk of post-
operative complications in the group with 1 NACT
(OR=14.33, 95% CI:6.80–30.16, P<0.001) and the group
with 2 or more NACTs (OR=21.34, 95% CI:9.40–48.43,
P<0.001) was higher than the group without NACT. These
seemed to herald a dose-determined relationship between
perioperative complications and times of NACT.
Discussion
Perioperative complications of radical hysterectomy of cer-
vical cancer usually lead to longer hospital stays, higher
medical cost, and delayed adjuvant therapy. The incidence
of perioperative complications is also an important indicator
for measuring the operative quality. However, there is still no
consensus on the definition and classification of perioperative
complications, which makes it difficult to evaluate the surgi-
cal procedure. The principles of complications classification
should be simple, reproducible, flexible and convenient, and
widely applicable.
16
To meet these requirements, we adopted
the well-standardized classification, known as the Clavien–
Table 4 Multivariate Analysis of Risk Factors for Perioperative
Complications After Robot-Assisted Radical Hysterectomy
Variables Perioperative Complications
OR 95% CI P-value
Tumor grade
Well differentiated Ref
Moderately differentiated 1.85 1.03–3.33 0.041
Poorly differentiated 4.63 3.08–6.96 <0.001
Neoadjuvant chemotherapy
No Ref
Yes 9.59 6.43–14.28 <0.001
Abbreviations: OR, odds ratio; CI, confidence interval.
Table 5 Association of Neoadjuvant Chemotherapy and Perioperative Complications
Complications Crude Model Adjusted Model I
a
Adjusted Model II
b
OR (95% CI) P-value OR (95% CI) P-value OR (95% CI) P-value
Severe complications 1.16 (0.67–2.01) 0.587 1.64 (0.64–4.20) 0.304 1.68 (0.64–4.41) 0.294
Intraoperative complications 0.82 (0.46–1.46) 0.819 0.49 (0.18–1.35) 0.165 0.51 (0.18–1.41) 0.194
Postoperative complications 9.77 (6.87–13.90) <0.001 17.19 (8.49–34.83) <0.001 17.65 (8.63–36.08) <0.001
Perioperative complications 7.89 (5.55–11.21) <0.001 10.83 (5.62–20.86) <0.001 11.08 (5.70–21.54) <0.001
Notes:
a
Adjust I: Estimates derived from two-level logistic regression models after adjusted for age, tumor grade, histopathological type, clinical FIGO stage, lymph node
metastasis;
b
Adjust II: Estimates derived from two-level logistic regression models after adjusted for not only the above variations but also for surgical time, blood loss,
number of pelvic lymph node dissection and dwelling time of drainage tube.
Abbreviations: OR, odds ratio; CI, confidence interval.
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Dindo classification system, which has been proven to be
a reliable tool for quality assessment for surgery in many
fields.
17,19–22
The complication is defined as “any deviation
from the normal postoperative course”and the severity is
classified according to the type of treatment required, such as
surgical intervention or pharmacological treatment. We ana-
lyzed and classified the perioperative complications of RRH
for cervical cancer.
Different clinical trials reported complication rates ran-
ging widely from 4.2% to 58.6%.
13–15,19,27
In the present
study, the perioperative and severe complication rates were
45.09% and 7.83%, respectively. However, the complication
rates in our previous studies seem to be somewhat higher
because most grade I complications, such as asymptomatic
fever and transient hepatic and renal function abnormality,
were included in the perioperative complications.
Meanwhile, the most common complications were Grade
I urinary retention and Grade II urinary tract infection, and
it is speculated that patients with robot-assisted surgery have
a higher incidence of nerve damage.
28
Therefore, it is recom-
mended that nursing staff should pay more attention to
patients after RRH to improve the quality of surgery.
Then, univariate and multivariate analyses were
performed in whole patients to investigate risk factors
correlating with perioperative and severe complications.
Poorly differentiated tumor and NACT were independent
risk factors for perioperative complications, while the only
classification of HPV was correlated with severe complica-
tions by univariate analysis.
Multivariate analysis indicated that a poorly differen-
tiated tumor was identified as an independent risk factor
related to perioperative complications. Previous studies
have shown the degree of differentiation was associated
with a recurrence rate of cervical cancer. Wang et al sug-
gested that moderately and highly differentiated tumor could
indicate a high recurrence rate of cervical cancer,
29
while
Gong et al found that low levels of tumor differentiation were
one of the independent risk factors for recurrent cervical
cancer.
30
Researches on differentiated tumor levels related
to the short-term effect were rare relatively. In the present
study, we found that a poorly differentiated tumor was sig-
nificantly associated with perioperative complications.
Patients with poorly differentiated tumor were always in
bad nutritional status, with common symptoms such as ane-
mia, weight loss, and hypoproteinemia. Although we
adjusted their nutritional status before the operation, it
might still influence the vulnerability of surgical stress and
the occurrence of perioperative complications. However, the
Table 6 Association Between Times of Neoadjuvant Chemotherapy with Complications
Times of NACT Crude Model Adjusted Model I
b
Adjusted Model II
c
OR (95CI) P-value OR (95CI) P-value OR (95CI) P-value
Severe complications
NA
a
Ref Ref Ref
One 1.23 (0.50–3.00) 0.657 1.67 (0.59–4.76) 0.334 1.64 (0.57–4.72) 0.357
Two or above 1.26 (0.69–2.30) 0.457 2.49 (0.79–7.78) 0.118 2.50 (0.78–8.00) 0.122
Intraoperative complications
NA
a
Ref Ref Ref
One 0.70 (0.24–2.00) 0.504 0.54 (0.16–1.85) 0.324 0.55 (0.16–1.89) 0.341
Two or above 0.96 (0.51–1.79) 0.897 0.60 (0.20–1.86) 0.380 0.64 (0.21–1.98) 0.443
Postoperative complications
NA
a
Ref Ref Ref
One 7.74 (4.41–13.59) <0.001 13.95 (6.66–29.23) <0.001 14.33 (6.80–30.16) <0.001
Two or above 10.97 (7.31–16.48) <0.001 21.91 (9.70–49.49) <0.001 21.34 (9.40–48.43) <0.001
Perioperative complications
NA
a
Ref Ref Ref
One 6.77 (3.80–12.06) <0.001 9.20 (4.53–18.68) <0.001 9.39 (4.61–19.14) <0.001
Two or above 8.54 (5.70–12.79) <0.001 11.39 (5.37–24.16) <0.001 10.90 (5.12–23.20) <0.001
Notes:
a
NA means not adopting neoadjuvant chemotherapy;
b
Adjust I: Estimates derived from two-level logistic regression models after adjusted forage, tumor grade,
histopathological type, clinical FIGO stage and lymph node metastasis;
c
Adjust II: Estimates derived from two-level logistic regression models after adjusted for not only the
above variations but also for surgical time, blood loss, number of pelvic lymph node dissection and dwelling time of drainage tube.
Abbreviations: OR, odds ratio; CI, confidence interval.
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association between tumor grade and complications still
needs further studies.
NACT was identified as another predictor for periopera-
tive complications in multivariate analysis. NACT was per-
formed in radical surgery for cervical cancer over 20 years.
31
Although NACT has chemotherapy toxicity such as gastro-
intestinal reactions and bone marrow inhibitory reactions,
32
possible advantages include the potential for decreasing
tumor size, reducing lymph nodes metastasis and distant
metastasis, which may provide a viable alternative to chemo-
radiotherapy when radiotherapy is unavailable or radiother-
apy is unavoidably delayed.
33–35
Although the safety and
effectiveness of NACT in the treatment of cervical cancer
were guaranteed in many reports,
25,31,33–36
the results of
retrospective cohort studies, randomized controlled trials,
37
and meta-analysis
38
showed that NACT did not improve the
survival outcome of patients with cervical cancer. More
specifically, patients who received NACT had a higher recur-
rence rate, longer median duration of RRH, and more median
estimated blood loss.
35
Therefore, from the available studies,
there is insufficient evidence to show that radical hysterect-
omy with or without NACT can improve the survival rate and
outcomes of patients with cervical cancer.
In our study, neither univariate nor multivariate ana-
lyses revealed any significant advantages of NACT in
perioperative complications. In contrast, NACT was asso-
ciated with postoperative complications, but not with
intraoperative or severe complications. As previously
reported, advanced cancer, aortic lymphadenectomy, open
surgery and malnutrition were associated with a higher
risk of complications.
9,39–41
In our study, NACT resulted
in more postoperative complications, the reasons of which
remained unclear. The systemic effects of NACT and
adverse reactions of chemotherapy reagents may be the
reason for the increased postoperative complications.
However, we found that NACT was not associated with
intraoperative and severe complications in this study.
Intraoperative complications here included transfusion within
72 h after surgery, bladder or ureter injury and bowel injury. In
previous studies, BMI >30kg/m
2
, previous abdominal surgery,
metabolic/endocrine disorders (excluding diabetes), surgical
complexity and final diagnosis were significantly associated
with intraoperative complications.
42,43
We speculated that the
occurrence of intraoperative complications would be probably
induced by insufficient experiences and learning curves of the
surgeon or the specific surgical situations, rather than NACT.
On the other hand, NACT was not associated with severe
complications in this study. In a Phase II clinical trial, the
results showed that the cervical cancer tissue of patients under-
going NACT was of high sensitivity, and because of the short
course chemotherapy and low degree of reactions, gastroin-
testinal reactions such as nausea and vomiting and bone mar-
row suppression reactions such as leukocyte, hemoglobin and
platelet reduction could be well tolerated in most of the
patients.
44
Therefore, we speculate that NACT may not
cause severe complications, which seems to reveal the feasi-
bility and safety of RRH for cervical carcinoma after NACT in
general.
In order to further clarify whether there is a “special”
effect between NACT and complications, we further
explored the association between the times of NACT and
complications. The results showed that the overall situa-
tion was very similar to the multivariate analysis, which
demonstrated the risk rate of perioperative complications,
especially postoperative complications, increased steadily
with the increase of NACT. This result is consistent with
the prospective clinical research.
45
For the “special”effect
between NACT and complications, we may speculate that,
on the one hand, with the increase of times of NACT, the
accumulation of chemical toxicity in patients was gradu-
ally obvious, thereby indeed increasing the incidence of
perioperative complications; on the other hand, the toxic
impacts of continuous NACT were not independent. The
impact of previous NACT would affect the effect of the
next NACT, which could lead to an increased incidence of
complications.
The main advantage of this study is the short-term
efficacy, and use of the well-standardized CDC for stan-
dard and uniform classification of the surgical complica-
tions to supplement the short-term effect of cervical cancer
after RRH. Meanwhile, the impact of NACT times on
perioperative complications was analyzed to fill the gap
in the short-term efficacy of NACT performed before RRH
of cervical cancer. However, our study has some limita-
tions. These data are limited to patients’condition during
the period of hospitalization. Our study does not consider
long-term complications, such as malnutrition recurrence
and survival outcome, which may influence the patients’
quality of life and mortality. Additionally, since this was
a retrospective study, recall bias and selection bias are
inevitable, and there is no follow-up statistics on the
survival rate, such as disease-free survival and overall
survival. In the future, large-scale randomized controlled
prospective research is needed with multi-center and
multi-sector cooperation to achieve more credible results,
eliminate bias, and obtain more surgical results.
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Conclusions
Our study demonstrates that NACT is a special risk factor of
perioperative complications for patients with cervical cancer
undergoing RRH, which seems to not lead to serious disease
burden due to tolerable clinical toxicity, that is, NACT was
closely related to mild postoperative complications. Hence,
our study demonstrates the feasibility and safety of RRH of
cervical carcinoma after NACT. However, the clinical appli-
cation of NACT should be selected discreetly. In general,
these results provide important clues for future research and
provide directions for the adjuvant therapy of cervical cancer.
Acknowledgments
This study was supported by the Key Research and
Development Program of Hunan Province (2017SK2011).
Disclosure
The authors declare no potential conflicts of interest
related to this work.
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