A Multicenter Noninferior Randomized Controlled Study Comparing the Efficacy of Laparoscopic Versus Abdominal Radical Hysterectomy for Cervical Cancer(Stage IB1,IB2,IIA1)
Phase: NA
Conditions: Cervical Cancer
Sponsor: Obstetrics & Gynecology Hospital of Fudan University

A multicenter noninferior randomized controlled study comparing the efficacy of laparoscopic versus abdominal
radical hysterectomy for cervical cancer (Stage IB1, IB2, and IIA1)
1
A multicenter noninferior randomized
controlled study comparing the efficacy of
laparoscopic versus abdominal radical
hysterectomy for cervical cancer
(Stage IB1, IB2, IIA1)
(Protocol number: NCT04929769)
Principle investigator: Xin Wu (Obstetrics and Gynecology Hospital of Fudan
University) (signed, dated December 2020)
Project team members: Hua Jiang, Weili Yan (Children's Hospital of Fudan
University), Xipeng Wang (Xinhua Hospital), Libing Xiang (Zhongshan Hospital),
Weihua Lou (Renji Hospital), Tao Zhu (Taizhou Hospital, Affiliated Cancer
Hospital of the University of Chinese Academy of Sciences), Yuyang Zhang (The
First Affiliated Hospital of Wenzhou Medical University), Yongrui Bai (Renji
Hospital), Yanli Hou (Renji Hospital), Yan Du, Weiguo Hu, Zhiling Zhu, Xiaohong
Xue, Hailin Yu, Hao Feng, Ling Qiu, Shurong Zhu (all people didn’t noted above
belong to Obstetrics and Gynecology Hospital of Fudan University)
Version number: 1.0, version date: December 21, 2020
OB&GY of Fudan University

Contents
I. Research Information
II. Research Background
2.1 Research Background
2.2 Research Objectives
2.3 Research Design
III. Research Methods
3.1 Research Setting
3.2 Eligibility Criteria
3.3 Interventions
IV. Allocation, Blinding and Unblinding
4.1 Method of Allocation of the Intervention
4.2 Blinding
V. Methods of Data Collection, Management and Analysis
5.1 Data Collection and Patient Retention
5.2 Data Management (Data entry, coding, encryption and storage schemes)
5.3 Statistical Analyses
VI. Quality of Life Questionnaire
6.1 Patient-reported Clinical Outcome Assessment Scale PRO 147 (V 1.0) for Cervical
Cancer
6.2 Generic quality of life questionnaire
VII. Methods of Data Monitoring
7.1 Study Monitoring
7.2 Interim Analysis
7.3 Quality Control
VIII. Definition and Treatment of Adverse Events
8.1 Definition of Adverse Events
8.2 Observation, Recording and Treatment of Adverse Events
IX. Cost-benefit Analysis
X. Review
XI. Ethics and Dissemination
11.1 Ethical Approval
11.2 Study Protocol Modification Plan
11.3 Informed Consent
XII. Confidentiality
XIII. Declaration of Competing Interests
XIV. Data Collection
XV. Affiliation and Post-test Care
XVI. Dissemination Policy
XVII. Appendices
OB&GY of Fudan University

A multicenter noninferior randomized controlled study comparing the efficacy of laparoscopic versus abdominal
radical hysterectomy for cervical cancer (Stage IB1, IB2, and IIA1)
2
I. Research Information
1) Article title: A multicenter randomized, controlled, non-inferiority trial comparing the
efficacy of laparoscopic versus abdominal radical hysterectomy for cervical cancer (Stage
IB1, IB2,and IIA1)
2) Clinical Trial Registration: the protocol has been registered by the Obstetrics and
Gynecology Hospital of Fudan University at https://clinicaltrials.gov/, registration
number: NCT04929769; all data sheets are included in the WHO clinical trial registration
data (www.annals.org)
3) Version number: LAUNCH 2 1.0, version date: December 21, 2020.
4) Funding: Shanghai Shenkang Hospital Development Center's Shenkang Promotion of
Clinical Skills and Clinical Innovation in Municipal Hospitals Three-Year Action Plan
(2020-2023) Major Clinical Research Project (Grant No. SHDC2020CR1048B).
5) List of investigators and their respective research roles and responsibilities
Name
Affiliated Institution
Role
Xin Wu
Obstetrics and Gynecology Hospital of
Fudan University
Principle Investigator
Hua Jiang
Obstetrics and Gynecology Hospital of
Fudan University
Leader of Main
Center
Xipeng Wang
Xinhua Hospital Affiliated to Shanghai
Jiao Tong University School of Medicine
Leader of Sub-center
Weihua Lou
Shanghai Jiao Tong University School of
Medicine, Renji Hospital
Leader of Sub-center
Libing Xiang
Zhongshan Hospital Affiliated to Fudan
University
Leader of Sub-center
Tao Zhu
Taizhou Hospital Affiliated Cancer
Hospital of the University of Chinese
Academy of Sciences
Leader of Sub-center
Yuyang Zhang
The First Affiliated Hospital of Wenzhou
Medical University
Leader of Sub-center
Weiguo Hu
Obstetrics and Gynecology Hospital of
Fudan University
Clinical Researcher
Zhiling Zhu
Obstetrics and Gynecology Hospital of
Fudan University
Clinical Researcher
XiaohongXue
Obstetrics and Gynecology Hospital of
Fudan University
Clinical Researcher
Yongrui Bai
Shanghai Jiao Tong University School of
Medicine, Renji Hospital
Radiotherapy
researcher
Yanli Hou
Shanghai Jiao Tong University School of
Medicine, Renji Hospital
Radiotherapy
researcher
Weili Yan
Children’s Hospital of Fudan University
Statistician
OB&GY of Fudan University

A multicenter noninferior randomized controlled study comparing the efficacy of laparoscopic versus abdominal
radical hysterectomy for cervical cancer (Stage IB1, IB2, and IIA1)
3
Yan Du
Obstetrics and Gynecology Hospital of
Fudan University
Epidemiologist
Shujun Gao
Obstetrics and Gynecology Hospital of
Fudan University
Researcher
Wenjing Diao
Obstetrics and Gynecology Hospital of
Fudan University
Researcher
Ming Du
Obstetrics and Gynecology Hospital of
Fudan University
Researcher
Hua Feng
Obstetrics and Gynecology Hospital of
Fudan University
Researcher
Hongwei Zhang
The Obstetrics and Gynecology Hospital
of Fudan University
Researcher
Rong Jiang
Zhongshan Hospital Affiliated to Fudan
University
Researcher
Jiarui Li
Xinhua Hospital Affiliated to Shanghai
Jiao Tong University School of Medicine
Researcher
Xuhong Fang
Xinhua Hospital Affiliated to Shanghai
Jiao Tong University School of Medicine
Researcher
Hailin Yu
Obstetrics and Gynecology Hospital of
Fudan University
Researcher
Hao Feng
Obstetrics and Gynecology Hospital of
Fudan University
Researcher
Ling Qiu
Obstetrics and Gynecology Hospital of
Fudan University
Researcher
Shurong Zhu
Obstetrics and Gynecology Hospital of
Fudan University
Researcher
Ming Li
Obstetrics and Gynecology Hospital of
Fudan University
Researcher
Yanan You
Obstetrics and Gynecology Hospital of
Fudan University
Researcher
Pengyao Jiang
Obstetrics and Gynecology Hospital of
Fudan University
Researcher
6) The composition, roles and respective responsibilities of the trial sponsor, trial
coordinating
center, steering
committee,
endpoint determination
committee,
data
management team and other teams.
The trial is sponsored by Shanghai Shenkang Hospital Development Center (contact:
021-96886), which is responsible for the management of hospital development in
Shanghai and has oversight responsibility for this project. The study design, collection,
management, analysis and interpretation of data, report writing, and publication of this
trial are the responsibility of the main center of the Obstetrics and Gynecology Hospital
of Fudan University, and the principle investigator has the final decision-making
OB&GY of Fudan University

A multicenter noninferior randomized controlled study comparing the efficacy of laparoscopic versus abdominal
radical hysterectomy for cervical cancer (Stage IB1, IB2, and IIA1)
4
authority. The ethics committee and the independent data monitoring body have the right
of supervision.
This study is conducted by Hua Jiang and Xin Wu of the Obstetrics and Gynecology
Hospital of Fudan University, who are responsible for the study design, implementation,
and management. Weili Yan and Yan Du are responsible for statistical analysis, and
quality control of the implementation. The all-round implementation rules have been
developed and validated previously, and can be applied normally. The surgical team of
this study consists of several groups in national or regional center hospitals, including:
Hua Jiang and Xin Wu’s team, Zhiling Zhu’s team, Weiguo Hu’s team and Xiaohong
Xue’s team in the Obstetrics and Gynecology Hospital of Fudan University; Rongyu
Zang, Libing Xiang, and Jiangrong Yu’s team in Zhongshan Hospital of Fudan University;
Wen Di and Weihua Lou’s team in Renji Hospital of Shanghai Jiao Tong University;
Xipeng Wang, Jiarui Li and Xuhong Fang’s team in Xinhua Hospital of Shanghai Jiao
Tong University; the team of Zhu Tao from Taizhou Cancer Hospital (Taizhou Hospital
Affiliated Cancer Hospital of the University of Chinese Academy of Sciences); and the
team of Yuyang Zhang from the First Affiliated Hospital of Wenzhou Medical University.
In terms of statistical analysis, Weili Yan's team from CTU, Clinical Trial Center of the
Children’s Hospital of Fudan University is the randomized clinical research team
(composed of epidemiologists and statisticians), responsible for statistical analysis,
drawing graphs and explaining statistical results. Xin Wu, Tao Zhu, and Libing Xiang
form the surgical quality control core team are responsible for surgical quality control.
Yan Du, as an epidemiologist, is responsible for the quality control of clinical study
implementation.
The main center and sub-centers of this study each established an internal staff
organization structure. The head of the main center regularly convenes the head of the
sub-center for phase meetings. Each center has a fixed information contact person, who is
managed by the main center. The information coordinator of the main center is
responsible for collecting and releasing data, and receiving feedback from the sub-centers
at any time, coordinating and handling temporary situations that arise in the work of the
sub-centers, and ensuring that the progress of each center in the research is consistent.
The endpoint determination committee consists of the Co-PIs of each center, the
ethics committee, the data inspection committee, and key members of the data
management team to make appropriate determinations based on trial progress and
analysis.
II. Background
2.1 Research Background
2.1.1 Overview of Cervical Cancer
Cervical cancer is one of the major malignancies that threaten women's health and
lives worldwide, and it is currently the 4th most prevalent malignancy in women[1]. The
OB&GY of Fudan University

A multicenter noninferior randomized controlled study comparing the efficacy of laparoscopic versus abdominal
radical hysterectomy for cervical cancer (Stage IB1, IB2, and IIA1)
5
National Comprehensive Cancer Network (NCCN) guidelines for cervical cancer state
that 528,000 new cases of cervical cancer occurred worldwide in 2012, and 85% of
cervical cancers occur in developing countries. Persistent HPV infection is an important
risk factor in the development of cervical cancer. Other high-risk factors for cervical
cancer include early sexual intercourse, multiple sexual partners, multiple pregnancies,
multiple births, smoking, long-term oral contraceptive use, and sexually transmitted
diseases. The factors such as early sexual intercourse and multiple sexual partners are
important synergistic factors for HPV infection. With the increase of HPV infection, the
incidence of cervical cancer is increasing and the age becomes younger. HPV vaccination
is the main strategy to prevent HPV-related cervical cancer. According to the WHO
Global Cervical Cancer Elimination Program, HPV vaccination is one of the important
components of the Cervical Cancer Elimination Program. However, due to the relatively
late implemmentation of HPV vaccine in China, the incidence and mortality of cervical
cancer in China have shown increasing trends, with around 110,000 new cases and
50,000 deaths of cervical cancer in China in 2018, accounting for about 20% and 16% of
the total global incidence and deaths, respectively. Among cervical cancer patients, the
young age group (≤35 years old) accounts for 8.5%-12.6% of cervical cancer patients,
and the survival benefits and quality of life of this group need particular attention.
Squamous cell carcinoma of the cervix accounts for approximately 80% of cervical
cancers and adenocarcinoma for roughly 20%. In developed countries, the incidence and
mortality of cervical squamous cell carcinoma have decreased significantly due to
effective
cervical
cytologic
screening.
However,
the
incidence
of
cervical
adenocarcinoma has gradually increased over the past 30 years probably due to
insensitivity
to
cytologic
screening,
while
the
early
identification
of
cervical
adenocarcinoma may be improved if HPV testing is used as a screening method for
cervical cancer; HPV vaccination may reduce not only the incidence of cervical
squamous cell carcinoma but also the incidence of cervical adenocarcinoma[2, 3]. In
addition to squamous and adenocarcinoma, cervical malignancies include other specific
pathological types: small cell neuroendocrine carcinoma of the cervix, microbiased
adenocarcinoma of the cervix, and malignant melanoma of the cervix.
Cervical cancer can infiltrate and directly spread to the parametrial tissues, vagina,
uterine corpus and adjacent organs (bladder and rectum) or through lymphatic vessels to
regional lymph nodes such as closed foramen, external and internal iliac lymph nodes and
then to the common iliac and para-abdominal aortic lymph nodes. The status of lymph
nodes correlates with the prognosis of cervical cancer. Previously, FIGO staging of
cervical cancer was clinical staging, and surgical pathological staging was not used. In
2018, FIGO updated the staging system of cervical cancer to include preoperative
imaging and postoperative lymph node status. In addition, the American Joint Committee
on Cancer (AJCC) also updated the TNM staging system of cervical cancer in 2018, so
the FIGO 2018 and AJCC (2021) TNM staging system are both used in this study [4].
OB&GY of Fudan University

A multicenter noninferior randomized controlled study comparing the efficacy of laparoscopic versus abdominal
radical hysterectomy for cervical cancer (Stage IB1, IB2, and IIA1)
6
2.1.2 Treatment of cervical cancer
The main treatment methods of cervical cancer include surgery and radiotherapy.
While surgery is the treatment of choice for early-stage cervical cancer (including stages
IA1, IA2, IB1, IB2, and IIA1), it can also be used for the initial treatment of stages IB3
and IIA2. The main treatment modalities for cervical cancer are as follows:
•
Radical cervical cancer surgery + pelvic lymph node dissection ± abdominal
para-aortic lymph node dissection ± adjuvant therapy
•
Radical radiotherapy
•
Extensive hysterectomy (capable of IA2 to IB1 stage, preserving fertility)
•
Cervical conization (stage IA1, preserving fertility)
The most appropriate treatment for cervical cancer requires consideration of a
combination of patient age, fertility requirements, cervical cancer stage, comorbidities,
patient and physician preferences, and the presence of risk factors associated with
recurrence in the postoperative pathology report. NCCN recommends concurrent
radiotherapy as the primary treatment for stage IB3 to IVA cervical cancer.
2.2.1 Surgical treatment
Radical cervical cancer surgery is the main procedure for the treatment of early-stage
cervical cancer and is mainly applicable to cervical cancer above stage IA1 (including
IA1 with LVSI, IA2, IB1, IB2, IIA1; and IB3 and IIA2). Compared with standard total
hysterectomy, radical hysterectomy for cervical cancer has higher surgical difficulty and
corresponding complications because of the larger surgical scope. Abdominal radical
hysterectomy for cervical cancer has a history of more than 120 years, and the surgical
approach has become very mature, while minimally invasive radical hysterectomy for
cervical cancer has also become increasingly mature after nearly 20 years of development.
Compared with traditional Abdominal Radical Hysterectomy (ARH), minimally invasive
radical hysterectomy has unique advantages, such as less abdominal wall trauma, less
pain, clearer vision and less bleeding, less interference with the intestine, and lower
postoperative
infection
rate. Therefore,
the 2014
NCCN guideline
recommends
laparoscopic radical hysterectomy (LRH) to perform radical cervical cancer surgery.
Modern standard surgery includes laparoscopic surgery (divided into conventional
laparoscopic surgery and robotic-assisted laparoscopic surgery, or multiport laparoscopic
surgery and single-port laparoscopic surgery), open surgery, and transvaginal surgery.
Because these three procedures are performed on different routes with the same extent of
resection, it is intuitively assumed that the results of these three procedures are the same,
and therefore most previous studies have focused on operative time, intraoperative
bleeding, length of hospital stay, and cost, rather than progression free survival (PFS) and
overall survival (OS). Only a few previous small studies have evaluated the survival
OB&GY of Fudan University

A multicenter noninferior randomized controlled study comparing the efficacy of laparoscopic versus abdominal
radical hysterectomy for cervical cancer (Stage IB1, IB2, and IIA1)
7
benefit of Laparoscopic Radical Hysterectomy (LRH) for cervical cancer: in terms of
PFS [5-10], LRH was not inferior to ARH, while laparoscopy was superior to open surgery
in terms of operative time, intraoperative bleeding, and length of hospital stay. In
November of 2018, the New England Journal of Medicine published two research reports
comparing abdominal and minimally invasive radical cervical cancer surgery in the same
period, which have shock the entire gynecology field. The retrospective cohort study
concluded [11] that over a median follow-up of 45 months, the 4-year mortality rate was
9.1% for women who underwent minimally invasive surgery and 5.3% for women who
underwent open surgery (hazard ratio 1.65; 95% confidence interval 1.22-2.22); prior to
the use of minimally invasive radical hysterectomy (i.e., from 2000 to 2006), the 4-year
overall survival rate for women undergoing radical hysterectomy remained stable; while
the overall survival rate decreased by 0.8% (95% CI, 0.3-1.4) per year after 2006 with the
application of minimally invasive surgery. Another study published in the New England
Journal of Medicine in late 2018 (the Laparoscopic Approach to Cervical Cancer, LACC
trial) was a Randomized Clinical Trial (RCT), which showed that the 4.5-year PFS rate
was 86.0% in the minimally invasive surgery group and 96.5% in the open surgery group,
with a difference of -10.6 percentage points (95% CI -16.4 to -4.7); minimally invasive
surgery was associated with lower disease-free survival (PFS) compared with open
surgery [(3-year PFS was 91.2% vs. 97.1%; hazard ratio for relapse or death of cervical
cancer was 3.74; 95% CI (1.63 to 8.58)] [12]. Both studies suggest that minimally invasive
radical cervical surgery is associated with lower PFS and OS rates compared with open
surgery. Following the publication of these studies, the version 3.2019 of the NCCN 2019
guidelines recommended open surgery as the standard procedure for cervical cancer,
while laparoscopic surgery is no longer recommended, which has caused a huge impact
on the gynecology community.
Lymph node resection
Cervical cancer not only involves adjacent organs through direct infiltration, but also
can metastasize to the pelvis and para-aortic lymph nodes through lymphatic vessels.
Therefore, lymph node dissection is usually performed at the same time as radical
cervical cancer surgery. The extent of lymph node dissection depends on the degree of
disease progression.
For stage IA1 cervical cancer without LVSI, the risk of lymph node metastasis is
very low, so lymph node dissection is not required. For stage IA1 cervical cancer with
LVSI, intraoperative evaluation of lymph node status and lymph node dissection or
sentinel lymph node biopsy are required.
OB&GY of Fudan University

A multicenter noninferior randomized controlled study comparing the efficacy of laparoscopic versus abdominal
radical hysterectomy for cervical cancer (Stage IB1, IB2, and IIA1)
8
For stage IA2 cervical cancer, modified radical cervical cancer surgery + bilateral
pelvic lymph node dissection is recommended. If preoperative imaging assessment of
pelvic lymph node metastasis is suspected, simultaneous abdominal para-aortic lymph
node dissection is recommended.
For stage IB1, IB2, and IIA1 cervical cancer, the preferred surgical procedure is
radical cervical cancer surgery + bilateral pelvic lymph node dissection ± abdominal
para-aortic lymph node dissection. It is found that in IB-IIB cervical cancer, pelvic lymph
node metastasis, tumor >2cm and common iliac lymph node metastasis are closely
related to abdominal para-aortic lymph node metastasis. Therefore, for patients with
suspected pelvic lymph node metastasis, parietal aortic lymph node dissection should be
performed intraoperatively [13, 14].
For stage IB3 and IIA2 cervical cancer, the NCCN guidelines recommend
simultaneous
radiotherapy
(Class
I
evidence)
as
the
preferred
treatment;
it
is
controversial whether surgery is feasible for stage IB3 and IIA2 cervical cancer. However,
some oncologists advocate surgery since stage IB3 and IIA2 tumors are larger (>4 cm)
and have a higher risk of metastasis to the para-aortic lymph nodes. So if surgery is
performed, radical cervical cancer surgery + bilateral pelvic lymph node dissection +
abdominal para-aortic lymph node dissection should be performed.
Sentinel Lymph Node Mapping (SLN)
Recent studies have shown certain significance of SLN in early-stage cervical cancer.
A meta-analysis has shown that the detection rate of sentinel lymph node mapping biopsy
is 89-92% and the sensitivity is 89-90% [15, 16]. At the same time, studies have shown that
sentinel lymph node mapping biopsy has some limitations, and intraoperative evaluation
of
sentinel
lymph
node
methods
(e.g.,
freezing
or
cell
blotting)
may
miss
micro-metastases in sentinel lymph nodes or isolated tumor cell metastases [17-19]. It has
been suggested that the sensitivity of sentinel lymph node biopsy seems to be higher in
cervical cancer with tumor size ≤2 cm [20, 21]; while the approach of sentinel lymph node
hyperstaging improves the detection of lymph node micrometastases[22, 23].
Surgery to preserve fertility
Cervical conization for stage IA1 cervical cancer
For patients with stage IA1 cervical cancer with fertility preservation requirements,
cervical conization ± pelvic lymph node dissection is recommended [24, 25]. The aim of
cervical conization is to ensure negative margins [absence of invasive cancer and
high-grade squamous intraepithelial lesions (HSIL)]. For those with negative margins and
no LVSI, postoperative observation and follow-up is sufficient; whereas in cases with
OB&GY of Fudan University

A multicenter noninferior randomized controlled study comparing the efficacy of laparoscopic versus abdominal
radical hysterectomy for cervical cancer (Stage IB1, IB2, and IIA1)
9
positive margins, a second conization may be considered to clarify the depth of
infiltration (to exclude stage IA2/IB) or to perform radical cervical hysterectomy. For
stage IA1 with LVSI, cervical conization (negative margins) + laparoscopic sentinel
lymph
node
mapping
biopsy/pelvic
lymph
node
dissection
or
radical
cervical
hysterectomy + SLN/pelvic lymph node dissection may be performed.
Radical cervical hysterectomy for stage IA2/IB1 cervical cancer
Patients with stage IA2 cervical cancer who have fertility preservation requirements
are recommended to undergo radical hysterectomy + pelvic lymph node dissection, or
can consider radical hysterectomy + SLN. If cervical cone margins are negative, pelvic
lymph node dissection can also be performed to assess lymph node status. If lymph node
status is negative, follow-up can be performed. Patients with stage IB1 cervical cancer
who have fertility preservation requirements are recommended to undergo radical
hysterectomy + pelvic lymph node dissection ±para-aortic lymph node dissection [26-28].
2.2.2 Indications for adjuvant therapy after cervical cancer surgery
The need for adjuvant therapy after radical surgery for cervical cancer is determined
by the stage of the disease and surgical pathological factors. Patients with stage IA2, IB1
or IIA1 who have no postoperative lymph node metastases, negative surgical margins,
negative parametrium and no other risk factors for relapse (Sedlis criteria) do not need
adjuvant therapy after surgery and should be followed-up regularly. However, if any
relapse risk factors are present, postoperative adjuvant therapy is recommended.
High risk disease cervical cancer
After radical cervical surgery, patients with three high-risk factors (positive lymph
nodes, positive surgical margins, and positive parametrium) are recommended to receive
postoperative adjuvant therapy: external-beam radiation therapy (EBRT) + synchronous
platinum-based chemotherapy + vaginal brachytherapy. Vaginal brachytherapy is a very
effective local thrust for patients with positive vaginal margins; while synchronized
radiotherapy significantly improves OS in patients with all three high-risk factors after
radical cervical surgery for early-stage cervical cancer [29].
Intermediate-risk disease cervical cancer
Postoperative adjuvant pelvic EBRT+-synchronous platinum-based chemotherapy is
required after radical cervical surgery for cervical cancer in the absence of high-risk
factors, but in the presence of large tumor size, deep interstitial infiltration, and LVSI (see
NCCN guidelines, Sedlis criteria) [30-32].
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A multicenter noninferior randomized controlled study comparing the efficacy of laparoscopic versus abdominal
radical hysterectomy for cervical cancer (Stage IB1, IB2, and IIA1)
10
2.2.3 Radical radiotherapy
Radical radiotherapy is indicated for the treatment of stage IB3, stage IIA2, and
advanced (stage IIB-IVA) cervical cancer.
For stage IB3 or IIA2 cervical cancer, the NCCN recommendation (Class 1 evidence)
is that concurrent radiotherapy is preferred: radical EBRT + concurrent platinum-based
chemotherapy + vaginal brachytherapy. For those with stage IB1, IB2, or IIA cervical
cancer
that
cannot
tolerate
surgery,
pelvic
EBRT
+
vaginal
brachytherapy
±
platinum-based concurrent chemotherapy can be performed.
For patients with advanced cervical cancer receiving radical radiotherapy, the target
area of radiotherapy is critical, which is determined by pelvic and abdominal para-aortic
lymph node metastases. Magnetic resonance imaging (MRI) helps to describe the extent
of localized lesions and aids in radiotherapy planning. However, fine needle aspiration
biopsy may be considered for suspicious imaging presentations outside the uterus to
clarify the diagnosis. Surgical evaluation of lymph node status (i.e., extraperitoneal or
laparoscopic lymph node dissection) is also an option for these patients (category 2B),
and surgical evaluation can also detect microscopic lymph node metastases that are not
detectable on imaging
[33, 34]. For those without lymph node metastases or lesions
confined to the pelvis, pelvic EBRT + synchronous platinum-based chemotherapy +
vaginal brachytherapy is feasible (class 1 evidence) [35] [36]. For patients with positive
pelvic and para-aortic lymph nodes, imaging is recommended to assess for distant
metastases. If there are no distant metastases, pelvic extension field EBRT +
simultaneous
platinum-containing
chemotherapy
+
vaginal
brachytherapy
is
recommended; in the presence of distant metastases and positive para-aortic lymph nodes,
systemic chemotherapy ±individualized EBRT is recommended [37].
Either pelvic radiotherapy or radiotherapy could lead to ovarian failure in
premenopausal women. To protect endocrine function of the ovaries, young women
(under 45 years of age, squamous carcinoma) can undergo ovarian transposition surgery
before pelvic radiotherapy [38-40].
2.2.4 Surgery vs. radiotherapy
Both radical cervical surgery and radical radiotherapy are main treatments for
early-stage
cervical
cancer;
while
radical
radiotherapy/radiochemotherapy
is
recommended for advanced-stage cervical cancer. Therefore, the choice of treatment
modality needs to take into account disease stage, fertility requirements, comorbidities,
quality of life, and the personal preference of both physicians and patients. Surgery is
OB&GY of Fudan University

A multicenter noninferior randomized controlled study comparing the efficacy of laparoscopic versus abdominal
radical hysterectomy for cervical cancer (Stage IB1, IB2, and IIA1)
11
indicated for patients with early stage cervical cancer, especially for those with fertility
preservation requirements. For patients with stage IA, IB1, IB2, and stage IIA1 cervical
cancer, the NCCN guidelines recommended surgery for the following reasons:
．Young women can preserve ovarian function.
．The possibility of preserving vaginal function after surgery is higher compared to
radiotherapy.
．Intraoperative lymph node dissection can be performed simultaneously during the
surgical treatment, if postoperative radiotherapy is needed. Individualized radiotherapy
formulation can be achieved.
For stage IB3 and IIA2 cervical cancer, the NCCN guidelines recommend
concurrent chemoradiotherapy (CCRT): radical EBRT + concurrent platinum-based
chemotherapy + vaginal brachytherapy. After synchronous radiochemotherapy, patients
may experience vaginal function loss, ovarian function decline, and poor quality of life. A
proportion of these patients are young women. Currently in China, there are issues of
uneven distribution of radiotherapy resources and imbalance in the quality of
radiotherapy. Therefore, patients with IB3 and IIA2 stage are also included as the target
population of receiving radical treatment in this study.
2.3 Prognosis
The main prognostic factors affecting squamous cervical cancer include tumor stage,
lymph
node status,
tumor size,
depth of cervical
interstitial infiltration,
LVSI
(lymphovascular interstitial infiltration), and histological type and grading of the tumor.
Tumor stage is the most important prognostic factor, followed by lymph node status.
After radical cervical cancer surgery + lymph node dissection for clinical stage IB or IIA
patients, the 5-year OS was 88-96% for those without lymph node metastasis, and
64-74% for those with lymph node metastasis [41, 42].The 2018 LACC trial found that in
stage IA1 with LVSI, IA2 and IB1 cervical cancer patients, the PFS and OS rates of
patients receiving minimally invasive radical cervical cancer surgery were lower than
those receiving open surgery, with a PFS rate of 91.2% vs. 97.1% at 3 years, and an OS
rate of 93.8% vs. 99.0% at 3 years for minimally invasive surgery versus open surgery,
respectively [12]. In contrast, another retrospective study in 2018 found [11] that the relative
survival of patients with cervical cancer decreased by 0.8% per year in the 4 years since
the use of minimally invasive surgery began in 2006. Therefore, the NCCN guidelines no
longer recommend minimally invasive radical cervical cancer surgery. To sum up, the
5-year overall survival rate for stage I cervical cancer is about 90% and for stage II
cervical cancer is about 60%.
OB&GY of Fudan University

A multicenter noninferior randomized controlled study comparing the efficacy of laparoscopic versus abdominal
radical hysterectomy for cervical cancer (Stage IB1, IB2, and IIA1)
12
2.4 Laparoscopic surgery
Laparoscopic radical cervical cancer surgery was originally reported by Canis [43]
and Nezhat[44] et al. In the last two decades, laparoscopic surgery has become
increasingly sophisticated. In addition to traditional laparoscopic surgery, robotic-assisted
surgery has been derived. Most studies have shown that laparoscopic surgery has less
intraoperative bleeding and shorter hospital stay, and some studies have reported that the
PFS rate of LRH was not inferior to that of ARH [5-10]. Therefore, laparoscopic surgery
has become the main treatment for early-stage cervical cancer in many countries, and the
2014 NCCN guidelines recommended a laparoscopic approach for radical cervical cancer.
In most of the prestige hospitals in China, laparoscopic radical cervical cancer treatment
accounts for more than 90% of the cases.
As previously mentioned, the LACC trial and the retrospective study published in
the New England Journal of Medicine in late 2018 caused a huge impact in the medical
community when they concluded that both PFS and OS rates for patients undergoing
minimally invasive radical cervical cancer treatment were lower than those undergoing
abdominal radical cervical cancer treatment. Following the publication of these articles,
the version 3.2019 NCCN guidelines have recommended open surgery as the standard
procedure for cervical cancer, and laparoscopic surgery is no longer recommended.
However, at our hospital (Obstetrics and Gynecology Hospital of Fudan University),
about 1500-200 cervical cancer surgeries were performed each year over the last 8 years.
According to our data, for laparoscopic radical cervical cancer surgery, the 5-year OS
rates are 100% in stage IA2 and 96.93% in stage IB1 patients, which are similar to open
surgery in the LACC trial. In addition, data from endometrial cancer have shown that
laparoscopy is superior to open surgery in terms of both recent surgery-related
complications and survival benefits, so NCCN guidelines recommended laparoscopic
surgery as the standard procedure for endometrial cancer. Until now, there is only one
RCT (the LACC trial) that compared minimally invasive and open radical cervical cancer
treatments. In view of the results of the LACC trial, should we completely abandon
minimally invasive surgery for cervical cancer, or are we looking for the root cause and
improvement methods to promote medical development? Therefore, we propose to design
this study in accordance with the high requirements of our ability and intraoperative
tumor-free principle, with the aim of further comparing LRH (or robotic-assisted) and
ARH in patients with early-stage cervical cancer: IA1 with intravascular infiltration
(LVSI), stage IA2; IB1, IB2, IIA1; stage IB3, IIA2 in terms of efficacy as well as quality
of life.
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A multicenter noninferior randomized controlled study comparing the efficacy of laparoscopic versus abdominal
radical hysterectomy for cervical cancer (Stage IB1, IB2, and IIA1)
13
2.5 Quality of life
Quality of life studies allow evaluation and comparison of surgical outcomes from
the patient's perspective and are therefore an extremely important assessment endpoints.
The quality of life survey used in this phase III clinical trial will include the use of the
EORTC Quality of Life Measurement Scale QLQC30 (V3.0), the EORTC QLQ-CX24
scale, and the PRO 147 (V 1.0), a patient-reported clinical outcome evaluation scale for
cervical cancer developed in-house by the research team.
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OB&GY of Fudan University

A multicenter noninferior randomized controlled study comparing the efficacy of laparoscopic versus abdominal
radical hysterectomy for cervical cancer (Stage IB1, IB2, and IIA1)
14
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A multicenter noninferior randomized controlled study comparing the efficacy of laparoscopic versus abdominal
radical hysterectomy for cervical cancer (Stage IB1, IB2, and IIA1)
15
cervical carcinoma with poor prognostic features: follow-up of a gynecologic oncology group
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[44].Nezhat, C.R., et al., Laparoscopic radical hysterectomy with paraaortic and pelvic node
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2.2 Research Objectives
2.2.1 Main study objective
To compare the 5-year progression free survival (PFS) of patients undergoing
Laparoscopic Radical Hysterectomy (LRH) versus Abdominal Radical Hysterectomy
(ARH) for cervical cancer.
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A multicenter noninferior randomized controlled study comparing the efficacy of laparoscopic versus abdominal
radical hysterectomy for cervical cancer (Stage IB1, IB2, and IIA1)
16
2.2.2 Secondary research objectives
To compare the 5-year overall survival (OS) of the two groups of patients with
different surgical procedures.
To compare the relapse rate and relapse pattern between the two groups of patients
with different surgical procedures.
To compare the functional status of each organ in the two groups.
To compare the effects of the two different surgical procedures on quality of life of
the patients in the two groups.
To compare the difference in cost effectiveness between the two groups of patients.
To compare the amount of surgical bleeding, the incidence of surgery-related
diseases, and intraoperative and postoperative complications between the two groups.
2.3 Research Design
STAGE1
The publication of the LACC trial has caused a huge impact in the gynecology field, and
the version 3.2019 NCCN guidelines no longer recommended laparoscopic surgery for
patients with cervical cancer. However, the investigators reviewed data from our hospital
for the last 8 years of laparoscopic radical cervical cancer surgery, which showed
different results from the LACC trial. During the Global Clinical Scholar Research
Training (GCSRT) program hosted by Harvard Medical School, the leader of the main
center discussed with local clinical research experts about the ethical feasibility of
redesigning the RCT study to validate the topic, and in the first draft of this project
design was completed as part of the Capstone Project course plan, and the study design
was recommended in the end-of-semester presentation.
STAGE2
According to the trial design, after the study passed by ethics, the research team started to
try the protocol according to the design process and successfully recruited 84 subjects. At
the beginning of the study design, the study mixed cervical cancer stages IA1 with LVSI,
IA2, IB1, IB2, IIA1, IB3, and IIA2 in one trial. However, as the trial progressed, we
found that the span of the trial stages was too large for a specific assessment of each stage
and for guiding the specific procedure for each stage. Also, when we submitted the
protocol, we received the same suggestion from the review responses.
STAGE3
This project is divided into three parallel studies based on the staging, LAUNCH 1 (LA1
with LVSI, IA2), LAUNCH 2 (IB1, IB2, IIA1), and LAUNCH 3 (IB3, IIA2). Previously
we
conducted
a
single-center
study
(study
protocol
registration
number:
ChiCTR1900025946) which included all above mentioned stages. There are 84 patients
enrolled in that study which will not be included in the current project, since those
patients do not meet the randomization strategy of the current project.
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A multicenter noninferior randomized controlled study comparing the efficacy of laparoscopic versus abdominal
radical hysterectomy for cervical cancer (Stage IB1, IB2, and IIA1)
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STAGE4
This study intends to sample and collect intraoperative tumor tissues from tumor patients,
and to conduct basic science research on the evaluation of genetic testing for specific
tumor stages, which can be used to guide later treatments such as targeted or immune
therapies. At the same time, we will conduct relevant histological studies on the
molecular tissues related to tumors in order to find the pathogenesis pattern that may
guide treatment.
III. Research methods
1. Study setup
This project is a multicenter study led by the Obstetrics and Gynecology Hospital of
Fudan University, which is one of the first national clinical class I key specialties in
China and a key discipline of the Ministry of Education. The Obstetrics and Gynecology
Hospital of Fudan University undertakes the task of diagnosis and treatment of malignant
tumors of the female reproductive system nationwide, with a leading annual volume of
cervical cancer surgery and treatment in China. The clinical centers of this study includes
Obstetrics and Gynecology Hospital of Fudan University (main center), Zhongshan
Hospital affiliated to Fudan University, Renji Hospital of Shanghai Jiaotong University,
Xinhua Hospital of Shanghai Jiao Tong University, Taizhou Hospital Affiliated Cancer
Hospital of the University of Chinese Academy of Sciences and the First Hospital of
Wenzhou Medical University (sub-centers). The CTU of the Clinical Trial Center of the
Children's Hospital of Fudan University is responsible for statistical analyses. All these
have provided adequate technical support and guarantee for the study.
2. Qualification criteria
2.1 Study subjects and study time
A total of 780 patients diagnosed with cervical cancer (stage IB1, IB2, and IIA1) and
meeting the enrollment criteria will be recruited from the aforementioned main center and
sub-centers. This project is expected to be completed in 3 years (April 2021 to April 2024)
from the date of formal ethical approval and completion of enrollment, and the study
patients will be followed-up for 5 years (April 2021 to April 2026).
2.2 Patient inclusion and exclusion criteria
Patient inclusion criteria:
a) Clinical diagnosis of squamous carcinoma of the cervix, adenocarcinoma, squamous
adenocarcinoma (stage IB1, IB2, and IIA1).
b) Age ≥21 years and ≤70 years.
c) Surgery type C (refer to Q-M surgical staging).
d) Normal range of liver and kidney function, and blood count:
Hemoglobin > 60g/L;
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A multicenter noninferior randomized controlled study comparing the efficacy of laparoscopic versus abdominal
radical hysterectomy for cervical cancer (Stage IB1, IB2, and IIA1)
18
Platelets > 70*109/L;
Leukocytes > 3*109/L;
Creatinine < 50mg/dL;
Transaminase abnormal indicators ≤3;
Maximum value of transaminases not exceeding 3 times the corresponding normal value.
e) No history of other malignancies.
f) Non-pregnancy.
g) Physical strength classification: Karnofsky score ≥60.
h) Voluntarily joined the study, sign the informed consent form, are compliant and
cooperative with the follow-up.
i) No psychiatric disorders and other serious immune system disorders (e.g. lupus
erythematosus, myasthenia gravis, HIV infection, etc.)
(Note: Maximum diameter measurement of cervical lesions is based on PET-CT, or CT,
or MRI)
Patient exclusion criteria:
a) Contraindicated for various surgeries and cannot undergo surgery.
b) Have received pelvic/abdominal radiotherapy irradiation or neoadjuvant chemotherapy
for cervical cancer.
c) With recurrent cervical cancer
d) With CT, MRI or PET-CT suggesting suspicious metastasis of pelvic lymph nodes with
maximum diameter >2cm after further improvement of preoperative examination.
2.3 Requirements of investigators and surgeons
Surgeons involved in this project were selected from each participating hospital and are
skilled in cervical cancer surgery. The lead surgeon must have experience in at least 50
surgeries each for both LRH and ARH and be able to provide the medical history of these
cases. The principal investigator and members of the surgical quality control team will be
on site to observe each surgeon's procedure and review the unedited video of the
procedure (1 ARH and 1 LRH) provided by each surgeon for surgical quality
measurement and documentation to ensure the extent of surgical resection and tumor-free
management of each surgeon.
3. Interventions
3.1 Overall intervention plans
Minimally invasive radical cervical cancer treatment includes laparoscopic
radical cervical cancer treatment (LRH) and robotic-assisted laparoscopic radical
cervical cancer treatment, either of which can be chosen by the operator. This project
focuses on the survival benefit of patients after minimally invasive and open radical
cervical cancer treatment, so radical cervical cancer treatment with preservation of
reproductive function will not be included. For both open and minimally invasive
radical cervical cancer surgery, the operation begins with a thorough abdominal
OB&GY of Fudan University

A multicenter noninferior randomized controlled study comparing the efficacy of laparoscopic versus abdominal
radical hysterectomy for cervical cancer (Stage IB1, IB2, and IIA1)
19
exploration, including careful exploration of the diaphragm, and any metastatic
lesions and metastatic sites should be described in detail in the operative record, with
biopsy for confirmative diagnosis. If intra-abdominal lesions are found, radical
cervical cancer surgery should not be used and should change to palliative treatment.
Pelvic lymph node dissection should be performed during radical cervical cancer
surgery. Sentinel Lymph Node Mapping (SLN) is not included in this project, since
there is no sufficient evidence for its sensitivity and specificity, and also the difficulty
in achieving lymph node hyperstaging considering the large sample size of this
project. If the tumor is ≥2 cm, or if the common iliac lymph node is positive for
intraoperative freezing (optional), or if the preoperative evaluation of the paraaortic
lymph nodes is positive, paraaortic lymph node dissection is preferred and followed
by paraaortic lymph node biopsy. When clear the para-aortic lymph nodes, the upper
border reaches the level of the inferior mesenteric artery is enough. The common iliac
lymph nodes should be sent separately for examination, and the resection should
include both sides of the common iliac vessels, with the upper border reaching the
midpoint of the bifurcation of the abdominal aorta and the common iliac vessels and
the lower border reaching the level of the bifurcation of the common iliac vessels.
If definite pelvic lymph node metastasis is found intraoperatively, continuation
of pelvic lymph node dissection and even radical cervical cancer surgery is not
required, but abdominal para-aortic lymph node sampling is recommended to assess
the degree of disease progression and to develop subsequent radiotherapy regimens. If
surgery is continued, radical cervical cancer surgery + pelvic lymph node dissection +
abdominal para-aortic lymph node dissection/biopsy is recommended.
For
patients
randomly
assigned
to
LRH,
the
surgeon
should
perform
laparoscopic/robotic-assisted radical laparoscopic cervical cancer surgery or perform
laparoscopic-assisted radical transvaginal cervical cancer surgery.
In performing radical cervical cancer surgery, the surgeon should provide
detailed
descriptions
of
the
special
surgical
instruments
used
in
the
laparoscopic/robotic-assisted laparoscopic group. In addition, the surgeon should
document the following information in the operative record:
．Time of surgery: time from the start of radical cervical cancer surgery to the
closure of all abdominal puncture sites or abdominal incisions.
．Amount of intraoperative blood loss.
．Intraoperative complications.
．If patients are randomized to the laparoscopic surgery group and are converted
to open surgery intraoperatively, the reasons should be recorded.
．In case of robotic-assisted laparoscopic radical cervical cancer surgery, the time
required to assemble and dock the robot should be recorded in the operative record,
which should be deducted from the total operative time.
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A multicenter noninferior randomized controlled study comparing the efficacy of laparoscopic versus abdominal
radical hysterectomy for cervical cancer (Stage IB1, IB2, and IIA1)
20
．If intraoperative parietal aortic lymph node dissection is performed
simultaneously, the time required for this operation should be recorded in the
operative record.
The surgical approach for stage IA1 with LVSI and stage IA2 is type B
(modified radical hysterectomy with bilateral pelvic lymph node dissection, i.e.,
resection of 1-2 cm of the parametrium and 1-2 cm of the vagina) with para-aortic
lymph node dissection if necessary (surgical staging according to FIGO 2018,
surgical staging according to Querleu-Morrow staging).
For stage IB1, IB2, and IIA1, the surgical approach is typeC1 (radical cervical
surgery with preservation of autonomic nerves + pelvic lymph node dissection,
recommended for tumor diameter <2 cm) or type C2 (radical cervical surgery with
bilateral pelvic lymph node dissection, resection of 3-4 cm of the parametrium and
the upper 1/4 to 1/3 of the vagina) with abdominal para-aortic lymph node dissection
if necessary (surgical staging according to FIGO 2018, staging according to
Querleu-Morrow staging). The depth of parametrial tissue removed should be below
the deep uterine vein, and if preoperative involvement of the vaginal wall is
considered, 1-2 cm of parametrial tissue should be removed.
Stage IB3, IIA2 The surgical approach is type C2 (radical cervical cancer +
bilateral pelvic lymph node dissection + para-aortic lymph node dissection, 3-4 cm of
parametrium and upper 1/4 to 1/3 of the vagina) (surgical staging according to FIGO
2018, surgical staging according to Querleu-Morrow staging). Parametrial tissue
should be removed to a depth below the deep uterine vein, and 1-2 cm of parametrial
tissue should be removed if preoperative involvement of the vaginal wall is
considered.
Figure 1A
Figure 1B
Figure 1A. Type B: Surgical resection range of modified radical hysterectomy
Figure 1B. Type C2: Surgical resection range radical cervical cancer
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A multicenter noninferior randomized controlled study comparing the efficacy of laparoscopic versus abdominal
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21
The tumor-free principle during surgery includes:
1) Severing the vagina before vaginal closure by: closure of the vagina with an obturator;
ligature ring ligation of the vagina; transvaginal suture of the vagina.
2) After laparoscopic ligation of the vagina, the vagina is irrigated with sterile water, and
then the vagina is severed and sutured; after open surgery, the vagina is closed with renal
clamps and the anterior vaginal wall is incised, gauze is inserted, then the posterior wall
is severed and the vaginal stump is sterilized.
3) Encourage sharp and gentle excision, and try to avoid vigorous tearing and plucking
movements.
4) Whole lymph nodes are removed without touching other parts and placed in a
specimen bag for final removal; extensive hysterectomy is performed in whole and
excessive straining is avoided intraoperatively.
5) Rinse the instruments that have contacted the tumor in the vagina and separate them
from other instruments; if suspicious metastatic tissue is encountered in the pelvic and
abdominal cavity, remove it directly into the specimen bag without contacting other parts
after excision.
6) Aspirate the pelvic and abdominal cavity after full postoperative rinsing with sterile
water, and avoid backflow of pelvic rinsing fluid into the upper abdomen when the head
is low and the feet are high.
7) Do not lift the uterus. Use other methods such as silk thread to pull the uterine body.
3.2 Standard treatment plan:
Open radical hysterectomy for cervical cancer + pelvic lymph node dissection/para-aortic
lymph node dissection
a) The preoperative prophylactic antibiotics are given at least 15 minutes before incision
of the skin.
b) The sequential compression device (antithrombotic pressure pump) is installed.
c) The patient is placed in the supine position or bladder lithotomy position.
d) Considering the wide range of surgical instruments used in this type of surgery, the
use of laparoscopic instruments depends on the operator's personal choice.
e) The incision is chosen as a median abdominal incision or a low transverse incision.
f)
After entering the abdomen, a thorough abdominal exploration is performed,
including careful exploration of the diaphragm. Any metastatic lesions and metastatic
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A multicenter noninferior randomized controlled study comparing the efficacy of laparoscopic versus abdominal
radical hysterectomy for cervical cancer (Stage IB1, IB2, and IIA1)
22
sites should be described in detail in the surgical record, and biopsy is performed to
confirm the diagnosis.
g) The lateral pelvic peritoneum is opened and any enlarged, suspicious lymph nodes
should be removed (if feasible) followed by intraoperative freezing. If these lymph
nodes are positive, abdominal para-aortic lymph node biopsy should be performed,
but radical cervical cancer surgery may be forgone and the treatment regimen for this
patient will be switched to radical radiotherapy; or radical cervical cancer surgery +
pelvic lymph node dissection + abdominal para-aortic lymph node dissection/biopsy
may continue.
h) The radical cervical cancer surgery with or without bilateral salpingo-oophorectomy
will be performed if there are no suspected pelvic lymph nodes.
i)
The Removal of ovaries: the ovaries may be preserved or removed, or ovarian
transposition may be performed, depending on the subject's condition.
j)
The scope of pelvic lymph node dissection: lymph nodes adjacent to the common
iliac artery, external iliac artery, internal iliac artery and lymph nodes in the closed
fossa should be removed.
k) The abdominal para-aortic lymph node dissection should reach the level of the
inferior mesenteric artery.
l)
Tumor-free principle: useopen surgical kidney pedicle forceps to clamp the vagina
close, then incision of the anterior vaginal wall, insertion of gauze, followed by
severance of the posterior wall and disinfection of the vaginal stump.
m) The abdominal drainage tube is non-compulsory and can be chosen by each center.
n) The closure of the abdomen layers: closure of the fascia and closure of the skin.
o) Indwelling urine catheter.
3.3 Intervention treatment:
Laparoscopic or robot-assisted laparoscopic radical hysterectomy for cervical cancer +
pelvic lymph node dissection/para-aortic lymph node dissection.
1) The preoperative prophylactic antibiotics are given at least 15 minutes before incision
of the skin.
2) The sequential compression device (antithrombotic pressure pump) is installed.
3) The patient is placed in bladder lithotomy position with the upper arms flat on the
sides of the body or on the chest.
4) The choice of laparoscopic instruments depends on the surgeon's personal preference,
considering the wide range of surgical instruments used for this type of procedure.
5) The approach to the abdomen and the number of puncture points for laparoscopic
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A multicenter noninferior randomized controlled study comparing the efficacy of laparoscopic versus abdominal
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surgery depend on the operator's personal choice.
6) After entering the abdomen, a thorough abdominal exploration, including careful
exploration of the diaphragm, should be performed first. Any metastatic lesions and
metastatic sites should be described in detail in the operative record, and a biopsy
should be performed to clarify the diagnosis.
7) The round ligament is separated in order to open the retroperitoneum. The lateral
pelvic peritoneum is opened and any enlarged, suscepted lymph nodes should be
resected (if feasible) followed by intraoperative cryopexy. If these lymph nodes are
positive, abdominal para-aortic lymph node biopsy should be performed, but radical
cervical cancer surgery may be forgone and the treatment plan will be changed to
radical radiotherapy in this subject; or radical cervical cancer surgery + pelvic lymph
node resection + abdominal para-aortic lymph node dissection/biopsy may be
continued.
8) The radical cervical cancer surgery with or without bilateral salpingo-oophorectomy
will be performed if there are no suscepted pelvic lymph nodes.
9) The removal of ovaries: the ovaries may be preserved or removed or ovarian
transposition may be performed depending on the patient's specific situation.
10) The scope of pelvic lymph node resection: the lymph nodes adjacent to the common
iliac artery, external iliac artery, internal iliac artery and the lymph nodes in the closed
fossa should be removed.
11) The uterus is not lifted, and methods such as silk traction of the uterine body are used.
12) The uterine artery is identified and dissociatedat the point where the internal iliac
artery divides from the uterine artery.
13) The parametrial tissue and the uterosacral ligament are excised to ensure adequate
surgical margins. Paying attention to the tumor- free principle, the vagina is closed
before severing it, which can be done by: closure of the vagina with an obturator;
closure of the vagina with a ligature ring; and closure of the vagina with transvaginal
sutures. After laparoscopic closure of the vagina, the vagina is irrigated with sterile
water, after which the vagina is severed and the vaginal stump is sutured.
14) Systematic lymphadenectomy: removal of lymph nodes adjacent to the common iliac
artery, external iliac artery, internal iliac artery and lymph nodes in the closed fossa ±
parietal aortic lymph nodes (up to the level of the inferior mesenteric artery).
15) The intraoperative lymph nodes are removed by en bloc resection, without touching
other parts, and will be placed in a specimen bag for final removal.
16) The postoperative pelvic and abdominal cavity will be suctioned after full flushing
with sterile water, and the pelvic flushing fluid should be avoided to back up into the
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upper abdomen duringtrendelenburg position.
17) Use of a vaginal apex closure device can be chosen by each surgeon.
18) The laparoscopic operation can also be performed through vagina.
3.4 Intraoperative sentinel lymph node localization biopsy:
Sentinel lymph node localization biopsy will not be used in this project.
3.5 Pelvic/Para-aortic lymphadenectomy:
The
surgeon
is
required
to
perform
pelvic
lymphadenectomy±
para-aortic
lymphadenectomy in both groups of patients; however, the surgeon may also choose not
to perform lymphadenectomy if the patient meets the following criteria:
1) Morbid obesity: (European and American criteria: weight over 100 pounds or
BMI≥40) BMI≥37.5 for the Asian population; or BMI ≥32.5 with two or more
metabolic complications.
2) Requires blood thinning medication.
3) The patient's physical condition is not suitable for lymphadenectomy from a
medical safety perspective.
3.6 Post-operative adjuvant radiotherapy or radiochemotherapy
If the postoperative pathology report suggests the presence of risk factors associated
with recurrence (high-risk factors or intermediate risk factors), postoperative adjuvant
therapy is required if necessary.
(1) High-risk factors: positive parametrium, positive incisional margins,
andpositive pelvic lymph nodes.
Positive parametrium:externalpelvic beam radiation therapy (EBRT) + cisplatin
concurrent chemotherapy. Cisplatin (DDP) 40 mg/m2/w (week, w), or carboplatin if
cisplatin is not tolerated (AUC=2). (If positive for parametrial tissue, local push of 5-10
Gy may be appropriate).
Positive vaginal incisional margins: external pelvic radiation therapy (EBRT) +
cisplatin concurrent chemotherapy + vaginal backloading radiotherapy, with cisplatin
(DDP) 40 mg/m2/w, or carboplatin (AUC=2) if cisplatin is intolerant.
Positive pelvic lymph nodes: one course of systemic chemotherapy + external
pelvic radiation radiotherapy (EBRT) ± extended field radiotherapy to the abdominal
aorta + concurrent chemotherapy with cisplatin (40 mg/m2/w) + 3-6 courses of adjuvant
systemic chemotherapy after radiotherapy (paclitaxel + cisplatin or carboplatin preferred
for large intravenous chemotherapy regimens, can use both domestic or imported). If the
pathology confirms positive abdominal aorta or positive common iliac lymph nodes,
irradiation of para-aortic extended field will be performed; when the pelvic lymph nodes
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are positive and the pathology result of abdominal aortalymph nodes clearance is
negative (if only abdominal main biopsy without clearance, positive irradiation will be
performed, negative is equivalent to no clearance), no extended field irradiation will be
performed; if the lymph nodes in the pelvic lymph nodes are positive and the lymph
nodes in the para-aortic lymph nodes are not cleared, but the image is suscepted of
metastasis in the para-aortic lymph nodes (full lymph nodes, length to diameter ratio
close to 1), it is recommended to extend field irradiation.
(2) Intermediate risk factors (tumor size, interstitial infiltration, positive
lymphovascular space), squamous carcinoma according to "Sedlis criteria": external
pelvic radiation therapy (EBRT) + cisplatin concurrent chemotherapy, cisplatin (DDP)
40mg/m2/w.
(3) Adenocarcinoma and adenosquamous carcinoma are treated according to
intermediate risk factors, following the four-factor approach (i.e. adenocarcinoma or
adenosquamous carcinoma with positive lymphovascular space, tumor ≥3 cm, and
infiltration of the outer 1/3 of the cervical canal should be treated with concurrent
radiotherapy). External pelvic radiation therapy (EBRT) + cisplatin concurrent
chemotherapy with cisplatin (DDP) 40 mg/m2/w, or carboplatin (AUC=2) if cisplatin is
not tolerated.
(4) Positive proximal margin (negative margin ≤0.5cm), treatment as positive
vaginal margin, external pelvic irradiation therapy + cisplatin concurrent chemotherapy +
brachytherapy.
The EBRT implementation：
(1) Recommend to start at 4 weeks postoperatively and no later than 8 weeks.
Prescribed dosage: squamous carcinoma, 45 Gy; adenocarcinoma, 50.4 Gy; conventional
segmentation 1.8 Gy per session, once daily, Monday through Friday each week. Large
unresectable metastatic lymph nodes are given a simultaneous additional push (SIB
2.1-2.2Gy) or sequential additional dose of 10-15Gy.
(2) Scope of irradiation: pelvic radiation field ± extended abdominal aortic field ±
brachytherapy.
(3) Pelvic radiation field: at least 3-4 centimeters below the vaginal dissection,
parametrial tissue and adjacent lymph node drainage areas (common iliac, internal and
external iliac lymph nodes, closed foramen, presacral) must be included.
(4) Para-aortic extension field: the upper border reaches the level of the left renal
vein, the left side reaches the inner edge of the psoas major muscle and the right side 3-5
millimeters around the inferior vena cava.
(5) Intensity-modulated radiation therapy (IMRT) or volumetric-modulated
arcadiotherapy (VAMT) is recommended for EBRT with weekly cone beam CT (CBCT)
once a week.
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The Implementation of retrovaginalradiotherapy：
(1) Retrovaginal radiotherapy is started after the completion of external pelvic
irradiation, twice per week. (It is recommended that the total duration of external
irradiation radiotherapy + retrovaginal radiotherapy treatment does not exceed 56 days).
(2) Recommend 3-D rear-loading technique: CT or MRI localization, using
columnar and ovoid applicators with 192Ir-source or 60Co, for high-dose-rate rear-loading
radiotherapy.
(3) High-risk clinical target volume (HR-CTV): including the area 5 millimeters
outside the vaginal mucosa and 1 centimeter above the vaginal stump.
(4) More than 90% of the volume of HR-CTV per session is included in the
prescribed dose range (6 Gy × 3 sessions); for two-dimensional rear-loading radiotherapy
plans, the prescribed dose point is 5 millimeters below the vaginal mucosa.
(5) The sum of external rectal irradiation and 2 Gy equivalent total dose (EQD2) of
postoperative radiotherapy (2cc) is less than 65~75 Gy; sigmoid colon is less than 70-75
Gy, and bladder 2cc is less than 80~90 Gy.
The implementation of CCRT.
CCRT is given weekly cisplatin (DDP) intravenous chemotherapy during EBRT.
Cisplatin (DDP) 40 mg/m2/w is recommended for the first 3 days of the first week of
radiotherapy initiation, with an expected 5 cycles.
Note: SEDLIS criteria
LVSI
Depth of interstitial invasion
Tumor size(cm)
(determined by clinical
gynecological examination)
+
Deep 1/3
Arbitrary
+
Medium 1/3
≥2cm
+
Shallow 1/3
≥5cm
-
Medium or deep 1/3
≥4cm
LVSI: Lymphovascular space invasion
3.7 Recording of follow-up data:
3.7.1 Preoperative assessment:
a) Standard preoperative laboratory tests determined by each center: (e.g., routine blood
and urine test, coagulation function, blood liver, kidney function, electrolytes, HIV, RPR,
hepatitis markers)
b) 12-lead ECG
c) Tumor indicators: SCC antigen test (SCCA) and CA-125
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d) HPV typing test and TCT test in the last 3 months (only one preoperative test is
required)
e) Pathology or pathology consultation at each center (LEEP or conization is required for
IA1 with LVSI and IA2).
f) Imaging (CT scan of the chest, enhanced CT of the upper abdomen and pelvis,
enhanced MRI to assess lesion size or PET-CT to assess retroperitoneal lymph node
metastases)
g) Collection of relevant medical history, height and weight, demographic data, and
health insurance-related information of the patients
h) Record all medications (including prescription drugs, over-the-counter drugs,
vaccination, antibiotics, herbal medicine) used by the patient in the past 3 months
i) Sign the informed consent form
j) Record an inclusion criteria screening form
k) Complete the randomization procedure, entering randomization codes for patients and
recording the results
l) Sign the informed consent form for the relevant surgery
m) Patients may scan the QR code to register for the web-based follow-up platform
[Note]:
- Pathologic evaluation: Each patient must have a clear histologic diagnosis of cervical
squamous cell carcinoma, cervical adenocarcinoma, or cervical adenosquamous
carcinoma prior to radical cervical cancer surgery. If the cervical lesion is relatively
evident, although the biopsy pathology shows patches of squamous cells without clear
interstitial infiltration, the clinical presentation of the lesion is consistent with invasive
cervical cancer, and then the patient may still be included in the study.
- Clinical assessment: cervical lesion size was measured by pelvic-enhanced MRI; the
presence of metastases in the parametrium was determined by physical examination of
the operator; and lymph node status was assessed by pelvic-enhanced MRI in
combination with other imaging such as PET-CT.
3.7.2 Documentation of the surgical procedure
a) Surgery based on randomized outcome: open or laparoscopic operation.
b) Record intraoperative and postoperative information (including details of the
procedure, duration of surgery, duration of anesthesia, intraoperative bleeding,
intraoperative complications, details of blood transfusion and any other special
circumstances surrounding the procedure).
3.7.3 Post-treatment follow-up records
One week after the end of treatment.
a) Record postoperative pathology results and corresponding follow-up treatment plan
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b) Review laboratory tests (e.g. blood and urine routinetest, coagulation function, blood
liver, kidney function, electrolytes, drainage fluid creatinine)
c) Postoperative indwelling catheter for 3-6 weeks and review of residual urine when the
catheter is removed
d) Postoperative complications (lymphatic cysts, dysuria, vaginal bleeding)
Review every 3 months for 2 years after completion of treatment with:
a) Imaging examinations (chest CT + pelvic enhancement MRI + upper abdomen
enhancement MRI or PET-CT)
b) Tumor indicators: SCC antigen test (SCCA) and CA-125
c) HPV and TCT test (once a year after completion of treatment)
d) Adverse events recording
e) Assessment of quality of survival and quality of sexual life using the Quality of
Survival Scale for Cancer Patients (EORTC QLQ-C30 v3.0), the Cervical Cancer Sexual
Life Scale (EORTC QLQ-CX24), and the Patient Reported Clinical Outcome Assessment
Scale for Cervical Cancer PRO147 (V1.0).
After 2 years, the study will be reviewed every 6 months until the end of the trial. The
review will includ gynecological examination, tumor indicators (SCC antigen detection
(SCCA) and CA-125), TCT examination and HPV examination, imaging (chest CT +
pelvic enhancement MRI + upper abdomen enhancement MRI or PET-CT), and adverse
event records.
3.8 Criteria for Patient Withdrawal
Patients have the right to withdraw from the trial treatment or study at any time
without any reason. The investigator also has the right to withdraw a patient from the trial
treatment or study in the event of secondary disease, adverse events, protocol violations,
administrative reasons, or other reasons. Participation in the study, whether or not the
affected patient participates, will not affect the relationship between the patient and the
physician and will not result in a loss of medical or other benefits to the patient. However,
in such cases, the investigator will make appropriate efforts to determine and document
the reasons for the patient's voluntary withdrawal from the study. If a patient withdraws
from the study, a complete final evaluation should be conducted at the time of patient
withdrawal. This will be reported along with the study results and all attempts to locate
patients lost to follow-up will also be documented.
Patients will be seen by their physician if they withdraw from the study. According
to routine gynecologic oncology protocols, they should continue to receive care and
treatment from an experienced physician until further follow-up is deemed unnecessary
by the treating physician.
Patients will be withdrawn from the study under the following circumstances:
1) Study completion/termination, or death
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2) Patient demands withdrawal
3) Patient is unable or unwilling to cooperate with follow-up
4) Patient has other serious, non-surgical complications
5) Patient's follow-up information cannot be obtained.
6) The study is terminated or cancelled at the request of the sponsor
7) Other relevant reasons.
If a patient moves to another study treatment and requires changing physician, the
investigator will make a reasonable attempt to locate that center's physician and request
cooperation in order to complete the follow-up.
In many cases, patient withdrawal from the study constitutes discontinuation of
treatment and/or discontinuation of completion of related forms, such as quality of life. In
these cases, the investigator should obtain the patient's permission to continue monitoring
their disease status (relapse, survival, toxicity, etc.) through the patient's record.
Excessive exit rates can make a study uninterpretable, and therefore, unnecessary
subject dropouts should be avoided.
3.9 Combination and simultaneous treatment：
Supplementary therapy will be administered according to the postoperative
pathological findings of the patients. Those with high-risk factors who have positive
parametrium will be supplemented with external pelvic irradiation therapy +
cisplatin/carboplatin concurrent chemotherapy, those with positive vaginal margins will
be selected for external pelvic irradiation therapy + retrovaginal radiotherapy +
cisplatin/carboplatin concurrent chemotherapy, and those with positive pelvic lymph
nodes will be treated with 1 course of systemic chemotherapy + external pelvic
irradiation radiotherapy ± extended field radiotherapy adjacent to the abdominal aorta +
cisplatin concurrent chemotherapy + 3-6 courses of adjuvant systemic chemotherapy after
radiotherapy. Those with intermediate risk factors will be treated with external pelvic
irradiation radiotherapy + cisplatin concurrent chemotherapy, and those with positive
proximal margins will be treated with external pelvic irradiation radiotherapy EBRT +
cisplatin concurrent chemotherapy + retrovaginal radiotherapy. Targeted
immunotherapeutic agents such as bevacizumab and PD-1, which have just obtained
some results in clinical studies, are not considered in this trial for the time being. It could
be used according doctor’s orders.
3.10 Outcome measurements：
1) Main outcome indicators: 5-year PFS, refer to RECIST criteria.
2) Secondary outcome measurements: 5-year OS.
3) Other outcome measurements: operation time, anesthesia time, intraoperative bleeding
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volume, intraoperative complications, postoperative complications, postoperative pain
score, postoperative hospital stay, one-month postoperative survival quality, one-year
postoperative survival quality, and sexual quality of life.
4) Other evaluation parameters: patient's demographic characteristics, signs and
symptoms, stage, pathological type, tumor site, comorbidities, medical history, length of
hospital stay and cost.
5) This study intends to sample and collect intraoperative tumor tissues from tumor
patients and evaluate specific tumor stages with genetic testing to guide later treatments
such as targeted or immune therapies. Histological studies and molecular studies will also
be conducted.
3.11 Subjective schedule
Note: For patients with stage IB1, IB2, IIA1, IB3, and IIA2, the surgical method will be
selected according to the maximum diameter of the mass. C1 type hysterectomy will be
Pre-phase
0-12
months
12-24
months
24-36
months
36-60
months
Meet the researchers
Ⅹ
Obtain IRB approval
Ⅹ
Funding application
Ⅹ
Enrollment of study patients
Ⅹ
Ⅹ
Ⅹ
Data monitoring
Ⅹ
Ⅹ
Ⅹ
X
Data collection
Ⅹ
Ⅹ
Ⅹ
X
Data analysis
X
Summary and discussion
Ⅹ
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A multicenter noninferior randomized controlled study comparing the efficacy of laparoscopic versus abdominal
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used for diameters <2 cm, C2 type hysterectomy will be used for diameters >4 cm, and
C1 type or C2 type hysterectomy will be selected by the surgical team members
according to the actual intraoperative condition for diameters between 2 cm and 4 cm.
3.12 Sample size
This study uses a non-inferiority trial design, and the primary outcome is the 5-year PFS
rate. The sample size is calculated based on the difference between the two groups of
5-year PFS rate. The 5-year OS rate of the patients in the open surgery group is estimated
to be 92% based on clinical data from our hospital, and the 5-year PFS rate is lacking.
To infer the relationship between 5-year PFS rate and 5-year OS rate in patients
undergoing open surgery, we refer to previous studies and construct a linear regression
equation with 5-year OS rate as the independent variable X and 5-year PFS rate as the
dependent variable Y (Y = 1.199 X-0.219). Therefore, the 5-year PFS rate of the open
surgery group is estimated to be 88%, when the 5-year OS rate is 92%.
Based on the assumptions of (i) a 5-year PFS rate of 88% in the open surgery group,
(ii) a non-inferiority margin of 7%, (iii) 80% power, and (iv) a one-sided alpha of 0.025,
the sample size estimation resulted in 350 subjects per group (calculated with SAS
software, version 9.4). Considering a 10% drop-out rate and the randomization scheme
with block size of 6, a total of 780 subjects should be randomized (390 per group).
3.13 Recruitment methods
The study centers will advertise this study at their cervical cancer clinic. If the patients
are willing to interested, they will be further introduced in detail about the study
background, randomization and surgical procedures, and the patients can voluntarily
choose whether to participate in the trial. After patients sign the informed consent forms,
members of the study team will review their eligibility according to the inclusion and
exclusion criteria. Patients will then be randomized to receive either of the surgical
procedures. Finally, the patients will be followed up according to the follow-up schedule.
IV. Allocation, Blinding and Unblinding
4.1 Allocation of the interventions
4.1.1 Allocation sequence generation: In this study, a centralized block randomization
with a block size of 6 will be used to randomly assign patients to the laparoscopic surgery
group or the open surgery group at a 1:1 ratio. The randomization scheme will be
completed by an independent statistical team at the Clinical Trial Center of the Children's
Hospital of Fudan University by creating and sequencing random seed numbers (SAS 9.4
software). The intervention protocols determined by the random assignment sequence
will be in sequentially numbered, non-transparent, sealed envelopes by zone: each of the
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6 subgroups for each zone will be placed sequentially in six small, non-transparent,
sealed envelopes numbered from 1 to 6, and then uniformly placed in the same large
envelope marked with the corresponding zone number. The randomization assignment
will be administered by the central coordinator at the Obstetrics and Gynecology Hospital
of Fudan University who was not involved in the implementation of the intervention or
the outcome observation. The enrollment is competitive, and the sub-center coordinator
will contact the central coordinator before the inclusion of the first patient in each group.
The central coordinator will follow the randomization scheme and assign the large
envelopes with the group numbers to each center following the order of contact. Each
sub-center will open the envelopes according to the order of signing the informed consent
form, and strictly follow the numbered order of the envelopes, and then inform the
participating physicians of the assignment scheme and complete a written registration
form.
4.1.2 Allocation concealment mechanism
1) In this study, the surgical procedures will be selected in a randomized manner, and the
CTU members will place the intervention modality in an envelope and give it to the each
center’s coordinator who is not involved in the implementation of the intervention or the
observation of the outcome to manage the allocation. The envelope will be opened by the
investigators at each center following the enrollment order, to realize blinded
preoperative randomization.
2) Date will be entered and by dedicated staff, who will be blinded to the randomization
allocation and surgical procedure.
4.1.3 Assignment implementation (who generates the serial numbers, who recruits
the subjects, and who assigns them)
1) The surgeons will perform the recruitment and obtain informed consent, and perform
the surgical procedure.
2) The CTU team designs the randomization method and generates the corresponding
envelopes.
3) The allocation of surgeries according to the order of informed consent signed by the
study participants in each center according to the randomization method to achieve an
equal distribution of reporters in the open and lumpectomy groups.
4) The randomization staff will record the randomization numbers and procedure.
5) Follow-up of each patient and recording of relevant data and adverse events will be
performed by dedicated follow-up personnel.
6) Data entry into the RedCap database will be performed by dedicated data entry
personnel.
7) The CTU and the principal investigator will perform statistical analyses.
4.2 Blinding
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4.2.1 Who to blind and how to implement it
1) The specific procedure will not be known to the surgical team of each center until after
the patients have been randomized during the administration phase of the intervention.
2) The randomization process will not be known to data entry personnel after the
operation.
3) Statisticians will also be unaware of the randomization process.
4) The randomization process is also unknown to the personnel responsible for endpoint
evaluation.
4.2.2 Unblinding
1) The total randomization form will be kept exclusively by the dedicated staff at each
center, and a letter which contains information of the group assignment and the surgical
method will be set up for each group with the number.
2) The unblinding will be conducted to reveal information of each patient with
corresponding surgical procedure, only after final data analyses.
3) Since this study does not involve a comparison of drug use, there is no emergency
unblinding process in place.
V. Methods of data collection, management and analysis
5.1 Data collection and patient retention
5.1.1 Protocols for estimating and collecting outcome indicators, baseline and other trial
data
Based on the study protocol and data analysis plan, a case report form (CRF) has been
developed and validated. Required fields are set to ensure the completeness of key data.
The CRF will be completed by a trained investigator at each site, and each enrolled case
has to complete the CRF, which will be reviewed by the investigator and handed over to
data manager for data entry and management at each site.
5.1.2 Improve patient engagement and completion of follow-up, including outcome data
to be collected for patients who withdraw or change treatment methods
1) Detailed patient orientation by study team members at each center during the
recruitment phase to achieve fully informed patients.
2) The study team members will provide long-term remote condition assessment services
and related information consultation services for all study patients
3) Patients will be followed up regularly by dedicated staff to reduce the rate of loss to
follow-up.
4) The follow-up system will regularly remind the subjects of the follow-up time and the
follow-up items according to the follow-up nodes.
5.2 Data management (entry, coding, encryption and storage)
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5.2.1 Entry and coding protocols:
A database for data management and entry is designed based on the finalized CRF form.
This study uses RedCap, which was developed by a professional CRO data management
team, and the project data entry and management will be handled by dedicated personnel.
To ensure the accuracy of the data, double entry should be performed by two research
members independently, and blind verification and statistical analysis will be performed
after software verification and manual error correction. The database will be locked after
accuracy confirmation. The locked data files then will be submitted to an independent
third-party statistical team for analysis. The statistical analysis plan (SAP) is developed
by the statistical team during the study subject inclusion process, and finalized after
repeated discussions with the investigator team, and uploaded to the clinical trial registry
website before the last patient data collection is completed at the study registry website,
or submitted for publication with the protocol.
5.2.2 Data storage and access
All information on research patients is collected and stored in locked cabinets by
dedicated personnel, and access to it is only possible after obtaining approval.
5.3 Statistical methods
5.3.1 Outcome statistical methods
Statistical analysis of the study will be undertaken by the CTU of the Children’s Hospital
of Fudan University. Interventions began at the study design stage, based on key
scientific questions, clear design protocols, and statistical analysis methods based on the
properties of the primary outcome indicators, whereby sample sizes were calculated
based on expected effects. After study inclusion begins until the last patient data
collection is completed, a detailed SAP is written and uploaded to the Clinical Trials
Registry website. The following is an overview of the statistical analysis strategy and
methods.
All analyses will be performed on an intention-to-treat (ITT) basis, except for sensitivity
analysis that will be performed according to per-protocol (PP) treatment.
5.3.2Analysis of primary outcome data
a) This study is non-inferiority trial design, and the primary outcome is the rate of PFS at
5 years. The hypothesis is as follows:
Hypothesis: Let π1 denote the rate of PFS at 5 years in the open surgery group, and let π2
denote the rate of PFS at 5 years in the minimally invasive surgery group, the
non-inferiority margin =7%. The null hypothesis is H0: π1 – π2 ≥
versus the
alternative hypothesis is H1: π1 – π2 <.
b) The curves of PFS at 5 years will be estimated using the Kaplan-Meier method. The
logrank test will be used to test the above hypothesis, the 5-year PFS rate difference and
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its 95% confidence interval (CI) for the comparison between the two groups will be
estimated. The minimally invasive surgery will be considered non-inferior to the open
surgery if the one-sided 95% upper limit is less than , where = 7%, the predetermined
non-inferiority margin.
c) Covariate adjusted analysis:
An analysis of the primary outcome adjusting for the blood loss during operation,
operative duration, and postoperative pain score will be performed using Cox
proportional hazards regression model. The hazard ratio of 5-year PFS and 95% CI will
be estimated.
d) Subgroup analysis:
We will stratify by tumour staging, and perform Cox proportional hazards regression
model to estimate the hazard ratio and 95% CI of the 5-year PFS rate.
e) Sensitivity analysis:
A sensitivity analysis of the primary outcome will be performed using the PP strategy.
5.3.3 Secondary outcome analysis
a) The rate of OS at 5 years:
Cox proportional hazards model will be used to estimate the hazard ratio and 95% CI for
the effect of treatment on the 5-year OS rate.
b) Analysis of continuous outcomes:
The continuous outcomes include operative duration, anesthesia time, blood loss during
operation, postoperative pain score and postoperative hospital stay. The outcomes with
normal distribution will be summarised using mean and standard deviation (SD), while
the outcomes with non-normal distribution will be summarised using median and
interquartile. The differences in the outcomes and 95% CIs will be analysed by
generalised linear model (GLM) with treatment as fixed effect and with normal
distribution and identity link function.
c) Analysis of binary outcomes:
The intraoperative complications, postoperative complications, one-month and one-year
postoperative quality of life and sexual life will be treated as binary outcomes and will be
summarised by number (%) of participants with the event. The differences in the
outcomes and 95% CIs will be analysed by GLM with treatment as fixed effect and with
binomial distribution and identity link function.
d) Safety analysis
Adverse events (AEs) will be summarised using the number of AEs, the number (%) of
participants with AEs by groups.
5.3.4 Definition of non-compliant population, and analysis and management of
missing data
All data will be monitored by an independent data monitoring committee consisting of
surgical experts, epidemiologists, RCT experts, statisticians and surgeons.
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5.3.5 Statistical analyses
All statistical analyses will be performed with a two-sided significance level of 0.05 and
conducted using SAS software, version 9.4 (SAS Institute).
VI. Quality of life questionnaire
6.1 Patient-reported clinical outcome assessment scale PRO 147 (V1.0) for Cervical
Cancer
The research team developed its own scale assessment related to patient reported
outcomes in cervical cancer, which is based on the patient's perspective to assess the
outcome after surgery. Cervical cancer is the fourth most common cancer in women, and
its incidence has been on the rise in recent years, especially in younger patients. Since the
uterus is located in the central pelvis, damage to pelvic floor tissues by surgery may cause
a variety of complications such as urinary, intestinal, vaginal and lower limb dysfunction,
which cannot be accurately assessed by conventional scales. Considering the high
survival rate of patients with early-stage cervical cancer, it is especially important to
study the short-term and long-term treatment effects for patients.
According to the U.S. Food and Drug Administration (FDA), patient reported
outcome (PRO), a measure of any aspect of a patient's health status that comes directly
from the patient, is a valid patient-centered, multifaceted means of evaluating treatment
outcomes (such as symptom improvement or related function) that is widely used in
clinical practice and trials.
The research team has developed the Patient-reported Clinical Outcome Assessment
Scale PRO 147 (V 1.0) for cervical cancer based on this concept. This scale is based on
three domains including daily life, psychological and social life, with 147 questions
covering 13 latitudes: urinary dysfunction (URI), bowel dysfunction (BOW), pelvic
organ prolapse (POP), loss of ovarian function (OVA), lymphatic dysfunction (LYM),
neurological dysfunction (NEU), sexual dysfunction (SEX), anxiety (ANX) depression
(DEP), stigma (SHA), life beliefs (BEL), social support (SUP), and daily life (LIF) to
assess patient prognosis. At present, our scale has been screened, and completed the
expert review, and now is in the pilot study phase. So far, there are about 100 patients
have completed the survey, and the information is very useful for future complication
management and surgical efficacy assessment.
6.2 Generic quality of life questionnaire
Other selected quality of life questionnaires relate to postoperative symptoms (e.g.,
pain) as well as disease-specific and general health-related quality of life. These surveys
are self-administrated and provide an understanding of the patient's quality of life, and
will take less than 30 minutes to complete.
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The current scale used for study follow-up is mainly the EORTC Quality of Life
Measurement Scale QLQC30 (V3.0) scale, which is intended for most oncology patients
and is a universal scale. From a systematic review including 156 studies, Casper Tax et al.
found that the European Organization for Research and Treatment of Cancer, Quality of
Life Questionnaire, Cervical Cancer Module (EORTC QLQ-CX24) and the Functional
Assessment of Cancer Therapy for Cervical Cancer (FACT-Cx) are the only cervical
cancer-specific instruments to date. EORTC-QLQ-CX24 appears to be the most
commonly used instrument to assess Health Related Quality of Life (HRQoL) in patients
with cervical cancer, and the developers of the EORTC QLQ-CX24 proposed in their
study that no test-retest analysis was performed and response over time. Both scales are
simple and universal, but can only distinguish between patients with early versus
advanced disease and those who receiving versus not receiving treatment. However,
whether the efficacy of different treatments (e.g., surgery versus chemotherapy) or
different surgical approaches (e.g., laparoscopic radical hysterectomy versus abdominal
radical hysterectomy) can be distinguished has not been reported. It indicates that
EORTC-QLQ-CX24 has some limitations in the evaluation of efficacy.
VII. Methods of Data Monitoring
7.1 Study monitoring
7.1.1 Trial Safety Committee
An independent Trial Safety Committee (TSC) will be established to review the safety
and efficacy data collected during the study. The TSC will be composed of individuals
who are independent of the study and not directly or indirectly involved in the
administration of the study. Members will include the following individuals.
Two gynecologic oncologists not involved in with the trial.
Two statisticians not involved in the trial.
Members of the Gynecologic Oncology Committee (Shanghai Medical Association
Obstetrics and Gynecology Section, Shanghai Physicians Association Obstetrics and
Gynecology Section)
7.1.2 Trial Management Committee
A Trial Management Committee (TMC) will be established for this study to review and
oversee data and analysis. The TMC will be composed of the main center study leader,
the sub-center leaders, and the study statistician, and will not have a conflict of interest
with the funding provider. The management committee will meet every four months, and
after each meeting, the committee will recommend that the study continue according to
the protocol or recommend modifications to the protocol based on the results of the data
review.
7.1.3 Data Monitoring Committee
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A multicenter noninferior randomized controlled study comparing the efficacy of laparoscopic versus abdominal
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A Data Monitoring Committee (DMC) will be established to independently review and
oversee data and analysis. The DMC not have a conflict of interest with the funding
agency.
7.2 Interim Analysis
The ethics committee has the right to terminate the study when the number of deaths
reaches a critical level or when the difference in progression-free survival or overall
survival between the two groups is significant; the ethics committee has the right to
terminate the study when there is a violation of ethics during the progress. To ensure the
compliance of the patients, participants in this study will be given priority for treatment at
our hospital, and there will be dedicated staff for post follow-up and data collection.
7.3 Quality Control
The study process will be closely followed by the project sponsor, the sub PIs of each
study center, the CRO manager, and the surgical team. Data quality is monitored by the
independent DMC, CRO project manager, and the surgical team.
Clinical
observation
and
follow-up:
surgical
treatment
plan,
surgery-related
indicators, intraoperative and postoperative complications, postoperative pathology
records, postoperative adjuvant treatment including radiotherapy and chemotherapy dose
and time, number of courses and adverse reactions; follow-up will be conducted every
three months for 2 years after surgery; then every 6 months from year 3 to year 5 after
surgery.
Measures to ensure patients' compliance: patients participating in this study will be
given priority in our hospital for treatment, and post-operative follow-up will also be
assigned.
VIII. Definition and treatment of adverse events
8.1 Definition of adverse events
The Adverse Event (AE) is an adverse medical event that occurs after a patient or a
subject in a clinical trial receives a drug, but is not necessarily causally related to the
treatment.
Any adverse medical event that occurs in this trial from the time the patient signs the
informed consent and receives the treatment until 1 month after the end of the treatment,
regardless of whether it is causally related to the surgery performed, is judged as an
adverse event, including symptoms, signs, diagnosis, and abnormal laboratory tests.
8.2 Observation, recording and treatment of adverse events
Observation and recording: the investigator should carefully observe any adverse events
occurring in the patient during the study, and require the patient to truthfully reflect the
changes in condition after treatment and avoid eliciting questions. Pay attention to
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A multicenter noninferior randomized controlled study comparing the efficacy of laparoscopic versus abdominal
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adverse reactions or unanticipated toxicities (including symptoms, signs and laboratory
tests) while observing side effects. Regardless of whether the adverse event is related to
the surgery performed, it should be recorded in detail in the CRF, including the time of
occurrence of the adverse reaction, symptoms, signs, extent, duration, laboratory test
indicators, treatment methods, process, results, follow-up time, etc. The combined use of
drugs should be recorded in detail for analysis of adverse event and test drug correlation,
and the record should be signed and dated.
Medical treatment of patients: When adverse reactions are reported, the investigator
should take necessary treatment measures according to the condition, such as dose
adjustment, temporary interruption of medication, etc., and decide whether to terminate
the trial. The occurrence of serious adverse events, the unit undertaking the pilot study
must immediately take the necessary measures to ensure the protection of the safety of
the subject.
The first safety analysis will be conducted after 20 patients have completed
treatment. TSC will review all safety data collected during the study twice a year.
IX. Cost-benefit Analysis
We will also assess the subjects' household income and sources of surgical treatment
costs, record their health insurance reimbursement rates, and evaluate the impact of
different health insurance rates on patients' household burden.
X. Review
The main center at the Obstetrics and Gynecology Hospital of Fudan University will
closely monitor the study. The monitor will maintain an effective understanding of the
study through observation, review of study records and source documents, and
discussions with investigators and staffs about the conduct of the study. The main center
or its designee will carefully monitor all aspects of the study to ensure that the study
complies with applicable government regulations regarding current good clinical practice
and current standard operating procedures.
Investigators and institutions involved in the study will allow trial-related
monitoring, review, Institutional Review Board (IRB) or Human Research Ethics
Committee (HREC) reviews and regulatory inspections through direct access to raw
data/documents.
XI. Ethics and Dissemination
11.1Ethical approval
A total of 780 patients will be recruited in six centers: Obstetrics and Gynecology
Hospital of Fudan University, Zhongshan Hospital affiliated to Fudan University, Xinhua
Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Renji Hospital
affiliated to Shanghai Jiao Tong University School of Medicine, Taizhou Hospital
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Affiliated Cancer Hospital of the University of Chinese Academy of Sciences, and the
First Affiliated Hospital of Wenzhou Medical University. All patients will be fully
informed of the purpose, methods, benefits and potential risks of this clinical trial and
sign the informed consent form.
The study protocol has been sent to each sub-center and has been reviewed and
approved by the ethics committees of respective hospitals.
11.2 Study protocol modification plan
The main objective of this study is to observe PFS and OS after cervical cancer
surgery. The patient sample size is large and the enrollment time is long, so it needs to
take more than 3 years to complete the enrollment. Major surgery, postoperative
treatment and initial follow-up could be completed during this period. It is expected that
initial outcomes can begin to be produced after 3 years. However, tumor follow-up will
require at least 5 years to obtain complete and comprehensive data, especially for PFS
and OS. Previous similar studies have taken about 10 years to reach a final and
convincing conclusion. After the initial 3 years of funding for this study, there is still
numerous and long-term workloads that need to be completed. As a result, it is expected
that regular follow-up and analysis will be needed for several years after the current grant
ends. Therefore, we hope that the time frame for the use of funds and the time frame for
the publication of results can be extended to facilitate the long-term implementation of
the project and the final interpretation of the research results. If the project does not
complete the study objectives or the task acceptance conclusion is false, the project lead
organizations should return the outstanding funds.
11.3 Informed consent
All patients have been fully informed of the purpose, methods, benefits and potential
risks of this clinical trial and should sign the informed consent form (see Appendices for
details).
Written informed consent should be obtained from each patient before enrollment. A
template of informed consent will be provided by the main center. Prior to recruitment
and enrollment, each prospective patient will be given details of the study and enough
time to understand the approved informed consent form. The investigator will inform the
patient of the study purpose, the randomization procedure and the follow-up schedule.
The investigator will discuss the potential benefits and risks . The investigator will inform
the patient that her medical records will be reviewed by the Shenkang Hospital
Administration Center and Hospital Department.
Patients will be informed by the investigator that they are free to decline
participation, and if they choose to participate, they may withdraw at any time without
affecting further medical care.
This study has complied with the Regulations of the People's Republic of China on
Human Genetic Resources Management in the collection, storage and utilization of
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biological specimens and genetic resources (see Appendices for details).
XII. Confidentiality
All medical record, relevant laboratory data, completed CRF forms, and protocol-related
documents will be kept in a special locked cabinet for each study participant, and access
to them will be granted only after providing relevant permissions.
XIII. Declaration of Competing Interests
The protocol designer and all study participants have no relevant ties or interests with the
manufacturers of the corresponding drugs, devices, etc. and fund providers.
XIV. Data Collection
Relevant experimental data and basic information about the study subjects will be
collected and filled out by the surgical team, and follow-up information will be collected
by the follow-up staff and enter into the RedCap system by designated research staff,
which were accessible to the project team members but did not know the corresponding
information.
Each investigator and organizations in this study need to sign the "Project Data
Submission Undertaking" (see Appendices for details), and commit to the standardized
operation of data collection, submission and disclosure.
XV. Affiliation and Post-test Care
The surgical procedures performed in this protocol are those that have been in use for
more than 10 years and meet international NCCN guideline standards, with no
operational abnormalities and no corresponding terms attached.
XVI. Dissemination Policy
The intellectual property rights of this study, include patents, copyrights, trademarks,
copyrights of computer software, technical secrets, and trade secrets that abiding the law.
New intellectual property rights generated in the course of this study belong to the main
center, which is responsible for declaring and enjoying priority, and the sub-centers are
ranked according to their contribution. Intellectual property rights resulting from the
independent completion of the research work
may be owned by each center
independently. No party shall disclose to other parties without the consent of the
collaborating party.
The main center has the right to use all the information and data, and the sub-centers
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have the right to use the information and data of their center. The main center is
responsible for statistical processing and analysis, writing summary reports and papers.
The authorship will be determined by the main center, based on the contribution ( number
of valid cases enrolled), and the results will be shared. For collective data and collective
results, the main center will be the first author and corresponding author, and sub-centers
will be assigned co-first author or co-corresponding author or co-authors based on their
contributions. The publication of each center's respective data will be signed by each
center. Results published separately by sub-centers are required to include the main
center as a co-corresponding author. The sub-center cannot publish the results related to
this study in any form until the main center has published the main results of this study.
All personnel of each center cannot duplicate or cross-report this project. The
"Three-Year Action Plan Major Clinical Research Project" and the project approval
number are indicated.
XVII. Appendices
1. Informed Consent Form
2. Commitment to the Regulations of the People's Republic of China on Human Genetic
Resources Management
3. Commitment to Submit Project Data
4. Statement of not involving the use of highly pathogenic microorganisms
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