Clinical trial NCT03778268: Sentinel Lymph Node Mapping In Cervical Cancer
Official title: Comparing the Diagnostic Value of Different Lymph Node Tracing Methods in Detecting Sentinel Lymph Node Metastasis in Early Cervical Cancer
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Uterine Cervical Neoplasms
Keywords: Sentinel Lymph Node Biopsy
Lead sponsor: Peking University People's Hospital
Sponsor class: OTHER
Collaborators: name: Chinese Academy of Medical Sciences
name: Peking University International Hospital
name: Shanghai First Maternity and Infant Hospital
name: Obstetrics & Gynecology Hospital of Fudan University
name: Sun Yat-sen University
name: Tianjin Central Hospital of Gynecology Obstetrics
name: Cancer Hospital of Guangxi Medical University
name: First People's Hospital of Foshan
name: The First Affiliated Hospital of Zhengzhou University
name: Second Affiliated Hospital of Zhengzhou University
name: Beijing Blue Sky Shared Health Management Co., Ltd.
name: Chongqing Lummy Pharmaceutical Co.,Ltd.
First posted: 2018-12-19
Enrollment: 1143
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: The procedure is listed as follows:

1. Recruiting early stage cervical cancer patients undergoing extra-fascial/sub-extensive/extensive hysterectomy, pelvic with or without aortic lymph node resection from July 2018 to June 2020.
2. Selecting the Standard-compliant patients according to the inclusion and exclusion criteria.
3. Numbering the above patients and collecting their clinical data.
4. Injecting carbon nanoparticles (CNP)\[Not Equipped with near-infrared fluorescent vascular imager\] or CNP combining Indocyanine Green(ICG)\[Equipped with near-infrared fluorescent vascular imager\].
5. Identifying and removing sentinel lymph nodes.
6. Completing the total hysterectomy, biadnexectomy and pelvic with or without para-aortic lymphadenectomy.
7. Staining all nodes using hematoxylin-eosin staining.
8. Calculating the sensitivity, negative predictive value, etc.
Primary purpose: DIAGNOSTIC

Brief summary: Lymph node assessment provides the crucial information about the prognosis of cervical cancer. Sentinel lymph node stands in the first station on the lymph node metastasis pathways. While traditional systemically lymph node resection would bring a lot of complications, sentinel node mapping and biopsy is a feasible way with less damage to evaluate whether lymph node metastasis occurs in early cervical cancer patients, due to less lymph nodes resected. However, the process of this technology isn't well established. The investigators intend to conduct a prospective and multicentric study to evaluate the effectiveness of different mapping methods to achieve a reliable lymph node assessment. Early cervical cancer patients in each center will be recruited in the investigators' study with inclusion and exclusion criteria. After the patients signing the informed consent form, the surgery process will be performed, including sentinel lymph node mapping with Carbon Nanoparticles (CNP) or CNP combining Indocyanine Green(ICG), extra-fascial/sub-extensive/extensive hysterectomy, pelvic with or without para-aortic lymph node resection, sequentially. All resected nodes will be pathologically exanimated. Then the data obtained will be analyzed and discussed deeply and finally lead to a conclusion.

Detailed description: Quality Control The investigators' quality assurance plan is as follows： A. Once the plan has been approved, it cannot be modified at will. If special circumstances such as difficulty in implementation are found after the start of the study, the proposal may be revised or supplemented by the discussion of the research group and the project leader, and the revised content shall be recorded in writing.

The program change process is as follows:

* Identify the problems and understand the necessary to change the plan;
* Convene the main members of the research team and the project leader to discuss and propose solutions;
* Revise the plan and update the version number, fill out the "Program Description";
* The revised plan and the "Revision of the Plan" need to be signed by the person in charge of the project. If necessary, they must be submitted to the ethics committee for approval or filing; if approved, the revised plan can be implemented.

B. In order to ensure that the research personnel have sufficient qualifications to undertake specific research work, the research personnel should at least complete the following training before the project starts:

* Research object protection and ethical requirements;
* Study protocols and related standard operating procedures (tracer injection methods, use of near-infrared fluorescent vascular imagers, and pathology);
* Case Report Form and gauge filling instructions (form entry criteria, surgical record methods, etc.);
* Clinical research project implementation considerations (such as research object screening, enrollment, data collection process); Project-related training should be carried out throughout the research process. The project leader and project coordinator can increase the training content according to the situation, such as training on weak links in the test, training on updating programs and various causes.

Data Management A. Case report form design The researcher is responsible for drafting the research case report form. B. Data Entry and Data Verification According to the final version of CRF, the project database is built using software. The data entry and verification is carried out by a dedicated person.

Statistical Analysis A. Statistical Analysis Plan and Statistical Software After the trial protocol is determined, the statistical professors and the main investigators are responsible for developing a statistical analysis plan. The statistical analysis software uses SAS® 9.2 software (software installation point authorization number: 11202165).

B. Calculation and reasoning of sample size The sample size is calculated using PASS11 software; the sample size is estimated based on the negative prediction value of the previous study, and the negative prediction value of SLNs is expected to be 90%; the allowable error is 2% (the range of the confidence interval is 88% to 92%). When the significant level is 0.05, 914 cases are needed to be studied. Considering the detection rate of 80% of SLNs, a total of 1143 cases are expected to be studied.

C. Statistical Analysis Methods General principle Using a two-sided test, a P value of less than 0.05 would be considered statistically significant.

The quantitative indicators will calculate the mean, standard deviation, median, minimum, maximum, lower quartile (Q1), upper quartile (Q3), and the classification indicators will describe the number of cases and percentages.

Comparison of clinicopathological features (age, body mass index, pathological type, tumor stage, grading, maximum tumor diameter, invasive myometrial depth, lymphatic vascular infiltration, and tracer method) for SLNs and undetected SLNs will be based on the type of indicator. For the comparison of quantitative data between groups, the t-test or Wilcoxon rank sum test will be used according to the data distribution. For the comparison of categorical data between groups, the data will be analyzed by chi-square test or exact probability method (if the chi-square test is not applicable). And the grade data was analyzed by Wilcoxon rank sum test or CMH test.

Clinical diagnostic index calculation According to the true positive (TP), false negative (FN), true negative (TN), and false positive (FP), the results of SLNs pathological examination and all lymph node pathological examination results will be compared. The comparison results will be plotted as a four-grid table to calculate sensitivity, false negative rate, and negative predictive value, respectively.

Chi-square test or exact probability method (if the chi-square test is not applicable) will be used to compare the clinical diagnosis value of SLNs biopsy of endometrial cancer patients with injection of carbon nanoparticles (CNP) or combined injection of CNP and indocyanine green(ICG).

Chi-square test or exact probability method (if the chi-square test is not applicable) will be used to analyze the clinic-pathological factors affecting the detection rate of SLNs.

Eligibility criteria: Inclusion Criteria:

* Diagnosis of early cervical cancer (FIGO IA1 with LVSI (+) to IIA).
* Decide to receive extra-fascial/sub-extensive/extensive hysterectomy, pelvic with or without aortic lymph node resection
* Agree to conduct the study and sign an informed consent form

Exclusion Criteria:

* Diagnosis of cervical cancer in FIGO IIB stage and above
* History of previous pelvic or inguinal lymphadenectomy or other history of surgery affecting the uterine lymphatic drainage
* Other history of pelvic or abdominal malignant tumors in the past 5 years
* Intolerable for surgery due to severe comorbidities
* During a period of pregnancy
* Allergic to the tracer
* Diagnosis of uncontrolled epilepsy, central nervous system disease or mental disorder, with the judgment from the investigator that the above diseases would affect clinical research compliance.

Primary outcomes:
measure: Negative Predictive Value
timeFrame: Through study completion, an average of 2 years
Secondary outcomes:
measure: SLNs detection rate
timeFrame: Through study completion, an average of 2 years
measure: Sensitivity
timeFrame: Through study completion, an average of 2 years
measure: False negative rate
timeFrame: Through study completion, an average of 2 years
Other outcomes:
Locations:
city: Beijing
country: China
facility: Peking University People's Hospital
state: Beijing
city: Beijing
country: China
facility: Peking University People's Hospital
state: Beijing
Study officials:
affiliation: Peking University People's Hospital
name: Jianliu Wang, Professor
role: STUDY_DIRECTOR
References:
citation: Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015 Mar 1;136(5):E359-86. doi: 10.1002/ijc.29210. Epub 2014 Oct 9.
citation: Creasman WT, Morrow CP, Bundy BN, Homesley HD, Graham JE, Heller PB. Surgical pathologic spread patterns of endometrial cancer. A Gynecologic Oncology Group Study. Cancer. 1987 Oct 15;60(8 Suppl):2035-41. doi: 10.1002/1097-0142(19901015)60:8+3.0.co;2-8.
citation: NCCN Guidelines Version 1. 2018. Cervical Cancer [EB/OL]. [2018-02-10]. http://www.nccn.org/professionals/physician_gls/pdf/cervical.pdf.
citation: Lu Y, Wei JY, Yao DS, Pan ZM, Yao Y. Application of carbon nanoparticles in laparoscopic sentinel lymph node detection in patients with early-stage cervical cancer. PLoS One. 2017 Sep 5;12(9):e0183834. doi: 10.1371/journal.pone.0183834. eCollection 2017.
citation: Holloway RW, Abu-Rustum NR, Backes FJ, Boggess JF, Gotlieb WH, Jeffrey Lowery W, Rossi EC, Tanner EJ, Wolsky RJ. Sentinel lymph node mapping and staging in endometrial cancer: A Society of Gynecologic Oncology literature review with consensus recommendations. Gynecol Oncol. 2017 Aug;146(2):405-415. doi: 10.1016/j.ygyno.2017.05.027. Epub 2017 May 28.
citation: Liang SC, Wang ZQ, Wang JL. [Clinical analysis of 76 cases of sentinel lymph node detection in cervical cancer and endometrial cancer]. Zhonghua Fu Chan Ke Za Zhi. 2017 Sep 25;52(9):605-611. doi: 10.3760/cma.j.issn.0529-567X.2017.09.006. Chinese.