Impact of Sentinel Lymph Node Mapping on Patient Reported Lower Extremity Limb Dysfunction in Stage I Endometrial Cancer

Phase 3

Recruiting

• Conditions: Stage I Uterine Corpus Cancer AJCC v8
• Interventions: Procedure: Biospecimen Collection; Procedure: Diagnostic Imaging; Procedure: Excisional Biopsy; Drug: Indocyanine Green Solution; Procedure: Minimally Invasive Surgery; Procedure: Pelvic Lymphadenectomy; Other: Questionnaire Administration; Procedure: Sentinel Lymph Node Mapping

• Registration Number: NCT05646316
• Lead Sponsor: NRG Oncology

Brief Summary

This phase III trial compares the effect of sentinel lymph node mapping to standard lymph node dissection in reducing the risk of swelling in the legs (lymphedema) in patients undergoing a hysterectomy for stage I endometrial cancer. Standard lymph node dissection removes lymph nodes around the uterus during a hysterectomy to look for spread of cancer from the uterus to nearby lymph nodes. Sentinel lymph node mapping uses a special dye and camera to look for cancer that may have spread to nearby lymph nodes. Comparing the results of the procedures may help doctors predict the risk of long-term swelling in the legs.

Detailed Description

PRIMARY OBJECTIVES:

I. To compare the rates of lower extremity limb dysfunction (defined as a \>= 4-point increase in Gynecologic Cancer Lymphedema Questionnaire \[GCLQ\] symptom score from baseline) in patients with apparent uterine confined endometrial cancer randomized to one of two lymphatic assessment strategies at time of hysterectomy:

Ia. Sentinel lymph node mapping and excision followed by side-specific lymphadenectomy on sides without a sentinel lymph node (SLN) identified according to a National Comprehensive Cancer Network (NCCN) guidelines approved algorithm (Arm 1); Ib. Sentinel lymph node mapping and excision according to an NCCN Guidelines approved algorithm followed by bilateral pelvic +/- para-aortic lymphadenectomy (Arm 2).

SECONDARY OBJECTIVE:

I. To compare changes in lower extremity limb circumference in patients with apparent uterine confined endometrial cancer randomized to one of two lymphatic assessment strategies at time of hysterectomy.

II. To validate the test characteristics of a SLN mapping algorithm including SLN detection rates, rate of perioperative complications, rate of identifying lymphatic metastases, and detection of micrometastases using pathologic ultra-staging.

EXPLORATORY OBJECTIVES:

I. To compare adjuvant therapy decisions in patients with apparent uterine confined endometrial cancer randomized to one of two lymphatic assessment strategies at time of hysterectomy.

II. To explore the impact of patient characteristics (age, body mass index \[BMI\], race), extent of lymph node dissection, and adjuvant therapy decisions (radiation, chemotherapy) on the development of lower extremity limb dysfunction - as well as their interaction with lymph node assessment strategies.

III. To evaluate the cost-effectiveness of SLN mapping with or without completion of lymphadenectomy for endometrial cancer.

SAFETY OBJECTIVE:

I. To compare progression free and overall survival in patients with apparent uterine confined endometrial cancer randomized to one of two lymphatic assessment strategies at time of hysterectomy.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM 1: Patients receive ICG dye via injection and undergo sentinel lymph node mapping and excision during standard minimally invasive hysterectomy. Lymph nodes around the uterus may be removed if the mapping and excision cannot be completed. Successful mapping requires no additional removal of lymph nodes.

ARM 2: Patients receive ICG dye via injection and undergo sentinel lymph node mapping and excision during standard minimally invasive hysterectomy. Additional lymph nodes around the uterus are removed per standard of care.

Patients in both arms also undergo imaging as clinically indicated and optional blood sample collection throughout the study.

After completion of study intervention, patients are followed every 3 months for one year and at 18 and 24 months.

Study Timeline

• Study First Submitted: 2022-12-02
• Study First Submitted QC: 2022-12-02
• Study Start: 2022-12-07
• Study First Posted: 2022-12-12
• Status Verified: 2024-07
• Last Update Submitted: 2024-07-11
• Last Update Posted: 2024-07-15
• Primary Completion: 2025-10-31
• Study Completion: 2026-10-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: Female
• Target Recruitment: 428

Inclusion Criteria

• Histologically proven diagnosis of endometrial cancer based on endometrial sampling with a plan to undergo laparoscopic or robotic hysterectomy and lymphatic assessment as part of primary management. Biopsy must be performed within 90 days prior to registration

• Clinical stage I endometrial cancer based on the following diagnostic workup:

  • History/physical examination within 30 days prior to registration is reassuring for the absence of metastatic disease

• Age >= 18 years

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1 or 2

• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial

• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information

• Patients must speak English or Spanish

Exclusion Criteria

• Patients whom the surgeon believes is not a candidate for pelvic lymphadenectomy due to medical comorbidities or other technical challenges (i.e. morbid obesity or prior surgery)

• History of chemotherapy or immunotherapy for the treatment of endometrial cancer. Progestin-containing therapies such as megestrol, medroxyprogesterone, or levonorgestrel-containing intrauterine device (IUD) are acceptable

• History of radiation to the pelvis, groin or lower extremities, or surgery to the pelvic lymph nodes or inguinal lymph nodes

• Patients who are going to undergo another elective surgery during the same operative event as their hysterectomy (i.e., sacrocolpopexy, cholecystectomy)

• Patients with severe, active co-morbidity defined as follows:

  • History of patient or provider identified lower extremity lymphedema
  • History of patient or provider identified chronic lower extremity swelling
  • History of lower extremity or pelvic deep venous thromboembolism within 90 days of registration
  • History of lower extremity cellulitis within 90 days of registration
  • For the bioimpedance sub study only: patients with implantable metal devices (i.e. defibrillator, metal joint replacements, etc.) will not be eligible to participate in the bioimpedance sub study but will be eligible to participate in the overall study

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm 1 (sentinel lymph node mapping)	Minimally Invasive Surgery	Patients receive ICG dye via injection and undergo sentinel lymph node mapping and excision during standard minimally invasive hysterectomy. Lymph nodes around the uterus may be removed if the mapping and excision cannot be completed. Successful mapping requires no additional removal of lymph nodes. Patients also undergo imaging as clinically indicated and optional blood sample collection throughout the study.
Arm 2 (sentinel lymph node mapping, pelvic lymphadenectomy)	Biospecimen Collection	Patients receive ICG dye via injection and undergo sentinel lymph node mapping and excision during standard minimally invasive hysterectomy. Additional lymph nodes around the uterus are removed per standard of care. Patients also undergo imaging as clinically indicated and optional blood sample collection throughout the study.
Arm 2 (sentinel lymph node mapping, pelvic lymphadenectomy)	Minimally Invasive Surgery	Patients receive ICG dye via injection and undergo sentinel lymph node mapping and excision during standard minimally invasive hysterectomy. Additional lymph nodes around the uterus are removed per standard of care. Patients also undergo imaging as clinically indicated and optional blood sample collection throughout the study.
Arm 2 (sentinel lymph node mapping, pelvic lymphadenectomy)	Questionnaire Administration	Patients receive ICG dye via injection and undergo sentinel lymph node mapping and excision during standard minimally invasive hysterectomy. Additional lymph nodes around the uterus are removed per standard of care. Patients also undergo imaging as clinically indicated and optional blood sample collection throughout the study.
Arm 1 (sentinel lymph node mapping)	Biospecimen Collection	Patients receive ICG dye via injection and undergo sentinel lymph node mapping and excision during standard minimally invasive hysterectomy. Lymph nodes around the uterus may be removed if the mapping and excision cannot be completed. Successful mapping requires no additional removal of lymph nodes. Patients also undergo imaging as clinically indicated and optional blood sample collection throughout the study.
Arm 1 (sentinel lymph node mapping)	Questionnaire Administration	Patients receive ICG dye via injection and undergo sentinel lymph node mapping and excision during standard minimally invasive hysterectomy. Lymph nodes around the uterus may be removed if the mapping and excision cannot be completed. Successful mapping requires no additional removal of lymph nodes. Patients also undergo imaging as clinically indicated and optional blood sample collection throughout the study.
Arm 1 (sentinel lymph node mapping)	Sentinel Lymph Node Mapping	Patients receive ICG dye via injection and undergo sentinel lymph node mapping and excision during standard minimally invasive hysterectomy. Lymph nodes around the uterus may be removed if the mapping and excision cannot be completed. Successful mapping requires no additional removal of lymph nodes. Patients also undergo imaging as clinically indicated and optional blood sample collection throughout the study.
Arm 1 (sentinel lymph node mapping)	Diagnostic Imaging	Patients receive ICG dye via injection and undergo sentinel lymph node mapping and excision during standard minimally invasive hysterectomy. Lymph nodes around the uterus may be removed if the mapping and excision cannot be completed. Successful mapping requires no additional removal of lymph nodes. Patients also undergo imaging as clinically indicated and optional blood sample collection throughout the study.
Arm 1 (sentinel lymph node mapping)	Excisional Biopsy	Patients receive ICG dye via injection and undergo sentinel lymph node mapping and excision during standard minimally invasive hysterectomy. Lymph nodes around the uterus may be removed if the mapping and excision cannot be completed. Successful mapping requires no additional removal of lymph nodes. Patients also undergo imaging as clinically indicated and optional blood sample collection throughout the study.
Arm 1 (sentinel lymph node mapping)	Indocyanine Green Solution	Patients receive ICG dye via injection and undergo sentinel lymph node mapping and excision during standard minimally invasive hysterectomy. Lymph nodes around the uterus may be removed if the mapping and excision cannot be completed. Successful mapping requires no additional removal of lymph nodes. Patients also undergo imaging as clinically indicated and optional blood sample collection throughout the study.
Arm 1 (sentinel lymph node mapping)	Pelvic Lymphadenectomy	Patients receive ICG dye via injection and undergo sentinel lymph node mapping and excision during standard minimally invasive hysterectomy. Lymph nodes around the uterus may be removed if the mapping and excision cannot be completed. Successful mapping requires no additional removal of lymph nodes. Patients also undergo imaging as clinically indicated and optional blood sample collection throughout the study.
Arm 2 (sentinel lymph node mapping, pelvic lymphadenectomy)	Diagnostic Imaging	Patients receive ICG dye via injection and undergo sentinel lymph node mapping and excision during standard minimally invasive hysterectomy. Additional lymph nodes around the uterus are removed per standard of care. Patients also undergo imaging as clinically indicated and optional blood sample collection throughout the study.
Arm 2 (sentinel lymph node mapping, pelvic lymphadenectomy)	Excisional Biopsy	Patients receive ICG dye via injection and undergo sentinel lymph node mapping and excision during standard minimally invasive hysterectomy. Additional lymph nodes around the uterus are removed per standard of care. Patients also undergo imaging as clinically indicated and optional blood sample collection throughout the study.
Arm 2 (sentinel lymph node mapping, pelvic lymphadenectomy)	Pelvic Lymphadenectomy	Patients receive ICG dye via injection and undergo sentinel lymph node mapping and excision during standard minimally invasive hysterectomy. Additional lymph nodes around the uterus are removed per standard of care. Patients also undergo imaging as clinically indicated and optional blood sample collection throughout the study.
Arm 2 (sentinel lymph node mapping, pelvic lymphadenectomy)	Sentinel Lymph Node Mapping	Patients receive ICG dye via injection and undergo sentinel lymph node mapping and excision during standard minimally invasive hysterectomy. Additional lymph nodes around the uterus are removed per standard of care. Patients also undergo imaging as clinically indicated and optional blood sample collection throughout the study.
Arm 2 (sentinel lymph node mapping, pelvic lymphadenectomy)	Indocyanine Green Solution	Patients receive ICG dye via injection and undergo sentinel lymph node mapping and excision during standard minimally invasive hysterectomy. Additional lymph nodes around the uterus are removed per standard of care. Patients also undergo imaging as clinically indicated and optional blood sample collection throughout the study.

Primary Outcome Measures

Name	Time	Method
Incidence of patient-reported lower extremity limb dysfunction	From 18 months post-hysterectomy after undergoing lymphatic assessment to 39 months	The primary endpoint is the incidence of patient-reported lower extremity limb dysfunction at 18 months post-hysterectomy after undergoing lymphatic assessment according to a National Comprehensive Cancer Network (NCCN) guideline-based sentinel lymph node (SLN) mapping algorithm with or without completion of lymphadenectomy. The primary endpoint will be assessed using the Gynecologic Cancer Lymphedema Questionnaire (GCLQ) questionnaire. Surveys will be performed at enrollment (pre-surgery) and at 3, 6, 9, 12, and 18 months post-surgery. Patient-reported lower extremity limb dysfunction will be defined as an increase in GCLQ symptom score of at least four (4) points from baseline at any time during the 18 months follow-up. The primary null hypothesis will be evaluated with an intent-to-treat chi-squared test, adjusted for stratification factors. Proportional hazards modeling will be used to generate a hazard ratio and 95% confidence limits of Arm 1 versus Arm 2.

Secondary Outcome Measures

Name	Time	Method
Rate of successful bilateral SLN identification	At time of surgery	Will be assessed in both, and only as the time of surgery.
Rate of successful identification of lymph node metastasis	At time of surgery	Will be assessed in both, and only as the time of surgery. The rate of lymph node metastasis identification during surgery will be compared between groups, with either t-tests or chi-squared tests where appropriate.
The incidence of lymphedema by quantifiable lower extremity limb changes	From enrollment and at 3, 6, 9, 12, and 18 months after surgery	Patients will undergo circumferential lower extremity limb measures at three locations along each leg. Change will be estimated as measurement at baseline subtracted from measurement at follow-up. This will be assessed in both legs separately.
The incidence of lymphedema by bioimpedance assessments (if available)	From enrollment and at 3, 6, 9, 12, and 18 months after surgery.	Patients will undergo circumferential lower extremity limb measures at three locations along each leg. Change will be estimated as measurement at baseline subtracted from measurement at follow-up. This will be assessed in both legs separately. The SOZO device by ImpediMed provides an L-Dex score for each leg at each assessment point as each limb is at risk for lower extremity lymphedema.
Rate of perioperative complications	At time of surgery	Will be assessed in both arms separately, and only as the time of surgery. The rate of perioperative complications during surgery will be compared between groups, with either t-tests or chi-squared tests where appropriate.

Trial Locations

Locations (41)

Fairview Southdale Hospital; 🇺🇸 Edina, Minnesota, United States

Northwestern Medicine Cancer Center Warrenville; 🇺🇸 Warrenville, Illinois, United States

Parkland Memorial Hospital; 🇺🇸 Dallas, Texas, United States

Regions Hospital; 🇺🇸 Saint Paul, Minnesota, United States

UM Sylvester Comprehensive Cancer Center at Deerfield Beach; 🇺🇸 Deerfield Beach, Florida, United States

Saint John's Hospital - Healtheast; 🇺🇸 Maplewood, Minnesota, United States

Houston Methodist The Woodlands Hospital; 🇺🇸 The Woodlands, Texas, United States

East Jefferson General Hospital; 🇺🇸 Metairie, Louisiana, United States

UM Sylvester Comprehensive Cancer Center at Coral Gables; 🇺🇸 Coral Gables, Florida, United States

McLaren Cancer Institute-Flint; 🇺🇸 Flint, Michigan, United States

Fairview Northland Medical Center; 🇺🇸 Princeton, Minnesota, United States

Fairview Lakes Medical Center; 🇺🇸 Wyoming, Minnesota, United States

University of Virginia Cancer Center; 🇺🇸 Charlottesville, Virginia, United States

University of Maryland/Greenebaum Cancer Center; 🇺🇸 Baltimore, Maryland, United States

UM Sylvester Comprehensive Cancer Center at Plantation; 🇺🇸 Plantation, Florida, United States

IU Health North Hospital; 🇺🇸 Carmel, Indiana, United States

George Washington University Medical Center; 🇺🇸 Washington, District of Columbia, United States

West Jefferson Medical Center; 🇺🇸 Marrero, Louisiana, United States

Weisberg Cancer Treatment Center; 🇺🇸 Farmington Hills, Michigan, United States

Fairview Clinics and Surgery Center Maple Grove; 🇺🇸 Maple Grove, Minnesota, United States

Bryn Mawr Hospital; 🇺🇸 Bryn Mawr, Pennsylvania, United States

Paoli Memorial Hospital; 🇺🇸 Paoli, Pennsylvania, United States

Women and Infants Hospital; 🇺🇸 Providence, Rhode Island, United States

UT Southwestern Clinical Center at Richardson/Plano; 🇺🇸 Richardson, Texas, United States

Northwestern University; 🇺🇸 Chicago, Illinois, United States

Houston Methodist Hospital; 🇺🇸 Houston, Texas, United States

Methodist Willowbrook Hospital; 🇺🇸 Houston, Texas, United States

Houston Methodist West Hospital; 🇺🇸 Houston, Texas, United States

University of Miami Miller School of Medicine-Sylvester Cancer Center; 🇺🇸 Miami, Florida, United States

Indiana University/Melvin and Bren Simon Cancer Center; 🇺🇸 Indianapolis, Indiana, United States

Women's Cancer Center of Nevada; 🇺🇸 Las Vegas, Nevada, United States

Wayne State University/Karmanos Cancer Institute; 🇺🇸 Detroit, Michigan, United States

Alegent Health Bergan Mercy Medical Center; 🇺🇸 Omaha, Nebraska, United States

University of Nebraska Medical Center; 🇺🇸 Omaha, Nebraska, United States

University of Oklahoma Health Sciences Center; 🇺🇸 Oklahoma City, Oklahoma, United States

Mercy Hospital Springfield; 🇺🇸 Springfield, Missouri, United States

Lankenau Medical Center; 🇺🇸 Wynnewood, Pennsylvania, United States

Houston Methodist Sugar Land Hospital; 🇺🇸 Sugar Land, Texas, United States

UT Southwestern/Simmons Cancer Center-Dallas; 🇺🇸 Dallas, Texas, United States

Louisiana State University Health Science Center; 🇺🇸 New Orleans, Louisiana, United States

University Medical Center New Orleans; 🇺🇸 New Orleans, Louisiana, United States