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

Study Overview
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Brief Summary
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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
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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 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 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 during standard minimally invasive hysterectomy. Lymph nodes around the uterus may be removed if the mapping 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 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. After completion of study intervention, patients are followed every 3 months for one year and at 18 and 24 months.

Official Title
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A Phase III Trial of the Impact of Sentinel Lymph Node Mapping on Patient Reported Lower Extremity Limb Dysfunction in Endometrial Cancer

Conditions
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Stage I Uterine Corpus Cancer AJCC v8

Intervention / Treatment
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* Procedure: Diagnostic Imaging
* Drug: Indocyanine Green Solution
* Procedure: Minimally Invasive Surgery
* Procedure: Pelvic Lymphadenectomy
* Other: Questionnaire Administration
* Procedure: Sentinel Lymph Node Mapping


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1 (sentinel lymph node mapping)<br>Patients receive ICG dye via injection and undergo sentinel lymph node mapping during standard minimally invasive hysterectomy. Lymph nodes around the uterus may be removed if the mapping cannot be completed. Successful mapping requires no additional removal of lymph nodes. Patients also undergo imaging as clinically indicated. | Procedure: Diagnostic Imaging<br>* Undergo imaging<br>* Other names: Medical Imaging;Drug: Indocyanine Green Solution<br>* Given via injection<br>* Other names: ICG Solution;Procedure: Minimally Invasive Surgery<br>* Undergo minimally invasive hysterectomy<br>* Other names: Surgery, Minimally Invasive;Procedure: Pelvic Lymphadenectomy<br>* Undergo pelvic lymphadenectomy<br>* Other names: Pelvic Lymph Node Dissection;Other: Questionnaire Administration<br>* Ancillary studies<br>Procedure: Sentinel Lymph Node Mapping<br>* Undergo sentinel lymph node mapping<br>* Other names: Sentinel Lymph Node Imaging;|
| Experimental: Arm 2 (sentinel lymph node mapping, pelvic lymphadenectomy)<br>Patients receive ICG dye via injection and undergo sentinel lymph node mapping during standard minimally invasive hysterectomy. Additional lymph nodes around the uterus are removed per standard of care. Patients also undergo imaging as clinically indicated. | Procedure: Diagnostic Imaging<br>* Undergo imaging<br>* Other names: Medical Imaging;Drug: Indocyanine Green Solution<br>* Given via injection<br>* Other names: ICG Solution;Procedure: Minimally Invasive Surgery<br>* Undergo minimally invasive hysterectomy<br>* Other names: Surgery, Minimally Invasive;Procedure: Pelvic Lymphadenectomy<br>* Undergo pelvic lymphadenectomy<br>* Other names: Pelvic Lymph Node Dissection;Other: Questionnaire Administration<br>* Ancillary studies<br>Procedure: Sentinel Lymph Node Mapping<br>* Undergo sentinel lymph node mapping<br>* Other names: Sentinel Lymph Node Imaging;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of patient-reported lower extremity limb dysfunction | 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. | From 18 months post-hysterectomy after undergoing lymphatic assessment to 39 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The incidence of lymphedema by quantifiable lower extremity limb changes | 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. | From enrollment and at 3, 6, 9, 12, and 18 months after surgery | 
| The incidence of lymphedema by bioimpedance assessments (if available) | 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. | From enrollment and at 3, 6, 9, 12, and 18 months after surgery. | 
| Rate of successful bilateral SLN identification | Will be assessed in both, and only as the time of surgery. | At time of surgery | 
| Rate of successful identification of lymph node metastasis | 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. | At time of surgery | 
| Rate of perioperative complications | 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. | At time of surgery |