Comparison of Sentinel Node Policy Versus Standard Staging in Intermediate and High-Risk Endometrial Carcinoma Using Patent Blue, Technetium (99mTc) Rheniumsulfide, and Indocyanine Green

The primary objective of this study is to compare the **morbidity** associated with lymph node dissection between a sentinel node policy and the national or European protocols of surgical staging in patients with intermediate-risk and high-risk endometrial cancer. This comparison is clinically relevant as it aims to evaluate the potential benefits of a sentinel node policy in reducing surgical morbidity, which is a significant concern in the management of endometrial cancer.

Secondary objectives include:

• Determining the rate of sentinel node detection, including its location and laterality.
• Assessing the rate of positive node detection (pN1).
• Estimating and testing the impact of the sentinel node policy on **Progression Free Survival (PFS)**.
• Evaluating the impact of the sentinel node policy on specific and overall survival, indicating if death is due to disease progression.
• Exploratory: Evaluating the association between L1CAM expression on uterine specimens and node involvement at diagnosis, and its prognostic value on the risk of recurrence.
• Exploratory: Conducting a proteomic diagnosis of node metastases.

The clinical trial involves a study population consisting exclusively of **female** participants, aged 18 years and older, diagnosed with **intermediate-risk or high-risk endometrial cancer**. The trial does not provide information on the total number of participants, as the sponsor has not disclosed this data. Participants were selected based on specific inclusion criteria, including early FIGO clinical stage I-II endometrial carcinoma, with stratification of recurrence risk according to the latest ESMO guidelines. The trial population is characterized by a performance status (OMS) of 2 or less, with no contraindications to surgery and no known hypersensitivity to specific substances. Participants are required to have signed informed consent and be affiliated with a health insurance system. Lifestyle considerations such as effective contraception are mandated for those with reproductive potential. The trial does not include male subjects and involves a vulnerable population, as indicated by the selection criteria.

The clinical trial is designed to evaluate the efficacy and safety of a **sentinel node** policy compared to current national or European surgical staging protocols in patients with early-stage **endometrial cancer** at intermediate and high risk of recurrence. This is a randomized, controlled, and double-blind study, ensuring that neither the participants nor the investigators know which treatment the participants are receiving, thus minimizing bias. The trial is expected to run from November 2015 to October 2027, with participant involvement lasting up to three years post-surgery.

Participants will undergo a series of study visits, beginning with an inclusion visit where eligibility is confirmed through clinical examination, imaging, and biopsy. The inclusion criteria require patients to have early-stage endometrial carcinoma, be at least 18 years old, and have no contraindications to surgery, among other conditions. Follow-up visits will occur at regular intervals to monitor for adverse effects and assess morbidity related to lymph node dissection, using the Oslo classification and Clavien-Dindo scale. The primary endpoint focuses on per-operative and early post-operative morbidity, while secondary endpoints include detection rates of sentinel nodes and survival outcomes.

The end-of-study visit will evaluate long-term complications and overall survival, with data collection continuing until the third year post-surgery. Participants may be withdrawn from the study if they experience significant adverse effects, fail to comply with study procedures, or withdraw consent. The trial aims to provide comprehensive data on the safety and effectiveness of the sentinel node policy in improving surgical outcomes for patients with intermediate and high-risk endometrial cancer.

The clinical trial involves the use of several experimental medications, each with specific pharmaceutical forms, dosages, and administration routes. **Patent Blue** is utilized in this study in a modified form where one volume (2ml) of Patent Blue V dye at a concentration of 2.5% is diluted with an equal volume of sterile saline solution to achieve a final volume of 4ml with a concentration of 1.25%. The maximum daily and total dose is 0.05 grams, administered via **intracervical use**. The treatment period is limited to one day.

**Technetium (99mTc) Rheniumsulfide Colloid** is another experimental medication used in the trial. It is administered intracervically with a maximum daily and total dose of 120 megabecquerels (MBq). The pharmaceutical form is identified as PHF00190MIG, and the treatment period is also restricted to one day.

**Indocyanine Green** is included in the study, prepared by diluting a 25mg vial of infracyanine powder in 20ml of aqueous sterile water to obtain a final volume of 4ml with a concentration of 1.25 mg/mL. The maximum daily and total dose is 5 milligrams, administered via intracervical use, with a treatment period of one day.

**Technetium (99mTc) Nanocolloid**, containing **Human Albumin Solution** as the active substance, is administered intracervically with a maximum daily and total dose of 120 MBq. The pharmaceutical form is PHF00243MIG, and the treatment period is limited to one day. This product is used in a different indication within the trial.

All experimental medications are of chemical origin and are not formulated for pediatric use. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial data provided.

Efficacy in the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints focus on evaluating **per-operative morbidity** during surgery, using the Oslo classification for intraoperative incidents. Adverse effects related to lymph node dissection will be assessed at the per-operative timepoint, with particular attention to vascular, urinary, digestive, and nervous system disorders. Early post-operative morbidity will be evaluated up to 30 days post-surgery, scored according to the Clavien-Dindo scale, and will include complications such as symptomatic lymphocysts and leg lymphedemas. Distant complications beyond 30 days will be assessed using the NCI-CTCAE scale v4.03, focusing on nervous and lymphatic complications.

Secondary endpoints include the detection rate of pelvic sentinel nodes (SN) in the experimental arm, calculated as the number of patients with at least one SN detected per-operatively divided by the total number of patients who underwent staging. The SN-positive detection rate is determined by the number of detected SNs divided by the total number of lymph nodes extracted. Disease-free survival is defined as the time from randomization to the first documentation of relapse or all-cause death, with observations censored at the last follow-up for patients alive and free of disease. Overall survival is measured from randomization to all-cause death, with specific survival focusing on cancer-related deaths. Exploratory endpoints involve standard staining with hematoxylin-eosin-safran and immunohistochemistry with polyclonal anti-L1CAM, with the rate of L1CAM positive samples reported in the final pathology report. Additionally, standard sections of SN are required for mass spectrometry analysis, with slides stored until transfer to the PRISM laboratory for further analysis.