Sentinel Node Biopsy in Endometrial Cancer

Surgery Clinical Trial

— ENDO-3  

Official title:

A Phase III Randomised Clinical Trial Comparing Sentinel Node Biopsy With No Retroperitoneal Node Dissection in Apparent Early-Stage Endometrial Cancer

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04073706
• Other study ID #: ENDO-3
• Status: Recruiting
• Phase: Phase 3
• Start date: January 18, 2021
• Est. completion date: January 2031

Study information

• Verified date: April 2023
• Source: Queensland Centre for Gynaecological Cancer
• Contact: Vanessa Behan, BSN
• Phone: +61 7 3346 5590
• Email: endo3trial[@]uq.edu.au
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Endometrial cancer (EC) is the most common gynaecological cancer. Current treatment of EC typically includes removal of the uterus and to determine the extent of the disease (removal of fallopian tubes, ovaries & if required a lymph node dissection (surgical staging)). While lymph node dissection may be valuable to guide the need for adjuvant treatment (chemo or radiotherapy) after surgery, it has been a topic of controversy for the last 30 years. In some patients it causes morbidity, specifically lymphoedema. This recently has been replaced with sentinel node biopsy (SNB). It requires an injection of a dye into the cervix with specific equipment & surgical dissection of the lymph node in which the dye first becomes visible. Despite this promising proposition & similar to a lymph node dissection, the value to patients, cost effectiveness & potential harms (e.g. lymphedema) of SNB compared to no-node dissection in EC has never been established. Aim: determine the value of SNB for patients, the healthcare system and exclude detriment to patients using a randomised approach 1:1. Stage 1 - 444 patients. Stage 2 additional 316 patients.

Primary Outcome Stage 1:

Proportion of participants returning to usual daily activities at 12 months from surgery using the EQ-5D which will determine when women in both groups can return to their usual activities.

Primary Outcome Stage 2:

Treatment non-inferiority as evaluated by disease-free survival status at 4.5 years post-surgery, as measured by the time interval between the date of randomisation and date of first recurrence. Confirmation of recurrent disease will be ascertained through clinical assessment, radiological work-up and/or histological results.

Description:

Hypothesis: The primary hypothesis is that SNB will not cause detriment to patients (lymphoedema, morbidity, loss of quality of life) and not increase costs compared to patients without a retroperitoneal node dissection. The secondary hypothesis is that disease-free survival in patients without retroperitoneal node dissection is not inferior to those receiving SNB.

Aims: To determine the value of SNB for patients, the healthcare system and to exclude detriment to patients.

Objectives:

Primary Stage 1:

To determine the recovery of participants (defined as incidence of adverse events, lower limb lymphoedema and health-related QOL) and to the healthcare system (cost) of Sentinel Node Biopsy (SNB) for the surgical treatment of endometrial cancer.

Primary Stage 2:

Compare disease-free survival at 4.5 years for participants randomised to receive hysterectomy, bilateral salpingo-oophorectomy with SNB compared to participants randomised to hysterectomy, bilateral salpingo-oophorectomy without retroperitoneal node dissection.

Secondary:

• Compare patterns of recurrence and overall survival (OS) between the groups

• Determine the cost-effectiveness of SNB

• Compare Patient Reported Outcomes (PROMS) between the groups at 12 months from surgery

• Compare Health Related Quality of Life (HRQL) and Fear of Recurrence between the groups at 12 months from surgery

• Compare perioperative outcomes (duration of surgery, length of hospital stay, intraoperative blood loss, blood transfusion requirements) and the incidence of intra- and postoperative adverse events within 12 months from surgery between the groups

• Compare lower limb lymphoedema at 12 months after surgery

• Compare the need for postoperative (adjuvant) treatments between groups

• Determine the impact of body composition and frailty on survival, quality of life, lymphoedema, peri-, intra- and postoperative outcomes

• Compare follow-up strategies (clinical vs symptom checklist)

• Translational Research - Trans-ENDO 3 - biobanking strategy - Compare the Molecular profile at 12 months from surgery between the groups

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 760
• Est. completion date: January 2031
• Est. primary completion date: January 2031
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Females, over 18 years, with histologically confirmed primary epithelial cancer of the endometrium of any cell type or uterine carcinosarcoma (mixed malignant mullerian tumour);

2. Clinically stage I disease (disease confined to body of uterus);

3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1;

4. Signed written informed consent;

5. Participant must meet criteria for a laparoscopic or robotic surgical approach as determined by the treating physician (e.g. suitable for TH BSO, ability to tolerate Trendelenberg positioning)

6. All available clinical evidence (physical examination findings, or medical imaging such as CT, MRI or ultrasound) demonstrates no evidence of extrauterine disease

7. Myometrial Invasion on MRI of not more than 50%. (Only if participant is <45yo, has ONLY Grade 1 EAC and wishes to retain their ovaries).

8. Negative (serum or urine) pregnancy test = 30 days of surgery in pre-menopausal women and women < 2 years after the onset of menopause.

Exclusion Criteria:

1. Evidence of extrauterine disease (apparent involvement of cervix, vagina, parametria, adnexa, lymph nodes, bladder, bowel or distant sites) by clinical examination and/or through medical imaging.

2. Enlarged retroperitoneal pelvic and/or aortic lymph nodes (>1 cm) on medical imaging;

3. Estimated life expectancy of less than 6 months;

4. Patients who have absolute contraindications for adjuvant radiotherapy and/or chemotherapy;

5. Patients who have previously received radiation treatment to the pelvis

6. Serious concomitant systemic disorders incompatible with the study (at the discretion of the investigator);

7. Patient compliance and geographic proximity that do not allow adequate follow-up;

8. Patients with allergy to Indocyanine Green (ICG)

9. Patients who have had previous retroperitoneal surgery

10. Patients who require a retroperitoneal (pelvic +/- para-aortic) lymph node dissection (lymphadenectomy)

11. Other prior malignancies <5 years before inclusion, except for successfully treated keratinocyte skin cancers, or ductal carcinoma of the breast insitu

12. Uterine perforation during endometrial tissue sampling

Related Conditions & MeSH terms

• Endometrial Cancer Stage I
• Endometrial Neoplasms
• Sentinel Lymph Node
• Surgery

Intervention

Procedure:
• TH BSO with SNB Note: If participants (=45yo), Grade 1 endometrial adenocarcinoma with myometrial invasion <50%, wish to retain their ovaries a BSO may be omitted
Removal of uterus, tubes and ovaries with a sentinel node biopsy. A tracer dye (ICG) +/- Methylene Blue Dye is injected into the surroundings of the primary tumour, it is transported via local lymphatic channels towards the draining lymphatic basin, and the first node that the tracer reaches is called the "sentinel node". These one or two nodes are thought to be first involved with cancer spread.
• TH BSO without retroperitoneal node dissection Note: If participants (=45yo), Grade 1 endometrial adenocarcinoma with myometrial invasion <50%, wish to retain their ovaries a BSO may be omitted
Removal of uterus, tubes and ovaries without retroperitoneal node dissection

Locations

Country	Name	City	State
Australia	The Wesley Hospital	Auchenflower	Queensland
Australia	Buderim Private Hospital	Buderim	Queensland
Australia	Chris O'Brien Lifehouse	Camperdown	New South Wales
Australia	Townsville Hospital	Douglas	Queensland
Australia	North West Private Hospital	Everton Park	Queensland
Australia	Mercy Hospital for Women	Heidelberg	Victoria
Australia	Royal Brisbane and Women's Hospital	Herston	Queensland
Australia	Royal Hobart Hospital	Hobart	Tasmania
Australia	St George Hospital	Kogarah	New South Wales
Australia	Royal Women's Hospital	Parkville	Victoria
Australia	Mater Hospital	South Brisbane	Queensland
Australia	Gold Coast University Hospital	Southport	Queensland
Australia	St Andrews War Memorial Hospital	Spring Hill	Queensland
Brazil	Hospital de Base	São José Do Rio Preto	Sao Paulo
India	Tata Medical Center	Kolkata	Delhi
Singapore	National University Hospital and National University Cancer Institute	Singapore	NUH Zone B
United States	Houston Methodist Hospital	Houston	Texas

Sponsors (2)

Lead Sponsor	Collaborator
Queensland Centre for Gynaecological Cancer	The University of Queensland

Countries where clinical trial is conducted

United States,  Australia,  Brazil,  India,  Singapore, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Stage 1: Return to usual activities	Proportion of participants returning to usual daily activities at 12 months from surgery using the EQ-5D which will determine when women in both groups can return to their usual activities.	12 months from surgery
Primary	Stage 2: Disease Free Survival	Compare disease-free survival for participants randomised to receive hysterectomy, bilateral salpingo-oophorectomy with SNB compared to participants randomised to hysterectomy, bilateral salpingo-oophorectomy without retroperitoneal node dissection	4.5 years from surgery
Secondary	Cost Effectiveness using QALYs using EuroQoL-5D (EQ-5D) Questionnaire	An assessment will be performed on the cost-effectiveness of TH + SNB relative to TH alone, calculated as the incremental cost per unit of improvement in functional outcome, measured in terms of the primary outcome. This will assess how much more money the proposed intervention will cost the health system and society, and whether this represents a sound investment in terms of the improvement in quality of life. We will also measure the quality-adjusted life years (QALYs) gained with the intervention and use this to undertake a cost-utility analysis. The QALY calculations will be based on health status measures for trial participants, with valuations of changes in health status and quality of life based on the EQ-5D	12 months from surgery
Secondary	Cost Effectiveness measuring Intervention costs	An assessment will be performed on the cost-effectiveness of TH + SNB relative to TH alone, calculated as the incremental cost per unit of improvement in functional outcome, measured in terms of the primary outcome. This will assess how much more money the proposed intervention will cost the health system and society.	12 months from surgery
Secondary	Cost Effectiveness measuring GP and specialist consultations	An assessment will be performed on the cost-effectiveness of TH + SNB relative to TH alone, calculated as the incremental cost per unit of improvement in functional outcome, measured in terms of the primary outcome. This will assess how much more money the proposed intervention will cost the health system and society, and whether this represents a sound investment in terms of the improvement in quality of life.	12 months from surgery
Secondary	Cost Effectiveness measuring radiology and imaging requirements	An assessment will be performed on the cost-effectiveness of TH + SNB relative to TH alone, calculated as the incremental cost per unit of improvement in functional outcome, measured in terms of the primary outcome. This will assess how much more money the proposed intervention will cost the health system and society.	12 months from surgery
Secondary	Cost Effectiveness measuring prescriptions and over the counter medicine requirements	An assessment will be performed on the cost-effectiveness of TH + SNB relative to TH alone, calculated as the incremental cost per unit of improvement in functional outcome, measured in terms of the primary outcome. This will assess how much more money the proposed intervention will cost the health system and society, and whether this represents a sound investment in terms of the improvement in quality of life.	12 months from surgery
Secondary	Cost Effectiveness measuring community and health service requirements and days off work and informal care required by family and friends using a combination of the Health Services Questionnaire and clinical files	An assessment will be performed on the cost-effectiveness of TH + SNB relative to TH alone, calculated as the incremental cost per unit of improvement in functional outcome, measured in terms of the primary outcome. This will assess how much more money the proposed intervention will cost the health system and society, and whether this represents a sound investment in terms of the improvement in quality of life.	12 months from surgery
Secondary	Cost Effectiveness: direct costs using a bottom-up approach by recording the volume of resource use in both groups of the trial, and then applying a unit cost to each component	Direct costs wukk be ibtained for smaples of participants, stratified by hospital, operation and outcome to assess the cost-effectiveness of TH + SNB relative to TH alone, calculated as the incremental cost per unit of improvement in functional outcome, measured in terms of the primary outcome. This will assess how much more money the proposed intervention will cost the health system and society.	12 months from surgery
Secondary	Perioperative Outcomes: Adverse Events	Compare perioperative outcomes and the incidence of intra- and postoperative adverse events within 12 months from surgery between groups using Common Terminology Criteria for Adverse Events (CTCAE version 5)	12 months from surgery
Secondary	Perioperative Outcomes: Length of Surgery	Compare the length of surgery between the two groups. This will be recorded in hh:mm on the surgery form.	At time of surgery
Secondary	Perioperative Outcomes: Blood Loss during Surgery	Compare the blood loss between the two groups during surgery. This will be recorded in ml.	At time of surgery
Secondary	Perioperative Outcomes: Blood Transfusion Requirements during Surgery	Compare the blood transfusion requirements between the two groups. This will be recorded in units and recorded on the Surgery Form and the Concomitant Medication Form.	At time of surgery
Secondary	Perioperative Outcomes: Length of Hospital Stay	Compare the length of hospital stay between the two groups. The duration will be measured in days. Date of surgery being day 0.	At time of discharge from hospital following surgery
Secondary	Health Related Quality of Life and Fear of Recurrence	Change in Quality of Life using Functional Assessment of Cancer General (FACT-EN), Fear of Recurrence and PROMS between baseline and 1 year after surgery	12 months from surgery
Secondary	Incidence of Lymphedema	Compare lower limb lymphedema between groups	12 months from surgery
Secondary	Adjuvant Treatment Requirements	Compare the need for postoperative (adjuvant) treatments between groups and evaluate the impact of SNB on clinical decisions regarding adjuvant treatment. Any chemotherapy or radiation therapy required will be recorded on specific chemotherapy or radiation forms. Chemotherapy will be recorded in mg received and number of doses required including start/end dates. Radiation treatment received will be recorded as total dose of Gy and how many fractions, including start and end dates.	12 months from surgery
Secondary	Value of Molecular Biomarkers	Translational Research - Compare Molecular profile from surgery between the groups that require adjuvant therapy for 24 months.	24 months from surgery
Secondary	Value of Molecular Biomarkers	Translational Research - Compare the Molecular profile of Germline DNA at 12 months from surgery between the groups	12 months from surgery
Secondary	Value of Molecular Biomarkers	Translational Research - Compare the Molecular profile of Circulating Tumour DNA at 12 months from surgery between the groups	12 months from surgery
Secondary	Value of Molecular Biomarkers	Translational Research - Compare the Molecular profile of Plasma at 12 months from surgery between the groups	12 months from surgery
Secondary	Value of Molecular Biomarkers	Translational Research - Compare the Molecular profile of Serum at 12 months from surgery between the groups	12 months from surgery
Secondary	Overall Survival	Compare overall survival for participants randomised to receive hysterectomy, bilateral salpingo-oophorectomy with SNB compared to participants randomised to hysterectomy, bilateral salpingo-oophorectomy without retroperitoneal node dissection	4.5 years from surgery
Secondary	Patterns of Recurrence - date and localization of 1st recurrence	Date and localization of 1st recurrence as confirmed histologically and/or radiologically - Compare these patterns of recurrences between the groups. These will also be adjudicated by an independent committee to ensure accuracy of documented recurrence	4.5 years from surgery
Secondary	Impact of body composition (sarcopenia) on surgical complications, recovery and overall survival	Body mass measures are practical & sensitive for predicting health risks & outcomes. Sarcopenia is defined as loss of skeletal muscle mass & strength. It's been found to be associated with procedure-related morbidity, survival in cancer patients and increased use of healthcare. The concurrent appearance of low muscle mass with high adiposity (sarcopenic obesity) is common in people with chronic diseases. The trial will determine the role sarcopenia has on participants pre-operatively (via CT images & Bioimpedance Spectroscopy (BIS - if available at site) & postoperatively using the BIS in regard to survival in gynaecological malignancies, if it is a predictive factor for treatment adverse events & participants tolerability of treatment & compare diagnostic methods to determine medical fitness for surgery. BIS sends non-detectable electrical currents, at a range of frequencies through the body allowing precise measurement & analysis of impedance to currents by extracellular fluid	4.5 years from surgery
Secondary	Impact of frailty on surgical complications, recovery and overall survival	It has been reported consistently that frailty has a significant impact on the occurrence of adverse postoperative outcomes. Therefore, measuring frailty is important to estimate risks, determine the best treatment options, and to aid diagnosis and care planning. Frailty will be measured prior to surgery suing the validated tool - Frailty Phenotype. This may determine the impact frailty has on survival, quality of life, lymphedema, peri-, intra- and postoperative outcomes	4.5 years from surgery
Secondary	Follow-Up Strategies	Current institutional & clinical guidelines suggest patients need to be seen at regular follow up visits. The risk of developing a recurrence is higher within the initial period after surgery & the majority of recurrences develop within those first 3 years. Participants will ideally be seen 3 monthly for the first 3 years & 6 monthly until 4.5 years. The objective of follow up is that local recurrences from endometrial cancer are potentially curable. It helps to diagnose local recurrences as early as possible so that they are amenable for curative or effective palliative management. We will compare these clinical findings to a symptom checklist that will be completed by participants every 3 months from surgery until 4.5 years. This records patient reported symptoms that may indicate a recurrence. Comparing these findings should determine effective follow up strategies for this group of patients.	4.5 years from surgery