Sentinel Node Biopsy in Endometrial Cancer

NCT04073706RecruitingPHASE3INTERVENTIONAL

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.

Key Facts

Lead Sponsor

Queensland Centre for Gynaecological Cancer

Enrollment

760

Start Date

2021-01-18

Completion Date

2031-01-01

Study Type

INTERVENTIONAL

Official Title

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

Interventions

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 omittedTH 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

Conditions

Endometrial Cancer Stage ISentinel Lymph NodeSurgery

Eligibility

Age Range

18 Years+

Sex

FEMALE

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

Outcome Measures

Primary Outcomes

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.

Time frame: 12 months from surgery

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

Time frame: 4.5 years from surgery

Secondary Outcomes

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

Time frame: 12 months from surgery

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.

Time frame: 12 months from surgery

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.

Time frame: 12 months from surgery

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.

Time frame: 12 months from surgery

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.

Time frame: 12 months from surgery

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.

Time frame: 12 months from surgery

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.

Time frame: 12 months from surgery

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)

Time frame: 12 months from surgery

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.

Time frame: At time of surgery

Perioperative Outcomes: Blood Loss during Surgery

Compare the blood loss between the two groups during surgery. This will be recorded in ml.

Time frame: At time of surgery

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.

Time frame: At time of surgery

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.

Time frame: At time of discharge from hospital following surgery

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

Time frame: 12 months from surgery

Incidence of Lymphedema

Compare lower limb lymphedema between groups

Time frame: 12 months from surgery

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.

Time frame: 12 months from surgery

Value of Molecular Biomarkers

Translational Research - Compare Molecular profile from surgery between the groups that require adjuvant therapy for 24 months.

Time frame: 24 months from surgery

Value of Molecular Biomarkers

Translational Research - Compare the Molecular profile of Germline DNA at 12 months from surgery between the groups

Time frame: 12 months from surgery

Value of Molecular Biomarkers

Translational Research - Compare the Molecular profile of Circulating Tumour DNA at 12 months from surgery between the groups

Time frame: 12 months from surgery

Value of Molecular Biomarkers

Translational Research - Compare the Molecular profile of Plasma at 12 months from surgery between the groups

Time frame: 12 months from surgery

Value of Molecular Biomarkers

Translational Research - Compare the Molecular profile of Serum at 12 months from surgery between the groups

Time frame: 12 months from surgery

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

Time frame: 4.5 years from surgery

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

Time frame: 4.5 years from surgery

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

Time frame: 4.5 years from surgery

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

Time frame: 4.5 years from surgery

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.

Time frame: 4.5 years from surgery

Locations

Houston Methodist Hospital, Houston, United States

Hospital Britanico, Buenos Aires, Argentina

Chris O'Brien Lifehouse, Camperdown, Australia

Liverpool Hospital, Liverpool, Australia

The Wesley Hospital, Auchenflower, Australia

Buderim Private Hospital, Buderim, Australia

North West Private Hospital, Everton Park, Australia

Royal Brisbane and Women's Hospital, Herston, Australia

Mater Hospital, South Brisbane, Australia

Gold Coast University Hospital, Southport, Australia

St Andrews War Memorial Hospital, Spring Hill, Australia

Mercy Hospital for Women, Heidelberg, Australia

Royal Women's Hospital, Parkville, Australia

Hospital de Base, São José do Rio Preto, Brazil

Fundacao Antonio Prudente, AC Camargo Cancer Center, São Paulo, Brazil

Hospital Israelita Albert Einstein, São Paulo, Brazil

Centro de tratamiento e investigación sobre Cáncer Luis Carlos Sarmiento Angulo, Bogotá, Colombia

Azienda Sanitaria Universitaria Friuli Centrale (ASUFC), Udine, Italy

National University Hospital and National University Cancer Institute, Singapore, Singapore

Linked Papers

2021-11-02

A phase III randomized clinical trial comparing sentinel node biopsy with no retroperitoneal node dissection in apparent early-stage endometrial cancer – ENDO-3: ANZGOG trial 1911/2020

Sentinel node biopsy is a surgical technique to explore lymph nodes for surgical staging of endometrial cancer, which has replaced full retroperitoneal lymph node dissection. However, the effectiveness of sentinel node biopsy, its value to patients, and potential harms compared with no-node dissection have never been shown in a randomized trial. Stage 1 will test recovery from surgery. Stage 2 will compare disease-free survival at 4.5 years between patients randomized to sentinel node biopsy versus no retroperitoneal node dissection. The primary hypothesis for stage 1 is that treatment with sentinel node biopsy will not cause detriment to patient outcomes (lymphedema, morbidity, loss of quality of life) and will not increase treatment-related morbidity or health services costs compared with patients treated without a retroperitoneal node dissection at 12 months after surgery. The primary hypothesis for stage 2 is that disease-free survival at 4.5 years after surgery in patients without retroperitoneal node dissection is not inferior to those receiving sentinel node biopsy. This phase III, open-label, two-arm, multistage, randomized non-inferiority trial (ENDO-3) will determine the value of sentinel node biopsy for surgical management of endometrial cancer. Patients with endometrial cancer are randomized to receive: (1) laparoscopic/robotic hysterectomy, bilateral salpingo-oophorectomy with sentinel node biopsy or (2) laparoscopic/robotic hysterectomy, bilateral salpingo-oophorectomy without retroperitoneal node dissection. In stage 1, 444 patients will be enrolled to demonstrate feasibility and quality of life. If this is demonstrated, we will enroll another 316 patients in stage 2. Inclusion criteria include women aged 18 years or older with histologically confirmed endometrial cancer; clinical stage 1, who meet the criteria for laparoscopic or robotic total hysterectomy and bilateral salpingo-oophorectomy. Patients with uterine mesenchymal tumors are excluded. The endpoint for stage 1 is surgical recovery, with the proportion of patients returning to usual daily activities at 3 months post-surgery as measured with the EQ-5D. Stage 2 is disease-free survival at 4.5 years. 760 participants (both stages). Stage 1 commenced in January 2021 and is planned to be completed in December 2024 when 444 participants have completed 12 months' follow-up. Stage 2 will enroll a further 316 participants for a total of 760 patients. NCT04073706.

Linked Investigators

Andreas Obermair

Carlos Salomon

Eva Baxter

Kristy Robledo

Ming Yin Lin

Monika Janda

Monika Janda is the Director of the Centre for Health Services Research, the University of Queensland, Faculty of Medicine, and Professor in Behavioural Sciences. She holds and NHMRC L3 fellowship (2025-29). She trained as clinical and health psychologist, and now has an extensive research background in cancer prevention and quality of life research. Her two main research interests are i) prevention and early detection of cancer (in particular melanoma); and ii) improving clinical and supportive care for cancer patients (in particular gynaecological cancers). In 2017, she won the Scopus highly cited researcher award for women in research. She serves on the The Australasian College of Dermatologists e-Health committee and standards committee; and served previously on the Australian Psychological Society Technology committee. She is an executive member of the Australian Skin and Skin Cancer Research Centre. She led 2019 and 2023 Melanoma Screening Summits, forging new ways towards targeted melanoma screening. She was the chair (2014-2016) of the scientific advisory committee of the psycho-oncology clinical trials group, now chairs its prevention special interest group, and was a member of the Queensland Epidemiology Group organising committee. Internationally she was an organising member of the prevention committee for the International Psycho-Oncology Society. Professor Janda has published over 200 refereed journal articles and several book chapters. Before she joined the University of Queensland in 2018, she was Principal Research Fellow with the School of Public Health and Social Work (2006-2017), and the Theme Leader Health Determinants and Health System, Institute for Health and Biomedical Innovation, Queensland University of Technology (2014-2017). Before joining QUT she was a research fellow for the Melanoma Screening trial with the Cancer Council Queensland. Prior to that she worked as a clinical Psychologist at the Department of Radiotherapy at the University Hospital Vienna, Austria.

Nicholas Graves

Sandra C. Hayes

Val Gebski