Clinical trial NCT04073706: Sentinel Node Biopsy in Endometrial Cancer
Official title: A Phase III Randomised Clinical Trial Comparing Sentinel Node Biopsy With No Retroperitoneal Node Dissection in Apparent Early-Stage Endometrial Cancer
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Endometrial Cancer Stage I
Sentinel Lymph Node
Surgery
Keywords: uterine cancer
sentinel node biopsy
Lead sponsor: Queensland Centre for Gynaecological Cancer
Sponsor class: OTHER_GOV
Collaborators: name: The University of Queensland
First posted: 2019-08-29
Enrollment: 760
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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

Eligibility criteria: 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

Primary outcomes:
measure: Stage 1: Return to usual activities
timeFrame: 12 months from surgery
measure: Stage 2: Disease Free Survival
timeFrame: 4.5 years from surgery
Secondary outcomes:
measure: Cost Effectiveness using QALYs using EuroQoL-5D (EQ-5D) Questionnaire
timeFrame: 12 months from surgery
measure: Cost Effectiveness measuring Intervention costs
timeFrame: 12 months from surgery
measure: Cost Effectiveness measuring GP and specialist consultations
timeFrame: 12 months from surgery
measure: Cost Effectiveness measuring radiology and imaging requirements
timeFrame: 12 months from surgery
measure: Cost Effectiveness measuring prescriptions and over the counter medicine requirements
timeFrame: 12 months from surgery
measure: 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
timeFrame: 12 months from surgery
measure: 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
timeFrame: 12 months from surgery
measure: Perioperative Outcomes: Adverse Events
timeFrame: 12 months from surgery
measure: Perioperative Outcomes: Length of Surgery
timeFrame: At time of surgery
measure: Perioperative Outcomes: Blood Loss during Surgery
timeFrame: At time of surgery
measure: Perioperative Outcomes: Blood Transfusion Requirements during Surgery
timeFrame: At time of surgery
measure: Perioperative Outcomes: Length of Hospital Stay
timeFrame: At time of discharge from hospital following surgery
measure: Health Related Quality of Life and Fear of Recurrence
timeFrame: 12 months from surgery
measure: Incidence of Lymphedema
timeFrame: 12 months from surgery
measure: Adjuvant Treatment Requirements
timeFrame: 12 months from surgery
measure: Value of Molecular Biomarkers
timeFrame: 24 months from surgery
measure: Value of Molecular Biomarkers
timeFrame: 12 months from surgery
measure: Value of Molecular Biomarkers
timeFrame: 12 months from surgery
measure: Value of Molecular Biomarkers
timeFrame: 12 months from surgery
measure: Value of Molecular Biomarkers
timeFrame: 12 months from surgery
measure: Overall Survival
timeFrame: 4.5 years from surgery
measure: Patterns of Recurrence - date and localization of 1st recurrence
timeFrame: 4.5 years from surgery
measure: Impact of body composition (sarcopenia) on surgical complications, recovery and overall survival
timeFrame: 4.5 years from surgery
measure: Impact of frailty on surgical complications, recovery and overall survival
timeFrame: 4.5 years from surgery
measure: Follow-Up Strategies
timeFrame: 4.5 years from surgery
Other outcomes:
Locations:
city: Houston
country: United States
facility: Houston Methodist Hospital
state: Texas
city: Ciudad
country: Argentina
facility: Hospital Britanico
state: Buenos Aires
city: Camperdown
country: Australia
facility: Chris O'Brien Lifehouse
state: New South Wales
city: Liverpool
country: Australia
facility: Liverpool Hospital
state: New South Wales
city: Auchenflower
country: Australia
facility: The Wesley Hospital
state: Queensland
city: Buderim
country: Australia
facility: Buderim Private Hospital
state: Queensland
city: Everton Park
country: Australia
facility: North West Private Hospital
state: Queensland
city: Herston
country: Australia
facility: Royal Brisbane and Women's Hospital
state: Queensland
city: South Brisbane
country: Australia
facility: Mater Hospital
state: Queensland
city: Southport
country: Australia
facility: Gold Coast University Hospital
state: Queensland
city: Spring Hill
country: Australia
facility: St Andrews War Memorial Hospital
state: Queensland
city: Heidelberg
country: Australia
facility: Mercy Hospital for Women
state: Victoria
city: Parkville
country: Australia
facility: Royal Women's Hospital
state: Victoria
city: Santa Catarina
country: Brazil
facility: Hospital Municipal Vila Santa Catarina
state: Nelson De Sena
city: Curibita
country: Brazil
facility: Liga Paranaense de Combate ao Câncer
state: PR
city: São José Do Rio Preto
country: Brazil
facility: Hospital de Base
state: Sao Paulo
city: Sao Paulo
country: Brazil
facility: Fundacao Antonio Prudente, AC Camargo Cancer Center
state: SP
city: Sao Paulo
country: Brazil
facility: Hospital Israelita Albert Einstein
state: SP
city: Astorga
country: Colombia
facility: Instituto Nacional de Cancerología
state: Medellin
city: Kolkata
country: India
facility: Tata Medical Center
state: Delhi
city: Udine
country: Italy
facility: Azienda Sanitaria Universitaria Friuli Centrale (ASUFC)
state: Via Pozzuolo
city: Singapore
country: Singapore
facility: National University Hospital and National University Cancer Institute
state: NUH Zone B
Study officials:
affiliation: Director, Queensland Centre for Gynaecological Cancer Research
name: Andreas Obermiar, MD
role: STUDY_CHAIR
References:
citation: Obermair A, Nicklin J, Gebski V, Hayes SC, Graves N, Mileshkin L, Lin MY, Beale P, Baxter E, Robledo K, Salomon C, Hanna GB, Janda M. 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. Int J Gynecol Cancer. 2021 Dec;31(12):1595-1601. doi: 10.1136/ijgc-2021-003029. Epub 2021 Nov 2.