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

Overview

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

Interventions

• 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.
• Procedure 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

Primary outcome measures

• Stage 1: Return to usual activities [Time frame: 12 months from surgery]
• Stage 2: Disease Free Survival [Time frame: 4.5 years from surgery]

Secondary outcome measures (12)

• Cost Effectiveness using QALYs using EuroQoL-5D (EQ-5D) Questionnaire [Time frame: 12 months from surgery]
• Cost Effectiveness measuring Intervention costs [Time frame: 12 months from surgery]
• Cost Effectiveness measuring GP and specialist consultations [Time frame: 12 months from surgery]
• Cost Effectiveness measuring radiology and imaging requirements [Time frame: 12 months from surgery]
• Cost Effectiveness measuring prescriptions and over the counter medicine requirements [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 [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 [Time frame: 12 months from surgery]
• Perioperative Outcomes: Adverse Events [Time frame: 12 months from surgery]
• Perioperative Outcomes: Length of Surgery [Time frame: At time of surgery]
• Perioperative Outcomes: Blood Loss during Surgery [Time frame: At time of surgery]
• Perioperative Outcomes: Blood Transfusion Requirements during Surgery [Time frame: At time of surgery]
• Perioperative Outcomes: Length of Hospital Stay [Time frame: At time of discharge from hospital following surgery]

Eligibility criteria

Inclusion criteria

• Females, over 18 years, with histologically confirmed primary epithelial cancer of the endometrium of any cell type or uterine carcinosarcoma (mixed malignant mullerian tumour);
• Clinically stage I disease (disease confined to body of uterus);
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1;
• Signed written informed consent;
• 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)
• All available clinical evidence (physical examination findings, or medical imaging such as CT, MRI or ultrasound) demonstrates no evidence of extrauterine disease
• 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).
• 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

• 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.
• Enlarged retroperitoneal pelvic and/or aortic lymph nodes (>1 cm) on medical imaging;
• Estimated life expectancy of less than 6 months;
• Patients who have absolute contraindications for adjuvant radiotherapy and/or chemotherapy;
• Patients who have previously received radiation treatment to the pelvis
• Serious concomitant systemic disorders incompatible with the study (at the discretion of the investigator);
• Patient compliance and geographic proximity that do not allow adequate follow-up;
• Patients with allergy to Indocyanine Green (ICG)
• Patients who have had previous retroperitoneal surgery
• Patients who require a retroperitoneal (pelvic +/- para-aortic) lymph node dissection (lymphadenectomy)
• Other prior malignancies <5 years before inclusion, except for successfully treated keratinocyte skin cancers, or ductal carcinoma of the breast insitu
• Uterine perforation during endometrial tissue sampling

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Australia · 11 centers

• Chris O'Brien Lifehouse — Camperdown
• Liverpool Hospital — Liverpool
• The Wesley Hospital — Auchenflower
• Buderim Private Hospital — Buderim
• North West Private Hospital — Everton Park
• Royal Brisbane and Women's Hospital — Herston
• Mater Hospital — South Brisbane
• Gold Coast University Hospital — Southport
• … and 3 more centers

Brazil · 3 centers

• Hospital de Base — São José do Rio Preto
• Fundacao Antonio Prudente, AC Camargo Cancer Center — São Paulo
• Hospital Israelita Albert Einstein — São Paulo

United States · 1 center

• Houston Methodist Hospital — Houston

Argentina · 1 center

• Hospital Britanico — Buenos Aires

Colombia · 1 center

• Centro de tratamiento e investigación sobre Cáncer Luis Carlos Sarmiento Angulo — Bogotá

Italy · 1 center

• Azienda Sanitaria Universitaria Friuli Centrale (ASUFC) — Udine

Singapore · 1 center

• National University Hospital and National University Cancer Institute — Singapore

Publications

• 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. PMID 34728527

Identifiers

NCT: NCT04073706 · ENDO-3

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗