PROfiling Based Endometrial Cancer Adjuvant Therapy

Study Overview
=================
Brief Summary
-----------------
This is a prospective, multicenter, randomized phase III trial among women with endometrioid adenocarcinoma with high-intermediate and intermediate risk features to investigate the role of integrated genomic-pathologic classification to determine if participants should receive no adjuvant therapy, vaginal brachytherapy, external beam radiotherapy or chemo-radiation therapy based on molecular features as compared to standard radiation therapy.

Detailed Description
-----------------
Adjuvant therapy for women with endometrial cancer has increasingly been tailored to prognostic factors to prevent overtreatment and select those women for adjuvant treatment who will have a clinically relevant reduction of the risk of relapse by the adjuvant treatment. Risk profiles have traditionally been based on clinicopathological factors such as age, stage, grade, Lymph-Vascular Space Invasion (LVSI) and depth of invasion. Newer, both molecular-genetic (the cancer genome atlas subgroups) have become available which are strongly related to outcomes and risk of cancer spread. Based on 2022 National Comprehensive Cancer Network (NCCN) guideline and the ongoing Portec-4a trial, this randomized trial using integrated genomic-pathologic classification to assign adjuvant treatment for women with stage I-II high-intermediate and intermediate risk endometrioid adenocarcinoma.

Official Title
-----------------
Randomized Phase III Trial of Molecular Profile-based Versus Standard Recommendations for Adjuvant Therapy for Women With Early Stage Endometrioid Adenocarcinoma

Conditions
-----------------
Endometrial Cancer Stage I, Endometrial Cancer Stage II

Intervention / Treatment
-----------------
* Radiation: Vaginal brachytherapy
* Radiation: External beam radiotherapy
* Other: Observation
* Combination Product: Chemoradiation therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Surgery consisting of a total abdominal or laparoscopic hysterectomy, bilateral salpingectomy, pelvic lymphadenectomy or sentinel lymph node mapping and dissection, with or without para-aortic lymphadenectomy, oophorectomy Histologically confirmed endometrioid type endometrial carcinoma, International Federation of Gynecology and Obstetrics (FIGO) 2009 stage I, with one of the following combinations of stage and grade: Stage I A, grade 3 Stage I B, grade 1 or 2 Stage I B, grade 3 Stage II World Health Organization (WHO)-performance status 0-2 Written informed consent Exclusion Criteria: With residual disease Any other stage and type of endometrial carcinoma Histological types serous carcinoma or clear cell carcinoma (at least 10% if mixed type), or undifferentiated or neuroendocrine carcinoma Uterine sarcoma (including carcinosarcoma) Previous malignancy (except for non-melanomatous skin cancer) Previous pelvic radiotherapy Expected interval between the operation and start of radiotherapy exceeding 8 weeks

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Molecular profile based treatment<br>Determination of the integrated genomic-pathologic profile to determine adjuvant treatment: observation for POLE-mutated profile; vaginal brachytherapy for intermediate profile; chemo-radiotherapy for p53-abnormal profile. | Radiation: Vaginal brachytherapy<br>* Internal radiation of the vaginal vault using a vaginal cylinder. For brachytherapy administered alone it is recommended: suggested dose is either 3 fractions of 7 Gy or 5 fractions of 6 Gy. For brachytherapy administered after completion of External beam radiotherapy (EBRT): Total dose should aim to be 65 Gy, and suggested dose is 2-3 fractions of 5-6 Gy<br>Other: Observation<br>* No adjuvant therapy, but active follow-up and quality of life questionnaires as in the groups who have adjuvant treatment<br>Combination Product: Chemoradiation therapy<br>* 4 adjuvant cycles carboplatin and paclitaxel followed by External beam pelvic radiotherapy (45-50 Gy )<br>|
| Active Comparator: Radiotherapy<br>Adjuvant vaginal brachytherapy for intermediate risk (stage I A with G3 or stage I B with G1-2) and external beam pelvic radiotherapy for high-intermediate risk (stage I B with G3, or stage II) (standard treatment) | Radiation: Vaginal brachytherapy<br>* Internal radiation of the vaginal vault using a vaginal cylinder. For brachytherapy administered alone it is recommended: suggested dose is either 3 fractions of 7 Gy or 5 fractions of 6 Gy. For brachytherapy administered after completion of External beam radiotherapy (EBRT): Total dose should aim to be 65 Gy, and suggested dose is 2-3 fractions of 5-6 Gy<br>Radiation: External beam radiotherapy<br>* External beam pelvic radiotherapy on a linear accelerator, 45-50 Gy in 25-28 out-patients sessions<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total recurrence | Vaginal, pelvic or distant recurrence as first failure | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relapse-free survival | Relapse-free survival (survival without relapse) | 3 years, 5 years | 
| Survival | Overall survival (all-cause death) | 3 years, 5 years | 
| Adverse events | Treatment-related symptoms according to CTCAE v 5.0 | 3 years, 5 years | 
| Health-related cancer-specific quality of life | Quality of Life Core Questionnaire (QLQC-30) - clinically relevant changes on Quality of Life Core Questionnaire-30 functioning scales, general quality of life and general cancer symptoms, quite a bit/very much vs no or mild symptoms | 3 years, 5 years | 
| Endometrial cancer related health care costs | All hospital based health care costs used with primary treatment or during followup for treatment of adverse events and/or treatment for relapse | 3 years, 5 years |