PORTEC-4a: Molecular Profile-based Versus Standard Adjuvant Radiotherapy in Endometrial Cancer

Study Overview
=================
Brief Summary
-----------------
This is prospective, multicenter, randomised phase III trial among women with endometrial cancer with high-intermediate risk features to investigate the role of an integrated clinicopathological and molecular risk profile to determine if participants should receive no adjuvant therapy, vaginal brachytherapy or external beam radiotherapy based on a favourable, intermediate or unfavourable profile as compared to standard adjuvant vaginal brachytherapy.

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, LVSI and depth of invasion. Newer, both molecular-genetic (the cancer genome atlas subgroups) or immunohistochemistry-based (L1-CAM) risk factors have become available which are strongly related to outcomes and risk of cancer spread. In a comprehensive analysis of the PORTEC-1 and-2 biobank an integrated clinicopathological and molecular risk profile was determined which separated the current high-intermediate risk group of endometrial cancer in 3 separate groups (favourable, intermediate or unfavourable) with clearly separated outcomes, which is now prospectively tested in the clinic to determine adjuvant treatment. This is the first randomised trial using the molecular risk factors to assign adjuvant treatment for women with stage I-II high-intermediate risk endometrial cancer.

Official Title
-----------------
Randomised Phase III Trial of Molecular Profile-based Versus Standard Recommendations for Adjuvant Radiotherapy for Women With Early Stage Endometrial Cancer: PORTEC-4a Trial

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

Intervention / Treatment
-----------------
* Radiation: Vaginal brachytherapy
* Radiation: External beam radiotherapy
* Other: Observation


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed endometrioid type endometrial carcinoma, International Federation of Gynecology and Obstetrics (FIGO) 2009 stage I, with one of the following combinations of stage, grade, age, and lymph-vascular space invasion (LVSI): Stage IA, grade 3 (any age, with or without LVSI) Stage IB, grade 1 or 2 and age >60 years Stage IB, grade 1-2 with documented LVSI Stage IB, grade 3 without LVSI Stage II (microscopic), grade 1 World Health Organization (WHO)-performance status 0-2 Written informed consent Exclusion Criteria: 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) < 5 yrs Previous pelvic radiotherapy Expected interval between the operation and start of radiotherapy exceeding 8 weeks

Ages Eligible for Study
-----------------
Minimum Age: 18 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
Interventional Model Description: 2:1 randomisation to adjuvant treatment assignment based on the integrated molecular risk profile or standard adjuvant vaginal brachytherapy
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Molecular profile based treatment<br>Determination of the integrated clinicopathological and molecular profile to determine adjuvant treatment: observation for favourable profile; vaginal brachytherapy for intermediate profile; external beam radiotherapy for unfavourable profile | Radiation: Vaginal brachytherapy<br>* Internal radiation of the vaginal vault using a vaginal cylinder, 21 Gy in 3 out-patient sessions over 2 weeks<br>Radiation: External beam radiotherapy<br>* External beam pelvic radiotherapy on a linear accelerator, 48.6 Gy in 27 out-patients sessions over 5.5 weeks<br>Other: Observation<br>* No radiation therapy, but active follow-up and quality of life questionnaires as in the groups who have adjuvant treatment<br>|
| Active Comparator: Vaginal brachytherapy<br>Adjuvant vaginal brachytherapy (standard treatment) | Radiation: Vaginal brachytherapy<br>* Internal radiation of the vaginal vault using a vaginal cylinder, 21 Gy in 3 out-patient sessions over 2 weeks<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vaginal recurrence | Total vaginal recurrence and vaginal recurrence as first failure | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events | Treatment-related symptoms according to CTCAE v 4.0 | 5 years | 
| Health-related cancer-specific quality of life | Cancer-specific quality of life (European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQC-30) - clinically relevant changes on QLQC30 functioning scales, general quality of life and general cancer symptoms | 5 years | 
| Endometrial cancer-related symptoms and quality of life | Endometrial cancer-related specific symptoms (EORTC EN24 module)- clinically relevant changes on these scales (quite a bit/very much vs no or mild symptoms) | 5 years | 
| Relapse-free survival | Relapse-free survival (survival without relapse) | 5 years | 
| Survival | Overall survival (all-cause death) | 5 years | 
| 5-year vaginal control including treatment for relapse | Long-term local control including salvage treatment for local relapse | 5 years | 
| Pelvic recurrence (total) | Total pelvic recurrences | 5 years | 
| Pelvic recurrence as first failure | Pelvic recurrence as first failure | 5 years | 
| Distant recurrence (total) | Total distant recurrences | 5 years | 
| Distant recurrence as first failure | Distant recurrence as first failure | 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 | 5 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Radiotherapy, Vaginal brachytherapy, Molecular risk factors