PORTEC-4a: international randomized trial of molecular profile-based adjuvant treatment for women with high-intermediate risk endometrial cancer

Abstract

BackgroundVaginal brachytherapy is currently recommended as adjuvant treatment in patients with high-intermediate risk endometrial cancer to maximize local control and has only mild side effects and no or limited impact on quality of life. However, there is still considerable overtreatment and also some undertreatment, which may be reduced by tailoring adjuvant treatment to the patients’ risk of recurrence based on molecular tumor characteristics.Primary objectivesTo compare the rates of vaginal recurrence in women with high-intermediate risk endometrial cancer, treated after surgery with molecular-integrated risk profile-based recommendations for either observation, vaginal brachytherapy or external pelvic beam radiotherapy or with standard adjuvant vaginal brachytherapyStudy hypothesisAdjuvant treatment based on a molecular-integrated risk profile provides similar local control and recurrence-free survival as current standard adjuvant brachytherapy in patients with high-intermediate risk endometrial cancer, while sparing many patients the morbidity of adjuvant treatment and reducing healthcare costs.Trial designA multicenter, international phase III randomized trial (2:1) of molecular-integrated risk profile-based adjuvant treatment (experimental arm) or adjuvant vaginal brachytherapy (standard arm).Major inclusion/exclusion criteriaWomen aged 18 years and over with a histological diagnosis of high-intermediate risk endometrioid endometrial cancer after total abdominal or laparoscopic hysterectomy and bilateral salpingo-oophorectomy. High-intermediate risk factors are defined as: (i) International Federation of Gynecology and Obstetrics stage IA (with invasion) and grade 3; (ii) stage IB grade 1 or 2 with age ≥60 and/or lymph-vascular space invasion; (iii) stage IB, grade 3 without lymph-vascular space invasion; or (iv) stage II (microscopic and grade 1).EndpointsThe primary endpoint is vaginal recurrence. Secondary endpoints are recurrence-free and overall survival; pelvic and distant recurrence; 5-year vaginal control (including treatment for relapse); adverse events and patient-reported symptoms and quality of life; and endometrial cancer-related healthcare costs.Sample size500 eligible and evaluable patients.Estimated dates for completing accrual and presenting resultsEstimated date for completing accrual will be late 2021. Estimated date for presentation of (first) results is expected in 2023.Trial registrationThe trial is registered at clinicaltrials.gov (NCT03469674) and ISRCTN (11659025).

New Pathological and Clinical Insights in Endometrial Cancer in View of the Updated ESGO/ESTRO/ESP Guidelines

“…In particular, the presence of CTNNB1 mutation may identify a subset at intermediate prognosis (similar to that of the MMRd group), while an expression of L1CAM in >10% of cancer cells may indicate poor prognosis (similar to that of the p53abn group); NSMP EECs that do not show these factors may have a good prognosis, similar to that of the POLEmut group [ 17 ]. The reliability of such refined risk stratification system is currently being assessed in a prospective trial [ 28 ]. Such substratification would allow overcoming the heterogeneous prognosis of the NSMP group and leading to a more precise risk stratification.…”

Major clinical research advances in gynecologic cancer in 2020

“…Patients with POLE mut or MMRd showed no benefit and a trend toward benefit from CCRT was observed in patients with NSMP partly due to small number of patients which deemed to be not fully powered to detect differences. The PORTEC-4a trial comparing standard adjuvant brachytherapy in women with intermediate-risk endometrial cancer with individualized adjuvant treatment on the basis of the patients' integrated molecular profile is ongoing [ 43 ] and CTNNB1 mut may become an additional molecular subgroup in NSMP patients according to the results. Although, there is still lack of evidence about the robust or cost-effective methods of detecting mutations of POLE or CTNNB1 , there seems to be no doubt to use the molecular classification in practice.…”

Innovative Follow-up Strategies for Endometrial Cancer

“…The orange arrows reflect the current reported lead time of ctDNA for detecting recurrent disease compared with radiological and clinical detection. molecular profile in higheintermediate-risk endometrial cancer [76]. Additionally, the RAINBO umbrella study is currently under development, which will randomise highrisk endometrial cancer patients based on molecular profile, and further prospective trials are required to evaluate the clinical outcomes, healthcare economics and patient acceptability of molecular-based triage strategies.…”