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

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

Vaginal 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. To 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 brachytherapy STUDY HYPOTHESIS: Adjuvant 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. A multicenter, international phase III randomized trial (2:1) of molecular-integrated risk profile-based adjuvant treatment (experimental arm) or adjuvant vaginal brachytherapy (standard arm). Women 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). The 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. 500 eligible and evaluable patients. Estimated date for completing accrual will be late 2021. Estimated date for presentation of (first) results is expected in 2023. The trial is registered at clinicaltrials.gov (NCT03469674) and ISRCTN (11659025).

Molecular profile-based adjuvant treatment for women with high-intermediate risk endometrial cancer (PORTEC-4a): results of a randomised, open-label, phase 3, multicentre, non-inferiority trial

PORTEC-4a investigated molecular risk profile-based individualised adjuvant treatment for women with high-intermediate risk endometrial cancer, aiming to reduce both overtreatment and undertreatment while optimising locoregional control. PORTEC-4a was a randomised, open-label, phase 3, multicentre, non-inferiority trial, conducted across eight European countries. Women (aged ≥18 years and with a WHO performance score of 0-2) with early stage high-intermediate risk endometrial cancer were eligible. Patients were randomly assigned post-surgery in a 2:1 ratio to either adjuvant treatment according to their molecular integrated risk profile or to standard vaginal brachytherapy. Allocation used a biased-coin minimisation with stratification for participating centre, grade, and lymphadenectomy. Adjuvant treatment in the molecular-profile group in case of favourable profile (POLE-mutated or no specific molecular profile [NSMP]-CTNNB1 wildtype) was observation, for intermediate profile (mismatch repair deficient or NSMP-CTNNB1 mutated) was brachytherapy (21 Gy in three fractions of 7 Gy given at 5 to 7 day intervals), and for unfavourable profile (p53 abnormal or substantial lymphovascular space invasion or L1 cell adhesion molecule overexpression) was pelvic radiotherapy (45·0-48·6 Gy in 1·8-2·0 Gy fractions, 5 days per week). The primary endpoint was overall 5-year cumulative incidence of vaginal recurrence as first event. Kaplan-Meier, Cox model, and cumulative incidence with competing risks were used for final analysis in the intention-to-treat population. Patient advocates were involved during grant application and trial conduct. The trial is registered with the Netherlands Trial Registry (NTR5841), the ISRCTN registry (ISRCTN11659025), and ClinicalTrials.gov (NCT03469674), and follow-up is ongoing. Between June 1, 2016, and Dec 24, 2021, 569 patients were enrolled in PORTEC-4a. After the addition of 23 favourable patients out of PORTEC-4, the final combined PORTEC-4a cohort consisted of 564 eligible and evaluable patients (367 in the molecular profile group and 197 in the standard group). All patients were female, the median age was 69·0 years (IQR 63·0-73·5), and data on race and ethnicity were not collected. Median follow-up was 58·1 months (IQR 40·7-63·6). In the molecular profile group 168 (46%) patients had a favourable profile, 148 (40%) had an intermediate profile, and 51 (14%) had an unfavourable profile. The 5-year cumulative incidence of vaginal recurrence was 4·5% (95% CI 2·23-6·76) in the molecular profile group and 1·6% (0·00-3·32) in the standard group (HR 2·71 [95% CI 0·79-9·34]). The upper-bound of the one-sided confidence interval of the difference (5·3%) was below the predefined-equivalence margin of 7·0% (p Individualised adjuvant treatment by molecular integrated risk profile is safe and effective for patients with high-intermediate risk endometrial cancer; it spared 46% of patients with a favourable profile from adjuvant treatment, and reduces both overtreatment and undertreatment. KWF Dutch Cancer Society.