Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): 10-year clinical outcomes and post-hoc analysis by molecular classification from a randomised phase 3 trial

Abstract

Background: The PORTEC-3 trial investigated the benefit of chemoradiotherapy versus pelvic radiotherapy alone for women with high-risk endometrial cancer. We present the preplanned long-term analysis of the randomised PORTEC-3 trial with a post-hoc analysis including molecular classification of the tumours.

Methods: PORTEC-3 was an open-label, multicentre, randomised, international phase 3 trial. Women were eligible if they had high-risk endometrial cancer (either International Federation of Gynecology and Obstetrics 2009 stage I, grade 3, with deep myometrial invasion and/or lymphovascular space invasion; stage II-III; or stage I-III with serous or clear-cell histology), were aged 18 years or older, and had a WHO performance score of 0-2. Participants were randomly assigned (1:1) to receive pelvic radiotherapy (486 Gy in 18 Gy fractions) or chemoradiotherapy (radiotherapy combined with two cycles of cisplatin 50 mg/m(2) intravenously in weeks one and four, followed by four cycles of carboplatin area-under-the-curve 5 and paclitaxel 175 mg/m(2) intravenously at 3-week intervals). Randomisation was done by use of biased-coin minimisation with stratification for participating centre, lymphadenectomy, stage, and histological type. We report the primary outcomes of overall survival and recurrence-free survival at 10 years. We also report primary outcomes by molecular subgroup in a post-hoc analysis. Survival was analysed in the intention-to-treat population. The study is registered with ClinicalTrials.gov (NCT00411138) and is now complete.

Findings: Between Nov 23, 2006, and Dec 20, 2013, 660 eligible and evaluable patients recruited at 103 centres in six clinical trial groups across seven countries were randomly assigned to chemoradiotherapy (n=330) or radiotherapy alone (n=330). Median follow-up was 101 years (IQR 98-110). Estimated 10-year overall survival was 744% (95% CI 698-794) in the chemoradiotherapy group and 673% (623-727) in the radiotherapy group (adjusted hazard ratio [HR] 073 [95% CI 054-097], p=0032), and 10-year recurrence-free survival was 728% (672-776) versus 674% (617-724; adjusted HR 074 [95% CI 056-098], p=0034). Molecular analysis was available for 411 (62%) patients (210 [64%] of 330 patients in the chemoradiotherapy group and 201 [61%] of 330 patients in the radiotherapy group), whose characteristics were similar to the overall trial population. Post-hoc analysis by molecular class showed that, for women with p53 abnormal tumours, 10-year overall survival was 527% (95% CI 408-681) with chemoradiotherapy versus 366% (250 to 537) with radiotherapy alone (adjusted HR 052 [95% CI 030-091], p=0021); 10-year recurrence-free survival was 526% (95% CI 383 to 650) versus 370% (95% CI 237 to 502; HR 042 [95% CI 024 to 074], p=00027). MMRd and POLEmut cancers did not seem to benefit from chemoradiotherapy over radiotherapy alone, whereas the effects for NSMP cancers were modulated by oestrogen-receptor status. Interpretation: 10-year overall survival and recurrence-free survival were improved for patients with high-risk endometrial cancer treated with adjuvant chemoradiotherapy versus radiotherapy alone, with most clinically relevant benefit suggested for p53 abnormal cancers.