PORTEC-3: Adjuvant chemoradiotherapy improves 10-year OS in high-risk endometrial cancer

Adjuvant chemoradiotherapy (CRT) improves both 10-year overall survival (OS) and recurrence-free survival (RFS) in women with high-risk endometrial cancer vs pelvic radiotherapy alone, with the most clinically relevant benefit observed in p53 abnormal cancers, according to the 10-year analysis of the phase III PORTEC-3 trial.

Approximately 10–20 percent of patients with endometrial cancer present with high-risk disease, defined as International Federation of Gynaecology and Obstetrics (FIGO) 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. [Lancet Oncol 2025;doi:10.1016/S1470-2045(25)00379-1]

10- vs 5-year OS data

The open-label, multicentre, international phase III PORTEC-3 trial investigated the benefit of pelvic radiotherapy alone (48.6 Gy in 1.8 Gy fractions; n=330) vs CRT (two cycles of intravenous [IV] cisplatin 50 mg/m² during radiotherapy, followed by four cycles of IV carboplatin area-under-the-curve 5 and paclitaxel 175 mg/m² Q3W; n=330) in this at-risk population.

“To our knowledge, this is the first randomized trial with a 10-year follow-up for high-risk endometrial cancer,” noted the researchers.

After a median follow-up of 10.1 years, adjuvant CRT significantly improved both 10-year OS (74.4 vs 67.3 percent; adjusted hazard ratio [HR], 0.73; 95 percent confidence interval [CI], 0.54–0.97; p=0.032) and 10-year RFS (72.8 vs 67.4 percent; adjusted HR, 0.74; 95 percent CI, 0.56–0.98; p=0.034) vs radiotherapy alone.

Final results of PORTEC-3 (median follow-up, 60.2 months), reported in 2018, showed that adjuvant CRT did not improve 5-year OS (81.8 vs 76.7 percent; HR, 0.76; 95 percent CI, 0.54–1.06; p=0.11) vs pelvic radiotherapy alone. However, a benefit in failure-free survival was noted with CRT (75.5 vs 68.6 percent; HR, 0.71; 95 percent CI, 0.53–0.95; p=0.022). [Lancet Oncol 2018;19: 295-309]

“There were few late recurrences after 5 years of follow-up, and OS benefit in the CRT group seemed to increase slightly over time, probably due to more endometrial cancer–related deaths occurring with longer follow-up,” explained the researchers.

Analysis by molecular class

Mismatch repair–deficient (MMRd) and POLE-mutated cancers were not found to have significant OS or RFS benefit from CRT over radiotherapy alone (p>0.05 for all). [Lancet Oncol 2025;doi:10.1016/S1470-2045(25)00379-1]

Approximately one-fourth of patients (23–25 percent) had p53 abnormal tumours at baseline. Post-hoc analysis by molecular class showed significantly improved 10-year OS (52.7 vs 36.6 percent; adjusted HR, 0.52; 95 percent CI, 0.30–0.91; p=0.021) and 10-year RFS (52.6 vs 37.0 percent; adjusted HR, 0.42; 95 percent CI, 0.24–0.74; p=0.0027) with adjuvant CRT vs pelvic radiotherapy alone in patients with p53 abnormal tumours.

“In line with previous PORTEC-3 analyses, patients with stage I–III endometrial cancers with p53 abnormal tumours had the greatest benefit from CRT,” pointed out the researchers. “Among patients with stage III disease, the treatment effect was primarily driven by p53 abnormal tumours and a subset of no specific molecular profile [NSMP] cancers.”

The NSMP subgroup is heterogeneous, with multiple studies showing oestrogen receptor (ER) status to be strongly prognostic. “In this [10-year] analysis, the differences in RFS decreased over time, implying that recurrences are delayed in some patients with NSMP tumours,” commented the researchers. “For NSMP ER-negative tumours, CRT should be considered instead of either chemotherapy or radiotherapy alone.”