Adjuvant ChemoRT Yields Long-Term Survival in High-Risk Endometrial Cancer

Patients with high-risk endometrial cancer experienced improved overall survival (OS) and recurrence-free survival (RFS) benefits with adjuvant chemoradiotherapy vs radiotherapy alone, per 10-year data from the phase 3 PORTEC-3 trial (NCT00411138) published in The Lancet Oncology.¹

At a median follow-up of 10.1 years (IQR, 9.8-11.0), the estimated 10-year OS rate was 74.4% (95% CI, 69.8%-79.4%) with chemoradiotherapy (n = 330) vs 67.3% (95% CI, 62.3%-72.7%) with radiotherapy alone (n = 330; adjusted HR, 0.73; 95% CI, 0.54-0.97; P = .032). Moreover, the estimated 10-year RFS rates with chemoradiotherapy vs radiotherapy alone were 72.8% (95% CI, 67.2%-77.6%) and 67.4% (95% CI, 61.7%-72.4%), respectively (adjusted HR, 0.74; 95% CI, 0.56-0.98; P = .034).

Findings from a post-hoc analysis by molecular class showed that for women with p53 abnormal tumors, the 10-year OS rate with chemoradiotherapy was 52.7% (95% CI, 40.8%-68.1%) vs 36.6% (95% CI, 25.0%-53.7%) with radiotherapy alone (adjusted HR, 0.52; 95% CI, 0.30-0.91; P = .021); the 10-year RFS rates in this group were 52.6% (95% CI, 38.3%-65.0%) and 37.0% (95% CI, 23.7%-50.2%), respectively (adjusted HR, 0.42; 95% CI, 0.24-0.74; P = .0027). Chemoradiotherapy did not appear to be of added value vs radiotherapy alone in mismatch repair–deficient (dMMR) or POLE-mutated endometrial cancers.

“PORTEC-3 was a multicentre trial conducted through strong international collaboration, making it highly representative of current practice,” Cathalijne CB Post, MD, of the Department of Radiation Oncology at Leiden University Medical Centre, in Leiden, Netherlands, and coauthors, wrote in the paper. “This long-term analysis shows improved 10-year overall survival and recurrence-free survival for patients with high-risk endometrial cancer treated with chemoradiotherapy versus radiotherapy alone, with most clinically relevant benefit from chemoradiotherapy suggested for p53 [abnormal] cancers.”

What was the design of the PORTEC-3 trial?

The open-label, multicenter, randomized, international, phase 3 trial enrolled patients with high-risk endometrial cancer who were at least 18 years of age, had a World Health Organization performance score ranging from 0 to 2, and acceptable bone marrow, kidney, and liver function. If they had uterine sarcoma or carcinosarcoma, a prior malignancy that was not nonmelanoma skin cancer within the past decade, or they had previously received pelvic radiotherapy, hormonal therapy, or chemotherapy, they were excluded.

Study participants were randomly assigned 1:1 to receive adjuvant chemoradiotherapy or radiotherapy alone via a web-based biased-coin minimization procedure that guaranteed overall balance as well as within the following stratification factors: participating group, surgery type (lymphadenectomy: yes vs no; laparoscopic vs abdominal), stage of cancer per International Federation of Gynecology and Obstetrics 2009 criteria (IA vs IB vs II vs III), and histological type (endometrioid vs serous or clear-cell carcinoma). All participants received abdominal or laparoscopic hysterectomy with bilateral salpingo-oophorectomy plus or minus lymphadenectomy.

Those in the radiotherapy alone arm were given pelvic radiotherapy at a dose of 48.6 Gy in 1.8 Gy fractions five times per week with a brachytherapy boost if the patient had cervical stromal involvement. Those in the chemoradiotherapy arm received two concurrent cycles of cisplatin at 50 mg/m² in the first and fourth weeks of radiotherapy; this was followed by four adjuvant cycles of area under the curve 5 of carboplatin and 175 mg/m² of paclitaxel administered at 3-week intervals.

The trial’s original dual end points were OS and failure-free survival at 5 years; original secondary end points included vaginal, pelvic, or distant recurrence; treatment-related adverse effects; and health-related quality of life. For this analysis, the primary outcomes were OS and RFS at 10 years.

A total of 686 patients were enrolled between November 2006 and December 2013; 343 of patients were included in the chemoradiotherapy arm, and 343 were included in the radiotherapy alone. A total of 660 patients comprised the intention-to-treat population (n = 330/each arm). The median patient age ranged from 62.0 years to 62.4 years (range, 55.8-68.2). In the chemoradiotherapy arm, 39% of patients were younger than 60 years, 44% were between the ages of 60 and 69 years, and 18% were aged 70 years or older; in the radiotherapy alone arm, these respective rates were 42%, 39%, and 19%. Just under half of patients in the respective arms had stage III disease (46% vs 43%).

In the chemoradiotherapy arm, 39% of patients had endometroid grade 1 to 2 disease, 32% had endometroid grade 3 disease, 16% had serous disease, 9% had clear cell disease, and 4% had other; these rates were 40%, 32%, 16%, 10%, and 2% in the radiotherapy alone arm. More patients in the chemoradiotherapy arm did not have lymphovascular space invasion (60%), whereas 58% of patients in the radiotherapy alone arm did (58%). Just under half of patients in both arms had total abdominal hysterectomy and bilateral salpingo-oophorectomy plus lymph node dissection or full staging (43% vs 40%). In the chemoradiotherapy arm, 32% had dMMR, 11% had POLE mutations, 25% had p53 abnormalities, and 32% had no specific molecular profile (NSMP); in the radiotherapy alone arm, 36%, 14%, and 23% of patients had dMMR, POLE mutations, p53 abnormalities, respectively, and 27% had NSMP.

The final database lock date was December 16, 2024. At this time point, at least 7 years of follow-up were completed for 95% of patients, and at least 9 years of follow-up were completed for 89% of patients. Of the 189 patients who died, 84 were in the chemoradiotherapy arm, and 105 were in the radiotherapy alone arm. The majority of deaths were attributed to endometrial cancer (84 deaths; 105 deaths), followed by a secondary malignancy (8 deaths; 11 deaths).

What additional efficacy data were reported with chemoradiotherapy vs radiotherapy alone?

Across treatment groups, patterns and timing of recurrence were broadly similar, with most recurrences happening within the first 2.5 years after treatment; however, distant recurrences were more frequent with radiotherapy alone than with chemoradiotherapy. Late recurrences beyond 5 years were uncommon but occurred more often in patients with low-grade, estrogen receptor (ER)–positive NSMP tumors than in those with earlier relapse, with no significant differences by treatment. Survival after recurrence was poor and comparable between groups, with a median OS of approximately 1.4 years and 5-year post-recurrence survival rates below 30%. Better outcomes were linked with younger age, low-grade endometrioid histology, ER-positive NSMP tumors, and limited metastatic burden, whereas p53 abnormal tumors and multiple distant sites predicted worse prognosis.

In preplanned subgroup analyses, chemoradiotherapy was linked with significantly improved 10-year OS and RFS vs radiotherapy alone in women with stage III disease and in those with stage I to III serous cancers, highlighting a long-term benefit in these higher-risk populations, particularly those with p53 abnormal and serous histologies.

Post-hoc molecular analyses showcased marked heterogeneity in long-term outcomes by tumor class, with 10-year OS and RFS highest in POLE-mutant cancers and lowest in p53 abnormal tumors; intermediate outcomes were observed in dMMR and NSMP subgroups. Chemoradiotherapy conferred a significant survival advantage vs radiotherapy alone, particularly in those with p53 abnormal disease, improving both 10-year OS and RFS, whereas no meaningful benefit was observed in POLE-mutant cancers, which had excellent outcomes irrespective of treatment, or in dMMR tumors.

In NSMP cancers, chemoradiotherapy was linked with numerically higher OS and RFS rates, although differences were not statistically significant, including in analyses stratified by stage or ER status; ER-positive NSMP tumors demonstrated similarly favorable long-term outcomes with either treatment, whereas ER-negative NSMP tumors recurred early and had poor prognosis. Overall, these data suggest that the long-term benefit of chemoradiotherapy is largely driven by patients with p53-abnormal endometrial cancer, supporting molecular class–guided treatment stratification.

What is the significance of these findings?

“This long-term analysis of the PORTEC-3 trial with 10-year outcomes supports previous findings of a significant improvement in both overall and recurrence-free survival with chemoradiotherapy compared with radiotherapy alone for patients with high-risk endometrial cancer,” the study authors concluded. “Most recurrences occurred at distant sites, with excellent local and regional nodal control in both treatment groups. In this 10-year analysis, the prognostic and predictive value of the molecular classification and the differences between the four molecular groups in terms of the added value of chemotherapy are highlighted as they have important therapeutic implications.”

Reference

Post CCB, de Boer SM, Powell ME, et al. 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. Lancet Oncol. 2025;26(10):1370-1381. doi:10.1016/S1470-2045(25)00379-1