10-Year PORTEC-3 Outcomes: Chemoradiotherapy in High-Risk Endometrial Cancer

The final long-term results of the PORTEC-3 trial, now with 10 years of follow-up data, provide refined evidence on the comparative effectiveness of adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer.

Published in The Lancet Oncology, this multicenter, randomized, phase 3 trial also incorporates a post-hoc molecular classification analysis, supporting treatment stratification based on tumor biology.

Trial Overview and Key Findings

The trial enrolled 660 eligible patients with high-risk endometrial cancer, which was defined as:

• Stage I, grade 3, with deep myometrial invasion and/or lymphovascular space invasion
• Stage II–III
• Stage I–III with serous or clear-cell histology.

Participants were randomized to receive either pelvic radiotherapy (48.6 Gy in 1.8 Gy fractions) o r chemoradiotherapy (two cycles of concurrent cisplatin during radiotherapy, followed by four cycles of carboplatin-paclitaxel).

At a median follow-up of 10 years:

• Overall survival (OS) was significantly higher in the chemoradiotherapy group: 74.4% vs. 67.3% (adjusted HR 0.73, 95% CI 0.54–0.97; p=0.032).
• Recurrence-free survival (RFS) was also improved: 72.8% vs. 67.4% (adjusted HR 0.74, 95% CI 0.56–0.98; p=0.034).

These findings are consistent with earlier 5-year outcomes from PORTEC-3 and affirm the long-term benefit of chemoradiotherapy in this patient population.

Molecular Classification and Differential Treatment Effect

A post-hoc molecular analysis, feasible in 62% of cases, stratified tumors into four subgroups: POLE ultramutated (POLEmut), mismatch repair deficient (MMRd), p53-abnormal (p53abn), and no specific molecular profile (NSMP).

Results indicated heterogeneity in treatment benefit by molecular class:

• p53abn tumors (n=99): Chemoradiotherapy was associated with improved 10-year overall survival (52.7% vs 36.6%; HR 0.52, 95% CI 0.30–0.91; p=0.021) and recurrence-free survival (52.6% vs 37.0%; HR 0.42, 95% CI 0.24–0.74; p=0.0027).
• POLEmut tumors (n=51): Excellent outcomes were observed regardless of treatment arm (96–100% 10-year OS and RFS), suggesting minimal added benefit from chemotherapy.
• MMRd tumors (n=139): There was no statistically significant difference in OS or RFS between treatment arms.
• NSMP tumors (n=122): Chemoradiotherapy showed a non-significant trend toward improved recurrence-free survival (72.8% vs 61.7%; adjusted HR 0.61, p=0.13). OS showed a similar trend (81.2% vs 74.1%; adjusted HR 0.60; p=0.21).

These findings support the prognostic and potentially predictive relevance of molecular classification, aligning with current international guidelines that incorporate molecular markers in endometrial cancer management.

Patterns of Recurrence and Late Outcomes

Most recurrences occurred within the first 2.5 years after treatment, predominantly at distant sites. Rates of vaginal and pelvic recurrence remained low across both groups, reflecting effective locoregional control with radiotherapy. Late recurrences (>5 years) were uncommon and more frequently observed in NSMP tumors with low-grade and ER-positive features.

Median overall survival after recurrence was 1.4 years, with modest survival differences between treatment groups.

Considerations for Clinical Application

The 10-year data from PORTEC-3 support the long-term benefit of chemoradiotherapy in improving survival for women with high-risk endometrial cancer, particularly those with stage III disease and p53-abnormal tumors. Conversely, the absence of significant benefit in POLEmut and MMRd tumors raises the possibility of treatment de-intensification or alternate systemic strategies, such as immunotherapy, which are currently under investigation in ongoing trials.

While molecular stratification appears to refine risk assessment and treatment allocation, limitations of the study include the post-hoc nature of the molecular subgroup analysis, lack of power for interaction testing, and incomplete molecular data in approximately one-third of patients. Nonetheless, the molecularly defined subgroups were well balanced between arms and reflective of the broader trial population.

Overall, these findings reinforce the role of integrated clinicopathological and molecular risk assessment in guiding adjuvant treatment for high-risk endometrial cancer.

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. The Lancet Oncology. 2025;26:1370-1381. https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(25)00379-1/fulltext