Chemoradiotherapy Enhances Long-Term Survival in High-Risk Endometrial Cancer

Highlight

– Adjuvant chemoradiotherapy improves 10-year overall survival (74.4% vs 67.3%) and recurrence-free survival in high-risk endometrial cancer.
– Patients with p53 abnormal tumors derive the greatest survival benefit from chemoradiotherapy.
– No significant survival advantage was observed for patients with POLE-mutated or mismatch repair-deficient tumors with added chemotherapy.
– Molecular classification is critical in treatment tailoring due to differential chemotherapy benefit and toxicity considerations.

Study Background and Disease Burden

Endometrial cancer is the most common gynecologic malignancy in developed countries, with rising incidence related to aging populations and obesity. Generally associated with favorable outcomes, about 15%-20% of patients present with high-risk disease characterized by aggressive histologic features such as serous or clear-cell histology, high-grade tumors with deep myometrial invasion, or lymphovascular space invasion (LVSI). These patients have a notably increased risk of recurrence and mortality. Optimal adjuvant treatment strategies for high-risk endometrial cancer remain a clinical challenge, with recent shifts toward multimodal approaches. The PORTEC-3 trial provides critical long-term data addressing whether combination chemoradiotherapy improves survival outcomes compared to pelvic radiotherapy alone, alongside insights into tumor molecular subtypes that may inform personalized therapy.

Study Design

The PORTEC-3 trial was an open-label, multicenter, randomized phase 3 study including 660 women with high-risk endometrial cancer defined as stage I, grade 3 with deep myometrial invasion and/or lymphovascular space invasion; stages II-III; or stages I-III with serous or clear-cell histology. Participants were randomized to receive either pelvic radiotherapy alone or combined chemoradiotherapy, consisting of pelvic radiotherapy plus two cycles of cisplatin during radiotherapy, followed by four cycles of carboplatin and paclitaxel chemotherapy. The primary endpoints for this updated long-term analysis were 10-year overall survival and recurrence-free survival. Tumor molecular classification was performed retrospectively on 411 (62%) tumor samples, categorizing them primarily by p53 status, POLE mutation, mismatch repair deficiency (MMRd), and hormone receptor expression.

Key Findings

With a median follow-up of 10 years, 189 deaths were reported, 77% attributable to endometrial cancer. The chemoradiotherapy arm demonstrated significant improvements in outcomes compared to radiotherapy alone. Specifically, 10-year overall survival was 74.4% versus 67.3% (adjusted hazard ratio [aHR] 0.73; P = .032), and 10-year recurrence-free survival was 72.8% versus 67.4% (aHR 0.74; P = .034). Most recurrences occurred within the first 2.5 years post-treatment and were predominantly distant, reflecting excellent local and nodal control in both groups.

In molecular subgroup analyses, approximately 25% of patients harbored p53 abnormal tumors, known to portend unfavorable prognosis. These patients experienced the largest benefit from chemoradiotherapy, with 10-year overall survival improving from 36.6% with radiotherapy alone to 52.7% when combined with chemotherapy (aHR 0.52; P = .021). Conversely, patients with pathogenic POLE mutations showed excellent survival exceeding 96% with radiotherapy alone, without additional benefit from chemotherapy. Similarly, no survival advantage was observed in mismatch repair-deficient tumors when chemotherapy was added.

For tumors lacking a specific molecular profile, results were mixed. Among estrogen receptor-positive tumors, no survival benefit was evident with chemoradiotherapy (81.8% vs 82.3%). Estrogen receptor-negative tumors appeared to benefit, but this finding is limited by a small sample size and warrants cautious interpretation.

Expert Commentary

The PORTEC-3 long-term results substantiate prior evidence supporting the integration of chemotherapy with pelvic radiotherapy to improve survival in high-risk endometrial cancer. Notably, the benefit is predominantly confined to tumors with p53 abnormalities, aligning with molecular insights that these tumors exhibit aggressive biology and increased sensitivity to systemic chemotherapy. This finding emphasizes the clinical imperative for routine molecular classification of endometrial tumors to optimize adjuvant treatment selection.

However, the heterogeneous impact across molecular subgroups underscores that chemotherapy may be unnecessary—and potentially harmful—in certain patients, such as those with POLE mutations or mismatch repair deficiency, who tend to have favorable or intermediate prognoses treated effectively with radiotherapy alone. The study also exemplifies the evolving definition of high-risk disease, reflecting the dynamic integration of molecular profiling in risk stratification.

Limitations include underpowered molecular subgroup analyses due to limited sample sizes and not reaching predefined overall survival event thresholds, which may affect statistical robustness. Furthermore, open-label design introduces potential bias, although endpoints like survival are less susceptible.

Guidelines are increasingly incorporating molecular data for therapeutic decisions. The PORTEC-3 findings provide concrete clinical evidence supporting chemoradiotherapy for p53 abnormal high-risk endometrial cancer, reinforcing current expert consensus while highlighting areas for individualized treatment approaches.

Conclusion

The updated 10-year outcomes from the PORTEC-3 trial confirm that adjuvant chemoradiotherapy significantly improves long-term overall and recurrence-free survival in women with high-risk endometrial cancer, with the greatest benefit observed in patients with p53 abnormal tumors. The data support routine molecular classification to guide treatment intensity, potentially sparing low-risk molecular subtypes from the added toxicity of chemotherapy without compromising outcomes. Future research should focus on refining risk stratification, minimizing treatment-related morbidity, and exploring novel systemic agents tailored to molecular profiles to further improve survival and quality of life in this patient population.

References

Post CCB, de Boer SM, Powell ME, Mileshkin L, Katsaros D, Bessette P, Leary A, Ottevanger PB, McCormack M, Khaw P, D’Amico R, Fyles A, Chargari C, Kitchener HC, Do V, Lissoni A, Provencher D, Genestie C, Nijman HW, Whitmarsh K, Jürgenliemk-Schulz IM, Feeney A, Lutgens LCHW, Bouma J, Leon-Castillo A, Nout RA, Putter H, Bosse T, Creutzberg CL. 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 Sep 5:S1470-2045(25)00379-1. doi: 10.1016/S1470-2045(25)00379-1 IF: 35.9 Q1 B1