Adjuvant Chemoradiotherapy Yields 10-Year OS and RFS Advantages in High-Risk Endometrial Cancer

October 15, 2025

Chemoradiotherapy improved survival vs radiotherapy alone in the adjuvant setting in high-risk endometrial cancer, particularly in p53-abnormal disease.

Adjuvant chemoradiotherapy improved survival outcomes vs pelvic radiotherapy alone in patients with high-risk endometrial cancer, with the most clinically relevant benefit observed in those with p53 abnormalities, according to preplanned long-term efficacy results from the phase 3 PORTEC-3 trial (NCT00411138), which were published in The Lancet Oncology.1

At a median follow-up of 10.1 years (interquartile range [IQR], 9.8-11.0), the estimated 10-year overall survival (OS) rate was 74.4% (95% CI, 69.8%-79.4%) among patients who received chemoradiotherapy (n = 330) vs 67.3% (95% CI, 62.3%-72.7%) among those who received radiotherapy alone (n = 330; HR, 0.73; 95% CI, 0.54-0.97; P = .032). The respective 10-year recurrence-free survival (RFS) rates were 72.8% (95% CI, 67.2%-77.6%) and 67.4% (95% CI, 61.7%-72.4%; HR, 0.74; 95% CI, 0.56-0.98; P = .034).

“The 10-year [OS] and [RFS rates] deviate minimally from the previous published 5-year results,” lead study author Cathalijne C. B. Post, MD, of the Department of Radiation Oncology at Leiden University Medical Centre in Netherlands, and coauthors, wrote in the paper.1,2 “Most recurrences occurred at distant sites, with excellent local and regional nodal control in both treatment groups.”1

What Was the Design of the PORTEC-3 Trial?

The open-label, multicenter, randomized, international PORTEC-3 trial enrolled patients at least 18 years of age with high-risk endometrial cancer and a World Health Organization performance score of 0 to 2.1,2 Patients also needed to have adequate bone marrow, kidney, and liver function.

All patients underwent hysterectomy with bilateral salpingo-oophorectomy with or without lymphadenectomy. Patients were then randomly assigned 1:1 to receive pelvic radiotherapy or chemoradiotherapy. Pelvic radiotherapy was administered at 48.6 Gy in 1.8-Gy fractions 5 times per week. Chemoradiotherapy consisted of the same radiotherapy regimen plus 2 concurrent cycles of intravenous (IV) cisplatin at 50 mg/m2 in weeks 1 and 4, followed by 4 cycles of adjuvant carboplatin at an area under the curve of 5 and IV paclitaxel at 175 mg/m2 in 3-week intervals.

The trial’s original coprimary end points were 5-year OS rate and failure-free survival rate. The original secondary end points were vaginal, pelvis, or distant recurrence; treatment-related toxicity; and health-related quality of life.

In the 10-year analysis, the primary end points were 10-year OS rate and RFS rate.1 Secondary end points included long-term recurrence patterns.

What Additional Efficacy Findings Were Observed in the 10-Year PORTEC-3 Analysis?

At median follow-up, 189 patients had died, 84 from the chemoradiotherapy arm and 105 from the radiotherapy-alone arm. The deaths in these respective arms were most commonly related to endometrial cancer (77% vs 81%) and a secondary malignancy (10% vs 10%).

PORTEC-3 Trial 10-Year Analysis: Key Takeaways

Adjuvant chemoradiotherapy significantly improved the long-term outcomes for patients with high-risk endometrial cancer, resulting in higher estimated 10-year OS and RFS rates compared with pelvic radiotherapy alone.
The most clinically relevant therapeutic benefit of adjuvant chemoradiotherapy was concentrated in the molecular subgroup of patients with p53 abnormalities, a population that otherwise has a poor prognosis.
The subgroups of patients with POLE mutations and dMMR disease did not experience statistically significant benefits from the addition of chemotherapy to radiotherapy alone.

Patterns of first recurrence at 5 and 10 years were not significantly different between the 2 arms. However, there were fewer distant recurrences in the chemoradiotherapy arm (86 events) compared with in the radiotherapy-alone arm (101 events). Across both arms, most recurrences occurred within the first 2.5 years after treatment (67% vs 81%, respectively). In total, 15% of all recurrences (1 vaginal, 13 distant) in the chemoradiotherapy arm occurred after 5 years of follow-up (late recurrence); this rate was 7% (2 pelvic, 6 distant) in the radiotherapy-alone arm.

Patients with late recurrence were more likely to have low-grade disease instead of high-grade disease compared with those who had a recurrence within the first 5 years of follow-up, at rates of 68% (n = 15/22) vs 30% (n = 53/176), respectively (P = .0010). Patients with late recurrence were also more likely to have NSMP tumors (all ER positive) vs those who had a recurrence within the first 5 years of follow-up, at respective rates of 64.7% (n = 11/17) vs 25.4% (n = 29/114; P = .011).

The median OS after recurrence was 1.4 years (IQR, 0.4-4.3); this value was 1.2 years (IQR, 0.4-8.8) after chemoradiotherapy vs 1.4 years (IQR, 0.7-3.9) after radiotherapy alone (P = .90). The 5-year OS rates following recurrence in these respective arms were 27.7% (95% CI, 19.6%-39.1%) vs 21.5% (95% CI, 14.0%-30.0%). In total, 4 patients died within 5 years after recurrence due to intercurrent disease.

Factors associated with better prognosis after recurrence included:

Younger age
Low-grade endometrioid histology
ER-positive NSMP tumors
Para-aortic lymph node or single-organ lung metastases

Factors associated with poor prognosis after recurrence included:

p53 abnormalities
multiple distant sites of recurrence

Among patients with stage III disease (n = 295), the 10-year OS rate was 69.5% (95% CI, 62.4%-77.4%) in the chemoradiotherapy arm vs 56.1% (95% CI, 48.3%-65.3%) in the radiotherapy-alone arm (adjusted HR, 0.66; 95% CI, 0.45-0.97; P = .033). The respective 10-year RFS rates in this population were 67.0% (95% CI, 58.3%-74.2%) and 55.5% (95% CI, 46.5%-63.5%; adjusted HR, 0.65; 95% CI, 0.45-0.93; P = .020).

Among patients with serous cancers stages I to III (n = 105), the 10-year OS rate was 57.1% (95% CI, 45.0%-72.5%) in the chemoradiotherapy arm vs 41.8% (95% CI, 30.3%-57.8%) in the radiotherapy-alone arm (adjusted HR, 0.55; 95% CI, 0.31-0.98; P = .044). The respective 10-year RFS rates in this population were 56.4% (95% CI, 41.9%-68.5%) and 46.0% (95% CI, 32.5%-58.6%; adjusted HR, 0.47; 95% CI, 0.26-0.86; P = .013).

What Findings Were Observed in the 10-Year PORTEC-3 Post Hoc Analysis?

Molecular analysis results were available for 64% of patients in the chemoradiotherapy arm vs 61% of those in the radiotherapy alone arm. The characteristics of these patients were similar to those of the overall trial population. A post hoc molecular class analysis demonstrated that among patients with p53-abnormal tumors, the 10-year OS rate was 52.7% (95% CI, 40.8%-68.1%) with chemoradiotherapy 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 respective 10-year RFS rates in this subgroup were 52.6% (95% CI, 38.3%-65.0%) and 37.0% (95% CI, 23.7%-50.2%; HR, 0.42; 95% CI, 0.24-0.74; P = .0027). Investigators did not observe a significant OS or RFS benefit with chemoradiotherapy vs radiotherapy alone in patients with dMMR disease or POLE mutations.

The effects of treatment for patients with NSMP disease were modulated by ER status. Among patients with ER-positive NSMP disease across all stages, the respective 10-year OS rates in the chemoradiotherapy and radiotherapy-alone arms were 81.8% (95% CI, 72.2%-92.7%) vs 82.3% (95% CI, 71.8%-94.2%; log-rank P = 1.00). The respective 10-year RFS rates in this population were 75.6% (95% CI, 60.4%-85.6%) vs 67.3% (95% CI, 51.1%-9.2%; log-rank P = .40).

Among patients with ER-positive, stage III NSMP disease, the respective 10-year OS rates were 78.9% (95% CI, 66.2%-94.1%) vs 83.8% (95% CI, 70.5%-99.7%; log-rank P = .70). The respective 10-year RFS rates in this population were 74.3% (95% CI, 53.7%-86.7%) vs 60.0% (95% CI, 38.0%-76.4%; log-rank P = .30).

Among patients with ER-negative NSMP tumors, all recurrence events (chemoradiotherapy arm, n = 2/6; radiotherapy-alone arm, n = 5/7) occurred within 2.5 years after treatment. Patients with grade 3 NSMP tumors who received chemoradiotherapy had a higher 10-year RFS rate vs those who received radiotherapy alone, although this difference was not statistically significant.

Across all patients included in the post hoc analysis, the 10-year OS rates by molecular class were:

p53 abnormalities: 45.1% (95% CI, 36.2%-56.1%)
POLE mutations: 98.0% (95% CI, 94.3%-100.0%)
dMMR disease: 71.7% (95% CI, 64.2%-80.0%)
NSMP disease: 77.9% (95% CI, 70.7%-85.8%)

The 10-year RFS rates by molecular subgroup were:

p53 abnormalities: 45.3% (95% CI, 35.5%-54.7%)
POLE mutations: 98.0% (95% CI, 86.9%-99.7%)
dMMR disease 74.7% (95% CI, 67.7%-81.7%)
NSMP disease 67.8% (95% CI, 58.1%-75.8%)

“Our results emphasize the value of identifying the p53abn status of tumors compared with evaluating serous histology alone,” the authors concluded.

References

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
de Boer SM, Powell ME, Mileshkin L, et al. Adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): final results of an international, open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2018;19(3):295-309. doi:10.1016/S1470-2045(18)30079-2