As reported in The Lancet Oncology by Stephanie de Boer, MD, of the Department of Radiation Oncology, Leiden University Medical Center, and colleagues, a post hoc updated survival analysis of the phase III PORTEC-3 trial has shown a significant overall survival benefit of adjuvant chemoradiotherapy vs radiotherapy in women with high-risk endometrial cancer alone after an additional year of follow-up.¹ A benefit in failure-free survival was maintained. Previously reported results showed a significant failure-free survival benefit but no significant overall survival benefit after a median follow-up of 60.2 months.² The current report included an analysis of patterns of recurrence in the trial.

Stephanie de Boer, MD

Study Details

In the open-label trial, 660 women from 103 sites within 6 clinical trial groups collaborating in the Gynecological Cancer Intergroup were randomly assigned between November 2006 and December 2013 to receive radiotherapy alone at 48.6 Gy in 1.8-Gy fractions on 5 days per week (n = 330) or chemoradiotherapy with 2 cycles of cisplatin at 50 mg/m² during radiotherapy followed by 4 cycles of carboplatin AUC = 5 and paclitaxel at 175 mg/m² (n = 330). Patients had to have International Federation of Gynecology and Obstetrics 2009 stage I endometrioid grade 3 cancer with deep myometrial invasion or lymphovascular space invasion, or both; stage II or III disease; or stage I to III disease with serous or clear cell histology. Randomization was stratified by participating center, lymphadenectomy, stage, and histologic type. The co-primary endpoints were overall survival and failure-free survival.

Overall and Failure-Free Survival Rates

At a median follow-up of 72.6 months, the estimated 5-year overall survival adjusted for stratification factors was 81.4% in the chemoradiotherapy group vs 76.1% in the radiotherapy group (adjusted hazard ratio [HR] = 0.70, P = .034). The rate of 5-year failure-free survival was 76.5% vs 69.1% (HR = 0.70, P = .016).

In post hoc exploratory analyses, the 5-year rates were 78.5% vs 68.5% (HR = 0.63, P = .043) for overall survival and 70.9% vs 58.4% (HR = 0.61, P = .011) for failure-free survival among women with stage III endometrial cancer. Among women with stage I or II disease, the 5-year rates were 83.8% vs 82.0% (HR = 0.83, P = 0.45) for overall survival and 81.3% vs 77.3% for failure-free survival (HR = 0.86, P = .51). Among patients with serous cancers, the 5-year rates were 71.4% vs 52.8% (HR = 0.48, P = .037) for overall survival and 59.7% vs 47.9% (HR = 0.42, P = .008) for failure-free survival.

Patterns of Recurrence

Distant metastases, the most common type of recurrence, constituted the first type of recurrence in 78 patients in the chemoradiotherapy group vs 98 in the radiotherapy group (5-year probability = 21.4% vs 29.1%, HR = 0.74, P = .047). Overall, distant metastases occurred in 80 vs 99 patients (5-year probability = 22.1% vs 29.4%, P = .057). Pelvic recurrence was observed in 20 vs 31 patients (5.5% vs 8.5%, HR = 0.63, P = .11), and vaginal recurrence was observed in 8 vs 8 patients (2.1% vs 2.1%, HR = 0.99, P = .99). Pelvic recurrence was the first recurrence in three vs four patients, and vaginal recurrence was the first recurrence in one patient in each group.

Adverse Events

With additional follow-up from the time of prior reports, no significant differences between groups were observed in grade ≥ 3 adverse events at 12, 36, or 60 months after randomization. At 60 months, grade 3 adverse events were reported in 8% of 201 women in the chemoradiotherapy group vs 5% of 187 women in the radiotherapy group (P = .24). One grade 4 adverse event (ileus or obstruction) was reported in a patient in the chemoradiotherapy group. The most common grade 3 adverse events were hypertension (2% vs 2%) and any pain (1% vs 2%). Grade ≥ 2 adverse events were more common in the chemoradiotherapy group, occurring in 38% of 201 women vs 23% of 187 women (P = .002); grade ≥ 2 sensory neuropathy was observed in 6% vs 0%. No treatment-related deaths were observed.

The investigators concluded: “This updated analysis shows significantly improved overall survival and failure-free survival with chemoradiotherapy vs radiotherapy alone. This treatment schedule should be discussed and recommended especially for women with stage III or serous cancer, or both, as part of shared decision making between doctors and patients. Follow-up is ongoing to evaluate long-term survival.”

The study was funded by the Dutch Cancer Society, Cancer Research UK, National Health and Medical Research Council, Project Grant, Cancer Australia Grant, Italian Medicines Agency, and the Canadian Cancer Society Research Institute. 

DISCLOSURE: For full disclosures of the study authors, visit www.thelancet.com.

REFERENCES

1. de Boer SM, Powell ME, Mileshkin L, et al: Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): Patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trial. Lancet Oncol 20:1273-1285, 2019.

2. 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 19:295-309, 2018.