PORTEC-4a Trial Reports Molecular Profile Guided Adjuvant Treatment

Key Takeaways

• Five-year vaginal recurrence was numerically higher with the molecular-profile strategy, although the prespecified non-inferiority criterion was met.
• Favorable profiles were assigned observation, intermediate profiles brachytherapy, and unfavorable profiles pelvic radiotherapy.
• Adverse events were mainly grade 1–2, severe genitourinary toxicities were uncommon in both groups, and the investigators described the strategy as safe and effective.

After surgery for high-intermediate risk endometrial cancer, PORTEC-4a found that molecular profile-guided adjuvant treatment met the prespecified non-inferiority test against standard vaginal brachytherapy for 5-year vaginal recurrence. The 5-year cumulative incidence of vaginal recurrence was 4.5% with the molecular-profile strategy and 1.6% with standard brachytherapy. Women entered the randomized comparison after surgical management of early stage disease. The trial evaluated individualized adjuvant allocation based on favorable, intermediate, or unfavorable integrated risk profiles after surgery. PORTEC-4a was conducted across multiple European centres.

PORTEC-4a was a randomized, open-label, phase 3, multicenter, non-inferiority trial across eight European countries. Eligible women were aged 18 years or older, had WHO performance status 0–2, and had early stage high-intermediate risk endometrial cancer after surgery. Patients were assigned in a 2:1 ratio to molecular integrated risk profile-guided adjuvant treatment or standard vaginal brachytherapy, using biased-coin minimization with stratification for centre, grade, and lymphadenectomy. The final eligible and evaluable cohort included 564 patients, with 367 in the molecular-profile group and 197 in the standard group, and median follow-up was 58.1 months. Within the molecular-profile group, 168 patients had favorable profiles, 148 intermediate profiles, and 51 unfavorable profiles, corresponding to observation, brachytherapy, and pelvic radiotherapy.

The primary endpoint was overall 5-year cumulative incidence of vaginal recurrence as the first event. In the final analysis, rates were 4.5% in the molecular-profile group and 1.6% in the standard group, with a hazard ratio of 2.71. The upper bound of the one-sided confidence interval for the difference was 5.3%, below the predefined 7.0% margin. The p value for non-inferiority was 0.005, supporting the trial’s prespecified non-inferiority conclusion. In the favorable-profile analysis, 5-year vaginal recurrence was 4.1% versus 0.9%, with a hazard ratio of 3.97.

Adverse events were mainly grade 1–2, with no substantial safety differences between groups. Grade 3 or higher related genitourinary toxicities occurred in four patients (1%) in the molecular-profile group and four patients (2%) in the standard group. Five serious adverse events occurred overall, including one case of vaginal scar dehiscence that was possibly treatment related. No treatment-related deaths were reported during follow-up.

The investigators described the molecular-profile strategy as safe and effective and said it spared 46% of favorable-profile patients from adjuvant treatment while reducing overtreatment and undertreatment overall.