Materials/Methods: Women with HREC (FIGO-stage I grade 3 with deep myometrial invasion and/or LVSI; stage II or III; or serous/ clear cell histology) were randomized (1:1) to CTRT (two cycles of cisplatin 50 mg/ m 2 in week 1&4 of RT, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m 2 at 3-week intervals) or RT alone (48.6 Gy in 1.8 Gy fractions). The co-primary endpoints were overall survival (OS) and failure-free survival (FFS). Secondary endpoints vaginal, pelvic, and distant recurrence were analyzed according to first site of recurrence. The Kaplan-Meier method, log-rank test, and Cox regression analysis were used according to intention-to-treat, and competing risk methods for FFS and recurrence. Analysis of the primary endpoints was adjusted for the stratification factors (participating group, lymphadenectomy, stage of cancer and histological type). PORTEC-3 is registered with ISRCTN (ISRCTN14387080) and ClinicalTrials.gov (NCT00411138). Results: Six hundred eighty-six women were enrolled between 2006 and 2013; 26 were excluded for immediate informed consent withdrawal or ineligibility, leaving 660 patients in the final analysis, 330 CTRT and 330 RT. Median follow-up was 72.6 months (IQR 59.9-85.6). 5-year OS was 81.4% vs 76.1% for CTRT vs RT [HR 0.70, 95% CI 0.51-0.97, pZ0.034], and 5-year FFS was 76.5% vs 69.1% [HR 0.70, 95% CI 0.52-0.94, pZ0.016]. Women with serous cancers had significantly lower OS compared with other histologies (62.0% vs 81.9% at 5 years), while 5-year OS for serous cancer was 71.4% with CTRT vs 52.8% with RT [HR 0.48, 95% CI 0.24-0.96, pZ0.037], and 5-year FFS was 59.7% vs 47.9% [HR 0.42, 95% CI 0.22-0.80, pZ0.008]. For women with stage III disease an absolute 5-year OS improvement of 10% (HR 0.63, 95% CI 0.41-0.99, pZ0.043) and FFS improvement of 12.5% at (HR 0.61 (95% CI 0.42-0.89, pZ0.011) was found with CTRT. Distant metastases were the first site of recurrence in the majority of patients, 21.4% (CTRT) vs 29.1% (RT) (pZ0.047), and most patients received chemotherapy for recurrence. Survival after recurrence was 1.2 vs 1.4 years (pZ0.7). Pelvic control was high in both arms with isolated vaginal or pelvic recurrence in only 1.2%. Conclusion: This updated analysis with median FU of 6 years showed a significantly improved OS and FFS with combined adjuvant chemotherapy and radiation therapy for HREC. The largest improvement was found for women with stage III and/or serous cancers. Shared decision making remains essential to weigh the costs and benefits for individual patients.
