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BACKGROUND:The PORTEC-3 trial investigated the benefit of combined adjuvant chemotherapy and radiotherapy versus pelvic radiotherapy alone for women with high-risk endometrial cancer. We updated the analysis to investigate patterns of recurrence and did a post-hoc survival analysis.METHODS:In the multicentre randomised phase 3 PORTEC-3 trial, women with high-risk endometrial cancer were eligible if they had International Federation of Gynaecology and Obstetrics (FIGO) 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-III disease with serous or clear cell histology; were aged 18 years and older; and had a WHO performance status of 0-2. Participants were randomly assigned (1:1) to receive radiotherapy alone (48·6 Gy in 1·8 Gy fractions given on 5 days per week) or chemoradiotherapy (two cycles of cisplatin 50 mg/m2 given intravenously during radiotherapy, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m2 given intravenously), by use of a biased coin minimisation procedure with stratification for participating centre, lymphadenectomy, stage, and histological type. The co-primary endpoints were overall survival and failure-free survival. Secondary endpoints of vaginal, pelvic, and distant recurrence were analysed according to the first site of recurrence. Survival endpoints were analysed by intention-to-treat, and adjusted for stratification factors. Competing risk methods were used for failure-free survival and recurrence. We did a post-hoc analysis to analyse patterns of recurrence with 1 additional year of follow-up. The study was closed on Dec 20, 2013; follow-up is ongoing. This study is registered with ISRCTN, number ISRCTN14387080, and ClinicalTrials.gov, number NCT00411138.FINDINGS:Between Nov 23, 2006, and Dec 20, 2013, 686 women were enrolled, of whom 660 were eligible and evaluable (330 in the chemoradiotherapy group, and 330 in the radiotherapy-alone group). At a median follow-up of 72·6 months (IQR 59·9-85·6), 5-year overall survival was 81·4% (95% CI 77·2-85·8) with chemoradiotherapy versus 76·1% (71·6-80·9) with radiotherapy alone (adjusted hazard ratio [HR] 0·70 [95% CI 0·51-0·97], p=0·034), and 5-year failure-free survival was 76·5% (95% CI 71·5-80·7) versus 69·1% (63·8-73·8; HR 0·70 [0·52-0·94], p=0·016). Distant metastases were the first site of recurrence in most patients with a relapse, occurring in 78 of 330 women (5-year probability 21·4%; 95% CI 17·3-26·3) in the chemoradiotherapy group versus 98 of 330 (5-year probability 29·1%; 24·4-34·3) in the radiotherapy-alone group (HR 0·74 [95% CI 0·55-0·99]; p=0·047). Isolated vaginal recurrence was the first site of recurrence in one patient (0·3%; 95% CI 0·0-2·1) in both groups (HR 0·99 [95% CI 0·06-15·90]; p=0·99), and isolated pelvic recurrence was the first site of recurrence in three women (0·9% [95% CI 0·3-2·8]) in the chemoradiotherapy group versus four (0·9% [95% CI 0·3-2·8]) in the radiotherapy-alone group (HR 0·75 [95% CI 0·17-3·33]; p=0·71). At 5 years, only one grade 4 adverse event (ileus or obstruction) was reported (in the chemoradiotherapy group). At 5 years, reported grade 3 adverse events did not differ significantly between the two groups, occurring in 16 (8%) of 201 women in the chemoradiotherapy group versus ten (5%) of 187 in the radiotherapy-alone group (p=0·24). The most common grade 3 adverse event was hypertension (in four [2%] women in both groups). At 5 years, grade 2 or worse adverse events were reported in 76 (38%) of 201 women in the chemoradiotherapy group versus 43 (23%) of 187 in the radiotherapy-alone group (p=0·002). Sensory neuropathy persisted more often after chemoradiotherapy than after radiotherapy alone, with 5-year rates of grade 2 or worse neuropathy of 6% (13 of 201 women) versus 0% (0 of 187). No treatment-related deaths were reported.INTERPRETATION:This updated analysis shows significantly improved overall survival and failure-free survival with chemoradiotherapy versus radiotherapy alone. This treatment schedule should be discussed and recommended, especially for women with stage III or serous cancers, or both, as part of shared decision making between doctors and patients. Follow-up is ongoing to evaluate long-term survival.FUNDING: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.

Introduction Here we aimed to evaluate the prevalence and prognosis of Lynch Syndrome (LS)-associated endometrial cancer (EC) in relation to sporadic mismatch repair deficient EC (MMRd-EC) in the combined PORTEC-1,-2 and 3 trials comprising 1336 ECs. Methods MMR-status was determined by MMR-immunohistochemistry (MLH1/PMS2/MSH6/MSH2). MMRd-ECs with detected promoter hypermethylation of MLH1 were classified as sporadic (methylated MMRd-EC). For unmethylated MMRd-EC cases tumor and normal tissue next-generation sequencing was performed. ECs with MMR germline mutations were classified as LS-associated (LS MMRd-EC). Unmethylated MMRd-ECs without MMR germline mutations were classified as MMRd-EC due to other causes (other MMRd-EC). Overall and recurrence-free survival were estimated and compared using Kaplan-Meier method and pairwise log-rank test. Results Among the 1336 ECs, 926 were MMR proficient. Of the 410 MMRd-EC, 376 could be fully triaged; 281 (75%) were methylated MMRd-ECs; 37 (10%) LS MMRd-ECs, and 58 (15%) other MMRd-ECs. The overall LS prevalence was 2.8%. Overall 5-year survival for LS MMRd-EC was 89% (95%CI 79–100%; p=0.055), other MMRd-EC 96% (92–100%; p=0.001), both compared to methylated MMRd-EC 79% (74–84%); 5-year recurrence-free survival was 92% (84–100%; p=0.123), 95% (89–100%; p=0.002), compared to 79% (74–84%), respectively. Conclusion The prevalence of LS in the PORTEC EC trial population was 3% and within the MMRd group 10%. LS MMRd-EC seems to have a better overall and recurrence-free survival than sporadic MMRd-EC caused by hypermethylation. Further research into the underlying causes of non-hypermethylated somatic MMRd-EC is ongoing.

Of the 172 patients with carcinoma of the esophagus or the gastro-esophageal junction seen between January 1978 and January 1981, 69 patients had combined treatment, radiotherapy and resection, and 38 had curative radiotherapy. The remaining 65 were treated palliatively. The 4-year actuarial survival of the first two treatment groups was respectively 40% and 4%. The resectability rate of the operated patients was 84% with a post-operative mortality of 20%. The tumor size and sex were two important prognostic factors. Patients with combined treatment and a tumor size of less than two corresponding underlying vertebrae, had a 4-year actuarial survival of 60%.