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A randomized trial compared standard chemotherapy plus dostarlimab or placebo. Patients with mismatch repair–deficient tumors had 2-year progression-free survival of 61.4% with dostarlimab and 15.7% with placebo.

In patients with advanced or recurrent endometrial cancer, the addition of pembrolizumab to standard chemotherapy resulted in significantly longer progression-free survival than with chemotherapy alone.

After a median of nearly 4 years of follow-up, the use of radiotherapy combined with chemotherapy in patients with stage III or IVA endometrial carcinoma was not associated with longer relapse-free survival than the use of chemotherapy alone.

Although women with endometrial cancer generally have a favourable prognosis, those with high-risk disease features are at increased risk of recurrence. The PORTEC-3 trial was initiated to investigate the benefit of adjuvant chemotherapy during and after radiotherapy (chemoradiotherapy) versus pelvic radiotherapy alone for women with high-risk endometrial cancer. PORTEC-3 was an open-label, international, randomised, phase 3 trial involving 103 centres in six clinical trials collaborating in the Gynaecological Cancer Intergroup. Eligible women had high-risk endometrial cancer with FIGO 2009 stage I, endometrioid-type grade 3 with deep myometrial invasion or lymph-vascular space invasion (or both), endometrioid-type stage II or III, or stage I to III with serous or clear cell histology. Women were randomly assigned (1:1) to receive radiotherapy alone (48·6 Gy in 1·8 Gy fractions given on 5 days per week) or radiotherapy and chemotherapy (consisting of two cycles of cisplatin 50 mg/m2 given during radiotherapy, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m2) using a biased-coin minimisation procedure with stratification for participating centre, lymphadenectomy, stage of cancer, and histological type. The co-primary endpoints were overall survival and failure-free survival. We used the Kaplan-Meier method, log-rank test, and Cox regression analysis for final analysis by intention to treat and adjusted for stratification factors. The study was closed on Dec 20, 2013, after achieving complete accrual; follow-up is ongoing. PORTEC-3 is registered with ISRCTN, number ISRCTN14387080, and ClinicalTrials.gov, number NCT00411138. 686 women were enrolled between Nov 23, 2006, and Dec 20, 2013. 660 eligible patients were included in the final analysis, of whom 330 were assigned to chemoradiotherapy and 330 were assigned to radiotherapy. Median follow-up was 60·2 months (IQR 48·1–73·1). 5-year overall survival was 81·8% (95% CI 77·5–86·2) with chemoradiotherapy versus 76·7% (72·1–81·6) with radiotherapy (adjusted hazard ratio [HR] 0·76, 95% CI 0·54–1·06; p=0·11); 5-year failure-free survival was 75·5% (95% CI 70·3–79·9) versus 68·6% (63·1–73·4; HR 0·71, 95% CI 0·53–0·95; p=0·022). Grade 3 or worse adverse events during treatment occurred in 198 (60%) of 330 who received chemoradiotherapy versus 41 (12%) of 330 patients who received radiotherapy (p<0·0001). Neuropathy (grade 2 or worse) persisted significantly more often after chemoradiotherapy than after radiotherapy (20 [8%] women vs one [1%] at 3 years; p<0·0001). Most deaths were due to endometrial cancer; in four patients (two in each group), the cause of death was uncertain. One death in the radiotherapy group was due to either disease progression or late treatment complications; three deaths (two in the chemoradiotherapy group and one in the radiotherapy group) were due to either intercurrent disease or late treatment-related toxicity. Adjuvant chemotherapy given during and after radiotherapy for high-risk endometrial cancer did not improve 5-year overall survival, although it did increase failure-free survival. Women with high-risk endometrial cancer should be individually counselled about this combined treatment. Continued follow-up is needed to evaluate long-term survival. Dutch Cancer Society, Cancer Research UK, National Health and Medical Research Council Project Grant and Cancer Australia, L'Agenzia Italiana del Farmaco, and Canadian Cancer Society Research Institute.

Women with advanced endometrial cancer that progressed during platinum-containing therapy were randomly assigned to lenvatinib plus pembrolizumab or physician’s choice of chemotherapy (doxorubicin or paclitaxel). The median progression-free survival was 7.2 months with lenvatinib plus pembrolizumab and 3.8 months with chemotherapy; the median overall survival was 18.3 months and 11.4 months, respectively.

After surgery for intermediate-risk endometrial carcinoma, the vagina is the most frequent site of recurrence. This study established whether vaginal brachytherapy (VBT) is as effective as pelvic external beam radiotherapy (EBRT) in prevention of vaginal recurrence, with fewer adverse effects and improved quality of life. In this open-label, non-inferiority, randomised trial undertaken in 19 Dutch radiation oncology centres, 427 patients with stage I or IIA endometrial carcinoma with features of high-intermediate risk were randomly assigned by a computer-generated, biased coin minimisation procedure to pelvic EBRT (46 Gy in 23 fractions; n=214) or VBT (21 Gy high-dose rate in three fractions, or 30 Gy low-dose rate; n=213). All investigators were masked to the assignment of treatment group. The primary endpoint was vaginal recurrence. The predefined non-inferiority margin was an absolute difference of 6% in vaginal recurrence. Analysis was by intention to treat, with competing risk methods. The study is registered, number ISRCTN16228756. At median follow-up of 45 months (range 18–78), three vaginal recurrences had been diagnosed after VBT and four after EBRT. Estimated 5-year rates of vaginal recurrence were 1·8% (95% CI 0·6–5·9) for VBT and 1·6% (0·5–4·9) for EBRT (hazard ratio [HR] 0·78, 95% CI 0·17–3·49; p=0·74). 5-year rates of locoregional relapse (vaginal or pelvic recurrence, or both) were 5·1% (2·8–9·6) for VBT and 2·1% (0·8–5·8) for EBRT (HR 2·08, 0·71–6·09; p=0·17). 1·5% (0·5–4·5) versus 0·5% (0·1–3·4) of patients presented with isolated pelvic recurrence (HR 3·10, 0·32–29·9; p=0·30), and rates of distant metastases were similar (8·3% [5·1–13·4] vs 5·7% [3·3–9·9]; HR 1·32, 0·63–2·74; p=0·46). We recorded no differences in overall (84·8% [95% CI 79·3–90·3] vs 79·6% [71·2–88·0]; HR 1·17, 0·69–1·98; p=0·57) or disease-free survival (82·7% [76·9–88·6] vs 78·1% [69·7–86·5]; HR 1·09, 0·66–1·78; p=0·74). Rates of acute grade 1–2 gastrointestinal toxicity were significantly lower in the VBT group than in the EBRT group at completion of radiotherapy (12·6% [27/215] vs 53·8% [112/208]). VBT is effective in ensuring vaginal control, with fewer gastrointestinal toxic effects than with EBRT. VBT should be the adjuvant treatment of choice for patients with endometrial carcinoma of high-intermediate risk. Dutch Cancer Society.

The PORTEC-3 trial investigated the benefit of chemoradiotherapy versus pelvic radiotherapy alone for women with high-risk endometrial cancer. We present the preplanned long-term analysis of the randomised PORTEC-3 trial with a post-hoc analysis including molecular classification of the tumours. PORTEC-3 was an open-label, multicentre, randomised, international phase 3 trial. Women were eligible if they had high-risk endometrial cancer (either International Federation of Gynecology and Obstetrics 2009 stage I, grade 3, with deep myometrial invasion and/or lymphovascular space invasion; stage II–III; or stage I–III with serous or clear-cell histology), were aged 18 years or older, and had a WHO performance score of 0–2. Participants were randomly assigned (1:1) to receive pelvic radiotherapy (48·6 Gy in 1·8 Gy fractions) or chemoradiotherapy (radiotherapy combined with two cycles of cisplatin 50 mg/m2 intravenously in weeks one and four, followed by four cycles of carboplatin area-under-the-curve 5 and paclitaxel 175 mg/m2 intravenously at 3-week intervals). Randomisation was done by use of biased-coin minimisation with stratification for participating centre, lymphadenectomy, stage, and histological type. We report the primary outcomes of overall survival and recurrence-free survival at 10 years. We also report primary outcomes by molecular subgroup in a post-hoc analysis. Survival was analysed in the intention-to-treat population. The study is registered with ClinicalTrials.gov (NCT00411138) and is now complete. Between Nov 23, 2006, and Dec 20, 2013, 660 eligible and evaluable patients recruited at 103 centres in six clinical trial groups across seven countries were randomly assigned to chemoradiotherapy (n=330) or radiotherapy alone (n=330). Median follow-up was 10·1 years (IQR 9·8–11·0). Estimated 10-year overall survival was 74·4% (95% CI 69·8–79·4) in the chemoradiotherapy group and 67·3% (62·3–72·7) in the radiotherapy group (adjusted hazard ratio [HR] 0·73 [95% CI 0·54–0·97], p=0·032), and 10-year recurrence-free survival was 72·8% (67·2–77·6) versus 67·4% (61·7–72·4; adjusted HR 0·74 [95% CI 0·56–0·98], p=0·034). Molecular analysis was available for 411 (62%) patients (210 [64%] of 330 patients in the chemoradiotherapy group and 201 [61%] of 330 patients in the radiotherapy group), whose characteristics were similar to the overall trial population. Post-hoc analysis by molecular class showed that, for women with p53 abnormal tumours, 10-year overall survival was 52·7% (95% CI 40·8–68·1) with chemoradiotherapy versus 36·6% (25·0 to 53·7) with radiotherapy alone (adjusted HR 0·52 [95% CI 0·30–0·91], p=0·021); 10-year recurrence-free survival was 52·6% (95% CI 38·3 to 65·0) versus 37·0% (95% CI 23·7 to 50·2; HR 0·42 [95% CI 0·24 to 0·74], p=0·0027). MMRd and POLEmut cancers did not seem to benefit from chemoradiotherapy over radiotherapy alone, whereas the effects for NSMP cancers were modulated by oestrogen-receptor status. 10-year overall survival and recurrence-free survival were improved for patients with high-risk endometrial cancer treated with adjuvant chemoradiotherapy versus radiotherapy alone, with most clinically relevant benefit suggested for p53 abnormal cancers. Dutch Cancer Society, Cancer Research UK, National Health and Medical Research Council Australia, Cancer Australia, Italian Medicines Agency, and the Canadian Cancer Society Research Institute.

Early endometrial cancer with low-risk pathological features can be successfully treated by surgery alone. External beam radiotherapy added to surgery has been investigated in several small trials, which have mainly included women at intermediate risk of recurrence. In these trials, postoperative radiotherapy has been shown to reduce the risk of isolated local recurrence but there is no evidence that it improves recurrence-free or overall survival. We report the findings from the ASTEC and EN.5 trials, which investigated adjuvant external beam radiotherapy in women with early-stage disease and pathological features suggestive of intermediate or high risk of recurrence and death from endometrial cancer. Between July, 1996, and March, 2005, 905 (789 ASTEC, 116 EN.5) women with intermediate-risk or high-risk early-stage disease from 112 centres in seven countries (UK, Canada, Poland, Norway, New Zealand, Australia, USA) were randomly assigned after surgery to observation (453) or to external beam radiotherapy (452). A target dose of 40–46 Gy in 20–25 daily fractions to the pelvis, treating five times a week, was specified. Primary outcome measure was overall survival, and all analyses were by intention to treat. These trials were registered ISRCTN 16571884 (ASTEC) and NCT 00002807 (EN.5). After a median follow-up of 58 months, 135 women (68 observation, 67 external beam radiotherapy) had died. There was no evidence that overall survival with external beam radiotherapy was better than observation, hazard ratio 1·05 (95% CI 0·75–1·48; p=0·77). 5-year overall survival was 84% in both groups. Combining data from ASTEC and EN.5 in a meta-analysis of trials confirmed that there was no benefit in terms of overall survival (hazard ratio 1·04; 95% CI 0·84–1·29) and can reliably exclude an absolute benefit of external beam radiotherapy at 5 years of more than 3%. With brachytherapy used in 53% of women in ASTEC/EN.5, the local recurrence rate in the observation group at 5 years was 6·1%. Adjuvant external beam radiotherapy cannot be recommended as part of routine treatment for women with intermediate-risk or high-risk early-stage endometrial cancer with the aim of improving survival. The absolute benefit of external beam radiotherapy in preventing isolated local recurrence is small and is not without toxicity. Medical Research Council, National Cancer Research Network, National Cancer Institute of Canada, with funds from the Canadian Cancer Society.

Background: Breast cancer 1, early onset ( BRCA1 ) is a tumour-suppressor gene associated with familial epithelial ovarian cancer (EOC). Reduced BRCA1 expression is associated with enhanced sensitivity to platinum-based chemotherapy. We sought to examine the prognostic relevance of BRCA1 expression in EOC patients treated with intraperitoneal platinum/taxane. Methods: The GOG-172 was a phase III, multi-institutional randomised trial of intravenous paclitaxel and cisplatin (IV therapy) vs intravenous paclitaxel, intraperitoneal cisplatin plus paclitaxel (IP therapy) in patients with optimally resected stage III EOC. The BRCA1 expression was assessed with immunohistochemistry (IHC) staining blinded to clinical outcome in archival tumour specimens. Slides with ⩽10% staining were defined as aberrant and >10% as normal. Correlations between BRCA1 expression and progression-free survival (PFS) and overall survival (OS) were analysed using Kaplan–Meier method and Cox regression analysis. Results: Of the 393 patients, 189 tumours had aberrant expression, and 204 had normal BRCA1 expression. There was an interaction between BRCA1 expression and route of administration on OS ( P =0.014) but not PFS ( P =0.054). In tumours with normal BRCA1 expression, the median OS was 58 months for IP group vs 50 months for IV group ( P =0.818). In tumours with aberrant BRCA1 expression, the median OS was 84 vs 47 months in the IP vs IV group, respectively ( P =0.0002). Aberrant BRCA1 expression was an independent prognostic factor for better survival in women randomised to IP therapy (hazard ratio (HR)=0.67, 95% confidence interval (CI)=0.47–0.97, P =0.032). Similar survival was observed in the IV and IP patients with normal BRCA1 expression. Multivariate but not univariate modelling demonstrated that IV patients with aberrant vs normal BRCA1 expression had worse survival. Conclusion: Decreased BRCA1 expression is associated with a 36-month survival improvement in patients with EOC treated with IP chemotherapy. Although these results merit validation in future studies, the results suggest that decreased BRCA1 expression predicts for improved response to cisplatin-based IP chemotherapy with cisplatin and paclitaxel.

Single-agent maintenance poly(ADP-ribose) polymerase (PARP) inhibition may represent an effective strategy in patients with advanced/metastatic endometrial cancer responding to platinum-based chemotherapy, including for molecular subtypes with suboptimal options. To explore this approach, we initiated the randomized phase IIb UTOLA trial (NCT03745950). Female patients without progression following front-line platinum-based chemotherapy for advanced/metastatic endometrial cancer were randomized 2:1 to twice-daily maintenance oral olaparib 300 mg or placebo until progression or intolerance, stratified by p53 status, mismatch repair status, and response to initial chemotherapy. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. Secondary endpoints were PFS in subgroups, time to second progression or death, time to first and second subsequent therapy, objective response rate, overall survival, patient-reported outcomes, and safety. In the intention-to-treat population ( n  = 145), there was no PFS difference between olaparib and placebo (median 5.6 vs. 4.0 months, respectively; hazard ratio 0.94, 95% confidence interval 0.65–1.35; p  = 0.74). However, intriguing numerical PFS effects were observed in exploratory analyses of pre-specified subgroups (p53-abnormal, complete response to initial chemotherapy, chromosomal instability). There was no overall survival difference between treatments. Grade 3/4 adverse events occurred in 36% versus 10% of olaparib- versus placebo-treated patients and were consistent with the olaparib safety profile in other cancers. Maintenance olaparib did not improve PFS, but promising numerical effects in subsets of patients warrant prospective evaluation. Single-agent maintenance PARP inhibition may represent an effective strategy for advanced/metastatic endometrial cancer treatment. Here this randomized phase IIb UTOLA trial evaluates the efficacy and safety of orally administered olaparib in female patients ( n = 145) without progression following front-line platinum-based chemotherapy for advanced/metastatic endometrial cancer.