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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.

Radical hysterectomy and complete pelvic lymphadenectomies are the most commonly performed procedures for women with early-stage cervical cancer. Sentinel lymph node (SLN) mapping could be an alternative to routine pelvic lymphadenectomy, aiming to diagnose accurately nodal extension and decrease lymphatic morbidity. To compare 3-year disease-free survival and health-related quality of life after SLN biopsy or SLN biopsy + pelvic lymphadenectomy in early cervical cancer. We hypothesize that disease-free survival is non-inferior and health-related quality of life superior after SLN biopsy compared with SLN biopsy + pelvic lymphadenectomy. International, randomized, multicenter, single-blind trial. The study will be run by teams trained to carry out SLN biopsy, belonging to clinical research cooperative groups or recognized as experts in this field. Patients with an optimal mapping (Memorial Sloan Kettering Cancer Center [MSKCC] criteria) and a negative frozen section will be randomized 1:1 to SLN biopsy only or SLN biopsy + pelvic lymphadenectomy. Patients with early stages (Ia1 with lymphovascular invasion to IIa1) of disease. Histological types are limited to squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma. Main endpoint will be co-primary endpoint, associating 3-year disease-free survival and quality of life (QLQ-C30 and QLQ-CX24). 950 patients need to be randomized. Estimated dates for completing accrual and presenting results: study started on Q2 2018, last accrual is scheduled for Q2 2021, and last follow-up in Q2 2026. ClinicalTrials.gov identifier: NCT03386734.

Endometrial carcinosarcoma is a rare and aggressive high-grade endometrial carcinoma with secondary sarcomatous trans-differentiation (conversion theory). The clinical presentation and diagnostic work-up roughly align with those of the more common endometrioid counterpart, although endometrial carcinosarcoma is more frequently diagnosed at an advanced stage. Endometrial carcinosarcoma is not a single entity but encompasses different histological subtypes, depending on the type of carcinomatous and sarcomatous elements. The majority of endometrial carcinosarcomas are characterized by p53 abnormalities. The proportion of POLE and microsatellite instablity-high (MSI-H) is directly related to the epithelial component, being approximately 25% and 3% in endometrioid and non-endometrioid components.The management of non-metastatic disease is based on a multimodal approach with optimal surgery followed by (concomitant or sequential) chemotherapy and radiotherapy, even for early stages. Palliative chemotherapy is recommended in the metastatic or recurrent setting, with carboplatin/paclitaxel doublet being the first-line regimen. Although the introduction of immunotherapy plus/minus a tyrosine kinase inhibitor shifted the paradigm of treatment of patients with recurrent endometrial cancer, patients with endometrial carcinosarcoma were excluded from most studies evaluating single-agent immunotherapy or the combination. However, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved the use of pembrolizumab and lenvatinib in endometrial cancer (all histotypes) after progression on chemotherapy and single-agent immunotherapy in MSI-H cancers. In the era of precision medicine, emerging knowledge on molecular endometrial carcinosarcoma is opening new promising therapeutic options for more personalized treatment. The present review outlines state-of-the-art knowledge and future directions for patients with endometrial carcinosarcoma.

Cervical cancer is a global health problem which disproportionally affects women in low- and middle- income countries. The World Health Organization recently launched its global strategy to eliminate this disease in the next two decades. For those women diagnosed today with cervical cancer better strategies are needed to improve outcome and reduce treatment-related morbidity. Clinical trials are critical to shaping future treatment, and much has been achieved already. However, such opportunities are limited in low resource settings, and the Cervical Cancer Research Network is dedicated to expanding access to new technologies in surgery, radiation, and medical oncology. In this article we review the status of the trials portfolio and outline future objectives, including the launch of a number of research grants for aspiring or established researchers in low- and middle-income settings

ObjectiveDespite advances in cervical cancer prevention and diagnosis, outcomes for patients given a diagnosis of advanced and recurrent disease are poor. In the GOG240 trial, the addition of bevacizumab to paclitaxel-topotecan or paclitaxel-cisplatin has been shown to prolong survival compared with paclitaxel-topotecan or paclitaxel-cisplatin in patients with persistent, recurrent, or metastatic disease. However, standards of care vary between regions and countries. The purpose of this systematic review and network meta-analysis was to enable a comparison between bevacizumab + chemotherapy with multiple monotherapy or combination chemotherapy regimens in the treatment for women with advanced, recurrent, or persistent cervical cancer.Methods/MaterialsA systematic literature review was conducted to identify randomized or nonrandomized controlled trials of patients with recurrent, persistent, or metastatic cervical cancer published in English from 1999 to 2015. A feasibility study was performed to assess the heterogeneity of the trials, and a network meta-analysis was conducted. Fixed- and random-effects models were fitted to calculate the hazard ratio for overall survival (OS) for all pairwise comparisons and ranking of all interventions.ResultsTwenty-three studies (19 trials) met inclusion criteria and were included in the review. Sample sizes ranged from 69 to 452, and median patient age ranged from 45 to 53 years. There was a trend toward prolonged OS with cisplatin-paclitaxel-bevacizumab and topotecan-paclitaxel-bevacizumab compared with all non–bevacizumab-containing therapies. Cisplatin-paclitaxel-bevacizumab had the highest probability of being the most efficacious compared with all regimens (68.1%), and cisplatin monotherapy had the lowest (0%).ConclusionsThe results of this network meta-analysis show that bevacizumab in combination with paclitaxel-topotecan or paclitaxel-cisplatin is likely to prolong OS over other non–bevacizumab-containing chemotherapies (eg, paclitaxel-carboplatin), which were not included in the GOG240 trial. In patients with advanced, persistent, and recurrent cervical cancer, cisplatin-paclitaxel-bevacizumab and topotecan-paclitaxel-bevacizumab showed the highest efficacy in all regimens investigated in this analysis.

Patients treated with standard chemotherapy for metastatic or relapsed cervical cancer respond poorly to conventional chemotherapy (response achieved in 20–30% of patients) with an overall survival of less than 1 year. High tumour angiogenesis and high concentrations of intratumoural VEGF are adverse prognostic features. Cediranib is a potent tyrosine kinase inhibitor of VEGFR1, 2, and 3. In this trial, we aimed to assess the effect of the addition of cediranib to carboplatin and paclitaxel chemotherapy in patients with metastatic or recurrent cervical cancer. In this randomised, double-blind, placebo-controlled phase 2 trial, which was done in 17 UK cancer treatment centres, patients aged 18 years or older initially diagnosed with metastatic carcinoma or who subsequently developed metastatic disease or local pelvic recurrence after radical treatment that was not amenable to exenterative surgery were recruited. Eligible patients received carboplatin AUC of 5 plus paclitaxel 175 mg/m2 by infusion every 3 weeks for a maximum of six cycles and were randomised centrally (1:1) through a minimisation approach to receive cediranib 20 mg or placebo orally once daily until disease progression. The stratification factors were disease site, disease-free survival after primary therapy or primary stage IVb disease, number of lines of previous treatment, Eastern Cooperative Oncology Group performance status, and investigational site. All patients, investigators, and trial personnel were masked to study drug allocation. The primary endpoint was progression-free survival. Efficacy analysis was by intention to treat, and the safety analysis included all patients who received at least one dose of study drug. This trial is registered with the ISCRTN registry, number ISRCTN23516549, and has been completed. Between Aug 19, 2010, and July 27, 2012, 69 patients were enrolled and randomly assigned to cediranib (n=34) or placebo (n=35). After a median follow-up of 24·2 months (IQR 21·9–29·5), progression-free survival was longer in the cediranib group (median 8·1 months [80% CI 7·4–8·8]) than in the placebo group (6·7 months [6·2–7·2]), with a hazard ratio (HR) of 0·58 (80% CI 0·40–0·85; one-sided p=0·032). Grade 3 or worse adverse events that occurred in the concurrent chemotherapy and trial drug period in more than 10% of patients were diarrhoea (five [16%] of 32 patients in the cediranib group vs one [3%] of 35 patients in the placebo group), fatigue (four [13%] vs two [6%]), leucopenia (five [16%] vs three [9%]), neutropenia (10 [31%] vs four [11%]), and febrile neutropenia (five [16%] vs none). The incidence of grade 2–3 hypertension was higher in the cediranib group than in the control group (11 [34%] vs four [11%]). Serious adverse events occurred in 18 patients in the placebo group and 19 patients in the cediranib group. Cediranib has significant efficacy when added to carboplatin and paclitaxel in the treatment of metastatic or recurrent cervical cancer. This finding was accompanied by an increase in toxic effects (mainly diarrhoea, hypertension, and febrile neutropenia). Cancer Research UK and AstraZeneca.

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.

Cervical cancer is the third most common cancer among women worldwide, with a disproportionately high burden of disease in less-developed regions of the world. The Cervix Cancer Research Network was founded by the Gynecologic Cancer InterGroup with a mission to improve outcomes in cervical cancer by enhancing international access to clinical trials, specifically in under-represented, underdeveloped areas. The Cervix Cancer Research Network held its third international educational symposium in Bucharest in 2018 and is the subject of this report. The purpose of this symposium was to advance the international understanding of cervical cancer treatment patterns, to foster recruitment to Cervix Cancer Research Network clinical trials, and identify key Cervix Cancer Research Network clinical trial concepts to improve cervical cancer care worldwide.

Correspondence to Dr Gemma Eminowicz; gemmaeminowicz@nhs.net INTERLACE has shown a significant survival advantage with the addition of six cycles of weekly carboplatin and paclitaxel prior to standard chemoradiation in locally advanced cervical cancer.1 Here we present a practical guide to implementing the INTERLACE protocol in clinical practice. Chemoradiation consent can be completed during induction chemotherapy, allowing adequate time for bladder and bowel preparation if patients are overwhelmed with information at first consultation, but the patient should be fully aware of the entire treatment plan at the start of induction chemotherapy. Regular monitoring of blood counts is essential, minimum weekly, due to increased hematological toxicity, especially during chemoradiation.