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Increasing numbers of women are surviving for longer with epithelial ovarian cancer. Consequently, there is increased focus on long-term quality of life in national guidance. Psychosexual morbidity including vaginal dryness, pain during intercourse (dyspareunia), reduced libido, and negative perceived body image exacerbate stress and anxiety and impact intimate relationships. Although a priority for women with epithelial ovarian cancer, clinicians seldom discuss sexual problems. Therefore, psychosexual morbidity and the associated distress remain unaddressed. We synthesize evidence from primary qualitative and quantitative research studies exploring psychosexual morbidity in women with epithelial ovarian cancer to identify potential risk factors and common symptoms, to facilitate the identification and management of sexual problems in clinic. Literature (2008–19) from 10 databases identified 29 suitable publications (4116 patients). The papers were assessed to answer the question: “What are the key potential risk factors and presentations of psychosexual morbidity in women with epithelial ovarian cancer?” Current literature lacks consensus in defining clinically significant psychosexual morbidity in women with epithelial ovarian cancer. Discrepancies in measurement tools, questionnaires, and primary outcome measures confound result interpretation, limiting wider application. Key potential risk factors identified included: younger age (

Poly(ADP-ribose) polymerase (PARP) inhibitors improve survival in BRCA-mutant high-grade serous ovarian carcinoma. As a result, germline and somatic BRCA1/2 testing has become standard practice in women diagnosed with ovarian cancer. We outline changes in testing and detection rates of germline BRCA1/2 pathogenic variants (PVs) in cases of non-mucinous epithelial ovarian cancer diagnosed during three eras, spanning 12 years, within the North West of England, and compare the uptake of cascade testing in families identified by oncology-led mainstreaming versus regional genetics clinics. Eras included: Period 1 (20% risk threshold for testing): between January 2007 and May 2013; Period 2 (10% risk threshold for testing): between June 2013 and October 2017 and; Period 3 (mainstream testing): between November 2017 and November 2019. A total of 1081 women underwent germline BRCA1/2 testing between January 2007 and November 2019 and 222 (20.5%) were found to have a PV. The monthly testing rate increased by 3.3-fold and 2.5-fold between Periods 1–2 and Periods 2–3, respectively. A similar incidence of germline BRCA1/2 PVs were detected in Period 2 (17.2%) and Period 3 (18.5%). Uptake of cascade testing from first-degree relatives was significantly lower in those women undergoing mainstream testing compared with those tested in regional genetics clinics (31.6% versus 47.3%, P = 0.038). Mainstream testing allows timely detection of germline BRCA1/2 status to select patients for PARP inhibitors, but shortfalls in the uptake of cascade testing in first-degree relatives requires optimisation to broaden benefits within families.

Background The DREAMtherapy (Dual REctal Angiogenesis MEK inhibition radiotherapy) trial is a novel intertwined design whereby two tyrosine kinase inhibitors (cediranib and selumetinib) were independently evaluated with rectal chemoradiotherapy (CRT) in an efficient manner to limit the extended follow-up period often required for radiotherapy studies. Patients and methods Cediranib or selumetinib was commenced 10 days before and then continued with RT (45 Gy/25#/5 wks) and capecitabine (825 mg/m2 twice a day (BID)). When three patients in the cediranib 15-mg once daily (OD) cohort were in the surveillance period, recruitment to the selumetinib cohort commenced. This alternating schedule was followed throughout. Three cediranib (15, 20 and 30 mg OD) and two selumetinib cohorts (50 and 75 mg BID) were planned. Circulating and imaging biomarkers of inflammation/angiogenesis were evaluated. Results In case of cediranib, dose-limiting diarrhoea, fatigue and skin reactions were seen in the 30-mg OD cohort, and therefore, 20 mg OD was defined as the maximum tolerated dose. Forty-one percent patients achieved a clinical or pathological complete response (7/17), and 53% (9/17) had an excellent clinical or pathological response (ECPR). Significantly lower level of pre-treatment plasma tumour necrosis factor alpha (TNFα) was found in patients who had an ECPR. In case of selumetinib, the 50-mg BID cohort was poorly tolerated (fatigue and diarrhoea); a reduced dose cohort of 75-mg OD was opened which was also poorly tolerated, and further recruitment was abandoned. Of the 12 patients treated, two attained an ECPR (17%). Conclusions This novel intertwined trial design is an effective way to independently investigate multiple agents with radiotherapy. The combination of cediranib with CRT was well tolerated with encouraging efficacy. TNFα emerged as a potential predictive biomarker of response and warrants further evaluation.

AIMS:There is a need for predictive and surrogate response biomarkers to support treatment with antiangiogenic vascular endothelial growth factor (VEGF) inhibitors. We aimed to identify a minimally-invasive biomarker predicting benefit from cediranib pretreatment or early during treatment in patients with recurrent or metastatic cervical cancer.METHODS:Blood samples were collected before treatment, during treatment and upon disease progression where appropriate from patients enrolled in CIRCCa, a randomised phase II trial of carboplatin and paclitaxel with or without cediranib. Plasma concentrations of VEGF-A, VEGF-receptor 2, Ang1 and Tie2 were measured using multiplex enzyme-linked immunosorbent assay. Pretreatment and temporal changes of the biomarkers were investigated using proportional hazard regression and unsupervised clustering analysis.RESULTS:Samples (n = 556) from 52 patients were analysed. VEGF-receptor 2 (P = .0006) and Tie2 (P = .04) were downregulated following cediranib, while VEGF-A (P = .0025) was upregulated. High Eastern Cooperative Oncology Group performance status (P = .02, hazard ratio [HR] = 2.15, 95% confidence interval [CI] 1.13-4.09) and low pretreatment Tie2 concentrations (P = .003, HR = 0.57, 95%CI 0.39-0.83) were independent prognostic factors associated with reduced progression-free survival. Two patterns of changes in VEGF-A following cediranib were identified. Patients with elevated VEGF-A in the first 3 treatment cycles, regardless of magnitude, had reduced progression-free survival in the placebo arm but improved survival with the addition of cediranib (P = .019, HR = 0.13, 95% CI 0.02-0.71).CONCLUSION:Patterns of early elevation in plasma VEGF-A should be studied further as a potential biomarker to predict treatment benefit from cediranib.

Background Cediranib, an oral anti-angiogenic VEGFR 1-3 inhibitor, was studied at a daily dose of 20 mg in combination with platinum-based chemotherapy and as maintenance in a randomised trial in patients with first relapse of ‘platinum-sensitive’ ovarian cancer and has been shown to improve progression-free survival (PFS). Patients and methods ICON6 (NCT00532194) was an international three-arm, double-blind, placebo-controlled randomised trial. Between December 2007 and December 2011, 456 women were randomised, using stratification, to receive either chemotherapy with placebo throughout (arm A, reference); chemotherapy with concurrent cediranib, followed by maintenance placebo (arm B, concurrent); or chemotherapy with concurrent cediranib, followed by maintenance cediranib (arm C, maintenance). Due to an enforced redesign of the trial in September 2011, the primary endpoint became PFS between arms A and C which we have previously published, and the overall survival (OS) was defined as a secondary endpoint, which is reported here. Results After a median follow-up of 25.6 months, strong evidence of an effect of concurrent plus maintenance cediranib on PFS was observed [hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.44-0.72, P < 0.0001]. In this final update of the survival analysis, 90% of patients have died. There was a 7.4-month difference in median survival and an HR of 0.86 (95% CI: 0.67-1.11, P = 0.24) in favour of arm C. There was strong evidence of a departure from the assumption of non-proportionality using the Grambsch–Therneau test (P = 0.0031), making the HR difficult to interpret. Consequently, the restricted mean survival time (RMST) was used and the estimated difference over 6 years by the RMST was 4.8 months (95% CI: −0.09 to 9.74 months). Conclusions Although a statistically significant difference in time to progression was seen, the enforced curtailment in recruitment meant that the secondary analysis of OS was underpowered. The relative reduction in the risk of death of 14% risk of death was not conventionally statistically significant, but this improvement and the increase in the mean survival time in this analysis suggest that cediranib may have worthwhile activity in the treatment of recurrent ovarian cancer and that further research should be undertaken., Highlights • Cediranib is an oral VEGF receptor kinase inhibitor and ICON6 explored its activity in recurrent ovarian cancer. • In a randomised trial cediranib with chemotherapy and as maintenance significantly prolonged PFS. • Cessation of cediranib supply led to a reduction in sample size and OS was underpowered. • A mature survival analysis showed a non-significant increase in the median and Restricted Mean Survival Time (RMST) with cediranib. • There was a clinical benefit of cediranib but further research is needed to determine its role in recurrent ovarian cancer.

BackgroundTwo novel biological agents—cediranib targeting angiogenesis, and olaparib targeting DNA repair processes—have individually led to an improvement in ovarian cancer control. The aim of ICON9 is to investigate the combination of cediranib and olaparib maintenance in recurrent ovarian cancer following platinum-based therapy.Primary objectiveTo assess the efficacy of maintenance treatment with olaparib in combination with cediranib compared with olaparib alone following a response to platinum-based chemotherapy in women with platinum-sensitive ovarian, fallopian tube or peritoneal cancer during first relapse.Study hypothesisMaintenance therapy with cediranib and olaparib in combination is associated with improved patient outcomes compared with olaparib alone.Trial designInternational phase III randomized controlled trial. Following a response to platinum-based chemotherapy patients are randomized 1:1 to either oral olaparib and cediranib (intervention arm) or oral olaparib alone (control arm).Major inclusion criteriaPatients with a known diagnosis of high grade serous or endometrioid carcinoma of the ovary, fallopian tube or peritoneum, progressing more than 6 months after first-line platinum-based chemotherapy, who have responded to second-line platinum-based chemotherapy.Primary endpointsProgression-free and overall survival. Co-primary endpoints to be assessed using a fixed-sequence gatekeeping approach: (1) progression-free survival, all patients; (2) progression-free survival, BRCA wild type; (3) overall survival, all patients; (4) overall survival, BRCA wild type.Sample size618 patients will be recruited.Estimated dates for completing accrual and presenting resultsAccrual is expected to be completed in 2024 with presentation of results in 2025.Trial registrationClinicalTrials.gov: NCT03278717.

Summary Background Platinum-based neoadjuvant chemotherapy followed by delayed primary surgery (DPS) is an established strategy for women with newly diagnosed, advanced-stage epithelial ovarian cancer. Although this therapeutic approach has been validated in randomised, phase 3 trials, evaluation of response to neoadjuvant chemotherapy using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST), and cancer antigen 125 (CA125) has not been reported. We describe RECIST and Gynecologic Cancer InterGroup (GCIG) CA125 responses in patients receiving platinum-based neoadjuvant chemotherapy followed by DPS in the ICON8 trial. Methods ICON8 was an international, multicentre, randomised, phase 3 trial done across 117 hospitals in the UK, Australia, New Zealand, Mexico, South Korea, and Ireland. The trial included women aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0–2, life expectancy of more than 12 weeks, and newly diagnosed International Federation of Gynecology and Obstetrics (FIGO; 1988) stage IC–IIA high-grade serous, clear cell, or any poorly differentiated or grade 3 histological subtype, or any FIGO (1988) stage IIB–IV epithelial cancer of the ovary, fallopian tube, or primary peritoneum. Patients were randomly assigned (1:1:1) to receive intravenous carboplatin (area under the curve [AUC]5 or AUC6) and intravenous paclitaxel (175 mg/m2 by body surface area) on day 1 of every 21-day cycle (control group; group 1); intravenous carboplatin (AUC5 or AUC6) on day 1 and intravenous dose-fractionated paclitaxel (80 mg/m2 by body surface area) on days 1, 8, and 15 of every 21-day cycle (group 2); or intravenous dose-fractionated carboplatin (AUC2) and intravenous dose-fractionated paclitaxel (80 mg/m2 by body surface area) on days 1, 8, and 15 of every 21-day cycle (group 3). The maximum number of cycles of chemotherapy permitted was six. Randomisation was done with a minimisation method, and patients were stratified according to GCIG group, disease stage, and timing and outcome of cytoreductive surgery. Patients and clinicians were not masked to group allocation. The scheduling of surgery and use of neoadjuvant chemotherapy were determined by local multidisciplinary case review. In this post-hoc exploratory analysis of ICON8, progression-free survival was analysed using the landmark method and defined as the time interval between the date of pre-surgical planning radiological tumour assessment to the date of investigator-assessed clinical or radiological progression or death, whichever occurred first. This definition is different from the intention-to-treat primary progression-free survival analysis of ICON8, which defined progression-free survival as the time from randomisation to the date of first clinical or radiological progression or death, whichever occurred first. We also compared the extent of surgical cytoreduction with RECIST and GCIG CA125 responses. This post-hoc exploratory analysis includes only women recruited to ICON8 who were planned for neoadjuvant chemotherapy followed by DPS and had RECIST and/or GCIG CA125-evaluable disease. ICON8 is closed for enrolment and follow-up, and registered with ClinicalTrials.gov , NCT01654146 . Findings Between June 6, 2011, and Nov 28, 2014, 1566 women were enrolled in ICON8, of whom 779 (50%) were planned for neoadjuvant chemotherapy followed by DPS. Median follow-up was 29·5 months (IQR 15·6–54·3) for the neoadjuvant chemotherapy followed by DPS population. Of 564 women who had RECIST-evaluable disease at trial entry, 348 (62%) had a complete or partial response. Of 727 women who were evaluable by GCIG CA125 criteria at the time of diagnosis, 610 (84%) had a CA125 response. Median progression-free survival was 14·4 months (95% CI 9·2–28·0; 297 events) for patients with a RECIST complete or partial response and 13·3 months (8·1–20·1; 171 events) for those with RECIST stable disease. Median progression-free survival for women with a GCIG CA125 response was 13·8 months (95% CI 8·8–23·4; 544 events) and 9·7 months (5·8–14·5; 111 events) for those without a GCIG CA125 response. Complete cytoreduction (R0) was achieved in 187 (56%) of 335 women with a RECIST complete or partial response and 73 (42%) of 172 women with RECIST stable disease. Complete cytoreduction was achieved in 290 (50%) of 576 women with a GCIG CA125 response and 30 (30%) of 101 women without a GCIG CA125 response. Interpretation The RECIST-defined radiological response rate was lower than that frequently quoted to patients in the clinic. RECIST and GCIG CA125 responses to neoadjuvant chemotherapy for epithelial ovarian cancer should not be used as individual predictive markers to stratify patients who are likely to benefit from DPS, but instead used in conjunction with the patient's clinical capacity to undergo cytoreductive surgery. A patient should not be denied surgery based solely on the lack of a RECIST or GCIG CA125 response. Funding Cancer Research UK, UK Medical Research Council, Health Research Board in Ireland, Irish Cancer Society, and Cancer Australia.

Purpose of Review Epithelial ovarian cancer is a disease that encompasses a number of histologically and molecularly distinct entities; the most prevalent subtype being high-grade serous (HGS) carcinoma. Standard first-line treatment of advanced HGS carcinoma includes cytoreductive surgery plus intravenous paclitaxel/platinum-based chemotherapy. Despite excellent responses to initial treatment, the majority of patients develop recurrent disease within 3 years. The introduction of the vascular endothelial growth factor (VEGF) inhibitor, bevacizumab, and poly(ADP-ribose) polymerase (PARP) inhibitors into first-line management has changed the outlook for this lethal disease. In this review, we summarise the most recent clinical trials that determine current primary therapy of advanced HGS carcinoma and the ongoing trials that aim to change management in the future. Recent Findings Recent phase III clinical trials have shown that delayed primary surgery after completing neo-adjuvant chemotherapy is non-inferior to immediate primary surgery, but could provide a survival benefit in FIGO (International Federation of Gynecology and Obstetrics) stage IV disease. The use of weekly intravenous chemotherapy regimens has not been proven to be more effective than standard 3-weekly regimens in Western patient populations, and the use of intraperitoneal chemotherapy remains controversial in the first-line setting. In contrast, newer systemic anti-cancer therapies targeting angiogenesis and/or HR-deficient tumours have been successfully incorporated into front-line therapeutic regimens to treat HGS carcinoma. Recent results from randomised trials investigating the use of PARP inhibitors as monotherapy and in combination with the anti-angiogenic agent, bevacizumab, have demonstrated highly impressive efficacy when combined with traditional first-line multi-modality therapy. Summary Management of HGS carcinoma is evolving, but further work is still required to optimise and integrate tumour and plasma biomarkers to exploit the potential of these highly efficacious targeted agents.

IntroductionPoly(ADP-ribose) polymerase inhibitors significantly improve progression-free survival in platinum-sensitive high-grade serous and endometrioid ovarian carcinoma, with greatest benefits observed in women with a pathogenic BRCA1/2 variant. Consequently, the demand for germline BRCA1/2 testing in ovarian cancer has increased substantially, leading to the screening of unselected populations of patients. We aimed to determine the prevalence of pathogenic germline BRCA1/2 variants in women diagnosed with epithelial ovarian cancer, categorised according to the established risk factors for hereditary breast and ovarian cancer syndrome and the Manchester BRCA Score, to inform risk stratification.MethodsA cohort of sequential epithelial ovarian cancer cases recruited between June 2013 and September 2018 underwent germline BRCA1/2 testing by next-generation sequencing and multiplex ligation-dependent probe amplification.ResultsFive hundred and fifty-seven patients were screened. Of these, 18% had inherited a pathogenic BRCA1/2 variant. The prevalence of pathogenic BRCA1/2 variants was >10% in women diagnosed with ovarian cancer earlier than 60 years of age (21%) and those diagnosed later than 60 years of age with a family history of breast and/or ovarian cancer (17%) or a medical history of breast cancer (34%). The prevalence of pathogenic BRCA1/2 variants was also >10% in women with a Manchester BRCA Score of ≥15 points (14%).DiscussionOur study suggests that age at diagnosis, family history of breast and/or ovarian cancer, medical history of breast cancer or a Manchester BRCA Score of ≥15 points are associated with a >10% prevalence of germline pathogenic BRCA1/2 variants in epithelial ovarian cancer.

Angiogenesis is a proven clinical target for the treatment of advanced epithelial ovarian cancer. Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) offer patients potential new treatment regimens as they can be given as monotherapy, in combination with poly(ADP-ribose) polymerase (PARP) inhibitors, or with and following cytotoxic chemotherapy. If VEGFR-TKIs are licensed for use in ovarian cancer, patients will require prompt and effective management of adverse events, including diarrhea, to optimize compliance and benefit. As diarrhea is one of the most prevalent toxicities of this class of drug, it is important to consider the potential causes, be they disease related (bowel obstruction), treatment related (VEGFR-TKI-related or infective/neutropenic septic diarrhea when patients are receiving cytotoxic chemotherapy combined with VEGFR inhibitor treatment), or incurred through diet. Here, we provide an overview of the possible mechanisms responsible for VEGFR-TKI-induced diarrhea. We review potential interventions that can help in the management of diarrhea induced by VEGFR-TKIs, when used in combination or as single agents, and we provide a diarrhea treatment algorithm to serve as a clinical reference point for the management of diarrhea in patients with ovarian cancer treated with a VEGFR-TKI in combination with chemotherapy or PARP inhibitors, or as monotherapy.

PurposePoly(ADP-ribose) polymerase inhibitors (PARPi) have changed the management of high-grade serous ovarian cancer (HGSOC). The rationale for the development of PARPi was based on the concept of synthetic lethality, in which a cell can survive a deficiency of one gene/gene product, but may die if there is a deficiency in a combination of genes/gene products. In women with BRCA1/2 deficiency within their ovarian cancer tissue, inhibition of PARP imposes an intolerable burden of DNA damage repair deficiency and may induce cell death.MethodsClinical trials have evaluated PARPi as single-agent therapeutics and as maintenance treatment following platinum-based chemotherapy for HGSOC. Clinical data suggest the most impressive anti-tumour activity occurs in women with platinum-sensitive ovarian cancer and germline or somatic BRCA1/2 mutations (g/sBRCAmt).ResultsIn the maintenance setting, randomised trials have shown that PARPi compared to placebo reduce the hazard ratio for the development of progressive disease to 0.2–0.27 for patients with a g/sBRCAmt; to 0.34–0.38 for patients with putative evidence of DNA damage repair deficiency; and to 0.35–0.45 in an unselected population with HGSOC. Furthermore, phase 1/2 trials have reported single-agent anti-tumour response rates in gBRCAmt of approximately 50% in platinum-sensitive and 25% in platinum-resistant disease.ConclusionHere, we discuss the evidence for the use of PARPi as single-agent therapeutics and maintenance treatment in HGSOC and evaluate the genetic assays used in clinical trials so far. We discuss the emerging role of platinum sensitivity as a broad eligibility criteria for the use of PARPi.

BACKGROUND:Malignant bowel obstruction is a common complication of ovarian cancer, resulting in limited oral intake. Home parenteral nutrition (HPN) may be offered to patients in this condition to meet nutritional requirements. However, it is not known how they experience being unable to eat. The present study reports how patients related to food when receiving HPN.METHODS:The investigation was a qualitative study underpinned by phenomenology with women with advanced ovarian cancer in bowel obstruction receiving parenteral nutrition. Interview transcripts were analysed thematically guided by the techniques of Van Manen.RESULTS:We recruited 20 women to the study. Participants were interviewed a maximum of four times and a total of 39 in-depth longitudinal interviews were conducted. Participants could tolerate minimal amounts of food, if they had a venting gastrostomy. Not being able to eat engendered a sense of sadness and loss, and most women found it challenging to be in the presence of others eating. They adopted strategies to cope, which included fantasising about food and watching cookery programmes. These approaches were not a long-term solution; either participants came to terms with their loss or the strategies became less effective in providing relief.CONCLUSIONS:Home parenteral nutrition meets the nutritional requirements of patients with malignant bowel obstruction but cannot replace the non-nutritive functions of food. Healthcare professionals can offer a patient-centred approach by acknowledging the difficulties that patients may face and, wherever possible, encourage them to focus on the positive benefits of interacting with people rather than the loss of eating on social occasions.

Objective Vascular co-option is a resistance mechanism to anti-angiogenic agents, but combinations of anti-vascular agents may overcome this resistance. We report a phase 1b and randomised phase 2 trial to determine the safety and efficacy of pazopanib with fosbretabulin. Methods Eligible patients had recurrent, epithelial ovarian cancer with a platinum-free interval (PFI) of 3 to 12 months. Patients were stratified according to PFI (>6 versus ≤6 months) and prior bevacizumab use. Results Twelve patients were treated in the phase 1b. Commonest grade ≥ 2 adverse events (AEs) were hypertension (100%), neutropenia (50%), fatigue (50%), vomiting (50%). There was one DLT (grade 3 fatigue). The recommended phase 2 dose level was fosbretabulin 54 mg/m2 on days 1, 8 and 15 and pazopanib 600 mg once daily (od), every 28 days, which was then compared to pazopanib 800 mg od in a randomised phase 2 trial. Twenty-one patients were randomised (1:1) in the phase 2 trial. In phase 1b and phase 2, four patients treated with pazopanib and fosbretabulin developed reversible, treatment-related cardiac AEs, leading to premature discontinuation of the study. In the phase 2 trial, the median PFS was 7.6 months (95% CI 4.1-not estimated) versus 3.7 months (95% CI 1.0–8.1) in favour of the experimental arm (HR 0.30, 95% CI 0.09–1.03, P = .06). Conclusions It remains unclear whether pazopanib with with fosbretabulin is an efficacious regimen to treat epithelial ovarian cancer. Effective cardiac risk mitigation is needed to increase the tolerability and maximize patient safety in future trials.

Background Cancer in patients with chronic kidney disease (CKD) is an added burden to their overall morbidity and mortality. Cancer can be a cause or an effect of CKD. In CKD patients, a better understanding of cancer distribution and associations can aid in the proper planning of renal replacement therapy (RRT) and in the choice of chemotherapeutic agents, many of which are precluded in more advanced CKD. This study aims to investigate the distribution and the association of cancer with mortality, renal progression and RRT assignment in a non-dialysis dependent CKD cohort, few studies have investigated this in the past. Methods The study was carried out on 2952 patients registered in the Salford Kidney Study (SKS) between October 2002 and December 2016. A comparative analysis was performed between 339 patients with a history of cancer (previous and current) and 2613 patients without cancer at recruitment. A propensity score matched cohort of 337 patients was derived from each group and used for analysis. Cox-regression models and Kaplan-Meier estimates were used to compare the association of cancer with mortality and end-stage renal disease (ESRD) outcomes. Linear regression analysis was applied to generate the annual rate of decline in estimated glomerular filtration rate (delta eGFR). Results Of our cohort, 13.3% had a history of cancer at recruitment and the annual rate of de novo cancers in the non-cancer patients was 1.6%. Urogenital cancers including kidney and bladder, and prostate and testicle in males, ovary and uterus in females, were the most prevalent cancers (46%), as expected from the anatomical or physiological roles of these organs and relationship to nephrology. Over a median follow-up of 48 months, 1084 (36.7%) of patients died. All-cause mortality was higher in the previous and current cancer group (49.6% vs 35%, p p = 0.004). There was no difference between the groups regarding reaching end-stage renal disease (26% in both groups) or the rate of decline in eGFR (− 0.97 for cancer vs − 0.93 mL/min/year for non-cancer, p = 0.93). RRT uptake was similar between the groups (17.2% vs 19.3%, p = 0.49). Conclusions Cancer status proved to be an added burden and an independent risk factor for all-cause mortality but not for renal progression. CKD patients with a previous or current history of cancer should be assessed on a case by case basis in planning for renal replacement therapy options, and the presence of cancer should not be a limitation for RRT provision including transplantation.

Background Malnutrition is a problem in advanced cancer, particularly ovarian cancer where malignant bowel obstruction (MBO) is a frequent complication. Parenteral nutrition is the only way these patients can received adequate nutrition and is a principal indication for palliative home parenteral nutrition (HPN). Giving HPN is contentious as it may increase the burden on patients. This study investigates patients’ and family caregivers’ experiences of HPN, alongside nutritional status and survival in patients with ovarian cancer and MBO. Methods This mixed methods study collected data on participant characteristics, clinical details and body composition using computed tomography (CT) combined with longitudinal in-depth interviews underpinned by phenomenological principles. The cohort comprised 38 women with ovarian cancer and inoperable MBO admitted (10/2016 to 12/ 2017) to a tertiary referral hospital. Longitudinal interviews (n = 57) were carried out with 20 women considered for HPN and 13 of their family caregivers. Results Of the 38 women, 32 received parenteral nutrition (PN) in hospital and 17 were discharged on HPN. Nutritional status was poor with 31 of 33 women who had a CT scan having low muscle mass, although 10 were obese. Median overall survival from admission with MBO for all 38 women was 70 days (range 8–506) and for those 17 on HPN was 156 days (range 46–506). Women experienced HPN as one facet of their illness, but viewed it as a “lifeline” that allowed them to live outside hospital. Nevertheless, HPN treatment came with losses including erosion of normality through an impact on activities of daily living and dealing with the bureaucracy surrounding the process. Family caregivers coped but were often left in an emotionally vulnerable state. Conclusions Women and family caregivers reported that the inconvenience and disruption caused by HPN was worth the extended time they had at home.

Background The use of home parenteral nutrition (HPN) for palliative indications is increasing internationally and is the leading indication in some countries. Discharge on HPN can be complex in metabolically unstable patients and requires intestinal failure expertise. Methods Between 2012 and 2018, we performed a retrospective analysis aiming to assess the impact of a novel remote discharge pathway for palliative HPN patients. This was evaluated using a quality improvement approach. Results One hundred and twenty-five patients with active malignancy [mean (range) age 58 (25-80) years] were referred to the intestinal failure unit (IFU) for remote discharge. Of 82 patients were discharged from the oncology Centre on HPN using the pathway. The remaining 43 patients either declined HPN or the Oncology team felt that the patient became too unwell for HPN or died prior to discharge. There was an increase in patients referred for remote discharge from 13 in 2012 to 43 in 2017. The mean number of days between receipt of referral by the IFU to discharge on HPN from the oncology centre reduced from 29.4 days to 10.1 days. Following remote discharge, the mean number of days on HPN was 215.9 days. Catheter-related blood stream infection rates in this cohort were very low at 0.169 per 1000 catheter days. Conclusions This is the first study to demonstrate the remote safe, effective and rapid discharge of patients requiring palliative HPN between two hospital sites. This allows patients with a short prognosis more time in their desired location.

Background: In the UK, trametinib (T) is recommended for the treatment of recurrent or progressive low grade serous ovarian cancer (LGSOC) following endocrine therapy (ET) and at least one platinum (Plat) based chemotherapy (ChT) regimen, as an alternative to cytotoxic ChT under interim COVID-19 arrangements. Methods: We conducted a multicentre retrospective study of patients (pts) treated with T in the UK. Eligible pts were adults with recurrent LGSOC who commenced T prior to November 2020. Results: Twenty-eight pts were included (median age 53.5, 19-75). 93% had stage 3-4 disease at presentation. Prior to commencing T, pts received a median of 1.5 lines of ChT (range 0-8) and 1 line (0-3) of ET. Four pts had received ≥3 lines of ChT. Thirty-six per cent had platinum resistant disease (relapse

Background Malignant bowel obstruction (MBO) is a common cause of morbidity and mortality in women diagnosed with ovarian cancer. Earlier detection of MBO may improve patient outcomes. There are currently no screening tools to assist detection.Aim We report a screening questionnaire that can be used to detect MBO, and how the severity score for key clinical symptoms correlate with radiological evidence of MBO from ovarian cancer.Design A case–control study in which patients with relapsed, metastatic ovarian cancer were asked to answer 10 questions related to key clinical symptoms associated with intestinal obstruction. The study group included women with CT-confirmed MBO, whereas the control group had no evidence of MBO. Patients scored each question according to severity from 1 (least severe) to 5 (most severe).Setting/participants Between 1 June and 31 December 2016, 37 women completed the screening questionnaire.Results Patients in the study group (n=17) reported significantly higher (ie, more severe) scores for abdominal pain, nausea, vomiting and constipation. In contrast, differences in severity scores between groups did not differ significantly in response to questions regarding abdominal swelling, borborygmi, diarrhoea or loss of appetite. All patients in the study group more frequently stated that their symptoms had deteriorated within the 2 months prior to completing the questionnaire.Conclusion Here we report the key clinical symptoms associated with radiologically-confirmed MBO in relapsed, metastatic ovarian cancer. We recommend healthcare practitioners focus on these specific symptoms during patient consultations in order to improve risk stratification of MBO.

IntroductionStandard of care treatment for women who develop relapsed ovarian cancer includes sequential platinum- and/or paclitaxel-based chemotherapy, with reducing disease-free intervals. Once platinum resistance develops, treatment options become limited and dose-dense regimens may be offered. We report the efficacy and safety of dose-dense cisplatin with gemcitabine chemotherapy for relapsed platinum-resistant ovarian cancer.MethodsA retrospective analysis of all patients with relapsed, platinum-resistant ovarian, primary peritoneal or fallopian tube cancer treated with cisplatin 35 mg/m2 of body surface area by intravenous infusion with gemcitabine 1000 mg/m2 of body surface area by intravenous infusion on days 1 and 8 of every 21-day treatment cycle between 1 January 2009 and 1 June 2017.ResultsNinety-four eligible patients had received a median of three (range one–eight) prior lines of cytotoxic therapy for relapsed ovarian cancer. Sixty patients (64%) had received ≥ 1 prior dose-dense chemotherapy regimen. Dose-dense cisplatin with gemcitabine was associated with a median progression-free survival (PFS) of 4.4 months (95% CI 3.6 to 5.3) and overall survival of 7.6 months (95% CI 5.6 to 9.6). The median PFS for dose-dense cisplatin with gemcitabine as first- (n = 34), second- (n = 42), and third-line or later (n = 18) dose-dense therapy was 4.2 (95% CI 3.2 to 5.2), 5.0 (95% CI 3.5 to 6.5), and 4.2 (95% CI 3.3 to 5.1) months respectively. The RECIST objective response rate for first-, second-, and third-line dose-dense cisplatin with gemcitabine was 23%, 14 %, and 7 % respectively. The most common grade 3 – 4 adverse events were thrombocytopenia (20%), anemia (18%), and neutropenia (14%).DiscussionDose-dense cisplatin with gemcitabine provides modest efficacy whether it is used as a first- or subsequent line of dose-dense chemotherapy to treat relapsed platinum-resistant ovarian cancer and the toxicity is manageable with supportive measures.

Background: People with advanced ovarian or gastrointestinal cancer may develop malignant bowel obstruction (MBO). They are able to tolerate limited, if any, oral or enteral (via a tube directly into the gut) nutrition. Parenteral nutrition (PN) is the provision of macronutrients, micronutrients, electrolytes and fluid infused as an intravenous solution and provides a method for these people to receive nutrients. There are clinical and ethical arguments for and against the administration of PN to people receiving palliative care. Objectives: To assess the effectiveness of home parenteral nutrition (HPN) in improving survival and quality of life in people with inoperable MBO. Search methods: We searched the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 1), MEDLINE (Ovid), Embase (Ovid), BNI, CINAHL, Web of Science and NHS Economic Evaluation and Health Technology Assessment up to January 2018, ClinicalTrials.gov (http://clinicaltrials.gov/) and in the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal (http://apps.who.int/trialsearch/). In addition, we handsearched included studies and used the 'Similar articles' feature on PubMed for included articles. Selection criteria: We included any studies with more than five participants investigating HPN in people over 16 years of age with inoperable MBO. Data collection and analysis: We extracted the data and assessed risk of bias for each study. We entered data into Review Manager 5 and used GRADEpro to assess the quality of the evidence. Main results: We included 13 studies with a total of 721 participants in the review. The studies were observational, 12 studies had only one relevant treatment arm and no control and for the one study with a control arm, very few details were given. The risk of bias was high and the certainty of evidence was graded as very low for all outcomes. Due to heterogeneity of data, meta-analysis was not performed and therefore the data were synthesised via a narrative summary. The evidence for benefit derived from PN was very low for survival and quality of life. All the studies measured overall survival and 636 (88%) of participants were deceased at the end of the study. However there were varying definitions of overall survival that yielded median survival intervals between 15 to 155 days (range three to 1278 days). Three studies used validated measures of quality of life. The results from assessment of quality of life were equivocal; one study reported improvements up until three months and two studies reported approximately similar numbers of participants with improvements and deterioration. Different quality of life scales were used in each of the studies and quality of life was measured at different time points. Due to the very low certainty of the evidence, we are very uncertain about the adverse events related to PN use. Adverse events were measured by nine studies and data for individual participants could be extracted from eight studies. This revealed that 32 of 260 (12%) patients developed a central venous catheter infection or were hospitalised because of complications related to PN. Authors' conclusions: We are very uncertain whether HPN improves survival or quality of life in people with MBO as the certainty of evidence was very low for both outcomes. As the evidence base is limited and at high risk of bias, further higher-quality prospective studies are required.

Summary Background The international standard of care for women with suspected advanced ovarian cancer is surgical debulking followed by platinum-based chemotherapy. We aimed to establish whether use of platinum-based primary chemotherapy followed by delayed surgery was an effective and safe alternative treatment regimen. Methods In this phase 3, non-inferiority, randomised, controlled trial (CHORUS) undertaken in 87 hospitals in the UK and New Zealand, we enrolled women with suspected stage III or IV ovarian cancer. We randomly assigned women (1:1) either to undergo primary surgery followed by six cycles of chemotherapy, or to three cycles of primary chemotherapy, then surgery, followed by three more cycles of completion chemotherapy. Each 3-week cycle consisted of carboplatin AUC5 or AUC6 plus paclitaxel 175 mg/m 2 , or an alternative carboplatin combination regimen, or carboplatin monotherapy. We did the random assignment by use of a minimisation method with a random element, and stratified participants according to the randomising centre, largest radiological tumour size, clinical stage, and prespecified chemotherapy regimen. Patients and investigators were not masked to group assignment. The primary outcome measure was overall survival. Primary analyses were done in the intention-to-treat population. To establish non-inferiority, the upper bound of a one-sided 90% CI for the hazard ratio (HR) had to be less than 1·18. This trial is registered, number ISRCTN74802813, and is closed to new participants. Findings Between March 1, 2004, and Aug 30, 2010, we randomly assigned 552 women to treatment. Of the 550 women who were eligible, 276 were assigned to primary surgery and 274 to primary chemotherapy. All were included in the intention-to-treat analysis; 251 assigned to primary surgery and 253 to primary chemotherapy were included in the per-protocol analysis. As of May 31, 2014, 451 deaths had occurred: 231 in the primary-surgery group versus 220 in the primary-chemotherapy group. Median overall survival was 22·6 months in the primary-surgery group versus 24·1 months in primary chemotherapy. The HR for death was 0·87 in favour of primary chemotherapy, with the upper bound of the one-sided 90% CI 0·98 (95% CI 0·72–1·05). Grade 3 or 4 postoperative adverse events and deaths within 28 days after surgery were more common in the primary-surgery group than in the primary-chemotherapy group (60 [24%] of 252 women vs 30 [14%] of 209, p=0·0007, and 14 women [6%] vs 1 woman [ vs 14 [6%] in the primary-chemotherapy group). 110 (49%) of 225 women receiving primary surgery and 102 (40%) of 253 receiving primary chemotherapy had a grade 3 or 4 chemotherapy related toxic effect (p=0·0654), mostly uncomplicated neutropenia (20% and 16%, respectively). One fatal toxic effect, neutropenic sepsis, occurred in the primary-chemotherapy group. Interpretation In women with stage III or IV ovarian cancer, survival with primary chemotherapy is non-inferior to primary surgery. In this study population, giving primary chemotherapy before surgery is an acceptable standard of care for women with advanced ovarian cancer. Funding Cancer Research UK and the Royal College of Obstetricians and Gynaecologists.

ObjectivesAdvanced-stage, platinum-resistant, ovarian cancer can be treated with dose-intense chemotherapy; one such regimen includes intravenous cisplatin and oral etoposide. To minimize the toxicity associated with weekly cisplatin, pretreatment and posttreatment hydration is required, often necessitating inpatient, overnight admission. We report a shorter, within-day regimen for delivering weekly cisplatin.MethodsThis was a retrospective study to assess the use of standard (inpatient; treatment time of 12 hours) versus modified (outpatient; treatment time of 4 hours) regimens. The primary outcome included all-grade and grade 3/4 adverse events. Secondary outcomes included clinical benefit response and, median progression-free survival and overall survival.ResultsBetween January 2012 and December 2014, 66 women with metastatic ovarian cancer received dose-intense weekly cisplatin and oral etoposide (n = 45 standard, n = 21 modified). The commonest all-grade adverse events were anemia (96% vs 90%, standard and modified, respectively), fatigue (73% vs 67%), neutropenia (71% vs 76%), hypocalcemia (51% vs 43%), and thrombocytopenia (49% vs 57%). There were no statistically significant differences in the incidence or grades of adverse events. The clinical benefit response was 53% in the standard group and 62% in the modified group (P = 0.9). The median progression-free survival was 4.2 and 6.5 months (incidence rate ratio, 1.22; 95% confidence interval, 0.71–2.15; P = 0.29), and median overall survival was 6.6 and 8.4 months (incidence rate ratio, 1.83; 95% confidence interval, 1.04–3.35; P = 0.03), in favor of the modified regimen.ConclusionsOur shorter, within-day regimen for delivering dose-intense weekly cisplatin and oral etoposide to treat platinum-resistant metastatic ovarian cancer is safe and efficacious.

Summary Background Individual patient data from two randomised trials comparing neoadjuvant chemotherapy with upfront debulking surgery in advanced tubo-ovarian cancer were analysed to examine long-term outcomes for patients and to identify any preferable therapeutic approaches for subgroup populations. Methods We did a per-protocol pooled analysis of individual patient data from the European Organisation for Research and Treatment of Cancer (EORTC) 55971 trial ( NCT00003636 ) and the Medical Research Council Chemotherapy Or Upfront Surgery (CHORUS) trial (ISRCTN74802813). In the EORTC trial, eligible women had biopsy-proven International Federation of Gynecology and Obstetrics (FIGO) stage IIIC or IV invasive epithelial tubo-ovarian carcinoma. In the CHORUS trial, inclusion criteria were similar to those of the EORTC trial, and women with apparent FIGO stage IIIA and IIIB disease were also eligible. The main aim of the pooled analysis was to show non-inferiority in overall survival with neoadjuvant chemotherapy compared with upfront debulking surgery, using the reverse Kaplan-Meier method. Tests for heterogeneity were based on Cochran's Q heterogeneity statistic. Findings Data for 1220 women were included in the pooled analysis, 670 from the EORTC trial and 550 from the CHORUS trial. 612 women were randomly allocated to receive upfront debulking surgery and 608 to receive neoadjuvant chemotherapy. Median follow-up was 7·6 years (IQR 6·0–9·6; EORTC, 9·2 years [IQR 7·3–10·4]; CHORUS, 5·9 years [IQR 4·3–7·4]). Median age was 63 years (IQR 56–71) and median size of the largest metastatic tumour at diagnosis was 8 cm (IQR 4·8–13·0). 55 (5%) women had FIGO stage II–IIIB disease, 831 (68%) had stage IIIC disease, and 230 (19%) had stage IV disease, with staging data missing for 104 (9%) women. In the entire population, no difference in median overall survival was noted between patients who underwent neoadjuvant chemotherapy and upfront debulking surgery (27·6 months [IQR 14·1–51·3] and 26·9 months [12·7–50·1], respectively; hazard ratio [HR] 0·97, 95% CI 0·86–1·09; p=0·586). Median overall survival for EORTC and CHORUS patients was significantly different at 30·2 months (IQR 15·7–53·7) and 23·6 months (10·5–46·9), respectively (HR 1·20, 95% CI 1·06–1·36; p=0·004), but was not heterogeneous (Cochran's Q, p=0·17). Women with stage IV disease had significantly better outcomes with neoadjuvant chemotherapy compared with upfront debulking surgery (median overall survival 24·3 months [IQR 14·1–47·6] and 21·2 months [10·0–36·4], respectively; HR 0·76, 95% CI 0·58–1·00; p=0·048; median progression-free survival 10·6 months [7·9–15·0] and 9·7 months [5·2–13·2], respectively; HR 0·77, 95% CI 0·59–1·00; p=0·049). Interpretation Long-term follow-up data substantiate previous results showing that neoadjuvant chemotherapy and upfront debulking surgery result in similar overall survival in advanced tubo-ovarian cancer, with better survival in women with stage IV disease with neoadjuvant chemotherapy. This pooled analysis, with long-term follow-up, shows that neoadjuvant chemotherapy is a valuable treatment option for patients with stage IIIC–IV tubo-ovarian cancer, particularly in patients with a high tumour burden at presentation or poor performance status. Funding National Cancer Institute and Vlaamse Liga tegen kanker (Flemish League against Cancer).

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the effectiveness and safety of home parenteral nutrition in people with inoperable malignant bowel obstruction.

Background Randomised phase 3 trials have demonstrated that poly (ADP-ribose) polymerase (PARP) inhibitors significantly improve progression-free survival in BRCA-mutant high-grade serous and endometrioid ovarian carcinoma. Consequently, the demand for germline and tumour BRCA1/2testing has increased significantly throughout the UK. We report results from a tumour BRCA1/2testing service available to cancer centres across England, Wales and Northern Ireland from July 2017 to February 2019. Methods DNA extracted from formalin fixed, paraffin-embedded tumour samples underwent next generation sequencing for BRCA1/2 variants. Eligibility criteria included relapsed, platinum-sensitive ovarian, fallopian tube or primary peritoneal cancer with germline BRCA1/2wild-type or unknown germline. Patients also had to have received ≥2 prior lines of platinum-based chemotherapy. A confirmatory histopathology report was requested as part of the tumour BRCA1/2testing service. Results Two hundred and ninety-three histologically-confirmed high-grade serous and/or endometrioid ovarian cancer tumour samples underwent tumour BRCA1/2testing. The prevalence of pathogenic (class 5) or likely pathogenic (class 4) variants was 17.7% (52/293). The germline BRCA1/2was wild-type for 185/293 (63.1%) of patients, with the remaining 36.9% (108/293) with germline BRCA1/2unknown. There were at least 36 (12.3%) pathogenic/likely pathogenic somatic BRCA1/2variants detected. The allele fraction for somatic BRCA1/2pathogenic variants ranged from 0.06 to 0.98, with 50% (18/36) reported with an allele fraction of ≥ 0.5 (50%), in keeping with putative biallelic loss-of-function. Conclusions Prospective evaluation of paired germline and tumour BRCA1/2testing in all women who are diagnosed with platinum-sensitive high-grade serous and/or endometrioid ovarian cancer in the UK is now required to validate these findings. Legal entity responsible for the study AstraZeneca. Funding AstraZeneca. Disclosure All authors have declared no conflicts of interest.

Background Enadenotucirev (EnAd) is a tumor selective Ad11/Ad3 group B adenovirus that has demonstrated pre-clinical activity in a model of platinum-resistant ovarian cancer. Synergy has also been reported between oncolytic adenoviruses and microtubule manipulating drugs such as paclitaxel (Pxl). This study aims to establish the tolerability and preliminary efficacy of EnAd delivered in combination with Pxl. Here we present data from the intravenous (IV) dose expansion group. Methods Patients with platinum-resistant or refractory ovarian cancer received a minimum of two 28-days cycles of IV infusional EnAd (1x1012 viral particles) on days 1, 3 and 5, and IV Pxl (80mg/m2) on days 9, 16 and 23. Baseline and on-treatment biopsies were taken. Primary endpoint was safety and tolerability; additional endpoints included, response rate (RECISTv1.1/GCIG CA125 criteria) and duration of response. Results Twenty patients, median age 60.5 years (range 37-78) who had received a median of 4 prior lines of therapy (range 1-12) were enrolled. Adverse events reported from the combination of EnAd and Pxl were as previously described (for both agents individually), with ‘flu-like symptoms reported in the majority of patients following EnAd administration. Hematological changes including neutropenia, previously identified at higher doses of EnAd IV monotherapy, were reported at the dose level tested in this study population. Virus kinetics, cytokine and anti-virus antibody responses were consistent with previous results with EnAd. As of 03May19, Investigator-assessed ORR is 37.5% (6/16), with median DoR of 16 weeks (range 8-32). Reductions in CA125 broadly follow the pattern of tumor regression, with 36% (4/11) achieving response according to GCIG CA125 criteria. Disease control rate (RECIST CR, PR, SD) is 75% (12/16). To date, matched biopsies (N = 2) have been analysed for pharmacodynamic markers, providing preliminary evidence of increased CD8 T cell infiltration in on-treatment tumour biopsies. Conclusions The combination of EnAd and Pxl has manageable tolerability. Favorable disease control is noted in this recurrent platinum-resistant population, which is worthy of further investigation. Clinical trial identification 2013-001276-38. Legal entity responsible for the study PsiOxus Therapeutics Ltd. Funding PsiOxus Therapeutics Ltd. Disclosure R. Brown: Shareholder / Stockholder / Stock options, Full / Part-time employment: PsiOxus Therapeutics Ltds. D. Krige: Full / Part-time employment: PsiOxus Therapeutics Ltds. J. Bendall: Full / Part-time employment: PsiOxus Therapeutics Ltds. G. Di Genova: Full / Part-time employment: PsiOxus Therapeutics Ltds. H. McElwaine-Johnn: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: PsiOxus Therapeutics Ltds. All other authors have declared no conflicts of interest.

Purpose Most dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) data are evaluated for individual patients with cohorts analyzed to detect significant changes from baseline values, repeating the process at each posttreatment timepoint. Our study aimed to develop a statistically valid model for the complete time course of DCE-MRI data in a patient cohort. Materials and Methods Data from 10 patients with colorectal cancer liver metastases were analyzed, including two baseline scans and four post-bevacizumab scans. Apparent changes in tumor median Ktrans were adjusted for changes in observed enhancing tumor fraction (EnF) by multiplying Ktrans by EnF (KEnF). A mixed-effects model (MEM) was defined to describe the KEnF time course for all patients simultaneously by assuming a three-parameter indirect response model with model parameters lognormally distributed across patients. Results The typical cohort time course showed a KEnF reduction to 59% of baseline at 24 hours, returning to 65% of baseline values by day 12. Interpatient variability of model parameters ranged from 11% to 307%. Conclusion The MEM approach has potential for comparing responses at a group level in clinical trials with different doses, schedules, or combination regimens. Furthermore, the KEnF biomarker successfully resolved confounds in interpreting Ktrans arising from therapy induced changes in the volume of enhancing tumor. J. Magn. Reson. Imaging 2015;41:132–141. © 2014 Wiley Periodicals, Inc.

Relatively few Chinese patients access tertiary cancer services in North West England. We investigated the reasons behind this using a culturally sensitive questionnaire. The questionnaire, completed by 214 Chinese people in English, Cantonese or Mandarin, evaluated the Chinese population's access and satisfaction with primary care, understanding of cancer and awareness of local cancer services. Ninety-five per cent of respondents were registered with a general practitioner (GP) and 75% had accessed primary care in the last year. Satisfaction with GP consultations was high but a third of respondents reported a lack of confidence in local National Health Service (NHS) services. Only 57% of eligible women had attended cervical screening programmes. The overall understanding of the causes and treatment of cancer and cancer services in the North West was poor. Despite registration with primary healthcare, the Chinese population under-utilise cancer prevention programmes and tertiary cancer services because of a lack of awareness and understanding of cancer services in the North West. A significant proportion of the population is dissatisfied with the perceived slow service and lack confidence in services, with 41% considering using healthcare abroad. These data highlight the critical need to engage with, educate and support the Chinese population if they are to access NHS cancer services.

Aim: Malignant bowel obstruction (MBO) in ovarian cancer is poorly understood. Methods: This retrospective cohort study analyzed 129 patients with ovarian cancer and MBO. Results: At presentation, 69 (53%) had platinum-resistant, 37 (29%) platinum-sensitive and 23 (18%) chemotherapy-naive disease. In patients receiving chemotherapy following the MBO episode, median overall survival (OS) was 107 days for chemotherapy-naive patients compared with 83 and 86 for platinum-sensitive or platinum-resistant patients (p = 0.98). OS was inferior for best supportive care (45 days) compared with chemotherapy (152 days) or surgery (124 days; p < 0.001). The Manchester Bowel Obstruction Score using Eastern Cooperative Oncology Group and obstruction level discriminated patients by median OS of 181 days (neither) versus 98 days (one) versus 42 days (both; p < 0.01). Conclusion: The Manchester Bowel Obstruction Score may aide treatment stratification.

Imaging biomarkers (IBs) are integral to the routine management of patients with cancer. IBs used daily in oncology include clinical TNM stage, objective response and left ventricular ejection fraction. Other CT, MRI, PET and ultrasonography biomarkers are used extensively in cancer research and drug development. New IBs need to be established either as useful tools for testing research hypotheses in clinical trials and research studies, or as clinical decision-making tools for use in healthcare, by crossing 'translational gaps' through validation and qualification. Important differences exist between IBs and biospecimen-derived biomarkers and, therefore, the development of IBs requires a tailored 'roadmap'. Recognizing this need, Cancer Research UK (CRUK) and the European Organisation for Research and Treatment of Cancer (EORTC) assembled experts to review, debate and summarize the challenges of IB validation and qualification. This consensus group has produced 14 key recommendations for accelerating the clinical translation of IBs, which highlight the role of parallel (rather than sequential) tracks of technical (assay) validation, biological/clinical validation and assessment of cost-effectiveness; the need for IB standardization and accreditation systems; the need to continually revisit IB precision; an alternative framework for biological/clinical validation of IBs; and the essential requirements for multicentre studies to qualify IBs for clinical use.

background: There is a critical need for predictive/resistance biomarkers for VEGF inhibitors to optimise their use. methods: Blood samples were collected during and following treatment and, where appropriate, upon progression from ovarian cancer patients in ICON7, a randomised phase III trial of carboplatin and paclitaxel with or without bevacizumab. Plasma concentrations of 15 circulating angio-biomarkers were measured using a validated multiplex ELISA, analysed through a novel network analysis and their relevance to the PFS then determined. results: Samples (n=650) were analysed from 92 patients. Bevacizumab induced correlative relationships between Ang1 and Tie2 plasma concentrations, which reduced after initiation of treatment and remained decreased until progressive disease occurred. A 50% increase from the nadir in the concentration of circulating Tie2 (or the product of circulating Ang1 and Tie2) predicted tumour progression. Combining Tie2 with GCIG-defined Ca125 data yielded a significant improvement in the prediction of progressive disease in patients receiving bevacizumab in comparison with Ca125 alone (74.1% vs 47.3%, P

The management of solid tumors has been transformed by the advent of VEGF pathway inhibitors. Early clinical evaluation of these drugs has used pharmacodynamic biomarkers derived from advanced imaging such as dynamic MRI, computed tomography (CT), and ultrasound to establish proof of principle. We have reviewed published studies that used these imaging techniques to determine whether the same biomarkers relate to survival in renal, hepatocellular, and brain tumors in patients treated with VEGF inhibitors. Data show that in renal cancer, pretreatment measurements of Ktrans and early pharmacodynamic reduction in tumor enhancement and density have prognostic significance in patients treated with VEGF inhibitors. A weaker, but significant, relationship is seen with subtle early size change (10% in one dimension) and survival. Data from high-grade glioma suggest that pretreatment fractional blood volume and Ktrans were prognostic of overall survival. However, lack of control data with other therapies prevents assessment of the predictive nature of these biomarkers, and such studies are urgently required. Clin Cancer Res; 18(24); 6588–98. ©2012 AACR.

About 100 early-phase clinical trials and investigator-led studies of targeted antivascular therapies--both anti-angiogenic and vascular-targeting agents--have reported data derived from T1-weighted dynamic contrast-enhanced (DCE)-MRI. However, the role of DCE-MRI for decision making during the drug-development process remains controversial. Despite well-documented guidelines on image acquisition and analysis, several key questions concerning the role of this technique in early-phase trial design remain unanswered. This Review describes studies of single-agent antivascular therapies, in which DCE-MRI parameters are incorporated as pharmacodynamic biomarkers. We discuss whether these parameters, such as volume transfer constant (K(trans)), are reproducible and reliable biomarkers of both drug efficacy and proof of concept, and whether they assist in dose selection and drug scheduling for subsequent phase II trials. Emerging evidence indicates that multiparametric analysis of DCE-MRI data offers greater insight into the mechanism of drug action than studies measuring a single parameter, such as K(trans). We also provide an overview of current data and appraise the future directions of this technique in oncology trials. Finally, major hurdles in imaging biomarker development, validation and qualification that hinder a wide application of DCE-MRI techniques in clinical trials are addressed.

Antiangiogenic therapies that target VEGF or its receptors have become a mainstay of cancer therapy in multiple malignancies. However, the clinical efficacy of these agents is less than originally anticipated and, in most settings, requires the addition of cytotoxic chemotherapy suggesting that, as for other targeted therapies, VEGF inhibitors will require selection of patient subpopulations to achieve maximal clinical benefit. Without the identification and use of predictive biomarkers for VEGF-targeted agents, and other agents that target the vasculature, further improvements in current clinical outcomes are unlikely. Exciting new data presented in 2011 at the ESMO conference showed that retrospective evaluation of plasma concentrations of VEGF-A predicted progression-free survival and/or overall survival benefit from bevacizumab in phase III trials in certain tumour types; prospective evaluation of the assay is required. This endeavour should be followed by further biomarker research, requiring inter-laboratory collaboration and high-quality, adequately powered clinical trials.

The prototypic anti-angiogenic agents, VEGF inhibitors, are increasingly used in clinical practice to treat a variety of tumours. Although generally well tolerated, their toxicities can be significant or occasionally life threatening. The ability to identify those patients whose disease will respond to VEGF inhibitors would minimise exposure to ineffective drugs for some patients. To date, there are no validated predictive or prognostic biomarkers for anti-angiogenic drugs. Toxicities such as hypertension and proteinuria are related to the effect of VEGF inhibition on the vasculature. This has led to the investigation of these toxicities as potential biomarkers of clinical outcome in patients treated with these agents.Putative mechanisms for the development of hypertension and proteinuria, and their potential role as clinically useful biomarkers in relation to anti-angiogenic drugs are discussed in this article. PUBMED, EMBASE and abstracts presented at the American Society of Clinical Oncology until July 2011 were searched to identify relevant English language articles. Studies of anti-angiogenic therapies testing the relationship of either hypertension or proteinuria with outcome were included.The evidence in support of the hypothesis that hypertension and proteinuria are biomarkers of response to anti-angiogenic drugs is inconclusive. Current evidence suggests that hypertension is a pharmacodynamic effect of anti-angiogenic agents. Future studies should aim to measure and report toxicities in a standardised manner to facilitate comparisons between studies.

PURPOSE: To evaluate the Akaike information criterion (AIC) model selection technique as a method for detecting differences in microvascular characteristics between tumorous and non-tumor liver tissue. MATERIALS AND METHODS: The AIC was applied to six patient datasets with liver metastases to determine, on a per voxel basis, which of two physiologically plausible candidate models gave a more appropriate description of the data. The dual-input single-compartment Materne model, extended to incorporate a novel portal input function estimation method, was chosen to represent liver tissue and the single-input dual-compartment extended Kety model was used for tumor. RESULTS: Median AIC probabilities when comparing tumor versus liver and tumor versus tumor-margins were significantly different (P ? 0.01) in five of the six patient datasets. Comparisons between tumor margins and liver regions were significantly different in four datasets. Median AIC probabilities selected for the extended Kety model in all tumor regions, with the Materne model being progressively more probable through tumor margins into liver. CONCLUSION: We present a viable method for assessing the spatially varying microvascular characteristics of tumor-bearing livers, with possible applications in lesion detection, assessment of tumor invasion, and measurement of drug efficacy.

Purpose Inhibiting angiogenesis is one of the most promising avenues for new therapies for ovarian cancer. We investigated the efficacy and safety of a novel agent, BIBF 1120, a triple angiokinase inhibitor, after chemotherapy for relapsed disease. Patients and Methods We conducted a randomized, double-blind, controlled phase II trial in 83 patients who had just completed chemotherapy for relapsed ovarian cancer, with evidence of response, but at high risk of further early recurrence. The patients were randomly assigned to receive maintenance therapy using BIBF 1120 250 mg or placebo, twice per day, continuously for 36 weeks. End points were progression-free survival (PFS), toxicity, and overall survival. Results Thirty-six–week PFS rates were 16.3% and 5.0% in the BIBF 1120 and placebo groups, respectively (hazard ratio, 0.65; 95% CI, 0.42 to 1.02; P = .06). Four patients continued on BIBF 1120, including two patients for another year or more. The proportion of patients with any grade 3 or 4 adverse events was similar between the groups (34.9% for BIBF 1120 v 27.5% for placebo; P = .49; mostly grade 3). However, more patients on BIBF 1120 experienced diarrhea, nausea, or vomiting (mainly grade 1 or 2 and no grade 4). There was a higher rate of grade 3 or 4 hepatotoxicity in patients on BIBF 1120 (51.2%) compared with patients on placebo (7.5%; P < .001), but this was rarely of clinical significance, and patients continued with the trial treatment. A single-level dose reduction to 150 mg was made in 15 patients, all on active drug. Conclusion BIBF 1120 is well tolerated and associated with a potential improvement in PFS. The observed treatment effect is sufficient to justify further study within a large phase III trial.

Background:Platinum-resistant and refractory cancers of the ovary, fallopian tube, and peritoneum have a poor prognosis, yet in some cases, they can respond to multiple lines of chemotherapy. Uncertainty remains over optimal drug choice and when therapeutic focus should be switched from active therapy to supportive care.Methods:A retrospective case note review was performed on 274 women treated for platinum-resistant/refractory ovarian, fallopian tube, or peritoneal carcinoma at the Christie Hospital between 2004 and 2008. Baseline data at onset of platinum resistance and outcomes from subsequent lines of therapy were recorded.Results:A total of 689 lines of therapy were administered with a median overall survival from initiation of first-line therapy for platinum-resistant disease of 61 weeks. Twenty-eight percent of women commenced cytotoxic therapy in the last 3 months of life. Treatment efficacy declined rapidly with successive lines of therapy particularly if disease progression occurred during first-line therapy. Factors independently associated with worse overall survival at recognition of platinum resistance were performance status, presence of stage IV disease, elevated cancer antigen 125, and platinum-refractory disease.Conclusions:A significant proportion of women who were treated received therapy within the last few months of life with little clinical benefit. Disease progression on 2 consecutive lines of therapy should be used as a guide to discontinue cytotoxic treatment. A subset of patients with poor prognosis at the onset of platinum resistance, who may have little gain from anticancer treatment, can be identified.

IntroductionPatients with advanced ovarian cancer can develop bowel obstruction. Oral intake is limited in these patients and home parenteral nutrition (PN) may be used to meet nutritional requirements.AimTo explore patient and family experience of home PN.MethodNinety-three longitudinal in-depth interviews were conducted with 20 women with ovarian cancer and inoperable bowel obstruction receiving PN, their lay-carers and healthcare professionals. Interviews were transcribed verbatim and analysed thematically influenced by the techniques of Van Manen (1990).ResultsWomen and their relatives viewed PN as increasing length of life and allowing the women to live at home with some normality. However, the treatment was not without problems which may not be acknowledged by healthcare professionals. These included difficulties with activities of daily living, incursions of physical freedom as patients were attached to heavy PN bags and dealing with the bureaucracy associated with PN. Healthcare professionals were working to a patient-centred rather than a family-centred palliative care model, which could be problematic for some families with frail relatives. However, carers coped but emotionally were often left in a vulnerable state.ConclusionsFor patients and carers the treatment was a life line and they appreciated the extra time the women received. However this was gained through many losses which healthcare professionals need to portray accurately and implement a family-centred palliative care model when appropriate. Nevertheless, patients are prepared to suffer losses in order to continue living.Reference. Van Manen M. Researching lived experience: Human science for an action sensitive pedagogy 1990. London Ont: Althouse Press.