Maintenance olaparib in patients with platinum-sensitive relapsed ovarian cancer: Outcomes by somatic and germline BRCA and other homologous recombination repair gene mutation status in the ORZORA trial.

BACKGROUND: The open-label, single-arm, multicenter ORZORA trial (NCT02476968) evaluated the efficacy and safety of maintenance olaparib in patients with platinum-sensitive relapsed ovarian cancer (PSR OC) who had tumor BRCA mutations (BRCAm) of germline (g) or somatic (s) origin or non-BRCA homologous recombination repair mutations (HRRm) and were in response to their most recent platinum-based chemotherapy after ≥2 lines of treatment. METHODS: Patients received maintenance olaparib capsules (400 mg twice daily) until disease progression. Prospective central testing at screening determined tumor BRCAm status and subsequent testing determined gBRCAm or sBRCAm status. Patients with predefined non-BRCA HRRm were assigned to an exploratory cohort. The co-primary endpoints were investigator-assessed progression-free survival (PFS; modified Response Evaluation Criteria in Solid Tumors v1.1) in BRCAm and sBRCAm cohorts. Secondary endpoints included health-related quality of life (HRQoL) and tolerability. RESULTS: 177 patients received olaparib. At the primary data cut-off (17 April 2020), the median follow-up for PFS in the BRCAm cohort was 22.3 months. The median PFS (95% CI) in BRCAm, sBRCAm, gBRCAm and non-BRCA HRRm cohorts was 18.0 (14.3-22.1), 16.6 (12.4-22.2), 19.3 (14.3-27.6) and 16.4 (10.9-19.3) months, respectively. Most patients with BRCAm reported improvements (21.8%) or no change (68.7%) in HRQoL and the safety profile was as expected. CONCLUSIONS: Maintenance olaparib had similar clinical activity in PSR OC patients with sBRCAm and those with any BRCAm. Activity was also observed in patients with a non-BRCA HRRm. ORZORA further supports use of maintenance olaparib in all patients with BRCA-mutated, including sBRCA-mutated, PSR OC.

Systemic treatment of hormone receptor positive, human epidermal growth factor 2 negative metastatic breast cancer: retrospective analysis from Leeds Cancer Centre.

BACKGROUND: Study aimed to characterise treatment and outcomes for patients with hormone receptor positive (HR+), human epidermal growth factor 2 negative (HER2-) metastatic breast cancer (MBC) within a large regional cancer centre, as a benchmark for evaluating real-world impact of novel therapies. METHODS: Retrospective longitudinal cohort, using electronic patient records of adult females with a first diagnosis of HR+/HER2- MBC January 2012-March 2018. RESULTS: One hundred ninety-six women were identified with HR+/HER2- MBC. Median age was 67 years, 85.2% were post-menopausal and median time between primary diagnosis and metastasis was 5.4 years. Most (75.1%) patients received endocrine therapy as first line systemic treatment (1st LoT); use of 1st LoT chemotherapy halved between 2012 and 2017. Patients receiving 1st LoT chemotherapy were younger and more likely to have visceral metastasis (p < 0.01). Median OS was 29.5 months and significantly greater for patients with exclusively non-visceral metastasis (p < 0.01). The adjusted hazard ratio for death of patients with visceral (or CNS) metastasis was 1.91 relative to those with exclusively non-visceral metastasis. CONCLUSIONS: Diverse endocrine therapies predominate as 1st LoT for patients with HR+/HER2- MBC, chemotherapy being associated with more aggressive disease in younger patients, emphasising the importance of using effective and tolerable therapies early.

The 5-HTTLPR and BDNF polymorphisms moderate the association between uncinate fasciculus connectivity and antidepressants treatment response in major depression.

Symptom improvement in depression due to antidepressant treatment is highly variable and clinically unpredictable. Linking neuronal connectivity and genetic risk factors in predicting antidepressant response has clinical implications. Our investigation assessed whether indices of white matter integrity, serotonin transporter-linked polymorphism (5-HTTLPR) and brain-derived neurotrophic factor (BDNF) val66met polymorphism predicted magnitude of depression symptom change following antidepressant treatment. Fractional anisotropy (FA) was used as an indicator of white matter integrity and was assessed in the uncinate fasciculus and superior longitudinal fasciculus using tract-based spatial statistics (TBSS) and probabilistic tractography. Forty-six medication-free patients with major depressive disorder participated in a diffusion tensor imaging scan prior to completing an 8-week treatment regime with citalopram or quetiapine XR. Indexed improvements in Hamilton Depression Rating Scale score from baseline to 8-week endpoint were used as an indicator of depression improvement. Carriers of the BDNF met allele exhibited lower FA values in the left uncinate fasciculus relative to val/val individuals [F(1, 40) = 7.314, p = 0.009]. Probabilistic tractography identified that higher FA in the left uncinate fasciculus predicted percent change in depression severity, with BDNF moderating this association [F(3, 30) = 3.923, p = 0.018]. An interaction between FA in the right uncinate fasciculus and 5-HTTLPR also predicted percent change in depression severity [F(5, 25) = 5.315, p = 0.002]. Uncorrected TBSS results revealed significantly higher FA in hippocampal portions of the cingulum bundle in responders compared to non-responders (p = 0.016). The predictive value of prefrontal and amygdala/hippocampal WM connectivity on antidepressant treatment response may be influenced by 5-HTTLPR and BDNF polymorphisms in MDD.

Phase 2 multicentre trial investigating intermittent and continuous dosing schedules of the poly(ADP-ribose) polymerase inhibitor rucaparib in germline BRCA mutation carriers with advanced ovarian and breast cancer.

BACKGROUND: Rucaparib is an orally available potent selective small-molecule inhibitor of poly(ADP-ribose) polymerase (PARP) 1 and 2. Rucaparib induces synthetic lethality in cancer cells defective in the homologous recombination repair pathway including BRCA-1/2. We investigated the efficacy and safety of single-agent rucaparib in germline (g) BRCA mutation carriers with advanced breast and ovarian cancers. METHODS: Phase II, open-label, multicentre trial of rucaparib in proven BRCA-1/2 mutation carriers with advanced breast and or ovarian cancer, WHO PS 0-1 and normal organ function. Intravenous (i.v.) and subsequently oral rucaparib were assessed, using a range of dosing schedules, to determine the safety, tolerability, dose-limiting toxic effects and pharmacodynamic (PD) and pharmacokinetic (PK) profiles. RESULTS: Rucaparib was well tolerated in patients up to doses of 480 mg per day and is a potent inhibitor of PARP, with sustained inhibition ⩾24 h after single doses. The i.v. rucaparib (intermittent dosing schedule) resulted in an objective response rate (ORR) of only 2% but with 41% (18 out of 44) patients achieved stable disease for ⩾12 weeks and 3 patients maintaining disease stabilisation for >52 weeks. The ORR for oral rucaparib (across all six dose levels) was 15%. In the oral cohorts, 81% (22 out of 27) of the patients had ovarian cancer and 12 out of 13, who were dosed continuously, achieved RECIST complete response/partial response (CR/PR) or stable disease (SD) ⩾12 weeks, with a median duration of response of 179 days (range 84-567 days). CONCLUSIONS: Rucaparib is well tolerated and results in high levels of PARP inhibition in surrogate tissues even at the lowest dose levels. Rucaparib is active in gBRCA-mutant ovarian cancer and this activity correlates with platinum-free interval. The key lessons learned from this study is that continuous rucaparib dosing is required for optimal response, the recommended phase 2 dose (RP2D) for continuous oral scheduling has not been established and requires further exploration and, thirdly, the use of a PD biomarker to evaluate dose-response has its limitations.

Radiomics in the evaluation of ovarian masses - a systematic review.

OBJECTIVES: The study aim was to conduct a systematic review of the literature reporting the application of radiomics to imaging techniques in patients with ovarian lesions. METHODS: MEDLINE/PubMed, Web of Science, Scopus, EMBASE, Ovid and ClinicalTrials.gov were searched for relevant articles. Using PRISMA criteria, data were extracted from short-listed studies. Validity and bias were assessed independently by 2 researchers in consensus using the Quality in Prognosis Studies (QUIPS) tool. Radiomic Quality Score (RQS) was utilised to assess radiomic methodology. RESULTS: After duplicate removal, 63 articles were identified, of which 33 were eligible. Fifteen assessed lesion classifications, 10 treatment outcomes, 5 outcome predictions, 2 metastatic disease predictions and 1 classification/outcome prediction. The sample size ranged from 28 to 501 patients. Twelve studies investigated CT, 11 MRI, 4 ultrasound and 1 FDG PET-CT. Twenty-three studies (70%) incorporated 3D segmentation. Various modelling methods were used, most commonly LASSO (least absolute shrinkage and selection operator) (10/33). Five studies (15%) compared radiomic models to radiologist interpretation, all demonstrating superior performance. Only 6 studies (18%) included external validation. Five studies (15%) had a low overall risk of bias, 9 (27%) moderate, and 19 (58%) high risk of bias. The highest RQS achieved was 61.1%, and the lowest was - 16.7%. CONCLUSION: Radiomics has the potential as a clinical diagnostic tool in patients with ovarian masses and may allow better lesion stratification, guiding more personalised patient care in the future. Standardisation of the feature extraction methodology, larger and more diverse patient cohorts and real-world evaluation is required before clinical translation. CLINICAL RELEVANCE STATEMENT: Radiomics shows promising results in improving lesion stratification, treatment selection and outcome prediction. Modelling with larger cohorts and real-world evaluation is required before clinical translation. KEY POINTS: • Radiomics is emerging as a tool for enhancing clinical decisions in patients with ovarian masses. • Radiomics shows promising results in improving lesion stratification, treatment selection and outcome prediction. • Modelling with larger cohorts and real-world evaluation is required before clinical translation.

Artificial intelligence in ovarian cancer histopathology: a systematic review.

This study evaluates the quality of published research using artificial intelligence (AI) for ovarian cancer diagnosis or prognosis using histopathology data. A systematic search of PubMed, Scopus, Web of Science, Cochrane CENTRAL, and WHO-ICTRP was conducted up to May 19, 2023. Inclusion criteria required that AI was used for prognostic or diagnostic inferences in human ovarian cancer histopathology images. Risk of bias was assessed using PROBAST. Information about each model was tabulated and summary statistics were reported. The study was registered on PROSPERO (CRD42022334730) and PRISMA 2020 reporting guidelines were followed. Searches identified 1573 records, of which 45 were eligible for inclusion. These studies contained 80 models of interest, including 37 diagnostic models, 22 prognostic models, and 21 other diagnostically relevant models. Common tasks included treatment response prediction (11/80), malignancy status classification (10/80), stain quantification (9/80), and histological subtyping (7/80). Models were developed using 1-1375 histopathology slides from 1-776 ovarian cancer patients. A high or unclear risk of bias was found in all studies, most frequently due to limited analysis and incomplete reporting regarding participant recruitment. Limited research has been conducted on the application of AI to histopathology images for diagnostic or prognostic purposes in ovarian cancer, and none of the models have been demonstrated to be ready for real-world implementation. Key aspects to accelerate clinical translation include transparent and comprehensive reporting of data provenance and modelling approaches, and improved quantitative evaluation using cross-validation and external validations. This work was funded by the Engineering and Physical Sciences Research Council.

Ovarian Real-World International Consortium (ORWIC): A multicentre, real-world analysis of epithelial ovarian cancer treatment and outcomes.

Introduction: Much drug development and published analysis for epithelial ovarian cancer (EOC) focuses on early-line treatment. Full sequences of treatment from diagnosis to death and the impact of later lines of therapy are rarely studied. We describe the establishment of an international network of cancer centers configured to compare real-world treatment pathways in UK, Portugal, Germany, South Korea, France and Romania (the Ovarian Real-World International Consortium; ORWIC). Methods: 3344 patients diagnosed with EOC (2012-2018) were analysed using a common data model and hub and spoke programming approach applied to existing electronic medical records. Consistent definition of line of therapy between sites and an efficient approach to analysis within the limitations of local information governance was achieved. Results: Median age of participants was 53-67 years old and 5-29% were ECOG >1. Between 62% and 84% of patients were diagnosed with late-stage disease (FIGO III-IV). Sites treating younger and fitter patients had higher rates of debulking surgery for those diagnosed at late stage than sites with older, more frail patients. At least 21% of patients treated with systemic anti-cancer therapy (SACT) had recurrent disease following second-line therapy (2L); up to 11 lines of SACT treatment were recorded for some patients. Platinum-based SACT was consistently used across sites at 1L, but choices at 2L varied, with hormone therapies commonly used in the UK and Portugal. The use (and type) of maintenance therapy following 1L also varied. Beyond 2L, there was little consensus between sites on treatment choice: trial compounds and unspecified combinations of other agents were common. Discussion: Specific treatment sequences are reported up to 4L and the establishment of this network facilitates future analysis of comparative outcomes per line of treatment with the aim of optimizing available options for patients with recurrent EOC. In particular, this real-world network can be used to assess the growing use of PARP inhibitors. The real-world optimization of advanced line treatment will be especially important for patients not usually eligible for involvement with clinical trials. The resources to enable this analysis to be implemented elsewhere are supplied and the network will seek to grow in coverage of further sites.

The Pitfalls of Using Open Data to Develop Deep Learning Solutions for COVID-19 Detection in Chest X-Rays.

Since the emergence of COVID-19, deep learning models have been developed to identify COVID-19 from chest X-rays. With little to no direct access to hospital data, the AI community relies heavily on public data comprising numerous data sources. Model performance results have been exceptional when training and testing on open-source data, surpassing the reported capabilities of AI in pneumonia-detection prior to the COVID-19 outbreak. In this study impactful models are trained on a widely used open-source data and tested on an external test set and a hospital dataset, for the task of classifying chest X-rays into one of three classes: COVID-19, non-COVID pneumonia and no-pneumonia. Classification performance of the models investigated is evaluated through ROC curves, confusion matrices and standard classification metrics. Explainability modules are implemented to explore the image features most important to classification. Data analysis and model evalutions show that the popular open-source dataset COVIDx is not representative of the real clinical problem and that results from testing on this are inflated. Dependence on open-source data can leave models vulnerable to bias and confounding variables, requiring careful analysis to develop clinically useful/viable AI tools for COVID-19 detection in chest X-rays.

AuguR: A Scalable Open-Source Interactive Web Application for Routinely Collected Data.

Most data collected by hospitals as a consequence of the delivery of routine care is not utilised for analytics or organisational intelligence. This project aims to develop tools to enhance the utilisation of routinely collected cancer data within hospitals across England. This was achieved by developing a web application using open source tools to provide health care professionals and hospital managers with easy to use, interactive analytics for cancer data. The application uses data items hospitals in England are mandated to collect as part of the Cancer Outcomes and Services Dataset (COSD), to provide clinical insight into survival outcomes, population distributions, service demands, waiting times, geographical case distributions and treatment information in real-time or near real-time. Development was guided by end user needs through the use of panels of clinical and non-clinical end users.

A data flow process for confidential data and its application in a health research project.

BACKGROUND: The use of linked healthcare data in research has the potential to make major contributions to knowledge generation and service improvement. However, using healthcare data for secondary purposes raises legal and ethical concerns relating to confidentiality, privacy and data protection rights. Using a linkage and anonymisation approach that processes data lawfully and in line with ethical best practice to create an anonymous (non-personal) dataset can address these concerns, yet there is no set approach for defining all of the steps involved in such data flow end-to-end. We aimed to define such an approach with clear steps for dataset creation, and to describe its utilisation in a case study linking healthcare data. METHODS: We developed a data flow protocol that generates pseudonymous datasets that can be reversibly linked, or irreversibly linked to form an anonymous research dataset. It was designed and implemented by the Comprehensive Patient Records (CPR) study in Leeds, UK. RESULTS: We defined a clear approach that received ethico-legal approval for use in creating an anonymous research dataset. Our approach used individual-level linkage through a mechanism that is not computer-intensive and was rendered irreversible to both data providers and processors. We successfully applied it in the CPR study to hospital and general practice and community electronic health record data from two providers, along with patient reported outcomes, for 365,193 patients. The resultant anonymous research dataset is available via DATA-CAN, the Health Data Research Hub for Cancer in the UK. CONCLUSIONS: Through ethical, legal and academic review, we believe that we contribute a defined approach that represents a framework that exceeds current minimum standards for effective pseudonymisation and anonymisation. This paper describes our methods and provides supporting information to facilitate the use of this approach in research.

Development and validation of multivariable machine learning algorithms to predict risk of cancer in symptomatic patients referred urgently from primary care: a diagnostic accuracy study.

OBJECTIVES: To develop and validate tests to assess the risk of any cancer for patients referred to the NHS Urgent Suspected Cancer (2-week wait, 2WW) clinical pathways. SETTING: Primary and secondary care, one participating regional centre. PARTICIPANTS: Retrospective analysis of data from 371 799 consecutive 2WW referrals in the Leeds region from 2011 to 2019. The development cohort was composed of 224 669 consecutive patients with an urgent suspected cancer referral in Leeds between January 2011 and December 2016. The diagnostic algorithms developed were then externally validated on a similar consecutive sample of 147 130 patients (between January 2017 and December 2019). All such patients over the age of 18 with a minimum set of blood counts and biochemistry measurements available were included in the cohort. PRIMARY AND SECONDARY OUTCOME MEASURES: sensitivity, specificity, negative predictive value, positive predictive value, Receiver Operating Characteristic (ROC) curve Area Under Curve (AUC), calibration curves RESULTS: We present results for two clinical use-cases. In use-case 1, the algorithms identify 20% of patients who do not have cancer and may not need an urgent 2WW referral. In use-case 2, they identify 90% of cancer cases with a high probability of cancer that could be prioritised for review. CONCLUSIONS: Combining a panel of widely available blood markers produces effective blood tests for cancer for NHS 2WW patients. The tests are affordable, and can be deployed rapidly to any NHS pathology laboratory with no additional hardware requirements.

Collection of cancer Patient Reported Outcome Measures (PROMS) to link with primary and secondary electronic care records to understand and improve long term cancer outcomes: A protocol paper.

INTRODUCTION: More people are living with and beyond a cancer diagnosis. There is limited understanding of the long-term effects of cancer and cancer treatment on quality of life and personal and household finances when compared to people without cancer. In a separate protocol we have proposed to link de-identified data from electronic primary care and hospital records for a large population of cancer survivors and matched controls. In this current protocol, we propose the linkage of Patient Reported Outcomes Measures data to the above data for a subset of this population. The aim of this study is to investigate the full impact of living with and beyond a cancer diagnosis compared to age and gender matched controls. A secondary aim is to test the feasibility of the collection of Patient Reported Outcomes Measures (PROMS) data and the linkage procedures of the PROMs data to electronic health records data. MATERIALS AND METHODS: This is a cross-sectional study, aiming to recruit participants treated at the Leeds Teaching Hospitals National Health Service Trust. Eligible patients will be cancer survivors at around 5 years post-diagnosis (breast, colorectal and ovarian cancer) and non-cancer patient matched controls attending dermatology out-patient clinics. They will be identified by running a query on the Leeds Teaching Hospitals Trust patient records system. Approximately 6000 patients (2000 cases and 4000 controls) will be invited to participate via post. Participants will be invited to complete PROMs assessing factors such as quality of life and finances, which can be completed on paper or online (surveys includes established instruments, and bespoke instruments (demographics, financial costs). This PROMs data will then be linked to routinely collected de-identified data from patient's electronic primary care and hospital records. DISCUSSION: This innovative work aims to create a truly 'comprehensive patient record' to provide a broad picture of what happens to cancer patients across their cancer pathway, and the long-term impact of cancer treatment. Comparisons can be made between the cases and controls, to identify the aspects of life that has had the greatest impact following a cancer diagnosis. The feasibility of linking PROMs data to electronic health records can also be assessed. This work can inform future support offered to people living with and beyond a cancer diagnosis, clinical practice, and future research methodologies.

The prognostic and predictive value of CA-125 regression during neoadjuvant chemotherapy for advanced ovarian or primary peritoneal carcinoma.

PURPOSE: To assess the significance of CA-125 regression as a prognostic indicator and predictor of optimal cytoreduction at interval debulking surgery (IDS) in women with ovarian or primary peritoneal carcinoma receiving neoadjuvant chemotherapy (NAC). METHODS: 63 women treated between 2004 and 2007 with neoadjuvant platinum-based chemotherapy followed by IDS were studied retrospectively. Pre-operative CA-125 values were used to calculate a regression coefficient (CA-125r) using exponential regression analysis. Outcome endpoints were overall survival (OS), time to CA-125 progression (TTC) by Rustin criteria and time to second-line treatment (TTS). RESULTS: Women with a CA-125 half-life greater than 18 days had a significantly worse OS compared to those with a half-life less than 12 days on univariate testing (HR 3.34, 95% CI 1.25-8.94, p = 0.017). On multivariable analysis, CA-125r was an independent predictor of OS [HR 1.18 (per 0.01 increase in CA-125r), 95% CI 1.01-1.40, p = 0.043]. CA-125r was independently predictive of TTC and TTS (HR 1.17, p ≈ 0.03 for each). CA-125r was also predictive of achieving optimal cytoreduction at IDS (AUC 0.756, p < 0.001). CONCLUSIONS: CA-125 regression rate during pre-operative NAC is of independent prognostic value. CA-125 regression rate strongly predicts for optimal cytoreduction.

Process Mining to Explore Variations in Endometrial Cancer Pathways from GP Referral to First Treatment.

The main challenge in the pathway analysis of cancer treatments is the complexity of the process. Process mining is one of the approaches that can be used to visualize and analyze these complex pathways. In this study, our purpose was to use process mining to explore variations in the treatment pathways of endometrial cancer. We extracted patient data from a hospital information system, created the process model, and analyzed the variations of the 62-day pathway from a General Practitioner referral to the first treatment in the hospital. We also analyzed the variations based on three different criteria: the type of the first treatment, the age at diagnosis, and the year of diagnosis. This approach should be of interest to others dealing with complex medical and healthcare processes.

Treatment patterns and survival outcomes for patients with non-small cell lung cancer in the UK in the preimmunology era: a REAL-Oncology database analysis from the I-O Optimise initiative.

OBJECTIVES: To report characteristics, treatment and overall survival (OS) trends, by stage and pathology, of patients diagnosed with non-small cell lung cancer (NSCLC) at Leeds Teaching Hospital NHS Trust in 2007-2018. DESIGN: Retrospective cohort study based on electronic medical records. SETTING: Large NHS university hospital in Leeds. PARTICIPANTS: 3739 adult patients diagnosed with incident NSCLC from January 2007 to August 2017, followed up until March 2018. MAIN OUTCOME MEASURES: Patient characteristics at diagnosis, treatment patterns and OS. RESULTS: 34.3% of patients with NSCLC were clinically diagnosed (without pathological confirmation). Among patients with known pathology, 45.2% had non-squamous cell carcinoma (NSQ) and 33.3% had squamous cell carcinoma (SQ). The proportion of patients diagnosed at stage I increased (16.4%-27.7% in 2010-2017); those diagnosed at stage IV decreased (57.0%-39.1%). Surgery was the most common initial treatment for patients with pathologically confirmed stage I NSCLC. Use of radiotherapy alone increased over time in patients with clinically diagnosed stage I NSCLC (39.1%-60.3%); chemoradiation increased in patients with stage IIIA NSQ (21.6%-33.3%) and SQ (24.2%-31.9%). Initial treatment with systemic anticancer therapy (SACT) increased in patients with stages IIIB-IV NSQ (49.0%-67.5%); the proportion of untreated patients decreased (30.6%-15.0%). Median OS improved for patients diagnosed with stage I NSQ and SQ and stage IIIA NSQ over time. Median OS for patients with stages IIIB-IV NSQ and SQ remained stable, <10% patients were alive 3 years after diagnosis. Median OS for clinically diagnosed stages IIIB-IV patients was 1.2 months in both periods. CONCLUSIONS: OS for stage I and IIIA patients improved over time, likely due to increased use of stereotactic ablative radiation, surgery (stage I) and chemoradiation (stage IIIA). Conversely, OS outcomes remained poor for stage IIIB-IV patients despite increasing use of SACT for NSQ. Many patients with advanced-stage disease remained untreated.

Trends in the prescription of systemic anticancer therapy and mortality among patients with advanced non-small cell lung cancer: a real-world retrospective observational cohort study from the I-O optimise initiative.

OBJECTIVES: To assess how a decade of developments in systematic anticancer therapy (SACT) for advanced non-small cell lung cancer (NSCLC) affected overall survival (OS) in a large UK University Hospital. DESIGN: Real-world retrospective observational cohort study using existing data recorded in electronic medical records. SETTING: A large National Health Service (NHS) university teaching hospital serving 800 000 people living in a diverse metropolitan area of the UK. PARTICIPANTS: 2119 adults diagnosed with advanced NSCLC (tumour, node, metastasis stage IIIB or IV) between 2007 and 2017 at Leeds Teaching Hospitals NHS Trust. MAIN OUTCOMES AND MEASURES: OS following diagnosis and the analysis of factors associated with receiving SACT. RESULTS: Median OS for all participants was 2.9 months, increasing for the SACT-treated subcohort from 8.4 months (2007-2012) to 9.1 months (2013-2017) (p=0.02); 1-year OS increased from 33% to 39% over the same period for the SACT-treated group. Median OS for the untreated subcohort was 1.6 months in both time periods. Overall, 30.6% (648/2119) patients received SACT; treatment rates increased from 28.6% (338/1181) in 2007-2012 to 33.0% (310/938) in 2013-2017 (p=0.03). Age and performance status were independent predictors for SACT treatment; advanced age and higher performance status were associated with lower SACT treatment rates. CONCLUSION: Although developments in SACT during 2007-2017 correspond to some changes in survival for treated patients with advanced NSCLC, treatment rates remain low and the prognosis for all patients remains poor.

Using a Multi-Level Process Comparison for Process Change Analysis in Cancer Pathways.

The area of process change over time is a particular concern in healthcare, where patterns of care emerge and evolve in response to individual patient needs. We propose a structured approach to analyse process change over time that is suitable for the complex domain of healthcare. Our approach applies a qualitative process comparison at three levels of abstraction: a holistic perspective (process model), a middle-level perspective (trace), and a fine-grained detail (activity). Our aim was to detect change points, localise and characterise the change, and unravel/understand the process evolution. We illustrate the approach using a case study of cancer pathways in Leeds where we found evidence of change points identified at multiple levels. In this paper, we extend our study by analysing the miners used in process discovery and providing a deeper analysis of the activity of investigation in trace and activity levels. In the experiment, we show that this qualitative approach provides a useful understanding of process change over time. Examining change at three levels provides confirmatory evidence of process change where perspectives agree, while contradictory evidence can lead to focused discussions with domain experts. This approach should be of interest to others dealing with processes that undergo complex change over time.

Current Treatment and Outcomes Benchmark for Locally Advanced or Metastatic Urothelial Cancer From a Large UK-Based Single Centre.

Objectives: To characterize treatment patterns and survival outcomes for patients with locally advanced or metastatic malignancy of the urothelial tract during a period immediately preceding the widespread use of immune checkpoint inhibitors in the UK. Patients and Methods: We retrospectively examined the electronic case notes of patients attending the Leeds Cancer Center, UK with locally advanced or metastatic urothelial carcinoma, receiving chemotherapy between January 2003 and March 2017. Patient characteristics, treatment patterns, and outcomes were collected. Summary and descriptive statistics were calculated for categorical and continuous variables as appropriate. The Kaplan-Meier method was used to estimate median survival and Cox regression proportional hazards model was used to explore relationships between clinical variables and outcome. Results: Two hundred and sixteen patients made up the study cohort, with a median age of 66 years (range: 35-83) and 72.7% being male. First-line treatment consisted of either a cisplatin- (44%) or carboplatin-based regimen (48%) in the majority of patients. Twenty seven percent of patients received a second-line of treatment (most commonly single-agent paclitaxel) following a first-line platinum containing regimen. Grade 4 neutropenia was observed in 19 and 27% of those treated with a first-line cisplatin- and carboplatin-based regimen, respectively. The median overall survival (mOS) of the study cohort was estimated to be 16.2 months (IQR: 10.6-28.3 months). Receipt by patients of cisplatin-based chemotherapy was associated with a longer mOS and this association persisted when survival analysis was adjusted for age, sex, performance status and presence of distant metastases. Conclusions: This study provides a useful benchmark for outcomes achieved in a real-world setting for patients with locally advanced or metastatic UC treated with chemotherapy in the immediate pre-immunotherapy era.

A Randomized Phase II Trial of Epigenetic Priming with Guadecitabine and Carboplatin in Platinum-resistant, Recurrent Ovarian Cancer.

PURPOSE: Platinum resistance in ovarian cancer is associated with epigenetic modifications. Hypomethylating agents (HMA) have been studied as carboplatin resensitizing agents in ovarian cancer. This randomized phase II trial compared guadecitabine, a second-generation HMA, and carboplatin (G+C) against second-line chemotherapy in women with measurable or detectable platinum-resistant ovarian cancer. PATIENTS AND METHODS: Patients received either G+C (guadecitabine 30 mg/m2 s.c. once-daily for 5 days and carboplatin) or treatment of choice (TC; topotecan, pegylated liposomal doxorubicin, paclitaxel, or gemcitabine) in 28-day cycles until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints were RECIST v1.1 and CA-125 response rate, 6-month PFS, and overall survival (OS). RESULTS: Of 100 patients treated, 51 received G+C and 49 received TC, of which 27 crossed over to G+C. The study did not meet its primary endpoint as the median PFS was not statistically different between arms (16.3 weeks vs. 9.1 weeks in the G+C and TC groups, respectively; P = 0.07). However, the 6-month PFS rate was significantly higher in the G+C group (37% vs. 11% in TC group; P = 0.003). The incidence of grade 3 or higher toxicity was similar in G+C and TC groups (51% and 49%, respectively), with neutropenia and leukopenia being more frequent in the G+C group. CONCLUSIONS: Although this trial did not show superiority for PFS of G+C versus TC, the 6-month PFS increased in G+C treated patients. Further refinement of this strategy should focus on identification of predictive markers for patient selection.