NIHRDataInsights/HRCSData huggingface dataset:
Title: What is driving general practice variation in ‘two-week wait’ referrals and use of endoscopy and imaging investigations, and does it matter for cancer outcomes?
Funder: Cancer Research UK

Abstract: Background: Most cancer patients first present with poorly-specific symptoms to their general practitioner. Appropriate actions by general practitioners are therefore crucial for achieving a prompt diagnosis. However, there is substantial variation between general practices in use of the ‘two week wait’ (urgent referral) pathway for suspected cancer; or the use of endoscopy or imaging tests. Recent evidence indicates that patients with oesophageal or stomach cancer are more likely to be diagnosed at operable stage in practices which refer their patients for gastroscopy more often. We will explore whether similar associations exist for other cancers and diagnostic tests and examine factors that may explain practice variation in diagnostic processes. Aims: a) To characterise general practice variation in use of ‘two-week wait’ referrals and use of imaging and endoscopy investigations’ b) To explore associations between practice-level diagnostic processes and the proportion of cancer patients diagnosed as emergencies or at advanced stage; and c) To examine associations between practice variation in diagnostic processes and practice characteristics of organisation or quality. Methods: We will analyse data used to generate practice-level summary statistics on use of diagnostic processes for nearly all (~8,000) English practices. These data will be complemented by information on general practice organisational characteristics and quality measures, and cancer registration data. • Using appropriate mixed effect regression models we will first characterise variation between practices in use of the urgent referral pathway for suspected cancer (‘two week wait’ referrals) and use of endoscopy and imaging investigations (e.g. colonoscopy, or CT scan rates). We will explore the degree of apparent variation in these diagnostic processes that may be due to chance or reflect practice differences in population case-mix (age, gender, deprivation) or cancer incidence. • Similar models will then be used to explore whether practices with higher use of referrals or specialist investigations have lower proportions of cancer patients diagnosed as emergencies or at advanced stage. • Finally practice characteristics [e.g. practice performance in respect of clinical quality or patient experience (e.g. experience of doctor communication, care continuity or ease of access)] will be introduced to these models to explore whether variation in diagnostic processes can be explained by organisational or quality characteristics. How the results will be used: The findings will help us to better understand the extent, importance and reasons for practice variation in investigation and cancer outcomes, paving the way for the development and evaluation of appropriate improvement interventions.


Research activity codes: 4.3 INFLUENCES AND IMPACT;8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: CANCER AND NEOPLASMS
Title: Health First Advocacy Project
Funder: Cancer Research UK

Abstract: As outlined in a recent joint Cancer Research UK and Alcohol Health Alliance publication (Alcohol and Cancer, March 2013 ) alcohol is one of the most important preventable causes of cancer in the UK. Alcohol consumption can directly cause seven different types of cancer; Bowel, Breast, Liver, Mouth, Laryngeal, Pharyngeal , and Oesophageal cancers. While alcohol has risen up the agenda as a political priority, implementation of alcohol prevention strategies remains slow and in July 2013 the Government backtracked on their previous commitments (as outlined in the Government’s Alcohol Strategy published in March 2012) to introduce minimum unit pricing (MUP) in England and Wales. Scotland are due to implement MUP. The World Health Organisation has stated that the most effective public health actions for alcohol target availability marketing and price. Using this starting point, Health First was published in March 2013 by the University of Stirling and is an exemplar evidence based alcohol strategy for the UK and over 70 health organisations are signatories to the report. Health First puts forward ten recommendations to reduce alcohol related harm. The most high profile of those is to implement a minimum unit price for alcohol. The challenge is now to undertake advocacy work to achieve these recommendations in practice. We have learnt from the experience of ASH on tobacco and wish to roll out an advocacy and engagement programme along similar lines. To do so this would require additional campaigns capacity. This is an application for joint funding with contributions put forward by the Alcohol Health Alliance. Our activities will include; • Appointing a Policy and Advocacy Manager to undertake and coordinate the campaign to implement Health First recommendations as government and party political policy. • A meeting programme with key contacts around party manifestos including; parliamentary briefing sessions with experts, constituency visits to A&E and police night time shifts and information regarding cheap alcohol products. • Drawing from academic experts we will produce an up to date set of briefings and update the existing website www.minimumpricing.info • Hold biannual meetings with counterparts in the British Isles and act as the focal point to coordinate UK wide activity. • Public engagement programme including opinion polling to build public case and other direct engagement with the public as appropriate. • Promotion of reports on alcohol industry activities and lobbying.


Research activity codes: 8.2 HEALTH AND WELFARE ECONOMICS;3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION)
Health categories: CANCER AND NEOPLASMS
Title: Actively proliferating pancreatic myofibroblasts and their eventual senescence-changes in secretory phenotype and its implications in pancreatic cancer
Funder: Cancer Research UK

Abstract: Background Pancreatic stellate cells (PSC’s) are retinoid lipid storing cells, which under physiological conditions show benign behaviour but in pathological states play a key role in the development of chronic pancreatitis, fibrosis and pancreatic cancer. The incidence of these conditions is rapidly increasing and management options are very limited as patients often present late in the disease process. In pathological states PSCs can be activated by undergoing a phenotypic change to a proliferative myofibroblastic cell type (myofibroblast transdifferentiation, MTD) which modulates the extracellular matrix leading to fibrosis but also potentiating carcinogenesis through secretion of factors that support tumour development. A proportion of myofibroblasts eventually senesce and adopt senescence associated secretory phenotype (SASP), which can further potentiate tumour proliferation and growth. Aims The aim of this project is to identify some of the regulatory pathways involved in PSC activation/MTD and senescence, their role in promoting tumour growth and to identify potential therapeutic strategies to modulate this process. Methods Pancreatic stellate cells will initially be isolated, grown in-vitro and cultured until the activated phenotype is acquired. These will be treated with senescence inducing agents. Pancreatic cancer lines will then be co-cultured with senescent pancreatic myofibroblasts and an assessment will be made of the behaviour of both the tumour (e.g. increased proliferative capacity, aggressive migratory behaviour) as well as the senescent myofibroblasts. Following on from these in vitro studies, we would also obtain primary human pancreatic tissue from cancer resections and assess for the presence of activated and senescent myofibroblasts and their association with tumour. How the results of this research will be used This study of pancreatic stellate cell biology is a very important subject, and with an improved understanding of their behaviour will allow physicians to develop new therapeutic strategies to improve the very poor survival rates associated with this disease . Our institution has already identified therapeutic strategies to target carcinogenic pathways with relevance to hepatic stellate cells. It is therefore entirely feasible to test these methods on the pancreas if the pathways studied are shown to be similar. Patients could then be recruited into randomized controlled trials prior to surgical intervention to assess stromal modulation, with tissue samples assessed after surgical resection to evaluate any beneficial response.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: CRUK/13/029: FURVA A randomised double blind placebo controlled phase II study of fulvestrant with or without the addition of vandetanib as treatment for patients with metastatic breast cancer resistant to aromatase inhibitor therapy
Funder: Cancer Research UK

Abstract: Background In ER+ advanced breast cancer endocrine therapy is often the treatment of choice. However half of such cancers will progress through first line therapy (primary endocrine resistance) and the other half will progress after an initial period of disease control (secondary or acquired endocrine resistance). There is therefore a need to circumvent resistance mechanisms to endocrine therapies. Multiple potential mechanisms of endocrine resistance have been defined pre-clinically. These include EGFR and RET signalling - a number of lines of evidence suggest an important role for this pathway. Microarray studies have shown increased activity of RET and GFRa3 signalling pathways in hormone resistant cell lines. siRNA studies have shown that down regulation of either GFRa1 or GFRa3 RET signalling leads to inhibition of growth in hormone resistant cell lines. In addition RET and GFRa1 was detected in 29.7% and 59.4% of breast cancers, preferentially in ER positive specimens. Other data have indicated RET levels are increased in hormone resistant breast cancer specimens. More recently, in-vitro work utilising vandetanib (an inhibitor of EGFR, VEGFR, and RET) has shown it to be far superior to gefitinib (an EGFR inhibitor) in producing sustained inhibition of endocrine resistant cell lines. Given the clear implication of a RET signalling role in endocrine resistant breast cancer, and the explicit in vitro data showing the ability of vandetanib to overcome RET signalling and endocrine resistant cell growth, we propose to study the effect of vandetanib in patients with endocrine resistant breast cancer. Aims 1. To determine if inhibition of RET with vandetanib improves clinical outcomes in combination with fulvestrant versus fulvestrant alone in patients with endocrine resistant advanced breast cancer 2. To determine if the combination of vandetanib and fulvestrant is tolerable and safe to deliver 3. To determine if vandetanib activity is related to expression of GFR RET pathway components Methods This randomised phase II study of vandetanib in combination with fulvestrant versus fulvestrant alone will be conducted using PFS as the primary endpoint and clinical benefit, overall survival and toxicity as secondary endpoints. A retrospective analysis of paraffin fixed tissue will determine if vandetanib activity correlates with RET pathway activation. A safety analysis will occur after 20 and 40 patients have been recruited. Future The results of this phase II study will be used to generate efficacy data that is aimed to lead to a randomised phase III study in similar patient population.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Building the evidence base for the early symptomatic diagnosis of cancer (ABC-DEEP Consortium)
Funder: Cancer Research UK

Abstract: Brief background Symptomatic diagnosis of cancer is important and has been the subject of considerable innovation and intervention in recent years; the English NAEDI has made a major contribution to this effort. However, there is currently no up to date overview of the evidence regarding symptomatic presentation and diagnosis to inform clinical practice, policy and future research priorities. Specific aims The ABC-DEEP consortium aims to build on existing knowledge regarding early symptomatic presentation to promote earlier diagnosis and treatment in order to improve cancer outcomes. Outline plan of research Three Workstreams will run in parallel, corresponding to the three main questions in the commissioning brief. There is considerable synergy between Workstreams; this will be maximised by ensuring continued engagement and interaction between the Workstreams Workstream 1 is an updated systematic review assessing the evidence linking the durations of different intervals in the diagnostic process to outcomes (survival, morbidity, and stage). This will cover all cancers and include papers published 2010 to present. Workstream 2 will compile and review recent and ongoing research informing the evidence base on symptomatic diagnosis of cancer. Additionally a rapid review of the outcomes of and evaluations of awareness campaigns will be conducted, again to update a previous review. Workstream 3 will develop a stratification framework based on a ranking of different cancers for the size of potential benefits that can be expected by improving the timeliness of diagnosis among symptomatic patients. This will be done by combining data from the literature and then producing a league table by using Delphi consensus methods with an expert panel of specialists and patients. How the results of the research will be used The findings will provide an evidence base on symptomatic early diagnosis to inform CR-UK’s policy positions, messaging and campaign activity on this topic and identify areas for further work and research.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: CANCER AND NEOPLASMS
Title: Symptoms associated with cancer in the UK general population: Understanding prevalence, patterning and response to provide an evidence base for the development of interventions to reduce time to presentation
Funder: Cancer Research UK

Abstract: Background Existing interventions aimed at reducing time to presentation are hindered by a lack of knowledge about the prevalence and patterns of symptoms associated with cancer in the UK general population, how people appraise and respond to these symptoms, how long they take to seek help and what factors influence time to presentation. Without such information the evidence base to underpin the development of effective interventions to promote earlier diagnosis of cancer is lacking. Aims To examine the prevalence and patterns of the main symptoms of four cancers (colorectal, lung, breast, upper gastrointestinal tract) in the UK general population and understand how people interpret and respond to these symptoms in order to provide an evidence base for the development of interventions to reduce time to presentation. Methods We will undertake a three-phase study, using quantitative and qualitative methods which will allow triangulation of data to understand responses. Phase one - A general population cohort of 20,000 men and women aged 50+ will be established and used to determine the prevalence and patterns of the main symptoms associated with colorectal, lung, breast and upper gastrointestinal tract cancers and investigate how people respond to these symptoms Phase two - In-depth qualitative interviews to explore the general population’s appraisal of their symptoms in relation to knowledge, past experiences and emotional responses and to explore the rationale behind different behavioural responses. Phase three - A record review of electronic and paper-based primary care held records of individuals with a new potential cancer symptom in the preceding year to determine how often people with symptoms indicative of cancer present them to primary care and quantify time to presentation. Data collection and analysis will be underpinned by Walter’s Model of Pathways to Treatment which examines symptom appraisal and help-seeking. The Commonsense Self-Regulation Model, Illness Action Model and Network Episode Model will be used to guide investigation of how people respond to their symptoms in particular contexts. How the results of this research will be used The comprehensive information provided by this study will allow the development of robust models on the positive predictive values of symptoms in the community; refinement of current guidelines (which are based solely on symptoms presented to general practice) and provide an evidence base to underpin the development of new interventions aimed at reducing time to presentation for symptoms of potential cancer.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Does place of residence, distance and travelling times from health services within Northeast Scotland influence the diagnostic pathway and outcomes from eight common cancers: analysis of a linked dataset
Funder: Cancer Research UK

Abstract: Background There is international evidence that access to services influences cancer diagnosis and outcomes. This group found evidence that those living in remote and island communities had poorer outcomes from cancer than urban dwellers. International evidence suggests longer delays, differential access to services and different treatment received could explain these geographical effects, but this has never been confirmed. Much of the UK evidence is almost two decades and needs to be updated. Aims To explore whether distance and travelling time from key services affects: provider delay; stage at diagnosis; receiving treatment within target time; treatment received or survival following diagnosis with one of eight common cancers in Grampian. Methods Linkage Individual Community Health Index numbers will be used to link 11,800 patients diagnosed with eight common cancers (colorectal; lung; breast; prostate; melanoma; oesophagogastric; cervical; ovarian) between 2006 and 2013 in Grampian to several routine datasets to produce a uniquely powerful dataset. The datasets to be linked are the NHS Grampian Cancer Care Pathway database (CCPd); Scottish Cancer Registry (SMR06); Scottish Morbidity Record (SMR01) database of acute hospital discharges; General Register Office for Scotland (GROS) death records; the Scottish Index of Multiple Deprivation (SIMD), the Scottish Government Urban-Rural Classification, travelling distance and time between GP surgeries, centre of first investigation and centre of definitive treatment, calculated using geographic information systems (GIS). Data will be managed within the NHS Grampian/University of Aberdeen Safehaven. Statistical Power and Analysis A sample of 11,800 provides 90% power to detect a 3% difference in the primary outcome, number of patients receiving primary treatment within target (=62 days or =31 days depending on route of diagnosis) which will be analysed using multiple logistic regression with travelling time to cancer treatment centres the main predictor of interest, and adjusting for key confounders. Of secondary outcomes survival and provider delay will be explored using Cox regression; stage at diagnosis and treatment received using multiple logistical regression. Subsequent analysis we will use multivariate analysis with travelling time and distance to GP practices and other diagnostic facilities as main predictors. How the results of this research will be used This study will have two key outcomes. Firstly it will establish, for the first time, whether access to services is affecting treatment delays and cancer outcomes in Grampian, where 10% of the Scottish population live. Second, it will establish the methods for a Scotland-wide study.


Research activity codes: 4.3 INFLUENCES AND IMPACT
Health categories: CANCER AND NEOPLASMS
Title: Development of a risk prediction tool for early cancer detection in patients with type 2 diabetes
Funder: Cancer Research UK

Abstract: Background: In the UK, there are 2.9 million people affected by diabetes – 90% of whom have type 2 diabetes (T2D). This large patient population are at increased risk of several common cancer types compared with the non-diabetes population. While many epidemiological studies have evaluated associations between single risk factors and cancer risk among T2Ds, there is no global risk prediction tool with potential clinical utility for early cancer detection. Aim and hypothesis: To develop a ‘Framingham type’ risk prediction tool in patients with T2D for the development of cancer, using baseline and time-varying factors, routinely measured in primary care. We hypothesise that among the heterogeneity of the T2D population, there are subpopulations with high-risk for cancer development – as a trigger to targeted cancer screening. Study design: In a 2-year project, embedded within a MRC Health eResearch Centre, we will use two up-and-running primary care datasets: (i) the Salford Integrated Records (SIR) – as a deeply phenotyped dataset (N = 204,752; T2D = 11,380); and (ii) the Clinical Practice Records Database (CPRD) – as the validation set (N = 6.2 million: T2D = 203,909). We will identify cohorts in SIR (1998 to 2010) and CRPD (2001 to 2011) - aged 35 to 74 years, and generate derivation and validation cohorts by randomly assign 80% and 20% of each cohort to the respective validation datasets. We will use statistical modelling that takes account of the data complexity (e.g. flexible parametric time-to-event analyses, fractional polynomials for continuous variables) with overlaid clinical input as informed choices within the models. Our primary measure will be individual-level 5- and 10-year absolute cancer risk. Impact: The use of risk prediction tools (for non-cancer outcomes) are already commonly used in primary care and in the diabetes healthcare community to effectively prevent disease occurrence and complications. The results of the current proposal will similarly inform national and European guidelines to include cancer risk assessment within the annual diabetes check-up list. Relevance to the call: The call seeks proposals that use innovative, and relatively rapid approaches using pre-existing data sources. We will interrogate two up-and-running cancer-linked primary care databases, and within 2 years, develop and validate a risk prediction tool for identifying T2D patients at high-risk for development of diabetes-related cancers. We specifically envisage identifying patients with T2D with characteristics which fulfil high-risk cancer screening pathway criteria already established for other high-risk individuals i.e. early cancer detection.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS