Title: Liver transplantation as treatment for patients with hepatocellular carcinoma; a study using existing electronic data
Funder: Department of Health and Social Care

Abstract: Background: Annually over 4,000 new cases of hepatocellular carcinoma (HCC) are being diagnosed in the UK. Age- standardised rates have increased four-fold in the last three decades with obesity and viral hepatitis as major etiological factors. Overall survival of HCC patients is poor with less than 30% alive at one year. Prognosis is best for patients who receive a liver transplant with about 75% alive at five years. The emergence of liver transplantation as a curative option for HCC has resulted in HCC now being the most common indication for liver transplantation. This development has increased the disparity between patients waiting for transplantation and the availability of suitable livers. In response, livers from donation after cardiac death (DCD) are increasingly being used to expand the donor pool, although outcomes are postulated to be worse than with livers from donation after brain death (DBD). Aim of the research: The aim of my research is to use linked large-scale longitudinal health care data to improve the current evidence base on the best strategy for using liver transplantation, thus influencing the selection and organ allocation in potential recipients with HCC. Research Questions: 1) What are the time trends in the risk factors and incidence of HCC and its mortality from 1997-2015? 2) What are the sociodemographic and clinical factors associated with the transplantation of HCC versus other treatment options? 3) What are the prognostic factors determining outcomes in HCC patients undergoing liver transplantation? 4) What are the prognostic factors associated with patient survival in the transplantation of HCC patients with DCD livers? Plan of Investigation: I will use three linked national databases: the National Cancer Data Repository (NCDR) to identify all patients with HCC in England, the Hospital Episode Statistics (HES) database to determine comorbidities, treatments and outcomes, and the UK Liver Transplant Audit (UKLTA) database to evaluate the outcome of transplantation. I will use NCDR linked to HES to evaluate time trends in HCC incidence and mortality from 1997 to 2015 and changes in the distribution of risk factors such as ethnicity, socio-economic status and pre-existing liver disease (question 1).I will use NCDR linked to HES to investigate to what extent the treatments of HCC patients and their outcomes depend on the presence of sociodemographic and clinical factors using survival analysis techniques (question 2).I will carry out detailed analyses of prognostic factors of post-transplant cancer recurrence and graft and patient survival using the three linked national databases. This research will benefit from detailed information available in the UKLTA database, including specific aspects of the donor and the donor organ (question 3).The outcomes of the transplantation of DCD livers in HCC patients will be compared to outcomes in patients with other indications for transplantation (question 4).Benefit to NHS Services, Patients and Public:My proposed research will demonstrate the immediate benefit of evaluating liver transplantation as a curative treatment for HCC by exposing the patient and donor characteristics and treatments options associated with the best and worst outcome thus improving the information that is available for the selection of potential recipients of a liver transplant and the allocation of donor organs. The project could also benefit patients and their families by increasing the capacity of liver transplantation as a potentially curative treatment option for HCC by determining whether transplanting organs from DCD donors produces acceptable survival outcomes in HCC patients.

Lay abstract: Background: Hepatocellular carcinoma (HCC) is the most common liver cancer. Each year, more than 4,000 patients are being diagnosed with HCC in the UK. The incidence of HCC has increased four-fold in the last 30 years. Liver diseases such as obesity and hepatitis C lead to liver cirrhosis and eventually cancer. There is often a lag time of two decades between the acquisition of liver disease and the development of HCC. Overall survival of patients diagnosed with HCC is poor. Despite small improvements in outcome, less than 30% of the patients are alive at one year after diagnosis. The available treatment options depend on the size and spread of the cancer at the time of diagnosis. Patients who are eligible to receive a liver transplantation have the best prognosis with about 75% being alive at five years. Liver transplantation is increasingly being used as a treatment for patients with HCC. As a result, HCC is now the most common cause for liver transplantation. This development has increased the gap between the number of patients waiting for liver transplantation and the availability of suitable livers. In response, the transplant centres have started to use more and more livers from donors who have sustained a cardiac death. They accept that transplant outcomes with livers from these donors might be worse than with livers from the normal donors who have sustained brainstem death. However, transplant surgeons have little choice as they need to find a donor for patients with HCC before their disease spreads to the bloodstream and they become unfit for potentially curative transplantation.Project Aim: To maximise the benefit of liver transplantation as a treatment option for patients with HCC Research Questions and benefit to patients and public Research Question 1: What are the risk factors causing the rising incidence of HCC? Identifying the main risk factors causing the rise in HCC will encourage NHS services to better identify HCC earlier in patients and thus increase their treatment options. It will also help to educate the general public in avoiding the high risk behaviours that can lead to the development of liver disease and subsequent risk of HCC. Research Question 2: What factors are associated with the selection and outcome of the different treatment options in patient's with HCC? Evaluating treatment options for patients with HCC will help us identify the best treatment available for patients based on their individual disease and medical conditions. This will promote the use of effective alternative treatments for HCC whilst potentially easing the pressure on our liver transplant services. Research Question 3: What are the factors associated with the best and worst outcomes in patients with HCC who recieve a liver transplant? Identifying individual patient characteristics that are associated with the best and worst outcomes following liver transplantation will help us better identify HCC patients suitable for transplantation. This will lead to an improvement in post-operative survival and increase the number of patients with HCC who can undergo liver transplantation. Research Question 4: What are the factors associated with the best and worst outcomes in patients with HCC who receive a cardiac death donor liver? Exploring the transplantation of livers from cardiac death donors as compared with brainstem death donor livers could potentially increase the number of livers suitable for donation. This could lead to the earlier transplantation of patients with HCC and reduce the number of patients falling of the waiting list due to spread of their cancer. Design and Methods: We will combine three large national databases containing anonymised information on all patients in the last two decades who have had HCC and then gone on to have liver transplantation. After ensuring this combined database contains accurate information we will run a series of statistical analysis to answer our research questions. The databases include the National Cancer Data Repository (NCDR), The United Kingdom Liver Transplant Audit (UKTLA) and the Hospital Episode Statistics (HES) database. Patient and Public Involvement: We will collaborate throughout this project with patients who have been diagnosed with HCC and undergone liver transplantation. An HCC advisory group from two patient support groups LISTEN' and LIVAGAIN, has been established. These advisory group members have already been involved constructing the overall aim and research questions of the project.Dissemination of findings: Our research findings will be communicated to our patient advisory group and their respective patient members. Our results will also be presented at international conferences and published in appropriate scientific journals. All patient and public involvement will be officially acknowledged.

Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: CANCER AND NEOPLASMS