Title: The benefits, harms and costs of surveillance for hepatocellular carcinoma in people with cirrhosis: synthesis of observational and diagnostic test accuracy data and cost–utility analysis
Funder: Department of Health and Social Care

Abstract: BACKGROUND People with advanced liver damage (‘cirrhosis’) are more likely to get liver cancer. If we keep an eye on their livers (‘surveillance’), we might spot cancer early, when it should be easier to treat. In 2007, NIHR funded a project looking at the best ways to do this. Important decision-makers like NICE and WHO used it in their guidance. But a lot has changed since then. Twice as many people now get liver cancer. The causes of cirrhosis are changing, with many more cases in people who are overweight. We now have medicines that control liver disease caused by viruses (hepatitis) and reduce the risk of cancer. There are also more treatment options for people who get liver cancer. Tests to check for tumours have improved, too: there are more options for both blood tests and liver scans. Over the same period, we have also learned a lot about how to help patients to make decisions that are right for them, instead of acting as if ‘one size fits all’. Despite all these changes, UK liver centres still do surveillance for cancer pretty much as they did 15 years ago. We think it’s time to look at the topic again._x000D_ METHODS There will be 4 work-packages (WPs). WP1 will summarise research reports on how well surveillance works. Many studies compare liver cancers found by surveillance with those that only came to light when people started to show symptoms. Were the tumours smaller? Could more people have treatment? Did they end up living longer? As none of this evidence comes from randomised trials, the people who got surveillance are likely to be different from those who didn’t, and we will need to account for this. WP2 will combine all the published evidence we can find about scans and blood tests. Statistical techniques have also improved since 2007. We will use new tools to estimate how good each test is at picking up liver cancer – especially when tumours are small and treatment works best. In WP3, we will develop a new health economic model using the outputs of WP2. It will help us to work out what tests people should receive and how often. Surveillance for liver cancer has harms as well as benefits. Because no test is perfect, some people who don’t have cancer will be told they do. Other people will have a liver cancer found, but will die from other causes before the cancer causes them any problems, so finding it does not help them at all. Monitoring also costs the NHS money, and we want to know it is money well spent. The model will help us weigh up the pros and cons. To help doctors tailor their advice, we will look at the balance of benefits and harms in people with different risks, such as people with different causes of cirrhosis and those with other health problems. In WP4, we will develop a decision-aid bringing together what we have found in the other WPs. It will summarise benefits and harms to help people with cirrhosis decide whether they want to start – or stop – surveillance._x000D_ PPI We will recruit 2 patients as team members. We will hold 2 online workshops. Workshop 1 is to get feedback on our plans. Workshop 2 will present findings and test our decision-aid. British Liver Trust (BLT) are on our advisory group._x000D_ SHARING RESULTS BLT are going to help us share our findings with patients and professionals. We have lots of experience working with NICE and national liver organisations, so we know how to produce outputs they will find useful. We will publish results in scientific journals and present them at conferences.

Lay abstract: RESEARCH QUESTION What are the benefits, harms and costs of different surveillance regimens (compared with each other and no surveillance) for hepatocellular carcinoma (HCC) in people with cirrhosis?_x000D_ BACKGROUND An influential 2007 NIHR HTA assessed the cost effectiveness of HCC surveillance in people with cirrhosis. However, the liver disease environment has changed in many ways since then. Our project will provide an up-to-date assessment of whether and how surveillance should be offered to people with cirrhosis._x000D_ METHODS There will be 4 work-packages (WPs). WP1 is a systematic review and meta-analysis of cohort studies comparing HCCs found under surveillance with those diagnosed incidentally or symptomatically. Outcomes cover tumour characteristics, treatment received and survival. As all such evidence is subject to a high risk of bias, we will assess methods carefully and evaluate any attempts to adjust for known biases._x000D_ WP2 is a systematic review and synthesis of diagnostic accuracy data relating to tests for HCC in people with cirrhosis. We will look at imaging (ultrasound, CT, MRI), conventional biomarkers (AFP, DCP) and genomic analytes (microRNA, circulating tumour cells). We will use Bayesian statistical techniques to estimate how tests work at all possible thresholds and in comparison with each other, especially when it comes to picking up HCC at an early stage._x000D_ In WP3, we will develop a decision-model to estimate the lifetime costs, benefits and harms of different HCC surveillance regimens, incorporating estimates of test accuracy from WP2. It will simulate the natural history, diagnosis and treatment of HCC. As well as benefits, we will simulate harms associated with surveillance. We will explore whether the balance of benefits, harms and costs varies according to patients’ characteristics (e.g. aetiology of cirrhosis, presence of other long-term conditions, eligibility for HCC treatment)._x000D_ In WP4, we will develop a print-based patient decision-aid, using what we have learned in WPs1–3 to quantify the expected benefits and harms of surveillance. It will aim to support shared decision-making for people with cirrhosis about whether to start – or stop – surveillance._x000D_ PATIENT AND PUBLIC INVOLVEMENT Our PPI strategy comprises 3 elements: (1) recruiting 2 liver patients as co-investigators; (2) holding 2 online workshops with 10–15 participants; at the second, we will alpha-test the decision-aid developed in WP4; (3) partnering with British Liver Trust (BLT), who will sit on our advisory group and facilitate engagement with the liver disease community (c25,000 forum users; c16,000 social media followers) to shape our research and enhance dissemination._x000D_ DISSEMINATION BLT are going to help us share our findings with patients and professionals; they will be invited to badge and publicise the decision-aid from WP4. We will target NICE and national liver organisations to maximise the impact of our research for population-level decision-making. We will publish in scientific journals and present at conferences. We will make our statistical and economic code freely available for future researchers._x000D_ PROJECT PLAN The project will take 21 months. The project team includes clinicians with expertise in hepatology and radiology, statisticians, health economists, evidence reviewers and patient experts. We have recruited an advisory group of methods, clinical and patient experts who will provide oversight and advice throughout the project.

Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS
Health categories: CANCER AND NEOPLASMS