Health Technology Assessment 2007; Vol 11: number 34
Executive SummaryView/Download full monograph in Adobe Acrobat format (2.7 Mbytes)
J Thompson Coon,1* G Rogers,1 P Hewson,2 D Wright,2 R Anderson,1 M Cramp,3 S Jackson,4 S Ryder,5 A Price6 and K Stein1
1 Peninsula Technology Assessment Group (PenTAG), Peninsula Medical School, Exeter, UK
2 School of Mathematics and Statistics, University of Plymouth, UK
3 Hepatology Research Group, Peninsula Medical School, Exeter, UK
4 Radiology Department, Plymouth NHS Hospitals Trust, UK
5 Queen's Medical Centre, University of Nottingham, UK
6 Southampton Health Technology Assessments Group, University of Southampton, UK
* Corresponding author
Cirrhosis is long-term liver damage from the build-up of scar tissue (fibrosis) which, as it develops, impairs effective blood flow and inhibits the organ's vital functions. There are many causes of cirrhosis, including viral hepatitis [hepatitis B and C virus (HBV and HCV)], excessive alcohol intake, non-alcoholic fatty liver disease, primary biliary cirrhosis and haemochromatosis (iron overload).
Cirrhosis can remain in an asymptomatic (compensated) state for many years. The onset of overt liver failure (decompensation) is characterised by a variety of symptoms including ascites, portosystemic encephalopathy, gastrointestinal bleeding and hepatorenal syndrome, and is often the first indication of previously silent liver disease.
Hepatocellular carcinoma (HCC) is a malignant tumour arising from liver cells (hepatocytes) and occurs mainly in cirrhotic livers. HCC affects around twice as many men as women and is more common in those above the age of 40. There is some evidence for a recent rise in incidence of HCC in England with age-adjusted incidence rising from 1.8 per 100,000 men and 0.6 per 100,000 women in 1995 to 2.8 and 0.8, respectively, in 2002. Curative treatment options include resection and orthoptic liver transplantation. Palliative treatments include percutaneous ethanol injection, radiofrequency ablation and transarterialchemoablation.
Two diagnostic tests are routinely used to detect HCC in clinical practice: serum α-fetoprotein (AFP) and ultrasonography. The sensitivity of AFP as a diagnostic tool is restricted by the existence of non-AFP-secreting tumours. The reliability of ultrasonographic diagnosis depends on a range of factors, including the expertise of the operator, the sophistication of the equipment and the size and nature of the tumour.
Routine periodic surveillance of individuals with cirrhosis is currently recommended by UK, European and American clinical guidelines. A 2002 survey confirmed that approximately three-quarters of UK gastroenterologists undertake a formal programme of surveillance for HCC in cirrhosis, mostly using a combination of AFP and ultrasound. The optimal screening frequency has not been established, although an interval of 6 months is recommended in UK and European guidelines, purportedly on the basis of available evidence on tumour growth rate.
Observational data suggest that HCCs detected during formal surveillance are smaller and more likely to be a single lesion than those that present symptomatically or by chance. Consequently, patients whose disease is detected as a result of surveillance are more likely to receive curative treatment than those whose diagnosis is symptomatic or incidental.
The objective of this report was to evaluate the effectiveness, cost-effectiveness and cost–utility of surveillance of patients with cirrhosis [alcoholic liver disease (ALD)-, HBV- and HCV-related], using periodic serum AFP testing and/or liver ultrasound examination, to detect HCC, followed by treatment with liver transplantation or resection, where appropriate.
Electronic databases were searched for randomised clinical trials of surveillance (with AFP and ultrasound) of people with cirrhosis of known underlying cause (ALD, HBV, HCV) for HCC. Updated searches were performed in March 2006.
A computerised decision-analytic model was developed to compare various surveillance strategies. Comparisons were made between:
The study modelled a population with a diagnosis of compensated cirrhosis who are also eligible to enter a surveillance programme. Those deemed eligible were aged 70 years or less, with no pre-existing medical conditions that would preclude treatment with liver transplantation or hepatic resection (including current alcohol or intravenous drug abuse).
Previously published research and a panel of clinical experts helped to inform the structure of the model. A Markov model was used to capture both natural disease progression and diagnostic and treatment pathways reflective of current best clinical practice in the UK NHS. HCC tumours are detected as a result of regular surveillance and symptomatic or incidental diagnosis. Surgical treatment of small or medium-sized tumours is predominantly by liver transplantation; liver resection is also possible, particularly in people with small tumours. Surgical treatment of people with large tumours is not possible within the confines of the model. People with decompensated cirrhosis or a surgically treatable tumour enter the transplant waiting list and have an equal chance of receiving a liver transplant. People deemed to have surgically untreatable HCC enter a range of simpler model states which simulate the costs and effectiveness of palliative care and best supportive care.
Parameter estimates were obtained from comprehensive literature reviews. No methodological restrictions were applied, but searches were limited to papers published or available in English.
The technical performance of the alternative testing strategies was modelled using decision trees. Test sensitivity for AFP and ultrasound was varied according to tumour size. Expected costs and utilities for each surveillance strategy were calculated using both a cohort and a Monte Carlo simulation approach. The model runs for the lifetime of the cohort. Costs (base year 2004) and benefits (QALYs) were discounted at 3.5%.
The model was developed to allow separate analysis of each of the three main cirrhosis aetiologies (ALD, HBV and HCV).
Uncertainty in the model was explored using extensive one-way sensitivity analyses, selected scenario analyses and probabilistic sensitivity analysis. A value of information analysis was conducted to determine the maximum possible value of further research.
The searches returned 214 separate references. From screening of abstracts, 207 of these were excluded, leaving seven potentially relevant studies to be reviewed in full. All seven were excluded at this stage [no results for patients with cirrhosis (n = 3), modelling study (n = 1), narrative review (n = 2), uncontrolled cohort study (n = 1)].
Based on the assumptions used in the model, the most effective surveillance strategy uses a combination of AFP testing and ultrasound at 6-monthly intervals. Compared with no surveillance, this strategy is estimated to more than triple the number of people with operable HCC tumours at time of diagnosis, and almost halve the number who die from HCC. This is a result of the identification of over ten times as many small HCC tumours (less than 2 cm in diameter) and over twice as many medium-sized tumours (between 2 and 5 cm in diameter). Consequently, more tumours are suitable for surgical intervention. Under the conditions of the model, this surveillance strategy would lead to an increase in the percentage of liver transplantations performed for known HCC (as opposed to decompensated cirrhosis) from 8% to 28%, compared with no surveillance.
On all effectiveness measures and at both testing frequencies, AFP- and ultrasound-led surveillance strategies are very similar. This may be because test sensitivity was varied according to tumour size, which means that AFP testing is capable of identifying many more small tumours than ultrasound. The best available evidence suggests that AFP tests will detect approximately six times as many small tumours as ultrasound. Increasing the frequency of either test to 6-monthly intervals is more effective than performing combined testing on an annual basis.
The undiscounted lifetime cost of the surveillance strategies, including all care and treatment costs, ranges from £40,300 (annual AFP triage) to £42,900 (6-monthly AFP and ultrasound). The equivalent discounted costs are £28,400 and £30,400. Only a small proportion (<4% of undiscounted costs) of these total costs results from the cost of the screening tests. However, screening test costs, and the cost of liver transplants and caring for people post-transplant, accounted for most of the incremental cost differences between alternative surveillance strategies.
The results suggest that different surveillance strategies may provide the best value for money in patient groups of different cirrhosis aetiologies. The surveillance of people with HBV-related cirrhosis for HCC provides the best value for money, while surveillance in people with ALD-related cirrhosis provides the poorest value for money.
In people with HBV-related cirrhosis, at an assumed maximum willingness to pay (WTP) for a quality-adjusted life-year (QALY) of £30,000, both the deterministic and probabilistic cost–utility analyses suggest the optimal surveillance strategy would be 6-monthly surveillance with the combination of AFP testing and ultrasound.
In contrast, for those with ALD-related cirrhosis, annual screening with AFP as a triage test is the only surveillance strategy that is likely to be considered cost-effective at this WTP. NHS investment in more effective surveillance strategies probably represents an unacceptable cost for the extra benefits gained (e.g. £35,000 per QALY gained by moving to a 6-monthly AFP triage strategy). In addition, there is a high degree of uncertainty in the ALD model. The probabilistic analysis implies that the estimated benefits of a 6-monthly AFP triage strategy will only be worth the cost when society's WTP for a QALY exceeds around £40,000.
For people with HCV-related cirrhosis, and again applying this WTP threshold, the model suggests that the most cost-effective surveillance strategy would be surveillance with a 6-monthly AFP triage strategy.
It may not be considered practical to have separate screening strategies for people with cirrhosis of different aetiology. Results for an artificially produced mixed cohort containing people with HBV, ALD and HCV suggest that, if one surveillance policy had to be applied across cirrhosis cohorts of all three aetiologies, 6-monthly AFP with ultrasound is always the most effective option and, at commonly accepted levels of WTP for QALYs, 6-monthly AFP as a triage test is the most cost-effective strategy.
These results should be viewed with caution for a number of reasons. Considerable uncertainty still surrounds some of the underlying parameters that influence the cost-effectiveness estimates. In addition, some of the differences between aetiologies may be more attributable to the mean age at diagnosis than to any inherent differences in the nature of disease progression. Lastly, the discounting of costs and benefits has a major impact on the cost-effectiveness results.
In a mixed aetiology cohort, the most effective surveillance strategy is to screen each patient with AFP assay and ultrasound imaging on a 6-monthly basis. However, when costs are taken into account it is doubtful whether ultrasound should be routinely offered to those with blood AFP of less than 20 ng/ml, unless policy makers are prepared to pay a very high price (over £60,000 per QALY) for the extra benefits achieved. Furthermore, the cost-effectiveness of surveillance for HCC varies considerably depending on the aetiology of cirrhosis; it is much more likely to be cost-effective in those with HBV-related cirrhosis, and much less likely to be cost-effective in those with ALD-related cirrhosis. This may be largely due to the younger age at diagnosis of cirrhosis in patients with HBV. This raises the possibility that there may be further subgroups of patients with ALD and HCV, diagnosed with cirrhosis at a younger age, in whom more intensive surveillance might provide value for money.
The results show that surveillance strategies for HCC are effective, and can often be considered cost-effective in patients with cirrhosis. We believe that the implementation of formal surveillance programmes should be considered where they do not currently exist.
The results also suggest that different surveillance strategies in patient groups with different underlying causes of cirrhosis may provide the best value for money, if appropriate recall systems could be implemented, and also if this was judged to be ethically acceptable.
A surveillance strategy in which AFP testing is used as a triage step probably represents the best value for money.
These results also suggest a possible shift in the clinical settings where cirrhosis surveillance is conducted; as AFP triage appears to be a highly cost-effective strategy, either annually or 6-monthly, it may be more appropriate to perform the initial screening test in the primary care setting.
If effective surveillance programmes were to become widespread across the UK against a background of limited organ supply, the waiting list for liver transplants would undoubtedly increase. Detailed exploration of this was beyond the scope of this project, but preliminary findings suggest that this might be an important issue.
Thompson Coon J, Rogers G, Hewson P, Wright D, Anderson R, Cramp M, et al. Surveillance of cirrhosis for hepatocellular carcinoma: systematic review and economic analysis. Health Technol Assess 2007;11(34).
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