Hepatocellular carcinoma surveillance in Australia: time to improve the diagnosis of cirrhosis and use liver ultrasound

Timely diagnosis of cirrhosis and HCC surveillance using ultrasound may help improve patient outcomes

Hepatocellular carcinoma (HCC) is an important cause of cancer death in Australia (Box 1). A 2019 report on cancer in Australia, based on data from 1982 to 2015, showed that liver cancer (90% HCC) had the second largest increase (378%) in age‐standardised incidence rates from 1.8 to 8.6 per 100 000 population.1 Unfortunately, there was a matching threefold increase in liver cancer mortality rate from 2.3 deaths to 7.0 per 100 000 population. This was the largest increase for any cancer and, unlike other cancers, is likely an underestimate owing to under‐reporting by some state cancer registries.2 An Australia‐wide epidemiological study found survival from HCC had improved from a median of 2.1 months (95% CI, 1.6–2.6 months) between 1982 and 1984 to 12.1 months (95% CI, 11.2–13.0 months) between 2010 and 2014 (P < 0.001).3 However, survival remains poor and HCC is the only low survival cancer of all the cancers that are rapidly increasing in incidence in Australia.1 The average cost to treat HCC is $50 000 and liver transplantation costs $166 000.4,5 Therefore, with incidence showing no signs of slowing, health system costs will continue to increase substantially in the absence of preventive actions. This article reviews the present evidence for liver ultrasound surveillance in patients with cirrhosis, a major risk factor for the development of HCC.

Can we prevent HCC?

Prevention of cirrhosis is not discussed in detail here. However, the four major causes of cirrhosis in Australia are non‐alcoholic fatty liver disease, alcohol‐related liver disease, hepatitis C infection, and hepatitis B infection.6 At least 50% of patients with cirrhosis have at least two of these causes.7 Pharmaceutical Benefits Scheme‐funded treatments for hepatitis C will result in a reduction of HCC related to this cause in the next 10 years.8 Lifestyle modifications to reduce weight and decrease alcohol intake will be more problematic to achieve but are as important.

Who and how do we screen?

Patients with cirrhosis have a 1–8% per annum chance of developing HCC and should be screened.9 A major problem is that 47% of patients with cirrhosis are undiagnosed.10 Further, the diagnosis is made in 66% of cases based on incidental findings rather than by a diagnosis of intent.11 Gastroenterologists made a deliberate and early diagnosis of cirrhosis in 79% of cases compared with 15% for general practitioners and 6% for physicians (P < 0.001).11 Liver biopsy is not routinely used for the diagnosis of cirrhosis. A deliberate diagnosis of cirrhosis requires a detailed clinical history to ascertain the presence of risk factors for cirrhosis, examination to elicit physical findings of cirrhosis, and interpretation of routine blood tests.8 To overcome the underdiagnosis of cirrhosis, medical practitioners must be aware of the importance of performing this assessment, as patients with cirrhosis may be asymptomatic, with little in the way of abnormal liver function test results. The use of well validated non‐invasive tests for liver fibrosis can increase the accuracy of diagnosis by about 30% and is recommended in Australian guidelines.8 Unfortunately, such serum and liver stiffness tests are not currently rebated by the Medicare Benefits Schedule.

Ultrasound surveillance for HCC in patients with cirrhosis is a well established method for detection of early stage HCC and is recommended by all international liver disease societies (Box 2).12 The guidelines developed by the Gastroenterological Society of Australia will shortly be released and are expected to recommend ultrasound surveillance. A meta‐analysis of 13 studies found that ultrasound surveillance was highly accurate for HCC at any stage, with a pooled sensitivity of 94% and a pooled specificity of 94%.13 The pooled sensitivity for detecting early HCC with a 6‐monthly ultrasound was 70% compared with 50% with annual surveillance (P = 0.001). Experienced operators can detect HCC with a mean diameter of 1.6 ± 0.6 cm.14 Serum α‐fetoprotein testing adds little to the accuracy or cost‐effectiveness of ultrasound surveillance and is not recommended by all guidelines.9

Can HCC surveillance improve patient outcomes?

A diagnosis of early stage HCC allows potentially curative treatments (liver transplantation, liver resection) or radiological ablative treatments that can result in a cure or improve survival. A meta‐analysis of 47 studies from 1990 to 2013 of 15 158 patients with cirrhosis found that ultrasound surveillance increased early stage HCC detection (odds ratio [OR], 2.1; 95% CI, 1.8–2.4) and increased use of curative treatments (OR, 2.2; 95% CI, 2–2.5).15 HCC screening was associated with significantly prolonged survival (OR, 1.9; 95% CI, 1.7–2.2) and remained so after adjusting for lead‐time bias. The pooled 3‐year survival rate was 51% for those who had HCC surveillance, compared with 28% for those without prior surveillance (P < 0.001). Four Australian studies have also reported that early stage HCC diagnosis and improved patient survival was associated with ultrasound screening.10,11,16,17 After adjustment for age, sex, cirrhosis and cause of chronic liver disease, the hazard ratio of mortality for non‐screening was 1.9 (95% CI, 1.3–2.9; P = 0.001).10 The pooled survival from the Australian studies showed that ultrasound screening improved 2‐year survival from 40% to 69%.

Is liver ultrasound screening for HCC cost‐effective?

A recent cost‐effectiveness study included curative treatments (liver transplantation, liver resection, radiofrequency ablation) and compared biannual ultrasound screening with usual care.12 The screened group cost US$11 966 more than the non‐screened group ($93 795 v $81 829) and survival increased by 0.4 years (7.2 years v 6.8 years). The incremental cost‐effectiveness ratio was $32 415 per quality‐adjusted life‐year and was cost‐effective. Importantly, the health gain was from earlier diagnosis and increased use of first line curative treatments. No Australian cost‐effectiveness analysis of ultrasound screening has been performed and this should be addressed. The benefits and harms of the screening strategy need to be measured to allow for an accurate analysis to be performed and, just as importantly, to allow an individual with cirrhosis to make an informed decision. HCC is a unique cancer in that the diagnosis can be made based on well defined and validated magnetic resonance imaging (MRI) or computed tomography (CT) radiological characteristics without the need for a biopsy (Box 3).9 In about 15% of cases, a liver biopsy is required to make the diagnosis, as the radiological characteristics are suspicious for HCC but not diagnostic. The benefits and harms of false positive and indeterminant ultrasound screening results have been reported in a United States cohort.18 Most harms related to the performance of MRI or CT scans (23%), and liver biopsy was very uncommon (0.4%). These rates may not accurately reflect Australian practice, as there was high use of diagnostic CT and MRI in patients with liver lesions < 1 cm diameter. Guidelines recommend repeat ultrasound after 3 months in patients with these low risk lesions.9 In addition, a physician's decision to perform MRI or CT scans rather than ultrasound was likely a result of the lack of evidence of lesion stability owing to the prolonged ultrasound screening times of more than 1 year in 75% of patients.

How do we achieve it?

Surveillance uptake will never be 100%. The three national population‐based screening programs in Australia are BreastScreen Australia, the National Cervical Screening Program, and the National Bowel Cancer Screening Program. The uptake rates for screening are 55%, 55% and 41%, respectively, and are still cost‐effective.1 Before a national program for HCC screening can commence, evidence is required in specific populations to show that screening is effective in reducing cancer‐related morbidity and mortality. In the meantime, the screening tests and diagnostic tests for HCC are already funded by Medicare. If there is no regulatory or financial obstruction to performing 6‐monthly ultrasound, why does it not occur? Two factors need to be addressed: the underdiagnosis of cirrhosis, and adherence with ultrasound surveillance in patients with cirrhosis. Patients with chronic liver disease often have little knowledge regarding its significance and frequently belong to isolated or marginalised groups. Liver cancer is the third most common cause of cancer‐related death in the Indigenous population, compared with seventh in the general Australian population.1 Public education programs must specifically target different patient groups to improve engagement with health practitioners, and increase diagnostic rates for cirrhosis and adherence with ultrasound surveillance. Well established programs have been developed for the treatment of hepatitis C and could be modified for HCC.8 These would involve patient advocacy groups, the Liver Foundation, national and state Cancer Councils and others working with state and federal government agencies. GPs and physicians need to increase the rates of deliberate diagnosis of cirrhosis. The diagnostic clinical assessment for cirrhosis in patients with abnormal liver function test results and subsequent ultrasound screening should be incorporated into GP treatment plans. Medical education and models of care developed for hepatitis C management could again be used for this purpose.8 Most models include a clinical coordinator and, depending on the location of the patient group, may be based at a tertiary centre, in primary care or in other facilities accessible and appropriate for patients.17 Adherence rates in patients may be improved using memory triggers, linguistic aids and reminder systems for both patients and providers.19 A cost‐effectiveness clinical trial of such a model is currently underway and will report its outcomes in 2021 (https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=372421).

The future

The application of new and more accurate tests that improve prediction of individual HCC risk will reduce the need to perform ultrasound surveillance in low HCC risk patients with cirrhosis. These tests include improved imaging and blood tests using biochemical analyte panels, protein and/or DNA tumour panels, microRNA panels and metabolomics.6,20 More research is needed before any test can be recommended for general use.

Box 2 – Ultrasound screening of liver

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Sagittal and transverse images of the liver showing an 18 mm focal lesion (arrows) in segment 1 (caudate lobe). Note slight irregularity of liver contour in keeping with cirrhosis.

Box 3 – Diagnostic magnetic resonance imaging scan of liver

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Axial T1 magnetic resonance imaging following intravenous gadolinium administration demonstrating an arterially enhancing lesion in segment 1 in the arterial phase (A), with washout in the portal venous phase (B). Note liver parenchymal features of cirrhosis with splenomegaly.