Preventing Liver Cancer Mortality Through Imaging With Ultrasound vs. MRI

Study Design. The investigators propose to conduct a randomized controlled trial of screening for hepatocellular carcinoma (HCC) by ultrasound (US)+serum alpha fetoprotein (AFP) every 6 months (the current standard-of-care) versus abbreviated MRI (aMRI)+AFP every 6 months among patients with cirrhosis who have a high risk of HCC (estimated annual HCC risk >2.5%).

Study Population. Patients ages 18-75 with cirrhosis (standard histologic, radiologic, or clinical criteria) of any etiology, with estimated annual HCC risk >2.5%. Exclusion Criteria: Prior HCC; Child C Cirrhosis (CTP score 10); MELD score >20; Listed for liver transplantation; Contra-indications to MRI; Comorbidities with limited life expectancy defined by a cirrhosis-specific comorbidity index (CirCom) score 3.

Study Setting. 47 VA Medical Centers will recruit on average 100 patients/site over 3 years. These recruitment sites, which have already been identified, have adequate numbers of cirrhosis patients eligible for screening, a qualified hepatologist and radiologist to serve as local site investigators (LSIs), adequate MRI and US capacity, and access to a multidisciplinary liver tumor board (MLTB).

Target Sample Size. N=2350 per group, total N=4700.

Randomization. The randomization scheme will be random permuted with variable block size and will be stratified by medical center and MELD score.

Intervention. Participants will be randomized in a 1:1 ratio to one of two screening arms:

a. Abdominal aMRI+ serum AFP every 6 months, OR b. Abdominal US+ serum AFP every 6 months, from the time of recruitment until the end of study Year 8.

The aMRI protocol will include only T1-weighted pre-contrast and dynamic contrast-enhanced images utilizing an extracellular gadolinium-based contrast agent. aMRI takes only ~15 minutes to perform. Enrollment will occur in Years 1-3, screening per protocol will continue through Year 8, and follow-up for mortality will continue through Year 8. Analysis and publication will be in Year 9.

Primary Outcome. HCC-related mortality.

Power Calculations. The study is powered to detect a minimum relative reduction in HCC-related mortality of 35% in the aMRI+AFP arm compared to the US+AFP arm, i.e. a reduction in cumulative HCC-related mortality at Year 8 from 7.1 per 100 patients in the US+AFP arm to 4.6 per 100 patients in the aMRI+AFP arm (absolute difference in HCC-related mortality of 2.5 per 100 patients), adjusted for dropout due to death from other causes or withdrawals, with power 88% and two-sided alpha 0.05.

Inclusion criteria

• Cirrhosis due to any underlying etiology diagnosed by one or more of the following:

• Histology of liver biopsy
• Radiologic criteria (nodular liver, evidence of portal hypertension)
• Clinical signs of cirrhosis (gastroesophageal varices, ascites, hepatic encephalopathy)
• Vibration controlled transient elastography (VCTE, specifically Fibroscan, which is available in all participating sites) with liver stiffness >12.5kPa or magnetic resonance elastography >5.0 kPa
• High Risk of Liver Cancer: This will be defined by one or more of the following:

• Current HCV infection (detectable HCV RNA)
• FIB-4 score 3.25, within 6 months of randomization
• Estimated annual HCC incidence >2.5%, within 6 months of randomization, calculated by VA-specific models that the investigators developed (available on the national VA ALD Dashboard and at www.hccrisk.com).
• Age 18-75
• Able to provide informed consent

Exclusion criteria

• Prior diagnosis or of HCC
• Current suspicion of HCC
• Prior receipt of organ transplantation
• Currently listed for organ transplantation.
• Participation in a conflicting HCC screening trial
• Advanced liver dysfunction, defined by Child C Cirrhosis (CTP score 10), or MELD score >20, within 6 months prior to randomization
• Glomerular Filtration Rate (GFR) <30 ml/min
• Multiple comorbid conditions resulting in limited life expectancy, defined by a cirrhosis-specific comorbidity index (CirCom)112 score 3. Of note, early stage malignancies of the bladder, lung, or prostate will not be excluded.
• Estimated life expectancy <5 years as determined by the clinical judgement of the Study Investigator
• Contraindications to undergoing contrast-enhanced MRI:

• Allergy to gadolinium-based contrast agents
• MRI-incompatible implantable devices (e.g. pacemakers, defibrillators, resynchronization devices)
• Implantable neurostimulation device
• Implantable cochlear implant/ear implant
• Drug infusion pumps (e.g. insulin pump, analgesic or chemotherapy pumps)
• Metallic foreign bodies in or around the eye
• Metallic fragments, such as bullets, shotgun pellets or shrapnel
• Metallic body piercings that cannot be removed
• Cerebral artery aneurysm clips
• Severe claustrophobia
• Unable to fit on MRI machine due to weight (weight >400lbs) or body habitus
• Inability to complete planned study visits (e.g. lives too far from VA, no transportation, etc.)
• Currently pregnant