VA Cooperative Studies Program (CSP)

CSP #2023 PREventing liver cancer Mortality through Imaging with Ultrasound vs. MRI (PREMIUM STUDY)

CSP #2023 PREventing liver cancer Mortality through Imaging with Ultrasound vs. MRI (PREMIUM STUDY)

Overview

CSP #2023 study is multi-center research trial of surveillance for hepatocellular carcinoma (HCC). The study is also known as PREMIUM which stands for PREventing liver cancer Mortality through Imaging with Ultrasound vs. MRI. The goal of PREMIUM is to compare an abbreviated version of the diagnostic gold standard for HCC (aMRI) +AFP to the standard-of-care screening (US+AFP) in patients at high risk of developing HCC. We hypothesize that HCC will be detected at earlier stages, allowing for more curative treatments and resulting in a reduction in HCC-related mortality.

Background

The Veterans Health Administration is the largest healthcare provider in the U.S. for patients with cirrhosis. Cirrhosis is the leading risk factor for hepatocellular carcinoma (HCC) which is the now the 6th leading cause of cancer-related death in the U.S. While deaths related to lung, breast, prostate, and colorectal cancer are declining, HCC is the only major malignancy with rising mortality in both men and women.

While specialty societies endorse ultrasound (US) for HCC screening in the cirrhosis population, the sensitivity and specificity of US to detect HCC at early stages is poor, and studies suggest there may be little survival benefit. A complete, multiphasic abdominal MRI is the current gold-standard diagnostic test for HCC and has excellent sensitivity and specificity. Complete, multiphasic MRI is time-consuming (30-45 minutes scanner time) and costly, which reduces its cost-effectiveness as a screening modality in patients with cirrhosis. Abbreviated MRI (aMRI) protocols have been developed for HCC screening that have a similarly high sensitivity and specificity to complete MRI but can be completed in a much shorter time (~15 minutes) thus making them more suitable for screening. aMRI protocols include only limited sequences, specifically the sequences that are important for HCC detection (e.g. only T1-weighted pre-contrast and dynamic contrast-enhanced [DCE] images obtained after contrast injection). These are the sequences that are used to determine the major LI-RADS criteria for HCC (i.e. arterial phase hyperenhancement, nonperipheral washout, enhancing capsule, threshold growth). aMRI protocols that include DCE images are more sensitive and specific than ultrasound and almost equally as sensitive for HCC as complete MRI.  

However, it is not known whether screening for HCC in patients with cirrhosis by aMRI versus ultrasound results in a reduction in HCC-related mortality. Demonstration of a reduction in HCC-related mortality in adequately designed and powered randomized controlled trials is necessary to change the standard of care.

Study Design

We 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.

Study Population

Patients ages 18-75 with cirrhosis (standard histologic, radiologic, or clinical criteria) of any etiology, with high risk of HCC evidenced by factors including fibrosis-4 (FIB-4) score >3.25 or 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.

b. 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.

Study Rationale (Figure 5)

• Screening by aMRI will detect earlier stage HCC, as compared to screening by US
• Patients with HCC diagnosed at earlier stages as a result of aMRI will be more likely to receive curative treatments resulting in lower HCC-related mortality
• aMRI protocols can be implemented at any VA facility with an MRI scanner and have a relatively low cost due to the short scanner time.
• Therefore, if our study demonstrates a decrease in HCC-related mortality as a result of aMRI screening, we expect screening by aMRI to become the new standard of care and to be adopted and implemented widely and quickly to transform HCC management.

Figure 5. Schematic representation of study rationale.

return to top