Gadoxetic Acid-MRI Versus Ultrasonography for the Surveillance of Hepatocellular Carcinoma in High-risk Patients (PRIUS)

• The detection sensitivity of patients with early stage HCC [ Time Frame: during the 1.5-year study period (from the date of first screening to 6 months following the last screening) ] [ Designated as safety issue: No ]
  • The number of patients with early stage HCC detected by a given modality divided by the total number of patients with early stage HCC detected by any of 2 modalities plus interval cancers.
  • Early stage (stage A or 0) HCC is defined by the Barcelona Clinic Liver Cancer staging system (BCLC): A single HCC <5 cm or <=3 lesions each <3 cm in diameter, without gross vascular invasion or extrahepatic metastasis.
• The detection sensitivity of very early stage HCC [ Time Frame: during the 1.5-year study period (from the date of first screening to 6 months following the last screening) ] [ Designated as safety issue: No ]
  • The number of definite HCC nodules of very early stage detected by a given modality divided by the total number of definite HCC nodules of very early stage detected by any of 2 modalities plus interval cancers.
  • Very early stage (stage 0) HCC is defined by the Barcelona Clinic Liver Cancer staging system (BCLC): A single HCC <2 cm without gross vascular invasion or extrahepatic metastasis.
• The detection sensitivity of all stage HCC [ Time Frame: during the 1.5-year study period (from the date of first screening to 6 months following the last screening) ] [ Designated as safety issue: No ]
  - The number of definite HCC nodules detected by a given modality divided by the total number of definite HCC nodules detected by any of 2 modalities plus interval cancers.
• The detection specificity for all stage HCC [ Time Frame: during the 1.5-year study period (from the date of first screening to 6 months following the last screening) ] [ Designated as safety issue: No ]
  Number of true-negative results divided by the sum of true negative results and false-positive results (ie, examinations leading to a negative biopsy or CT scan)
• The cost-effectiveness for each surveillance tests [ Time Frame: during the 1.5-year study period (from the date of first screening to 6 months following the last screening) ] [ Designated as safety issue: No ]

• The detection sensitivity (the number of early stage HCCs detected by a given modality divided by the total number of cancers detected by all 2 modalities plus interval cancers) for very early stage (stage 0) HCC [ Time Frame: during the 1.5-year study period (from the date of first screen to 6 months following the last screen) ] [ Designated as safety issue: No ]
  Very early stage (stage 0) HCC is defined by the Diagnostic algorithm for suspected HCC proposed by the Barcelona Clinic Liver Cancer staging system (BCLC): A single HCC <2 cm without gross vascular invasion or extrahepatic metastasis
• Specificity (the number of lesions confirmed as HCC by pathology or by the BCLC Diagnostic algorithm for suspected HCC divided by the number of lesions suspected as HCC by each imaging modality) [ Time Frame: during the 1.5-year study period (from the date of first screen to 6 months following the last screen) ] [ Designated as safety issue: No ]

Current practice guidelines recommend surveillance for hepatocellular carcinoma (HCC) in liver cirrhosis patients with ultrasonography (USG) every 6 months. However, with the advancement of cirrhosis, the sensitivity of USG decreases, while the risk for HCC increases. Gadoxetic acid (Primovist®)-enhanced magnetic resonance imaging (MRI) has been demonstrated to be of clinical value for diagnosis of HCC with the detection sensitivity of 90-95%, which is significantly higher than USG. The hypothesis to be proved by this study is as follows; Primovist-MRI should show significantly higher sensitivity compared to USG for the detection of early stage HCC when both of these imaging modalities are used with the interval of 6 months in patients with cirrhosis at high risk of developing HCC.

Hepatocellular carcinoma (HCC) is currently the third leading cause of cancer-related deaths worldwide. Cirrhosis, particularly when related to viral hepatitis, is the most notable risk factor for HCC and is found in nearly 80-90% of cases.

The stage of disease at the time of diagnosis largely determines the effectiveness of treatment. The treatment of advanced HCC continues to be primarily palliative, with curative options only available for early HCC. Unfortunately, less than 30% of patients are diagnosed early enough to meet criteria for resection, transplantation, or local ablation.

Surveillance strives to detect HCC at an early stage when it is amenable to curative therapy to reduce mortality. Current practice guidelines recommend surveillance of cirrhotic patients with ultrasonography (USG) every 6 months. However, USG has been reported to have a sensitivity of between 65% and 80% when used as a screening test. However, with the advancement of cirrhosis, the sensitivity of USG decreases, while the risk for HCC increases.

Gadoxetic acid (Primovist®)-enhanced magnetic resonance imaging (MRI) of the liver has been demonstrated to be of clinical value for local staging before HCC surgery and for the assessment of patients with inconclusive conventional imaging findings. The detection sensitivity of Primovist-MRI has been known to be as high as 90-95%, which is significantly higher than USG or multiphase computer tomography (CT) scan. MRI does not have radiation exposure, which is a meaningful merit to be used as a surveillance test. However, MRI has never been considered for surveillance or screening of HCC.

Thus, the hypothesis to be proved by this study is as follows; Primovist-MRI should show significantly higher sensitivity compared to USG for the detection of early stage HCC when both of these imaging modalities are used with the interval of 6 months in patients with cirrhosis at high risk of developing HCC. The investigators will also analyze whether the specificity of Primovist-MRI are not compromised by its high sensitivity.

Hospital out-patient clinic

Inclusion Criteria:

Patients with liver cirrhosis with the 1 year risk of HCC of 5% or higher meeting all of following criteria;

1. The evidence of cirrhosis of any etiology within 12 months prior to screening Definition of cirrhosis by any of following methods

   • 1) Histologically by liver biopsy;

   • 2) Non-histologically by evidence of portal hypertension in the presence of chronic liver disease;

     • Evidence of portal hypertension, including any of followings;

       1. The identification of splenomegaly on USG, CT, or MRI examinations with typical features of cirrhosis
       2. The identification of esophageal or gastric varices on endoscopic examination
2. High Risk Index (>=2.33); Risk Index = 1.65 (if the prothrombin activity is <=75%) + 1.41 (if the age is 50 years or older) + 0.92 (if the platelet count is <=100x10(3)/mm3) + 0.74 (if the presence of anti-hepatitis C virus [HCV] or hepatitis B surface antigen [HBsAg] is positive).
3. Older than 20 years of age
4. Absence of previous or current history of HCC
5. Absence of HCC should be identified by liver USG, dynamic CT, or contrast-enhanced MRI within 6 months prior to screening
6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2
7. Patient is able to comply with scheduled visits, evaluation plans, and other study procedures.
8. Patient is willing to provide written informed consent

Exclusion Criteria:

Presence of any of following criteria;

1. Active or suspected cancer other than HCC, or a history of malignancy where the risk of recurrence is >20% within 2 years
2. Significant medical comorbidities in which survival is predicted to be less than 3 years
3. Estimated glomerular filtration rate (GFR) < 30 mL/min/1.73m2
4. Precautions for MRI (cardiac pacemaker, ferromagnetic implants, etc.)
5. Severe claustrophobia that may interfere with protocol compliance.
6. Any other condition which, in the opinion of the Investigator, would make the patient unsuitable for enrollment or could interfere with the completing the study.