Ablation of Hepatocellular Carcinoma: a Nationwide Study
Condition: Hepatocellular Carcinoma; Ablation; Hepatitis C
MeSH terms: Hepatitis C; Carcinoma; Carcinoma, Hepatocellular
Study type: Observational

Summary: 
      Background Hepatocellular carcinoma (HCC) is the most common primary malignancy in the liver.
      Chronic infection with hepatitis C virus (HCV) is a significant risk factor and may be
      associated with inferior outcome. According to the Danish national guidelines, ablation
      should be offered patients with early HCC (tumor < 3 cm) in a cirrhotic liver, who are not
      transplant candidates. However, the effect of size of the HCC tumor and Hepatitis C virus
      (HCV) as etiology are insufficiently investigated.

      Purposes

        1. Investigate association between HCC tumor size and survival and recurrence after
           ablation.

        2. Investigate survival and recurrence after ablation in patients with HCV-related HCC
           compared with HCC due to other etiologies.

      Methods This study is based on data from the Danish Liver and Bile Duct Cancer Database
      (DLGCD) and the Danish Database for Hepatitis B and C (DANHEP) and the laboratory database
      (DANVIR), which collectively include information on patient characteristics, tumor
      characteristic, laboratory results, and information regarding ablation, HCV status, and
      antiviral treatment, respectively.

      Perspectives Ablation has been widely used for decades, but studies investigating the effect
      of ablation for HCC in patients with HCV and size of HCC are lacking. This study will
      contribute considerably to the level of evidence and may impact both Danish and international
      guidelines for HCC treatment.
    

Detailed description: 
      Background Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver
      and accounts for 85-90% of liver cancer. The most important risk factor for HCC is cirrhosis
      of any etiology. Among other major risk factors for HCC are chronic viral infections with
      hepatitis C virus (HCV) and hepatitis B virus (HBV), chronic alcohol consumption and
      non-alcoholic steatohepatitis.

      Three nationwide databases and medical records will be used to address these important
      knowledge gaps. First, the association between survival and recurrence after ablation and HCC
      tumor size will be investigated. Second, the survival and recurrence after ablation in
      patients with HCC related to HCV will be investigated. due to HCV is different from that in
      patients with HCC due to other reasons than HCV. The nationwide data in these databases will
      reflect general clinical practice in an unselected population and provide novel information.

      Purpose

      With data from the Danish Liver and Bile Duct Cancer Database (DLGCD), the Danish Database
      for Hepatitis B and C (DANHEP), the National hepatitis laboratory database (DANVIR), and
      medical records, prognostic factors for survival in a large cohort of patients with HCC
      treated with ablation therapy will be investigated with the following aims:

        1. Investigate association between HCC tumor size and survival and recurrence after
           ablation therapy.

        2. Investigate survival and recurrence after ablation therapy in patients with HCV-related
           HCC compared with HCC due to other etiologies.

      Hypotheses

        1. Survival and recurrence after ablation is lower in patients with large HCC tumors than
           in patients with small tumors. However, the cut-off in current Danish guidelines is too
           conservative.

        2. The survival after ablation is lower in patients with HCC due to HCV than in patient
           with HCC due to other reasons.

      Methods This study is based on data from three large, nationwide databases in Denmark. DLGCD
      is an ongoing prospective nationwide database for patients treated for HCC,
      cholangiocarcinoma, colorectal liver metastases, or non-colorectal liver metastases. The
      database was established in 2012 and started collecting data in 2013. So far, data from the
      DLGCD have not been published. To date, the database includes data on 5056 surgical
      procedures in 2975 patients with HCC. To study the effect of etiology on survival and
      recurrence after treatment for HCC, data from the DANHEP and DANVIR databases will be
      incorporated. The three databases can be linked together as they all use CPR number to
      identify patients. DLGCD does not contain any information on HCV. However, DANHEP and DANVIR
      are nationwide databases that contain detailed information on individuals with chronic viral
      hepatitis in Denmark. DANHEP is a database with ongoing prospective registration of adult
      patients treated at a hospital (outpatient or inpatient) with chronic viral hepatitis B or C,
      established in 2002. DANVIR is a laboratory database containing information about HCV test
      (bot positive and negative) since 1991. The observation period of the study will be from 2013
      to 2022. With data from the DANHEP and DANVIR databases, patients with HCC that have been
      infected with HCV can be identified to study the effect of ablation in HCV-infected patients
      versus patients without HCV infection.

      Statistics The dataset will be described with frequencies and percentages for categorical
      variables and means or medians for continuous variables. For investigating differences,
      Student's t -test or Mann-Whitney U for continuous data and Pearson chi2 or Fisher's exact
      tests for categorical data will be used as appropriate. To determine risk factors affecting
      prognosis, recurrence and survival outcomes after ablation, Cox proportional hazard
      regression model will be used to calculate hazard ratios with 95% confidence intervals in
      both univariable and multivariable analyses. The multivariable analysis will be adjusted for
      age, sex, number of tumor, size of largest tumor, HCV-status, HBV-status, and Child-Pugh
      score. In addition, survival will be estimated by Kaplan-Meier methods with log-rank tests
      for HCV vs. non-HCV groups. It is possible that some patients with HCC never had a test for
      HCV. In a sensitivity analysis, only patients with HCC that had a HCV test (positive or
      negative) will be included. For recurrence we will use Fine-Gray proportional subhazards
      model and Aalen-Johansen estimator with death and transplantation as competing risks. The
      level of statistical significance will be set to p<0.05. All statistical analyses will be
      performed using R, version 4.0.3.

      Perspectives With data from nationwide databases, the aim is to investigate survival and
      recurrence for HCC and the significance of tumor size and etiology of HCC in a large group of
      patients. Ablation has been widely used for decades, but the majority of published studies
      within this area are from Asia and based on small cohorts of highly selected patients.
      Furthermore, to our knowledge, no previous larger studies have determined the effect of
      ablation in patients with HCV-related HCC. Evidence will be improved with a large, Danish
      cohort reflecting outcomes in general clinical practice in unselected patients. The study has
      potential to contribute to the future guidelines regarding indication for ablation.
    

Intervention name(s): Ablation therapy
Intervention type(s): Procedure
Intervention description(s): Radiofrequency or microwave ablation
Observational model: Cohort
Time perspective: Retrospective
Sampling method: Probability Sample
Study population: 
        All patients with hepatocellular carcinoma treated with ablation therapy as first treatment
        and no prior hepatic surgery.
      
Keywords: Radiofrequency ablation; RFA; Microwave ablation; MW; HCC; HCV