Extrahepatic Cancers Are the Leading Cause of Death in Patients Achieving Hepatitis B Virus Control or Hepatitis C Virus Eradication.
Allaire M et al, for the ANRS CO12 CirVir Group
Hepatology 2018 ; 68 : 1245-59

Abstract
Data on extrahepatic cancers (EHCs) in compensated viral cirrhosis are limited. The objective of the prospective multicenter Agence Nationale de Recherche sur le SIDA et les Hépatites virales CO12 CirVir cohort was to assess the occurrence of all clinical events in patients with compensated viral cirrhosis, including all types of cancer. Patients with the following inclusion criteria were enrolled in 35 French centers: (1) biopsy-proven hepatitis B virus (HBV) or hepatitis C virus (HCV) cirrhosis, (2) Child-Pugh A, or (3) absence of previous liver complications including primary liver cancer (PLC). Patients were followed up prospectively every 6 months. The standardized mortality ratio (SMR) was calculated according to age and gender using 5-year periods. The impact of sustained viral response (SVR) in HCV patients and maintained viral suppression in HBV patients were assessed using time-dependent analysis.
A total of 1,671 patients were enrolled between 2006 and 2012 (median age, 54.9 years; men, 67.3%; HCV, 1,323; HBV, 317; HCV–HBV, 31). Metabolic features and excessive alcohol and tobacco consumption were recorded in 15.2%, 36.4%, and 56.4% of cases, respectively. After a median follow-up of 59.7 months, 227 PLCs were diagnosed (5-year cumulative incidence [CumI] 13.4%) and 93 patients developed EHC (14 patients with lymphoid or related tissue cancer and 79 with solid tissue cancer; 5-year EHC CumI, 5.9%). Compared to the general French population, patients were younger at cancer diagnosis, with significantly higher risk of EHC in HCV patients (SMR, 1.31; 95 confidence interval [CI], 1.04-1.64; P = 0.017) and after SVR (SMR, 1.57; 95% CI, 1.08-2.22; P = 0.013). EHC was the fourth leading cause of death in the whole cohort and the
first in patients with viral control/eradication.
Conclusion: Compared to the general French population, HCV cirrhosis is associated with a higher risk of EHC and the first cause of death in patients with viral cirrhosis who achieve virological control/eradication.

Expert's Commentary

This relative large national prospective study was conducted in France in 1,671 patients with Child-Pugh A viral cirrhosis. The vast majority (80%) of the studied population was represented by HCV infected patients. Median follow-up was 5 years. The most important information of this study is that patients with HBV control or HCV cure remained at increased risk for developing lymphoid-related or extra-hepatic solid malignancies. In HCV infected patients achieving viral eradication, the standardized morbidity ratio, compared to the general population, was significantly higher (4.97) only for oral cavity cancers. Despite the long follow-up and large population studies, extra-hepatic cancers’ incidence was low, which could underpowered the statistical analysis for risk of individual cancers. Comparison to the general population, although from the best available dataset, i.e. nationwide tumour registries, did not avoid bias due differences in cancer screening and diagnosis as well as frequency of medical visits in study population.
Past excessive alcohol consumption and current tobacco use were clearly associated with occurrence of oral cancers.
As the study was conducted between 2006 and 2012, most HCV patients had received only IFN-based therapy. Dynamic interplay between interferon-induced immunomodulation and HCV-induced immune disturbances could be an explanation of the trend of increased risk of lymphoid-related malignancies. Whether this higher risk of lymphoproliferative diseases is also seen in HCV patients cured with DAA needs to be explored in further studies.
The take home message of this study is that beyond regular follow-up of cirrhotic patients with controlled HBV or HCV infection for the risk of hepatic cancer, there is also a need to consider this population at high risk for extra-hepatic cancers and to reinforce interventions to modify high-risk behaviours.

Pr François Raffi, Nantes