Impact of cirrhosis aetiology on incidence and prognosis of hepatocellular carcinoma diagnosed during surveillance

Abstract

Background & aims: In this study we aimed to analyse the impact of the aetiology of cirrhosis on the incidence, characteristics and prognosis of hepatocellular carcinoma (HCC) diagnosed during a surveillance program.

Methods: Individual data from a randomized trial and 2 prospective cohorts of patients with compensated histologically proven cirrhosis recruited between 2000 and 2016 were pooled. The influence of cirrhosis aetiology on survival after HCC detection was assessed using multivariable regression models.

Results: Among 3,533 patients (1,926 virus [VIR], 1,167 alcohol [ALC], 440 combined [MIX]), 431 were diagnosed with HCC after a median follow-up of 57.1 months. The 5-year HCC incidence was lowest in ALC (VIR 12.6%, ALC 9.1%, MIX 14.3%, p = 0.04). At the time of diagnosis, tumour burden and Child-Pugh score were comparable across aetiology groups, but early BCLC stages (0/A) were significantly less frequent in ALC (VIR 80%, ALC 37%, MIX 72%) as a result of worse ECOG performance status. However, similar access to first-line curative HCC treatment was reported across aetiology groups (p = 0.68). Median survival after HCC diagnosis was significantly reduced in ALC (VIR 39, ALC 21, MIX 34 months, p = 0.02). However, when adjusting for tumour size, ECOG and Child-Pugh score, the aetiology of the underlying cirrhosis no longer had a significant impact.

Conclusion: Compared to patients with virus-related cirrhosis, patients with alcohol-related compensated cirrhosis enrolled in a surveillance program have: i) the lowest 5-year HCC incidence; ii) worse overall prognosis, mostly driven by a poor general condition, despite similar access to first-line curative treatment.

Lay summary: It has been suggested that early detection of hepatocellular carcinoma (HCC) may be futile in patients with alcohol-related cirrhosis. By comparing outcomes in more than 3,000 patients with compensated cirrhosis included in surveillance programs, this study suggests that HCC surveillance enables early diagnosis in most patients with alcohol-related cirrhosis despite a higher competing risk of death in these patients. We also report similar access to first-line curative HCC treatment in these patients compared to those with viral cirrhosis, despite higher rates of comorbidities and impaired liver function. Following HCC detection, the later parameters were major drivers of death irrespective of the cause of cirrhosis.

Registration: CHC2000 (NCT00190385) and CIRRAL (NCT01213927) cohorts were registered at ClinicalTrials.gov and the full protocols are available at the following links (https://ichgcp.net/clinical-trials-registry/NCT00190385) and https://ichgcp.net/clinical-trials-registry/NCT01213927, respectively). The full CirVir protocol is available via the ANRS Web site (http://anrs.fr).

Keywords: ALC, alcohol-related; HCC, hepatocellular carcinoma; HR, hazard ratio; MIX, alcohol and virus-related; US, abdominal ultrasound; VIR, virus-related; alcoholic liver disease; cirrhosis; competing risk analysis; primary liver cancer.

Conflict of interest statement

Prof. Ganne-Carrié received honoraria from Bayer, Gilead, Ipsen and Shionogi. Prof Nahon has received honoraria/grants from 10.13039/100006483Abbvie, 10.13039/100004325AstraZeneca, 10.13039/100004326Bayer, 10.13039/100002491Bristol-Myers Squibb, 10.13039/100005564Gilead and 10.13039/501100014382Ipsen. Please refer to the accompanying ICMJE disclosure forms for further details.

© 2021 The Authors.

Figures

Graphical abstract

Fig. 1

Direct acyclic graph. Both active viral replication and excessive alcohol consumption, alone or combined, may favour the development of cirrhosis. Several comorbidities (in particular, metabolic syndrome) further increase this risk and are more often associated with alcohol-related liver disease. Once cirrhosis is established, the progression towards liver failure may lead to both liver decompensation and HCC development. Such progression is dramatically decreased in HCV- or HBV-infected patients in whom sustained virosuppression can be achieved. Liver decompensation and subsequent end-stage liver disease, more frequently encountered in patients with alcohol-related cirrhosis, may act as competing risks of death, both before HCC development and following cancer management. HCC, hepatocellular carcinoma.

Fig. 2

Outcomes in the whole population at the reference date of analysis (2019, November 18th).

Fig. 3

Outcomes of patients according to the aetiology of the liver disease. (A) The 1-year incidence of first decompensation and (C) the 5-year overall survival differed across groups, adjusting for age and sex (p <0.0001 for both comparisons, log-rank). (B) The cumulative incidence of HCC across aetiology groups also differed after adjusting for age and sex (p = 0.0011, log-rank), (D) together with different competing risks of death (p <0.0001, adjusted for age and sex, log-rank). HCC, hepatocellular carcinoma.

Fig. 4

Overall survival after the occurrence of HCC. (A) Overall median survival (35 months; 95% CI 27.5–43.1) and (B) median survival according to the aetiology of cirrhosis (VIR 39, ALC 21, and MIX 34 months; p = 0.0045, log-rank). ALC, alcohol-related; HCC, hepatocellular carcinoma; MIX, alcohol and virus-related; VIR, virus-related.