Systemic therapy for advanced hepatocellular carcinoma: a review

Abstract

Hepatocellular carcinoma (HCC) is a common cause of cancer mortality worldwide. Whilst local treatments are useful in selected patients, they are not suitable for many with advanced disease. Here, we review phase II and III trials for systemic therapy of advanced disease, finding no strong evidence that any chemotherapy, hormonal therapy, or immunotherapy regimen trialled to date benefits survival in this setting. Many trials were inadequately powered, single centre, and enrolled highly selected patients. From this review, we cannot recommend any therapeutic approach in these patients outside of a clinical trial setting. Including an untreated control arm in clinical trials in HCC is still justified. Every effort should be made to enroll these patients into adequately powered trials, and promising phase II results must be tested in a multicentre phase III setting, preferably against a placebo control arm. Prevention of hepatitis B and C remains vital to decrease deaths from HCC.

Introduction

Hepatocellular carcinoma (HCC) is the third commonest cause of cancer mortality worldwide, being responsible for over 500000 deaths annually [1]. Mortality rates vary between 1/100000/year in Northern Europe to over 20/100000/year throughout the Asia-Pacific region [2]. In the Asia-Pacific region, HCC mortality rates closely parallel the prevalence of chronic hepatitis B (HBV) infection, with the highest rates found in patients with established HBV-cirrhosis [3]. In Europe, North America and Australia, the incidence of HCC has doubled since 1983 despite a falling prevalence of HBV infection, reflecting the impact of the Hepatitis C (HCV) epidemic [4], [5], [6]. The numbers of HCV-related HCC will more than double by 2010 [7].

The median survival of HCC is less than 12 months from diagnosis, reflecting both late presentation and lack of effective therapy. Only 10–20% of HCC are suitable for resection at presentation [8], with a 5-year recurrence-free survival of only 10–20% [7], [9], [10]. Hence, most patients presenting with HCC will eventually develop advanced disease. Treatments trialled for advanced disease include cryotherapy, selective internal radiotherapy with lipiodol I¹³¹ or yttrium-90 microspheres, systemic and intra-arterial chemotherapy, hormonal therapy and immunotherapy. Arterial chemoembolisation is useful in selected patients with unresectable disease, and a meta-analysis favoured this treatment over conservative treatment or suboptimal therapies (Odds Ratio (OR) 0.53, 95% Confidence Interval (CI) 0.32–0.89) [11]. However, not all patients are suitable for chemoembolisation, nor is it universally available. This review is confined to systemic therapy of advanced disease, and does not include intra-arterial treatments. We comment on results of adjuvant post-operative treatment where relevant, but do not comprehensively address adjuvant therapy, which has been covered in two recent systematic reviews [12], [13].