Meta-Analysis and Evidence Based Management of Hepatocellular Carcinoma

Liver cancer cells. Coloured scanning electron micrograph (SEM) of two hepatocellular carcinoma (HCC) cells, showing the numerous filopodia (hair-like) covering their surface. Hepatocellular carcinoma is the most common type of liver cancer. It tends to occur in livers damaged by genetic defects, alcohol abuse, or chronic infection with diseases such as hepatitis B and C. Primary liver cancer, which starts in the liver, is relatively rare in the UK, with about 3,600 people diagnosed each year. However, because of the prevalence of hepatitis caused by contagious viruses, it accounts for up to half of all cancers in some undeveloped countries. Magnification: x3000 when printed at 10 centimetres wide.
Investigators analyzed the current evidence for treatment of hepatocellular carcinoma and what factors might impact response to therapies.

A meta-analysis of randomized controlled trials of systemic therapies for hepatocellular carcinoma demonstrated a link between outcomes from checkpoint inhibitor therapy and etiology of liver disease. The results published in Gastroenterology further suggest immunotherapies are potentially less effective against non-viral etiologies

Phase 3 randomized controlled trials across disease stages were reviewed and a meta-analysis conducted to examine the relationship between etiology and outcomes after systemic therapies with either tyrosine-kinase inhibitor/antiangiogenic or immune checkpoint inhibitor therapy.

Between 2002 and 2020, a total of 76 trials were identified and 49 were deemed high quality and included in the analysis. These trials included 22,113 patients receiving adjuvant (n=7) and primary treatment for early (n=2), intermediate (n=7), and advanced stage disease (first-line, n=21; second-line, n=12).

Of these, 9 trials reported positive results and 7 established the accepted drugs for advanced hepatocellular carcinoma: sorafenib, lenvatinib, atezolizumab+bevacizumab, regorafenib, cabozantinib, and ramucirumab. Treatments from 2 early-stage trials have not yet been adopted: adjuvant cytokine-induced killer cells and sorafenib-hepatic arterial infusion with folinic acid, fluorouracil, and oxaliplatin (FOLFOX).

A sub-group analysis of 8 trials involving immune checkpoint inhibiters found they were significantly more effective in patients with viral hepatitis compared with non-viral related hepatocellular carcinoma. There were no observable differences related to etiology in patients treated with tyrosine-kinase inhibitors and anti-vascular endothelial growth factor.

Study limitations included reliance on pooled data rather than individual patient data. Additionally, specific data on nonalcoholic steatohepatitis and alcohol-related hepatocellular carcinoma were not available. Finally, study authors noted heterogeneity among the included trials.

Investigators concluded that ongoing trials of novel combination regimens, including tyrosine-kinase inhibitors plus immunotherapies, are being tested in properly designed and high-quality randomized control trials. “[T]hus results will be instrumental in expanding the landscape of therapies for this highly lethal disease,” they concluded.

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 


Haber PK, Puigvehí M, Castet F, et al. Evidence-based management of HCC: systematic review and meta-analysis of randomized controlled trials (2002-2020). Gastroenterol. Published online June 11, 2021. doi:10.1053/j.gastro.2021.06.008