Milestones in the pathogenesis and management of primary liver cancer

Abstract

Liver cancer is a major global health problem whose incidence is on the rise. The improvement in the understanding of the pathogenesis, early detection, diagnosis, staging and treatment of liver cancer has been enormous. The landscape of molecular aberrations driving both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) have been unravelled. Several breakthroughs have occurred in the prevention, surveillance and treatment of HCC. Particularly, management of patients at advanced stages has changed dramatically during the last decade with the advent of effective systemic therapies such as sorafenib, lenvatinib, regorafenib, cabozantinib and ramucirumab. iCCA has long been considered a difficult to treat disease with few therapeutic options. However, recent advances in our understanding of its molecular pathogenesis, as well as the development of adjuvant therapy (capecitabine) and new systemic treatments (gemcitabine and cisplatin) have paved the way for further innovations in the management of patients with iCCA. In this manuscript, we aimed to highlight the main milestones in the medical history of primary liver cancer and report the most recent developments described within this special issue.

p53 functional loss, stemness and hepatocellular carcinoma

“…About 90% of HCC cases can be associated with four well-characterized underlying risk factors including chronic infection with hepatitis B and C viruses (HBV, HCV), ethanol consumption, and non-alcoholic fatty liver disease (NAFLD) [2] . Although the risk of developing HCC can be reduced in patients by treatment of the underlying cause -e.g., HCV eradication by direct-acting antivirals (DAAs) and HBV suppression by nucleos(t)ide analogs (NUCs) -strategies to prevent cancer development in patients with advanced fibrosis and established cirrhosis are still lacking [3,4] . Despite the recent improvements, treatment options for HCC remain largely unsatisfactory.…”

“…Currently, curative treatment options for patients with HCC include surgical resection and loco-regional ablation, frequently associated with tumor recurrence, and orthotopic liver transplantation, a resource-intensive solution [3,4] . However, due to its silent clinical character and the low sensitivity and specificity of currently available diagnostic biomarkers, HCC is commonly diagnosed at an advanced stage, when curative treatments are not feasible, leaving systemic drugs as the only option [3,4] . Patients with untreated advanced HCC carry a very poor prognosis with an expected survival of 4-6 months.…”

“…Patients with untreated advanced HCC carry a very poor prognosis with an expected survival of 4-6 months. Treatment modalities available for patients with advanced HCC not eligible for curative treatment include the multikinase inhibitors (MTKi) sorafenib and lenvatinib as first line treatment, with an increase in survival of approximately 3 months, and MTKi regorafenib or cabozantinib as second or third line treatment that enables extension of survival by an additional 3 months [3,4] . Immune checkpoint inhibitors (ICIs) in monotherapy achieve striking tumor responses in a few patients who have hugely improved outcomes [3,4] , but the low rate of responding patients does not allow significant improvements in the median overall survival.…”

“…Treatment modalities available for patients with advanced HCC not eligible for curative treatment include the multikinase inhibitors (MTKi) sorafenib and lenvatinib as first line treatment, with an increase in survival of approximately 3 months, and MTKi regorafenib or cabozantinib as second or third line treatment that enables extension of survival by an additional 3 months [3,4] . Immune checkpoint inhibitors (ICIs) in monotherapy achieve striking tumor responses in a few patients who have hugely improved outcomes [3,4] , but the low rate of responding patients does not allow significant improvements in the median overall survival. More recently, the combination of drugs targeting the liver microenvironment with PD1/PD-L1 inhibitors, such as the association of bevacizumab and atezolizumab, or the combination of ICIs have shown promising results [3][4][5] .…”

“…Immune checkpoint inhibitors (ICIs) in monotherapy achieve striking tumor responses in a few patients who have hugely improved outcomes [3,4] , but the low rate of responding patients does not allow significant improvements in the median overall survival. More recently, the combination of drugs targeting the liver microenvironment with PD1/PD-L1 inhibitors, such as the association of bevacizumab and atezolizumab, or the combination of ICIs have shown promising results [3][4][5] .…”