Current and future treatments for hepatocellular carcinoma

Table 1 Scoring/grading systems related to hepatocellular carcinoma

System	Description	When used
Milan Criteria[4], 1996	Single tumor ≤ 5 cm, or 2-3 tumors ≤ 3 cm, and no vascular invasion and/or extrahepatic spread.	Staging HCC
UCSF Criteria[5], 2001	Single tumor ≤ 6.5 cm, or 2-3 lesions, none exceeding 4.5 cm, with total tumor diameter ≤ 8 cm, no vascular invasion and/or extrahepatic spread.	Staging HCC
Model for End-Stage Liver Disease Score (MELD)[107], 2000	Specific equation looking at the variables of bilirubin, INR and serum creatinine.	Transplant prioritization, End-stage liver disease severity by estimating 3 mo mortality
Barcelona Clinic Liver Cancer (BCLC) Staging[108], 1999	Variables include tumor stage, liver functional status, physical status, and cancer-related symptoms	Widely accepted treatment algorithm of HCC
Child-Pugh-Turcott[109,110], 1964-1972	Variables include bilirubin, albumin, INR, Ascites and presence of encephalopathy	Prognosis/severity of liver disease including cirrhosis
Tumor-Node-Metastasis[111], 1997	Variables include the classic tumor size/location, lymph node positivity, and presence of metastasis.	Standard and poorly predictive staging system not currently in use
Okuda[112], 1985	Variables include albumin, ascites, bilirubin, and tumor stage (more or less than 50% of liver area involved)	Properly stratified patients with advanced/symptomatic stage and is useful to identify end-stage patients. Lacks early stage predictive capacity
Japan Integrated Staging (JIS)[113], 2000	Combines TMN with Child-Pugh	Prognostic staging system for hepatocellular carcinoma

HCC: Hepatocellular carcinoma.

Table 2 Select current molecular inhibitors under investigation as standalone or combination therapies for treatment of hepatocellular carcinoma

Drug name	Method of action	Clinical phase
Lenvatinib	VEGFR, PDGFR, FGFR, RET and c-Kit inhibitor	III, ongoing as 1st line
Brivanib	VEGFR2 and FGFR tyrosine kinases	III, negative as 1st line
Everolimus	mTOR inhibitor	III, negative
Tivantinib	c-MET inhibitor	III, ongoing as 2nd line
Linifanib	RTK, VEGF and PDGF inhibitor	III, negative as 1st line
Sorafenib (as adjuvant)	Raf/MEK/ERK inhibitor	III, negative
Ramucirumab	VEGFR2	II and III, negative
Foretinib	c-MET inhibitor	II
Refametinib	MEK1/2 inhibitor	II
Mapatumumab	TRAIL-receptor (death receptor 4)	II
Selumetinib	MAPK/ERK inhibitor	II
Erlotinib	EGFR tyrosine kinase inhibitor	II
Lapatinib	EGFR and HER2/neu inhibitor	II
Cabozantinib	VEGFR2, c-MET, RET, KIT, FLT4, AXL	III
MSC2156119J	c-MET/HGF	Ib/II
Lenalidomide	Immunomodulatory	II

HGF: Hepatocyte growth factor; VEGF: Vascular endothelial growth factor.