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Page 2 of 10 Reyngold et al. Hepatoma Res 2018;4:49 I http://dx.doi.org/10.20517/2394-5079.2018.84

able tumors, liver dysfunction and extrahepatic disease. It is important to note that death in patients with
unresectable HCC is often related to liver failure as a direct consequence of local tumor progression. The
mechanisms of liver failure include functional liver parenchymal loss, biliary obstruction, portal venous ob-
struction, and hepatic venous outflow obstruction resulting in ischemia (Budd Chiari). Some of these may
occur even with small tumors that are located near hilum or the confluence of the hepatic veins and inferior
vena cava. Although not well studied in patients with HCC, data on direct causes of death from another
primary liver tumor, intrahepatic cholangiocarcinoma, treated with radiation at The University of Texas MD
Anderson Cancer Center demonstrated that death resulted from tumor-related liver failure in 89% of patients
whose cause of death could be determined. Half of those deaths were from biliary obstruction and the other
[1]
half from vascular compromise or a combination . This underscores the importance of local therapies even
for patients with advanced disease and suggests that effective local control may translate into a major survival
benefit.

Current practice includes many options for liver directed-therapy in inoperable patients. Percutaneous
image-guided ablative options (radiofrequency, microwave, cryoablation or percutaneous ethanol injection)
are preferred for small peripheral tumors located away from segmental and main bile ducts, the liver surface,
and major vessels. Additional options include arterially directed options such as bland transarterial emboli-
zation, transarterial chemoembolization or radioembolization with yttrium-90 beads. Radiation therapy is
a complementary option for patients with liver tumors and is a preferred option for tumors near the biliary
tree, hilum of the liver, main portal vein, or inferior vena cava. For large liver tumors, radiation therapy may
be the most effective local therapy available.

Effective radiation therapy for liver tumors such as HCC is predicated on the ability to deliver ablative doses
with minimal risk of injury to the surrounding normal structures including liver parenchyma, which is often
compromised in this patient population-as well as the bile ducts, chest wall, stomach, duodenum and colon.
A number of treatment related factors can improve the therapeutic ratio of liver radiation therapy (RT), in-
cluding increasing the number of fractions, controlling respiratory motion, using soft tissue image guidance,
and using proton therapy to spare liver. In the following sections we examine how these factors enable the
delivery of ablative RT for HCC.

LIVER TOLERANCE
Historically, radiation therapy to the liver was thought to be unsafe based on the inability of the whole liver
[2]
to tolerate doses exceeding 30 Gy . Investigators from the University of Michigan subsequently showed that
partial liver volumes can tolerate high focal doses of radiation, defined the radiation dose-response relation-
ship for liver tumors, and described objective parameters to evaluate dose-volume relationships of ablative
[3,4]
liver treatments .
Notably, radiation-related liver toxicities may have distinct mechanisms and presentations in patients with
cirrhosis and without cirrhosis. Radiation induced liver disease (RILD) is now classified as either classic (triad
of anicteric hepatomegaly, elevated alkaline phosphatase and ascites) or non-classic (jaundice and markedly
elevated serum transaminases). Several reports have noted that patients with advanced cirrhosis are at a
[5-7]
higher risk of non-classic radiation-induced liver disease . Most recently, it has been recognized that pa-
90
[8]
tients who undergo radioembolization with Y are susceptible to radioembolization-induced liver disease ,
which presents with jaundice and ascites in the absence of tumor progression. The mechanisms underlying
these different presentations of radiation-related liver toxicities remain subjects of ongoing research; but it
is clear that the dose-volume relationship is altered in the presence of limited liver reserve [5-7,9] . In addition
to cirrhosis, other common reasons for limited liver reserve include limited normal-liver volume due to
previous resection or hepatotoxic chemotherapy, and tumor-related dysfunction due to biliary or vascular