6.1.1 Hepatocellular Carcinoma Overview

Hepatocellular carcinoma (HCC) is the sixth most common cancer in the world and the third leading cause of cancer mortality worldwide. Although HCC occurs more commonly in regions with a higher incidence of hepatitis, such as in Asia Pacific and Southern Europe, the National Cancer Institute (NCI) and the American Cancer Society (ACS) report the age-standardized incidence rate of HCC at 2.1 per 100,000 population in North America. Both the incidence and mortality rate related to HCC in the United States continue to rise with an estimated 30,640 new cases of HCC diagnosed in 2013 and 21,670 new deaths related to HCC. ¹

Risk factors for the development of HCC include viral hepatitis, alcohol abuse, nonalcoholic steatohepatitis (NASH), intake of aflatoxin-contaminated food, diabetes, obesity, and certain hereditary conditions, such as hemochromatosis. The main viruses associated with the development of HCC are the hepatitis B virus (HBV) and hepatitis C virus (HCV); indeed, 50% of HCC cases worldwide are associated with HBV infection, with a further 25% associated with HCV. ² The end stage of chronic inflammation in the liver, as best characterized by chronic viral infections, is hepatic cirrhosis. This is characterized by a decrease in hepatocyte proliferation and an increase in parenchymal fibrosis, which ultimately results in compromised hepatic function. In the progression of chronic inflammation to fibrosis, there is an upregulation of mitogenic pathways due to increased levels of cytokines (i.e., tumor growth factor, TGF-β1) and reactive oxygen species (ROS) released from damaged liver parenchymal cells, which lead to the propagation of monoclonal populations. ³ These clonal nests of hepatocytes contain telomerase erosions and chromosome aberrations, which limit the proliferative, and hence regenerative, capacity of the liver. ^{4 ,​ 5} The altered gene expression in these dysplastic hepatocytes predisposes them to becoming premalignant, and, over time, developing into HCC. Because HBV and HCV can also cause HCC independent of cirrhosis, other pathogenic mechanisms have also been postulated, including the integration of HBV DNA into the host genome (where it can cause gene deletions, rearrangements, and chromosome instability) and the synthesis of several oncogenic proteins by HCV. ⁶

6.2.2 Basic Principles

Selective internal radiation therapy (SIRT), also known as radioembolization and/or radiomicrosphere therapy in its current commercial form, uses yttrium-90 (⁹⁰Y) as a form of brachytherapy whereby microspheres loaded with ⁹⁰Y are permanently implanted in the target tumor vascular bed within the liver via intra-arterial administration. SIRT aims to selectively deliver radiation to liver tumors while limiting the dose delivered to normal liver parenchyma through the exploitation of the phenomenon of neovascularization of hepatic primary tumors originating exclusively via the hepatic arterial supply. This process allows for the deposition of ⁹⁰Y microspheres to preferentially implant within liver tumors in a 3 to 20:1 ratio, as compared to the normal liver parenchyma. ⁷ Although conventional external beam whole liver radiotherapy treatment is not well tolerated, radiotherapy to smaller portions of the liver is well tolerated without significant complications, provided a sufficient amount of normal liver parenchyma is spared. ⁸ Treatment with ⁹⁰Y can be currently delivered either as a resin (SIR-Spheres, Sirtex Medical Inc., Sydney, Australia) or as a glass microsphere (TheraSphere, BTG Ltd, Ottawa, Canada). As ⁹⁰Y decays, it emits high-energy β-radiation (0.97 mEv), which travels a mean of 2.5 mm from the physical microsphere. A single microparticle does not significantly contribute to the overall response to treatment; it is the collective effect of multiple microparticles that creates a cumulative isodose cloud of lethal radiation exposure (via crossfire) in the range of 100 to 1,000 gray (Gy) for a limited time (⁹⁰Y decays to zirconium-90 [⁹⁰Z] with a half-life of 64.2 h) ⁹ ( Fig. 6.1 ). The microparticle size used for SIRT is on average 20 to 60 µm, which is small enough for the particles to enter the tumor vascular network, but large enough to prevent arteriovenous shunting (in most situations). ¹⁰

6.2.3 Mechanism of Action of Selective Internal Radiation Therapy

SIRT’s mechanism of action is fundamentally different from that of chemoembolization; in fact, the term radio embolization is a misnomer because no significant effect or response has been demonstrated by the physical particle itself, even when angiographic embolization of nonradioactive microspheres has been performed. ¹¹ Chemoembolization relies on the occlusion of vessels of the tumor, thereby creating stasis and hence maximum exposure of the chemotherapeutic agent to the ischemic environment created within the tumor. In contrast, blood flow and oxygen are essential for SIRT to allow ROS generation via the ionization of water molecules from the emitted β-radiation. This, in turn, results in damage to DNA and activation of apoptosis via an increase in the ratio of BAX:BCL-2 gene expression. ¹² Furthermore, cancer cells are more susceptible to oxidative stress due to their relatively low concentration of superoxide dismutase (SOD) and their increased production of superoxide (^●O₂ ⁻) from their higher aerobic metabolism. ¹³ SOD is an antioxidant that quenches ^●O₂ ^– before it can react with hydroxyl radicals (OH^•) to produce hydrogen peroxide (H₂O₂). Direct double-strand DNA breaks also account for a significant proportion of cellular death. As such, the resin and glass microspheres used for SIRT are small enough to have little or no embolic effect on the medium- to small-sized hepatic arteries, thereby maintaining adequate tissue oxygenation. ¹¹

6.3.4 Staging Systems Used in Chronic Liver Disease

The severity of any underlying chronic liver disease can be assessed using two scoring systems, independent of whether or not the patient has HCC.

The Child–Pugh score is used to assess both the prognosis of underlying chronic liver disease (i.e., cirrhosis) and the necessity of treatment of liver transplantation ( Table 6.1 ). Based on the patient’s serum bilirubin, serum albumin, and international normalized ratio (INR), and the clinical presence of ascites or hepatic encephalopathy, patients are scored from 5 to 15 points based on a linear regression model. Depending on the score, patients are then placed in a class A to C, which reflects their likely mortality over the next year. Class A = 5–6 points with a 100% 1-year survival, class B = 7 to 9 points with an 81% 1-year survival, and class C = 10 to 15 points with a 45% 1-year survival.

The second scoring system used to assess the severity of chronic liver disease is the Model for End-Stage Liver Disease (MELD) score, which is based on the following equation:

Equation 6.1

This system was initially used to predict the 3-month mortality following a transjugular intrahepatic portosystemic shunt (TIPS) procedure but was also found to be useful for prioritizing recipients of a liver transplant. In hospitalized patients, the 3-month mortality is based on a patient’s MELD score ( Table 6.2 ).