Chapter 22: Hepatocellular Carcinoma

Hepatobiliary malignancies comprise a diverse group of tumors, including hepatocellular carcinoma (HCC), variants such as fibrolamellar HCC (FLHCC) and cholangiocellular carcinoma, cholangiocarcinoma, carcinoma of the gallbladder, and rare cancers such as sarcoma, angiosarcoma, and hepatoblastoma. The relative frequency of these tumors is shown in Table 22-1. The estimated new cases and deaths from liver and intrahepatic bile duct cancer in the United States in 2014 totaled 33,190 and 23,000, respectively (¹).

The majority of primary liver tumors are HCC or cholangiocarcinoma. These tumor types have different etiologies, epidemiology, clinical presentations, and treatment options. Thus, they are discussed separately.

Hepatocellular carcinoma is a malignancy of worldwide significance and has become increasingly important in the United States. It is the most common primary liver malignancy, the sixth most common cancer, and the third most common cause of cancer-related deaths worldwide (²). Eighty percent of new cases occur in developing countries, but the incidence is rising in economically developed regions, including Japan, Western Europe, and the United States (^3,4,5,6). The worldwide distribution of HCC and its associated etiologies are summarized in Table 22-2. Liver cirrhosis is the seventh leading cause of death in the world, the tenth most common cause of death in the United States, and acknowledged as a premalignant condition for developing HCC (^7,8,9).

In the United States, hepatitis C virus (HCV), alcohol use, and nonalcoholic fatty liver disease (NAFLD) are the most common causes of cirrhosis (⁹). The incidence of HCC doubled during the period 1975 to 1995 and continued to rise through 1998 (^10,11). This trend was previously expected to continue due to the estimated 4 million US individuals who are hepatitis C seropositive and the known latency of HCC development from the initial HCV infection, which may take two to three decades (¹¹). However, given the improved treatment regimens now available for patients with chronic hepatitis C, HCV-related HCC incidence may decrease in the next few years (¹²). It is also known that NAFLD-associated cirrhosis is on the rise in the United States (^13,14,15). A majority of patients present with advanced disease that is not amenable to curative procedures. Overall, HCC has a very poor prognosis, with a 5-year survival rate of 5%.

As shown in Table 22-1, HCC represents approximately 85% of all primary liver cancers (¹⁶). The distribution of HCC varies significantly by geography; it is endemic in parts of the world where hepatitis B virus (HBV) is also endemic. In Western countries, HCV infection and alcoholic cirrhosis are the principal risk factors for HCC. Due to rising incidence of HCV infection in American subpopulations, the incidence of HCC is projected to increase fourfold by 2015 (¹¹). Moreover, HCC incidence increases with age, with the age of peak incidence varying somewhat with population. The median age group of HCC is between the fifth and sixth decades. The disease is also seen in children and young adults in areas where HBV is endemic, and most of these infections occur perinatally. In all populations worldwide, there is a strong male predominance in HCC incidence. In the United States, the male-to-female ratio is 2.7 to 1, and HCC incidence rates are higher among African Americans than Caucasians (6.1 vs 2.8 per 100,000 in men). Hispanics, Asians, Pacific Islanders, and Native Americans have a much higher HCC frequency. Independent of HBV status, a family history of HCC in first-degree relatives carries a relative risk (RR) of 2.4 and overall risk (OR) of 2.9 (¹⁷). Familial aggregation and germline mutations of the APC (adenomatous polyposis coli) gene have been reported in hepatoblastoma (¹⁸).

Hepatocellular carcinoma develops commonly, but not exclusively, in a setting of liver cell injury, which leads to inflammation, hepatocyte regeneration, liver matrix remodeling, fibrosis, and ultimately cirrhosis. The major etiologies of liver cirrhosis are diverse and include chronic HBV and HCV infection, alcohol consumption, certain medications or toxic exposures, and genetic metabolic diseases. The mechanisms by which these varied etiologies lead to HCC are not fully elucidated. The principal risk factors that have been associated with cirrhosis and HCC are listed in Table 22-3.

Chronic Viral Hepatitis

Chronic hepatitis B or C viral infection is the most important risk factor for developing HCC. Alone, HCV causes about 40% of HCCs in the United States. Chronic HBV or HCV carriers usually take 10 to 20 years to develop hepatic cirrhosis and 30 to 40 years to develop HCC. Hepatitis B virus is a DNA virus that commonly integrates into the host hepatocyte genome and may play a direct procarcinogenic role. Hepatitis C virus is an RNA virus with no insertional mutagenesis. Although HBV and HCV contain no known viral oncogene to immortalize hepatocytes, hepatitis Bx antigen may inactivate p53 protein and downregulate DNA repair ability (^19,20). Some of the principal differences between HBV- and HCV-associated HCC are listed in Table 22-4.

Alcohol and Cirrhosis

Excessive alcohol consumption can lead to hepatic cirrhosis and thus is a risk factor for HCC. The autopsies of patients with alcoholic cirrhosis have reported up to 10% undiagnosed HCC. In the United States, alcoholic cirrhosis is associated with about 15% of HCC and cholangiocarcinoma (^21,22). In HCV carriers, alcohol increases circulating HCV viral titer and HCC risk. Other types of cirrhosis and parenchymal liver diseases—such as primary biliary cirrhosis, hemochromatosis, Wilson disease, alpha-1 antitrypsin deficiency, and glycogen storage disease—significantly increase HCC risks when alcohol is a cofactor.

Aflatoxin

Food contaminated with aflatoxin, a mycotoxin found in grains, can induce HCC in animals. There is also a strong association between aflatoxin exposure and HBV carrier status. Relative risks of HCC are 3-fold for aflatoxin, 9-fold for chronic HBV infection, and 59-fold for concurrent aflatoxin and chronic HBV infection. The underlying mechanism is polymorphism variants of glutathione-S-transferase M1 and epoxide hydrolase genes and G-to-T point mutation of the p53 gene (²⁰).

Other Environmental Factors

The use of oral contraceptive pills (OCPs) significantly increases the incidence of benign hepatic adenomas. There is some evidence that OCPs also increase HCC risk. Multiple studies of tobacco smoking and HCC risk have yielded mixed conclusions. Occupational exposure to arsenic or vinyl chloride significantly increases the risk of liver angiosarcoma. Exposure to the x-ray contrast medium thorium dioxide from 1930 to 1955 is associated with an extremely high risk of hemangiosarcoma, cholangiocarcinoma, and HCC.

Most cases of HCC are identified incidentally or through screening programs of high-risk individuals. It is common for patients to be asymptomatic until their disease is very far advanced; fewer than 30% of patients are candidates for surgery or other liver-directed therapy at presentation. Many patients present with symptoms of advanced liver dysfunction from both cirrhosis and HCC. The most common initial symptom is right upper quadrant abdominal pain. Anorexia or early satiety with weight loss is the second most common symptom. Also, HCC may present with various paraneoplastic symptoms through the secretion of numerous hormones. Late-stage symptoms include jaundice, tumor fever, bone pain due to metastatic lesions, and complications from portal venous hypertension, such as esophagogastric varices, hypoalbuminemia, ascites, thrombocytopenia, and coagulopathy.

On physical examination, hepatomegaly is present in over 90% of patients. A hepatic arterial bruit or a friction rub, ascites, splenomegaly, and jaundice are found in up to 50% of patients. Muscle wasting, fever, and dilated abdominal veins are also common. The Budd-Chiari syndrome is caused by malignant invasion and occlusion of the hepatic veins. The HCC marker alpha-fetoprotein (AFP) is often elevated to above 400 ng/mL.

Based on the growth pattern, HCC may be classified into four major gross anatomic types: spreading, multifocal, encapsulated, and combined patterns (²³). Normal liver parenchyma is shown in Fig. 22-1. The spreading type of HCC grows in nodular, pseudolobular, or invasive patterns with poorly defined margins, occurs in the setting of hepatic cirrhosis, and accounts for nearly 50% of cases in the United States. The multifocal type has numerous tumors of similar size that make it difficult to determine whether the lesions are intrahepatic metastases or second primary tumors (Figs. 22-2A and 22-2B). The encapsulated type of tumor grows by expanding, compressing, and distorting the surrounding liver tissue. Satellite or metastatic lesions are seen in late-stage disease. This type is most common in Asia and Africa but seen in only 13% of cases in the United States. The combined patterns of the three are seen in up to 25% of cases. Figure 22-3 shows an HCC histopathology specimen.

Approximately 60% to 70% of Caucasian and 80% to 90% of Asian HCC cases show elevated AFP, which is the most useful marker for HCC. Originally, AFP is produced by the fetal liver and yolk sac but falls to below 10 ng/mL in adult serum. A transient elevation of AFP to 20 to 400 ng/mL may occur when there is hepatocyte regeneration, as in cirrhosis, active hepatitis, or partial hepatectomy. The HCC positive predictive value of an AFP level of 400 ng/mL is over 95%, and normal AFP levels may exist in patients with low tumor burden. The lectin-reactive isoenzyme of AFP (AFP-L3) has shown increased sensitivity. Other markers, such as gamma-glutamyl transferase isoenzymes, alkaline phosphatase, isoferritins, and monoclonal antibodies are not more useful than AFP (²⁴). Currently, serum AFP level and ultrasonography are the “gold standard” for HCC screening in high-risk populations (²⁴).

Variants of Hepatocellular Carcinoma

There are five HCC variants: HCC with biliary differentiation, clear cell HCC, cholangiocellular carcinoma (CCC), FLHCC, and focal nodular hyperplasia (FNH). Cholangiocellular carcinoma is a combination of cholangiocarcinoma and HCC. It occurs in the noncirrhotic liver and behaves like a cholangiocarcinoma; it has a predominance for men. The outcome of patients with CCC is uniformly fatal.

Fibrolamellar HCC is predominantly seen in the right hepatic lobe, accounts for 2% to 4% of HCC, and occurs equally in men and women. It typically occurs in adolescents and young adults; the etiology is unknown. It is characterized by fibrosis arranged in lamellar fashion around HCC cells. Fibrolamellar HCC consists of well-circumscribed, large, solitary lesions without hepatic cirrhosis or elevated AFP (²⁵). The imaging studies often show a heterogeneous mass with a central scar that is similar to FNH. In comparison to classic HCC, FLHCC demonstrates a higher resection rate and better survival, with a 3-year survival of almost 100%.

Focal nodular hyperplasia occurs predominantly in young women. Liver function studies and the serum AFP level are normal. A technetium sulfur colloid radioisotope scan of the liver shows increased radioisotope uptake in FNH compared with hepatic adenomas or carcinomas. The prognosis is excellent.

Clear cell HCC has a distinguishing appearance and better prognosis. Hepatocellular carcinoma with biliary differentiation has a much poorer prognosis because of its rapid growth, decreased vascularity, and resistance to embolic therapy.

Rare primary liver neoplasms include hepatoblastoma, sarcoma, angiosarcoma, rhabdomyosarcoma, and epithelioid hemangioendothelioma. Patients may present with fatigue, anorexia, weight loss, and abdominal pain. Hemorrhagic ascites is common, and AFP level is normal. Angiography and contrast-enhanced computed tomography (CT) of the liver are the best diagnostic tools. Open or percutaneous liver biopsy is needed for diagnosis. Surgical resection is still the principal means of therapy if tumors are diagnosed at relatively early stages. They are often resistant to chemotherapy and radiotherapy (RT), and the overall prognosis is poor.

Benign Liver Tumors

Hemangiomas are the most common benign tumors of the liver. Their size ranges from a few millimeters to 25 cm. They appear as calcified solitary lesions in up to 7% of the general population. Magnetic resonance imaging (MRI) is much better than CT in distinguishing HCC from hemangioma on heavily T2-weighted images. Surgical resection is used for symptomatic lesions or when malignancy cannot be excluded. Hepatic artery ligation is an alternative for large cavernous hemangiomas. Hepatic adenoma is another common benign solitary tumor seen in women who have used OCPs for more than 10 years. It is composed of sinusoids, central veins, and arteries without well-defined portal tracts or bile ducts. Hepatic angiography is the most valuable diagnostic tool. Small adenomas usually regress when OCPs are discontinued. Symptomatic lesions are treated with resection.

In addition to performing a complete medical history and physical examination, the diagnostic workup for a patient suspected of having HCC should include serum for complete blood cell count, electrolytes, liver function tests (LFTs), albumin, prothrombin time, hepatitis B and C serologies, and tumor markers (AFP, CA19-9, CA125). The medical history should include a thorough review of potential HCC risk factors: transfusions, tattoos, intravenous drug abuse, high-risk sexual practices, familial syndromes, OCP or hormone replacement use, androgenic steroid use, and chemical exposures.

Several radiographic imaging modalities are useful in evaluating a patient with HCC. Ultrasound often serves as the initial screening modality, followed by triple-phase CT scan or MRI. Randomized studies have shown that hepatic ultrasonography has 78% sensitivity and 93% specificity to detect HCC in high-risk populations, especially for patients with normal AFP levels (^26,27). Color-flow Doppler can assist preoperative assessment and planning.

Abdominal CT has relatively higher sensitivity and specificity than ultrasonography. With special arterial- and venous-phase scans, CT also makes it possible to evaluate the blood supply of the normal liver parenchyma (portal vein) and neoplastic lesions (hepatic artery). Magnetic resonance imaging is useful in distinguishing benign lesions from malignant tumors by the combination of T2-weighted phase contrast and spin echo sequences. Also, MRI can demonstrate fatty degeneration of tumor and vascular invasion (²⁸).

Hepatic radionuclide imaging has low spatial resolution and is only about 70% sensitive in demonstrating neoplasms. Using the glucose metabolic difference between neoplastic and normal cells, positron emission tomography (PET) differentiates benign lesions from malignant tumors, detects extrahepatic metastasis, and evaluates response to therapy.

In summary, ultrasonography is the most cost-effective HCC screening test in high-risk populations. Abdominal CT with liver protocol is the most helpful in accurately staging patients prior to surgery. No single diagnostic modality has greater than 50% to 60% sensitivity in detecting lesions less than 1 cm in size. The combination of AFP level, ultrasonography, and CT provides the best hope of early diagnosis.

A variety of staging and prognostic systems has been developed to evaluate patients with HCC. Four staging systems (Okuda; CLIP, Cancer of the Liver Italian Program; CUPI, Chinese University Prognostic Index; and American Joint Committee on Cancer [AJCC] TNM) have evolved since the 1980s. Currently, we use a combined AJCC-TNM staging system at MD Anderson Cancer Center (MDACC) (Table 22-5) (²⁵). The Child-Pugh Classification System (Fig. 22-4 and its Appendix C) provides an estimate of a patient’s functional liver reserve and is used principally to assist in evaluating a patient’s suitability for hepatic resection.

Based on a review of the database developed at MDACC, patients with HCC had an overall 3-year survival rate of 10% and a median survival time of 7.8 months. Favorable prognostic factors are female gender, absence of cirrhosis, and resection of the tumor; these factors correlated with longer survival, especially if the tumors were located in the left hepatic lobe. For patients with unresectable HCC, systemic chemotherapy or supportive care yielded a 44% 1-year survival rate, and no patient survived for 3 years. The size and number of nodules were not determinants of survival. Poor prognostic factors included advanced stage, unresectability associated with cirrhosis, and vascular invasion.

The current treatment options for HCC are summarized in Table 22-6. At present, liver transplantation is considered the only potentially “curative” treatment. The current 1- and 5-year survival rates for patients with HCC undergoing orthotopic liver transplantation are 77.0% and 61.1%, respectively. The 5-year survival rate has steadily improved, from 25.3% in 1987 to 61.1% in the most recent period studied (1996-2001) (²⁹). The authors attributed this improvement to the incorporation of the “Milan” criteria as guidelines for patient selection at most US liver transplantation centers. These criteria, as published by Mazzaferro et al, suggest that long-term survival after liver transplantation is highest in patients with HCC with either a single lesion 5 cm or smaller or three lesions 3 cm or smaller each and no evidence of gross vascular invasion (³⁰). A large number of liver transplant candidates remain on the waiting list until they die of tumor progression or cirrhosis-related complications. Partial hepatectomy is the current standard treatment for localized T1 to T3, N0, M0 HCC. Resectability is determined by the extent of liver cirrhosis, the future liver remnant (FLR), and an adequate surgical margin. An FLR of 35% to 40% is considered the minimal cutoff for a safe liver remnant. Patients of Child-Pugh class B and C or with significant signs of portal hypertension are not surgical candidates.

Minor or major resection is based on the following criteria: (1) minor resection: Child A, normal LFTs (bilirubin ≤1.0 mg/dL), absence of ascites, and platelet count above 100,000/mm; and (2) major resection: minor criteria as in criterion 1, absence of portal hypertension, and portal vein embolization for a small future remnant (³¹). The perioperative mortality has decreased from 20% in the 1980s to less than 5% at present (³¹). The median disease-free survival after partial hepatectomy is about 2 years. Tumor size less than 5.0 cm (0.6 RR) was associated with improved survival, while the presence of vascular invasion, AFP greater than 2,000 mg/mL, and advanced Child-Pugh classification was associated with worse outcome. Patients with cirrhosis generally are not considered good candidates for surgical resection due to the high morbidity and mortality associated with cirrhosis and its complications. For those who do undergo resection, recurrence rates are among the highest of any solid tumor and approach 75% to 100% at 5 years. Estimated 5-year survival rates are in the range of 26% to 50%, and disease-free survival is 13% to 29% (³²).

Locoregional Therapy for Hepatocellular Carcinoma

Hepatocellular carcinoma derives its blood supply almost exclusively from the hepatic artery. This important anatomic feature offers unique advantages for catheter-based therapies because arterial embolization interrupts blood flow to the tumor while preserving the portal vein and normal liver parenchyma. The combination of tissue ischemia with highly concentrated chemotherapy delivered into the hepatic artery enhances tumor necrosis. Transarterial chemoembolization (TACE) was first described by Yamada and incorporates these concepts (³³). It has since become one of the most commonly utilized procedures in interventional radiology practice.

Landmark prospective randomized clinical trials published in 2002 validated the use of chemoembolization for unresectable advanced HCC. In the multicenter study by Llovet et al including 112 patients, when compared to bland embolization or best supportive therapy, patients who underwent TACE with a combination of doxorubicin and iodized oil followed by gelatin sponge demonstrated a clear survival advantage, leading to premature stoppage of the trial (³⁴). Survival in the chemoembolization group at 1 and 2 years was 82% and 63%, respectively. Survival in the bland embolization group was 75% and 50%, respectively; in the best supportive care group, survival was 63% and 27%, respectively, and reached statistical significance.

Lo et al conducted a single-center study comparing 80 patients with unresectable HCC randomized to TACE with cisplatin and iodized oil followed by gelatin sponge or best supportive care (³⁵). Survival in the chemoembolization group at 1 and 2 years was 57% and 31%, respectively. Survival for the patients randomized to the supportive care group was 32% and 11%, respectively, also reaching statistical significance. The difference in survival rates between the Llovet and Lo studies can be attributed to the inclusion of a larger proportion of patients with more advanced stages of underlying chronic liver disease in the latter study. Chemoembolization is contraindicated in patients with overt signs of portal hypertension and advanced underlying liver disease.

An important limitation of conventional chemoembolization using iodized oil lies in the uncontrolled washout of the cytotoxic drugs into the systemic circulation. Recently, a drug-eluting bead that allows controlled and sustained release of chemotherapeutic agents into the surrounding tumor was made available. This device enables delivery of a higher concentration of drugs with low systemic toxicity. Initial studies demonstrated that chemoembolization using drug-eluting beads is safe, with potentially increased effectiveness for patients with more advanced disease (^36,37,38).

At MD Anderson, TACE is routinely utilized for patients with HCC with more than three lesions measuring up to 3 cm each or a single lesion greater than 5 cm. In patients with portal vein thrombosis, infiltrative disease, or more than four lesions, radio embolization with yttrium-90 microspheres is well tolerated and has been shown to improve outcomes. A recent study assessing the use of radio embolization in HCC showed response rates of 42% based on World Health Organization criteria (³⁹).

Radiofrequency ablation causes tissue necrosis by controlled deposition of thermal energy. This technique is highly effective in the treatment of small and early HCC, with outcomes similar to surgical resection (⁴⁰). Radiofrequency ablation is limited by lesion proximity to adjacent structures such as colon, gallbladder, and diaphragm. In addition, vascular structures adjacent to the target lesion steal heat from the area and decrease effectiveness of the ablation. The combination of chemoembolization followed by radiofrequency ablation may improve cell death because occlusion of blood flow leads to larger ablation zones (^41,42).

Systemic Chemotherapy and Hormonal Therapy

A majority (>80%) of patients diagnosed with HCC have advanced disease at presentation and—based on the number, size, and location of lesions, as well as the severity of the underlying cirrhosis—are not candidates for transplantation, surgical resection, or liver-directed therapies. At present, systemic chemotherapy is ineffective in HCC, as evidenced by low response rates and no demonstrated survival benefit (see Table 22-6). HCCs are inherently chemotherapy resistant (⁴³) and known to express the multidrug-resistance gene MDR-1 (^44,45).

Few well-controlled, randomized chemotherapy trials have been published regarding HCC. That being said, we conducted a retrospective analysis of patients with unresectable HCC at MD Anderson who received either a conventional or a modified neoadjuvant PIAF chemotherapy regimen, consisting of cisplatin, interferon a-2b, doxorubicin, and 5-fluorouracil (5-FU). We found that select patients with HCC (patients who are noncirrhotic and without hepatitis B with good performance status [PS]) benefit from neoadjuvant-modified PIAF chemotherapy with improved response rates, resectability, and survival (⁴⁶). Therefore, we consider this regimen in the neoadjuvant setting in select patients with unresectable tumors as bridge to surgery. Unfortunately, the ability to conduct controlled clinical trials of systemic regimens in patients with HCC has been hampered by many factors, including the multiple comorbidities of cirrhosis (Table 22-7), the advanced nature of HCC at presentation, rapid disease progression in many instances, and the distribution of patients primarily in developing nations, where multidisciplinary treatment of HCC may not be available.

Approximately 15% to 40% of HCCs are estrogen receptor positive. Hormonal therapy with tamoxifen or octreotide analogues has demonstrated some survival benefit (⁴⁷); however, the results of other studies are conflicting.

Clinical Trials of Antiangiogenesis Agents

Several systemic targeted agents have recently been tested in clinical trials for patients with advanced HCC, including agents targeting the vascular endothelial growth factor (VEGF) pathway, either alone (^{48,49,50,51,52,53,54,55,56,57,58,59,60}) or in combination with other systemic therapies (^{61,62,63,64,65,66,67,68}). The cancer cell has been the only target of anticancer systemic therapy for more than 50 years. However, the cancer cell is genetically unstable, leading to accumulation of mutations. On the other hand, antiangiogenic therapy agents target endothelial cells that are genetically stable. Interestingly, the mechanism of action of thalidomide was thought to be partly based on its antiangiogenic effects. Nevertheless, several clinical trials of thalidomide showed rare responses, ranging from 0% to 6.3% (^58,59).

Newer agents that target this antiangiogenic mechanism include sunitinib and sorafenib. Sunitinib is an oral multikinase inhibitor that exerts its antiangiogenic effects by targeting VEGF receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) tyrosine kinases. Sorafenib, another oral multikinase inhibitor, exerts its antitumor effect by targeting Raf/MEK/ERK signaling at the level of Raf kinase and possesses an antiangiogenic effect by targeting VEGFR-2/-3. Recently, two phase III trials of sorafenib have been reported (^48,60). The pivotal randomized, placebo-controlled phase III trial of sorafenib in patients with advanced HCC (SHARP trial [Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol Study group trial]) reported modest activity with a 2.8-month improvement in median overall survival (OS) (P = .0006). In addition, it demonstrated an increased time to progression and disease control rate while showing a response rate of 2.3% as defined by RECIST criteria (⁴⁸). This led to Food and Drug Administration (FDA) approval of sorafenib for advanced HCC in 2007, and it remains the only FDA-approved drug for this indication.

Other agents that target antiangiogenesis include bevacizumab and erlotinib. Bevacizumab is a recombinant, humanized monoclonal antibody that exerts its antitumor activity by targeting VEGF and may augment chemotherapy administration by making tumor vasculature less permeable, which decreases the elevated tumor interstitial pressure. Erlotinib is an oral tyrosine kinase inhibitor that blocks phosphorylation at the intracellular domain level of the EGFR. Most recently, we reported a phase II single-arm, open-label trial of bevacizumab and erlotinib that showed improved response rate, median OS, and progression-free survival (⁵³).

Collectively, application of antiangiogenesis agents to patients with advanced HCC has eventually led to improved survival despite surprisingly low response rates. Notably, there is a poor correlation between survival benefit and conventional methods of response assessment, namely, RECIST. This poses questions regarding how best to evaluate response to antiangiogenic agents and quantify efficacy of antiangiogenic agents. Despite tumors increasing in size sometimes, the observation of tumor necrosis in many studies is intriguing. Therefore, in 2000, a panel of experts recommended that the response criteria be amended to take into account tumor necrosis induced by targeted agent therapy (⁶⁹). Although its utility in assessing efficacy of anticancer agents in HCC needs to be established, tumor necrosis is a potentially significant clinical end point that warrants further investigation in future studies.

Targeted Therapies in Hepatocellular Carcinoma: Beyond Sorafenib

Given the paucity of available FDA-approved medications for advanced HCC, a number of other targeted agents have been tested in clinical trials in the adjuvant and advanced/metastatic setting. In the adjuvant setting, sorafenib did not show improved OS versus placebo in patients with previously resected or ablated HCC (⁷⁰). Similar results were seen for orantinib, a multireceptor tyrosine kinase inhibitor of VEGFR2, PDGFR, and fibroblast growth factor receptor (FGFR), in patients who received previous transcatheter arterial embolization (⁷¹).

In the advanced, unresectable or metastatic setting, first-line therapy with linifanib (VEGFR and PDGFR tyrosine kinase inhibitor), sunitinib (VEGFR and PDGFR), and brivanib (VEGFR and FGFR) have all been tested in phase III trials against sorafenib with no improvement in OS (^72,73,74). In the second-line setting, brivanib, everolimus (mTOR pathway inhibitor), and ramicirumab (fully human immunoglobulin G1 monoclonal antibody against VEGFR2) have all been tested versus placebo in patients who have either progressed on or were intolerant to sorafenib. None of these trials showed any significant improvement in OS (^75,76,77). Two other agents, tivantinib (MET inhibitor) and cabozantinib (MET, RET, and VEGFR tyrosine kinase inhibitor) are currently being studied in clinical trials for patients in the second-line setting described. Enrollment in these trials is ongoing, and results are incomplete (^78,79). At present, no therapy has better proven efficacy than sorafenib in the advanced, unresectable, or metastatic setting. Table 22-8 is a summary of targeted therapies in HCC.

Radiation

Advances in our understanding of partial liver tolerance of RT, ability to visualize target tumors during respiration, and radiation planning and delivery techniques have permitted us to escalate the dose of radiation to focal HCCs without dose-limiting toxicity. This improved ability to deliver tumoricidal doses of RT safely has led to a resurgence of interest in treatment of HCC using RT. Promising clinical data from multiple studies suggested that HCCs are indeed radiosensitive. Sustained local control rates ranging from 71% to 100% have been reported following 30 to 90 Gy delivered over 1 to 8 weeks (^80,81).

Investigators from Michigan have used conformal RT (1.5 Gy twice daily over 6-8 weeks) with concurrent hepatic arterial fluorodeoxyuridine to treat HCCs safely to doses as high as 90 Gy and achieved a median survival duration of 15.2 months (⁸²). Analysis of these data suggested that doses greater than 75 Gy resulted in more durable in-field local control than lower doses.

A prospective French phase II trial administered 66 Gy in 33 fractions to HCCs ineligible for curative therapies and noted 92% tumor responses and 78% 1-year local control rates (⁸³). Using higher doses and fewer fractions (hypofractionated RT), Canadian researchers have noted excellent local control rates ranging from 70% to 90% when the radiation beam can be directed from multiple planes (stereotactic RT) converging on the tumor; the majority of the liver can be spared from irradiation, and treatment is image guided (^81,84,85).

In contrast to photon irradiation, for which the dose delivered to the tumor is limited by the entrance and exit doses that can potentially harm normal tissues, accelerated proton beams deposit a dose within the tumor without exiting through normal tissues beyond the tumor (⁸⁶). Japanese investigators have reported mature results of the treatment of 162 patients with 192 unresectable HCCs with 72 Gy in 16 fractions of proton beam therapy (⁸⁷). The 5-year local control rate of 87% and OS rate of 23.5% in the absence of significant toxicity are clinically noteworthy. Furthermore, an impressive 5-year survival rate of 53.5% was achieved in a subset of 50 patients with solitary tumors and Child-Pugh Class A cirrhosis.

Our own experience reflects these observations that higher doses are associated with better overall, in-field progression-free and biochemical progression-free survival (⁸⁸). Across all partial liver radiation paradigms, the most common site of first recurrence is intrahepatic but outside the high-dose irradiated volume, and toxicities are more common in Child-Pugh class B patients.

Given the excellent local control rate as noted with RT alone, RT has been combined with TACE to overcome treatment resistance. Korean researchers initially noted more than 60% response rates and a significant drop in tumor marker levels using this combination treatment strategy (^89,90). It was reported that TACE followed by RT improved OS over TACE alone in a retrospective analysis of this experience. Similar results have been reported by other groups as well (^91,92,93).

For the treatment of unfavorable tumors, multiple groups have reported favorable outcomes in patients with portal venous tumor thrombus (PVTT) treated with RT (^{94,95,96,97,98,99,100,101,102,103}). Response rates ranged from 37.5% to 100%, and median survival durations ranged from 3.8 to 10.7 months.

Taken together, these advances have permitted the escalation of radiation dose to unresectable HCCs without causing undue toxicity. Strategies that combine RT with other therapies merit continued evaluation to maximize the relative benefits of each approach.

Hepatocellular carcinoma and other primary liver tumors require multidisciplinary input, and patients benefit from clinical care that integrates the expertise of surgical oncology, liver transplantation, diagnostic and interventional radiology, gastroenterology and hepatology, radiation oncology, and medical oncology. New cases of HCC are reviewed at a weekly multidisciplinary liver tumor conference to develop a consensus approach to each patient’s case. Careful attention is paid to precise tumor staging, histopathologic diagnosis, and each patient’s PS.

Patients with HCC who meet current United Network for Organ Sharing (UNOS) criteria are offered liver transplantation or resection if they are highly likely to benefit. Liver-directed therapies, principally RFA and TACE, are commonly employed in patients who are not candidates for surgical intervention. In addition, select patients who present with unresectable tumors are considered for neoadjuvant chemotherapy as a bridge to surgery. Patients with good PS with advanced HCC are encouraged to participate in a clinical trial of systemic therapy. Figure 22-4 depicts the general approach followed by the multidisciplinary hepatobiliary team in managing patients with HCC evaluated at MDACC.