Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. The annual global incidence is approximately 1 million cases, with a male-to-female ratio of approximately 4:1 (1:1 without cirrhosis to 9:1 in many high-incidence countries). The incidence rate equals the death rate. In the United States, approximately 22,000 new cases are diagnosed annually, with 18,000 deaths. The death rates in males in low-incidence countries such as the United States are 1.9 per 100,000 per year; in intermediate areas such as Austria and South Africa, they range from 5.1–20; and in high-incidence areas such as in the Orient (China and Korea), they are as high as 23.1–150 per 100,000 per year (Table 41-1). The incidence of HCC in the United States is approximately 3 per 100,000 persons, with significant gender, ethnic, and geographic variations. These numbers are rapidly increasing and may be an underestimate. Approximately 4 million chronic hepatitis C virus (HCV) carriers are in the United States alone. Approximately 10% of them, or 400,000, are likely to develop cirrhosis. Approximately 5%, or 20,000, of these patients may develop HCC annually. Add to this the two other common predisposing factors—hepatitis B virus (HBV) and chronic alcohol consumption—and 60,000 new HCC cases annually seem possible. Future advances in HCC survival will likely depend in part on immunization strategies for HBV (and HCV) and earlier diagnosis by screening of patients at risk of HCC development.
TABLE 41-1Age-Adjusted Incidence Rates for Hepatocellular Carcinoma ||Download (.pdf) TABLE 41-1 Age-Adjusted Incidence Rates for Hepatocellular Carcinoma
|Country ||Persons per 100,000 per Year |
|Male ||Female |
|Argentina ||6.0 ||2.5 |
|Brazil, Recife ||9.2 ||8.3 |
|Brazil, Sao Paulo ||3.8 ||2.6 |
|Mozambique ||112.9 ||30.8 |
|South Africa, Cape: Black ||26.3 ||8.4 |
|South Africa, Cape: White ||1.2 ||0.6 |
|Senegal ||25.6 ||9.0 |
|Nigeria ||15.4 ||3.2 |
|Gambia ||33.1 ||12.6 |
|Burma ||25.5 ||8.8 |
|Japan ||7.2 ||2.2 |
|Korea ||13.8 ||3.2 |
|China, Shanghai ||34.4 ||11.6 |
|India, Bombay ||4.9 ||2.5 |
|India, Madras ||2.1 ||0.7 |
|Great Britain ||1.6 ||0.8 |
|France ||6.9 ||1.2 |
|Italy, Varese ||7.1 ||2.7 |
|Norway ||1.8 ||1.1 |
|Spain, Navarra ||7.9 ||4.7 |
With the U.S. HCV epidemic, HCC is increasing in most states, and obesity-associated liver disease (nonalcoholic steatohepatitis [NASH]) is increasingly recognized as a cause.
There are two general types of epidemiologic studies of HCC—those of country-based incidence rates (Table 41-1) and those of migrants. Endemic hot spots occur in areas of China and sub-Saharan Africa, which are associated both with high endemic hepatitis B carrier rates as well as mycotoxin contamination of foodstuffs (aflatoxin B1), stored grains, drinking water, and soil. Environmental factors are important, for example, Japanese in Japan have a higher incidence than Japanese living in Hawaii, who in turn have a higher incidence than those living in California.
Causative agents for HCC have been studied along two general lines. First are agents identified as carcinogenic in experimental animals (particularly rodents) that are thought to be present in the human environment (Table 41-2). Second is the association of HCC with various other clinical conditions. Probably the best-studied and most potent ubiquitous natural chemical carcinogen is a product of the Aspergillus fungus, called aflatoxin B1. This mold and aflatoxin product can be found in a variety of stored grains in hot, humid places, where peanuts and rice are stored in unrefrigerated conditions. Aflatoxin contamination of foodstuffs correlates well with incidence rates in Africa and to some extent in China. In endemic areas of China, even farm animals such as ducks have HCC. The most potent carcinogens appear to be natural products of plants, fungi, and bacteria, such as bush trees containing pyrrolizidine alkaloids as well as tannic acid and safrole. Pollutants such as pesticides and insecticides are known rodent carcinogens.
TABLE 41-2Factors Associated with an Increased Risk of Developing Hepatocellular Carcinoma ||Download (.pdf) TABLE 41-2 Factors Associated with an Increased Risk of Developing Hepatocellular Carcinoma
|Common ||Unusual |
|Cirrhosis from any cause ||Primary biliary cirrhosis |
|Hepatitis B or C chronic infection ||Hemochromatosis |
|Ethanol chronic consumption ||α1 Antitrypsin deficiency |
|NASH/NAFL ||Glycogen storage diseases |
|Aflatoxin B1 or other mycotoxins || |
Porphyria cutanea tarda
Both case-control and cohort studies have shown a strong association between chronic hepatitis B carrier rates and increased incidence of HCC. In Taiwanese male postal carriers who were hepatitis B surface antigen (HBsAg)-positive, a 98-fold greater risk for HCC was found compared to HBsAg-negative individuals. The incidence of HCC in Alaskan natives is markedly increased related to a high prevalence of HBV infection. HBV-based HCC may involve rounds of hepatic destruction with subsequent proliferation and not necessarily frank cirrhosis. The increase in Japanese HCC incidence rates in the last three decades is thought to be from hepatitis C. A large-scale World Health Organization (WHO)-sponsored intervention study is currently under way in Asia involving HBV vaccination of the newborn. HCC in African blacks is not associated with severe cirrhosis but is poorly differentiated and very aggressive. Despite uniform HBV carrier rates among the South African Bantu, there is a ninefold difference in HCC incidence between Mozambicans living along the coast and inland. These differences are attributed to the additional exposure to dietary aflatoxin B1 and other carcinogenic mycotoxins. A typical interval between HCV-associated transfusion and subsequent HCC is approximately 30 years. HCV-associated HCC patients tend to have more frequent and advanced cirrhosis, but in HBV-associated HCC, only half the patients have cirrhosis, with the remainder having chronic active hepatitis.
Other etiologic conditions
The 75–85% association of HCC with underlying cirrhosis has long been recognized, more typically with macronodular cirrhosis in Southeast Asia, but also with micronodular cirrhosis (alcohol) in Europe and the United States. It is still not clear whether cirrhosis itself is a predisposing factor to the development of HCC or whether the underlying causes of the cirrhosis are actually the carcinogenic factors. However, ~20% of U.S. patients with HCC do not have underlying cirrhosis. Several underlying conditions are associated with an increased risk for cirrhosis-associated HCC (Table 41-2), including hepatitis, alcohol, autoimmune chronic active hepatitis, cryptogenic cirrhosis, and NASH. A less common association is with primary biliary cirrhosis and several metabolic diseases including hemochromatosis, Wilson’s disease, α1 antitrypsin deficiency, tyrosinemia, porphyria cutanea tarda, glycogenesis types 1 and 3, citrullinemia, and orotic aciduria. The etiology of HCC in those 20% of patients who have no cirrhosis is currently unclear, and their HCC natural history is not well-defined.
Many patients have multiple etiologies, and the interactions of HBV, HCV, alcohol, smoking, and aflatoxins are just beginning to be explored.
These include abdominal pain, weight loss, weakness, abdominal fullness and swelling, jaundice, and nausea (Table 41-3). Presenting signs and symptoms differ somewhat between high- and low-incidence areas. In high-risk areas, especially in South African blacks, the most common symptom is abdominal pain; by contrast, only 40–50% of Chinese and Japanese patients present with abdominal pain. Abdominal swelling may occur as a consequence of ascites due to the underlying chronic liver disease or may be due to a rapidly expanding tumor. Occasionally, central necrosis or acute hemorrhage into the peritoneal cavity leads to death. In countries with an active surveillance program, HCC tends to be identified at an earlier stage, when symptoms may be due only to the underlying disease. Jaundice is usually due to obstruction of the intrahepatic ducts from underlying liver disease. Hematemesis may occur due to esophageal varices from the underlying portal hypertension. Bone pain is seen in 3–12% of patients, but necropsies show pathologic bone metastases in ~20% of patients. However, 25% of patients may be asymptomatic.
TABLE 41-3Hepatocellular Carcinoma Clinical Presentation (N = 547) ||Download (.pdf) TABLE 41-3 Hepatocellular Carcinoma Clinical Presentation (N = 547)
|Symptom ||No. of Patients (%) |
|No symptom ||129 (24) |
|Abdominal pain ||219 (40) |
|Other (workup of anemia and various diseases) ||64 (12) |
|Routine physical exam finding, elevated LFTs ||129 (24) |
|Weight loss ||112 (20) |
|Appetite loss ||59 (11) |
|Weakness/malaise ||83 (15) |
|Jaundice ||30 (5) |
|Routine CT scan screening of known cirrhosis ||92 (17) |
|Cirrhosis symptoms (ankle swelling, abdominal bloating, increased girth, pruritus, GI bleed) ||98 (18) |
|Diarrhea ||7 (1) |
|Tumor rupture || 1 |
|Patient Characteristics |
|Mean age (yr) ||56 ± 13 |
|Male:Female ||3:1 |
|Ethnicity || |
| White ||72% |
| Middle Eastern ||10% |
| Asian ||13% |
| African American ||5% |
|Cirrhosis ||81% |
|No cirrhosis ||19% |
|Tumor Characteristics |
|Hepatic tumor numbers |
| 1 ||20% |
| 2 ||25% |
| 3 or more ||65% |
|Portal vein invasion ||75% |
|Unilobar ||25% |
|Bilobar ||75% |
Hepatomegaly is the most common physical sign, occurring in 50–90% of the patients. Abdominal bruits are noted in 6–25%, and ascites occurs in 30–60% of patients. Ascites should be examined by cytology. Splenomegaly is mainly due to portal hypertension. Weight loss and muscle wasting are common, particularly with rapidly growing or large tumors. Fever is found in 10–50% of patients, from unclear cause. The signs of chronic liver disease may often be present, including jaundice, dilated abdominal veins, palmar erythema, gynecomastia, testicular atrophy, and peripheral edema. Budd-Chiari syndrome can occur due to HCC invasion of the hepatic veins, with tense ascites and a large tender liver.
Most paraneoplastic syndromes in HCC are biochemical abnormalities without associated clinical consequences. They include hypoglycemia (also caused by end-stage liver failure), erythrocytosis, hypercalcemia, hypercholesterolemia, dysfibrinogenemia, carcinoid syndrome, increased thyroxin-binding globulin, changes in secondary sex characteristics (gynecomastia, testicular atrophy, and precocious puberty), and porphyria cutanea tarda. Mild hypoglycemia occurs in rapidly growing HCC as part of terminal illness, and profound hypoglycemia may occur, although the cause is unclear. Erythrocytosis occurs in 3–12% of patients and hypercholesterolemia in 10–40%. A high percentage of patients have thrombocytopenia associated with their fibrosis or leukopenia, resulting from portal hypertension, and not from cancer infiltration of bone marrow, as in other tumor types. Furthermore, large HCCs have normal or high platelet levels (thrombocytosis), as in ovarian and other gastrointestinal cancers, probably related to elevated interleukin 6 (IL-6) levels.
Multiple clinical staging systems for HCC have been described. A widely used one has been the American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) classification. However, the Cancer of the Liver Italian Program (CLIP) system is now popular because it takes cirrhosis into account, based on the original Okuda system (Table 41-4). Patients with Okuda stage III disease have a dire prognosis because they usually cannot be curatively resected, and the condition of their liver typically precludes chemotherapy. Other staging systems have been proposed, and a consensus is needed. They are all based on combining the prognostic features of liver damage with those of tumor aggressiveness and include the Barcelona Clinic Liver Cancer (BCLC) system from Spain (Fig. 41-1), which is externally validated and incorporates baseline survival estimates; the Chinese University Prognostic Index (CUPI); the important and simple Japan Integrated Staging Score (JIS); and SLiDe, which stands for s tage, li ver damage, and de s-γ-carboxy prothrombin. CLIP and BCLC appear most popular in the West, whereas JIS is favored in Japan. Each system has its champions. The best prognosis is for stage I, solitary tumors less than 2 cm in diameter without vascular invasion. Adverse prognostic features include ascites, jaundice, vascular invasion, and elevated α fetoprotein (AFP). Vascular invasion in particular has profound effects on prognosis and may be microscopic or macroscopic (visible on computed tomography [CT] scans). Most large tumors have microscopic vascular invasion, so full staging can usually be made only after surgical resection. Stage III disease contains a mixture of lymph node–positive and–negative tumors. Stage III patients with positive lymph node disease have a poor prognosis, and few patients survive 1 year. The prognosis of stage IV is poor after either resection or transplantation, and 1-year survival is rare.
Barcelona Clinic Liver Cancer (BCLC) staging classification and treatment schedule. Patients with very early hepatocellular carcinoma (HCC) (stage 0) are optimal candidates for resection. Patients with early HCC (stage A) are candidates for radical therapy (resection, liver transplantation [LT], or local ablation via percutaneous ethanol injection [PEI] or radiofrequency [RF] ablation). Patients with intermediate HCC (stage B) benefit from transcatheter arterial chemoembolization (TACE). Patients with advanced HCC, defined as presence of macroscopic vascular invasion, extrahepatic spread, or cancer-related symptoms (Eastern Cooperative Oncology Group performance status 1 or 2) (stage C), benefit from sorafenib. Patients with end-stage disease (stage D) will receive symptomatic treatment. Treatment strategy will transition from one stage to another on treatment failure or contraindications for the procedures. CLT, cadaveric liver transplantation; LDLT, living donor liver transplantation; PST, Performance Status Test. (Modified from JM Llovet et al: JNCI 100:698, 2008.)
TABLE 41-4Clip and Okuda Staging Systems for Hepatocellular Carcinoma ||Download (.pdf) TABLE 41-4 Clip and Okuda Staging Systems for Hepatocellular Carcinoma
|CLIP Classification |
|Variables ||Points |
|0 ||1 ||2 |
|i. Tumor number ||Single ||Multiple ||– |
| Hepatic replacement by tumor (%) ||<50 ||<50 ||>50 |
|ii. Child-Pugh score ||A ||B ||C |
|iii. α Fetoprotein level (ng/mL) ||<400 ||≥400 ||– |
|iv. Portal vein thrombosis (CT) ||No ||Yes ||– |
|CLIP stages (score = sum of points): CLIP 0, 0 points; CLIP 1, 1 point; CLIP 2, 2 points; CLIP 3, 3 points. |
|Okuda Classification |
|Tumor Extenta ||Ascites ||Albumin (g/L) ||Bilirubin (mg/dL) |
|≥50% ||<50 ||+ ||− ||≤3 ||>3 ||≥ 3 ||<3 |
|(+) ||(−) ||(+) ||(−) ||(+) ||(−) ||(+) ||(−) |
|Okuda stages: stage 1, all (−); stage 2, 1 or 2 (+); stage 3, 3 or 4 (+). |
Consensus is needed on staging. These systems will soon be refined or upended by proteomics.
APPROACH TO THE PATIENT: Hepatocellular Carcinoma HISTORY AND PHYSICAL
The history is important in evaluating putative predisposing factors, including a history of hepatitis or jaundice, blood transfusion, or use of intravenous drugs. A family history of HCC or hepatitis should be sought and a detailed social history taken to include job descriptions for industrial exposure to possible carcinogenic drugs as well as contraceptive hormones. Physical examination should include assessing stigmata of underlying liver disease such as jaundice, ascites, peripheral edema, spider nevi, palmar erythema, and weight loss. Evaluation of the abdomen for hepatic size, masses or ascites, hepatic nodularity and tenderness, and splenomegaly is needed, as is assessment of overall performance status and psychosocial evaluation. SEROLOGIC ASSAYS
AFP is a serum tumor marker for HCC; however, it is only increased in approximately one-half of U.S. patients. The lens culinaris agglutinin-reactive fraction of AFP (AFP-L3) assay is thought to be more specific. The other widely used assay is that for des-γ-carboxy prothrombin (DCP), a protein induced by vitamin K absence (PIVKA-2). This protein is increased in as many as 80% of HCC patients but may also be elevated in patients with vitamin K deficiency; it is always elevated after warfarin use. It may also predict for portal vein invasion. Both AFP-L3 and DCP are U.S. Food and Drug Administration (FDA) approved. Many other assays have been developed, such as glypican-3, but none have greater aggregate sensitivity and specificity. In a patient presenting with either a new hepatic mass or other indications of recent hepatic decompensation, carcinoembryonic antigen (CEA), vitamin B12, AFP, ferritin, PIVKA-2, and antimitochondrial antibody should be measured, and standard liver function tests should be performed, including prothrombin time (PT), partial thromboplastin time (PTT), albumin, transaminases, γ-glutamyl transpeptidase, and alkaline phosphatase. γ-Glutamyl transpeptidase and alkaline phosphatase may be particularly important in the 50% of HCC patients who have low AFP levels. Decreases in platelet count and white blood cell count may reflect portal hypertension and associated hypersplenism. Hepatitis A, B, and C serology should be measured. If HBV or HCV serology is positive, quantitative measurements of HBV DNA or HCV RNA are needed. New Directions
Newer biomarkers are being evaluated, especially tissue- and serum-based genomics profiling. Newer plasma biomarkers include glypican-3, osteopontin, insulin-like growth factor I, and vascular endothelial growth factor. However, they are still in process of validation. Furthermore, the commercial availability of kits for isolating circulating tumor cells is permitting the molecular profiling of HCCs without the need for further tissue biopsy. RADIOLOGY
An ultrasound examination of the liver is an excellent screening tool. The two characteristic vascular abnormalities are hypervascularity of the tumor mass (neovascularization or abnormal tumor-feeding arterial vessels) and thrombosis by tumor invasion of otherwise normal portal veins. To determine tumor size and extent and the presence of portal vein invasion accurately, a helical/triphasic CT scan of the abdomen and pelvis, with fast-contrast bolus technique, should be performed to detect the vascular lesions typical of HCC. Portal vein invasion is normally detected as an obstruction and expansion of the vessel. A chest CT is used to exclude metastases. Magnetic resonance imaging (MRI) can also provide detailed information, especially with the newer contrast agents. Ethiodol (Lipiodol) is an ethiodized oil emulsion retained by liver tumors that can be delivered by hepatic artery injection (5–15 mL) for CT imaging 1 week later. For small tumors, Ethiodol injection is very helpful before biopsy because the histologic presence of the dye constitutes proof that the needle biopsied the mass under suspicion. A prospective comparison of triphasic CT, gadolinium-enhanced MRI, ultrasound, and fluorodeoxyglucose positron emission tomography (FDG-PET) showed similar results for CT, MRI, and ultrasound; PET imaging appears to be positive in only a subset of HCC patients. Abdominal CT versus MRI/CT uses a faster single breath-hold, is less complex, and is less dependent on patient cooperation. MRI requires a longer examination, and ascites can cause artifacts, but MRI is better able to distinguish dysplastic or regenerative nodules from HCC. Imaging criteria have been developed for HCC that do not require biopsy proof, as they have >90% specificity. The criteria include nodules >1 cm with arterial enhancement and portal venous washout and, for small tumors, specified growth rates on two scans performed less than 6 months apart (Organ Procurement and Transplant Network). Nevertheless, explant pathology after liver transplant for HCC has shown that ~20% of patients diagnosed without biopsy did not actually have a tumor. New Directions
The altered tumor vascularity that is a consequence of molecularly targeted therapies is the basis for newer imaging techniques including contrast-enhanced ultrasound (CEUS) and dynamic MRI. PATHOLOGIC DIAGNOSIS
Histologic proof of the presence of HCC is obtained through a core liver biopsy of the liver mass under ultrasound guidance, as well as random biopsy of the underlying liver. Bleeding risk is increased compared to other cancers because (1) the tumors are hypervascular and (2) patients often have thrombocytopenia and decreased liver-dependent clotting factors. Bleeding risk is further increased in the presence of ascites. Tracking of tumor has an uncommon problem. Fine-needle aspirates can provide sufficient material for diagnosis of cancer, but core biopsies are preferred. Tissue architecture allows the distinction between HCC and adenocarcinoma. Laparoscopic approaches can also be used. For patients suspected of having portal vein involvement, a core biopsy of the portal vein may be performed safely. If positive, this is regarded as an exclusion criterion for transplantation for HCC. New Directions
Immunohistochemistry has become mainstream. Prognostic subgroupings are being defined based on growth signaling pathway proteins and genotyping strategies, including a prognostically significant five-gene profile score. Furthermore, molecular profiling of the underlying liver has provided evidence for a “field-effect” of cirrhosis in generating recurrent or new HCCs after primary resection. In addition, characteristics of HCC stem cells have been identified and include EpCAM, CD44, and CD90 expression, which may form the basis of stem cell therapeutic targeting strategies.
SCREENING HIGH-RISK POPULATIONS
There are two goals of screening, both in patients at increased risk for developing HCC, such as those with cirrhosis. The first goal is to detect smaller tumors that are potentially curable by ablation. The second goal is to enhance survival, compared with patients who were not diagnosed by surveillance. Evidence from Taiwan has shown a survival advantage to population screening in HBV-positive patients, and other evidence has shown its efficacy in diagnosis for HCV. Prospective studies in high-risk populations showed that ultrasound was more sensitive than AFP elevations alone, although most practitioners request both tests at 6-month intervals for HBV and HCV carriers, especially in the presence of cirrhosis or worsening of liver function tests. However, an Italian study in patients with cirrhosis identified a yearly HCC incidence of 3% but showed no increase in the rate of detection of potentially curable tumors with aggressive screening. Prevention strategies including universal vaccination against hepatitis are more likely to be effective than screening efforts. Despite absence of formal guidelines, most practitioners obtain 6-month AFP and ultrasound (cheap and ubiquitous, even in poor countries) or CT (more sensitive, especially in overweight patients, but more costly) studies when following high-risk patients (HBV carriers, HCV cirrhosis, family history of HCC).
Cost-benefit analysis is not yet convincing, even though screening is intuitively sound. However, studies from areas with high HBV carrier rates have shown a survival benefit for screening as a result of earlier stage at diagnosis. A definitive clinical trial on screening is unlikely, due to difficulties in obtaining informed consent for patients who are not to be screened. γ-Glutamyl transpeptidase appears useful for detecting small tumors.
Prevention strategies can only be planned when the causes of a cancer are known or strongly suspected. This is true of few human cancers, with significant exceptions being smoking and lung cancer, papilloma virus and cancer of the cervix uteri, and cirrhosis of any cause or dietary contamination by aflatoxin B1 for HCC. Aflatoxin B1 is one of the most potent known chemical carcinogens and is a product of the Aspergillus mold that grows on peanuts and rice when stored in hot and humid climates. The obvious strategy is to refrigerate these foodstuffs when stored and to conduct surveillance programs for elevated aflatoxin B1 levels, as happens in the United States, but not usually in Asia. HBV is commonly transmitted from mother to fetus in Asia (except Japan), and neonatal HBV vaccination programs have resulted in a big decrease in adolescent HBV and, thus, in predicted HCC rates. There are millions of HBV and HCV carriers (4 million with HCV in the United States) who are already infected. Nucleoside analogue–based chemoprevention (entecavir) of HBV-mediated HCC in Japan resulted in a fivefold decrease in HCC incidence over 5 years in cirrhotic but not in noncirrhotic HBV patients. More powerful and effective HCV therapies promise the possibility of prevention of HCV-based HCC in the future.
TREATMENT Hepatocellular Carcinoma
Most HCC patients have two liver diseases, cirrhosis and HCC, each of which is an independent cause of death. The presence of cirrhosis usually places constraints on resection surgery, ablative therapies, and chemotherapy. Thus patient assessment and treatment planning have to take the severity of the nonmalignant liver disease into account. The clinical management choices for HCC can be complex (Fig. 41-2, Tables 41-5 and 41-6). The natural history of HCC is highly variable. Patients presenting with advanced tumors (vascular invasion, symptoms, extrahepatic spread) have a median survival of ~4 months, with or without treatment. Treatment results from the literature are difficult to interpret. Survival is not always a measure of the efficacy of therapy because of the adverse effects on survival of the underlying liver disease. A multidisciplinary team, including a hepatologist, interventional radiologist, surgical oncologist, resection surgeon, transplant surgeon, and medical oncologist, is important for the comprehensive management of HCC patients. TNM STAGES I AND II HCC
Early-stage tumors are successfully treated using various techniques, including surgical resection, local ablation (thermal, radiofrequency [RFA], or microwave ablation (MWA]), and local injection therapies (Table 41-6). Because the majority of patients with HCC suffer from a field defect in the cirrhotic liver, they are at risk for subsequent multiple primary liver tumors. Many will also have significant underlying liver disease and may not tolerate major surgical loss of hepatic parenchyma, and they may be eligible for orthotopic liver transplant (OLTX). Living related donor transplants have increased in popularity, resulting in absence of waiting for a transplant. An important principle in treating early-stage HCC in the nontransplant setting is to use liver-sparing treatments and to focus on treatment of both the tumor and the cirrhosis. Surgical Excision
The risk of major hepatectomy is high (5–10% mortality rate) due to the underlying liver disease and the potential for liver failure, but acceptable in selected cases and highly dependent on surgical experience. The risk is lower in high-volume centers. Preoperative portal vein occlusion can sometimes be performed to cause atrophy of the HCC-involved lobe and compensatory hypertrophy of the noninvolved liver, permitting safer resection. Intraoperative ultrasound is useful for planning the surgical approach. The ultrasound can image the proximity of major vascular structures that may be encountered during the dissection. In cirrhotic patients, any major liver surgery can result in liver failure. The Child-Pugh classification of liver failure is still a reliable prognosticator for tolerance of hepatic surgery, and only Child A patients should be considered for surgical resection. Child B and C patients with stages I and II HCC should be referred for OLTX if appropriate, as well as patients with ascites or a recent history of variceal bleeding. Although open surgical excision is the most reliable, the patient may be better served with a laparoscopic approach to resection, using RFA, MWA, or percutaneous ethanol injection (PEI). No adequate comparisons of these different techniques have been undertaken, and the choice of treatment is usually based on physician skill. However, RFA has been shown to be superior to PEI in necrosis induction for tumors <3 cm in diameter and is thought to be equivalent to open resection and, thus, is the treatment of first choice for these small tumors. As tumors get larger than 3 cm, especially ≥5 cm, the effectiveness of RFA-induced necrosis diminishes. The combination of transcatheter arterial chemoembolization (TACE) with RFA has shown superior results to TACE alone in a prospective, randomized trial. Although vascular invasion is a preeminent negative prognostic factor, microvascular invasion in small tumors appears not to be a negative factor. Local Ablation Strategies
RFA uses heat to ablate tumors. The maximum size of the probe arrays allows for a 7-cm zone of necrosis, which would be adequate for a 3- to 4-cm tumor. The heat reliably kills cells within the zone of necrosis. Treatment of tumors close to the main portal pedicles can lead to bile duct injury and obstruction. This limits the location of tumors that are anatomically suited for this technique. RFA can be performed percutaneously with CT or ultrasound guidance, or at the time of laparoscopy with ultrasound guidance. Local Injection Therapy
Numerous agents have been used for local injection into tumors, most commonly ethanol (PEI). The relatively soft HCC within the hard background cirrhotic liver allows for injection of large volumes of ethanol into the tumor without diffusion into the hepatic parenchyma or leakage out of the liver. PEI causes direct destruction of cancer cells, but it is not selective for cancer and will destroy normal cells in the vicinity. However, it usually requires multiple injections (average three), in contrast to one for RFA. The maximum size of tumor reliably treated is 3 cm, even with multiple injections. Current Directions
Resection and RFA each obtain similar results. However, a distinction has been made between the causes and prevention strategies needed to prevent early versus late tumor recurrences after resection. Early recurrence has been linked to tumor invasion factors, especially microvascular tumor invasion with elevated transaminases, whereas late recurrence has been associated with cirrhosis and virus hepatitis factors and, thus, the development of new tumors. See the section on virus-directed adjuvant therapy below. Liver Transplantation (OLTX)
A viable option for stages I and II tumors in the setting of cirrhosis is OLTX, with survival approaching that for noncancer cases. OLTX for patients with a single lesion ≤5 cm or three or fewer nodules, each ≤3 cm (Milan criteria), resulted in excellent tumor-free survival (≥70% at 5 years). For advanced HCC, OLTX has been abandoned due to high tumor recurrence rates. Priority scoring for OLTX previously led to HCC patients waiting too long for their OLTX, resulting in some tumors becoming too advanced during the patient’s wait for a donated liver. A variety of therapies were used as a “bridge” to OLTX, including RFA, TACE, and hepatic arterial 90Y-radioembolization. These pretransplant treatments allow patients to remain on the waiting list longer, giving them greater opportunities to be transplanted, because they can stabilize the tumor and prevent it from growing in the months until a donor liver becomes available. What remains unclear, however, is whether this translates into prolonged survival after transplant. Further, it is not known whether patients who have had their tumor(s) treated preoperatively follow the recurrence pattern predicted by their tumor status at the time of transplant (i.e., post–local ablative therapy), or if they follow the course set by their tumor parameters present before such treatment. The United Network for Organ Sharing (UNOS) point system for priority scoring of OLTX recipients now includes additional points for patients with HCC. The success of living related donor liver transplantation programs has also led to patients receiving transplantation earlier for HCC and often with greater than minimal tumors. Current Directions
Expanded criteria for larger HCCs beyond the Milan criteria (one lesion <5 cm or three lesions, each <3 cm), such as the University of California, San Francisco (UCSF) criteria (single lesion ≤6.5 cm or two lesions ≤4.5 cm with a total diameter ≤8 cm; 1- and 5-year survival rates of 90 and 75%, respectively), are being increasingly accepted by various UNOS areas for OLTX with satisfactory longer-term survival comparable to Milan criteria results. Furthermore, downstaging of HCCs that are too large for the Milan criteria by medical therapy (TACE) is increasingly recognized as acceptable treatment before OLTX with equivalent outcomes to patients who originally were within Milan criteria. Within-criteria patients with AFP levels >1000 ng/mL have exceptionally high post-OLTX recurrence rates. Also, the use of “salvage” OLTX after recurrent HCC after resection has produced conflicting outcomes. Shortages of organs combined with advances in resection safety have led to increasing use of resection for patients with good liver function. Adjuvant Therapy
The role of adjuvant chemotherapy for patients after resection or OLTX remains unclear. Both adjuvant and neoadjuvant approaches have been studied, but no clear advantage in disease-free or overall survival has been found. However, a meta-analysis of several trials revealed a significant improvement in disease-free and overall survival. Although analysis of postoperative adjuvant systemic chemotherapy trials demonstrated no disease-free or overall survival advantage, single studies of TACE and neoadjuvant 131I-Ethiodol showed enhanced survival after resection.
Antiviral therapy, instead of anticancer therapy, has been successful in decreasing postresection tumor recurrences in the postresection adjuvant setting. Nucleoside analogues in HBV-based HCC and peg-interferon plus ribavirin for HCV-based HCC have both been effective in reducing recurrence rates. Current Directions
A large adjuvant trial examining resection and transplantation, with or without sorafenib (see below) is in progress. The success of viral therapies in decreasing HCC recurrence after resection is part of a broader focus on the tumor microenvironment (stroma, blood vessels, inflammatory cells, and cytokines) as mediators of HCC progression and as targets for new therapies. TNM STAGES III AND IV HCC
Fewer surgical options exist for stage III tumors involving major vascular structures. In patients without cirrhosis, a major hepatectomy is feasible, although prognosis is poor. Patients with Child A cirrhosis may be resected, but a lobectomy is associated with significant morbidity and mortality rates, and long-term prognosis is poor. Nevertheless, a small percentage of patients will achieve long-term survival, justifying an attempt at resection when feasible. Because of the advanced nature of these tumors, even successful resection can be followed by rapid recurrence. These patients are not considered candidates for transplantation because of the high tumor recurrence rates, unless their tumors can first be downstaged with neoadjuvant therapy. Decreasing the size of the primary tumor allows for less surgery, and the delay in surgery allows for extrahepatic disease to manifest on imaging studies and avoid unhelpful OLTX. The prognosis is poor for stage IV tumors, and no surgical treatment is recommended. Systemic Chemotherapy
A large number of controlled and uncontrolled clinical studies have been performed with most of the major classes of cancer chemotherapy. No single agent or combination of agents given systemically reproducibly leads to even a 25% response rate or has any effect on survival. Regional Chemotherapy
In contrast to the dismal results of systemic chemotherapy, a variety of agents given via the hepatic artery have activity for HCC confined to the liver (Table 41-6). Two randomized controlled trials have shown a survival advantage for TACE in a selected subset of patients. One used doxorubicin, and the other used cisplatin. Despite the fact that increased hepatic extraction of chemotherapy has been shown for very few drugs, some drugs such as cisplatin, doxorubicin, mitomycin C, and possibly neocarzinostatin, produce substantial objective responses when administered regionally. Few data are available on continuous hepatic arterial infusion for HCC, although pilot studies with cisplatin have shown encouraging responses. Because the reports have not usually stratified responses or survival based on TNM staging, it is difficult to know long-term prognosis in relation to tumor extent. Most of the studies on regional hepatic arterial chemotherapy also use an embolizing agent such as Ethiodol, gelatin sponge particles (Gelfoam), starch (Spherex), or microspheres. Two products are composed of microspheres of defined size ranges—Embospheres (Biospheres) and Contour SE—using particles of 40–120, 100–300, 300–500, and 500–1000 μm in size. The optimal diameter of the particles for TACE has yet to be defined. Consistently higher objective response rates are reported for arterial administration of drugs together with some form of hepatic artery occlusion compared with any form of systemic chemotherapy to date. The widespread use of some form of embolization in addition to chemotherapy has added to its toxicities. These include a frequent but transient fever, abdominal pain, and anorexia (all in >60% of patients). In addition, >20% of patients have increased ascites or transient elevation of transaminases. Cystic artery spasm and cholecystitis are also not uncommon. However, higher responses have also been obtained. The hepatic toxicities associated with embolization may be ameliorated by the use of degradable starch microspheres, with 50–60% response rates. Two randomized studies of TACE versus placebo showed a survival advantage for treatment (Table 41-6). In addition, it is not clear that formal oncologic CT response criteria are adequate for HCC. A loss of vascularity on CT without size change may be an index of loss of viability and thus of response to TACE. A major problem that TACE trials have had in showing a survival advantage is that many HCC patients die of their underlying cirrhosis, not the tumor. Nevertheless, two randomized controlled trials, one using doxorubicin and the other using cisplatin, showed a survival advantage for TACE versus placebo (Table 41-6). However, improving quality of life is a legitimate goal of regional therapy. Drug-eluting beads using doxorubicin (DEB-TACE) have been claimed to produce equivalent survival with less toxicity, but this strategy has not been tested in a randomized trial. Kinase Inhibitors
A survival advantage has been observed for the oral multikinase inhibitor, sorafenib (Nexavar), versus placebo in two randomized trials. It targets both the Raf mitogenic pathway and the vascular endothelial growth factor receptor (VEGFR) endothelial vasculogenesis pathway. However, tumor responses were negligible, and the survival in the treatment arm in Asians was less than the placebo arm in the Western trial (Table 41-7). Sorafenib has considerable toxicity, with 30–40% of patients requiring “drug holidays,” dose reductions, or cessation of therapy. The most common toxicities include fatigue, hypertension, diarrhea, mucositis, and skin changes, such as the painful hand-foot syndrome, hair loss, and itching, each in 20–40% of patients. Several “look-alike” new agents that also target angiogenesis have either proved to be inferior or more toxic. These include sunitinib, brivanib, linifanib, everolimus, and bevacizumab (Table 41-8). The idea of angiogenesis alone as a major HCC therapeutic target may need revision. New Therapies
Although prolonged survival has been reported in phase II trials using newer agents, such as bevacizumab plus erlotinib, the data from a phase III trial were disappointing. Several forms of radiation therapy have been used in the treatment of HCC, including external-beam radiation and conformal radiation therapy. Radiation hepatitis remains a dose-limiting problem. The pure beta emitter 90Yttrium attached to either glass (TheraSphere) or resin (SIR-Spheres) microspheres injected into a major branch hepatic artery has been assessed in phase II trials of HCC and has encouraging tumor control and survival effects with minimal toxicities. Randomized phase III trials comparing it to TACE have yet to be completed. The main attractiveness of 90Yttrium therapy is its safety in the presence of major branch portal vein thrombosis, where TACE is dangerous or contraindicated. Furthermore, external-beam radiation has been reported to be safe and useful in the control of major branch portal or hepatic vein invasion (thrombosis) by tumors. The studies have all been small. Vitamin K has been assessed in clinical trials at high dosage for its HCC-inhibitory actions. This idea is based on the characteristic biochemical defect in HCC of elevated plasma levels of immature prothrombin (DCP or PIVKA-2), due to a defect in the activity of prothrombin carboxylase, a vitamin K–dependent enzyme. Two vitamin K randomized controlled trials from Japan show decreased tumor occurrence, but a major phase III trial aimed at limiting postresection recurrence was not successful. Current Directions
A number of new kinase inhibitors are being evaluated for HCC (Tables 41-9 and 41-10). These include the biologicals, such as Raf kinase and vascular endothelial growth factor (VEGF) inhibitors, and agents that target various steps of the cell growth pathway. Current hopes focus particularly on the Met pathway inhibitors such as tivantinib and several IGF receptor antagonists. 90Yttrium looks promising and without chemotherapy toxicities. It is particularly attractive because, unlike TACE, it seems safe in the presence of portal vein thrombosis, a pathognomonic feature of HCC aggressiveness. The bottleneck of liver donors for OLTX is at last widening with increasing use of living donors, and criteria for OLTX for larger HCCs are slowly expanding. Patient participation in clinical trials assessing new therapies is encouraged (www.clinicaltrials.gov).
The main effort now is the evaluation of combinations of the compounds listed in Tables 41-7,41-8,41-9 that target different pathways, as well as the combination of any of these targeted therapies, but especially sorafenib, with TACE or 90Yttrium radioembolization. Combining TACE with sorafenib appears to be safe in phase II studies with promising survival data, but randomized studies are still in progress. The same is true for intra-arterial 90Yttrium plus sorafenib as therapy for HCC and as bridge to transplant therapy.
Hepatocellular carcinoma (HCC) treatment algorithm. The initial clinical evaluation is aimed at assessing the extent of the tumor and the underlying functional compromise of the liver by cirrhosis. Patients are classified as having resectable disease or unresectable disease or as being candidates for transplantation. AFP, α fetoprotein; LN, lymph node; MWA, microwave ablation; OLTX, orthotopic liver transplantation; PEI, percutaneous ethanol injection; RFA, radiofrequency ablation; TACE, transcatheter arterial chemoembolization; UNOS, United Network for Organ Sharing. Child’s A/B/C refers to the Child-Pugh classification of liver failure.
TABLE 41-5Treatment Options for Hepatocellular Carcinoma ||Download (.pdf) TABLE 41-5 Treatment Options for Hepatocellular Carcinoma
Local Ablative Therapies
Radiofrequency ablation (RFA)
Microwave ablation (MWA)
Percutaneous ethanol injection (PEI)
Regional Therapies: Hepatic Artery Transcatheter Treatments
Transarterial drug-eluting beads
Proton beam radiation
Conformal External-Beam Radiation and Intensity-Modulated Radiation Therapy
Molecularly targeted therapies (sorafenib, etc.)
Hormonal therapy + growth control
|Supportive Therapies |
TABLE 41-6Some Randomized Clinical Trials Involving Transhepatic Artery Chemoembolization (Tace) for Hepatocellular Carcinoma ||Download (.pdf) TABLE 41-6 Some Randomized Clinical Trials Involving Transhepatic Artery Chemoembolization (Tace) for Hepatocellular Carcinoma
TABLE 41-7Targeted Therapies in Hepatocellular Carcinoma: Trials ||Download (.pdf) TABLE 41-7 Targeted Therapies in Hepatocellular Carcinoma: Trials
|Phase III ||Target ||Survival (mo) |
|Sorafenib vs placebo ||Raf, VEGFR, PDGFR ||10.7 vs 7.9 |
|Sorafenib vs placebo (Asians) ||Raf, VEGFR, PDGFR ||6.5 vs 4.2 |
TABLE 41-8Promising Targeted Therapies that Failed Their Clinical Trial Goals ||Download (.pdf) TABLE 41-8 Promising Targeted Therapies that Failed Their Clinical Trial Goals
TABLE 41-9New Targeted Agents and their Targets in Current Clinical Trials ||Download (.pdf) TABLE 41-9 New Targeted Agents and their Targets in Current Clinical Trials
TABLE 41-10Some Novel Medical Treatments for Hepatocellular Carcinoma ||Download (.pdf) TABLE 41-10 Some Novel Medical Treatments for Hepatocellular Carcinoma
|EGF receptor antagonists: erlotinib, gefitinib, lapatinib, cetuximab, brivanib |
|Multikinase antagonists: sorafenib, sunitinib |
|VEGF antagonist: bevacizumab |
|VEGFR antagonist: ABT-869 (linifanib) |
|mTOR antagonists: sirolimus, temsirolimus, everolimus |
|Proteasome inhibitors: bortezomib |
|Vitamin K |
|131I–Ethiodol (lipiodol) |
|90Yttrium microspheres (TheraSphere, SIR-Spheres) |
|166Holmium, 188Rhenium |
|Three-dimensional conformal radiation |
|Proton beam high-dose radiotherapy |
|Gamma knife, CyberKnife |
|New targets: inhibitors of cyclin dependent kinases (Cdk), TRAIL induction caspases, and stem cells |
SIGNIFICANCE AND EVALUATION OF RESPONSES TO NONSURGICAL THERAPIES
Tumor growth or spread is considered a poor prognostic sign and evidence of treatment failure. By contrast, patients receiving chemotherapy are judged to have a response if there is shrinkage of tumor size. Lack of response/size decrease has been thought of as treatment failure. Three considerations in HCC management have completely changed the views concerning nonshrinkage after therapy. First, the correlation between response to chemotherapy and survival is poor in various tumors; in some tumors, such as ovarian cancer and small-cell lung cancer, substantial tumor shrinkage on chemotherapy is followed by rapid tumor regrowth. Second, the Sorafenib HCC Assessment Randomized Protocol (SHARP) phase III trial of sorafenib versus placebo for unresectable HCC showed that survival could be significantly enhanced in the treatment arm with only 2% of the patients having tumor response but 70% of patients having disease stabilization. This observation has led to a reconsideration of the usefulness of response and the significance of disease stability. Third, HCC is a typically highly vascular tumor, and the vascularity is considered to be a measure of tumor viability. As a result, the Response Evaluation Criteria in Solid Tumors (RECIST) have been modified to mRECIST, which requires measurement of vascular/viable tumor on the CT or MRI scan. A partial response is defined as a 30% decrease in the sum of diameters of viable (arterially enhancing) target tumors. The need for semiquantitation of tumor vascularity on scans has led to the introduction of diffusion-weighted MRI imaging. Tissue-specific imaging agents such as gadoxetic acid (Primovist or Eovist) and the move to functional and genetic imaging mark a shift in approaches. Furthermore, plasma AFP response may be a biologic marker of radiologic response.
Long-term survival is associated with resection or ablation or transplantation, all of which can yield >70% 5-year survival. Liver transplant is the only therapy that can treat the tumor and the underlying liver disease simultaneously and may be the most important advance in HCC therapy in 50 years. Unfortunately, it benefits only patients with limited size tumors without macrovascular portal vein invasion. Untreated patients with multinodular asymptomatic tumors without vascular invasion or extrahepatic spread have a median survival of approximately 16 months. Chemoembolization (TACE) improves their median survival to 19–20 months and is considered standard therapy for these patients, who represent the majority of HCC patients, although 90Yttrium therapy may provide similar results with less toxicity. Patients with advanced-stage disease, vascular invasion, or metastases have a median survival of around 6 months. Among this group, outcomes may vary according to their underlying liver disease. It is this group at which kinase inhibitors are directed.
The most common modes of patient presentation
A patient with known history of hepatitis, jaundice, or cirrhosis, with an abnormality on ultrasound or CT scan, or rising AFP or DCP (PIVKA-2) (Table 41-5)
A patient with an abnormal liver function test as part of a routine examination
Radiologic workup for liver transplant for cirrhosis
Symptoms of HCC including cachexia, abdominal pain, or fever
History and physical examination
Clinical jaundice, asthenia, itching (scratches), tremors, or disorientation
Hepatomegaly, splenomegaly, ascites, peripheral edema, skin signs of liver failure
Blood tests: full blood count (splenomegaly), liver function tests, ammonia levels, electrolytes, AFP and DCP (PIVKA-2), Ca2+ and Mg2+; hepatitis B, C, and D serology (and quantitative HBV DNA or HCV RNA, if either is positive); neurotensin (specific for fibrolamellar HCC)
Triphasic dynamic helical (spiral) CT scan of liver (if inadequate, then follow with an MRI); chest CT scan; upper and lower gastrointestinal endoscopy (for varices, bleeding, ulcers); and brain scan (only if symptoms suggest)
Core biopsy: of the tumor and separate biopsy of the underlying liver
HCC <2 cm: RFA, PEI, or resection (Tables 41-5 and 41-6)
HCC >2 cm, no vascular invasion: liver resection, RFA, or OLTX
Multiple unilobar tumors or tumor with vascular invasion: TACE or sorafenib
Bilobar tumors, no vascular invasion: TACE with OLTX for patients with tumor response
Extrahepatic HCC or elevated bilirubin: sorafenib or bevacizumab plus erlotinib (combination agent trials are in progress)