Approximately one million new cases of hepatocellular carcinoma are diagnosed per year world-wide. This disease continues to be one of the most lethal human malignancies with a mortality index of 0.94. Hepatocellular carcinoma accounts for more than half of all malignancies in some countries and is the leading cause of death in many populations.1 This review will look at the etiology and advances in treatment for hepatocellular carcinoma.
Several risk factors have been associated with hepatocellular carcinoma. The biggest is the increased incidence of viral hepatitis C (HCV) infections, as well as viral hepatitis B (HBV) infections. Essentially any disease process which causes cirrhosis of the liver will predispose a person to hepatocellular carcinoma.2 Etiologic factors for cirrhosis include viral hepatitis infections, ethanol ingestion, primary biliary cirrhosis, primary sclerosing cholangitis, hemochromatosis, alpha 1 antitrypsinase deficiency, glycogen storage disease, and Wilson's disease. Also, various chemical exposures, which are hepatotoxic, include thorotrast, polyvinyl chloride, and tetrachloride.3
Viral hepatitis B is endemic in southern Africa and Southeast Asia, affecting approximately 6-10% of the population. Central and South America as well as northern Africa, eastern Europe and Asia have incidences of approximately 2-5%, while the incidence is less than 0.5% in North America. Viral hepatitis B carriers have a 5% increased risk of developing hepatocellular carcinoma.4 In Southeast Asia nearly 100% of adults have serologic evidence of viral hepatitis B infections; vertical transmission accounts for greater than 60% of all new viral hepatitis B infections.5 The latency period for development of hepatocellular carcinoma and viral hepatitis B is estimated at 10-20 years. The viral DNA inserts into the host DNA at multiple sites inducing alterations in genus control and cell growth. This causes nonspecific cytotoxic effects, persistent hepatocyte damage and hepatocyte regeneration. Also, there is inappropriate activation of oncogenes, including HBV-X (HBX) activating gene as a possible cause for increased viral transmission. HBX can complex with the C-terminus of the P-53 gene causing functional mutation.6
The incidence of viral hepatitis C is rapidly increasing throughout the world as well as the United States.5 Hepatitis C is a risk factor for hepatocellular carcinoma with a latency period of 15-25 years. The hepatitis C virus is a blood-born virus that was found in 7-10% of all patients who received transfusions as late as the 1980s.7 Hepatocellular carcinoma has increased seventeen fold in HBV and HCV-infected patients.8 Eight-five percent of patients with HCV will develop a chronic infection and carrier state. Twenty to thirty percent will develop cirrhosis. Again, there are no specific mechanisms related to chronic hepatocellular damage and regeneration. However, it is thought that the hepatitis C virus may have an encoded oncogene within its genome
Hepatotoxic agents have long been known to be a cause of hepatocellular carcinoma. Aflatoxin is produced by molds and combines with nuclear DNA. In areas of Africa and Asia up to 60% of food is contaminated by aflatoxin.
Sixty to ninety percent of patients with hepatocellular carcinoma have underlying cirrhosis. At autopsy, 20 to 40% of cirrhotics are found to have previously undiagnosed hepatocellular carcinoma. In France 92% of hepatocellular carcinoma is related to alcoholic cirrhosis. The overall incidence of hepatocellular carcinoma worldwide ranges based on the incidence of viral hepatitis infections. In the United States with a relatively low prevalence of viral hepatitis, the incidence of hepatocellular is approximately 3 per 100,000.9 In parts of Asia and Africa where viral hepatitis is endemic, the incidence of hepatocellular carcinoma is 30 per 100,000. The incidence of hepatocellular carcinoma in the United States has increased 71% since 1980 and the mortality rate has increased 35%.10 There has been an overall increase of 48% from 15,000 patients in 1993 to 20,200 diagnosed with hepatocellular carcinoma in 2000. This is most likely related to an increased survival of patients with cirrhosis, the increased incidences of viral hepatitis infections, and the immigration from countries with high viral hepatitis prevalence. Currently 4 million Americans are infected with viral hepatitis C; and in this population there has been a three-fold increase of the incidence of hepatocellular carcinoma, from 2.3 per 100,000 from 1993 to 1995 to 7 per 100,000 from 1996-1998.11
Unfortunately there can be minimal signs or symptoms associated with the development of hepatocellular carcinoma. Fifty percent of patients may experience non-specific dull upper abdominal pain. Also, abdominal mass, anorexia, weight loss and ascites may develop with an advanced malignancy. Hepatomegaly is present at the time of diagnosis in 90% of African and Asian patients with hepatocellular carcinoma. Occasionally this can be associated with abdominal bruit. Anemia, jaundice, or bone pain may develop as the disease advances. One percent of patients present with rupture of hepatocellular carcinoma. In high incidence areas, ruptures are the cause of death in 10% of patients with hepatocellular carcinoma.
Hepatocellular carcinoma continues to be a lethal tumor with untreated median survival of approximately 9 months in North America. Common causes of death of patients with hepatocellular carcinoma include upper GI bleed in 34%, cachexia, tumor rupture and metastatic disease in 32%, and hepatic failure in approximately 25%.12 Metastases are present in 25-50% of patients with hepatocellular carcinoma at the time of death and autopsy. At the time of diagnosis, extrahepatic disease is seen in 10=15% of patients with HCC. At the time of death 6-7% of patients will have metastatic disease of regional lymph nodes, 60% to lungs, 25% to adrenals, 20% to bone, and 10% to peritoneal surfaces.2
Treatment decisions for patients with hepatocellular carcinoma are based on a number of factors such as stage and extent of disease, underlying hepatic function, and overall clinical status of the patient. Work up usually consists of a basic physical examination with determination of ascites and other stigmata of chronic liver disease. Pretreatment laboratory data should include complete blood count, coagulation profile, liver function tests, albumin level, alpha fetoprotein (AFP) and carcinogenic embryonic antigen (CEA) levels. Diagnostic imaging should include a high resolution triple contrast abdominal computed tomography (CT) scan to evaluate the size of the primary liver tumor and to determine the presence of intrahepatic or other metastatic tumor, chest CT scan; head and bone scan should also be considered if the patient is clinically symptomatic.
Screening for hepatocellular carcinoma should be carried out in high-risk patients. AFP levels should be performed every 6 to 12 months for patients with cirrhosis and viral hepatitis B and C.13 Those levels can be elevated with benign regeneration; however, we use a cut off of 300 ng/ ml, which is 50% sensitive and 90% specific for the presence of hepatocellular carcinoma. Small hepatocellular carcinomas along with well-differentiated and other subtypes of hepatocellular carcinomas may not elevate the alpha fetoprotein level. Transcutaneous abdominal ultrasound is sensitive in 80% and specific in 50-70% of patients with hepatocellular carcinomas. This is a reasonable screening tool for patients at high-risk or with elevated AFP levels. Ultrasound is limited in patients with macronodular cirrhosis and for detecting lesions less than 1 cm in size. High resolution CT scanning is a highly accurate means of diagnosing and evaluating hepatocellular carcinoma. Diagnostic CT scans should include a three phase protocol, which includes a non-contrast, arterial phase, as well as a portal venous phase. These studies are 61-96% sensitive with a specificity of 80 to 90%. Although this is an excellent way to evaluate hepatocellular carcinoma it is impractical as a screening tool. Magnetic resonance imaging (MRI), is 40 to 80% sensitive and 80 to 90% specific for hepatocellular carcinoma. MRI can be used to demonstrate vessel invasion as well as metastases and may be more sensitive for smaller lesions, not detected by CT scan. MRI still may be of limited value in patients with macronodular cirrhosis.14 We have evaluated several contrast agents, including gadolidium, iron and manganese-based contrast agents and have not demonstrated an advantage of one over the other.
There are multiple treatments for hepatocellular carcinoma, including hepatic resection, tumor ablation, systemic chemotherapy, regional chemotherapy and combination therapy. Hepatic resection continues to be the standard treatment for hepatocellular carcinoma and is associated with the best chance for long-term survival.15 Patients undergoing hepatic resection should have an objective evaluation of their residual hepatic function. This can be carried out through measurement of hepatic clearance of the indocyanin green or galactose elimination capacity. Residual hepatic volume calculation by diagnostic imaging; however, the most basic and still very reliable method is evaluation of the Child's Pugh score. (Table 1 ) Patients with Child's A cirrhosis could undergo resection of approximately 60 - 80% of the liver; patients with Child's B 30-40% and Child's C less than 10%. In higher incidence regions of the world with hepatocellular carcinoma only 10-15% of patients are candidates for resection of their tumor, whereas in western countries, 15-30% patients present with resectable disease. There have been significant advances in hepatic resection for hepatocellular carcinoma; however, surgical risks continue to be elevated in cirrhotics.16 Key factors for patients undergoing resection for hepatocellular carcinoma include control of blood loss, which can be carried out in a variety of ways. These most commonly include vascular inflow occlusion (Pringle maneuver), total vascular isolation, selective devascularization, as well as regional blood flow occlusion of the liver.'' It is estimated that a normal liver can tolerate warm ischemia up to one hour during hepatic resection, safely. Increased intraoperativc blood loss does increase mortality in cirrhotic patients undergoing hepatic resection and intraoperative transfusion is an independent risk factor for decreasing disease free and overall survival in patients with hepatocellular carcinoma.18 Resections of hepatocellular carcinoma with free surgical margins result in an estimated five-year survival of approximately 31% with a chance of recurrence up to 80%. Despite the survival and high recurrence rates, hepatic resection is the most effect treatment for hepatocellular carcinoma.19 Orthotopic liver transplant for liver cirrhosis in the presence of incidental hepatocellular carcinoma is associated with a five year survival rate of 85%.20 Transplant is indicated for patients with cirrhosis and hepatocellular carcinoma for solitary lesions less than 5 cm in diameter or 3 or fewer lesions each with a diameter of less than 3 cm with no evidence of vascular invasion.21
Ablation of hepatocellular carcinoma has been utilized for the past several decades. There are many modalities for tumor ablation, including alcohol injection (PEI), cryotherapy and, most recently, radiofrequency ablation. Alcohol injections cause cellular dehydration, coagulative necrosis and vascular thrombosis followed by tissue ischemia. Percutaneous alcohol ablation is a useful treatment for hepatocellular carcinoma for small nodular lesions, less than 3 cm in size. Long-term survival rates following percutaneous alcohol injection of tumors within this classification is up to 70%.22,23 Cryosurgical ablation causes tissue death via ice crystal formation in the extracellular space. This causes cell dehydration with membrane and protein denaturation. During the thawing phase, water rushes into the cell and causes cellular disruption. In the fast freeze phase intracellular ice crystal formation leads immediately to cell death. Treatment of hepatocellular carcinoma with cryotherapy results in 2 year survivals of 30-60%, and 5 year survivals up to 30%.24 There appears to be a higher rate of recurrence when tumors are juxtaposed to major vessels.25 Radiofrequency ablation is the fastest growing modality of tumor ablation in the United States and the world. It is carried out either surgically, laparoscopically or percutaneously under real-time image guidance. A radiofrequency probe is inserted into the tumor and waves of 450-500 kHz are emitted at the tip. The current causes local tissue ion vibration and factional heat raises the temperature up to 100°C. Multi-prong probes can cause coagulative necrosis in the areas up to 5 cm in diameter.26 Overlapping areas of coagulative necrosis are used to treat larger tumors27. Radiofrequency ablation was FDA approved in 1997 and most published data demonstrates good short-term resuits; however, recent reports demonstrate long-term results for comparison to other treatment modalities.28 In the largest published series of treatment of hepatocellular carcinoma by radiofrequency ablation, 149 lesions were treated in 110 patients with follow-up in 19 months. 76 patients were treated percutaneous, 31 open and 3 laparoscopically. All surgical ablations were complete. Eight percent of percutaneous ablations were incomplete. Follow-up demonstrated an overall local recurrence rate of 3.6% and distant liver recurrence was identified in 49% of patients. The remaining patients at the time of follow-up had no evidenceof recurrent disease.29 In our experience at Rhode Island Hospital, 55 patients with hepatocellular carcinoma had been treated with hepatic radiofrequency ablation. The overall survival of patients was 80% at one year, 25% at three years and 7% at four years (Table 2) with a median survival of 24 months. Radiofrequency ablation for hepatocellular carcinoma is an excellent choice for patients with lesions less than 5 cm in size and long-term results may rival that of hepatic resection.
Hepatocellular carcinomas continue to be highly chemotherapy resistant tumors. Treatment with 5-fluorourasil (5-FU) has resulted in a response rate of less than 10% with a median survival of 3-5 months. Adriamycin (Doxorubicin) is the traditional agent to systemically treat hepatocellular carcinoma, unfortunately is associated with a less than 20% response rate with median survivals averaging 3-4 months. Adriamycin is a highly toxic chemotherapy agent with particular cardiac toxicity. Combination agents such as Gemcitabine and Cisplatin results in a partial response rates of 25%. More aggressive therapies, including Cisplatin, Interferon, Doxorubicin, and 5-FU have also resulted in partial responses of 26%; however, a few patients have become respectable.30,31
At Brown University, we have explored a number of agents through clinical trials. We have evaluated liposomal doxorubicin (TLC-D99), which was noted to have less toxicity than the standattl adriamycin, but without significant improvement in survival over standard adriamycin therapy. Forty-one percent of hepatocellular carcinomas express somatostatin receptors. Octreotide, which is a somatostatin analog has been noted to have antimitotic activity, however, response rates to octreotide are less than 10%.32,33 Thalidomide is an anti-angiogenic and immuno-modulatory agent that is used for treatment of patients with advanced hepatocellular carcinoma. Response is less than 25%; however, patients who do respond to thalidomide therapy seem to have long-lasting responses to treatment.34
Regional chemotherapy via hepatic artery infusion has had more success than systemic therapy for hepatocellular carcinoma. Initial trials utilizing 5-FU and FUDR have demonstrated response rates up to 50%. [The oncological definition of response rate is >50% reduction of tumor size by diagnostic imaging.] Our current treatment for regional chemotherapy for hepatocellular carcinoma includes hepatic artery infusion of doxorubicin, cisplatin and mitomycin-C. These agents are usually mixed in ethiodized oil (Lipiodol) and have resulted in response rates of tip to 50% patients with two year survival rates of up to 25%. Hepatic artery infusion can also be utilized in hepatic artery regional arterial embolization, which results in a higher tumor response rate to therapy.35 These treatments can be repeated on an every six to eight week basis36. Hepatic artery, chemo-infusion or embolization is useful for patients with larger lesions that are surgically unresectable, involving one region or lobe of the liver.37
Patients with regional disease who arc either considered non-resectable or borderline resectable can be treated with a combination of hepatic artery chemoembolization as well as portal vein embolization. Portal vein embolization is currently a growing technique to further decrease tumor volume while allowing for contralateral hepatic lobe hypertrophy. Portal vein embolization is carried out through a percutaneous approach where the portal venous system is cannulated, then embolized with Gelfoam or alcohol micro-particles. The segmentai portal vein branches to the region of the tumor are selectively embolized. Portal vein embolization can increase the residual volume of the liver by 30-4%.38 It is estimated that in a patient with normal hepatic function the required ratio of residual liver and total body weight is greater than 0.8%. If that percentage can be increased to 1-2%, this will increase the safety and decrease the risk of postoperative hepatic failure in patients subsequently undergoing hepatic resection.39
Throughout the world the incidence of hepatocellular carcinoma continues to rise, along with the incidence of viral hepatitis B ancl d infections. Untreated hepatocellular carcinoma has an average survival of 9 months and treatment is based on the state of disease and functional capacity of the liver. Currently the most active systemic agents for hepatocellular carcinoma are adriamycin and thalidomide. Regional chemotherapy with hepatic artery infusion or embolization with combination chemotherapy appears to be the most effective means of treatment for regional non-metastatic but unresectable disease. The addition of portal vein embolization may increase the resectability for selected patients. Radiofrequency ablation is an increasing treatment modality for localized, less than 5 cm hepatocellular carcinomas, while hepatic resection continues to be the standard treatment for localized disease. We, as well as other institutions, continue to evaluate novel agents for treatment of hepatocellular carcinoma. Agents of interest include vascular endothelial growth factor receptor inhibitors (VEGF inhibitors), antibodies directed at hepatocellular carcinoma cell surface antigens, as well as adenoviruses for gene therapy.40,41 These agents are being evaluated in clinical and preclinical trials at this time.42 Microwave coagulative therapy is also being evaluated as the new modality for ablation of hepatocellular carcinoma.43,44 Continued multidisciplinary approaches for the treatment of hepatocellular carcinoma offer the most promise for patients with this disease.
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DAVID A. IANNITTI, MD, FACS
David A. Iannitti, MD, FACS, is Assistant Professor of Surgery, Brown Medical School.
David A. Iannitti, MD, FACS
University Surgical Associates
2 Dudley St., Suite 470
Providence, RI 02905
Phone: (401) 553-8312
Fax: (401) 868-2306
Copyright Rhode Island Medical Society Feb 2004
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