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Treatment of hepatocellular carcinoma
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2003;1:10 –18
Treatment of Hepatocellular Carcinoma ZIAD HASSOUN and GREGORY J. GORES Division of Gastroenterology and Hepatology, Mayo Medical School, Clinic, and Foundation, Rochester, Minnesota
epatocellular carcinoma (HCC) accounts for approximately 6% of all human cancers. It represents the fifth most common cancer and the third most frequent cause of cancer death worldwide. In the United States, the overall incidence is 2.4 per 100,000 persons per year. The incidence of HCC in the United States has been growing during the past two decades, and the age-specific incidence of this cancer has progressively shifted toward younger people. This is most likely related to the increased prevalence of hepatitis C virus– related cirrhosis. Several risk factors are associated with HCC.1 Hepatitis B virus (HBV) is the most frequent underlying cause worldwide. About 85% of HCC cases occur in eastern and southeastern Asia and sub-Saharan Africa, where chronic HBV infection is endemic, and about 80% of the cases in these locations have been associated with chronic hepatitis B. Between 70% and 90% of HBV-related HCC develop in patients with cirrhosis. There is also a strong causal association between hepatitis C virus (HCV) infection and HCC. Indeed, HCV-related HCC has now become a clinical problem that most gastroenterologists encounter in their practice. Almost all HCVrelated HCCs occur among patients with cirrhosis. Other risk factors for HCC include alcohol abuse, which can act synergistically with HCV to promote liver carcinogenesis; cirrhosis that results from any cause (the magnitude of the HCC risk being greater when it is associated with a viral origin); inherited metabolic disorders such as hemochromatosis, tyrosinemia, and glycogen storage disease; and dietary aflatoxin exposure. In the United States, chronic viral hepatitides account for no more than 30%– 40% of reported cases of HCC. Men are 2 to 4 times more frequently affected by HCC than are women.
H
ated in part by free radical species and inflammatory cytokines, plays a key role in the development of HCC. Multiple mutations of the p53 tumor suppressor gene have been described. These mutations can be early events in neoplastic transformation but can also occur late in this process. One of these mutations has been linked to aflatoxin exposure. Clinical gene therapy trials for HCC using vectors expressing wild-type p53 have been developed, but the results of these phase I trials have not yet been published. Molecular genetic studies have consistently demonstrated that HCCs fall into 2 categories, with either low or high levels of chromosomal changes, probably reflecting differences in genomic instability. The first group tends to have low-grade histology and a better prognosis. In addition to oncogenes, tumor-suppressor genes, and other genetic factors, a number of growth factors involved in cell signaling pathways have also been shown to play a role in hepatocarcinogenesis. Angiogenic stimuli are also required for the continual growth of HCC, which is usually a hypervascular tumor. Angiogenesis inhibitors, in particular, may have a future role in the treatment of HCC. A subset of molecular alterations may preferentially contribute to virus-induced carcinogenesis. Chronic hepatitis B and integration of the HBV genome have been associated with a high rate of genomic instability. In particular, the HBV HBx gene product and other viral proteins have been shown to interfere with several mechanisms of cellular growth control. In patients with chronic HCV infection, the HCV core protein is a potent stimulator of cell proliferation via cell signaling activation; other viral proteins may also have an oncogenic potential. Because HBV integration is likely associated with the development of HCC, antiviral agents will
Pathogenesis Carcinogenesis is a stepwise process involving sequential genetic mutations that lead to oncogene activation or tumor suppressor gene inactivation through a variety of mechanisms. The molecular steps in the development of HCC have not been fully elucidated yet, and no dominant pathways of hepatocellular carcinogenesis have been identified. Persistent liver damage, medi-
Abbreviations used in this paper: CT, computed tomography; EBRT, external beam radiation therapy; HCC, hepatocellular carcinoma; ILC, interstitial laser coagulation; MCT, microwave coagulation therapy; OLT, orthotopic liver transplantation; PEI, percutaneous alcohol injection; RFA, radiofrequency ablation; TACE, transarterial chemoembolization. © 2003 by the American Gastroenterological Association 1542-3565/03/$35.00 doi:10.1053/jcgh.2003.50003
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Figure 1. Actuarial rate of HCC development in 34 dysplastic nodules. (Data from Terasaki et al., Gastroenterology 1998;115:1216 – 1222.)
probably not eliminate the risk for developing HCC in patients with established cirrhosis. In contrast, eradication of HCV with antivirals such as interferon may decrease the risk of HCC. From the histopathologic standpoint, malignant transformation proceeds from adenomatous hyperplasia through dysplasia to early, well-differentiated HCC. The term dysplastic nodule has been coined to describe premalignant lesions. The histopathologic distinction between a dysplastic nodule and early HCC is difficult, and worldwide consensus criteria have not been firmly established. The risk of developing HCC in patients with dysplastic nodules is 14% over 2 years (Figure 1). Thus, such patients should undergo vigilant surveillance with repeated biopsies or perhaps even be treated as if they have cancer.
Natural History, Prognosis, and Staging The natural history2 of HCC depends on the severity of the underlying cirrhosis, tumor characteristics (i.e., size, multicentricity, presence or absence of vascular invasion, pathologic grade, and extrahepatic metastases), performance status of the patient, comorbid conditions, and the efficacy of treatment interventions. Four prognostic classifications have been developed for HCC (Table 1). None of them is perfect. The Okuda classification uses a gross assessment of tumor factors and is not very useful in the clinical evaluation of patients. The Barcelona Clinic Liver Cancer (BCLC), the Cancer of the Liver Italian Program (CLIP), and the Groupe d’Etude et de Traitement du Carcinome Hepatocellulaire (GETCHC) classifications use more refined assessments. These models cannot provide a precise prognosis for individual
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patients but are nevertheless helpful as a guide to the prognosis of groups of patients. For example, according to the BCLC classification, untreated patients with unicentric disease, no symptoms, and no evidence of vascular invasion or extrahepatic spread have a 50% 3-year survival. On the other hand, patients with severe cancerrelated symptoms reflected by a deteriorated performance status and a marked impairment of their liver function have a 50% survival of less than 3 months, no matter what their tumor characteristics are. The information provided by these models needs to be kept in mind when considering treatment options for each patient. The staging evaluation depends in part on the aggressiveness of the treatment considered.2,3 All patients should undergo at least 2 imaging studies to assess intrahepatic disease and to rule out vascular invasion (ultrasonography, contrast computed tomography [CT], or contrast magnetic resonance imaging) (Figure 2). However, current radiographic modalities frequently fail to detect small tumors. A chest x-ray should be performed to look for pulmonary metastases. If liver transplantation is contemplated, many centers will also perform a CT scan of the chest and a bone scan. The presence of abdominal lymphadenopathy is a frequent finding in cirrhosis, especially with hepatitis C. In suspicious cases, endoscopic ultrasonography permits fine-needle aspiration of regional lymph nodes to determine the presence or absence of metastases.
Treatment The staging of the disease and its prognosis will influence the choice of the treatment modality.2–5 In Table 1. Parameters Used in the Prognostic Classifications for HCC Parameters Patient factors Performance status Tumor characteristics Tumor size Vascular invasion Extrahepatic spread AFP Liver function CTP stage Portal hypertension Ascites Bilirubin Albumin ALP
BCLC
CLIP
X X X X
X X X
GETCHC
Okuda
X X X
X
X
X
X
X
X
X X X
X
AFP, alpha-fetoprotein; ALP, alkaline phosphatase; BCLC, Barcelona Clinic Liver Cancer; CLIP, Cancer of the Liver Italian Program; CTP, Child-Turcotte-Pugh; GETCHC, Groupe d’Etude et de Traitement du Carcinome He´patocellulaire.
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Figure 2. CT scan of the liver demonstrating an early HCC. This lesion is hypervascular, thus enhancing after contrast injection and appearing as a hyperdense nodule.
addition to the prognostic models discussed above, poor prognostic factors identified in several studies include a single tumor greater than 5 cm in diameter, the presence of more than 3 lesions, satellite lesions adjacent to the main tumor (which indicate tumor invasion), and vascular invasion. In particular, HCC has a striking tendency to invade portal vein branches, and this represents a contraindication to radical therapies. Patients with very poor prognosis will be treated symptomatically. Those with the best prognostic factors will be considered for surgical resection or liver transplantation (Figures 3 and 4). Others may benefit from local ablative therapies (Figure 4), transarterial chemoembolization, or systemic therapies (Figure 5).
Figure 3. Management algorithm for a solitary HCC nodule. PLT, platelets.
Figure 4. Management algorithm for early HCC. OLT, orthotopic liver transplantation; PEI, percutaneous ethanol injection; RFA, radiofrequency ablation.
Surgical Resection Surgical resection is generally accepted as the mainstay of therapy for localized HCC, despite the absence of randomized controlled trials proving its efficacy.6,7 Often, the tumor size or its multicentricity, the presence of vascular invasion, a limited hepatic functional reserve, or the presence of portal hypertension will preclude this approach. It remains nevertheless the main treatment option in patients without underlying cirrhosis. In such patients, up to 75% of liver tissue can be removed with relatively low morbidity. In the presence
Figure 5. Management algorithm for large solitary or multicentric HCC.
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of cirrhosis, the risk of decompensation or liver failure limits the extent of resection. Partial hepatectomy is associated with relatively good medium-term outcomes in patients with well-preserved liver function (ChildTurcotte-Pugh class A). However, tumor recurrence and progression of liver disease have an adverse effect on long-term survival. Resection is associated with significant morbidity and mortality in patients with Child’s class B and C cirrhosis. The best predictors of survival after surgical resection appear to be the absence of clinically relevant portal hypertension (defined as the presence of varices, splenomegaly with a platelet count ⬍100,000/mm3, or a hepatic vein pressure gradient ⱖ10 mm Hg) and a bilirubin level ⬍1 mg/dL. With careful patient and tumor selection and improvement of the surgical techniques, perioperative mortality rates are currently around 5%–10%, and survival rates are 30%– 50% at 5 years. The risk of intrahepatic tumor recurrence after resection is high (around 50% at 3 years) in patients who undergo an apparently curative hepatectomy. Tumor size is the most important predictor of recurrence. However, many of these recurrences are a result of the metachronous growth of new tumors. Besides, the preoperative workup frequently misses small HCCs or preneoplastic lesions. In an attempt to improve the results of surgery, a number of procedures have been used to “down-stage” tumors, including chemoembolization, combined chemotherapy and radiation, and immunochemotherapy. However, only a small proportion of patients will respond to these treatments, and the responders cannot be predicted. Adjuvant therapy has also been used, with disappointing results. Finally, chemoprevention may prove to be an interesting option to avoid postoperative HCC recurrence. These forms of treatment will be discussed in more detail subsequently. Liver Transplantation The initial goal of orthotopic liver transplantation (OLT) for HCC was to provide a cure for patients with unresectable disease.6,8 However, because of the high incidence of tumor recurrence, OLT could not fulfill this goal. Nevertheless, it offers a therapeutic option for patients with advanced liver disease and otherwise resectable HCC. Tumor stage (size and number of tumor nodules) appears to be an important predictor of recurrence. Several studies have demonstrated that the results of liver transplantation for small HCCs (1 lesion smaller than 5 cm or up to 3 lesions, each smaller than 3 cm) are comparable to those obtained with nonmalignant disease (85% actuarial survival at 4 years in 1 series). Indeed, for patients with cirrhosis and portal hypertension, OLT is
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the treatment of choice in most Western countries. More limited data suggest that in the presence of some favorable histopathologic characteristics (such as the presence of a capsule, the absence of vascular invasion, or a welldifferentiated tumor), OLT can be performed for larger tumors with satisfactory outcomes. Finally, survival after liver transplantation in patients with an “incidental” HCC (discovered at pathologic examination of the explanted liver) is identical to that obtained with benign end-stage liver disease. Organ shortage represents an important limitation to OLT in this setting. A long waiting period puts the patients at risk for tumor progression, to the point at which it could represent a contraindication to OLT. For this reason, many transplant centers in the United States use ablative therapies or chemoembolization in an attempt to prevent tumor growth and dissemination before OLT. However, none of these approaches has been evaluated by prospective randomized trials. Some centers also use adjuvant chemotherapy to improve the outcome of liver transplantation for HCC, but its usefulness remains to be determined. Finally, the role that post-transplant immunosuppression may play in promoting tumor recurrence is unknown. Local Ablative Therapies Local ablative therapies include percutaneous alcohol injection, radiofrequency ablation, and other less well-documented forms of local therapy.9 –11 Percutaneous alcohol injection (PEI) consists of the instillation of absolute ethanol through a fine needle into the tumor under ultrasound or CT guidance (Figure 6). This should be distributed as uniformly as possible throughout the nodule. Large lesions may require several treatment sessions. The extent of the necrosis induced by the infiltration of the tumor depends on the size of the latter, with small nodules (⬍3 cm) usually being completely destroyed and larger lesions only partially. Regular CT scan follow-up is necessary. The absence of contrast enhancement on CT scan is considered evidence for complete necrosis of the tumor. Local recurrences or new lesions can be treated repeatedly. PEI has gained a wide popularity because it is simple and inexpensive and can be used in patients with relatively advanced liver disease. Moreover, some studies have suggested that its efficacy is comparable to that of surgery for small tumors, providing identical survival. Investigators have reported a long-term survival rate as high as 70% in this setting (in patients with preserved liver function). Treatment of larger tumors is possible, but it is associated with higher rates of relapse and decreased survival. PEI is usually well tolerated. Avoid-
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Besides, they are less irritating than ethanol in case they are injected in a blood vessel or leak into the peritoneum. Radiofrequency ablation (RFA) has been proposed recently9 as an alternative to PEI. This technique delivers thermal energy into the tumor through a needle electrode introduced percutaneously under ultrasound guidance. Energy is generated with a high-frequency alternating electric current. It produces local tissue temperatures that exceed 100°C, resulting in coagulative necrosis of the tumor. The tissue temperature falls rapidly with increasing distance away from the electrode. Needles with multiple array hook electrodes have been developed. When deployed, they create a series of electrodes with a diameter of 2 to 5 cm, thus permitting the ablation of a much larger zone of tissue. The aim of the treatment is to ablate the tumor and a rim of normal tissue surrounding it, thus mimicking a surgical margin. Contrast-enhanced CT scans are used to assess tumor necrosis after the procedure. Successful treatment results in a cystic-density lesion that decreases slightly in size over time (Figure 7). If the tumor is not completely necrosed or if there is evidence of tumor recurrence on follow-up, the treatment can be repeated. The advantages that RFA has over other local ablative therapies include the predictability of the ablation effect as a result of a more uniform area of necrosis. Moreover, with the expandable needle electrodes, a larger tumor volume can be destroyed without repositioning the electrode, and repeated treatments can be avoided. However, RFA has some limitations. It is not effective for lesions adjacent to large blood vessels, because they dissipate the heat. It is also more technically difficult to treat lesions located high in the dome of the liver with this method. In a prospective randomized trial comparing RFA with PEI, complete tumor necrosis was achieved in 90% of tumors with RFA and in 80% of tumors with PEI. RFA Figure 6. (A) HCC appearing as a hypoechoic nodule on ultrasound; (B) after PEI, the nodule becomes hyperechoic.
ing quick needle removal can prevent abdominal pain due to the leakage of ethanol in the peritoneal cavity. A low-grade fever may be present for a few days after the procedure and is due to tumor necrosis. Less frequently, vascular thrombosis or peritoneal bleeding can occur. Tumor dissemination along the needle track is also possible but is rare. PEI is contraindicated in the presence of a large volume of ascites, coagulopathy, and obstructive jaundice. Acetic acid and hot saline injection have also been used successfully for the ablation of small HCCs. These fluids would diffuse more easily within the tumor and require smaller volumes to effectively induce its necrosis.
Figure 7. CT scan performed after RFA of HCC, showing a cysticdensity lesion, thus confirming treatment success.
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required fewer sessions to obtain this result. However, complications were more frequent with RFA in this study. Moreover, a recent study reported a high rate of needle track neoplastic seeding with RFA, but this was principally related to lesions adjacent to the capsule. Finally, there are no data supporting the superiority of RFA in terms of survival rates. Other forms of local therapy are also described. Microwave coagulation therapy (MCT) is based on the same principle as RFA but uses microwaves. Unlike RFA, in which normal cells are more resistant to lethal damage compared to malignant cells, necrosis is not limited to the tumor with MCT but can encompass surrounding normal tissue or neighboring intrahepatic metastases. Interstitial laser coagulation (ILC) therapy uses laser energy to achieve local hyperthermia in the tumor nodule. The laser beam is delivered through thin flexible fibers and causes tissue coagulation. Like RFA, MCT and ILC can be applied percutaneously under local anesthesia or through laparoscopy or laparotomy. Currently, there are not enough data to support the use of these techniques routinely for the treatment of HCC. Until recently, cryotherapy was only performed during laparotomy. Hence, its use has been limited to patients with relatively well-preserved liver function, and treatmentrelated morbidity is more common. A probe cooled with circulating liquid nitrogen at ⫺196°C is used to freeze the tumor in situ. Laparoscopic and percutaneous approaches are now possible but have not been studied extensively yet. This technique also carries the risk of cryoshock syndrome (i.e., systemic inflammatory response with multiple organ failure). Besides, malignant cells are more resistant to lethal damage from freezing than normal cells, and cryotherapy is therefore not a selective form of local treatment. Chemoembolization HCCs are hypervascular tumors and derive their blood supply mainly from the hepatic artery.12,13 Thus, the infusion of cytotoxic drugs into this artery theoretically allows attainment of higher drug concentrations within the tumor, with a lower systemic exposure. This depends nevertheless on the blood supply to the tumor and the extraction of the drug by the liver. Very few chemotherapy agents have an increased hepatic extraction, although some have been found to induce significant objective responses. However, in practice, transarterial chemotherapy appears to offer little pharmacokinetic or clinical advantage over systemic chemotherapy for the treatment of HCC. On the other hand, the interruption of the blood supply to the tumor by the embolization of the hepatic artery could theoretically
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induce ischemia of the tumor. Because the main blood supply to the liver itself is from the portal vein, the embolization of the hepatic artery causes minimal damage to the nontumoral liver parenchyma. The combination of the 2 above-mentioned modalities is known as transarterial chemoembolization (TACE). It is widely used throughout the world for the treatment of HCC. Recent data demonstrate a survival benefit with TACE in a selected subset of patients.12 Moreover, there is now evidence that chemoembolization is more effective than embolization alone. The procedure requires the cannulation of a peripheral artery (generally the femoral artery) followed by the advancement of a catheter selectively into the branch of the hepatic artery feeding the tumor. A cytotoxic agent such as doxorubicin or cisplatin, usually mixed with Lipiodol, is then injected; alternatively, occlusion of the artery with Gelfoam (Pharmacia and Upjohn, Kalamazoo, MI) or Ivalon (M-PACT, Eudora, KS) particles may be performed (Figure 8). Lipiodol is an oily contrast agent that is selectively concentrated in the tumor and persists for several weeks or months. It serves a dual role by carrying the chemotherapeutic drug to the tumor and embolizing the vasculature. However, its inherent density on CT scan precludes a good radiographic assessment of tumor necrosis, which is based on the absence of uptake of contrast material. However, tumor necrosis can be evaluated by MR angiography. TACE is commonly associated with fever, abdominal pain, nausea and vomiting, and occasionally an ileus. These symptoms usually resolve spontaneously within a few days. In addition, liver biochemical test results can remain elevated for up to 2 weeks; the deterioration of liver function can manifest as transient ascites. As with any angiographic procedure, there is a risk of contrast allergy, renal function deterioration, and local bleeding or pseudoaneurysm formation at the puncture site. Major complications include hepatic abscess, hepatic artery dissection or thrombosis, ischemic cholecystitis, and liver failure. The treatment-related mortality rate is 4.1% according to one study. The risk for fatal complications such as liver failure is higher in the presence of marked liver dysfunction. TACE is therefore contraindicated in the presence of Child’s class C cirrhosis. Portal vein thrombosis is another contraindication, as is the presence of a portosystemic shunt, whether surgical or intrahepatic (TIPS). Because tumor necrosis is reported with TACE and this procedure avoids the risk of needle track seeding, many transplant centers use it as a bridge to transplantation for patients with HCC. The objective is to prevent tumor progression while the patient is on the waiting
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Figure 8. Chemoembolization. (A) The HCC nodule appears on the initial angiogram as a hypervascular lesion. (B) The angiogram performed at the end of the procedure demonstrates the occlusion of the artery feeding the tumor.
list. The usefulness of TACE before OLT has not been evaluated in a randomized trial. Systemic Therapies These forms of therapy are considered noncurative and have been applied to the treatment of patients with advanced HCC who do not qualify for potentially curative treatments but who have not reached a terminal stage. They include systemic chemotherapy, hormonal therapy, and immunotherapy. Chemotherapy has been attempted for unresectable HCC with various cytotoxic drugs, given as single agents or in combination. No regimen has been shown to be effective, and their use is frequently limited by hepatic insufficiency.13 Chemotherapy has also been evaluated in the neoadjuvant and adjuvant settings for operable HCC.
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There is no strong evidence that any of the regimens used prolong survival or disease-free survival after curative resection for HCC. Thus, the current consensus is that systemic chemotherapy should not be recommended outside of a clinical trial. Hormonal therapy for HCC was justified by the presence of sex hormone receptors in the liver and by experimental evidence suggesting a trophic role for these hormones in HCC. Antiandrogens have never been shown to provide any survival benefit for patients with unresectable HCC. Data regarding antiestrogens have been more controversial. Several studies have reported a survival advantage in patients with unresectable HCC treated with tamoxifen, an estrogen-receptor antagonist, and meta-analyses have suggested a limited survival benefit at 1 year. However, the 2 largest randomized controlled trials have not shown any survival benefit, and antiestrogen therapy is not currently considered to be effective. Finally, an antimitotic activity has been demonstrated for somatostatin in a variety of tumors, and somatostatin receptors have been described in HCC. Octreotide, a somatostatin analogue with longer duration of action than its parent compound, was evaluated in a small, nonrandomized pilot study that suggested an improvement in survival of treated patients with inoperable HCC. These results require confirmation in larger investigations. Immunotherapy with high doses of interferon has been reported to improve survival of patients with inoperable HCC. However, these results were not replicated in a recent study. Because this treatment was evaluated in a few studies only, including relatively small numbers of patients; the results are therefore insufficient to allow any definite conclusion to be drawn. Moreover, the doses of interferon used were associated with a high rate of side effects. Consequently, further assessment of this potential treatment option is required. Other forms of immunotherapy, with lymphokine activated natural killer cells or intratumoral administration of interleukin 2, have been reported as having some antitumoral activity in isolated studies. However, these treatments are difficult to implement and are associated with significant toxicity and have not been widely adopted as therapeutic options. Radiation Therapy External beam radiation therapy (EBRT) can cause necrosis of small tumors but carries the risk of inducing liver injury or damage to neighboring organs, the bowel in particular.14 The maximum tolerated dose is considered to be lower than the curative dose for HCC. Three-dimensional treatment planning (conformal irradiation) allows the delivery of high dose EBRT to the
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tumor while relatively sparing the surrounding normal liver parenchyma. EBRT with concomitant administration of radiosensitizing chemotherapy, either intravenously or through the hepatic artery, has been reported to slow progression of unresectable HCC and to improve patient survival. Favorable results have also been reported with proton beam radiation therapy, and the results of ongoing studies are awaited. Finally, internal radiation techniques have been developed to deliver therapeutic doses of radiation to the tumor while limiting the irradiation of the rest of the liver, thus minimizing the risk of radiation-induced liver injury. These techniques are based on a selective uptake of radioisotopes by the tumor. Two isotopes have been used to this end, iodine 131 (131I) used with Lipiodol and yttrium 90 (90Y) incorporated into resin-based or glass microspheres. 90Y microspheres can be injected directly into the tumor under ultrasonographic guidance, but these isotopes are more commonly infused into the hepatic artery. Preliminary results are encouraging, but no randomized controlled trial has been performed so far. An even more specific delivery of radioisotopes to the tumor could theoretically be achieved by radiolabeled monoclonal antibodies directed against tumor-associated antigens and administered systemically. Unfortunately, the results obtained in clinical studies are rather disappointing. Prevention Because of the close association of HCC with chronic hepatitis B, a preemptive strategy aiming at the prevention of HBV infection15 would be the most effective way to prevent HCC, especially in developing countries. Vaccination of infants at birth against HBV has indeed decreased the incidence of HCC in areas of high prevalence. Treatment of chronic hepatitis B with interferon appears to reduce the incidence of HBV-related HCC, when administered at a precirrhotic stage and if successful in achieving virologic remission. Treatment of chronic hepatitis C with interferon, on the other hand, appears to impact on the incidence of HCC, whether administered to cirrhotic or noncirrhotic patients. However, these data are derived essentially from retrospective or noncontrolled studies and have to be interpreted with caution. Oltipraz, an antischistosomal agent that is an effective inhibitor of aflatoxin-induced hepatocarcinogenesis in rats, is being tested in a phase II trial of primary chemoprevention of HCC in China. Other potential chemopreventive agents include S-adenosylmethionine, cyclooxygenase inhibitors, and inhibitors of inducible nitric oxide.
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Long-term postoperative maintenance therapy of chronic hepatitis C patients with interferon appeared protective against the recurrence of HCC after surgical resection or local ablation in 2 small studies. In addition, polyprenoic acid, an acyclic retinoid, significantly reduced the incidence of second primary tumors after surgical resection or percutaneous ethanol ablation of HCC in one study. These results need to be replicated.
Summary Only 5%–10% of patients with cirrhosis and HCC seen at tertiary care centers will be candidates for surgical resection. Surgery is restricted to patients with solitary HCC, usually less than 5 cm in diameter, without evidence of vascular invasion or extrahepatic spread, and preserved liver function. The presence of significant portal hypertension or an abnormal bilirubin level should be considered contraindications to surgical resection. This would avoid significant postoperative impairment of liver function. However, HCC recurrence after hepatectomy has a negative impact on long-term survival, and adjuvant chemotherapy or preoperative chemoembolization has not been shown to reduce the risk of recurrence or to improve survival. OLT has several advantages over surgical resection for patients with HCC: (1) It can be used in patients with all stages of liver disease and (2) it simultaneously treats the cancer and addresses the neoplastic potential of the remaining liver as well as the liver disease itself. The current guidelines for eligibility are 1 lesion ⬍ 5 cm or ⱕ 3 lesions, each ⱕ 3 cm. In patients who are candidates for both resection and transplantation, the best outcomes are currently obtained with transplantation. However, organ shortage limits the availability of OLT. For patients who are not candidates for surgical approaches, locoregional forms of treatment are available. Percutaneous ethanol ablation is currently considered the standard form of direct ablation. It is safe, simple, and inexpensive. To be suitable for this technique, HCCs must be less than 3 cm in size and have fewer than 3 nodules. The results could be comparable to those of surgery in a selected group of patients with small solitary tumors and mild liver dysfunction. PEI entails less procedure-related morbidity and mortality than surgery and fewer complications. As with surgical resection, tumor recurrences occur in one half of the patients; repeat therapy is often feasible in these cases. The experience with RFA is still limited, but its results appear promising. It appears to be an effective technique for the ablation of small liver tumors. RFA has some advantages over PEI, but prospective controlled studies are needed to determine which should be considered the method of
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choice for local ablation. The experience with other forms of local therapy (MCT, laser coagulation therapy, and cryotherapy) remains limited. TACE provides a survival advantage for patients not amenable to ablation therapies, Childs A and B cirrhosis, no vascular invasion, and lack of systemic symptoms. TACE is, therefore, only indicated in approximately 15% of patients with HCC.12 There is no convincing evidence that cytotoxic chemotherapy prolongs survival or improves the quality of life of these patients. Similarly, hormonal therapy with antiandrogens or antiestrogens has not demonstrated any benefit. Other forms of treatment such as with octreotide, interferons, radiation, or gene therapy are still experimental. In the United States, survival of patients with HCC has not changed significantly during the past 20 years. A limited proportion of patients with HCC are eligible for potentially curative forms of treatment. Despite improvements in early diagnosis, most patients still present with advanced disease. There is currently no treatment option that provides an unequivocal survival benefit for such patients. Important efforts should therefore be directed toward the development of effective screening, surveillance, and prevention strategies, along with prompt referral of cases to specialized centers for optimal multidisciplinary evaluation and management. Universal vaccination against HBV has the potential to reduce significantly the worldwide incidence of HCC. Other strategies, including chemoprevention, need better assessment.
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References 1. Bosch FX, Ribes J, Borras J. Epidemiology of primary liver cancer. Semin Liver Dis 1999;19:271–285. 2. Bruix J, Llovet JM. Prognostic prediction and treatment strategy in hepatocellular carcinoma. Hepatology 2002;35:519 –524. 3. Bruix J, Sherman M, Llovet JM, Beaugrand M, Lencioni R, Bur-
roughs AK, et al. Clinical management of hepatocellular carcinoma: conclusions of the Barcelona-2000 EASL conference— European Association for the Study of the Liver. J Hepatol 2001; 35:421– 430. Hann LE, Winston CB, Brown KT, Akhurst T. Diagnostic imaging approaches and relationship to hepatobiliary cancer staging and therapy. Semin Surg Oncol 2000;19:94 –115. Souto E, Gores GJ. When should a liver mass suspected of being a hepatocellular carcinoma be biopsied? Liver Transpl 2000;6: 73–75. Llovet JM, Bruix J, Gores GJ. Surgical resection versus transplantation for early hepatocellular carcinoma: clues for the best strategy. Hepatology 2000;31:1019 –1021. Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology 1999;30:1434 –1440. Bismuth H, Majno PE, Adam R. Liver transplantation for hepatocellular carcinoma. Semin Liver Dis 1999;19:311–322. Grasso A, Watkinson AF, Tibballs JM, Burroughs AK. Radiofrequency ablation in the treatment of hepatocellular carcinoma: a clinical viewpoint. J Hepatol 2000;33:667– 672. Hargreaves GM, Adam R, Bismuth H. Results after nonsurgical local treatment of primary liver malignancies. Langenbecks Arch Surg 2000;385:185–193. Okada S. Local ablation therapy for hepatocellular carcinoma. Semin Liver Dis 1999;19:323–328. Llovet JM, Real MI, Montana X, Planas R, Coll S, Aponte J, Ayuso C, Sala M, Muchart J, Sala R, Rodes J, Bruix J. Arterial embolization or chemoembolization versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomized controlled trial. Lancet 2002;359:1734 –1739. Mathurin P, Rixe O, Carbonell N, Bernard B, Cluzel P, Bellin MF, Khayat D, Opolon P, Poynard T. Review article: overview of medical treatments in unresectable hepatocellular carcinoma—an impossible meta-analysis? Aliment Pharmacol Ther 1998;12: 111–126. Ho S, Lau WY, Leung TW, Johnson PJ. Internal radiation therapy for patients with primary or metastatic hepatic cancer: a review. Cancer 1998;83:1894 –1907. Collier J, Sherman M. Screening for hepatocellular carcinoma. Hepatology 1998;27:273–278.
Address requests for reprints to: Gregory J. Gores, M.D. Professor of Medicine, Mayo Medical School, Clinic, and Foundation, 200 First Street SW, Rochester, Minnesota 55905. e-mail: gores.gregory@ mayo.edu; fax: (507) 284-0762.
Treatment of Hepatocellular Carcinoma ZIAD HASSOUN and GREGORY J. GORES Division of Gastroenterology and Hepatology, Mayo Medical School, Clinic, and Foundation, Rochester, Minnesota
epatocellular carcinoma (HCC) accounts for approximately 6% of all human cancers. It represents the fifth most common cancer and the third most frequent cause of cancer death worldwide. In the United States, the overall incidence is 2.4 per 100,000 persons per year. The incidence of HCC in the United States has been growing during the past two decades, and the age-specific incidence of this cancer has progressively shifted toward younger people. This is most likely related to the increased prevalence of hepatitis C virus– related cirrhosis. Several risk factors are associated with HCC.1 Hepatitis B virus (HBV) is the most frequent underlying cause worldwide. About 85% of HCC cases occur in eastern and southeastern Asia and sub-Saharan Africa, where chronic HBV infection is endemic, and about 80% of the cases in these locations have been associated with chronic hepatitis B. Between 70% and 90% of HBV-related HCC develop in patients with cirrhosis. There is also a strong causal association between hepatitis C virus (HCV) infection and HCC. Indeed, HCV-related HCC has now become a clinical problem that most gastroenterologists encounter in their practice. Almost all HCVrelated HCCs occur among patients with cirrhosis. Other risk factors for HCC include alcohol abuse, which can act synergistically with HCV to promote liver carcinogenesis; cirrhosis that results from any cause (the magnitude of the HCC risk being greater when it is associated with a viral origin); inherited metabolic disorders such as hemochromatosis, tyrosinemia, and glycogen storage disease; and dietary aflatoxin exposure. In the United States, chronic viral hepatitides account for no more than 30%– 40% of reported cases of HCC. Men are 2 to 4 times more frequently affected by HCC than are women.
H
ated in part by free radical species and inflammatory cytokines, plays a key role in the development of HCC. Multiple mutations of the p53 tumor suppressor gene have been described. These mutations can be early events in neoplastic transformation but can also occur late in this process. One of these mutations has been linked to aflatoxin exposure. Clinical gene therapy trials for HCC using vectors expressing wild-type p53 have been developed, but the results of these phase I trials have not yet been published. Molecular genetic studies have consistently demonstrated that HCCs fall into 2 categories, with either low or high levels of chromosomal changes, probably reflecting differences in genomic instability. The first group tends to have low-grade histology and a better prognosis. In addition to oncogenes, tumor-suppressor genes, and other genetic factors, a number of growth factors involved in cell signaling pathways have also been shown to play a role in hepatocarcinogenesis. Angiogenic stimuli are also required for the continual growth of HCC, which is usually a hypervascular tumor. Angiogenesis inhibitors, in particular, may have a future role in the treatment of HCC. A subset of molecular alterations may preferentially contribute to virus-induced carcinogenesis. Chronic hepatitis B and integration of the HBV genome have been associated with a high rate of genomic instability. In particular, the HBV HBx gene product and other viral proteins have been shown to interfere with several mechanisms of cellular growth control. In patients with chronic HCV infection, the HCV core protein is a potent stimulator of cell proliferation via cell signaling activation; other viral proteins may also have an oncogenic potential. Because HBV integration is likely associated with the development of HCC, antiviral agents will
Pathogenesis Carcinogenesis is a stepwise process involving sequential genetic mutations that lead to oncogene activation or tumor suppressor gene inactivation through a variety of mechanisms. The molecular steps in the development of HCC have not been fully elucidated yet, and no dominant pathways of hepatocellular carcinogenesis have been identified. Persistent liver damage, medi-
Abbreviations used in this paper: CT, computed tomography; EBRT, external beam radiation therapy; HCC, hepatocellular carcinoma; ILC, interstitial laser coagulation; MCT, microwave coagulation therapy; OLT, orthotopic liver transplantation; PEI, percutaneous alcohol injection; RFA, radiofrequency ablation; TACE, transarterial chemoembolization. © 2003 by the American Gastroenterological Association 1542-3565/03/$35.00 doi:10.1053/jcgh.2003.50003
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Figure 1. Actuarial rate of HCC development in 34 dysplastic nodules. (Data from Terasaki et al., Gastroenterology 1998;115:1216 – 1222.)
probably not eliminate the risk for developing HCC in patients with established cirrhosis. In contrast, eradication of HCV with antivirals such as interferon may decrease the risk of HCC. From the histopathologic standpoint, malignant transformation proceeds from adenomatous hyperplasia through dysplasia to early, well-differentiated HCC. The term dysplastic nodule has been coined to describe premalignant lesions. The histopathologic distinction between a dysplastic nodule and early HCC is difficult, and worldwide consensus criteria have not been firmly established. The risk of developing HCC in patients with dysplastic nodules is 14% over 2 years (Figure 1). Thus, such patients should undergo vigilant surveillance with repeated biopsies or perhaps even be treated as if they have cancer.
Natural History, Prognosis, and Staging The natural history2 of HCC depends on the severity of the underlying cirrhosis, tumor characteristics (i.e., size, multicentricity, presence or absence of vascular invasion, pathologic grade, and extrahepatic metastases), performance status of the patient, comorbid conditions, and the efficacy of treatment interventions. Four prognostic classifications have been developed for HCC (Table 1). None of them is perfect. The Okuda classification uses a gross assessment of tumor factors and is not very useful in the clinical evaluation of patients. The Barcelona Clinic Liver Cancer (BCLC), the Cancer of the Liver Italian Program (CLIP), and the Groupe d’Etude et de Traitement du Carcinome Hepatocellulaire (GETCHC) classifications use more refined assessments. These models cannot provide a precise prognosis for individual
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patients but are nevertheless helpful as a guide to the prognosis of groups of patients. For example, according to the BCLC classification, untreated patients with unicentric disease, no symptoms, and no evidence of vascular invasion or extrahepatic spread have a 50% 3-year survival. On the other hand, patients with severe cancerrelated symptoms reflected by a deteriorated performance status and a marked impairment of their liver function have a 50% survival of less than 3 months, no matter what their tumor characteristics are. The information provided by these models needs to be kept in mind when considering treatment options for each patient. The staging evaluation depends in part on the aggressiveness of the treatment considered.2,3 All patients should undergo at least 2 imaging studies to assess intrahepatic disease and to rule out vascular invasion (ultrasonography, contrast computed tomography [CT], or contrast magnetic resonance imaging) (Figure 2). However, current radiographic modalities frequently fail to detect small tumors. A chest x-ray should be performed to look for pulmonary metastases. If liver transplantation is contemplated, many centers will also perform a CT scan of the chest and a bone scan. The presence of abdominal lymphadenopathy is a frequent finding in cirrhosis, especially with hepatitis C. In suspicious cases, endoscopic ultrasonography permits fine-needle aspiration of regional lymph nodes to determine the presence or absence of metastases.
Treatment The staging of the disease and its prognosis will influence the choice of the treatment modality.2–5 In Table 1. Parameters Used in the Prognostic Classifications for HCC Parameters Patient factors Performance status Tumor characteristics Tumor size Vascular invasion Extrahepatic spread AFP Liver function CTP stage Portal hypertension Ascites Bilirubin Albumin ALP
BCLC
CLIP
X X X X
X X X
GETCHC
Okuda
X X X
X
X
X
X
X
X
X X X
X
AFP, alpha-fetoprotein; ALP, alkaline phosphatase; BCLC, Barcelona Clinic Liver Cancer; CLIP, Cancer of the Liver Italian Program; CTP, Child-Turcotte-Pugh; GETCHC, Groupe d’Etude et de Traitement du Carcinome He´patocellulaire.
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Figure 2. CT scan of the liver demonstrating an early HCC. This lesion is hypervascular, thus enhancing after contrast injection and appearing as a hyperdense nodule.
addition to the prognostic models discussed above, poor prognostic factors identified in several studies include a single tumor greater than 5 cm in diameter, the presence of more than 3 lesions, satellite lesions adjacent to the main tumor (which indicate tumor invasion), and vascular invasion. In particular, HCC has a striking tendency to invade portal vein branches, and this represents a contraindication to radical therapies. Patients with very poor prognosis will be treated symptomatically. Those with the best prognostic factors will be considered for surgical resection or liver transplantation (Figures 3 and 4). Others may benefit from local ablative therapies (Figure 4), transarterial chemoembolization, or systemic therapies (Figure 5).
Figure 3. Management algorithm for a solitary HCC nodule. PLT, platelets.
Figure 4. Management algorithm for early HCC. OLT, orthotopic liver transplantation; PEI, percutaneous ethanol injection; RFA, radiofrequency ablation.
Surgical Resection Surgical resection is generally accepted as the mainstay of therapy for localized HCC, despite the absence of randomized controlled trials proving its efficacy.6,7 Often, the tumor size or its multicentricity, the presence of vascular invasion, a limited hepatic functional reserve, or the presence of portal hypertension will preclude this approach. It remains nevertheless the main treatment option in patients without underlying cirrhosis. In such patients, up to 75% of liver tissue can be removed with relatively low morbidity. In the presence
Figure 5. Management algorithm for large solitary or multicentric HCC.
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of cirrhosis, the risk of decompensation or liver failure limits the extent of resection. Partial hepatectomy is associated with relatively good medium-term outcomes in patients with well-preserved liver function (ChildTurcotte-Pugh class A). However, tumor recurrence and progression of liver disease have an adverse effect on long-term survival. Resection is associated with significant morbidity and mortality in patients with Child’s class B and C cirrhosis. The best predictors of survival after surgical resection appear to be the absence of clinically relevant portal hypertension (defined as the presence of varices, splenomegaly with a platelet count ⬍100,000/mm3, or a hepatic vein pressure gradient ⱖ10 mm Hg) and a bilirubin level ⬍1 mg/dL. With careful patient and tumor selection and improvement of the surgical techniques, perioperative mortality rates are currently around 5%–10%, and survival rates are 30%– 50% at 5 years. The risk of intrahepatic tumor recurrence after resection is high (around 50% at 3 years) in patients who undergo an apparently curative hepatectomy. Tumor size is the most important predictor of recurrence. However, many of these recurrences are a result of the metachronous growth of new tumors. Besides, the preoperative workup frequently misses small HCCs or preneoplastic lesions. In an attempt to improve the results of surgery, a number of procedures have been used to “down-stage” tumors, including chemoembolization, combined chemotherapy and radiation, and immunochemotherapy. However, only a small proportion of patients will respond to these treatments, and the responders cannot be predicted. Adjuvant therapy has also been used, with disappointing results. Finally, chemoprevention may prove to be an interesting option to avoid postoperative HCC recurrence. These forms of treatment will be discussed in more detail subsequently. Liver Transplantation The initial goal of orthotopic liver transplantation (OLT) for HCC was to provide a cure for patients with unresectable disease.6,8 However, because of the high incidence of tumor recurrence, OLT could not fulfill this goal. Nevertheless, it offers a therapeutic option for patients with advanced liver disease and otherwise resectable HCC. Tumor stage (size and number of tumor nodules) appears to be an important predictor of recurrence. Several studies have demonstrated that the results of liver transplantation for small HCCs (1 lesion smaller than 5 cm or up to 3 lesions, each smaller than 3 cm) are comparable to those obtained with nonmalignant disease (85% actuarial survival at 4 years in 1 series). Indeed, for patients with cirrhosis and portal hypertension, OLT is
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the treatment of choice in most Western countries. More limited data suggest that in the presence of some favorable histopathologic characteristics (such as the presence of a capsule, the absence of vascular invasion, or a welldifferentiated tumor), OLT can be performed for larger tumors with satisfactory outcomes. Finally, survival after liver transplantation in patients with an “incidental” HCC (discovered at pathologic examination of the explanted liver) is identical to that obtained with benign end-stage liver disease. Organ shortage represents an important limitation to OLT in this setting. A long waiting period puts the patients at risk for tumor progression, to the point at which it could represent a contraindication to OLT. For this reason, many transplant centers in the United States use ablative therapies or chemoembolization in an attempt to prevent tumor growth and dissemination before OLT. However, none of these approaches has been evaluated by prospective randomized trials. Some centers also use adjuvant chemotherapy to improve the outcome of liver transplantation for HCC, but its usefulness remains to be determined. Finally, the role that post-transplant immunosuppression may play in promoting tumor recurrence is unknown. Local Ablative Therapies Local ablative therapies include percutaneous alcohol injection, radiofrequency ablation, and other less well-documented forms of local therapy.9 –11 Percutaneous alcohol injection (PEI) consists of the instillation of absolute ethanol through a fine needle into the tumor under ultrasound or CT guidance (Figure 6). This should be distributed as uniformly as possible throughout the nodule. Large lesions may require several treatment sessions. The extent of the necrosis induced by the infiltration of the tumor depends on the size of the latter, with small nodules (⬍3 cm) usually being completely destroyed and larger lesions only partially. Regular CT scan follow-up is necessary. The absence of contrast enhancement on CT scan is considered evidence for complete necrosis of the tumor. Local recurrences or new lesions can be treated repeatedly. PEI has gained a wide popularity because it is simple and inexpensive and can be used in patients with relatively advanced liver disease. Moreover, some studies have suggested that its efficacy is comparable to that of surgery for small tumors, providing identical survival. Investigators have reported a long-term survival rate as high as 70% in this setting (in patients with preserved liver function). Treatment of larger tumors is possible, but it is associated with higher rates of relapse and decreased survival. PEI is usually well tolerated. Avoid-
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Besides, they are less irritating than ethanol in case they are injected in a blood vessel or leak into the peritoneum. Radiofrequency ablation (RFA) has been proposed recently9 as an alternative to PEI. This technique delivers thermal energy into the tumor through a needle electrode introduced percutaneously under ultrasound guidance. Energy is generated with a high-frequency alternating electric current. It produces local tissue temperatures that exceed 100°C, resulting in coagulative necrosis of the tumor. The tissue temperature falls rapidly with increasing distance away from the electrode. Needles with multiple array hook electrodes have been developed. When deployed, they create a series of electrodes with a diameter of 2 to 5 cm, thus permitting the ablation of a much larger zone of tissue. The aim of the treatment is to ablate the tumor and a rim of normal tissue surrounding it, thus mimicking a surgical margin. Contrast-enhanced CT scans are used to assess tumor necrosis after the procedure. Successful treatment results in a cystic-density lesion that decreases slightly in size over time (Figure 7). If the tumor is not completely necrosed or if there is evidence of tumor recurrence on follow-up, the treatment can be repeated. The advantages that RFA has over other local ablative therapies include the predictability of the ablation effect as a result of a more uniform area of necrosis. Moreover, with the expandable needle electrodes, a larger tumor volume can be destroyed without repositioning the electrode, and repeated treatments can be avoided. However, RFA has some limitations. It is not effective for lesions adjacent to large blood vessels, because they dissipate the heat. It is also more technically difficult to treat lesions located high in the dome of the liver with this method. In a prospective randomized trial comparing RFA with PEI, complete tumor necrosis was achieved in 90% of tumors with RFA and in 80% of tumors with PEI. RFA Figure 6. (A) HCC appearing as a hypoechoic nodule on ultrasound; (B) after PEI, the nodule becomes hyperechoic.
ing quick needle removal can prevent abdominal pain due to the leakage of ethanol in the peritoneal cavity. A low-grade fever may be present for a few days after the procedure and is due to tumor necrosis. Less frequently, vascular thrombosis or peritoneal bleeding can occur. Tumor dissemination along the needle track is also possible but is rare. PEI is contraindicated in the presence of a large volume of ascites, coagulopathy, and obstructive jaundice. Acetic acid and hot saline injection have also been used successfully for the ablation of small HCCs. These fluids would diffuse more easily within the tumor and require smaller volumes to effectively induce its necrosis.
Figure 7. CT scan performed after RFA of HCC, showing a cysticdensity lesion, thus confirming treatment success.
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required fewer sessions to obtain this result. However, complications were more frequent with RFA in this study. Moreover, a recent study reported a high rate of needle track neoplastic seeding with RFA, but this was principally related to lesions adjacent to the capsule. Finally, there are no data supporting the superiority of RFA in terms of survival rates. Other forms of local therapy are also described. Microwave coagulation therapy (MCT) is based on the same principle as RFA but uses microwaves. Unlike RFA, in which normal cells are more resistant to lethal damage compared to malignant cells, necrosis is not limited to the tumor with MCT but can encompass surrounding normal tissue or neighboring intrahepatic metastases. Interstitial laser coagulation (ILC) therapy uses laser energy to achieve local hyperthermia in the tumor nodule. The laser beam is delivered through thin flexible fibers and causes tissue coagulation. Like RFA, MCT and ILC can be applied percutaneously under local anesthesia or through laparoscopy or laparotomy. Currently, there are not enough data to support the use of these techniques routinely for the treatment of HCC. Until recently, cryotherapy was only performed during laparotomy. Hence, its use has been limited to patients with relatively well-preserved liver function, and treatmentrelated morbidity is more common. A probe cooled with circulating liquid nitrogen at ⫺196°C is used to freeze the tumor in situ. Laparoscopic and percutaneous approaches are now possible but have not been studied extensively yet. This technique also carries the risk of cryoshock syndrome (i.e., systemic inflammatory response with multiple organ failure). Besides, malignant cells are more resistant to lethal damage from freezing than normal cells, and cryotherapy is therefore not a selective form of local treatment. Chemoembolization HCCs are hypervascular tumors and derive their blood supply mainly from the hepatic artery.12,13 Thus, the infusion of cytotoxic drugs into this artery theoretically allows attainment of higher drug concentrations within the tumor, with a lower systemic exposure. This depends nevertheless on the blood supply to the tumor and the extraction of the drug by the liver. Very few chemotherapy agents have an increased hepatic extraction, although some have been found to induce significant objective responses. However, in practice, transarterial chemotherapy appears to offer little pharmacokinetic or clinical advantage over systemic chemotherapy for the treatment of HCC. On the other hand, the interruption of the blood supply to the tumor by the embolization of the hepatic artery could theoretically
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induce ischemia of the tumor. Because the main blood supply to the liver itself is from the portal vein, the embolization of the hepatic artery causes minimal damage to the nontumoral liver parenchyma. The combination of the 2 above-mentioned modalities is known as transarterial chemoembolization (TACE). It is widely used throughout the world for the treatment of HCC. Recent data demonstrate a survival benefit with TACE in a selected subset of patients.12 Moreover, there is now evidence that chemoembolization is more effective than embolization alone. The procedure requires the cannulation of a peripheral artery (generally the femoral artery) followed by the advancement of a catheter selectively into the branch of the hepatic artery feeding the tumor. A cytotoxic agent such as doxorubicin or cisplatin, usually mixed with Lipiodol, is then injected; alternatively, occlusion of the artery with Gelfoam (Pharmacia and Upjohn, Kalamazoo, MI) or Ivalon (M-PACT, Eudora, KS) particles may be performed (Figure 8). Lipiodol is an oily contrast agent that is selectively concentrated in the tumor and persists for several weeks or months. It serves a dual role by carrying the chemotherapeutic drug to the tumor and embolizing the vasculature. However, its inherent density on CT scan precludes a good radiographic assessment of tumor necrosis, which is based on the absence of uptake of contrast material. However, tumor necrosis can be evaluated by MR angiography. TACE is commonly associated with fever, abdominal pain, nausea and vomiting, and occasionally an ileus. These symptoms usually resolve spontaneously within a few days. In addition, liver biochemical test results can remain elevated for up to 2 weeks; the deterioration of liver function can manifest as transient ascites. As with any angiographic procedure, there is a risk of contrast allergy, renal function deterioration, and local bleeding or pseudoaneurysm formation at the puncture site. Major complications include hepatic abscess, hepatic artery dissection or thrombosis, ischemic cholecystitis, and liver failure. The treatment-related mortality rate is 4.1% according to one study. The risk for fatal complications such as liver failure is higher in the presence of marked liver dysfunction. TACE is therefore contraindicated in the presence of Child’s class C cirrhosis. Portal vein thrombosis is another contraindication, as is the presence of a portosystemic shunt, whether surgical or intrahepatic (TIPS). Because tumor necrosis is reported with TACE and this procedure avoids the risk of needle track seeding, many transplant centers use it as a bridge to transplantation for patients with HCC. The objective is to prevent tumor progression while the patient is on the waiting
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Figure 8. Chemoembolization. (A) The HCC nodule appears on the initial angiogram as a hypervascular lesion. (B) The angiogram performed at the end of the procedure demonstrates the occlusion of the artery feeding the tumor.
list. The usefulness of TACE before OLT has not been evaluated in a randomized trial. Systemic Therapies These forms of therapy are considered noncurative and have been applied to the treatment of patients with advanced HCC who do not qualify for potentially curative treatments but who have not reached a terminal stage. They include systemic chemotherapy, hormonal therapy, and immunotherapy. Chemotherapy has been attempted for unresectable HCC with various cytotoxic drugs, given as single agents or in combination. No regimen has been shown to be effective, and their use is frequently limited by hepatic insufficiency.13 Chemotherapy has also been evaluated in the neoadjuvant and adjuvant settings for operable HCC.
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There is no strong evidence that any of the regimens used prolong survival or disease-free survival after curative resection for HCC. Thus, the current consensus is that systemic chemotherapy should not be recommended outside of a clinical trial. Hormonal therapy for HCC was justified by the presence of sex hormone receptors in the liver and by experimental evidence suggesting a trophic role for these hormones in HCC. Antiandrogens have never been shown to provide any survival benefit for patients with unresectable HCC. Data regarding antiestrogens have been more controversial. Several studies have reported a survival advantage in patients with unresectable HCC treated with tamoxifen, an estrogen-receptor antagonist, and meta-analyses have suggested a limited survival benefit at 1 year. However, the 2 largest randomized controlled trials have not shown any survival benefit, and antiestrogen therapy is not currently considered to be effective. Finally, an antimitotic activity has been demonstrated for somatostatin in a variety of tumors, and somatostatin receptors have been described in HCC. Octreotide, a somatostatin analogue with longer duration of action than its parent compound, was evaluated in a small, nonrandomized pilot study that suggested an improvement in survival of treated patients with inoperable HCC. These results require confirmation in larger investigations. Immunotherapy with high doses of interferon has been reported to improve survival of patients with inoperable HCC. However, these results were not replicated in a recent study. Because this treatment was evaluated in a few studies only, including relatively small numbers of patients; the results are therefore insufficient to allow any definite conclusion to be drawn. Moreover, the doses of interferon used were associated with a high rate of side effects. Consequently, further assessment of this potential treatment option is required. Other forms of immunotherapy, with lymphokine activated natural killer cells or intratumoral administration of interleukin 2, have been reported as having some antitumoral activity in isolated studies. However, these treatments are difficult to implement and are associated with significant toxicity and have not been widely adopted as therapeutic options. Radiation Therapy External beam radiation therapy (EBRT) can cause necrosis of small tumors but carries the risk of inducing liver injury or damage to neighboring organs, the bowel in particular.14 The maximum tolerated dose is considered to be lower than the curative dose for HCC. Three-dimensional treatment planning (conformal irradiation) allows the delivery of high dose EBRT to the
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tumor while relatively sparing the surrounding normal liver parenchyma. EBRT with concomitant administration of radiosensitizing chemotherapy, either intravenously or through the hepatic artery, has been reported to slow progression of unresectable HCC and to improve patient survival. Favorable results have also been reported with proton beam radiation therapy, and the results of ongoing studies are awaited. Finally, internal radiation techniques have been developed to deliver therapeutic doses of radiation to the tumor while limiting the irradiation of the rest of the liver, thus minimizing the risk of radiation-induced liver injury. These techniques are based on a selective uptake of radioisotopes by the tumor. Two isotopes have been used to this end, iodine 131 (131I) used with Lipiodol and yttrium 90 (90Y) incorporated into resin-based or glass microspheres. 90Y microspheres can be injected directly into the tumor under ultrasonographic guidance, but these isotopes are more commonly infused into the hepatic artery. Preliminary results are encouraging, but no randomized controlled trial has been performed so far. An even more specific delivery of radioisotopes to the tumor could theoretically be achieved by radiolabeled monoclonal antibodies directed against tumor-associated antigens and administered systemically. Unfortunately, the results obtained in clinical studies are rather disappointing. Prevention Because of the close association of HCC with chronic hepatitis B, a preemptive strategy aiming at the prevention of HBV infection15 would be the most effective way to prevent HCC, especially in developing countries. Vaccination of infants at birth against HBV has indeed decreased the incidence of HCC in areas of high prevalence. Treatment of chronic hepatitis B with interferon appears to reduce the incidence of HBV-related HCC, when administered at a precirrhotic stage and if successful in achieving virologic remission. Treatment of chronic hepatitis C with interferon, on the other hand, appears to impact on the incidence of HCC, whether administered to cirrhotic or noncirrhotic patients. However, these data are derived essentially from retrospective or noncontrolled studies and have to be interpreted with caution. Oltipraz, an antischistosomal agent that is an effective inhibitor of aflatoxin-induced hepatocarcinogenesis in rats, is being tested in a phase II trial of primary chemoprevention of HCC in China. Other potential chemopreventive agents include S-adenosylmethionine, cyclooxygenase inhibitors, and inhibitors of inducible nitric oxide.
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Long-term postoperative maintenance therapy of chronic hepatitis C patients with interferon appeared protective against the recurrence of HCC after surgical resection or local ablation in 2 small studies. In addition, polyprenoic acid, an acyclic retinoid, significantly reduced the incidence of second primary tumors after surgical resection or percutaneous ethanol ablation of HCC in one study. These results need to be replicated.
Summary Only 5%–10% of patients with cirrhosis and HCC seen at tertiary care centers will be candidates for surgical resection. Surgery is restricted to patients with solitary HCC, usually less than 5 cm in diameter, without evidence of vascular invasion or extrahepatic spread, and preserved liver function. The presence of significant portal hypertension or an abnormal bilirubin level should be considered contraindications to surgical resection. This would avoid significant postoperative impairment of liver function. However, HCC recurrence after hepatectomy has a negative impact on long-term survival, and adjuvant chemotherapy or preoperative chemoembolization has not been shown to reduce the risk of recurrence or to improve survival. OLT has several advantages over surgical resection for patients with HCC: (1) It can be used in patients with all stages of liver disease and (2) it simultaneously treats the cancer and addresses the neoplastic potential of the remaining liver as well as the liver disease itself. The current guidelines for eligibility are 1 lesion ⬍ 5 cm or ⱕ 3 lesions, each ⱕ 3 cm. In patients who are candidates for both resection and transplantation, the best outcomes are currently obtained with transplantation. However, organ shortage limits the availability of OLT. For patients who are not candidates for surgical approaches, locoregional forms of treatment are available. Percutaneous ethanol ablation is currently considered the standard form of direct ablation. It is safe, simple, and inexpensive. To be suitable for this technique, HCCs must be less than 3 cm in size and have fewer than 3 nodules. The results could be comparable to those of surgery in a selected group of patients with small solitary tumors and mild liver dysfunction. PEI entails less procedure-related morbidity and mortality than surgery and fewer complications. As with surgical resection, tumor recurrences occur in one half of the patients; repeat therapy is often feasible in these cases. The experience with RFA is still limited, but its results appear promising. It appears to be an effective technique for the ablation of small liver tumors. RFA has some advantages over PEI, but prospective controlled studies are needed to determine which should be considered the method of
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choice for local ablation. The experience with other forms of local therapy (MCT, laser coagulation therapy, and cryotherapy) remains limited. TACE provides a survival advantage for patients not amenable to ablation therapies, Childs A and B cirrhosis, no vascular invasion, and lack of systemic symptoms. TACE is, therefore, only indicated in approximately 15% of patients with HCC.12 There is no convincing evidence that cytotoxic chemotherapy prolongs survival or improves the quality of life of these patients. Similarly, hormonal therapy with antiandrogens or antiestrogens has not demonstrated any benefit. Other forms of treatment such as with octreotide, interferons, radiation, or gene therapy are still experimental. In the United States, survival of patients with HCC has not changed significantly during the past 20 years. A limited proportion of patients with HCC are eligible for potentially curative forms of treatment. Despite improvements in early diagnosis, most patients still present with advanced disease. There is currently no treatment option that provides an unequivocal survival benefit for such patients. Important efforts should therefore be directed toward the development of effective screening, surveillance, and prevention strategies, along with prompt referral of cases to specialized centers for optimal multidisciplinary evaluation and management. Universal vaccination against HBV has the potential to reduce significantly the worldwide incidence of HCC. Other strategies, including chemoprevention, need better assessment.
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roughs AK, et al. Clinical management of hepatocellular carcinoma: conclusions of the Barcelona-2000 EASL conference— European Association for the Study of the Liver. J Hepatol 2001; 35:421– 430. Hann LE, Winston CB, Brown KT, Akhurst T. Diagnostic imaging approaches and relationship to hepatobiliary cancer staging and therapy. Semin Surg Oncol 2000;19:94 –115. Souto E, Gores GJ. When should a liver mass suspected of being a hepatocellular carcinoma be biopsied? Liver Transpl 2000;6: 73–75. Llovet JM, Bruix J, Gores GJ. Surgical resection versus transplantation for early hepatocellular carcinoma: clues for the best strategy. Hepatology 2000;31:1019 –1021. Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology 1999;30:1434 –1440. Bismuth H, Majno PE, Adam R. Liver transplantation for hepatocellular carcinoma. Semin Liver Dis 1999;19:311–322. Grasso A, Watkinson AF, Tibballs JM, Burroughs AK. Radiofrequency ablation in the treatment of hepatocellular carcinoma: a clinical viewpoint. J Hepatol 2000;33:667– 672. Hargreaves GM, Adam R, Bismuth H. Results after nonsurgical local treatment of primary liver malignancies. Langenbecks Arch Surg 2000;385:185–193. Okada S. Local ablation therapy for hepatocellular carcinoma. Semin Liver Dis 1999;19:323–328. Llovet JM, Real MI, Montana X, Planas R, Coll S, Aponte J, Ayuso C, Sala M, Muchart J, Sala R, Rodes J, Bruix J. Arterial embolization or chemoembolization versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomized controlled trial. Lancet 2002;359:1734 –1739. Mathurin P, Rixe O, Carbonell N, Bernard B, Cluzel P, Bellin MF, Khayat D, Opolon P, Poynard T. Review article: overview of medical treatments in unresectable hepatocellular carcinoma—an impossible meta-analysis? Aliment Pharmacol Ther 1998;12: 111–126. Ho S, Lau WY, Leung TW, Johnson PJ. Internal radiation therapy for patients with primary or metastatic hepatic cancer: a review. Cancer 1998;83:1894 –1907. Collier J, Sherman M. Screening for hepatocellular carcinoma. Hepatology 1998;27:273–278.
Address requests for reprints to: Gregory J. Gores, M.D. Professor of Medicine, Mayo Medical School, Clinic, and Foundation, 200 First Street SW, Rochester, Minnesota 55905. e-mail: gores.gregory@ mayo.edu; fax: (507) 284-0762.