ABSTRACT: Hepatocellular carcinoma (HCC) is responsible for a significant amount of morbidity and mortality throughout the world. In many countries, including the United States, a definite increase in the incidence of HCC has been reported recently, largely attributable to the increasing incidence of hepatitis C infection. Unfortunately, the current management of HCC is confusing due to the large number of treatment options available. The difficulty of managing a patient with HCC is compounded by the lack of well-designed, randomized clinical trials comparing the various treatment modalities. Nevertheless, many exciting management options are currently available that may prove valuable in the treatment of this disease. Partial hepatic resection or, in some instances, liver transplantation offers the best chance for cure. However, various ablative therapies, including percutaneous ethanol injection, radiofrequency ablation, and cryosurgery, may produce a survival benefit. In the future, systemic chemotherapy and transarterial chemoembolization, employed either alone or as adjuncts to ablation or resection, may play an increasing role in palliating or downstaging a patient with advanced HCC. This overview of the state-of-the-art management of HCC attempts to guide the practicing physician in selecting the best treatment plan for an individual with HCC. [ONCOLOGY 14(7):1085-1098, 2000]
Hepatocellular carcinoma (HCC) is the most common primary neoplasm of the liver, accounting for almost half a million deaths annually worldwide. Although the incidence of HCC is particularly high in parts of Asia and Africa, recent studies have documented a clear rise in the number of cases in Japan, Western Europe, and the United States.
The rising incidence in the United States, as well as other parts of the world, is attributed largely to the increase in hepatitis C–related liver disease, a known risk factor for the disease. In the United States alone, the seroprevalence of hepatitis C virus is estimated to be 3.9 million cases. Other risk factors for HCC include hepatitis B viral infection, alcoholic cirrhosis, aflatoxin exposure, and a variety of inherited metabolic disorders.
Complex management options confront clinicians treating patients with HCC, making a multidisciplinary team comprised of hepatologists, interventional radiologists, medical oncologists, radiation oncologists, and surgeons necessary for optimal care. Unfortunately, there are few randomized clinical trials comparing the multitude of treatment options. Furthermore, many published studies lack statistical power and fail to stratify treatment arms by known prognostic indicators. In this report, an effort is made to provide an overview of the current management modalities available for patients with HCC and to describe the most appropriate clinical contexts in which they should be employed.
Because patients with HCC most commonly manifest nonspecific symptoms of advanced disease, including abdominal pain, weakness, and weight loss, routine use of serum alpha-fetoprotein (AFP) levels and transabdominal ultrasound (US) are used to screen individuals at high risk (ie, those with chronic hepatitis and/or cirrhosis). A normal level of AFP is less than 20 ng/mL, and a measurement above 500 ng/mL is considered diagnostic. Intermediately elevated levels, although indicative of HCC, can also be associated with benign conditions.
In high-incidence regions, the sensitivity of an abnormal AFP level is 80% to 90%; however, this drops to 50% to 70% in areas of low incidence. The specificity is 90%.
Many imaging modalities are available to help establish the diagnosis of HCC. Their respective sensitivities for detecting lesions £ 3 cm are listed in Table 1.[5-9] Dynamic magnetic resonance imaging (MRI) and helical computed tomography (CT) are commonly used to screen high-risk patients for HCC because they are less invasive than other available imaging techniques (Figure 1).
The sensitivity of most modalities significantly drops for lesions < 1 cm. However, Lipiodol CT still has a sensitivity of about 70% for detecting lesions of this size, making it the most sensitive preoperative imaging technique currently available.
Lipiodol is an iodized oily agent that accumulates selectively in vascular HCC liver nodules after intra-arterial injection. Although used most commonly therapeutically as part of transarterial chemoembolization, some centers employ diagnostic Lipiodol CT routinely in cases of suspected HCC or to rule out multifocal or metastatic disease.
The sensitivity of intraoperative ultrasound (US) for detecting HCC tumors is 98% for lesions 1 to 3 cm in size and 86% for those < 1 cm. Therefore, exploratory laparotomy with intraoperative US remains the gold standard for determining resectability of HCC.
Recently, encouraging results of staging of liver malignancies by laparoscopy with laparoscopic US have been reported. In particular, for patients with HCC, laparoscopy with laparoscopic US may avoid unnecessary laparotomy in certain instances.
Preoperative needle biopsy is rarely necessary in resectable patients with a clear diagnosis of HCC (ie, AFP > 500 ng/mL and a lesion identified on imaging studies). In most cases, the diagnosis is evident, and preoperative biopsy rarely alters management. Moreover, needle biopsy can be associated with the potential risks of bleeding, tumor rupture, and dissemination of malignant cells along the needle biopsy tract.
Percutaneous biopsy is most useful if the patient has unresectable HCC or is being considered for liver transplantation. In selected cases in which the diagnosis is unclear or multifocal disease is being ruled out, needle biopsy should be considered prior to major resection. Other roles of biopsy include evaluation of cases in which nonoperative ablation is being contemplated and determination of the extent of cirrhosis in the nontumorous liver.
Evaluating Hepatic Function
Assessment of hepatic functional reserve is important for deciding whether resection, liver transplantation, or other treatment modalities should be pursued. Prognostically useful data for both surgical and medical patients may be obtained from staging using the functional Child-Pugh classification system (Table 2).[15-17]
Another method, the indocyanine green retention rate, may also provide an estimate of underlying liver function. Although this test is used in some centers, it is not employed in most cases.
Imaging techniques may shed light on the extent of cirrhosis in some cases. For example, a CT scan or MRI can identify the loss of liver volume or hepatic contour changes indicative of more extensive cirrhosis. Visualization of portal vein collaterals, splenomegaly, or ascites can indicate more advanced disease.
Overall, there is no consensus on specific guidelines for evaluating hepatic function prior to treatment of HCC.
Once diagnosed, the clinical staging of HCC is based on tumor size and number, whether there is vascular invasion, and the presence of regional lymph node or distant metastases (Table 3). A shortcoming of the TNM staging system is the absence of liver functional status, which is an important prognostic indicator for HCC. Collectively, performance status, comorbidities, liver function, and extent of disease greatly influence the range of treatment options available to a patient with HCC.
For patients without cirrhosis, surgical resection with partial hepatectomy is clearly the treatment of choice. However, no more than 30% of patients with HCC present with resectable disease, and up to 90% of patients have cirrhosis on presentation.[20,21] Extrahepatic disease, lack of sufficient hepatic functional reserve, multifocal disease within the liver, tumors in locations not amenable to resection, and main portal vein involvement, as well as comorbid disease, are all contraindications to resection.
In patients with well-compensated, mild cirrhosis (Child-Pugh class A-B) (Table 2), partial hepatectomy should be considered. Overall, the presence of cirrhosis is associated with worse long-term survival following resection.[19,22,23] In addition to cirrhosis, poor prognostic factors include large tumor size, multifocality, presence of vascular invasion, and poorly differentiated grade.[19,21,23,24] Following partial hepatectomy, overall 5-year survival rates range between 35% and 50% (Table 4).[25,19,26-31]
In recent years, improvements in operative mortality can be attributed to advances in preoperative imaging, better patient selection, development of new operative techniques and equipment, and advances in operative and postoperative anesthesia and critical care. Although earlier reports demonstrated substantially increased operative mortality (up to 20%) following resection in patients with cirrhosis, more current studies from both western and eastern investigators showed similar postoperative mortality (< 5%) for patients with and without cirrhosis.[19,24,28-30] Centers in which a higher volume of liver resections are performed have a lower perioperative mortality.
Even among patients in whom resection is performed with curative intent, intrahepatic recurrence is seen in up to 70% of cases. It is thought that some intrahepatic recurrences may actually be de novo multifocal disease or metachronous new tumors within the liver. These distinctions can be difficult to make. Nevertheless, with aggressive management of recurrences, long-term survival can also be achieved in these patients.
Orthotopic Liver Transplantation
In light of the high concomitant incidence of cirrhosis and HCC and the potential for multifocal malignancy, the prospect of removing the entire liver containing the tumor and replacing it with a healthy one is attractive. However, limited donor availability with attendant long waiting lists, high cost, significant morbidity, and the potential cytostimulatory effect of systemic immunosuppression remain formidable obstacles to transplantation.
Stage for stage, liver transplantation can achieve 5-year survival rates comparable or superior to those of partial hepatic resection in selected cases (Table 5).[13,25,34-39] Transplantation has a more favorable prognosis in patients with a solitary tumor < 5 cm or those with no more than three nodules, each £ 3 cm (the so-called “3-3 rule”).
More extensive disease should be considered an absolute contraindication to transplantation. Importantly, in patients with cirrhosis, a 4-year survival rate of 75% is achievable following total hepatectomy and transplantation for unresectable tumors < 5 cm or no more than three nodules, each £ 3 cm. Bilobar disease, by itself, is not considered a contraindication to transplantation.
Contraindications to liver transplantation include the presence of extrahepatic disease and comorbid factors precluding transplantation for benign indications. Other relative contraindications include the presence of vascular invasion or a poorly differentiated grade.
Due to the long wait times for cadaveric donor organs (often more than 1 year), various alternatives to standard organ availability have been considered. These include increasing the priority status of patients with HCC for transplantation, utilizing split liver techniques, or considering marginal donor organ quality for patients with a malignancy. In addition, the increasing use of adult living donor transplantation may improve transplant availability for the cancer patient.
Attempts have been made to restrain HCC growth while patients await transplantation. Many institutions have published small series employing preoperative chemotherapy, radiotherapy, and/or transarterial chemoembolization administered prior to transplantation; these studies have had mixed results.[41-44] Similarly, the role of postoperative adjuvant chemotherapy is undefined.
At present, conclusions cannot be made, and definitive recommendations for the use of preoperative or adjuvant therapy await the results of ongoing, multicenter, randomized clinical trials. Currently, only selected patients with small tumors and moderate to severe cirrhosis should undergo liver transplantation.
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