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Viral Hepatitis

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Hepatitis C and Hepatocellular Carcinoma

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Hepatitis C and Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) in 2005 is a cancer that is becoming increasingly common in the United States.(1) Its effects on the health of Americans, and particularly veterans, likely will grow substantially over the next several decades, as the later health consequences of the hepatitis C epidemic play themselves out.(2)

HCC is the fifth most common cancer in the world and the most common type of liver cancer. The incidence of HCC in the United States is approximately 2.4 per 100,000 persons per year, and rising.(3) Chronic infection with hepatitis C virus (HCV) is now a major risk factor for the development of HCC in developed countries. Patients with advanced liver disease, particularly cirrhosis, are those at risk for HCC and should be screened every 6 months for its development. The risk of developing HCC for a patient with HCV-related cirrhosis is approximately 2-6% per year.(4)

Risk Factors

Chronic hepatitis B virus (HBV) infection, chronic HCV-related cirrhosis, and cirrhosis of any etiology are the major risk factors for the development of HCC. Patients with HBV are known to be at risk for HCC even without cirrhosis, so all patients with chronic HBV (those who are hepatitis B surface antigen positive) should be considered for screening for HCC.(5) Individuals with chronic HBV who are at increased risk for HCC include men, anyone over age 45, and those with cirrhosis or a family history of HCC. (6)

In patients with HCV, only those with advanced liver disease (particularly cirrhosis) have been shown to be at high risk for HCC, so screening should be applied only to these patients.(7) Other HCC risk factors include inherited metabolic diseases such as hemochromatosis and tyrosinemia. Additional risk factors for HCC development include older age, alcohol use, and exposure to aflatoxin, particularly in developing countries.

Screening Modalities

Screening for HCC in at-risk patients is expensive and time consuming, and only recently has it been shown to lead to improved patient outcomes.(4, 8) Nonetheless, it is considered standard practice within the gastroenterology/liver community in developed areas of the world.(7) Screening generally is performed using both serum alpha fetoprotein (AFP) and hepatic imaging by ultrasound, computerized tomography (CT) scanning, or magnetic resonance imaging (MRI). Screening intervals generally are every 6 months. No screening strategy is perfect, and patients have been found at transplant to have tumors that were not seen on imaging, or to have no tumor in areas that were suspicious by imaging.(9)

No randomized controlled trial of screening/surveillance in patients at risk for HCC, with disease-specific or all-cause mortality as end points, has been published. Nor is one expected, as screening of cirrhotic patients for HCC with serial liver imaging and measurement of serum AFP is now considered standard practice. However, studies that reflect improved outcomes with these screening strategies are being published. An Italian group found that patients undergoing screening and aggressive therapy for HCC diagnosed after 1997 had smaller tumors and improved yearly mortality compared with patients who had been diagnosed during earlier time periods.(4)

Serum Testing for AFP

Between 50% and 85% of hepatocellular carcinomas produce AFP, which normally is not present at high levels in the blood of adults. Elevation of AFP in the blood is fairly sensitive for the detection of HCC. In one study of patients with chronic HCV, the sensitivity and specificity of an AFP of >20 ng/mL for the diagnosis of HCC were 67% and 89%, respectively.(10) It should be noted, however, that pregnancy, germ cell tumors, and even chronic inflammatory liver diseases also can elevate AFP levels. The positive predictive value of an AFP >20 ng/mL is poor since minor elevations are common in patients with chronic liver disease. In one prospective study of 200 patients with chronic HCV infection, 13% of those without cirrhosis and 47% of those with cirrhosis had a serum AFP level of >10 ng/mL.(11) When AFP has been studied in patients with HCV-related cirrhosis specifically, an AFP >200 ng/mL in the setting of a hepatic mass was found to be essentially diagnostic of HCC, although lower levels were not as specific.(12) African Americans with HCC also tended to have less AFP elevation than Caucasians with HCC, making AFP a less helpful marker in them.

Ultrasonography

Ultrasound is the standard imaging modality for HCC screening, and a skilled operator can often visualize tumors that are ≥1 cm in diameter.(13) Ultrasound sensitivity for detection of such tumors across several studies is in the range of 60%, with specificity of around 90%.(14) The cirrhotic liver can make visualization of small HCCs very difficult, however, so screening practices should be individualized based on available resources at each location where screening is performed.

Other Imaging Studies

Other radiological techniques including CT scans and MRI are even more sensitive than ultrasound in detecting small lesions in the liver. One study found the sensitivity of HCC detection to be 79.4% for ultrasound, 81.6% for CT scan, and 88.9% for MRI.(15) The cost effectiveness of these imaging studies compared with ultrasound remains to be demonstrated, however, as unrelated abnormalities of the liver that require evaluation are detected by the increasingly sensitive techniques.

Diagnosis

Clinical Presentation

Clinical signs and symptoms present in later stages of HCC. These signs and symptoms may include:

  • right upper quadrant pain or fullness
  • weight loss
  • elevated liver function tests, particularly an elevated alkaline phosphatase
  • increases in AFP levels
  • infrequently: polycythemia, hypoglycemia, hypercalcemia, dysfibrinogenemia, or intraperitoneal bleeding due to tumor rupture

Histological Evaluation

Because clinical presentations of HCC are not entirely specific, histological evaluation with a percutaneous biopsy sometimes is performed to aid in the diagnosis. This often is not done, however, in patients with known cirrhosis who are found to have a new mass lesion concerning for HCC during screening. Particularly, a nodule >2 cm in diameter in this setting has >95% likelihood of being an HCC.(16) According to European Association for the Study of Liver guidelines, confirmation of arterial hypervascularity of the lesion by 2 additional imaging techniques (CT, MRI, or angiography), or 1 additional imaging technique if the AFP is >400 ng/mL, is sufficient for a diagnosis of HCC without a biopsy.(17) Smaller lesions in a cirrhotic patient also often represent early HCCs. If a patient with a concerning lesion is being considered for referral for listing for liver transplantation, consultation with the referring center also can be undertaken prior to proceeding with a percutaneous biopsy of the lesion.

Prognosis

Staging is essential for the optimal management of HCC, as a wide variety of treatments are applied based on HCC stage. Residual hepatic function and tumor extent tend to be the two factors that most influence HCC prognosis. Hepatic function tends to be assessed by the Child-Pugh classification or the MELD score. Unfortunately, no single scoring system for HCC staging has been accepted as the best one. Staging systems that have been widely used are the Okuda system,(18) the tumor, node, metastasis (TNM) system of the International Union Against Cancer,(19) the Cancer of the Liver Italian Program (CLIP) score,(20) the Barcelona Clinic Liver Cancer (BCLC) system,(21) and several others. The TNM system takes into account only the extent of the tumor; the Okuda system adds serum albumin, serum bilirubin, and the extent of ascites; and the CLIP system includes Child-Pugh class, tumor morphology, whether or not the AFP is >400 ng/mL, and the presence or absence of portal vein thrombosis. The BCLC system is similar to the CLIP, but incorporates the performance status of the patient, and does not include AFP. A recent study comparing the predictive value of 7 staging systems in a group of HCC patients in the United States found that all 7 systems were valid, with survival declining in direct correlation with higher score, but that the BCLC system, incorporating performance status, had the best independent predictive power for survival.(22) Practitioners caring for many HCC patients likely will find it useful to have a working knowledge of several of the systems.

The median survival of HCC patients after diagnosis generally has been a little more than 1 year. Survival usually is between 3-6 months if a patient is diagnosed after the onset of symptoms. Median survivals as short as 8-10 weeks have been reported in some studies, including a retrospective study of 157 untreated patients, 18% of whom had extrahepatic metastases at the time of diagnosis.(23) Causes of death in these patients were upper gastrointestinal bleeding in 34%, cancer-related causes (cachexia and metastatic disease) in 32%, and hepatic failure in 25%.

Treatment Modalities

It is likely that <50% of patients with HCC undergo definitive treatment because of age, liver function, general medical condition, and patient refusal. The treatment modalities outlined here are based on a literature review. They do not represent official guidelines for the treatment of hepatocellular carcinoma in the VA health care system. For more information on treatment modalities, please visit www.cancer.gov/cancertopics/types/liverLink will take you outside the VA website.. Of the available treatments for HCC, only surgical resection and transplantation are potentially curative treatments.(24, 25) Other treatments are palliative, although they may be used in combination with resection or liver transplantation.

See update to topic review: Sorafenib: A New Treatment for Advanced Hepatocellular Carcinoma

Surgical Resection

Surgical resection may be curative if HCC is detected at an early stage. Patients who are <65 years of age, have Child-Pugh Class A cirrhosis, and have only 1 or 2 tumors are the best candidates for hepatic resection. However, the rate of recurrence of HCC after resection is very high, approaching 25% per year. Once a liver has formed HCC, it can be considered a premalignant organ, at risk for forming additional tumors. Although early detection undoubtedly increases the likelihood of a tumor being resected, and early outcomes with resection are superior to those in patients whose tumors are first detected clinically, the 5-year recurrence-free survival rate after surgical resection is only 20%.(26) Moreover, less than 20% of HCC patients are good candidates for surgical resection. That is, only 1 of 5 patients has HCC small enough and liver function good enough to perform a safe, curative resection that leaves no residual tumor and sufficient hepatic reserve. An anatomical resection can be performed safely only in noncirrhotic patients or in cirrhotic patients with fully compensated liver function. In such patients who undergo resection, the 3-year survival rate is 80% and the 3-year recurrence-free survival rate is 40%. Resection will not limit the development of new primary cancers in the diseased liver. Tumor size plays an important role in the likelihood of recurrence after resection.(24) Contraindications to resection include (27):

  • decompensated liver disease
  • anatomically unresectable disease
  • extrahepatic and vascular spread
  • comorbid conditions precluding major abdominal surgery

Liver Transplantation

Liver transplantation likely affords the best long-term survival to patients with localized HCC. It is an option for patients who are good transplant candidates and have small hepatocellular carcinomas. Limits on tumor size traditionally have been a solitary, encapsulated tumor <5 cm in diameter or no more than 3 lesions, each <3 cm in diameter. In one study, patients who met these selection criteria and underwent liver transplantation had a survival rate of 75% at 4 years posttransplant.(28) Transplantation of patients with hepatocellular cancer slightly beyond these dimensions also has been successful,(15) although it remains controversial. Many patients in 2005 also undergo therapy for HCC prior to transplantation. In a recent nonrandomized study, such pretransplant therapy has even been found to confer some benefit to posttransplant clinical course.(29)

Transcatheter Arterial Chemoembolization

Transcatheter arterial chemoembolization (TACE) is a combination of targeted chemotherapy and arterial embolization that has both selective ischemia and chemotherapeutic effects on HCC. This technique, or similar techniques involving ischemia without the use of chemotherapy, tend to be used in patients with several small tumors who cannot undergo resection or in patients immediately pretransplant to achieve a "tumor kill" before replacement of the organ. TACE causes minimal damage to normal liver parenchyma because of the dual blood supply to the liver. The hepatic artery supplies 80-100% of blood flow to liver tumors. In contrast, this artery supplies only 20-30% of blood flow to normal liver tissue. The portal vein supplies the liver with the remaining 70-80% of its blood flow.(30)

For the TACE procedure, a cytotoxic agent such as doxorubicin or cisplatin can be mixed with iodized oil (Lipiodol) to form a suspension, which is then injected into the artery supplying the tumor.(31) Access is obtained via the femoral artery, and angiography is utilized throughout the procedure. The iodized oil serves as a vehicle to carry the cytotoxic agent to the tumor and is also the embolizing agent that blocks the tumor's vessels. Major complications from TACE include portal vein thrombosis, hepatic abscess, hepatic artery dissection or thrombosis, and liver failure. One retrospective study found a morbidity rate of 5.1% and a treatment-related mortality rate of 4.1%.(32) Contraindications for the TACE procedure include advanced (Child-Pugh Class C) cirrhosis, portal vein thrombosis, hepatic encephalopathy, and biliary obstruction.

The most important prognostic factor in evaluating the efficacy of TACE for HCC is the size of the main tumor. One study found a 100% survival at 3 years after TACE for tumors <2 cm in diameter, whereas, for tumors >5 cm in diameter, the 3-year survival rate was <1%.(33) Other studies of TACE showed significant prolongation of survival in patients with tumor volumes <200 mL and an iodized oil retention ≥75%.(34) In another study, a comparison was made between 69 patients treated with TACE vs 64 untreated patients.(35) The 1-year and 3-year survival rates for patients treated with TACE were 64% and 28%, respectively. In comparison, the 1-year and 3-year survival rates for untreated patients were 16% and 3%, respectively.

TACE should not be recommended as the sole therapy to patients with operable HCC who are surgical or transplant candidates.

Percutaneous Ethanol Injection

Percutaneous injection of high-concentration ethanol directly into HCCs is another localized form of therapy. It is most effective for smaller HCCs,(36) and is performed under direct tumor visualization, generally with ultrasound, either percutaneously or intraoperatively. The therapeutic response to percutaneous ethanol injection (PEI) can be evaluated by CT examination before the procedure, 1 month after the procedure, and then every 4-6 months. Necrosis is deemed to be complete when the CT shows no areas of enhancement remaining within the tumor. Contraindications to PEI include advanced cirrhosis, severe bleeding diathesis, portal vein thrombosis, and diffuse HCC. Major complications (intraperitoneal hemorrhage, right pleural effusion, cholangitis, liver abscess, hemobilia, arterioportal shunt, shock) are rare, ranging from 1.3% to 2.4%, and usually are treated conservatively. Compared with surgery, PEI causes minimal loss of normal liver tissue. Also, PEI can be repeated easily when new lesions appear, as they do in the majority of patients. The overall 5-year survival in 628 patients with lesions <5 cm in diameter and compensated cirrhosis was 48%, comparable to a 49% 5-year survival rate in a similar population of 1,272 patients who underwent surgical resection.(37) To achieve more complete necrosis of large (>3 cm in diameter) HCC tumors, PEI has been combined with TACE.(38) The 1-year and 3-year survival rates of PEI in combination with TACE were 100% and 85%, respectively. The partial response rate significantly increased from 10% with TACE alone to 45% with the combination of TACE and PEI. Also, the combination of TACE and PEI was significantly better than TACE alone in terms of the rate of primary tumor recurrence during follow-up.

Radiofrequency Ablation

Radiofrequency ablation (RFA) is another localized form of HCC therapy, usually performed under sonographic guidance. With RFA, an alternating electric current causes thermal injury around a needle electrode that is inserted into the tumor. The goal of each procedure is to ablate the tumor and a small margin of normal tissue around the tumor. One study of RFA was performed in 39 patients with 1 or more HCC tumor nodules <3 cm in diameter that were treated with intent to cure.(39) Approximately 50% of the patients had tumor recurrence during follow-up. The 1-year and 3-year survival rates for patients treated with RFA were 95% and 67%, respectively. No complications were observed in any of the patients. The effectiveness of RFA also has been compared with that of PEI. In one study of 86 patients with HCCs <3 cm in diameter, the patients were treated with either RFA (42 patients) or PEI (44 patients). Complete tumor necrosis was achieved in 90% of tumors with RFA and in 80% of tumors with PEI. In contrast with other RFA series, 1 major complication and 4 minor complications were reported with RFA. In the patients treated with PEI, no complications were reported.(40)

Hepatic Artery Chemotherapy

Chemotherapeutic agents can be delivered via hepatic arterial infusion through an implantable pump directly to HCCs. This increases local drug concentrations while minimizing adverse systemic effects. This approach is not widely used at present, but has been shown to be of some efficacy. The chemotherapeutics most commonly used alone or in combination with this technique include 5-fluorouracil (5-FU) and 5-fluorouracil deoxyribonucleoside (FUDR). The complications of hepatic artery chemotherapy include impaired liver function, biliary sclerosis, liver abscess, and dislodged catheter tip. In one study, 14 patients were treated with intrahepatic etoposide, 5-FU, and cisplatin (EFP) and another 14 patients were treated with etoposide, Adriamycin, and cisplatin (EAP).(41) The partial response rate was 46% in the EFP group and 53% in the EAP group. In another study, 29 patients with nonresectable HCC confined to the liver were treated with intrahepatic FUDR, leucovorin, Adriamycin, and cisplatin (FLAP).(42) The partial response rate was 41%, and the median time to disease progression was 13 months, with median survival of 15 months. Of note, patients in the latter study with hepatitis B or C experienced increased myelotoxicity from chemotherapy compared with patients with other forms of liver disease.

Systemic Chemotherapy

No systemic chemotherapeutic strategy has been shown to lead to improved outcomes in HCC compared with localized therapies. The first chemotherapeutic agent to be used in the treatment of HCC was 5-FU. As a single agent, the overall response rate of 5-FU is around 10% and the median survival time is 3-5 months.(43) Adriamycin seems to be the most active single agent, with a response rate of 25%, as documented in one of the few randomized trials comparing therapy with supportive care.(44) Finally, a combination of cisplatin, interferon-alfa-2b, Adriamycin, and 5-FU showed a partial response in 26% of the 50 patients studied.(45) Disease previously considered unresectable became resectable in 9 patients (18%), and no evidence of tumor was seen with short-term follow-up in 4 patients (9%). Patients with advanced cirrhosis cannot tolerate cisplatin because associated portal hypertension and hypoalbuminemia precludes the necessary intravascular volume expansion necessary to prevent renal toxicity.

Prevention of HCC

Prevention efforts in the area of HCC have been directed at prevention of underlying liver disease. Primary prevention of HCV infection includes thorough screening of the blood supply and risk-reduction interventions in injection drug users. Secondary prevention of the progression from HCV-related cirrhosis to HCC has been shown following interferon-alfa treatment of cirrhosis.(46, 47) Limiting alcohol intake and reducing obesity in patients with HCV also may lead eventually, through decreased liver disease progression, to a reduction in HCC.

HBV immunization programs have successfully reduced the incidence of HBV-associated HCC. In Taiwan, the rate of HCC in children aged 6-9 decreased from 5.2 per million before a neonatal vaccination program for HBV began in 1984 to 1.3 per million in the first vaccinated cohort.(48)

Secondary Prevention

Kubo and colleagues randomized 30 HCV-positive men after HCC resection to either 2 years of interferon-alfa or no postoperative therapy.(49) The rate of tumor recurrence was significantly lower in the interferon-alfa group than in the control group, and the authors concluded that postoperative interferon-alfa therapy had a role in decreasing the incidence of recurrence after resection of HCV-related HCC. Agents such as polyprenoic acid and acyclic retinoids are also being investigated in the hopes of preventing second primaries following resection of HCC.(50)

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