WORKUP	Section 5 of 10
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Lab Studies:

• Expect total bilirubin, aspartate aminotransferase (AST), alkaline phosphatase, albumin, and prothrombin time to show results consistent with cirrhosis.

• Alpha-fetoprotein (AFP) is elevated in 75% of cases.

• The level of elevation correlates inversely with prognosis.

• An elevation of greater than 400 ng/mL predicts for HCC with specificity greater than 95%. In the setting of a growing mass, cirrhosis, and the absence of acute hepatitis, many centers use a level greater than 1000 ng/mL as presumptive evidence of HCC (without biopsy).

Imaging Studies:

	TREATMENT	Section 6 of 10
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Medical Care: Available treatment options depend on the size, number, and location of tumors; presence or absence of cirrhosis; operative risk based on extent of cirrhosis and comorbid diseases; overall performance status; patency of portal vein; and presence of metastatic disease.

Before instituting definitive therapy, it is best to treat the complications of cirrhosis with diuretics, paracentesis for ascites, lactulose for encephalopathy, ursodiol for pruritus, sclerosis or banding for variceal bleeding, and antibiotics for spontaneous bacterial peritonitis.

Surgical resection and liver transplantation are the only chances of cure but have limited applicability. The main prognostic factors for resectability are tumor size and liver function. Other local therapies are chemoembolization, ethanol ablation, radiofrequency ablation, cryoablation, and radiotherapy. Systemic treatment with chemotherapy may be used.

• Systemic chemotherapy
  • For patients with advanced HCC who are not candidates for surgical resection, liver transplantation, or localized tumor ablation, systemic chemotherapy remains the mainstay of therapy. Unfortunately, HCC is a relatively chemotherapy-resistant tumor; therefore, outcomes using this mode of treatment are unsatisfactory. Resistance to chemotherapy may be caused by the universal expression of the multidrug resistance gene protein on the surface of the malignant cells, leading to active efflux of chemotherapeutic agents. Chemotherapy is usually not well tolerated and seems to be less efficacious in patients with HCC with underlying hepatic dysfunction. Younger patients with well-compensated cirrhosis due to chronic hepatitis B or C infections have better outcomes with chemotherapy than older patients with alcoholic cirrhosis and other comorbid diseases.

• The most active single agent drugs tested have been doxorubicin, cisplatin, and fluorouracil. Response rates are about 10%, and treatment shows no clear impact on overall survival. More recently, gemcitabine and capecitabine have been evaluated in clinical trials; response rates have been low and short term.

• A variety of combination chemotherapy regimens have also been studied. Recently, cisplatin-based combination regimens have shown improved response rates around 20%, but to date, no survival advantage as compared to supportive care alone has been shown. No difference seems to exist in response rates between 2 or 3-drug regimens. Moreover, some of these combination regimens cause considerable toxicity.

• Chemoimmunotherapy uses a combination of chemotherapy and immunomodulatory agents, such as interferon-alpha, to try to achieve better tumor response rates. Immunotherapy has had encouraging results in patients with certain types of cancers such as renal cell carcinoma and melanoma. PIAF is a combination of cisplatin, interferon-alpha, doxorubicin, and infusional 5-fluorouracil that is associated with a response rate of 26%, which is higher than the response rates with single chemotherapy agents. Although overall median survival is longer with PIAF than single-agent doxorubicin, treatment-related toxicity is significant. The best candidates for this therapy are young patients without liver cirrhosis and normal bilirubin levels.

• Antiangiogenesis agents (ie, bevacizumab), which work by disrupting the formation of blood vessels that feed tumors, are a new class of drugs that may prove to be of benefit in the treatment of HCC. The highly vascular nature of HCC tumors makes therapy with an antiangiogenesis agent a promising and exciting new option. Further evaluation of these drugs in the setting of clinical trials is needed to determine their efficacy.

• Chemoembolization

• Chemoembolization is the delivery of high concentrations of chemotherapeutic agents directly to the HCC tumor via the hepatic artery, which provides the tumor with most of its blood supply. The remainder of the liver may be spared because it can rely on the portal vein for its blood supply.

• Embolizing agents such as cellulose, microspheres, lipoidal, and gelatin foam particles are used to deliver intra-arterial chemotherapy (mitomycin, doxorubicin, cisplatin) to the tumor via the hepatic artery.

• Morbidity from this procedure is greatly dependent on the extent of cirrhosis. In general, patients with portal vein thrombosis, encephalopathy, or biliary obstruction are not candidates for chemoembolization.

• Response rates of 60-80% are seen. In addition, 2 recent clinical trials from Spain and Hong Kong showed a modest survival benefit with the use of doxorubicin (Adriamycin) or cisplatin with embolization as compared to supportive care only in patients with unresectable tumors.

Surgical Care:

• Partial hepatectomy

• In the United States, resection is possible in only 5% of patients. In general, solitary HCC lesions confined to the liver without vascular invasion with well-preserved hepatic function have the best outcomes. Although there are no strict criteria in terms of tumor size, many surgeons use less than 5 cm as their cutoff.

• Five-year survival rates for resectable lesions vary widely from 40% to as high as 90% for very early stage HCC lesions. Fibrolamellar HCC may have a better prognosis for survival after surgical resection because of a more favorable size, predominantly left lobe location, and the absence of cirrhosis in the unaffected portion of the liver.

• Appropriate evaluation of patients prior to resection is crucial since intraoperative mortality is doubled in cirrhotic versus noncirrhotic patients. Preoperative laparoscopic inspection aids in diagnosing both the tumor and extent of cirrhosis.

• Transplantation

• Many patients are not candidates for partial hepatectomy due to extent of underlying liver disease. Some of these patients are good candidates for liver transplantation since it has the potential for eliminating the cancer as well as curing the underlying liver disease.

• Orthotopic liver transplantation can be considered for patients who meet the Milan criteria—one tumor less than 5 cm or up to 3 tumors all less than 3 cm. These highly selected patients have excellent survival rates, similar to those of patients who undergo liver transplantation for end-stage liver disease without HCC.

• Although availability of donor organs is still limited, the Organ Procurement and Transplantation Network (OPTN) and the United Network for Organ Sharing (UNOS) have recognized the urgency of proceeding to transplantation in patients with limited stage HCC. Over the past 5 years, revision of the UNOS policy has established medical criteria by which a patient with early/small HCC can be assigned additional priority for liver allocation so as to increase the likelihood of a favorable transplant outcome. This has resulted in shorter wait times to transplantation and better overall outcomes. Bridging therapy with local therapies, such as chemoembolization or radiofrequency ablation (RFA), is sometimes considered for patients on the transplant waiting list.

• Local tumor ablation

• Intratumoral injections of ethanol or acetic acid, heat (via radiofrequency, microwave, or laser ablation), or cold (cryoablation with liquid nitrogen) may be used to locally control tumors smaller than 4-5 cm. These techniques are frequently performed percutaneously as outpatient procedures. In general, these procedures are reserved for patients who do not meet criteria for surgical resection but yet are candidates for a liver-directed procedure based on the presence of limited liver-only disease.

• Radiofrequency ablation (RFA) is the delivery of radiofrequency thermal energy to the HCC lesion causing necrosis of the tumor. During RFA, a high frequency alternating current is delivered from the tip of an electrode into the surrounding tissue. The ions within the tissue attempt to follow the direction of the alternating current resulting in friction and eventual heating of the tissue. As tissue temperature elevates above 60°C, tumor cells begin to die resulting in an area of tumor necrosis. The needle electrode is advanced into the HCC lesion usually via a percutaneous route with the guidance of ultrasonography. The procedure can also be performed surgically via laparoscopy or laparotomy.

• RFA is usually used for treatment of tumors less than 4 cm in size. For small tumors, studies show good initial local tumor control with an average local recurrence rate of 5-6% within the first 20 months. The treatment of larger tumors results in much higher rates of local recurrence. Unfortunately, a significant proportion of patients eventually develop clinically detectable hepatic or extrahepatic disease from their preexisting micrometastatic lesions. RFA is usually well-tolerated, but complications including fever, pain, bleeding, pleural effusion, hematoma, and intermittent transaminitis among others have been reported.

• Percutaneous ethanol or acetic acid ablation is reserved for patients with small tumors; however, in many areas, the ease and efficacy of RFA has now replaced these older techniques. Radiation therapy is limited by dose-related radiation hepatitis, which precludes the administration of external beam radiation in doses effective for tumor eradication. Doses of 2500 cGy may be used for palliative measures.

• CyberKnife system is a new technology that uses a combination of robotics and image guidance to deliver concentrated and highly focused beams of radiation to the tumor while minimizing radiation exposure to the surrounding healthy liver tissue. CyberKnife stereotactic radiosurgery is a promising new treatment tool for localized HCC lesions. Currently, its availability is limited to a few medical centers, and long-term efficacy for HCC lesions is yet to be determined.

Consultations:

• Hepatobiliary surgeon

• Oncologist

• Interventional radiologist

• Interventional gastroenterologist

	FOLLOW-UP	Section 7 of 10
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Further Outpatient Care:

• Monitor the progression of disease or adequacy of treatment with imaging studies every 2-3 months and LFTs and AFP monthly or as appropriate for the stage of disease and patient's performance status. These interventions, however, have little or no impact on prognosis for survival and therefore should be performed in accordance with the patient's functional status.

Deterrence/Prevention:

• Patients should avoid alcohol and other hepatic toxins because prognosis is related to worsening cirrhosis and tumor stage.

Complications:

• Symptoms of hepatic failure may signify tumor recurrence and/or progression.

Prognosis:

• Overall prognosis for survival depends on the extent of cirrhosis and tumor stage, which then determine the appropriate treatment. Patients able to undergo a curative resection have a median survival of as long as 4 years; patients who present when they are too ill to be treated have a median survival of 3 months.

Patient Education:

	MISCELLANEOUS	Section 8 of 10
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Medical/Legal Pitfalls:

• Consider HCC in any person with possible risk factors who develops symptoms of liver disease, such as unexplained jaundice, increased abdominal girth, or pruritus.

• Family members of patients with hepatitis B infections should undergo screening for the virus.

• Consider screening of patients with cirrhosis, especially those with hepatitis C infection.

Special Concerns:

• Screening for HCC

• Despite the widespread use of screening and surveillance programs for HCC, the efficacy and cost-effectiveness of screening programs for at-risk patients is unclear.

• In general, the annual incidence of developing HCC in the setting of cirrhosis is approximately 1-4%. Screening studies have shown that, although lesions may be discovered at an earlier stage, the lack of curative treatment options in patients with cirrhosis may not lead to improvements in survival.

• Patients with chronic hepatitis B without cirrhosis have a much lower annual incidence of developing HCC of 0.46%. The incidence of HCC in patients with chronic hepatitis C without cirrhosis is even lower. Screening programs using AFP and an imaging modality in patients with hepatitis B or C without cirrhosis is not cost-effective given the low incidence of HCC in these patients and the high cost of imaging techniques.

• Survival advantage with screening in these at-risk populations has not been demonstrated. The retrospective screening studies that have shown modest survival advantages are confounded by lead-time and length-time bias.

• If screening is to be undertaken, AFP should not be used alone as a screening test. Instead, AFP should be combined with an imaging modality (ultrasonography, CT scan) to improve sensitivity and specificity.