ADJUVANT AND PALLIATIVE THERAPIES
Given the high risk of recurrence after resection, the multifocal nature of hepatocellular carcinoma, and its association with chronic liver disease, nonresectional therapies can play an important role in management. A number of prognostic factors have been identified for patients with unresectable hepatocellular carcinoma. These factors, taken alone, can have a great effect on survival rates, making cross-treatment comparisons more difficult because considerable selection bias may be present in any nonrandomized trial. Radiation therapy
Adjuvant treatment Intrahepatic recurrence has been observed in up to two-thirds of patients treated with partial hepatectomy for hepatocellular carcinoma. Such a recurrence may represent growth at the resected edge, metastatic disease, or a new primary tumor. There is no evidence, however, that adjuvant radiation therapy can reduce this risk. Unresectable disease Whole-liver radiation therapy can provide palliation in patients with unresectable tumors but is limited to a total dose of ≤ 30 Gy due to the risk of radiation-induced liver disease. Whole-liver irradiation has been combined with chemotherapy and transcatheter arterial chemoembolization, with objective response rates of approximately 40%-50% and median survival rates of about 18 months. Patients with tumor regrowth after chemoembolization may respond to radiotherapy. Radiation therapy has also been delivered using yttrium-90 microspheres infused via the hepatic artery. This approach has encouraging response rates, and a low toxicity profile and may be complementary with other forms of therapy. Three-dimensional conformal radiation therapy treatment planning can allow patients with nondiffuse disease to be safely irradiated to doses well above the whole-liver tolerance dose, with doses up to 90 Gy given safely to selected patients. Multiple institutions have reported response rates as high as 90% with acceptable toxicity when conformal radiation therapy was combined with transcatheter arterial chemoembolization (TACE). Good response and local control rates have also been reported for proton, carbon ion, and stereotactic radiotherapy. Hepatic TACE
Normal hepatocytes receive most of their blood supply from the portal vein, whereas tumors create new blood vessels from branches of the hepatic arterial system. This target is exploited by embolization of the hepatic artery with any number of substances, resulting in radiographic response rates in about 50% of patients and evidence of tumor liquefaction in over two-thirds of patients. Embolization is accomplished by advancing a catheter within the tumor-feeding branch of the hepatic artery. Materials injected have included Gelfoam powder, polyvinyl alcohol, iodized oil (Lipiodol), collagen, and autologous blood clot. Chemoembolization should be reserved for symptomatic tumors, reducing tumor size for resection or ablation, or as a bridge while awaiting transplant. The effect of TACE on survival remains controversial, with randomized studies returning mixed results. A randomized, controlled trial in Spain was stopped early due to a survival benefit, but the number of analyses of data performed represents a potential problem for interpreting these data. Intratumoral ethanol injection
The direct injection of 95% ethanol into a neoplastic lesion causes cellular dehydration and coagulation necrosis. Intratumoral ethanol ablation is employed via a percutaneous route under ultrasonographic guidance. Percutaneous intratumoral ethanol injection is best suited for use in patients with few lesions, each < 5 cm, although larger lesions may be injected multiple times. Although intratumoral ethanol injection appears to be an effective palliative modality in certain patients, its effect on patient survival is unclear. CRYOTHERAPY AND RADIOFREQUENCY ABLATION
Similar to ethanol ablation, cryotherapy and radiofrequency ablation (RFA) techniques are suitable for treatment of localized disease. Cryotherapy has been used intraoperatively to ablate small solitary tumors outside a planned resection (ie, in patients with bilobar disease). Cryotherapy must be performed using laparotomy, which limits its use in the palliative setting. RFA can be performed either via laparotomy or percutaneously and has limitations similar to those of ethanol ablation. As with ethanol ablation, there are no data about a survival advantage with these therapies, which may prove to be most useful for temporary tumor control in patients awaiting liver transplants. A cautionary note regarding percutaneous RFA has been raised by publication of a report from Barcelona, citing 4 of 32 patients in a series who developed needle-track tumor seeding relating to subcapsular tumor location and poorly differentiated tumors. Chemotherapy
Systemically administered chemotherapy has, for the most part, been disappointing in hepatocellular carcinoma patients. This fact relates to both low rates of response to available agents and to difficulty with toxicity for modestly active agents because of liver dysfunction. Agents with partial response rates near or above 10% include doxorubicin, fluorouracil (5-FU), and cisplatin. Two newer agents, oxaliplatin (Eloxatin) and gemcitabine (Gemzar), which do not require liver metabolism or excretion, have garnered some interest. Both agents appear to be more active when partnered with a second agent. At present, there is no apparent role for adjuvant systemic chemotherapy. Intra-arterial chemotherapy (HAI) Use of HAI, principally floxuridine (fluorodeoxyuridine [FUDR]), has good biologic rationale but is hampered by high rates of biliary complications and the requirement for surgical pump placement in patients who are generally poor surgical candidates. A metaanalysis concluded that HAI after curative liver resection improved survival significantly at both 2 (23% benefit) and 3 (28% benefit) years. Biologic therapy Interferon-alfa (IFN-α) has been shown to have potential beneficial effects in prevention of hepatocellular carcinoma; however, recent randomized studies have failed to show a benefit in patients with preexisting cirrhosis and advanced cancers. Adjuvant interferon, however, was associated with a reduction in recurrence in two small randomized trials. This finding needs to be confirmed in a much larger trial. Moderateto- high doses of interferon are poorly tolerated by patients with frankly cirrhotic livers. Retinoid therapy In one Japanese randomized trial, polyprenoic acid has been shown to significantly decrease the rate of recurrence of hepatocellular carcinoma after cura-tive resection. A survival advantage was also demonstrated with long-term follow-up. Unfortunately, this compound has been unavailable for further study. Hormone therapy A small trial reported a survival benefit at 1 year for patients treated with medroxyprogesterone acetate. This result needs to be validated. In one randomized study, people with variant estrogen receptors had a significant improvement in median survival from 7 to 18 months when megestrol acetate was given. Biochemotherapy Recent results of combination biochemotherapy in a study of 154 patients by Leung et al have been encouraging. Using a combination of cisplatin, interferon-α-2a (Roferon-A), doxorubicin, and 5-FU for 4 days out of 28 days, they have shown a response rate of around 20%. Moreover, 10% of patients whose tumors were initially thought to be unresectable subsequently underwent complete resection. Eight of these patients had documented pathologic complete remissions. The question of whether this regimen can be used routinely in the neoadjuvant setting will be the subject of further study. Of note, all patients in this series had hepatitis B-associated hepatocellular carcinoma. More recently, Patt et al studied a less-toxic regimen of continuous 5-FU with interferon- α-2b (Intron A), demonstrating a median survival of 15.5 months. Targeted Therapies
Novel agents are now being studied in hepatocellular carcinoma (see boxed items), and some show promise for improving the outlook of this difficult disease. BILIARY TRACT CANCERS Gallbladder carcinoma is diagnosed approximately 5,000 times a year in the United States, making it the most common biliary tract tumor and the fifth most common GI tract cancer. Approximately 4,500 cases of bile duct tumors occur each year in the United States. Epidemiology GALLBLADDER CANCER
Gender Women are more commonly afflicted with gallbladder cancer than are men, with a female-to-male ratio of 1.7:1. Age The median age at presentation of gallbladder cancer is 73 years. Race An incidence five to six times that of the general population is seen in southwestern Native Americans, Hispanics, and Alaskans. BILE DUCT CANCER
Gender Bile duct tumors are found in an equal number of men and women. Age Extrahepatic bile duct tumors occur primarily in older individuals; the median age at diagnosis is 70 years. Etiology and risk factors GALLBLADDER CANCER
The risk of developing gallbladder cancer is higher in patients with cholelithiasis or calcified gallbladders and in typhoid carriers. BILE DUCT CANCER
Ulcerative colitis is a clear risk factor for bile duct tumors. Patients with ulcerative colitis have an incidence of bile duct cancer that is 9-21 times higher than that of the general population. This risk does not decline after total colectomy for ulcerative colitis. Other risk factors Primary sclerosing cholangitis, congenital anomalies of the pancreaticobiliary tree, and parasitic infections are also associated with bile duct tumors. No association of bile duct cancer with calculi, infection, or chronic obstruction has been found.