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. Meta-analysis of studies does indicate a positive impact on overall survival.

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 randomized trial comparing RFA with ethanol injection found a significant benefit to RFA for local recurrence-free survival (96% vs 62% at 2 years) but not for overall survival (98% vs 88%).

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 patients with hepatocellular carcinoma. 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, but results from phase II combination studies are mixed.

Hepatic arterial infusion (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 meta-analysis concluded that HAI after curative liver resection improved survival significantly at both 2 (23% benefit) and 3 (28% benefit) years.

Biologic therapy Interferon-alpha (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. Moderate-to-high doses of interferon are poorly tolerated by patients with frankly cirrhotic livers.

Biochemotherapy Results of combination biochemotherapy in a study of 154 patients by Leung et al were encouraging. Using a combination of cisplatin, interferon-α-2a (Roferon-A), doxorubicin, and 5-FU for 4 days out of 28 days, resulted in 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. A phase III study of PIAF (cisplatin [Platinol]/interferon-α-2b/doxorubicin[Adriamycin]/5-FU) versus single-agent doxorubicin has confirmed a higher response rate for PIAF, but survival was not significantly better than with doxorubicin. Of note, all patients in this series had hepatitis B-associated hepatocellular carcinoma. Patt et al have studied a less-toxic regimen of continuous 5-FU with interferon-α-2b, demonstrating a median survival of 15.5 months.

Targeted therapies

A group led by Philip at Karmanos Cancer Institute has reported results of a phase II trial of the epidermal growth factor receptor (EGFR)-targeting agent erlotinib (Tarceva) in HCC and biliary tumors. Erlotinib was administered orally, 150 mg daily, to 35 patients with HCC. The response rate was only 9%, but OS for the group was an encouraging 13 months.

Sorafenib (Nexavar), an inhibitor of RAF and VEGF kinases, was recently demonstrated to be the first systemic agent to convinicingly improve survival in a placebo-controlled randomized study. This now represents standard of care for patients with advanced disease that is not amenable to locoregional therapy such as embolization. Studies in conjunction with embolization are already underway. The drug is the first approved for this indication by the FDA.