Stage C and D Adult Primary Liver Cancer
Transarterial Embolization (TAE) and Transcatheter Arterial Chemoembolization (TACE)
TAE is the most widely used primary treatment for hepatocellular carcinoma (HCC) when HCC is not amenable to curative treatment by excision or ablation. The majority of the blood supply to the normal liver parenchyma comes from the portal vein, while blood flow to the HCC comes mainly from the hepatic artery. Furthermore, HCC tumors are generally hypervascular compared with the surrounding normal parenchyma. The obstruction of the arterial branch(es) feeding the tumor may reduce the blood flow to the tumor and result in tumor ischemia and necrosis.
Embolization agents, such as microspheres and particles, may also be administered along with concentrated doses of chemotherapeutic agents (generally doxorubicin or cisplatin) mixed with lipiodol or other emulsifying agents during chemoembolization, arterial chemoembolization, usually via percutaneous access; and TACE. TAE-TACE is considered for patients with nonsurgical HCC, who are also not amenable to percutaneous ablation in the absence of extrahepatic disease. In patients with cirrhosis, any interference with arterial blood supply may be associated with significant morbidity and is relatively contraindicated in the presence of portal hypertension, portal vein thrombosis, or clinical jaundice. In patients with liver decompensation, TAE-TACE could increase the risk of liver failure.
A number of randomized, controlled trials have compared TAE and TACE with supportive care. Those trials have been heterogeneous in terms of patient baseline demographics and treatment. The survival advantage of TAE-TACE over supportive care has been demonstrated by two trials.[1-3] No standardized treatment for a TAE approach has been determined (e.g., embolizing agent, chemotherapy agent and dose, treatment schedule). However, a meta-analysis has shown that TAE-TACE improves survival more than supportive treatment.
The use of drug-eluting beads (DEB) for TACE has the potential of reducing systemic side effects of chemotherapy and may increase objective tumor response.[4-7] Only one study has suggested that DEB-TACE may offer an advantage in overall survival (OS).
At this time, there is no evidence supporting a survival benefit for patients with advanced HCC receiving systemic cytotoxic chemotherapy when compared with no treatment or best supportive care.
Sorafenib is an oral multikinase inhibitor that prolongs survival in patients with advanced HCC and well-compensated liver function.
The SHARP [NCT00105443] trial randomly assigned 602 patients with advanced HCC to receive either sorafenib 400 mg twice daily or a placebo. All but 20 of the patients had a Childs-Pugh A liver disease score; 13% were women. After 321 deaths, the median survival was significantly longer in the sorafenib group (10.7 months vs. 7.9 months on placebo; hazard ratio [HR] favoring sorafenib, 0.69; 95% confidence interval [CI], 0.55–0.87; P < .001).
A subsequent, similar trial conducted in 23 centers in China, South Korea, and Taiwan included 226 patients (97% with Child-Pugh A liver function) with a 2:1 randomized assignment to sorafenib versus placebo. The median OS rate was 6.5 months for the sorafenib group versus 4.2 months for the placebo group (HR, 0.68; 95% CI, 0.50–0.93; P = .014). Adverse events attributed to sorafenib in both of these trials included hand-foot skin reactions and diarrhea.
These studies established a role for sorafenib in locally advanced and advanced hepatocellular cancers extending beyond the liver, which are not amenable to regional modalities.
Little is known about the efficacy of sorafenib for the patient with Child B or C liver function. At this time, further studies are needed before sorafenib can be recommended for a patient with Child B or C cirrhosis.
Studies are also ongoing to evaluate the role of sorafenib after TACE, with chemotherapy, or in the presence of more-advanced liver disease.
The efficacy of other targeted therapy agents (e.g., sunitinib and brivanib) is currently being investigated.
The role of radiation therapy for HCC has traditionally been limited by the low dose tolerance of the liver to radiation. However, recent technological developments in radiation therapy, including breathing motion management and image-guided radiation therapy, have allowed for more precise and targeted radiation therapy delivery to the liver. As a result of these advances, conformal liver irradiation has become feasible in the treatment of focal HCC. Several phase II studies have suggested a benefit in local control and OS compared with historical controls for patients with locally advanced HCC unsuitable for standard locoregional therapies.[12,13][Level of evidence: 3iiDiii] An ongoing, multi-institutional, randomized, phase III study (RTOG 1112 [NCT01730937]) evaluating sorafenib versus stereotactic body radiation therapy followed by sorafenib in HCC is currently open for patient accrual. This study aims to definitively evaluate the role of radiation therapy for locally advanced HCC.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with adult primary liver cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
- Llovet JM, Bruix J: Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival. Hepatology 37 (2): 429-42, 2003. [PUBMED Abstract]
- Llovet JM, Real MI, Montaña X, et al.: Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet 359 (9319): 1734-9, 2002. [PUBMED Abstract]
- Lo CM, Ngan H, Tso WK, et al.: Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 35 (5): 1164-71, 2002. [PUBMED Abstract]
- Malagari K, Pomoni M, Kelekis A, et al.: Prospective randomized comparison of chemoembolization with doxorubicin-eluting beads and bland embolization with BeadBlock for hepatocellular carcinoma. Cardiovasc Intervent Radiol 33 (3): 541-51, 2010. [PUBMED Abstract]
- Varela M, Real MI, Burrel M, et al.: Chemoembolization of hepatocellular carcinoma with drug eluting beads: efficacy and doxorubicin pharmacokinetics. J Hepatol 46 (3): 474-81, 2007. [PUBMED Abstract]
- Poon RT, Tso WK, Pang RW, et al.: A phase I/II trial of chemoembolization for hepatocellular carcinoma using a novel intra-arterial drug-eluting bead. Clin Gastroenterol Hepatol 5 (9): 1100-8, 2007. [PUBMED Abstract]
- Lammer J, Malagari K, Vogl T, et al.: Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study. Cardiovasc Intervent Radiol 33 (1): 41-52, 2010. [PUBMED Abstract]
- Dhanasekaran R, Kooby DA, Staley CA, et al.: Comparison of conventional transarterial chemoembolization (TACE) and chemoembolization with doxorubicin drug eluting beads (DEB) for unresectable hepatocelluar carcinoma (HCC). J Surg Oncol 101 (6): 476-80, 2010. [PUBMED Abstract]
- Llovet JM, Ricci S, Mazzaferro V, et al.: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359 (4): 378-90, 2008. [PUBMED Abstract]
- Cheng AL, Kang YK, Chen Z, et al.: Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 10 (1): 25-34, 2009. [PUBMED Abstract]
- Abou-Alfa GK, Schwartz L, Ricci S, et al.: Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol 24 (26): 4293-300, 2006. [PUBMED Abstract]
- Bujold A, Massey CA, Kim JJ, et al.: Sequential phase I and II trials of stereotactic body radiotherapy for locally advanced hepatocellular carcinoma. J Clin Oncol 31 (13): 1631-9, 2013. [PUBMED Abstract]
- Kawashima M, Furuse J, Nishio T, et al.: Phase II study of radiotherapy employing proton beam for hepatocellular carcinoma. J Clin Oncol 23 (9): 1839-46, 2005. [PUBMED Abstract]