Localized and Locally Advanced Unresectable Adult Primary Liver Cancer
Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)
For selected patients with T1, T2, T3, or T4; N0; M0 disease.
Patients whose tumors are localized but unresectable due to location in the liver, concomitant medical considerations (such as cirrhosis), or even limited bilateral tumors, may be candidates for chemoembolization, cryosurgery, percutaneous ethanol injection, or radiofrequency ablation for cancers smaller than 5 cm. Survivals equivalent to resection have been reported. One randomized trial in cirrhosis patients with small hepatocellular carcinomas demonstrated improved local recurrence-free survival in patients who underwent radiofrequency ablation as compared to percutaneous ethanol injections as their only form of treatment,[Level of evidence: 1iiDiii] but overall survival was not changed.[Level of evidence: 1iiA]
Clinical trials that use systemic chemotherapy, regional chemotherapy, and/or labeled or radiolabeled antibodies have demonstrated remission of unresectable hepatoma. Other approaches include embolization of the hepatic artery with gelatin foam powder or muscle fragments and chemotherapy, usually doxorubicin. These approaches often produce central tumor necrosis, reduction in tumor size, and relief of pain, but the benefits are usually transient. Any interference with arterial blood supply (including infusion chemotherapy) may be associated with significant morbidity and is contraindicated in the presence of portal hypertension, portal vein thrombosis, or clinical jaundice. A randomized study of chemoembolization versus conservative treatment found no survival advantage for chemoembolization. This study was terminated early and was underpowered to detect any but large survival differences.
Standard treatment options:
- Radiofrequency ablation, chemoembolization, cryosurgery, or percutaneous ethanol injection: These techniques may be used in patients with small (<5 cm), localized, unresectable tumors.[1,4-8]
- Liver transplantation: For selected patients with localized unresectable hepatoma, particularly patients with fibrolamellar hepatomas, liver transplantation may offer a potentially curative treatment option.
- Chemotherapy (regional infusion of the liver): Chemotherapeutic agents may be infused with a subcutaneous portal or implantable pump via a catheter placed in the hepatic artery. Older studies that use standard agents have demonstrated responses in 15% to 30% of such cases, but newer agents and techniques (i.e., biodegradable microspheres) have been evaluated in pilot trials,[10-12] as has regional chemotherapy with external-beam radiation therapy. Many patients are not candidates for these approaches, which often require surgical intervention.
- Systemic chemotherapy and/or targeted therapy: Prior to the SHARP trial (NCT00105443), durable remissions had rarely been reported, and randomized series had shown no significant survival benefits when compared with no treatment. In the SHARP trial, 602 patients with advanced hepatocellular carcinoma (slightly less than 50% of the patients in each group had carcinomas that were confined to the liver but were unresectable and had extrahepatic spread) who had not received prior systemic treatment were assigned to receive either sorafenib 400 mg twice daily or placebo. All but 20 patients had 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).[Level of evidence: 1iA] While median time to symptoms was not significantly different, the percent achieving radiologic responses was higher in the sorafenib group.
A subsequent similar trial conducted with 271 patients from 23 centers in China, South Korea, and Taiwan with a 2:1 randomization on sorafenib achieved a median overall survival rate of 6.5 months on sorafenib versus 4.2 months on placebo (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 establish a role for sorafenib in locally advanced as well as advanced hepatocellular cancers extending beyond the liver, which are not amenable to regional modalities. Studies are ongoing to evaluate the role of sorafenib after transarterial chemoembolization (TACE), with chemotherapy, or in the presence of more advanced liver disease.
- Surgery, chemotherapy, and radiation therapy: These modalities may be combined in clinical trials for patients with a dominant hepatic mass and multifocal involvement with small amounts of tumor; surgical resection, radiofrequency ablation, or cryosurgery of the mass may be followed by hepatic infusion of the remaining liver with chemotherapeutic agents alone or in combination with hyperthermia, radiation, or radiation with radiosensitizers. Chemotherapy plus radiation has also been used to shrink tumors prior to resection. However, the whole liver is not tolerant of large doses of radiation therapy.
- Radiosensitizers and external-beam radiation therapy without chemotherapy: The relative radiosensitivity of normal liver tissue compared with tumor tissue must always be considered when radiation therapy is contemplated.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with localized unresectable 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.References
- Zhou XD, Tang ZY: Cryotherapy for primary liver cancer. Semin Surg Oncol 14 (2): 171-4, 1998. [PUBMED Abstract]
- Lencioni RA, Allgaier HP, Cioni D, et al.: Small hepatocellular carcinoma in cirrhosis: randomized comparison of radio-frequency thermal ablation versus percutaneous ethanol injection. Radiology 228 (1): 235-40, 2003. [PUBMED Abstract]
- A comparison of lipiodol chemoembolization and conservative treatment for unresectable hepatocellular carcinoma. Groupe d'Etude et de Traitement du Carcinome Hépatocellulaire. N Engl J Med 332 (19): 1256-61, 1995. [PUBMED Abstract]
- Livraghi T, Goldberg SN, Lazzaroni S, et al.: Small hepatocellular carcinoma: treatment with radio-frequency ablation versus ethanol injection. Radiology 210 (3): 655-61, 1999. [PUBMED Abstract]
- Tanaka K, Nakamura S, Numata K, et al.: The long term efficacy of combined transcatheter arterial embolization and percutaneous ethanol injection in the treatment of patients with large hepatocellular carcinoma and cirrhosis. Cancer 82 (1): 78-85, 1998. [PUBMED Abstract]
- Livraghi T, Bolondi L, Lazzaroni S, et al.: Percutaneous ethanol injection in the treatment of hepatocellular carcinoma in cirrhosis. A study on 207 patients. Cancer 69 (4): 925-9, 1992. [PUBMED Abstract]
- Livraghi T, Benedini V, Lazzaroni S, et al.: Long term results of single session percutaneous ethanol injection in patients with large hepatocellular carcinoma. Cancer 83 (1): 48-57, 1998. [PUBMED Abstract]
- Curley SA, Izzo F, Delrio P, et al.: Radiofrequency ablation of unresectable primary and metastatic hepatic malignancies: results in 123 patients. Ann Surg 230 (1): 1-8, 1999. [PUBMED Abstract]
- Hemming AW, Cattral MS, Reed AI, et al.: Liver transplantation for hepatocellular carcinoma. Ann Surg 233 (5): 652-9, 2001. [PUBMED Abstract]
- Ensminger W, Niederhuber J, Dakhil S, et al.: Totally implanted drug delivery system for hepatic arterial chemotherapy. Cancer Treat Rep 65 (5-6): 393-400, 1981 May-Jun. [PUBMED Abstract]
- Dakhil S, Ensminger W, Cho K, et al.: Improved regional selectivity of hepatic arterial BCNU with degradable microspheres. Cancer 50 (4): 631-5, 1982. [PUBMED Abstract]
- Choi BI, Kim HC, Han JK, et al.: Therapeutic effect of transcatheter oily chemoembolization therapy for encapsulated nodular hepatocellular carcinoma: CT and pathologic findings. Radiology 182 (3): 709-13, 1992. [PUBMED Abstract]
- Epstein B, Ettinger D, Leichner PK, et al.: Multimodality cisplatin treatment in nonresectable alpha-fetoprotein-positive hepatoma. Cancer 67 (4): 896-900, 1991. [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]
- Sitzmann JV, Abrams R: Improved survival for hepatocellular cancer with combination surgery and multimodality treatment. Ann Surg 217 (2): 149-54, 1993. [PUBMED Abstract]
- Di Bisceglie AM, Rustgi VK, Hoofnagle JH, et al.: NIH conference. Hepatocellular carcinoma. Ann Intern Med 108 (3): 390-401, 1988. [PUBMED Abstract]