Treatment of Hepatocellular Carcinoma
Medially reviewed by Dr. C.H. Weaver M.D. Medical Editor 8/2018
The following is a general overview of the treatment of hepatocellular carcinoma, the most common type of primary liver cancer. Choice of treatment will depend on the extent and location of the cancer, the health of the liver, and the overall health of the patient.
The preferred treatment for early stage liver cancer is surgical removal of the cancer when surgically feasible. Doctors may give systemic treatment with chemotherapy or precision cancer medicines to further shrink a cancer to make surgery more feasible. Individuals who cannot undergo surgery due to more advanced disease are treated with these systemic treatments.
Surgical Treatment of Hepatocellular Carcinoma
For patients who are healthy enough to undergo surgery and who have early-stage cancer confined to the liver, treatment may involve surgical resection or liver transplantation.
Resection: Resection refers to surgical removal of the cancer and some surrounding normal tissue. This is often the treatment of choice in patients without cirrhosis.(1) Although resection is potentially curative, an estimated 70% of patients will develop a cancer recurrence during the first five years after treatment. Furthermore, resection is only possible when the remaining part of the liver is healthy enough to function on its own after surgery. For many patients with cirrhosis or other liver disease, this will not be the case and other treatment options will need to be considered.
Liver transplantation: For selected patients who have cancer that is confined to the liver but cannot be resected, liver transplantation may be an option. A benefit of liver transplantation is that it treats not only the cancer but also any underlying liver disease such as cirrhosis. Because the number of donor livers is limited, however, liver transplantation is generally reserved for those patients who are expected to have the best survival and the lowest risk of recurrence after transplantation. According to the commonly used “Milan criteria,” for example, transplant candidates should have a single liver nodule that measures no more than 5 cm or two or three nodules that measure no more than 3 cm each. These criteria are fairly restrictive, and the question of whether and how to expand the criteria to include more patients is currently being evaluated.(2)
Non-surgical Treatment of Hepatocellular Carcinoma
Even when the cancer is confined to the liver, not all patients will be candidates for surgery. Fortunately, there are several non-surgical treatment approaches available.
Ablation: Ablation refers to the destruction of the tumor using techniques such as injection of alcohol into the tumor (percutaneous ethanol injection) or use of electrical energy and heat (radiofrequency ablation). Ablation tends to be most effective when tumors are small and limited in numbers.(3)
Chemoembolization: Cancers rely on an adequate blood supply in order to grow and survive. The blood supply to liver tumors is provided primarily by the hepatic artery. In the process of transarterial chemoembolization (TACE), chemotherapy is injected into the branch of the hepatic artery that supplies the tumor. This allows the chemotherapy to concentrate in the area of the tumor. In addition, the hepatic artery is blocked (embolized) in order to reduce blood supply to the tumor. This procedure is not curative, but it can improve survival.(4)In general, patients must have adequate blood flow through the portal vein (the other main blood supply to the liver) in order to undergo TACE.(5)
Systemic therapy is treatment directed at destroying liver cancer cells throughout the body. Systemic treatment may be used
- As neoadjuvant therapy before surgery to shrink the cancer.
- As adjuvant therapy after surgery to destroy any liver cancer cells that spread away from the liver and could not be treated with surgery.
- As primary treatment of liver cancer for individuals who cannot undergo surgery or to treat recurrent or more advanced cancer.
Nexavar® (sorafenib): Nexavar is the first systemic therapy to improve survival in hepatocellular carcinoma, and became a standard treatment for patients with advanced hepatocellular carcinoma. Nexavar inhibits biological pathways involved in cell proliferation and the development of new blood vessels.(6,7) Nexaver was the only approved treatment, until recently however several new precision cancer medicines have recently become available and more are in development.
**Stirvaga (regorafenib)**is an oral multikinase inhibitor that has shown antiangiogenic activity.(3,4)
Cyramza (ramucirumab) is a type of targeted agent known as a monoclonal antibody. It belongs to a class of drugs known as angiogenesis inhibitors that work by blocking the growth of new blood vessels to the cancer to starve it of nutrients. Cyramza has been shown to improve survival in a subset of patients with hepatocellular carcinoma who have high levels of the plasma protein α-fetoprotein (AFP), which is associated with a poor prognosis.(8)
Cabometyx™ (cabozantinib) is an oral inhibitor of multiple receptor tyrosine kinases, including RET, MET, and vascular endothelial growth factor 2 (VEGFR2), which are all involved in both normal cellular function and pathologic processes, such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment. Cabometyx has been shown to reduce the risk of cancer progression in patients who had experienced disease progression with Nexavar, or other systemic therapies.(9)
Checkpoint Inhibitors are a novel precision cancer immunotherapy that helps restore the body’s immune system. The medications fight cancer by releasing checkpoints that cancer uses to shut down the immune system. PD-1 and PD -L1 are proteins that inhibit certain types of immune responses, allowing cancer cells to evade an attack by the body’s immune cells. Checkpoint inhibitor drugs bind to and block the PD-1 pathway which enhance the ability of the immune system to fight cancer by restoring an immune cells’ ability to recognize and fight the liver cancer cells. Keytruda and Opdivo have both been evaluated in liver cancer and there are several other checkpoint inhibitors in development.(10,11)
- Keytruda® (pembrolizumab)
- Opdivo (nivolumab)
- Imfinzi (durvalumab)
- Tecentriq® (atezolizumab)
Opdivo: The CheckMate 040 clinical trial confirmed that Opdivo produces durable responses with long-term survival rates in patients with liver cancer, regardless of whether or not patients were infected with Hepatitis B or C. An overall response rate of 19.3% was reported in patients previously treated with Nexaver and responses were ongoing in 71% of patients. Overall ~ 60% of these advanced patients were alive greater than one year from beginning Opdivo.(10)
Keytruda: In the Keynote 224 clinical study Keytruda produced and overall response rate of 16.3% in patients with refractory liver cancer. Durable responses were seen, and there was promising progression-free survival (PFS) and overall survival.(11)
Strategies to Improve Treatment
The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. Patients who are interested in participating in a clinical trial should discuss the risks and benefits of clinical trials with their physician.
Nexavar Plus TACE
For patients with unresectable hepatocellular carcinoma (HCC), combining Nexavar with transarterial chemoembolization (TACE) appears to improve outcomes compared to the use of TACE alone.
For this clinical trial, researchers randomly assigned 156 patients with unresectable HCC to be treated with TACE, or Nexavar plus TACE, and directly compared the outcomes. The duration of overall survival without cancer progression was significantly longer; 25.2 months for patients who received combination treatment as compared to 13.5 months for those treated with TACE alone.
Adjuvant therapy: Recurrence rates after treatment with resection or ablation are high, highlighting the importance of finding effective adjuvant treatments. Although the search for effective adjuvant therapy for hepatocellular carcinoma has been frustrating, studies are ongong evaluating the newer precision cancer medicines alone or with chemotherapy.
Treatment prior to liver transplantation: Due to the limited availability of donor livers, wait times for a liver transplant can be long. During the wait the cancer may progress to the extent that the patient is no longer eligible for transplantation. In order to control cancer growth during the wait for a donor liver, patients may receive treatment such as ablation or chemoembolization.(1) The effect of these treatments on the survival of transplant candidates remains uncertain.
Living donor liver transplantation: Liver transplantation from a living donor is one strategy to increase the availability of donor livers. In this procedure a living person donates part of their liver (usually the right hepatic lobe if the recipient is an adult).(2) The primary disadvantage of this procedure is the risk to the donor.
Identifying candidates for liver transplantation: Identification of patients who are candidates for liver transplantation remains challenging. The goal is to identify those patients who are most likely to benefit. In part, this involves determining which patients are least likely to experience a cancer recurrence following transplantation. Traditional criteria consider factors such as the number and size of liver tumors, but it may be possible to improve upon these criteria by assessing specific biological characteristics of the tumor.(3) Research on this question is underway.
Radiation therapy: Historically, radiation therapy has played a limited role in the treatment of hepatocellular carcinoma because of the damage it caused to normal liver tissue. Advances in radiation therapy, however, have allowed for more targeted delivery of effective doses of radiation. These advances include newer approaches to the delivery of external radiation therapy, (4) as well as techniques such as TheraSphere® that deliver radiation directly to the liver. TheraSphere involves the use of microscopic glass beads that contain a radioactive material. The beads are delivered through a catheter into the hepatic artery. The beads become trapped in the blood vessels that feed the tumor and deliver radiation to the tumor.
Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology. 2005;42:1208-1236.
Mazzaferro V, Llovet JM, Miceli R et al. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis. Lancet Oncology. 2009;10:35-43.
Llovet JM, Bruix J. Novel advances in the management of hepatocellular carcinoma in 2008. Journal of Hepatology. 2008;48:S20-S37.
Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology. 2003;37:429-442.
Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology. 2005;42:1208-1236.
Llovet JM, Ricci S, Mazzaferro V et al. Sorafenib in advanced hepatocellular carcinoma. New EnglandJournal of Medicine. 2008;359:378-90.
Kelley RK, Venook AP. Sorafenib in hepatocellular carcinoma: separating the hype from the hope. Journal of Clinical Oncology. 2008;26:5845-5849.
20th World Congress on Gastrointestinal Cancer (WCGC). Abstract LBA-001. Presented June 20, 2018.
Gastrointestinal Cancers Symposium (GICS) 2018. Abstract 206, presented January 19, 2018.
Melero I, et al. Nivolumab dose escalation and expansion in patients with advanced hepatocellular carcinoma (HCC): The CheckMate 040 study. J Clin Oncol. 2017;35 (suppl 4S: abstract 226.
Gastrointestinal Cancers Symposium (GICS) 2018. Abstract 209. Presented January 19, 2018.