The following is a general overview of the treatment of liver (hepatocellular carcinoma), the most common type of primary liver cancer. Treatment may consist of surgery, liver directed therapy, and systemic treatment with precision cancer medicines or chemotherapy. Choice of treatment will depend on the extent and location of the cancer, the presence of treatment directing biomarkers identified with genomic testing, the health of the liver, and the overall health of the patient.

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 typically consists of surgical resection of the cancer 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. 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.1

Liver transplantation: For selected patients who have cancer that is confined to the liver but cannot be surgically 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.2,3

Non-surgical Liver Directed Therapy

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 designed treat cancer of the liver.

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 number.3

Chemoembolization: Cancers rely on an adequate blood supply in order to grow and survive. The blood supply to cancers in the liver is provided primarily via the hepatic artery. In the process of transarterial chemoembolization (TACE), chemotherapy is injected into the branch of the hepatic artery that supplies the cancer allowing the chemotherapy to concentrate in that area. In addition, the hepatic artery is blocked (embolized) in order to reduce blood supply to the cancer and further prevent its growth. This procedure is not curative, but it can improve survival. 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.4,5

Systemic Therapies: Precision Cancer Medicine and Chemotherapy

Systemic therapy is any treatment directed at destroying cancer cells throughout the body, and may include chemotherapy, precision cancer medicines, or immunotherapy. Most patients with advanced cancers will be treated with systemic therapy in order to attack cancer cells throughout the body. The goal of administering systemic therapy is to reduce the risk of cancer recurrence, relieve symptoms, delay cancer progression and prolong survival. Systemic therapy is typically delivered by a medical oncologist and may include one or a combination of medications.1

Precision Cancer Medicines

In recent years the greatest progress in the management of liver cancer treatment is the development of effective precision cancer medicines and immunotherapy. Precision cancer medicine utilizes molecular diagnostic testing, including DNA sequencing, to identify cancer-driving abnormalities in a cancer’s genome. Once a genetic abnormality is identified, a specific targeted therapy can be designed to attack a specific mutation or other cancer-related change in the DNA programming of the cancer cells. Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack the cancer cells with specific abnormalities, leaving normal cells largely unharmed.4,5

Nexavar® (sorafenib): The targeted therapy Nexavar was the first systemic therapy demonstrated to improve survival in hepatocellular carcinoma (HCC) and is a standard treatment option. Nexavar inhibits biological pathways involved in cell proliferation and the development of new blood vessels. Newer precision cancer medicines produce better outcomes than Nexavar which is now typically used as a second, or third line treatment. The most common side effects of Nexavar are diarrhea, weight loss, and hand-foot skin reaction.5,6

Lenvima (lenvatinib) is an oral anti-angiogenic therapy that targets new blood vessel growth and “starves” cancer of the nutrients it needs to grow. The REFLECT clinical trial enrolled 954 treatment-naive patients with metastatic or unresectable HCC to receive treatment with either Lenvima or Nexavar.  Overall 41% of Lenvima treated patients responded to treatment compared to 12% for Nexavar. The average time to cancer progression nearly doubled to 7.3 months for Lenvima compared to 3.6 months for Nexavar.7

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.  In a clinical trial involving 707 patients with HCC who had experienced disease progression with Nexavar, or other systemic therapies Cabometyx™ treated patients survived longer and had a 56% reduction in the risk for progression or compared to no further treatment.8,9

Stivarga (regorafenib): The FDA approved the multi-kinase inhibitor Stivarga in April 2017 for patients with HCC who have been previously treated with Nexavar Patients with advanced HCC who were treated with second-line Stivarga experienced prolonged overall survival according to a 2-year updated analysis of key findings from the pivotal RESORCE clinical trial which compared Stivarga to no further treatment in patients with HCC.  The survival rates for Stivarga compared with placebo at 12, 18, and 30 months were 47% versus 28%, 32% versus 15%, and 16% versus 8%, respectively.10,11

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 was demonstrated to improves 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 leading to U.S. Food and Drug Administration (FDA) approval in May 2019.12,13

Checkpoint Inhibitor Immunotherapy

Checkpoint inhibitors are a novel precision cancer immunotherapy that helps to restore the body’s immune system in fighting liver cancer by releasing checkpoints that cancer uses to shut down the immune system. PD-1 and PD -L1 are proteins that inhibit certain immune responses, allowing cancer cells to evade an attack by the body’s immune cells. Checkpoint inhibitor drugs that block the PD-1 pathway enhance the ability of the immune system to fight cancer. By blocking the binding of the PD-L1 ligand these drugs restore an immune cells’ ability to recognize and fight the liver cancer cells. A diagnostic test to measure the level of PD-L1 is available.

  • Keytruda® (pembrolizumab)
  • Opdivo (nivolumab)
  • Imfinzi (durvalumab)
  • Tecentriq® (atezolizumab)

Some patients with HCC respond to treatment with checkpoint inhibitors and patients should discuss the role of this immunotherapy with their doctor.

Chemotherapy

Chemotherapy uses medications that can be taken orally as a pill or are injected into a vein to kill cancer cells. In some situations, chemotherapy is combined with immunotherapy or other precision cancer medicines to achieve the best results.

Radiation therapy

Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. Radiation therapy works by damaging the DNA in the cancer cell, thereby disabling the cancer cells from reproducing and growing.

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, as well as techniques such as TheraSphere® that deliver radiation directly to the liver.14

Strategies to Improve Treatment

The major research focus in liver cancer is the identification of additional cancer driving mutations as targets for precision cancer medicines and the development of immunotherapy treatment strategies to be used alone or in combination with precision cancer medicines.

References

1 EASL-EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol. 2012;56:908-943.

2 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.

3 Llovet JM, Bruix J. Novel advances in the management of hepatocellular carcinoma in 2008. Journal of Hepatology. 2008;48:S20-S37.

4 Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology. 2003;37:429-442.

5 Llovet JM, Ricci S, Mazzaferro V et al. Sorafenib in advanced hepatocellular carcinoma. New England Journal of Medicine. 2008;359:378-90.

6 Kelley RK, Venook AP. Sorafenib in hepatocellular carcinoma: separating the hype from the hope. Journal of Clinical Oncology. 2008;26:5845-5848.

7 http://eisai.mediaroom.com/2018-08-16-Eisai-And-Merck-Announce-FDA-Approval-Of-LENVIMA-R-lenvatinib-Capsules-For-First-line-Treatment-Of-Unresectable-Hepatocellular-Carcinoma-HCC

8 2018 Gastrointestinal Cancers Symposium. Abstract 207, presented January 19, 2018.

9 Gastrointestinal Cancers Symposium (GICS) 2018. Abstract 206, presented January 19, 2018.

10 Bruix J, Merle P, Granito A, et al. Overall survival (OS) update: 2-year follow-up from the phase 3 RESORCE trial of regorafenib for patients with hepatocellular carcinoma (HCC) progressing on sorafenib. Presented at: 2018 International Liver Cancer Association Annual Meeting; September 14-16; London, England. O-023. ilca2018.org/wp-content/uploads/2018/08/ILCA-2018-Final-Programme-and-Book-of-Abstracts_LR_compressed-2.pdf.

11 Bruix J, Qin S, Merle P, et al; RESORCE Investigators. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial [erratum in 2017;389(10064):36. doi: 10.1016/S0140-6736(16)32615-0].

12 Lancet. 2017;389;10064):56-66. doi: 10.1016/S0140-6736(16)32453-9.

13 20th World Congress on Gastrointestinal Cancer (WCGC). Abstract LBA-001.

14 SIR-Spheres® microspheres (Yttrium-90 Microspheres) Product Information. Available at: http://www.sirtex.com/us/clinicians/package-insert/.

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