by Dr. C.H. Weaver M.D. updated 10/2022
Treatment & Management of Liver Cancer
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 treatments available for the management of liver cancers and tumors.
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 Therapy: 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 & Immunotherapy
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
Checkpoint Inhibitor Immunotherapy
Checkpoint inhibitors are a novel precision cancer immunotherapy that helps to restore the body’s immune system in fighting 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. There are several checkpoint inhibitors available and when used alone to treat HCC are unimpressive but when used in combination have become a new standard of care and largely replaced the previous standard of single agent Nexavar (Sorafenib) and Lenvima (lenvatinib).
Tecentriq + Avastin
Tecentriq (atezolizumab) is a precision immunotherapy medication that enables the activation of the immune system to treat a cancer. Avastin (bevacizumab) is a biologic antibody designed to specifically interfere with a cancers blood supply which is thought to be critical for a cancers ability to grow and spread in the body. The Tecentriq and Avastin combination enhances the potential of the immune system to combat a broad range of cancers, further enhances Tecentriq’s ability to restore anti-cancer immunity and is the standard systemic therapy for HCC.
The Phase III IMbrave150 clinical trial compared Tecentriq® in combination with Avastin® to Nexavar in 501 people with unresectable HCC who had not received prior systemic therapy. The combination treatment regimen significantly delayed cancer progression and prolonged survival compared to Nexavar.16 Tecentriq in combination with Avastin reduced the risk of death by 42% and reduced the risk of disease worsening or death by 41% compared with Nexavar.
Is Combination Immunotherapy Better Than Immunotherapy + Avastin?
The current standard initial treatment for HCC is Tecentriq + Avastin which improved the average overall survival duration from 13 months with Nexavar to 24 months with the Tecentriq-Avastin combination. Perhaps even more importantly the combination also improved quality of life compared to Nexavar.
Immunotherapy has changed the management of HCC and researchers have also asked the question can two immunotherapy agents further improve outcomes? A phase 3 trial that evaluated the immunotherapy combination of Imfinzi (durvalumab) plus tremelimumab has also compared treatment to Nexavar. The immunotherapy combinations differs from other treatments in that it targets two immune checkpoint proteins. Imfinzi blocks the PD-L1 protein on the surface of immune cells, while tremelimumab targets the CTLA-4 receptor.
This regimen is called the STRIDE regimen (Single Tremelimumab Regular Interval Durvalumab) and produced an average overall survival of 16 months versus 14 for Nexavar in the Himalaya clinical trial. The trial also tested Imfinzi monotherapy which produced an average overall survival of 16.6 months. Grade 3 or 4 treatment-related adverse events were experienced by 26% of patients treated with the STRIDE regimen and by 13% of patients treated with Imfinzi alone.
The STRIDE combination immunotherapy regimen did not produce survival superior to that seen with Tecentriq immunotherapy plus Avastin and the addition of tremelimumab appears only to have increased side effects. The FDA did however approve the combination in October 2022.18,19
Several other immunotherapy medications are being evaluated in HCC.
- Keytruda (pembroluzumab)
- Opdivo (nivolumab)
- Imfinzi (durvalumab)
Keytruda produced an overall response rate of 16.3%, and rates were similar across subgroups of HCC with different causes, including those with HBV and HCV infection. The median time to response was 2.1 months and 94% of responders were estimated to have a response duration of 6 months or longer.13
Opdivo: The CheckMate 040 clinical trial was designed to evaluate Opdivo in patients with advanced liver cancer who were previously treated with Nexavar and were not suitable for surgery. An overall response rate of 19%, and an average overall survival of 16.7 months was reported. Responses to Opdivo occurred regardless of PD-1 ligand expression on cancer cells.11
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
Nexavar® (sorafenib): The targeted therapy Nexavar was the first systemic therapy demonstrated to improve survival in HCC and was a standard treatment option until the combination of Tecentriq-Avastin was found to be superior. 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
Understanding DNA Damage Response or DDR and Cancer Treatment
What is DNA Damage Response or DDR?
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
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.10-12
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
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 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.
Proton Therapy Improves Survival Over Photon Therapy in HCC
Two advances have potentially changed the treatment landscape for HCC. The first is stereotactic ablative radiation therapy, which allows for the delivery of higher doses per fraction due to improved target precision and patient immobilization. The second is proton radiotherapy.
The more commonly available treatment modality for ablative radiotherapy is with photons, which continues to deposit dose along the exit beam path beyond the target volume, leading to unwanted dose to non-target liver and other normal tissues. In contrast, proton beam therapy utilizes charged particles which come to rest within the patient and have no exit dose beyond a pre-specified target range.
Harvard researchers conducted a single-institution, retrospective study of 133 patients with unresectable HCC treated at Massachusetts General Hospital between 2008 and 2017, including 49 (37%) who were treated with protons. The main finding of the study was that proton radiotherapy was associated with improved overall survival – the median overall survival of patients treated with protons versus photons was 31 and 14 months, respectively. In addition, patients treated with protons had lower incidence of non-classic radiation induced liver disease. Although retrospective in nature the study suggests that protons appear to be a better choice than photons.17
SIR-Spheres Y-90 resin microspheres are a medical device used in an interventional radiology procedure known as selective internal radiation therapy (SIRT), or radioembolization, which targets high doses of radiation directly to liver tumors. The treatment consists of tens of millions of radioactive Y-90 coated resin particles, each no bigger in diameter than a human hair. SIR-Spheres Y-90 are injected into the hepatic artery, which is the main blood supply to the liver via a catheter inserted into the femoral artery through an incision in the groin. The Y-90 resin microspheres become lodged in the smaller blood vessels that surround cancer in the liver, where they deliver a high dose of radiation to the cancer, while sparing healthy liver tissue.14
Child-Pugh Scoring and Clinical Trials of Systemic Therapy in Advanced HCC
A challenge in managing advanced HCC is that most of the clinical trials supporting the use of approved systemic therapies were conducted in populations of patients with good liver function. Doctors often assess the severity of the underlying cirrhosis before providing a treatment recommendation by using the Child-Pugh scoring system.
The Child-Pugh scoring system uses rates ascites, bilirubin, albumin, prothrombin time, and encephalopathy—to classify the severity of liver cirrhosis. Patients with the lowest scores (and, as such, the least severe liver disease) are classified as having Child-Pugh A disease; those with more severe cirrhosis are classified as having Child-Pugh B or C liver function. As may be expected, patients with Child-Pugh B liver function have significantly decreased OS compared with patients with Child-Pugh A liver function. Because of this, patients with Child-Pugh B liver function are often excluded from clinical trials of novel therapies for HCC due to their poor prognosis. As a result, most approved systemic therapies for HCC have only been prospectively studied in Child-Pugh A populations, with little information to guide treatment in patients with more severe levels of liver impairment.
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.
Adjuvant therapy: Recurrence rates after treatment with resection or ablation are high, highlighting the importance of finding effective adjuvant treatments (treatments given after the primary treatment to reduce the risk of recurrence). Although the search for effective adjuvant therapy for HCC has been frustrating, evaluation of newer precision cancer medicines may hold promise.
Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack the cancer cells with specific abnormalities, leaving normal cells largely unharmed. New precision medicines are being developed for the treatment of liver cancer and patients should make sure their cancer undergoes genomic profiling. This can also be accomplished with blood testing using a "liquid biopsy" if tissue is not available.
Immunotherapy Combinations: Imfinzi plus tremelimumab is reported to significantly improve overall survival in the HIMALAYA phase III clinical trial as 1st-line treatment of unresectable HCC.
The HIMALAYA trial compared Imfinzi monotherapy, Imfinzi + tremelimumab, and sorafenib in a total of 1,324 patients with unresectable, advanced HCC who had not been treated with prior systemic therapy
- Imfinzi (durvalumab) is a human monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering a cancers immune-evading tactics and releasing the inhibition of immune responses.
- Tremelimumab is a human monoclonal antibody that targets the activity of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Tremelimumab blocks the activity of CTLA-4, contributing to T-cell activation, priming the immune response to cancer and fostering cancer cell death.
The HIMALAYA Phase III clinical trial suggests a single priming dose of tremelimumab added to Imfinzi (durvalumab) improves survival duration when compared to sorafenib as 1st-line treatment for patients with unresectable HCC. The current standard of care combines the immunotherapy drug Tecentriq with Avastin which targets new blood vessels necessary for cancer cells to grow. Tecentriq and Avastin improves survival and delays cancer recurrence compared to sorafenib. The dual immunotherapy combination of Imfinzi and Tremelimumab has not been compared to the current standard of care consisting of Tecentriq and Avastin.
TKI-Checkpoint Inhibitor Combinations are undergoing evaluation in clinical trials. Keytruda® plus Lenvima® combination treatment was given on July 23, 2019 for the potential first-line treatment of patients with advanced HCC not amenable to local regional treatment based on updated interim results from the Phase 1b trial KEYNOTE-524/Study 116. Tecentriq + Cabometyx is also being evaluated.
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). The primary disadvantage of this procedure is the risk to the donor.
- EASL-EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol. 2012;56:908-943.
- 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.
- Llovet JM, Ricci S, Mazzaferro V et al. Sorafenib in advanced hepatocellular carcinoma. New England Journal 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;26:5845-5848.
- Eisai And Merck Announce FDA Approval Of LENVIMA® (lenvatinib) Capsules For First-line Treatment Of Unresectable Hepatocellular Carcinoma (HCC)
- 2018 Gastrointestinal Cancers Symposium. Abstract 207, presented January 19, 2018.
- Gastrointestinal Cancers Symposium (GICS) 2018. Abstract 206, presented January 19, 2018.
- 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.
- 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].
- Lancet. 2017;389;10064):56-66. doi: 10.1016/S0140-6736(16)32453-9.
- 20th World Congress on Gastrointestinal Cancer (WCGC). Abstract LBA-001.
- SIR-Spheres® microspheres (Yttrium-90 Microspheres) Product Information. Available here.
- EISAI AND MERCK & CO., INC., KENILWORTH, N.J., U.S.A. ANNOUNCE DATA AT 2018 ASCO ANNUAL MEETING FROM INVESTIGATIONAL STUDIES OF LENVIMA® AND KEYTRUDA® COMBINATION THERAPY IN FOUR DIFFERENT TUMOR TYPES
- Lee M, Ryoo B-Y, Hsu C-H, et al. Randomised efficacy and safety results for atezolizumab (Atezo) + bevacizumab (Bev) in patients (pts) with previously untreated, unresectable hepatocellular carcinoma (HCC). Presented at 2019 ESMO Congress; September 27 to October 1, 2019; Barcelona, Spain. Abstract LBA39.
- Protons versus Photons for Unresectable Hepatocellular Carcinoma: Liver Decompensation and Overall Survival
Imjudo (tremelimumab) in combination with Imfinzi approved in the US for patients with unresectable liver cancer. News release. AstraZeneca. October 24, 2022. Accessed October 24, 2022. https://bit.ly/3VUsQTw
Abou-Alfa GK, Lau G, Kudo M, et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. N Eng J Evid. 2022;1(8). doi: 10.1056/EVIDoa2100070