Hepatocellular cancer (HCC) and cholangiocarcinoma represent the most common forms of liver cancer with the former accounting for over 80% of cases1 . Cholangiocarcinomas arise from the bile ducts and will not be discussed in this article however should be highlighted as a rising cause of liver cancer. Indeed the numbers of new cases and deaths from liver cancer are expected to increase by more than 55% by 20401. This highlights the urgent need for national strategies and international collaboration to deal with this impending disease burden. The management of HCC has seen remarkable changes in the past 5 years. Up until 2017 sorafenib was the only drug available to patients with advanced HCC. We now have two new standard immune checkpoint inhibitor (ICI) combinations in the first line setting, demonstrating superiority over sorafenib while lenvatinib represents a further oral therapy. A number of additional oral tyrosine kinase inhibitors have shown benefit in the second line setting. It is now inevitable that these agents will be integrated earlier in the management of HCC, with trials in the adjuvant and neoadjuvant setting ongoing. How countries will cope with the cost of these new therapies has not been addressed and highlights continued global disparities in cancer care.
Hepatocellular carcinoma is the 3rd most common cause of cancer related mortality world-wide with an estimated 5 year survival rate of 18%. The majority of HCC arise on a background of chronic liver disease with 80-90% of patients having underlying liver cirrhosis. HCC most commonly occurs in the 6th decade and occurs more frequently in males. The spectrum of underlying liver disease varies globally with a predominance of hepatitis B and C in Asia while alcohol and non-alcoholic fatty liver disease (NAFLD) dominate in Western Societies. Less common causes of HCC include haemochromatosis, alpha-1antitrypsin deficiency and drug induced liver injury.
Notably there has been a rise in the incidence of HCC in Ireland and Europe due to obesity and the prevalence of fatty liver disease while levels of alcohol consumption remain high 2. Europe has the highest levels of alcohol intake in the world3, while NAFLD and non-alcoholic steatohepatitis (NASH) are predicted to become the leading cause of end stage liver disease 4. Excessive alcohol use, obesity and diabetes are risk factors for HCC that require urgent public health strategies.
Prevention and screening
Globally, the advent of hepatitis B vaccination, has together with the development of antivirals agents for hepatitis C resulted in a decline in viral associated HCC highlighting effective prevention strategies. NAFLD and progression to NASH is inextricably linked to obesity and diabetes and is largely due to modern Western diets enriched in excess sugars and fats together with a more sedentary lifestyle. Smoking may contribute to HCC risk particularly in the presence of other risk factors while aspirin and coffee have been found to be protective5 6. The risks of alcohol and liver cirrhosis are well known , however tackling the issues of obesity and excessive alcohol consumption will require significant cultural changes and government intervention. The EASL-Lancet liver commission have provided recommendations on achieving healthier livers for all Europeans underscoring the need for multi-disciplinary input and national policies 7 The prevention of chronic liver disease will represent one of the most effective ways in reducing mortality from HCC.
Earlier detection of HCC is further critical, particularly as management strategies evolve. International guidelines and liver societies recommend surveillance of high risk populations using ultrasound with or without alpha fetoprotein (AFP)8. Its noteworthy that not everyone with liver disease or indeed cirrhosis will develop HCC. Nevertheless HCC when detected early is highly curable. Ultrasound screening in the presence of obesity can be challenging and the role of AFP in screening has been controversial. Novel strategies such as a liquid biopsy or a blood test to evaluate cell free circulating tumour DNA will likely become part of screening protocols in the future.9
Making a Diagnosis and staging HCC
HCC is unusual compared to other cancers in that a diagnosis can be made without a biopsy confirming histology. Liver imaging with a CT or MRI in the setting of chronic liver disease reveals characteristic features of tumour enhancement which is specific for HCC. However not all HCC will have such obvious characteristics on CT or MRI and as such the liver imaging reporting and data system (LI-RADS, LR) was developed for radiology reporting without need for a biopsy. This is an important point so that registries adequately capture the burden of HCC that exists if pathology has not been obtained. The role of biopsy of early lesions has been controversial because of concerns with regard to seeding. Biopsy however is increasingly being employed especially as systemic therapies are being used before surgery or transplant. Furthermore it has been demonstrated that imaging alone wrongly calls 9% of cases labelled as HCC in the advanced setting. This would mean inappropriate treatments in those patients10
The staging of HCC is integral to prognosis and management and the Barcelona Clinic Liver Criteria (BCLC) staging system is the most widely used. While the tumour burden and presence of portal vein invasion and or extrahepatic disease is critical to staging, equally important is the assessment of liver function and the consideration of patient performance status11. BCLC classifies HCC into very early stage (BCLC 0), early stage (BCLC A), intermediate stage (BCLC B), advanced stage (BCLC C) and terminal stage (BCLC D).
Curative options BCLC 0, A and B
BCLC 0 and A HCC should be considered for curative options including surgical resection, transplant and ablation. Resection is ideal for single lesions where liver function is preserved. In patients where there is multifocal disease or where there is decompensated cirrhosis, liver transplant is a potential option. Surgical considerations in the presence of cirrhosis are complex and all eligible patients should be discussed at a multidisciplinary team meeting at a high volume centre. Liver transplantation in eligible patients has a 5 year survival rate of 75-80%12. Liver transplantation has the advantage of treating underlying liver cirrhosis while providing the widest possible surgical margin. Most commonly the Milan Criteria13 are used to select patients considered eligible for liver transplant. These criteria (one lesion ≥ 2 cm and ≤ 5 cm, or up to 3 lesions, each ≥ 1 cm and ≤ 3 cm, with no evidence of vascular invasion or extra-hepatic metastases) are today in many centres considered too restrictive and downstaging protocols will seek to employ locoregional or systemic therapies to render patients beyond Milan criteria eligible. This accepts that tumour biology is superior to size and number when considering patients for transplant and a number of extended criteria exist across the world14. In addition to surgical options, thermal ablative strategies are usually employed for tumours < 3cm15 or in larger lesions unsuitable to other curative options. To date adjuvant drug trials have been negative however a number of adjuvant studies evaluating immune checkpoint inhibitor combinations are due to report this year.
Intermediate stage disease (BCLC B) and local approaches
One of the biggest changes to the BCLC 2022 update was in intermediate stage disease. It is now recognized that some BCLC B HCC are amenable to curative therapies in extended transplant criteria and there are also some BCLC B HCC with a larger tumour volume who should be considered for a systemic first approach.
Historically this cohort of patients were predominantly treated with trans-arterial chemoembolization (TACE). HCC are hypervascular tumours deriving most blood supply from the hepatic artery. After accessing the bloody supply to the HCC, TACE should be completed in a selective manner. This can be performed conventionally (cTACE) where a drug carried by lipiodol is give in an arterial injection, followed by arterial embolization. The second option is using drug eluding beads (DEB-TACE). Both are equally effective in controlling disease however DEB-TACE is thought associated with less toxic side effects including abdominal pain15. Although DEB TACE is more expensive, patients can be managed with oral analgesia and have a shorter inpatient stay16 Both options can be delivered on an outpatient based protocol, where resources are in place which can save substantially on costs17
TACE has been shown to improve survival over symptom control and in early studies 63% of patients where alive at 2 years when treated with TACE18. TACE can also be used as a bridge to transplant providing tumour control while patients are on a transplant waiting list. TACE has also been shown to effectively downstage patients to within transplant criteria. Other locoregional therapies that can be used in these settings include stereotactic body radiation (SBRT) together with transarterial radioembolization (TARE). The role of SBRT is gaining particular attention, especially in the setting of macrovascular invasion. Locoregional therapy decisions should be made at an MDT and all should be considered in the treatment paradigm.
In 2023, in the era of rapidly evolving drug strategies the sequencing of local therapies and systemic treatments or how these can be combined becomes an important question19. What is crucial is that patients receiving locoregional treatments are discussed regularly to ensure that patients move treatments at the time of refractory disease and that liver function is preserved in order to afford patients the opportunities to receive systemic treatments including immunotherapy combinations. Systemic therapies are being increasingly utilized in intermediate stage disease as a first option, ensuring access to drug with the possibility of employing locoregional therapies at a later stage. Many trials are currently ongoing in this space.
Advanced Disease (BCLC B/C)
Immune checkpoints are molecules expressed on a number of cells including immune cells and tumour cells that prevent an overactive immune response in organs such as the liver thus maintaining self-tolerance. In HCC, immune checkpoint inhibitors (ICIs) targeting programmed death-1 (PD-1)/programmed deathligand 1 (PD-L1) and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) have demonstrated activity particularly when combinations strategies are used and have resulted in new standards of care.
There are now four options (received EMA approval) for patients in the first line advanced setting for HCC: atezolizumab/ bevacizumab (preferred choice); durvalumab/tremelimumab (STRIDE regimen), lenvatinib and sorafenib.
Sorafenib, a multi-tyrosine kinase inhibitor was the only systemic oral therapy available to patients with advanced disease and preserved liver function until 2017 based on the results of the SHARP trial. There has now been a rapid growth in the armamentarium of agents exhibiting activity in HCC. In 2018 the REFLECT randomized phase III trial demonstrated the noninferiority of Lenvatinib ( an oral tyrosine kinase inhibitor with broader receptor target) compared with sorafenib. The median overall survival (OS) was 13.6 months for patients treated with Lenvatinib compared with 12.3 months for patients treated with sorafenib (HR: 0.92; 95% CI: 0.79 to 1.06)20. Notably the progression free survival was almost double in the Lenvatinib arm (7.4 months vs. 3.7 months).
The landmark IMbrave150 trial however has changed the landscape of drug treatment in HCC. In this randomized phase III trial patients received either sorafenib or atezolizumab/ bevacizumab. Atezolizumab is a PD-L1 inhibitor and bevacizumab a VEGF antibody. The trial was interrupted at first analysis with the combination of atezolizumab/ bevacizumab demonstrating a superior survival of 19.2 months versus 13.2 months in the sorafenib arm21. Importantly the combination also showed benefits in quality of life with a median time to deterioration of 11.2 months with atezolizumab/bevacizumab compared to 3.6 months with sorafenib22. Because of the risks of bleeding with bevacizumab, especially in the population of patients with advanced HCC, all patients entering the study were required to have had an OGD which is still a requirement before prescribing the drugs today. The durability of immune checkpoint inhibitors is of particular interest in those achieving a response. In this regard the HIMALAYA trial demonstrated superiority over single agent tremelimumab (CTLA4 inhibitor)/durvalumab (PD-L1 inhibitor) – known as the STRIDE regimen versus sorafenib23 At three years with this regimen 30.7% of patients were alive compared to 20.7% with sorafenib. The STRIDE regimen provides an ICI combination option in patients with high risk varices not suitable for bevacizumab, while lenvatinib and sorafenib (less commonly) are alternatives. Studies in the second line setting were performed when sorafenib was the first choice of agent in first-line. Nevertheless the RESOURCE trial, CELESTIAL-2 and REACH-2 have demonstrated the efficacy of regorafenib, cabozantinib and ramucirumab post sorafenib in HCC expanding therapeutics available to patients.
Conclusions and future strategies
HCC is a rapidly rising cause of cancer related mortality in Ireland and Europe linked in particular to obesity and alcohol consumption. It is imperative that all patients with HCC and liver tumours are discussed at a multidisciplinary tumour board with radiologists, interventional radiologists, hepatologists, medical oncologists, HPB surgeons, radiation oncologists, nurse specialists and pathologists present. Palliative care physicians are also a crucial part of the team. This ensures patients access all possible treatment options, particularly curative approaches in a field that’s rapidly evolving. It is now inevitable that immunotherapy combinations will be utilized earlier in HCC management including in the neo/adjuvant setting. Clinical trials access in Ireland needs to increase to allow for patients to avail of novel combinations given that many drugs available globally are not accessible to patients in Ireland as of yet. Biomarkers to select patients for the right treatment options are urgently needed and much research is ongoing in this area. Screening strategies are likely to evolve to include liquid biopsies, but novel approaches including new drugs and new diagnostics can be costly. It is therefore crucial that the government work with members of the multidisciplinary team, patients and key stakeholders to develop national strategies to tackle obesity, the metabolic syndrome and excess alcohol consumption while providing the infrastructure needed for continued research.
Written by Dr. Ruth Hutch, Oncology SHO, Trinity St. James’s Cancer Institute and Prof. Grainne O’Kane, Medical Oncologist, Trinity St James’s Cancer Institute