Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer and usually arises in people with existing chronic liver disease. It is the sixth-most-frequent cancer and the fourth-leading cause of cancer-related death globally.¹ In the United States, HCC has been the fastest-increasing cause of cancer-related death since the early 2000s and is projected to become the third-leading cause of cancer-related mortality if this trend continues.²

Historically, viral hepatitis and alcohol consumption have been the leading causes of chronic liver disease around the world. Today, however, metabolic dysfunction-associated steatotic liver disease (MASLD), formerly called non-alcoholic fatty liver disease (NAFLD), is an increasingly common cause of chronic liver disease and subsequent HCC, particularly in Western societies.^1,3 In the United States, the incidence of HCC has more than tripled since the 1980s and is expected to continue to rise due to the increasing prevalence of MASLD.⁴

HCC diagnosis is usually based on a combination of blood tests for diagnostic biomarkers and imaging studies such as ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI). A set of blood tests comprising a liquid biopsy may provide information about the presence of tumors and characteristics that can be used to detect cancer early and individualize the treatment approach.⁵

Strategies for preventing and treating liver disease are critical for reducing HCC incidence and improving its course. These include antiviral therapy for hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, vaccination against HBV, treatment for alcohol abuse disorder, smoking cessation, metabolic health maintenance, and treatment for metabolic disease.^6,7 In addition, HCC surveillance in high-risk populations can increase early detection and improve prognosis.⁸

Treatment options for patients with HCC vary from surgical and liver-targeted therapies at early stages; radiation therapy in selected patients with early, intermediate, and advanced stages; to systemic therapies at more advanced stages. Along with the number, size, and extent of tumors when treatment is started, liver function and overall health status are important factors determining prognosis and impacting treatment options.⁸ Therefore, dietary and lifestyle strategies to address underlying liver disease are important for all patients with HCC. Some supplements, such as melatonin and branched-chain amino acids, may be helpful in the context of HCC given their relative safety and preliminary evidence of their potential benefit. Repurposing existing drugs in HCC treatment is an emerging research area and may lead to new options for improving outcomes.

HCC is most often thought to result from the culmination of long-standing liver disease marked by ongoing inflammation, imbalanced immune activity, high oxidative stress, endoplasmic reticulum stress, mitochondrial dysfunction, and tissue damage and fibrosis.^9,10 Liver disease can lead to genetic mutations or epigenetic modifications in mature liver cells (hepatocytes) or liver stem cells and trigger abnormal cell signaling that initiates tumor development. Abnormal signaling pathways that have been implicated in HCC include¹⁰:

• PI3K/AKT/mTOR. Phosphoinositide 3-kinase (PI3K), protein kinase B (PKB, also known as AKT), and mammalian target of rapamycin (mTOR) form a complex network of signaling enzymes (also called the PAM pathway). This network regulates cellular functions like metabolism, differentiation, proliferation, and apoptosis (programmed cell death).¹¹ Abnormal PI3K/AKT/mTOR activation appears to have a role in promoting HCC and treatment resistance.¹⁰
• Wnt/β-catenin. Wnt and β-catenin are a family of proteins that help regulate cellular polarity, migration, and proliferation, especially during embryonic development and tissue regeneration and repair.¹² Although dysregulated Wnt/β-catenin signaling is not sufficient to initiate cancer, it appears to play a role in many cases of HCC and may influence treatment response.¹⁰
• Non-coding RNA.Most of the ribonucleic acid (RNA) generated within cells does not provide code that can be used to make proteins. While the exact functions of non-coding RNA are still poorly understood, some types are now known to play fundamental roles in regulating cellular processes.¹³
  • Micro-RNA (miRNA) are small, non-protein-coding RNA molecules and are important regulators of gene expression. They are essential for cell differentiation, proliferation, apoptosis, and organ development and function.¹⁴ MiRNAs have been implicated in HCC onset, growth, metastasis, and recurrence.¹⁰
  • Circular-RNA (circRNA) are long strands of non-coding nucleotides with linked ends. Among other functions, circRNA has been shown to modulate miRNA activity and is implicated in cancer initiation and progression.¹³

The gut microbiome is an important factor in HCC development, as specific bacteria have been linked to HCC risk and its responsiveness to treatment.^10,15 Metabolic by-products from gut microbes can stimulate inflammation, generate free radicals, alter the function of specialized liver immune cells, reduce normal apoptosis, promote angiogenesis (new blood vessel formation, which supports tumor growth), and inhibit tumor-suppressing miRNAs in the liver.¹⁰ Conditions associated with HCC risk, such as alcohol-related liver disease and MASLD, may increase intestinal permeability, allowing bacteria and their products to enter circulation and reach the liver.¹⁵

Chronic liver disease is the most important risk factor for HCC and is present in 80–90% of cases.⁵ Historically, viral hepatitis has been the leading cause of chronic liver disease and HCC. Hepatitis B virus (HBV) infection is responsible for about 50% of HCC worldwide, and hepatitis C virus (HCV) infection accounts for another 30%.¹⁶ The presence of advanced fibrosis or cirrhosis (severe fibrosis with loss of liver function) is closely linked to HCC risk in viral hepatitis patients.¹⁶

Metabolic dysfunction-associated steatotic liver disease (MASLD, formerly known as non-alcoholic fatty liver disease [NAFLD]) is another common cause of chronic liver disease, cirrhosis, and HCC. MASLD is closely and bi-directionally associated with other metabolic disorders, especially type 2 diabetes, overweight and obesity, and abnormal lipid levels. Its global prevalence, estimated to be almost 31%, has grown rapidly in recent decades, and it is thought MASLD will soon overtake viral hepatitis as the most common cause of HCC, particularly in regions where HBV vaccination is common and HCV treatment is widely available.^17,18 As many as 2.6% of individuals with MASLD develop HCC, and the presence of cirrhosis is the primary risk factor for this transition. In fact, approximately 80% of HCC in MASLD patients is preceded by cirrhosis.¹⁷

Alcohol use disorder is a well-known cause of liver disease, cirrhosis, and HCC. Alcohol is readily transported from the digestive tract to the liver, where it is metabolized into products that cause hepatocyte injury.¹⁹ In people with another chronic liver disease, including viral hepatitis or MASLD, alcohol contributes to liver disease progression and further increases HCC risk.^19,20

As many as 10% of HCC cases arise in patients without chronic liver disease or liver fibrosis.²¹ Although risk factors for HCC without fibrosis are still being explored, its likelihood appears to be increased in those with metabolic diseases, such as type 2 diabetes and obesity.^18,21 Patients with hepatocellular adenoma (a benign liver tumor that, in rare cases, can transform into HCC) and multiple primary malignancies (a condition in which primary tumors appear at more than one site in the body) have also been reported to have a higher chance of developing non-fibrotic HCC.²¹

Less common causes of liver disease are also associated with increased HCC risk. These include hemochromatosis (a genetic disorder in which excess iron accumulates in the liver and other tissues), primary biliary cholangitis (a condition in which small bile ducts in the liver become injured, inflamed, and eventually destroyed), and Wilson disease (a rare genetic disease in which excess copper accumulates in the liver and other tissues).²²

In addition to chronic liver disease, the following factors also influence HCC risk:

• Gender. Men are 2–3 times more likely to develop HCC than women and are also 2–3 times more likely to die from its complications.²³
• Obesity. Obesity and overnutrition expose the liver to excess carbohydrates, protein, and fat, leading to lipid accumulation, inflammation, oxidative stress, mitochondrial dysfunction, fibrosis, and increasing the likelihood of cancerous transformation.²⁴
• Type 2 diabetes. Type 2 diabetes is marked by insulin resistance, elevated blood glucose levels, and triglyceride accumulation in the liver, all of which can stimulate cancer-promoting processes in the liver.²⁴
• Dyslipidemia. Excess cholesterol and triglycerides, in the context of metabolic disturbance, have toxic effects on liver cells and increase the risks of MASLD and HCC; however, in viral hepatitis, cholesterol and triglycerides can become depleted as liver damage progresses, and lower levels are considered a marker of HCC risk.²⁵
• Smoking. Smoking has been associated with increased HCC risk. Carcinogens in cigarette smoke act directly on the liver. Smoking also increases oxidative stress and promotes fibrotic processes that increase the likelihood of HCC. Furthermore, smoking accelerates liver damage from alcohol, making this combination of habits especially dangerous. Smoking and alcohol consumption may act synergistically to increase HCC risk.²⁶
• Toxic exposures. Dietary toxins like aflatoxins (fungal toxins found on some contaminated foods, such as corn, peanuts, tree nuts, and cottonseed) and environmental or plant-derived toxins like pesticides, biocides, dioxins, bisphenols, phthalates, parabens, polyaromatic hydrocarbons, and aristolochic acid add to HCC risk and can exacerbate the carcinogenic effects of metabolic, infectious, and microbiome disturbances.^2,6
• Genetics. Certain genetic variants have been strongly correlated with HCC risk, particularly in individuals with MASLD.²⁷

HCC typically causes no symptoms in its early and most treatable stages. Unfortunately, most HCC is not detected until it is more advanced and causing symptoms, contributing to its poor prognosis.³⁸ Symptoms of HCC may include³⁹:

• Abdominal pain
• Fatigue
• Loss of appetite
• Nausea and vomiting
• Weight loss
• Ascites (edema in the abdominal cavity)
• Edema in the arms and legs
• Jaundice
• Itching
• Fever

In general, HCC is diagnosed on the basis of imaging tests and blood tests. Depending on the size of the lesion, the patient’s background HCC risk, and the availability of imaging technologies at the center where the patient seeks care, various non-invasive imaging tests may be involved in the diagnosis: computed tomography (CT), magnetic resonance imaging (MRI), and/or ultrasound. Biopsy may be necessary if the diagnosis cannot be reached conclusively based on imaging. Blood biomarker tests may be helpful in confirming diagnosis and/or for following-up HCC in tumors that secrete them (eg, alpha-fetoprotein [AFP]).⁴⁰

Imaging

Imaging is an important part of HCC diagnosis. Ultrasound is used to diagnose chronic liver disease and screen for the presence of HCC nodules. Follow-up imaging using CT or MRI with multiphasic contrast dye is recommended when a nodule ≥1 cm in size is found on ultrasound.³⁸ MRI has been shown in some studies to be more sensitive than CT for small tumors (1–2 cm).⁵ CT or MRI may also be useful for screening high-risk patients with obesity or nodular cirrhosis, conditions that limit the accuracy of ultrasound.^38,41 Multiphasic liver CT or MRI and CT of the chest, abdomen, and pelvis are staging imaging tests for HCC, prior to treatment.

General Blood Tests

Blood tests are used as an aid to diagnosis and guide treatment choices. Tests that assess liver function and overall organ function provide a non-specific indication of liver damage and health status. These include^42,43:

• Complete blood count (red blood cells, white blood cells, and platelets)
• Basic blood chemistry (electrolytes, glucose, and cholesterol)
• Liver enzymes (gamma-glutamyl transferase [GGT], aspartate transaminase [AST], alanine transaminase [ALT], alkaline phosphatase [ALP], and lactate dehydrogenase [LDH])
• Liver function tests (albumin, bilirubin, and prothrombin time or international normalized ratio [INR])
• Kidney function tests (creatinine or glomerular filtration rate [GFR])
• Virus-specific tests (eg, HBV, HCV)

Biomarker Tests

Alpha-fetoprotein (AFP), a protein made by liver cells as they grow and divide, is the most widely used biomarker for HCC. AFP levels are high in developing fetuses but drop dramatically after birth and remain low in healthy children and non-pregnant adults. When elevated, AFP can be a sign of liver, ovarian, or testicular cancer; however, since liver disease can also cause AFP levels to rise, and early-stage HCC is not always accompanied by a rise in AFP levels, AFP measurement is not accurate as a stand-alone test for HCC.^38,44 AFP is instead often used in conjunction with ultrasound surveillance in high-risk patients and increases detection of early stage HCC from 45% with ultrasound alone to 63% with ultrasound plus AFP.³⁸ A form of AFP known as AFP-L3 is only made by HCC cells and elevated levels are therefore considered diagnostic, and recent evidence suggests AFP-L3% testing may help predict HCC recurrence after liver transplant, but more research is needed.^5,45,218

Tissue Biopsy

A liver tissue biopsy may be indicated for liver lesions found in the absence of cirrhosis that cannot be definitively diagnosed with imaging.⁵ A tumor biopsy is not only used to diagnose HCC, but may also be used to measure tumor expression of proteins. Such protein expression has been found to be useful to guide treatment decisions in other cancers. For example, high amounts of programmed death-ligand 1 (PD-L1) on tumor cells may indicate greater potential benefits from immunotherapy using ICIs, although this correlation has not been consistently shown in HCC.^56,57 However, as of mid-2024, biopsy is neither necessary nor routinely recommended for diagnosis in patients with underlying liver disease and lesions that are >1 cm in size and for which two separate imaging studies are in agreement. The imaging studies must include use of multiphasic IV contrast and demonstrate enhancement in the early arterial phase and washout in the venous or delayed phase on CT or MRI to be used for HCC diagnosis. Liver biopsy is associated with a small risk of complications such as pain, puncture of the gallbladder, bile peritonitis (inflammation due to leakage of bile into the abdominal cavity), and bleeding.⁵

Liquid Biopsy

A liquid biopsy is a blood test used to examine tumor cells and their fragments in circulation. Circulating tumor cells and their molecular and genetic characteristics, as well as cell-free DNA and RNA, may be useful for tumor staging and guiding and monitoring therapy, as detailed above.⁵ Advances in artificial intelligence (AI) technologies may improve the ability to detect very low levels of circulating tumor DNA and distinguish possible mutation signals, increasing the potential value of liquid biopsy in HCC diagnosis and monitoring.⁵⁸ Liquid biopsies are not yet available for HCC diagnosis, outside of clinical trials.

Stool and Urine Tests

The gut microbiome can be a source of biomarkers of HCC. Findings from a number of studies suggest microbiome composition is distinctly different in HCC compared with chronic liver disease or liver health.⁵⁹ Microbiome composition has been shown to change during immunotherapy, and the presence of specific bacterial species in stool tests has been correlated with a greater or lesser likelihood of response to treatment with ICIs.^57,59 In addition, microbial patterns generally associated with better health, with a high presence of Prevotellaspecies, normal ratios of representation from the Firmicutes and Bacteroidetesphyla, and presence of Akkermansia species, have been linked to greater treatment responsiveness, whereas bacterial imbalance (dysbiosis) has been associated with poorer treatment response.^59,60

Urine testing is an emerging field of research into cancer prevention, diagnosis, and staging. Urine levels of metabolic by-products, immune and inflammatory markers, tumor-related proteins, and molecular and genetic biomarkers can provide insights about HCC risk, presence, and character. If validated in clinical trials, urine tests may be useful as a complement to blood tests in diagnosing and monitoring HCC.⁶¹

Staging

HCC staging is used to guide the treatment approach. The Barcelona Clinic Liver Cancer (BCLC) staging system is the most widely used guideline for staging HCC and is based on the tumor burden from multiphasic liver imaging and body CT scans, liver function, and physical performance status (using the Eastern Cooperative Oncology Group [ECOG] performance status scoring system). BCLC stages are as follows^62,63:

• BCLC 0/very early stage:
  • a single tumor of ≤ 2 cm
  • no vascular invasion or metastasis
  • preserved liver function (no jaundice, ascites, or encephalopathy [confusion due to excessive neurotoxins in the brain that the liver dose not filter out])
  • ECOG performance status 0/no cancer-related disability
• BCLC A/early stage:
  • a single nodule of any size or three or fewer nodules of ≤ 3 cm
  • no vascular invasion or metastasis
  • preserved liver function
  • ECOG performance status 0/no cancer-related disability
• BCLC B/intermediate stage:
  • more than three nodules
    or
  • 2 or more nodules, with at least one > 3 cm
  • no vascular invasion or metastasis
  • preserved liver function
  • ECOG performance status 0/no cancer-related disability
• BCLC C/advanced stage:
  • any degree of tumor with invasion of the portal vascular system or metastasis to sites outside of the liver
  • preserved liver function
    or
  • ECOG performance status 1–2/capable of self-care but limited in other activities
• BCLC D/terminal stage:
  • any degree of tumor with end-stage liver failure
  • ECOG performance status 3–4/capable of limited or no self-care and confined more than half or all of the day to a chair or bed

Resection (surgical tumor removal), ablation (tumor destruction), and liver transplant are the primary curative treatment options for HCC. Eligibility for these therapies depends on each patient’s tumor characteristics, liver function, and overall health status. Less than one-third of patients with HCC are eligible for resection.¹ When possible, it is important for HCC patients to be evaluated at a National Cancer Institute (NCI)-designated comprehensive cancer center for multidisciplinary evaluation to increase the likelihood of curative treatment selection, including liver transplantation, that will improve survival, and to allow for access to other therapies that may improve survival or quality of life.^1,64

For transplant-ineligible patients and those whose tumors are not amenable to ablation or resection or transplant, liver focused and/or systemic therapies may be available and may improve overall survival and quality of life.⁶⁵ Sometimes, patients initially ineligible for curative-intent treatment may become eligible after first undergoing tumor-reducing therapies.⁶⁶ Also, adjuvant (used after the main therapy) and neoadjuvant (used before the main therapy) treatments that may improve outcomes of curative-intent therapies are under investigation and showing promise. Neoadjuvant and adjuvant therapies are not widely recommended as of mid-2024. It is important to inquire about potential clinical trial eligibility at an NCI-designated comprehensive cancer center, especially in cases of advanced HCC.

The NCI provides a directory of Comprehensive Cancer Centers on its website, here: https://www.cancer.gov/research/infrastructure/cancer-centers/find

Early-Stage HCC

In general, patients with very early (BCLC 0) and early stage (BCLC A) HCC may be candidates for transplantation, resection, or ablation. Certain cases of intermediate stage (BCLC B) HCC may also be eligible for transplantation or resection.⁸ For unresectable patients or patients medically unsuitable for surgery, and for HCC unsuitable for or recurrent post-surgery or ablation, external beam radiation therapy may be considered.

Transplantation

The goal of transplant oncology is to radically cure cancer by replacing the entire affected organ. Liver transplantation has shown particularly promising results as a curative therapy in HCC patients: five-year survival after liver transplant exceeds 70% and recurrence rates are less than 10–15%, compared with 50% five-year survival and up to 80% recurrence rates following tumor resection.^1,72 Some studies have indicated patients with MASLD-related HCC who have undergone liver transplantation have worse overall survival in the short term, possibly due to increased cardiovascular deaths, than those with HCC from other causes; however, in the long term, post-transplant outcomes in MASLD-related HCC appear to be similar to or better than in HCC from other causes.⁷³

Immune modulating medications like ICIs may have a supportive role as neoadjuvant (pre-transplant) therapy by decreasing the chance of organ rejection. Their possible benefit as an adjuvant (post-transplant) therapy is also being explored.^72,74

Unfortunately, only a small percentage of HCC patients are eligible for liver transplant. Down-staging therapies (described below) offer the possibility to extend eligibility to more HCC patients.⁷²

Resection and Ablation

Liver resection is a viable option for appropriately selected patients; generally speaking, single tumors or more than one smaller size tumor, confinement of the tumor to the liver, and preserved liver function (as well as adequate future liver remnant following resection) increase the odds of resection viability.^62,75 In such cases, resection is associated with 5-year survival of up to 78%, with the best outcomes reported in individuals without metastasis within the liver, without vascular invasion and with a cancer-free surgical margin of greater than 1 cm.⁷⁶

Ablation with curative intent may be an option in appropriately selected HCC patients, generally with a maximum of three tumors of up to 3 cm in size.^62,77 A number of comparison studies have suggested that liver resection results in better outcomes than ablation in early-stage HCC and is usually the treatment of choice when feasible.^78-81 However, other studies in very early HCC have demonstrated similar outcomes following ablation or resection, and ablation is an option in these patients.

Types of Ablation

There are several ablation techniques used in clinical practice by interventional radiologists. Most ablation systems involve the delivery of thermal (heating) energy directly into the tumor via a probe that can be guided to the target area through the skin (percutaneously), laparoscopically, or during open surgery.^82,83 Radiofrequency ablation is the most common type and involves heat-killing tumor cells using high-frequency radio waves emitted by the probe. Microwave ablation is another widely used method and employs electromagnetic energy to heat and destroy the tumor. Although technologies are evolving, microwave ablation appears to have several advantages compared with radiofrequency ablation, including^1,82,83:

• larger zone of heating with better outcomes in cases of tumors between 3 and 5 cm
• more uniform tumor heating with more predictable results
• shorter procedure time
• less pain after the procedure
• potential to target multiple lesions using multiple antennae

A 2023 meta-analysis included data from 11 studies that evaluated microwave ablation and radiofrequency ablation in patients with HCC or liver metastases from primary colorectal cancer. The analysis also compared laparoscopic to percutaneous delivery of microwave ablation. The analysis showed radiofrequency ablation and microwave ablation had similar effectiveness. In addition, percutaneous and laparoscopic microwave ablation led to similar outcomes, but the complication rate was lower for percutaneous than laparoscopic procedures.⁸⁴

Cryoablation damages tumors through extreme cooling. It is not as commonly used as thermal ablation, as there is less experience among providers and potentially more toxicity with cryoablation. However, a meta-analysis of eight randomized controlled trials comparing cryoablation to standard of care with radiofrequency ablation in a total of 943 participants with liver malignancies found no differences in rates of complications, complete ablation of tumors, local recurrence, and one-year survival.⁸⁵

A newer technique known as a “no-touch” ablation method, in which the probe end is positioned in proximity to, but not within, the tumor, may have advantages in certain HCC tumors, particularly those located close to the liver’s edge (subcapsular).⁸⁶ A systematic review and meta-analysis published in 2023 evaluated data from 12 studies and found no-touch percutaneous radiofrequency ablation was an effective treatment option for HCC patients with tumors as large as 5 cm. Compared with conventional percutaneous radiofrequency ablation, the no-touch approach resulted in an approximately 75% lower risk of local tumor progression.⁸⁷ Another meta-analysis, also published in 2023, concluded similarly that no-touch percutaneous radiofrequency ablation was a safe and effective treatment option for patients with HCC up to 5 cm.⁸⁸ This approach is not widely available as of mid-2024.

A retrospective cohort study that evaluated 321 patients with subcapsular HCC found microwave ablation was generally comparable to resection in terms of 5-year local tumor progression rates, disease-free survival, and overall survival.⁸⁹ Some authors have suggested that patients with very early stage (BCLC 0) HCC may be the best candidates for microwave ablation.⁹⁰ Generally, microwave ablation may be a good option for HCC patients whose tumors are less than 2 cm and are in anatomically favorable locations (eg, the dome of the liver) and who have good liver function.^91,92

Recurrence Following Resection or Ablation

Recurrence is common after initial resection or ablation among HCC patients, with a rate of 70–80% after five years.⁹³ The high likelihood of recurrence is thought to be due to residual microscopic cancer and/or the development of new tumors related to underlying chronic liver disease.⁹⁴

Recently published and ongoing clinical trials explore various neoadjuvant or adjuvant regimens to see if they can reduce the risk of recurrence following curative-intent treatment in early-stage HCC; unfortunately, most have not been shown to meaningfully improve overall survival and many carry considerable risk of side effects.⁷⁶ One randomized, controlled, open-label trial that included 662 HCC patients at high risk for recurrence following resection or ablation found adjuvant immunotherapy with atezolizumab (Tecentriq) plus bevacizumab (Avastin) for one year improved recurrence-free survival after a median of 17.4 months compared with no adjuvant therapy (78% vs. 65%). However, severe or potentially life-threatening toxicity occurred substantially more frequently in patients who received treatment (41% vs. 13%).^76,95 Overall survival data from this trial has not been reported as of the time of this writing (late December 2023). In another randomized, controlled, open-label trial in 315 HCC patients with microvascular invasion who had undergone resection, 1–2 cycles of adjuvant chemotherapy with fluorouracil plus leucovorin and oxaliplatin (FOLFOX), administered directly into the hepatic artery, doubled median disease-free survival compared with routine follow-up (20.3 months vs. 10.0 months). However, FOLFOX did not improve overall survival.^76,96

Transplantation may be an option for patients with recurrent HCC after initial resection, but for ineligible cases or those who do not prefer transplantation, repeat resection or ablation are possible treatments. A meta-analysis published in 2023 that analyzed data from seven studies found overall survival did not differ with repeat resection versus radiofrequency ablation in patients with recurrent HCC who had undergone a previous liver resection.⁹⁷ In a meta-analysis published in 2022 that included data from two randomized controlled trials and 28 observational studies, repeat resection was associated with more complications than ablation, but prolonged recurrence-free survival; nevertheless, overall survival did not differ between those who underwent repeat resection versus ablation.⁹⁸ In another 2022 meta-analysis that included data from 12 studies, one-year overall survival was similar for radiofrequency ablation and repeat resection, but repeat resection resulted in better three- and five-year survival at the expense of more treatment-related complications.⁹⁹

External Beam Radiation Therapy

For patients with unresectable HCC who are not candidates for ablation, who have a high risk of complications following ablation (near heart, deep in caudate lobe, near gallbladder), high risk of recurrence (eg, near large vessel or diaphragm, or > 3 or 5 cm), or who have recurrences following ablation, external beam radiation therapy may be used with curative intent. External beam radiation therapy refers to the delivery of ionizing radiation therapy from outside the body. These strategies include using photons to deliver radiation conformally around the tumor using multiple beams or arcs (eg, stereotactic body radiation therapy [SBRT]) or using protons that are associated with a steep dose fall off to reduce the dose to normal tissues. SBRT and proton therapy have been used to treat HCC in large single-arm studies, cohort comparison studies, and randomized studies.²¹⁹

A single-center study of 318 patients with 375 HCCs found that five-year local control was 94%. Two- and five-year progression-free survival was 62% and 13%, and two- and five-year overall survival was 72% and 11%, respectively.¹⁰⁰ A meta-analysis of 32 studies of 1,950 patients with a median HCC size of 3.3 cm (range 1.6–8.6 cm) found a three-year local control rate of 84%.¹⁰¹ In a propensity score analysis comparison of TACE and SBRT in 209 patients with HCC, the two-year local control rate was higher with SBRT than TACE (91% vs. 23%, p < 0.001), with no significant difference in overall survival after adjusting for known prognostic factors.¹⁰²

One study of proton radiotherapy versus TACE (n=74) reported a similar two-year overall survival rate (68% and 65%, respectively), improved progression-free survival with radiotherapy (median not reached vs. 12 months with TACE), and improved local control with radiotherapy.¹⁰³ In two other small randomized controlled trials that were stopped early, SBRT was associated with improved local control and two-year progression-free survival compared with TACE or transcatheter arterial embolization (TAE) alone.^104,105

Post-Treatment Surveillance

Ongoing surveillance for HCC patients who have received curative-intent treatment is associated with better long-term outcomes. Although guidelines vary,the National Comprehensive Cancer Network and others recommend CT or MRI imaging every three to six months for two years, then every six months until at least five years, with some recommending annual imaging thereafter. Note, all patients with HCC are at higher risk of developing de novo HCC. Alpha-fetoprotein may be checked at the same intervals in patients whose HCC was AFP secreting prior to treatment.^77,106,107

Intermediate and Advanced HCC

Most patients whose HCC has reached the intermediate stage (BCLC B) are not eligible for resection, though some may become eligible with downstaging therapy. For those with advanced stage HCC (BCLC C), the goal of therapy is to prolong survival while preserving quality of life.⁸ Participation in a clinical trial is often encouraged for patients with advanced unresectable HCC. For patients with terminal stage HCC (BCLC D), the goal of therapy is to improve quality of life or cancer-related symptoms. Supportive or palliative care is often the best option for these patients.

Local-Regional Therapy

In patient with intermediate stage HCC, treatment options include:

• Transarterial bland embolization or chemoembolization (TACE), in which the artery supplying blood to the tumor is used to deliver a highly concentrated dose of chemotherapy and then blocked to cut off tumor blood supply.¹⁰⁸ TACE improves survival compared to supportive or palliative care in patients with good liver function and non-bulky HCC without vascular invasion.
• Yttrium-90 (Y90) radioembolization, which is a type of radiation therapy where radioactive beads are delivered to the tumor via a catheter through the hepatic artery (often referred to as transarterial radioembolization [TARE]). TARE appears to be at least as effective as TACE and is associated with a higher chance of tumor response.^109,110
• External beam radiation therapy (see above): SBRT or proton therapy are generally reserved for three or fewer HCCs, with highest chance of sustained local control in HCCs less than 8 cm. Long-term responses have also been seen in HCCs up to 20 cm in diameter.
• Ablation (see above): Ablation is generally reserved for three or less HCCs, each less than 3 cm.

Downstaging Therapy

For some patients initially ineligible for resection or transplantation, locally or regionally targeted (locoregional) therapies may reduce tumor size and number enough to permit curative-intent therapy. This is called downstaging therapy. Reported success rates of downstaging therapy vary widely—from 24% to 90%—and depend on several factors such as initial tumor burden, type of downstaging therapy utilized, and presence of vascular invasion, as well as definitions of success. Some potential therapeutic interventions that may be used in downstaging therapy include the local-regional therapies described above⁶⁶:

• TACE¹⁰⁸
• TARE^109,110
• SBRT or proton therapy

Systemic Therapy

For patients with advanced HCC, several approved systemic therapies exist. Drugs used in systemic treatment of HCC include multikinase inhibitors, immune checkpoint inhibitors, and monoclonal antibodies.²

Multikinase inhibitors. Sorafenib (Nexavar), a multi-targeted tyrosine kinase (or multikinase) inhibitor, was the only first-line treatment option for advanced HCC from 2007–2017, when additional multikinase inhibitors became available. Sorafenib targets pathways involved in angiogenesis (new blood vessel growth) and cell proliferation.¹¹¹ Its main adverse side effects are diarrhea, weight loss, and a hand-and-foot skin reaction. Recent research suggests lenvatinib (Lenvima), another multikinase inhibitor that targets a different group of receptors, is as effective as sorafenib at prolonging survival and may have a higher response rate. Side effects of lenvatinib include high blood pressure, protein loss via the kidneys, and diarrhea. Additional multikinase inhibitors have recently been approved as second-line systemic therapies for HCC that progresses during treatment with sorafenib: regorafenib (Stivarga) and cabozantinib (Cometriq). In addition, the monoclonal antibody ramucirumab (Cyramza) is approved as a second-line therapy.¹¹²

Immune checkpoint inhibitors. Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that intercept molecules made by tumor cells to suppress immune activation. Atezolizumab (Tecentriq), nivolumab (Opdivo), pembrolizumab (Keytruda), durvalumab (Imfinzi), and ipilimumab (Yervoy) are ICIs that have been investigated in HCC.¹¹² Although some have shown promising effects in HCC treatment, such as higher response rates than sorafenib, most ICIs have not been found to prolong survival compared with sorafenib when used as single agents.¹¹³

A randomized controlled trial involving 674 HCC patients who had not yet received systemic therapies found a new ICI called tislelizumab (Tevimbra), with a similar action to atezolizumab and durvalumab, performed as well as sorafenib in prolonging survival, but had a higher response rate. Common adverse side effects from tislelizumab included liver inflammation and hypothyroidism.¹¹⁴ Based on these promising findings, tislelizumab may be considered for approval as another first-line systemic therapy option for unresectable HCC.¹¹⁵

Combination therapies. Clinical trials have shown that combination therapies, such as dual ICIs, ICIs and multikinase inhibitors, have advantages over single-agent therapies. In addition, combining ablation techniques with regional or systemic therapies may improve efficacy, especially in cases of multiple tumors.¹¹²

The combination of atezolizumab, an ICI that targets PD-L1, plus bevacizumab, a monoclonal antibody that inhibits VEGF, was recently approved as a first-line therapy for unresectable HCC.¹¹¹ The approval was based on findings from a randomized, controlled, open-label trial involving 501 advanced HCC patients who had not received prior systemic therapy; those treated with atezolizumab plus bevacizumab had longer progression-free survival (6.9 months vs. 4.3 months) and overall survival (19.2 months vs. 13.4 months) than those treated with sorafenib.^112,116 Furthermore, those receiving sorafenib suffered a reduced quality of life due to more diarrhea, appetite suppression, and skin problems, while those receiving combination therapy experienced more hypertension, a known side effect of bevacizumab.¹¹²

A combination of two ICIs, tremelimumab (Imjudo, a cytotoxic T-lymphocyte–associated antigen-4 [CTLA-4] inhibitor) plus durvalumab (a PD-L1 inhibitor), has also been approved as a first-line therapy for unresectable HCC. The randomized controlled clinical trial that led to its approval involved 1,171 patients with unresectable HCC who were treated with durvalumab plus tremelimumab, durvalumab alone, or sorafenib. The trial found durvalumab worked as well as sorafenib while the combination of ICIs worked better for prolonging overall survival: after 48 months, the survival rate was 25.2% in the combination therapy group and 15.1% in the sorafenib group; however, serious treatment-related adverse side effects were more common in the combination therapy group.¹¹⁷

Combining systemic therapies with TACE has also been explored. The combination of sorafenib plus TACE may be more effective than either TACE or sorafenib alone, although results have been inconsistent.^118-120 Lenvatinib plus TACE may improve outcomes relative to lenvatinib alone. In a randomized controlled trial with 338 participants who had not received prior systemic therapy, median progression-free and overall survival were 10.6 and 17.8 months, respectively, in those receiving lenvatinib plus TACE, compared with 6.4 and 11.5 months in those receiving lenvatinib alone.¹²¹ Ongoing studies are examining the effects of combinations of multikinase inhibitors and/or ICIs with TACE as possible first-line approaches to unresectable HCC.¹¹⁵

Two randomized controlled trials have compared external beam radiation therapy (prior to sorafenib or in combination with TACE) to sorafenib alone in patients with macroscopic vascular invasion. In a phase 2 randomized controlled trial, 90 treatment-naive patients with portal vein invasion were randomized to sorafenib versus TACE (every six weeks) plus hypofractionated radiation therapy. Twelve-week progression-free survival was improved with radiation therapy plus TACE (86.7% vs. 34.3%), as was overall survival (median 55 vs. 43 weeks).¹²² The NRG/RTOG 1112 phase 3 trial randomized patients with locally advanced HCC to sorafenib versus SBRT followed by sorafenib.¹²³ In this trial, 177 patients (74% with vascular invasion) had improved survival with SBRT. On a pre-planned multivariable analysis, in addition to other prognostic factors, the use of SBRT was associated with improved overall survival. PFS was also improved with SBRT.

Importantly, many clinical trials are ongoing to test new drugs and combinations of therapeutics in advanced HCC.¹¹⁵ In addition, research into second-line combination therapies that might extend survival following these new first-line approaches is underway.¹¹² For instance, ongoing research is exploring the potential role of neoantigen-targeted cancer vaccines following ICI therapy.¹²⁴ The MYCHELANGELO I trial is testing the safety and preliminary efficacy of a novel drug called OTX-2002 in patients with advanced HCC who have received at least one prior line of systemic therapy and for whom there is no established standard of care. OTX-2002 is a first-in-class mRNA therapeutic drug described as an epigenome controller. It downregulates expression of MYC protein, a transcription factor involved in cell proliferation, differentiation, and apoptosis. Preliminary safety data have been encouraging, and initial efficacy studies are underway. OTX-2002 has been granted orphan drug status (meaning it was developed for treating a rare condition) for HCC.^125-127 Patients with advanced HCC can discuss clinical trial eligibility with their oncology team.

Preventive measures and surveillance in those at high risk are critical for reducing HCC mortality. When detected and treated early, HCC is associated with a five-year survival rate that is higher than 70%; but because it is frequently diagnosed in its later stages, five-year survival overall is much lower (eg, approximately 22% in the United States).^38,128

Antiviral Therapy

In patients with HBV and HCV, antiviral therapies can play an important role in HCC prevention. An observational study that included 855 adults with chronic HBV in the indeterminant phase (neither fully active nor fully inactive) and without advanced fibrosis found those treated with long-term antiviral therapy had a 15-year HCC risk of 9%, while the risk in untreated patients was 19%.¹²⁹ In HCV infection, antiviral therapy is curative in more than 95% of cases and successful treatment lowers the risk of HCC by 50–80% compared with persistent HCV.^16,130 Nevertheless, the risk of HCC remains somewhat elevated even following successful HCV treatment, possibly due to virally-induced changes in DNA expression (epigenetic modification).^131,132 In addition, screening for HCV in high-risk individuals (intravenous drug users, sex workers, and men who have sex with men) and getting treatment to those who test positive remain significant challenges.¹³⁰ All patients with HCC with HBV or HCV should be considered for antiviral therapy, before starting HCC therapy.

Avoiding Other Causes of Liver Damage

Having more than one condition affecting the liver has a dramatic negative impact on risk of HCC. For example, co-infection with HBV and HCV is far more likely to cause HCC than expected based on the risk associated with each single infection.⁷ Human immunodeficiency virus (HIV), which frequently co-occurs with HCV, promotes progression and worsens prognosis of liver disease.^7,133 Metabolic disease, including MASLD, increases liver fibrosis and cirrhosis risk and accelerates HCC risk in those with viral hepatitis.⁶ In addition, alcohol consumption and smoking are more toxic to a liver compromised by viral hepatitis or MASLD than a healthy liver.^6,7 Preventive measures therefore include:

• abstinence from alcohol and smoking⁶
• maintaining metabolic health through diet, exercise, stress management, and adequate sleep^7,134,135
• vaccination against HBV⁷
• avoiding behaviors associated with HBV, HCV, and HIV transmission, such as unprotected sex and intravenous drug equipment sharing^7,133
• avoiding environmental and occupational exposure to toxins as much as possible⁶
• judicious use of medications metabolized by the liver⁶
• bariatric (weight loss) surgery in those with MASLD and severe obesity¹⁷

Low-Dose Aspirin

Among people with chronic HBV or HCV, long-term use of low-dose aspirin has been associated with reduced HCC risk. For example, a large registry study of over 50,000 people in Sweden who had a diagnosis of chronic HBV or HCV but were not initially taking low-dose aspirin (defined as <160 mg daily in this study) evaluated the incidence of HCC among those who started to take low-dose aspirin and those who did not. Among participants who began low-dose aspirin therapy and continued to take it for at least three years, the incidence of HCC was about one-third lower than among those who did not begin taking aspirin. Among those who took low-dose aspirin for five years or more, HCC incidence was 43% lower compared with those who did not take it. The 10-year liver-related mortality was 11% among low-dose aspirin users and about 18% among non-users.¹³⁶ A meta-analysis published in 2023 that evaluated data from studies involving over 2.5 million people found that aspirin use was associated with a 30% reduced HCC risk. However, there was an 11% increased risk of bleeding events among aspirin users. The authors of the meta-analysis called for more prospective research to better define the patient population most likely to benefit and least likely to be harmed by aspirin use in the context of HCC prevention.¹³⁷

Diet and Exercise

A whole-foods plant-based diet can improve liver health and may lower the risk of HCC in people with chronic liver disease.²⁶ This means eating an abundance of vegetables, fruits, nuts and seeds, whole grains, and legumes, which are nutrient-dense, high in liver-protective flavonoids, and rich in fibers that maintain a balanced gut microbiome.^26,138,139 It also means avoiding alcohol, ultra-processed foods (foods made mostly or entirely from manufactured ingredients), sugar-sweetened beverages, refined grains and sugars, red and processed meats, saturated fats, and overeating in general.^26,138,140

Coffee consumption has been linked to lower HCC risk in multiple observational studies and meta-analyses. The association is more consistently seen with caffeinated, rather than decaffeinated, coffee-drinking and appears to begin at two cups per day and increase with each additional cup. In general, the likelihood of HCC has been shown to be 22–46% lower in coffee drinkers than non-coffee drinkers.¹⁴⁰

Weight loss is an important goal for those who have overweight or obesity, which compromise liver health and are associated with increased HCC risk and worse HCC prognosis.^141,142 Calorie reduction, time-restricted eating, and increased physical activity may help achieve meaningful weight loss that results in reduced steatosis and decreased liver inflammation.^138,140 Physical activity, even independent of weight loss, has also been shown to improve liver health and lower HCC risk.¹⁴⁰

A ketogenic (very low-carbohydrate/high-fat) diet may have positive effects on metabolic health and has shown promise in treating obesity, type 2 diabetes, metabolic syndrome, and MASLD.¹⁴³ A ketogenic diet has been found to improve glucose metabolism and mitochondrial function, reduce oxidative stress and inflammation in the liver, and slow the progression of liver disease related to metabolic dysfunction.¹⁴⁴ Observational evidence has linked a plant-based low-carbohydrate diet, but not an animal-based low-carbohydrate diet, with reduced risk of HCC.²⁶ Because of its apparent ability to reduce cancer cell proliferation through metabolic reprogramming and stabilizing gene expression, a ketogenic diet has been proposed as a therapeutic diet in cancer patients.^145,146 However, preclinical evidence has been mixed and the possible role of a ketogenic diet as part of a treatment approach to HCC remains under investigation.^146-148

For a comprehensive overview of dietary and lifestyle changes in the context of NAFLD, see Life Extension’s Non-Alcoholic Fatty Liver Disease (NAFLD) Protocol. Other relevant Life Extension Protocols include Cirrhosis, Hepatitis B, and Hepatitis C.

Surveillance

Because HCC generally does not cause noticeable symptoms in its most treatable stages, early detection is critical to increasing survival. Despite the existence of surveillance guidelines for people with increased HCC risk, these screening tests are woefully underused, with an implementation rate of less than 25%.¹⁴⁹

The American Association for the Study of Liver Diseases, Asian Pacific Association for the Study of the Liver, National Comprehensive Cancer Network, and European Association for the Study of the Liver all recommend abdominal ultrasound at six-month intervals for people with cirrhosis for any reason.⁸ In addition, regular monitoring is recommended for high-risk individuals with chronic HBV (Asian men at least 40 years of age; Asian women at least 50 years of age; African [not African American] persons at least 20 years of age; and those with a family history of HCC) and, in some guidelines, those with advanced HCV-related fibrosis.⁴¹

Although approximately 20% of MASLD-related HCC occurs in patients without cirrhosis, there are currently no surveillance guidelines for people with non-cirrhotic MASLD.^8,41 More research is needed to develop strategies for identifying MASLD patients who will benefit most from a screening program using demographic data, such as the presence of other metabolic disease and older age, as well as tests such as liver enzyme levels, ultrasound elastography (a measure of liver stiffness), and Fibrosis-4 (FIB-4, a scoring system used to estimate the severity of liver fibrosis).^149,150

The addition of alpha-fetoprotein (AFP) testing to ultrasound evaluation increases the likelihood of detecting early-stage HCC, but slightly increases the risk of false-positive findings.⁸ Nevertheless, ultrasound plus AFP appears to be the most effective screening strategy for most patients with cirrhosis.⁴¹ However, ultrasound has limited ability to detect HCC in a nodular cirrhotic liver and in patients with obesity.⁴¹ In patients with obesity (many of whom have MASLD), CT or MRI, with or without AFP, may be a better method of surveillance.¹⁵⁰

Summarized in this section are studies of variable methodological quality covering a variety of nutritional supplement interventions for HCC. Although the supplements on this list are considered safe in most circumstances, patients with HCC are advised to consult with their oncology team before initiating any supplement regimen.

Melatonin

Preclinical research has shown that melatonin may modulate several aspects of metabolism in liver cancer cells.¹⁵¹ For instance, melatonin downregulated the expression of some genes involved in drug resistance in cultured liver cells and inhibited their proliferation.¹⁵² Other laboratory experiments found melatonin suppressed mitochondrial activity and glucose metabolism in HCC cells.¹⁵³ Melatonin has also been shown to enhance the vulnerability of HCC cells to sorafenib.¹⁵⁴ A retrospective observational study found that higher blood melatonin levels before transplantation were associated with better survival one year following liver transplantation among patients with HCC.¹⁵⁵

In a randomized controlled pilot trial, melatonin (50 mg/kg body weight) or placebo was administered via gastric tube at the time of anesthesia in 50 patients undergoing major liver resection. The primary study endpoint was safety, and post-surgery outcomes were secondary endpoints. Melatonin administration in this fashion was shown to be safe, and there was some preliminary evidence of shorter intensive care requirement and reduced postoperative liver transaminase levels among melatonin recipients.¹⁵⁶ In a prospective clinical trial, 100 patients with advanced inoperable HCC were treated with transarterial chemoembolization (TACE) with or without 20 mg of melatonin (by mouth) for seven days before TACE. TACE plus melatonin was judged to be more effective than TACE alone. Survival was better among the subjects who received melatonin as well—the one-year survival rate in the TACE-only group was 54% and the two-year survival rate was 26%, compared with 68% and 40%, respectively, in the TACE-plus-melatonin group.¹⁵⁷

Rice Bran Arabinoxylan (MGN-3)

In a randomized trial, 68 patients with HCC were assigned to interventional treatment with transarterial oily chemoembolization (TOCE) or TOCE plus ablation using ethanol injection, with 38 participants receiving interventional treatment plus 1 g/day of rice bran-derived arabinoxylan (MGN-3) and 30 receiving interventional treatment alone for 12 months. The group receiving the arabinoxylan showed lower recurrence rates (31.6% vs. 46.7%), greater survival after year 2 (35% vs. 6.7%), greater reduction in alpha-fetoprotein levels (38% decrease vs. no significant change), and a greater decrease in tumor volume compared with control.¹⁵⁸ Given the small sample size, this has not led to wide spread recommendations to take MGN-3.

Coenzyme Q10

A single-blinded, randomized, placebo-controlled study enrolled 41 patients with primary HCC. Participants took either 300 mg coenzyme Q10 (CoQ10) or placebo daily after they underwent surgery. CoQ10 supplementation for 12 weeks significantly reduced markers of inflammation and oxidative stress after surgery, and markers of antioxidant enzyme activity increased in the CoQ10 group. No effects on clinical outcomes were reported.¹⁵⁹

Branched-Chain Amino Acids

Evidence from five studies indicates an uncertain effect of branched-chain amino acid (BCAA) supplementation on event-free survival after HCC resection.¹⁶⁰ However, BCAA supplementation does seem to improve albumin levels (one marker of liver function) and quality of life among HCC patients who undergo locoregional therapy.¹⁶¹ Data from two retrospective studies suggest patients with HCC receiving sorafenib in particular may derive some benefit from BCAA supplementation; however, this evidence is weak.¹⁶⁰

In a randomized controlled trial, 51 subjects with early-stage HCC received supplemental BCAAs (n = 25) or diet alone (n = 26) beginning two weeks before undergoing local ablation therapy. The BCAA formulation used in this study is called Aminoleban EN and contains several vitamins, minerals, and other nutrients in addition to BCAAs. Participants consumed one 50-gram packet of Aminoleban twice daily. During a follow-up of up to five years, BCAA-treated participants had fewer recurrences of HCC at new sites within the liver than the control group (58% vs. 93%). In addition, overall survival was higher (88% vs. 61.5%) and the combined rate of complications and liver failure during follow-up was lower (40% vs. 69%) in the BCAA group.¹⁶² In another clinical trial, among 84 patients undergoing TACE for HCC, 41 received 11 grams BCAA supplementation daily and 43 did not. Those who received the BCAAs had fewer episodes of ascites and peripheral edema, greater improvement in liver health biomarkers, and better self-reported quality of life compared with those not receiving them.¹⁶³ Similar results have been reported from other clinical trials.^164-167

Vitamin K2

Mixed evidence suggests vitamin K2 may have a complementary role in HCC treatment. Small trials have shown some outcome benefits for treatment with vitamin K2 and MK-4 (menatetrenone, one of nine forms of vitamin K2) specifically.^168-170 In one trial, 61 patients who had undergone resection for HCC received either 45 mg MK-4 daily or no treatment. In the MK-4 group, the recurrence rates at 12 months (12.5%), 24 months (39%), and 36 months (64.3%) were significantly lower than the corresponding rates in the control group (12 months: 55.2%, 24 months: 83.2%, and 36 months: 91.6%). The three-year survival rate in the MK-4 group was 87% vs. 64% in the control group, which was just barely statistically significant.¹⁶⁹ Another small trial with 44 participants found adding MK-4, at 45 mg per day, to treatment with sorafenib led to a better objective response rate than sorafenib alone (27.3% vs 4.5%).¹⁷¹ Interestingly, a small study suggested that 45 mg MK-4 per day in combination with 4 mg of the ACE-inhibitor perindopril per day might reduce the cumulative recurrence of HCC after curative-intent treatment, possibly by suppressing new blood vessel growth.¹⁷²

On the other hand, a larger randomized controlled trial in 548 HCC patients who had undergone ablation or resection found vitamin K2 supplementation at 45 mg or 90 mg daily did not reduce the risk of disease recurrence or death compared with placebo after about 18 months.^173,174

Active Hexose Correlated Compound

Active hexose correlated compound, or AHCC, is a standardized cultured extract of several medicinal mushroom mycelia. A prospective cohort study enrolled 269 consecutive patients with HCC who underwent liver resection. One hundred thirteen of the patients took AHCC after surgery and the remaining 156 subjects served as a control group. Those taking 3,000 mg AHCC daily had a significantly longer period without recurrence and better overall survival compared with controls. Although the survival improvements observed in this study were statistically significant, the study had some methodological limitations that need to be taken into consideration when interpreting these results. For example, the study was not randomized—participants were free to choose to be in the AHCC or control (no additional treatment) groups.¹⁷⁵ Further randomized controlled trials are needed to evaluate the efficacy of AHCC in the context of HCC.

Omega-3 Fatty Acids (Fish Oil)

A trial involving 98 subjects receiving liver transplantation due to HCC or end-stage liver disease found that intravenous (IV, or parenteral) nutrition supplemented with omega-3 fatty acids for seven days following surgery led to better recovery, improved nutritional status, fewer infections, shorter hospital stays, lower ALT levels, and less liver tissue injury than those who received IV nutrition without omega-3 fatty acids.¹⁷⁶

Carnitine

For patients with HCC who undergo treatment with lenvatinib, supplemental carnitine might be worthwhile. One study found carnitine insufficiency was correlated with increased fatigue in HCC patients receiving lenvatinib, and that lenvatinib may contribute to carnitine depletion.¹⁷⁷ Interventional clinical trials are needed to determine if carnitine supplementation has a role in reducing fatigue or otherwise improving quality of life in HCC patients.

Several existing drugs used for other conditions are under investigation for their potential to improve prognosis in patients with HCC. Although consistent results from randomized clinical trials are lacking, patients may want to consult their oncology team to discuss whether one or more of these drugs might have a place in an individualized treatment program.

Statins

Statins are a family of drugs used to treat high cholesterol levels. Several studies have investigated the role of statins as repurposed drugs for HCC.^178,179 In a randomized controlled trial, 83 patients under 71 years of age with advanced unresectable HCC received standard treatment with or without 40 mg of pravastatin (Pravachol) daily for an average of 16.5 months. Median survival was significantly longer in the pravastatin group (18 months) than in the standard care group (9 months).¹⁸⁰ In a prospective study, 183 patients with advanced HCC were treated with TACE alone or TACE plus 20–40 mg pravastatin daily and observed for up to five years. Median survival was 20.9 months in participants treated with TACE plus pravastatin and 12 months in those treated with TACE alone.¹⁸¹ On the other hand, a retrospective study of medical records from 275 HCC patients found those who used statins before and for one year following resection (presumably to treat high cholesterol levels) did not have longer overall survival.¹⁸²

Statin use also appears to reduce the risk of developing HCC. In a systematic review and network meta-analysis of five observational studies with a total of 87,127 participants, fluvastatin (Lescol) and atorvastatin (Lipitor) were each found to be associated with significantly reduced HCC risk, with fluvastatin showing the more promising protective effect. The analysis also found evidence suggesting the use of simvastatin (Zocor), cerivastatin (Baycol), pravastatin, lovastatin (Mevacor), or rosuvastatin (Crestor) may lower HCC risk.¹⁸³ A meta-analysis that evaluated evidence from 29 observational studies and three randomized controlled trials found the use of a lipid-soluble statin (simvastatin, fluvastatin, lovastatin, pitavastatin [Livalo], or atorvastatin) was associated with prevention of HCC, while use of a water-soluble statin (rosuvastatin or pravastatin) was not. The analysis also found high-dose statin therapy was associated with greater protection than low-dose therapy.¹⁸⁴ In a meta-analysis of 10 studies evaluating associations between HCC risk and use of statins, metformin, and aspirin, statin use had the strongest association with reduced risk.¹⁸⁵ In an observational study that included 734 patients with HCC who had undergone resection, a medication use review showed those who received statin therapy to treat high cholesterol levels for more than 90 days following surgery had a significantly increased recurrence-free survival, but not overall survival, during approximately three years of follow-up.¹⁸⁶ In a database analysis published in 2023 that included data from over 1.7 million people from the UK Biobank, the TriNetX cohort, and the Penn Medicine Biobank, statin use was associated with a 42–74% lower risk of HCC and a 28% lower risk of liver disease-related death.¹⁸⁷

Preclinical research has identified several potential mechanisms by which statins may exert anticancer effects. These include inhibiting proliferation, inducing apoptosis (programmed cell death), modulating tumor cell adhesion and invasion capacity, anti-inflammatory effects, immune modulation, and modulating activation of enzyme pathways involved in cancer progression or suppression.^179,188,189

Canagliflozin

Canagliflozin (Invokana) is an inhibitor of a metabolic enzyme called sodium-glucose transport protein (SGLT)-2 and is approved for treating type 2 diabetes. Several preclinical studies have found that canagliflozin may suppress HCC cell growth by modulating glucose metabolism and cellular energy production. For instance, in one laboratory study that used a cell-based model of HCC, treating the cells with canagliflozin prior to radiation therapy enhanced their vulnerability to radiation.¹⁹⁰ Other laboratory studies have indicated canagliflozin may reduce proliferation and metastasis of HCC cells by altering important cellular metabolic pathways.^191-193 Canagliflozin has also been found to decrease tumor growth and improve survival in mouse models of HCC.^192,194,195 Other evidence from animal research suggests canagliflozin may help prevent the transition from metabolic dysfunction-associated steatohepatitis (MASH, the most advanced form of MASLD) to HCC.¹⁹⁶

It is important to note that research in rats has suggested canagliflozin may interact with some medications used to treat HCC, specifically, sorafenib, donafenib (Zepsun), and lenvatinib, and thus it is not recommended for patients taking those medications.^197,198

Niclosamide Ethanolamine

Niclosamide (Niclocide) is a drug used to treat parasitic worm infestation. Niclosamide and its ethanolamine salt, niclosamide ethanolamine, have been shown to alter expression of several genes that appear to be involved in HCC growth and progression.^199-201 In mouse models of HCC, niclosamide ethanolamine plus sorafenib slowed tumor growth more than either agent alone.¹⁹⁹ In rats with HCC, niclosamide treatment inhibited cancer cell signaling and induced apoptosis.²⁰²

Artesunate

Artesunate is an antimalarial drug identified as a candidate for repositioning as an anti-HCC agent. Artesunate has demonstrated anticancer effects in cell and computer models of HCC.^203-205 Artesunate has also been shown to act synergistically with sorafenib in studies involving HCC cell lines.^206,207 In mice with HCC, artesunate decreased tumor burden and blood vessel density—effects that were enhanced in the presence of sorafenib.²⁰⁵ In a rat model of HCC, artesunate reduced pathological changes, including tumor nodule occurrence in carcinogen-treated animals.²⁰⁸

Flubendazole

Flubendazole (Fluvermal) has been used for decades to treat parasitic worm infestations. Some preliminary research suggests that overexpression of an enzyme involved in regulating low density lipoprotein (LDL) metabolism, called proprotein convertase subtilisin/kexin type 9 (PCSK9), may be correlated with a poor prognosis in HCC, and flubendazole may reduce PCSK9 expression. Using cell cultures and animal models, flubendazole was shown to suppress HCC cell viability and enhance the effectiveness of the chemotherapy drug lenvatinib against HCC.²⁰⁹

Labetalol

Labetalol (Trandate) is a beta-blocker used to treat high blood pressure. Researchers have discovered labetalol strongly interacts with a protein called cell division cycle 20 (CDC20) that is highly expressed in HCC. In the laboratory, labetalol inhibited the growth of cultured HCC-like cells. This evidence suggests labetalol may have anticancer activity against HCC through its ability to target an important tumor cell protein.²¹⁰

Nutlin-3

Nutlins are potential anticancer agents in early-stage development that appear to work by stabilizing a tumor-suppressing protein called p53. Preclinical studies have shown that nutlin-3 in particular has anticancer activity against HCC cells under various conditions.^211-215 One study found that nutlin-3 and aspirin acted synergistically to induce an antitumor effect in laboratory and animal models of HCC.²¹⁶

Sildenafil

Sildenafil (Viagra) is a selective phosphodiesterase (PDE)-5 inhibitor that dilates certain blood vessels and is used to treat erectile dysfunction and pulmonary arterial hypertension. Sildenafil was found to modulate glucose metabolism and multidrug resistance in an animal model of HCC. It was predicted these effects might lead to reduced HCC development and progression.²¹⁷