Hepatocellular Carcinoma (HCC) Treatment & Management

Management of hepatocellular carcinoma (HCC) is best performed in a multidisciplinary setting. Patients should be cooperatively managed by hepatologists, transplant and hepatobiliary surgeons, medical oncologists, interventional radiologists, and palliative care specialists. Specifically, this is crucial to ensure that patients who are candidates for liver transplantation are referred in a timely manner, while their tumors are within the Milan criteria. ^[38]

Treatment options for hepatocellular carcinoma depend on the following ^[49] :

• Size, number, and location of tumors
• Presence or absence of cirrhosis
• Operative risk based on extent of cirrhosis and comorbid diseases
• Overall performance status
• Portal vein patency
• Presence or absence of metastatic disease

Before instituting definitive therapy, it is best to treat the complications of cirrhosis, as follows:

• Sodium restriciton, diuretics, and paracentesis for  ascites
• Lactulose for encephalopathy
• Ursodiol for pruritus
• Sclerosis or banding for variceal bleeding
• Antibiotics for s pontaneous bacterial peritonitis

Surgical resection and liver transplantation provide the only chances of cure but have limited applicability. The main prognostic factors for resectability are tumor size and liver function. Only about 5% of hepatocellular carcinoma patients are suitable for transplantation; these patients may have a 5-year survival of greater than 75% with tumor recurrence rates as low as 15% at 5 years. ^[50]  

Thus, other treatments should be used to bridge patients to transplant or to delay recurrence if possible; these include resection; radiofrequency ablation (RFA); and, potentially, systemic therapy with sorafenib (or, if sorafenib fails, with regorafenib, nivolumab, lenvatinib, pembrolizumab, cabozantinib, or ramucirumab). In patients who experience a recurrence following resection or transplantation, aggressive surgical treatment appears to be associated with the best possible outcome. ^[51]

See also Hepatocellular Carcinoma Treatment Protocols.

In patients who are not candidates for liver transplantation or resection, tumor ablation can be offered to extend life and potentially to downstage the tumor so as to permit transplantation or resection. Alternatively, patients who have advanced disease may benefit from palliative care interventions rather than be subjected to often ineffective therapies.

Transcatheter arterial chemoembolization

The most commonly offered therapy is transcatheter arterial chemoembolization (TACE). ^{[52, 53]} TACE is performed by an interventional radiologist who selectively cannulates the feeding artery to the tumor and delivers high local doses of chemotherapeutic agents, including doxorubicin, cisplatin, or mitomycin C. To prevent systemic toxicity, the feeding artery is occluded with gel foam or coils to prevent flow.

Because most HCCs derive 80-85% of their blood flow from the hepatic artery, the therapy can be well targeted, leaving the normal parenchyma, which is primarily supplied by portal blood, minimally affected. A reduction in tumor burden can be achieved in 16-61% of treated patients.

The impact of TACE on clinical outcome remains unclear. ^[54] Some studies suggested no benefit, but others reported a marked improvement in survival, including an increase in the 2-year survival rate from 27% to 63% in a group of 112 patients. ^[55] One meta-analysis of seven randomized controlled trials with 516 patients suggested a survival advantage for chemoembolization (odds ratio for death, 0.53) as compared with medical therapy.

A phase II study using data from the TACTICS trial (33 institutions, N = 156) found evidence that adding sorafenib to TACE may yield significantly longer progression-free survival (PFS) than TACE alone in patients with unresectable HCC. ^[56]  Adverse events were consistent with findings from previous TACE combination trials. The patients in this trial received sorafenib for a median of 38.7 weeks, compared with a range of 17-21 weeks in earlier combination studies.

Because TACE is reasonably well tolerated and has minimal morbidity, it can be offered to well-compensated patients with cirrhosis as a method to reduce their disease burden and to potentially extend their life.

The most common complication is postembolization syndrome, which is characterized by fever, elevated alanine aminotransferase (ALT), and abdominal pain; it occurs in 32-80% of treated patients. ^[57] However, in patients with advanced cirrhosis and hepatic decompensation, TACE is contraindicated, because the ischemic damage associated with embolization can lead to a rapid decline in liver function with worsening encephalopathy, increased ascites, and potentially death.

Brachytherapy

Another treatment option involves the local delivery of low-dose brachytherapy to the tumor. One such treatment, TheraSphere (BTG, Ottawa, Ontario, Canada), uses 20- to 40-μm glass beads that are loaded with radioactive yttrium and delivered angiographically. The radiotherapy is then delivered over 10-12 days with a total dose of about 150 Gy. The maximum distance affected is 1 cm. ^[58]

Early reports suggested that a small number of patients can be successfully downstaged and subsequently transplanted by using this approach. Risks include radiation damage to nearby organs (eg, the gastrointestinal tract).

Systemic Therapy

Systemic therapy remains the mainstay of treatment for patients with advanced HCC who are not candidates for surgical resection, liver transplantation, or localized tumor ablation. Unfortunately, HCC is minimally responsive to systemic chemotherapy. Resistance may be caused by the universal expression of the multidrug resistance gene protein on the surface of the malignant cells, leading to active efflux of chemotherapeutic agents.

Chemotherapy is usually not well tolerated and seems to be less efficacious in patients with HCC who have underlying hepatic dysfunction. Younger patients with well-compensated cirrhosis due to chronic hepatitis B or C infections have better outcomes with chemotherapy than older patients with alcoholic cirrhosis and other comorbid diseases.

However, there is also no apparent benefit to chemotherapy in the adjuvant setting following resection or radiofrequency ablation (RFA). ^[57]

Since systemic chemotherapy has questionable benefits compared with risks (eg, toxicities), targeted therapy and immunotherapy have been the main treatments for advanced, unresectable HCC. For many years, sorafenib has been the only systemic therapy option for advanced disease. However, new targeted therapies and immunotherapies have expanded the treatment algorithm for these patients. ^[2]

Tremelimumab in combination with durvalumab

A new first-line combination therapy, tremelimumab (Imjudo) and durvalumab (Imfinzi), was approved by the US Food and Drug Administration (FDA) in November 2022 for the treatment for unresectable advanced HCC. Approval was based on results from the phase III, multicenter HIMALAYA trial, in which patients (n=1171) were randomized to receive tremelimumab plus durvalumab, durvalumab, or sorafenib. Median overall survival (OS) was superior in the tremelimumab-durvalumab group compared with sorafenib (16.4 months versus 13.8 months with a hazard ratio of 0.78, P=0.0035). Objective response rate (ORR) was 20.8% in the tremelimumab-durvalumab group versus 5.1% in the sorafenib group. Durvalumab monotherapy was noninferior to sorafenib for patients with unresectable HCC. ^[59]

Atezolizumab plus bevacizumab

In 2020, the FDA approved atezolizumab in combination with bevacizumab for systemic treatment–naïve patients with unresectable or metastatic HCC. ^[60] Approval was based on the results of IMbrave150, a global, open-label, phase III trial in systemic treatment–naïve patients with unresectable HCC, in which both OS and PFS were better with atezolizumab plus bevacizumab than with sorafenib. OS at 12 months was 67.2% (95% CI, 61.3 to 73.1) in patients (n = 329) treated with atezolizumab–bevacizumab and 54.6% (95% CI, 45.2 to 64.0) in patients (n = 156) treated with sorafenib. Median PFS was 6.8 months (95% CI, 5.7 to 8.3) versus 4.3 months (95% CI, 4.0 to 5.6), respectively. The hazard ratio for disease progression or death with atezolizumab–bevacizumab compared with sorafenib was 0.59 (95% CI, 0.47 to 0.76; P < 0.001). ^[61]

Lenvatinib

In 2018, the FDA approved lenvatinib, a vascular endothelial growth factor (VEGF) inhibitor, for first-line treatment of unresectable HCC. Approval was based on the phase III REFLECT trial, which showed that lenvatinib was noninferior to sorafenib for first-line treatment of HCC. ^[62]  Median OS was 13.6 months with lenvatinib vs 12.3 months with sorafenib. Median progression-free survival (PFS) was 7.4 months for lenvatinib versus 3.7 months for sorafenib. Time to progression was 8.9 months for lenvatinib vs 3.7 months for sorafenib.

Sorafenib

Sorafenib is an oral agent that has antiangiogenic, proapoptotic, and Raf-kinase inhibitory properties. ^{[63, 64, 65]} ​ In 2007, it was approved by the FDA for use in patients with unresectable HCC. Sorafenib is regarded as a standard medical treatment for advanced HCC. ^{[66, 67]}  In addition, data from the TACTICS trial suggest that adding it to TACE may lead to improved survival as compared with TACE alone in patients with unresectable HCC. ^[56]

The following additional systemic drug options exist for patients with HCC who have stopped responding to initial treatment with sorafenib:

• Regorafenib
• Pembrolizumab
• Cabozantinib
• Ramucirumab
• Nivolumab plus ipilimumab
• Dostarlimab
• Selpercatinib

Regorafenib

In 2017, regorafenib was approved by the FDA for use in patients with HCC who have been previously treated with sorafenib. Approval was based on the RESORCE trial results (N = 573) in patients with progressive HCC who had undergone treatment with sorafenib. ^[68] In this trial, regorafenib improved OS in comparison with placebo (10.6 vs 7.8 months). Median PFS was also significantly better with regorafenib than with placebo (3.1 vs 1.5 months), as were the disease control rate (65.2% vs 36.1%) and the complete or partial response rate (10.6% vs 4.1%).

Pembrolizumab

In 2018, the FDA granted pembrolizumab an accelerated approval for patients with HCC previously treated with sorafenib. Approval was based on the KEYNOTE-224 trial, in which single-agent pembrolizumab induced an objective response of 17% among 104 patients with advanced HCC previously treated with sorafenib. ^[69] The overall response rate was 1%, and the partial response rate was 16%; meanwhile, 44% of patients had stable disease, 33% had progressive disease, and 6% were considered not assessable. Pembrolizumab treatment resulted in durable responses and favorable PFS and OS in patients with advanced HCC previously treated with sorafenib.

Cabozantinib

In January 2019, cabozantinib was approved for HCC in patients previously treated with sorafenib. Cabozantinib is an inhibitor of multiple tyrosine kinases, including RET, MET, and VEGFR-2. Approval was based on the phase III CELESTIAL trial (N = 707). OS was 2.2 months longer with cabozantinib (10.2 months) than with placebo (8.0 months). The improvement in median OS with cabozantinib represented a 24% reduction in the risk of death (HR, 0.76). ^[70]

Ramucirumab

In May 2019, ramucirumab, a VEGFR2 antagonist, was approved by the FDA as monotherapy in patients with HCC who have an alpha fetoprotein (AFP) level of 400 ng/mL or higher and have been previously treated with sorafenib. Approval was based on the REACH‑2 randomized double-blind placebo-controlled study (N = 292). ^[71] Patients were randomized (2:1) to receive ramucirumab 8 mg/kg plus best supportive care (BSC) or placebo plus BSC every 2 weeks until disease progression or unacceptable toxicity. Estimated median OS was 8.5 months (range, 7.0-10.6) for ramucirumab and 7.3 months (range, 5.4-9.1) for placebo (HR 0.71).

Nivolumab plus ipilimumab

The combination of nivolumab with ipilimumab received accelerated approval from the FDA in 2020 for treatment of HCC in patients previously treated with sorafenib. Accelerated approval was based on the overall response rate and duration of response in the phase I/II open-label CheckMate-040 trial. Investigator-assessed objective response rate was 32% (95% CI, 20-47%) in patients who received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, every 3 weeks (4 doses), followed by nivolumab 240 mg every 2 weeks. Median range duration of response was not reached (8.3-33.7+). ^[72] Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Nivolumab had received accelerated approval by the FDA in 2017 as monotherapy for patients with HCC previously treated with sorafenib, based on the CheckMate-040 trial. ^[72] However, in July 2021 this indication was voluntarily withdrawn in the US by the manufacturer when the confirmatory CheckMate-459 trial failed to show a statistically significant benefit in OS with nivolumab versus sorafenib as first-line therapy for advanced HCC. ^[73]

Dostarlimab

In  2021, FDA granted accelerated approval to dostarlimab (Jemperli) for adults with mismatch repair deficient (dMMR) recurrent or advanced solid tumors that have progressed on or following prior treatment and who have no satisfactory alternative treatment options.

Efficacy was based on the GARNET trial, a multicenter, open-label, multicohort trial, patients (n=209) with dMMR recurrent or advanced solid tumors who progressed following systemic therapy and had no satisfactory alternative treatment. The overall response rate (ORR) was 41.6%, with 9.1% complete response rate and 32.5% partial response rate. Median duration of response was 34.7 months, with 95.4% of patients with duration ≥6 months.  ^[74]

Selpercatinib

In September 2022, the FDA granted accelerated approval to selpercatinib (Retevmo) for adults with locally advanced or metastatic solid tumors with a rearranged during transfection (RET) gene fusion that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options. Approval was based on the multicenter, open-label LIBRETTO-001, conducted in patients with a variety of RET-fusion–positive tumors, in which the overall response rate was 44% with a duration of response of 24.5 months. In addition to HCC, tumor types with responses included pancreatic adenocarcinoma, colorectal, salivary, unknown primary, breast, soft tissue sarcoma, bronchial carcinoid, ovarian, and small intestine. ^[75]

Other nonsurgical measures

For most patients, treatment options other than palliative care are limited. For patients with Child-Pugh class C cirrhosis and contraindications for transplantation, any intervention has the potential to result in progressive hepatic decompensation. In these patients, treatment focuses on pain control, ascites, edema, and portosystemic encephalopathy management.

Pain control may provoke worsening of portosystemic encephalopathy, in that some patients are sensitive to narcotics and sometimes benzodiazepines. Insomnia may be the consequence of depression and fear, but it can also be a reflection of portosystemic encephalopathy. The latter can be worsened by (narcotic-induced) constipation that should be prevented. Lactulose can be helpful, and the ideal dosage should lead to not more than and not fewer than two or three bowel movements daily.

Aspirin and aspirinlike products, as a rule, are contraindicated in the patient with fluid retention because prostaglandin inhibition can strongly enhance retention of water and salt. In addition, consequences of platelet dysfunction may occur.

Fluid overload is best managed with a combination of spironolactone (50-400 mg/day), replaced by amiloride (10-20 mg/day) in case of painful gynecomastia, and furosemide (40-160 mg/day). Excessive diuresis leading to a weight loss of more than 1-2 lb daily usually causes worsening renal and electrolyte problems. Large-volume paracentesis in excess of 5-7 L, even accompanied by intravenous albumin, can result in renal decompensation and worsening of portosystemic encephalopathy.

In terminal patients, hypoglycemia can be confused with hepatic coma and can be managed with glucose infusions. Patients with large tumors have a short life expectancy, and every effort should be made to preserve and enhance quality of life. Early referral to palliative care practitioners should be considered.

In 2018, the second-generation orally administered thrombopoietin receptor agonist avatrombopag was approved by the FDA for the treatment of thrombocytopenia in patients with chronic liver disease who are scheduled to undergo a medical or dental procedure. Approval was based on the ADAPT-1 and ADAPT-2 trials. ^[76]

In view of the absence of effective chemotherapy and the insensitivity of HCC to radiotherapy, complete tumor extirpation represents the only opportunity for a long-term cure. Resection of the tumor by partial hepatectomy (see the videos below) can be accomplished in a limited number of patients (generally < 15-30%) in most Western series due to the degree of underlying cirrhosis.

In patients with decompensated liver disease, liver transplantation offers the potential for a long-term cure in patients with limited tumor burden. Alternative treatments, including local ablative therapy, TACE, and transarterial brachytherapy, can be considered in patients who are not candidates for curative procedures.

Surgical resection

Advances in the technique of liver resection, better patient selection, improved postoperative care, and expert anesthetic management have resulted in a dramatic reduction in perioperative morbidity and mortality. Liver resection is the operation of choice for patients with tumors smaller than 5 cm in the absence of cirrhosis. These patients can often tolerate resection of up to 50% of the total liver volume. In these patients, an operative mortality of less than 2% can be expected in experienced centers. ^[45]

In patients with cirrhosis, the extent of liver resection that can be tolerated is significantly more limited. Clinically evident portal hypertension (defined as a hepatic vein–to–right atrial pressure gradient in excess of 10), esophageal varices, or splenomegaly with a platelet count lower than 100,000/μL predicts poor outcome with significant resection. In general, resection of more than two segments is contraindicated in patients with Child class B or C cirrhosis. However, among patients who do undergo successful resection, long-term survival is possible, with 5-year survival rates as high as 74% in patients without significant decompensation.

After liver resection, as many as 75% of patients will develop intrahepatic recurrence within 5 years. ^{[77, 78]} This recurrence can be either de-novo HCC or local spread. Pathologic characteristics associated with a higher rate of recurrence include the following:

• Tumor at the resection margin
• Presence of cirrhosis
• Vascular invasion
• Advanced tumor grade
• Number of tumor nodules
• Microvascular portal vein thrombosis

Other clinical factors associated with a higher rate of HCC recurrence include the following:

• Preresection serum alpha-fetoprotein (AFP) level higher than 10,000 ng/mL
• Large intraoperative transfusion requirements
• Preoperative aspartate aminotransferase (AST) level greater than twice normal
• Diagnosis of hepatitis C

In patients with recurrence and preserved liver function, repeat resection may be indicated. In one single-center series, operative resection was associated with prolonged survival (44 months vs 10.6 months) in comparison with medical management. ^[79]

Resection of HCCs that are 2 cm or smaller has been shown to be safe and effective in both Asian and Western populations, though recurrence is common. The presence of satellites and platelet count are associated with survival in these patients, and the presence of satellites, cirrhosis and nonanatomic resection are associated with recurrence. ^[80]

Liver transplantation

Compared with resection for HCC, orthotopic liver transplantation (OLT) offers several potential advantages. Complete hepatectomy eliminates the possibility of local recurrence at the resection margin and, moreover, removes the cirrhotic liver, which is clearly predisposed to tumor formation. Liver transplantation also eliminates concerns about the capacity of the postresection liver remnant to provide adequate liver volume.

The initial experience with liver transplantation for patients with HCC was unrewarding with high rates of recurrence in the allograft (transplanted liver) and extrahepatically. ^[81] Reports from the national transplant tumor registry in 1991 revealed a 5-year survival rate of only 18%. ^[82] In the survivors, only 9% remained tumor-free at 2 years.

These dismal survival data led to a moratorium on transplantation for HCC in the early 1990s. However, further investigations suggested that these results were likely the result of poor patient selection and transplantation in the face of extensive tumor burden. In patients with incidentally discovered small tumors, the results were actually quite good, leading to the subsequent reassessment of HCC as an indication for OLT.

The approach to patients with HCC was dramatically altered by the 1996 publication of the results from Mazzaferro et al in Milan, ^[83] who demonstrated that patients with limited HCC tumor burden could achieve posttransplant patient survival rates equivalent to patients without malignancies. Mazzaferro defined the Milan criteria, which have been used to determine candidacy for OLT.

In the experience of the Milan investigators, patients with established cirrhosis and either a single HCC no larger than 5 cm in diameter or as many as three HCCs no larger than 3 cm had a 4-year overall survival rate of 85% and a tumor-free survival rate of 92%. By comparison, patients with a large tumor burden had a 4-year survival rate of 50%. After this report, OLT was established as the therapy of choice for patients with significant cirrhosis and limited tumor burden. ^{[83, 84, 85, 86]}

These results were subsequently duplicated by several other transplant centers (see Table 3 below). ^[83]

Table 3. Patient Survival Rates Following Liver Transplantation for Hepatocellular Carcinoma (Open Table in a new window)

In addition to tumor burden, survival after transplantation has also been correlated with a variety of anatomic and pathologic features. Poor prognosis has been associated with the following ^{[52, 87, 88]} :

• Bilobar distribution of tumor
• Vascular invasion (particularly macroscopic tumor invasion)
• Higher histologic grade
• Pretreatment AFP level higher than 300 ng/mL

In these patients, tumor recurrence is highly likely. Whereas fibrolamellar histology has been associated with improved prognosis following resection, posttransplant survival appears to be equivalent to hepatocellular carcinoma in general. Finally, clinically evident reinfection with hepatitis B virus (HBV) or hepatitis C virus (HCV) has been correlated with tumor recurrence. In patients with hepatitis C, active viral recurrence is associated with a 40% risk of tumor development in the transplanted organ. ^[89]

The application of OLT to HCC has also been limited by access to deceased donor organs. Until 2002, patient waiting time was the primary driver of liver allocation, leading to high dropout rates among patients listed for transplant. In their report in 2002, Yao et al reported that as a result of tumor progression, as many as 37.8% of waitlist patients were no longer eligible at 12 months. ^[90]

Beginning in February 2002, liver allografts have been allocated according to the patients’ likelihood of dying from their liver disease. In general, liver allografts are allocated to patients according to their Model for End Stage Liver Disease (MELD) score. MELD is a complex equation, including creatinine, bilirubin, and international normalized ratio (INR), which accurately predicts mortality from complications of cirrhosis (see the MELD Score calculator). Under the MELD system, the patient with the highest MELD score and, therefore, the highest risk of dying without a liver transplant, is transplanted first.

Because patients with HCC are more likely to die from their malignancy than they are from their liver disease, surgeons feared that patients with HCC would be disadvantaged under the MELD system. To ensure access to deceased donor organs, patients with HCC with stage 1 or 2 tumors were assigned higher MELD scores based on tumor stage rather than tumor function. Patients with stage 3 or greater were precluded from transplantation. This change in allocation systems led to a dramatic reduction in waiting time and near-elimination of patients dropping out from tumor progression. Early reports suggested that the waitlist dropout rates were less than 5% at 8 months.

The priority accorded to patients with HCC has been challenged, and a number of authors have suggested that these patients have been disproportionately advantaged compared to the rest of the waiting list. This has led to a reduction in the MELD point upgrade. ^[91]

Additional strategies to provide OLT to patients with HCC have included the use of living-donor liver transplantation and split-liver transplant. These techniques expand the organ pool and appear to offer equivalent survival to whole-organ transplant. They have also been used in patients undergoing transplantation whose tumor burden exceeds the Milan criteria.

On the basis of this experience, several centers have advocated expanding the maximum tumor burden that can be considered for MELD upgrades to include patients with one tumor no larger than 6.5 cm or three or fewer tumors no larger than 4.5 cm with a total tumor diameter no larger than 8 cm. Transplantation in this population resulted in a survival rate of 90% at 1 year and 72.5% at 5 years. ^[92] Further refinement in both listing criteria and degree of MELD upgrade accorded to patients with HCC is likely in the future.

Ablative therapies

Curative treatment of patients with HCC who are not candidates for resection or OLT is limited. However, local ablative therapies can be used either as a bridge to transplant by reducing the risk of tumor progression or as a palliative procedure to extend disease-free survival. Ablative procedures, including ethanol injection, RFA, and cryotherapy, can be performed percutaneously, laparoscopically, or via an open surgical approach.

Percutaneous ethanol injection (PEI) was the first ablative technique used for HCC. PEI involves the injection of alcohol directly into the tumor leading to complete ablation of up to 70% of lesions, which are less than or equal to 3 cm. It is generally performed under the guidance of ultrasonography (US) and requires four to six sessions to complete the ablation.

In patients with Child class A cirrhosis, 40-55% survival can be achieved with PEI at 3 years. ^[93] PEI has not been compared with surgery in a randomized fashion; however, in retrospective reviews, the 3-year survival rates with PEI and surgery were 71% and 79%, respectively, in patients with Child class A cirrhosis and 40% and 41% in those with Child class B disease.

Although generally well tolerated, PEI can result in death and rare instances of tumor seeding. Unfortunately, PEI-treated lesions have a high rate of local recurrence (ie, 33% for tumors ≤3 cm, 43% for larger tumors).

In the United States, PEI has largely been supplanted by RFA, in which a conducting needle is placed within the tumor and current travels to a large dispersive electrode (grounding pad). The electric current leads to agitation of the ions in the tissue, heat generation, and desiccation of the tissues surrounding the probe. The coverage of the electric field can be extended with water cooling, multiple deployable tines within the needle, and other modified electrodes. ^[94]

Treatment with RFA is generally performed at a single session (in contrast to the multiple sessions required for PEI). The procedure can be done under the guidance of US, computed tomography (CT), or laparoscopy, depending upon the patient’s health, the location of the tumor, and the expertise available in the center.

When compared with PEI in a prospective trial, RFA was associated with a trend toward improved 24-month patient survival rates (98% vs 88%), but this trend did not achieve statistical significance. ^[93] However, significant differences in recurrence-free survival rates clearly favor RFA at 24 months (64% vs 43%). Complication rates are low, with a 0.3% mortality and a 2.2% incidence of major complications. Tumor seeding occurred in 0.5% of 1610 lesions treated in a large study reported by Llovet et al. ^[92]

RFA success may also be limited by the presence of large blood portal or hepatic vein branches adjacent to the tumor. Flowing blood can act as a heat sink and limit the ability to heat the tissue to a sufficient temperature. The temporary use of selective arterial/venous occlusion can be used to reduce the amount of heat sink.

RFA can also be used as an adjunctive therapy for patients waiting for transplantation. ^[95] In these patients, tumor progression can be delayed without the increased morbidity associated with liver transplantation following open resection.

Preliminary data are available in a variety of newer technologies, including microwave ablation, laser ablation, and focal external beam radiation. Unfortunately, no randomized trial data are available for this population. Cryoablation of tumors using a liquid nitrogen filled probe had been used historically for ablation. However, as a result of higher complication rates and lower efficacy rates, it has largely fallen out of the clinical armamentarium. ^[52]

Patients should avoid alcohol and other hepatic toxins because prognosis is related to worsening cirrhosis and tumor stage. The consumption of fish and fish-associated fatty acids is associated in a dose-dependent fashion with a lower risk of the development of HCC, regardless of hepatitis status. ^[96]

Although it is currently one of the most common worldwide causes of cancer death, a major impact on the incidence of hepatocellular carcinoma should be achieved through current vaccination strategies for hepatitis B virus (HBV) infection. Assuming that present HBV vaccination trends continue, between 2020 and 2050, the number of new HBV infections is estimated to drop by 70%. ^[29]

Additional primary prevention approaches include decreasing harmful use of alcohol, implementation of safe injection and transfusion practices, improved diagnoses of chronic infections, and increased treatment for HBV and HCV including increased accessibility and affordability of the highly effective HCV antiviral medication. ^[29]

Analysis of patients from the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) trial found that in patients with chronic hepatitis C who did not have a sustained virologic response to therapy, long-term pegylated interferon therapy does not reduce the incidence of HCC. ^[97]

The Centers for Disease Control and Prevention (CDC) recommends one-time HCV testing for everyone born from 1945 to 1965 because this cohort  accounts for about three-fourths of HCV-infected individuals in the US. Preventive measures for HBV and HCV infection recommended by the CDC include screening of donated blood, organs, and tissues; adherence to infection control practices during medical and dental procedures; needle-exchange programs for injection drug users; and practicing safe sex. ^[98]

Other preventive approaches include programs to reduce obesity and type 2 diabetes. ^[19]  A nationwide study in Sweden reported low-dose aspirin use reduced the risk of HCC in patients with chronic viral hepatitis by 31% and reduced the risk of liver-related death by 27%. ^{[99, 100]}

Consultation with the following specialists is recommended:

• Hepatobiliary surgeon
• Oncologist
• Interventional radiologist
• Interventional gastroenterologist

Despite optimal treatment, HCC continues to have a high recurrence rate. It recurs in 50-80% of patients following resection, with the majority of recurrences developing within 2 years. ^[101] Careful follow-up in the postoperative period is mandatory. Early recurrence after resection is associated with a dismal prognosis, reducing 5-year survival rates from 70% to 30%. ^[101] Factors that increase the likelihood of recurrence include the presence of multiple foci of HCC, liver capsule invasion, and tumor size greater than 5 cm. Vascular invasion, both microscopic and macroscopic, also correlates with a higher risk of recurrence.

Among patients undergoing liver transplantation, the rate of recurrence is dependent upon the characteristics of the tumor in the explanted liver. ^[102] Overall recurrence in patients transplanted within the Milan criteria is 4-10%. ^[83] The majority of these recurrences occur early (8-14 months); however, as many as 30% of recurrences may occur late. ^[103] In these patients, 23% develop only intrahepatic recurrence, 39% develop both intrahepatic and extrahepatic recurrence, and 39% develop only extrahepatic recurrence. Common extrahepatic sites of metastatic disease include lung, bone, central nervous system, and adrenal glands.

Resection in the posttransplant population can be accomplished in as many as one third of patients. In those patients who undergo successful resection, 4-year survival rates increase from 14% to 57%, justifying an aggressive approach. ^[104]

Unfortunately, no established guidelines exist regarding the frequency of imaging procedures in the postoperative period. In general, CT should be performed at 1 month post resection to ensure complete tumor clearance. After this initial scan, serum AFP measurements and repeat imaging studies (eg, US, CT, or magnetic resonance imaging [MRI]) should be obtained every 3-6 months, depending on the likelihood of recurrence. After 2-3 years, it appears safe to increase the follow-up interval.