Management of potentially resectable hepatocellular carcinoma: Prognosis, role of neoadjuvant and adjuvant therapy, and posttreatment surveillance

INTRODUCTION — Hepatocellular carcinoma (HCC) is an aggressive tumor that often occurs in the setting of chronic liver disease, which may be related to hepatitis B virus (HBV), hepatitis C virus (HCV), alcohol, and/or nonalcoholic steatohepatitis (NASH), among other causes. It is important to note that HCC can occur in a background of normal liver. (See "Epidemiology and risk factors for hepatocellular carcinoma".)

Potentially curative partial hepatectomy is one optimal treatment for HCC, but many patients are not eligible for resection because of extrahepatic disease spread, the anatomical constraints of the intrahepatic tumor, or poor underlying liver function, as reflected by the Child-Pugh classification (table 1) or the Model for End-stage Liver Disease (MELD) score (calculator 1 and calculator 2). (See "Assessing surgical risk in patients with liver disease", section on 'MELD score and Mayo risk score' and "Model for End-stage Liver Disease (MELD)".)

Even after a potentially curative resection, liver recurrence rates are significant. This has led to efforts to develop neoadjuvant and adjuvant therapy approaches to improve outcomes, although no clear treatment has emerged to significantly reduce recurrence or improve survival to date.

This topic will cover prognosis and neoadjuvant and adjuvant therapy for potentially resectable hepatocellular cancer, as well as post-treatment surveillance. The clinical manifestations and diagnosis of HCC, preoperative evaluation and surgical management, nonsurgical options for local ablation, role of liver transplantation, treatment of advanced disease, and an overview of treatment approaches to HCC are presented separately.

●(See "Epidemiology and risk factors for hepatocellular carcinoma".)

●(See "Surgical resection of hepatocellular carcinoma".)

●(See "Localized hepatocellular carcinoma: Liver-directed therapies for nonsurgical candidates who are eligible for local ablation".)

●(See "Liver transplantation for hepatocellular carcinoma".)

●(See "Systemic treatment for advanced hepatocellular carcinoma".)

●(See "Overview of treatment approaches for hepatocellular carcinoma".)

IMPORTANCE OF COMPREHENSIVE MULTIDISCIPLINARY CARE — A majority of patients with HCC have underlying cirrhosis, which is most often related to chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV), alcohol, and/or nonalcoholic steatohepatitis (NASH). Cure of HCV does not eliminate risk for future. Patients who undergo therapy for HCC are at high risk not only for progressive and/or recurrent HCC, but also for liver-related morbidity and mortality. It is important that patients have proper monitoring and assessment of their underlying liver disease, which may have a major impact on long-term survival. Prognostic scoring systems to assess the severity of underlying liver disease in patients undergoing treatment for HCC are discussed in detail separately. (See "Staging and prognostic factors in hepatocellular carcinoma", section on 'Staging and prognostic scoring systems'.)

Comprehensive care for patients with cirrhosis includes treatment of the underlying liver disease (eg, antiviral therapy for HBV or HCV), immunization against hepatitis A and HBV (if indicated), and cirrhosis management, including endoscopic screening and treatment for varices. (See "Epidemiology and risk factors for hepatocellular carcinoma" and "Cirrhosis in adults: Overview of complications, general management, and prognosis".)

PREOPERATIVE EVALUATION — The preoperative evaluation for resection of HCC focuses on two main issues: the likelihood of disease being confined to the liver, and whether the anatomical constraints of the intrahepatic tumor and underlying liver function will permit resection:

●Anatomic delineation of tumor extent is best achieved with dynamic multiphase computed tomography (CT; in which nonenhanced, hepatic arterial phase and portal venous/delayed phase are assessed separately) or magnetic resonance imaging (MRI) scanning. According to the current (eighth edition, 2017) American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) tumor, node, metastasis (TNM) staging system for HCC (table 2), most consider stages IIIB, IVa, and IVb disease to be incurable by resection. These stages are defined by invasion of a major portal or hepatic vein, direct invasion of organs other than the gallbladder, perforation of the visceral peritoneum, and nodal as well as distant metastases. However, hepatic resection for stages IIIB and IVA disease may be considered in a center of excellence because clinical benefits and long-term survival can be achieved in a properly selected, though admittedly small, minority of patients. (See "Surgical resection of hepatocellular carcinoma", section on 'Delineate tumor extent'.)

A chest CT is recommended to complete the staging evaluation. Although characterized in few reports, the recognized sites of metastatic spread of HCC are lung, bone, peritoneum, adrenals, and lymph nodes. These sites of disease may be demonstrated by standard imaging techniques, but peritoneal disease is frequently missed. (See "Clinical features and diagnosis of hepatocellular carcinoma", section on 'Extrahepatic metastases'.)

Less than 10 percent of HCC spontaneously rupture. Although these patients have a high likelihood of peritoneal seeding and usually a poor outcome from resection, this is not inevitable. If bleeding can be controlled, a formal staging evaluation should be undertaken, followed by laparoscopic exploration and subsequent resection, if feasible. (See "Surgical resection of hepatocellular carcinoma", section on 'Delineate tumor extent'.)

●Among patients undergoing potentially curative partial hepatectomy for HCC, most perioperative deaths, particularly following major hepatectomy, are due to postoperative liver failure. Degree of liver disease and liver function are the most important predictors of postresection liver failure and death. There are several strategies, including careful patient selection based on overall liver tests, extent of resection to tailored liver function assessed by volumetry and other means (discussed below), and preoperative portal vein embolization (PVE) to produce hypertrophy in the future liver remnant and demonstrate the diseased liver is capable of regeneration, that can mitigate these risks. (See "Surgical resection of hepatocellular carcinoma", section on 'Portal vein embolization' and "Surgical resection of hepatocellular carcinoma", section on 'Postoperative morbidity and mortality'.)

Eligible candidates for resection must have a suitable tumor location, adequate liver reserve, and a sufficient liver remnant as assessed by clinical and biochemical measures and, in the case of major hepatectomy, by hepatic volumetry. As a general rule, for patients who would potentially have an insufficient future liver remnant but have preserved liver function and no severe portal hypertension, techniques such as preoperative PVE or transarterial radioembolization (TARE) [1] can initiate hypertrophy of the anticipated future liver remnant to enable a major resection that would not otherwise be possible. Failure of the liver to regenerate sufficiently after PVE is an indication that resection should not be pursued. (See "Surgical resection of hepatocellular carcinoma", section on 'Portal vein embolization'.)

LONG-TERM OUTCOMES — There is a wide variability in outcomes after resection for HCC, attributable to both tumor-related factors and the underlying liver disease [2-20].

Long-term overall survival rates of ≥40 percent can be achieved with limited hepatic resections for small tumors (<5 cm) in patients with Child-Pugh class A cirrhosis (table 1) [4,9,12,21]. The best outcomes are reported in carefully selected patients who have solitary lesions without intrahepatic metastasis or vascular invasion (gross or microscopic invasion of branches of the portal or hepatic veins), tumor diameter ≤5 cm, and a negative surgical margin of >1 cm; five-year survival rates are as high as 78 percent [3,11,13,14,17,22]. Recent series demonstrate prolonged survival for more advanced HCC with proper patient selection, despite major hepatectomy [23].

By contrast, studies with lower long-term survival rates usually include populations of patients with liver dysfunction (Child-Pugh class B or C (table 1)) or tumors greater than 8 cm in diameter, which require resection of more hepatic parenchyma. These patients have higher operative morbidity and mortality, and their intrinsic liver disease is a major contributor to reduced long-term survival [24,25]. (See 'Underlying liver dysfunction' below.)

Several staging systems have been developed to prognostically stratify outcomes from treatment of HCC. Some, such as the tumor, node, metastasis (TNM) staging system of the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) (table 2), are based entirely upon pathologic disease extent [26].

By contrast, other staging systems, such as that of the Barcelona Clinic Liver Cancer (BCLC) (figure 1) [20], Japan Integrated Scoring (JIS) [27], and others [28-30] take underlying liver function into account. There is ongoing debate as to which staging system is optimal for use in HCC patients. Among hepatologists, the BCLC staging classification is the most widely used staging system, but many groups challenge the validity of the system because of good results in selected, higher stage BCLC patients treated with surgery (where BCLC advises nonsurgical therapy) [20,31-33]. More recently, staging systems incorporating expanded surgical indications, such as the Hong Kong Liver Cancer Staging System, have been proposed [34]. (See "Staging and prognostic factors in hepatocellular carcinoma", section on 'Choice of staging system'.)

Specific prognostic factors in patients undergoing potentially curative resection are summarized below. A more general discussion about prognostic factors in HCC is presented separately. (See "Staging and prognostic factors in hepatocellular carcinoma", section on 'Other factors influencing survival'.)

Tumor-related prognostic factors — The most important tumor-related prognostic factors in patients undergoing potentially curative resection of HCC are the presence and degree of vascular invasion, tumor number and size, and surgical margin status:

●Gross or microscopic invasion of branches of the portal or hepatic veins is associated with a lower probability of survival following resection [3,35]. In one report, there were no three-year survivors among patients with vascular invasion, compared with a 32 percent five-year survival rate in those without vascular invasion [35].

●Tumor size is an important prognostic factor [36]. Both intrahepatic and extrahepatic spread of HCC are more common with tumors >5 cm, particularly when associated with venous invasion [3,12,37-41]. In a report that compared 1000 patients with tumors ≤5 cm and 1366 patients with tumors >5 cm, all of whom underwent hepatectomy over the same period, five-year survival rates were significantly better for patients with smaller tumors (63 versus 37 percent) [41]. Nevertheless, several series indicate five-year survival rates ranging from 19 to 27 percent in selected patients undergoing resection for a single HCC ≥10 cm [24,42,43].

Although increasing tumor size is associated with increased risk for vascular invasion, large solitary tumors without vascular invasion have the same prognosis as small solitary tumors without vascular invasion. (See "Surgical resection of hepatocellular carcinoma", section on 'Delineate tumor extent'.)

●The importance of wide resection margins is debated. In a study of 225 patients who underwent resection for HCC, three-year survival was significantly better when a >1 cm tumor-free margin was achieved (77 versus 21 percent, respectively) [7]. However, larger series suggest that a negative margin of <1 cm is acceptable [44].

Other tumor-related poor prognostic indicators in patients undergoing potentially curative hepatectomy are absence of a tumor capsule [15], high preoperative alpha fetoprotein (AFP) levels [45-51], spontaneous tumor bleeding, tumor rupture [52], and poor histologic grade of differentiation [53]. (See "Clinical features and diagnosis of hepatocellular carcinoma" and "Surgical resection of hepatocellular carcinoma", section on 'Delineate tumor extent'.)

Underlying liver dysfunction — Preoperative liver dysfunction and cirrhosis are important negative prognostic factors [12,20,54]. The majority of cases (approximately 80 percent) in the United States and Europe arise in cirrhotic livers. In general, reports of HCC resection in noncirrhotic livers are scarce outside of Asia [12,55-57]. However, outcomes in these noncirrhotic patients appear to be better than those achieved in patients with cirrhosis. In one series of 295 patients undergoing resection of HCC, the four-year survival was more than twofold higher for noncirrhotic compared with cirrhotic patients (81 versus 35 percent) [12]. This difference in outcome is likely related to a higher competing risk of liver-related mortality in patients with cirrhosis, but may also be related in part to the higher frequency of multicentric HCC in patients with cirrhosis.

As a general rule, the degree of liver dysfunction (eg, Child-Pugh classification, presence of portal hypertension, ALBI score), rather than the presence of the cancer, limits long-term survival in patients with cirrhosis with small, early stage HCC. (See "Staging and prognostic factors in hepatocellular carcinoma", section on 'Staging and prognostic scoring systems'.)

The presence of cirrhosis creates a competing risk of liver-related mortality, and contributes to a higher risk of developing a second primary HCC. These principles were illustrated in one multi-institutional series of 591 patients undergoing resection of HCC, of whom 145 survived longer than five years [40]. While the status of surgical margins, type of resection, preoperative AFP level, and presence of multiple tumors or microscopic vascular invasion were important predictors of five-year survival, they had no bearing on survival beyond five years. However, patients who survived for at least five years had significantly longer survival and cancer-specific survival beyond that point if they had normal underlying liver or minimal periportal fibrosis, rather than underlying cirrhosis. Severe fibrosis/cirrhosis and microscopic vascular invasion have similar increased relative risk for HCC recurrence in multivariable analysis of outcome for resection of HCC [28].

In Western countries where HCC is less frequently associated with chronic hepatitis B virus (HBV) infection, five-year survival rates are better (27 to 49 percent) [4,8,58] than they are in locations where HBV is endemic and incidence rates of HCC are high (11 percent or less) [6,25,59,60]. This is likely due to differences in screening rates and the proportion of patients found at early stages, the degree of liver dysfunction and fibrosis, comorbid conditions, and treatment patterns and patient selection for curative treatments, including resection. (See "Staging and prognostic factors in hepatocellular carcinoma", section on 'Hepatitis B and C' and "Staging and prognostic factors in hepatocellular carcinoma", section on 'High- versus low-incidence regions'.)

Among patients with cirrhosis related to HBV infection, active hepatitis is also a poor prognostic factor. This was illustrated in a report comparing surgical outcomes in 146 patients with resected HCC and HBV-related Child-Pugh class A or B cirrhosis with those of 155 noncirrhotic patients [39]. Although the prognosis after resection of tumors <5 cm in patients with compensated HBV-related cirrhosis was comparable to that of noncirrhotic patients, the outcome was less favorable in those with underlying active hepatitis, as indicated by a preoperative serum aspartate aminotransferase level >100 international units/L (median survival 10 versus 51 months for those with serum aspartate aminotransferase >100 versus ≤100 international units/L, respectively). Nomograms have been developed to predict survival after resection in Asian populations with HBV-related HCC that include effect of positivity for hepatitis B e antigen (HBeAg), a marker of HBV replication [61]. Whether this nomogram is useful in Western populations is unclear. (See "Assessing surgical risk in patients with liver disease" and "Hepatitis B virus: Screening and diagnosis in adults", section on 'Hepatitis B e antigen and antibody' and "Staging and prognostic factors in hepatocellular carcinoma", section on 'Hepatitis B and C'.)

Effective antiviral therapy (ideally before resection) is an important aspect of optimizing outcomes in patients with HBV-related HCC [62]. The benefit of postoperative antiviral therapy after potentially curative resection of HBV-related HCC is addressed below. (See 'HBV-related HCC and nucleoside/nucleotide analogs' below.)

Hepatitis C virus (HCV) infection may be a negative prognostic factor; in several reports, HCV-infected patients fare worse after liver resection than do HBV-infected patients [63-66], though some data suggest that liver and tumor factors overcome viral type as prognostic factors (HCV is associated with a higher incidence of fibrosis, HBV is associated with a higher incidence of larger tumors with vascular invasion) [67]. Hepatologists frequently recommend HCC treatment before HCV therapy in patients with well compensated liver disease due to concern that direct-acting antiviral agents may induce progression, though this is disputed. (See 'HCV-related HCC' below and "Staging and prognostic factors in hepatocellular carcinoma", section on 'Hepatitis B and C'.)

Patterns of relapse — The majority of recurrences are intrahepatic and may reflect local recurrence or a new second primary tumor [68-71]. Late recurrences (ie, beyond two years) are more likely to represent a de novo second primary tumor [72,73]. Fewer than 20 percent of disease recurrences have an extrahepatic component, which may present simultaneously with or develop after an intrahepatic recurrence or represent the only site of disease recurrence [74].

Management of relapsed disease — For patients with isolated local recurrence, several effective treatment modalities can provide disease control, including repeat hepatectomy [75-79], thermal ablation, liver transplantation, and transarterial chemoembolization or radioembolization. (See "Localized hepatocellular carcinoma: Liver-directed therapies for nonsurgical candidates not eligible for local thermal ablation" and "Localized hepatocellular carcinoma: Liver-directed therapies for nonsurgical candidates who are eligible for local ablation" and "Liver transplantation for hepatocellular carcinoma".)

Patients with extrahepatic spread have a poor prognosis overall and are best treated with systemic therapy. (See "Systemic treatment for advanced hepatocellular carcinoma".)

NEOADJUVANT THERAPY — Given the high rates of local recurrence after hepatic resection, several types of locoregional neoadjuvant therapy have been evaluated prior to resection. Given the lack of survival benefit in most studies, and the heterogeneity of the populations that have been studied using these approaches, we suggest not pursuing neoadjuvant therapy prior to hepatic resection, unless in the context of a clinical trial.

Despite potentially curative surgery, local recurrence develops in most patients. It is believed that many recurrences do not arise because of inadequate surgical resection but because of preexisting, clinically occult, microscopic tumor foci, thus providing the impetus to evaluate neoadjuvant therapies to eradicate this disease prior to definitive resection.

Various approaches to neoadjuvant therapy have been evaluated, including systemic chemotherapy [80], regional approaches (TACE [81-88], hepatic artery infusion of radiolabeled lipiodol [89], transarterial infusional chemotherapy alone [90], and regional irradiation with or without chemotherapy or TACE [91-93]), and immunotherapy-based regimens [94]. (See "Localized hepatocellular carcinoma: Liver-directed therapies for nonsurgical candidates who are eligible for local ablation".)

Although many of these therapies can decrease tumor size, this has not translated into a survival benefit in most studies. In addition, the small size of many studies, the relative paucity of randomized controlled trials, and the heterogeneity in the patient populations under study limit the generalizability of the results, and the ability to interpret and compare data. As examples:

●TACE followed by portal vein embolization (PVE) has been proposed as an approach to prepare for major hepatectomy in patients with and without cirrhosis with preserved liver function and minimal portal hypertension. At least some data suggest better tumor control, very low surgical morbidity and mortality, and favorable long-term outcomes, although there are no randomized trials with a surgery alone or PVE alone control group [23,95-97].

Furthermore, a number of uncontrolled series and at least one randomized controlled trial have suggested that TACE used prior to an attempt at resection is associated with worse survival [83-86,88]. In a randomized controlled trial, 52 patients with resectable, large HCC were randomly assigned to preoperative TACE (one to five courses) or surgery without delay [86]. Patients randomized to TACE had a slightly longer operative time and a higher rate of concomitant resection of adjacent organs. Despite similar disease-free survival in the two groups, the incidence of extrahepatic cancer was higher in those who had been treated with TACE (57 versus 23 percent), and the actuarial survival rate was significantly worse in this group. The delay in surgical treatment may have contributed to this detrimental impact on survival.

The use of TACE as a nonsurgical therapy for localized HCC, including its use in patients awaiting orthotopic liver transplantation for HCC (termed "bridging therapy"), is discussed in further detail elsewhere, as is the role of PVE, with or without TACE, prior to resection of HCC. (See "Liver transplantation for hepatocellular carcinoma", section on 'Chemoembolization' and "Surgical resection of hepatocellular carcinoma", section on 'Portal vein embolization'.)

●For patients with resectable HCC and portal vein tumor thrombus (PVTT), at least one randomized trial suggests better postoperative survival among Chinese patients who receive neoadjuvant three-dimensional conformal radiation therapy (3D-CRT) [93]. In this multicenter trial, in which all 164 enrolled patients had hepatitis B virus (HBV)-associated HCC, patients with potentially resectable HCC and right- or left-side branch or main portal vein thrombus of Cheng type II or III [98] were administered radiation therapy (RT) at a dose of 18 Gy in daily 3 Gy fractions, with treatments administered five days per week. Of note, approximately 83 percent of patients did not have cirrhosis. They grouped noncirrhotic patients with Child-Pugh A cirrhotics. Patients receiving RT were reevaluated four weeks after completion of RT, and surgery was carried out within five days in the absence of a contraindication to surgery.

A partial remission (as defined by any downstaging in the Cheng classification or any conspicuous restoration of blood flow in the portal vein) was achieved by 21 percent of patients within four weeks of RT. Seven patients had disease progression after RT and two developed grade 3 liver toxicity that rendered them unsuitable for subsequent hepatic resection. At a median follow-up of 15.2 months, overall survival rates were superior in the RT group (89, 75, 44, and 27 percent at 6, 12, 18, and 24 months; corresponding rates with surgery alone were 82, 43, 17, and 9 percent, respectively).

In our view, this single trial is not adequate to recommend routine neoadjuvant RT prior to resection of HCC with or without major PVTT for several reasons:

•The population under study in this trial was unique, and it is not clear whether the results are generalizable to other populations. Western guidelines, including those based on the classification (figure 1) [20], consider HCC with portal vein tumor thrombus to represent advanced, incurable cancer for which systemic therapy alone is advised. Surgery is more frequently adopted in China and Southeast Asia, where the majority of patients (as in this trial) have HBV-associated HCC and better liver function reserves and long-term survival outcomes after hepatectomy, in comparison with patients in Europe, North America, and Japan, where hepatitis C virus (HCV) infection and nonalcoholic steatohepatitis (NASH) predominate [99,100]. This subject is discussed in detail elsewhere. (See "Overview of treatment approaches for hepatocellular carcinoma", section on 'Patients with portal vein tumor thrombus'.)

Much larger trials with patients who have other causes of HCC, including chronic HCV infection, alcoholic cirrhosis, and NASH, are needed before adopting routine use of neoadjuvant therapy. (See "Staging and prognostic factors in hepatocellular carcinoma", section on 'Hepatitis B and C'.)

•It is not known whether this is the optimal dose and number of fractions to treat HCC with PVTT. Rigorous trials to optimize external beam irradiation are needed to determine maximizing response while minimizing toxicity (particularly since small variations in the delivery of RT can significantly impact resection risk due to radiation-induced changes in the hepatic parenchyma).

In our view, more extensive confirmatory work is completed and reported. Whether other locoregional treatment methods, such as transarterial radioembolization, which appears effective in patients with PVTT, may serve as a better neoadjuvant approach to resection in patients with PVTT has not been studied. (See "Localized hepatocellular carcinoma: Liver-directed therapies for nonsurgical candidates not eligible for local thermal ablation", section on 'Patients with large intrahepatic tumor volume or PVTT'.)

POSTOPERATIVE THERAPY — The high recurrence rate following curative resection for HCC has prompted a search for effective postoperative (adjuvant) therapies. For patients with HCC, the goals of postoperative therapy are to eliminate residual neoplastic cells and prevent recurrent HCC (ie, secondary chemoprevention).

Adjuvant antiviral therapy improves overall survival outcomes after potentially curative treatment of hepatitis B virus (HBV) and hepatitis C virus (HCV)-related HCC and is recommended for those with active viral infection. The use of other adjuvant therapies following potentially curative resection of HCC is not established and remains investigational. Patients interested in these approaches are encouraged to enroll on clinical trials, where available. This position is consistent with clinical guidelines from the National Comprehensive Cancer Network (NCCN) [101-103].

Antiviral therapy — Adjuvant antiviral therapy improves outcomes after potentially curative treatment of HBV-related HCC. For patients with HBV-related HCC and active HBV-related liver disease, we recommend the use of nucleos(t)ide analogs. The benefits of nucleos(t)ide analogs on oncologic outcomes in resected patients who do not have active hepatitis and/or a high viral load remain uncertain and require confirmation in large controlled trials with adequate follow-up before this approach can be widely adopted.

The chemopreventive benefits of antiviral therapy, particularly with direct-acting antiviral (DAA) agents, after resection of HCV-related HCC are less certain. Nevertheless, for those with active viral infection, treatment is indicated to attempt to diminish liver morbidity and mortality. Some postulate that DAA post-treatment may be associated with early recurrence, though this is disputed. (See 'HCV-related HCC' below.)

HBV-related HCC and nucleoside/nucleotide analogs — Among patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), higher viral load (serum HBV DNA of >10⁶ copies/mL) has been associated with higher rates of recurrence after resection, particularly late recurrence (which is more likely to represent a de novo second primary tumor rather than metastasis from the primary HCC) [104,105].

Treatment with nucleos(t)ide analogs can reduce the risk of recurrence and improve the prognosis of HBV-related HCC after curative therapy. (See "Hepatitis B virus: Overview of management".)

The association between nucleos(t)ide analog use and outcomes after resection in patients with HBV-related HCC has been addressed in multiple cohort studies, two randomized controlled trials, and two meta-analyses:

●The benefits of nucleos(t)ide analogs on prognosis of HBV-related, surgically treated HCC were directly addressed in a randomized trial in which 180 patients with previously untreated, HBV-related, potentially resectable HCC, without HCV coinfection, with Child-Pugh A or B cirrhosis and a preoperative serum HBV DNA load of more than 500 copies/mL were randomly assigned to postoperative antiviral therapy (lamivudine 100 mg daily, starting within one week of surgery; adefovir or entecavir were used for patients who were drug resistant) or control [106]. At a median follow-up of 40 months, patients assigned to antiviral therapy had significantly better two-year overall (94 versus 62 percent) and recurrence-free survival (56 versus 20 percent). No adverse effects caused by antiviral treatment were reported, except one patient treated with lamivudine plus adefovir dipivoxil developed transient anorexia.

Interpretation of these data is limited by imbalances in the study arms that favored better outcomes in the antiviral group (smaller tumor burden, smaller proportion of incomplete or no tumor encapsulation, lower levels of serum alpha-fetoprotein [AFP], fewer poorly differentiated tumors, and lower Barcelona Clinic Liver Cancer [BCLC] stage).

●Benefit was also suggested in a second randomized trial in which 200 patients undergoing complete (R0) resection for HBV-related HCC who had not previously received antiviral treatment and who had an HBV DNA level of more than 2000 international unites/mL were randomly assigned to adefovir (100 mg daily, continued until unacceptable toxicity or withdrawal of consent) or no treatment [107]. At five-year follow-up, overall survival was significantly better in the group receiving antiviral therapy (adjusted hazard ratio [HR] 0.42, 95% CI 0.271-0.651). Antiviral therapy was an independent prognostic factor for late recurrences (HR 0.348, 95% CI 0.177-0.687) but not recurrence within two years of resection (HR 0.949, 95% CI 0.617-1.459).

●A meta-analysis of 13 cohort studies of HBV-related HCC and one of the two randomized controlled trials described above [106] totaling 6350 patients (1227 treated with and 5123 without antiviral treatment) concluded that nucleos(t)ide analog treatment could significantly reduce the risk of HCC recurrence by 34 percent after curative treatment and diminished overall mortality (HR for death 0.56, 95% CI 0.43-0.73) [108]. Notably, the impact of HBV viral load was not addressed; the randomized controlled trial only included patients with HBV DNA of more than 500 copies/mL, while the cohort studies mostly did not include information on the percentage of patients who had a detectable viral load. The available data suggested no serious adverse events attributed to therapy. Lamivudine resistance developed in 29 to 38 percent of treated patients but could be "rescued" by alternative forms of antiviral therapy.

The validity of the results is limited by the quality of the available data (particularly that derived from a large nationwide cohort study of 4569 patients from Taiwan [109], which make up the majority of the patents studied). Data were not available from this database series on the completeness of resection, recurrences were only counted if they required rehospitalization and administration of HCC treatment after the index admission, and there was a potential for survivor bias. Follow-up of the untreated cohort began on the first day after the index admission, while follow-up of the treated cohort began on the day of the first prescription of the nucleos(t)ide analog, which occurred a median of 0.66 years (mean 1.19 years) after resection. Excluding early recurrences, which are less likely to benefit from antiviral therapy, might have amplified the overall survival benefit from nucleos(t)ide therapy.

●A later updated meta-analysis of these same 13 cohort studies and both of the randomized controlled trials (totaling 8060 patients) came to the same conclusion: recurrence rates were significantly decreased among those who received treatment (one-year recurrence RR 0.50, 95% CI 0.36-0.68; three-year recurrence RR 0.70, 95% CI 0.56-0.87) [110]. Overall survival was also significantly higher with antiviral treatment (five-year survival RR 1.40, 95% CI 1.24-1.58). Furthermore, when the data from the Taiwanese cohort study were not included, there was still a significant reduction in the risk of recurrence at one year (RR 0.41, 95% CI 0.28-0.61) and three years (RR 0.63, 95% CI 0.43-0.94) attributed to the use of adjuvant nucleos(t)ide therapy. The impact of pretreatment viral load was not addressed.

In our view, these data support a recommendation for nucleos(t)ide therapy after potentially curative therapy in individuals with resected HCC and active HBV-related liver disease (ie, high serum HBV DNA, abnormal transaminases). The benefits of nucleos(t)ide analogs on oncologic outcomes in resected patients who do not have active hepatitis and/or a high viral load remain uncertain and require confirmation in large controlled trials with adequate follow-up before this approach can be widely adopted. The main drawbacks of the long-term use of antiviral therapy are the need for life-long therapy; emergence of drug resistance, although this concern is lower with more recent agents such as tenofovir and entecavir; potential long-term toxicities such as renal dysfunction; and associated costs [111]. (See "Hepatitis B virus: Overview of management".)

HCV-related HCC

Benefits of antiviral therapy — For patients with hepatitis C virus (HCV)-related HCC, we endorse the use of direct-acting antiviral (DAA) agents used for HCV therapy. A major benefit of HCV antiviral treatment among those with active viral infection is a reduction in liver-disease-related morbidity and mortality.

The chemopreventive benefits of antiviral therapy after potentially curative resection of hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) are debated. The available data suggest decreased recurrences and improved survival with IFN-based HCV therapy, which is no longer recommended for HCV antiviral therapy. There are also some data supporting a survival benefit for DAA agents used for HCV therapy after a complete response to HCC treatment. Whether these benefits are attributable to a reduction in liver-disease-related morbidity/mortality from uncontrolled viremia or truly reflect a decrease in HCC deaths (the goal of a chemopreventive agent) is unclear. Nevertheless, a major benefit of HCV antiviral treatment with DAA agents among those with active viral infection is a reduction in liver-disease-related morbidity and mortality.

There are no randomized trials examining the impact of antiviral therapy on outcomes after resection of HCV-related HCC. Historically, HCV sustained viral response (SVR) using IFN-based therapy was associated with significant reductions in HCC recurrence rates after curative treatment. In an analysis of eight studies (totaling 1519 patients) examining the impact of an SVR on outcomes after potentially curative therapy (resection, local ablation), patients who achieved an SVR had significantly improved overall survival (HR 0.18, 95% CI 0.11-0.29) and better relapse-free survival (HR 0.5, 95% CI 0.40-0.63) than those who did not achieve SVR [112]. However, all included studies used IFN-based therapy, which is no longer recommended for HCV antiviral therapy.

DAA agents offer increased tolerability and a higher level of viral eradication. Similar to IFN-based therapy, DAAs can reduce the risk of cirrhosis progression and hepatic decompensation in most HCV-infected patients; however, whether the chemopreventive benefits are similar to those of IFN-based antiviral therapy is unclear:

●Although some observational studies suggested an unexpectedly high risk of early HCC recurrence following DAA therapy, other large studies have not. (See "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection", section on 'Hepatocellular carcinoma'.)

●Support for a potential benefit of DAA therapy was provided by a retrospective, multicenter cohort study of 797 patients with HCV-related HCC who achieved a complete response to initial therapy (resection in 14 percent, local ablation in 34 percent, transarterial chemoembolization (TACE) in 45 percent, or radioembolization/radiation therapy in the remainder) over a four-year period [113]. Overall, 383 (48 percent) received DAA therapy, while 414 (52 percent) did not. The two groups had similar tumor burden at diagnosis. DAA therapy was associated with significantly reduced mortality in both crude (HR 0.37, 95% CI 0.26-0.54) and weighted models (HR 0.54, 95% CI 0.33-0.90). The benefits were greater among patients who underwent resection or ablation than among those who received TACE, and there was a significantly greater DAA benefit among patients who remained recurrence free (HR for death 0.09, 95% CI 0.02-0.29) compared with those who did not (HR 0.86, 95% CI 0.49-1.52). Furthermore, among the DAA-treated patients, those with an SVR had significantly reduced mortality from the time of DAA initiation compared with those without an SVR (HR 0.27, 95% CI 0.13-0.57). In a post hoc analysis, the proportion of deaths that were liver related was significantly lower in DAA-treated patients than in untreated patients (16.3 versus 34 percent, p = 0.03), whereas the proportion of HCC-related deaths was similar between the groups (30.2 versus 29.1 percent). These data suggest that the beneficial effect of DAA treatment was related to improvement in liver dysfunction, rather than a direct chemopreventive effect.

Similar results were also found in a smaller prospective analysis in which 163 consecutive patients with HCV-related cirrhosis and a first diagnosis of early HCC who had achieved a complete radiologic response after curative resection or ablation and were subsequently treated with DAAs were compared with a historical cohort of 328 DAA-untreated patients treated for early HCC [114]. Therapy with DAAs significantly improved overall survival (HR 0.39, 95% CI 0.17-0.91), but it did not reduce HCC recurrence rates.

Indications for antiviral therapy in patients with HCV infection, including those with HCC, are addressed separately. (See "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection".)

Timing of antiviral therapy — An unresolved issue is the optimal timing of anti-HCV therapy in relation to HCC treatment. At least some data suggest that outcomes are improved regardless of whether a sustained virologic response is achieved before or after hepatectomy [115]. However, data comparing preoperative versus postoperative therapy are extremely limited, and clinical practice is variable, including that of the authors and editors associated with this review.

Those who favor treating prior to surgery raise the following issues:

●Although concern as to whether initiating DAAs prior to surgical treatment of HCC is associated with aggressive progression of the HCC has been raised in small single-institution observational studies [116-118], several large studies have refuted this association [113,119-121].

●Many liver surgeons, including some of the authors of this topic review, prefer that untreated HCV patients undergo antiviral treatment with DAAs prior to planned surgery, citing poor hepatic function and renal function after even minimally invasive resection in untreated patients with low viral load and normal liver function tests preoperatively that are not seen in treated patients. There are few published data in this regard.

On the other hand, at some institutions (and consistent with guidelines from the American Gastroenterological Association [AGA] [122] and the NCCN [123]), postoperative therapy is a standard approach for the following reasons:

●There is no urgency to HCV therapy given at least some evidence of similar outcomes regardless of timing.

●HCV therapy is 8 to 12 weeks, and surgery does not need to be delayed.

●Antiviral therapy can be deferred four to six months to confirm a complete response to HCC therapy.

●Active HCC may be associated with a lower likelihood of obtaining a sustained viral response to DAAs [124-127].

In our view, either approach is acceptable.

What is the role of adjuvant interferon? — The use of interferon alfa (IFNa) as adjuvant therapy following complete resection of HCC is not established. Although randomized trials suggest that adjuvant IFNa reduces early mortality, there are limited data on long-term survival [128], so it is unclear whether disease recurrence is being delayed or truly prevented with this approach. IFNa is also associated with significant side effects and high rates of patient discontinuation. Furthermore, nucleos(t)ide analogs for HBV are preferred given the need for maintained viral suppression. (See 'HBV-related HCC and nucleoside/nucleotide analogs' above.)

IFN suppresses the replication of HBV and HCV. The benefit of postoperative IFNa (and in one case interferon beta [IFNb] [129]) has been addressed in several randomized controlled clinical trials, most of which were conducted in populations from China and Japan with predominantly hepatitis virus associated HCC [16,128-136]. In a meta-analysis of six trials of postoperative IFN after curative resection of HCC in patients with viral hepatitis [129,131-133,136], adjuvant IFNa significantly decreased early (within two years of surgery) mortality after curative resection for HCC (pooled risk ratio [RR] 0.65, 95% CI 0.52-0.80) [137]. The effect on tumor recurrence was less pronounced but still significant (RR 0.86, 95% CI 0.76-0.97).

Investigational approaches

Atezolizumab plus bevacizumab — For patients with treated hepatocellular carcinoma at high risk for recurrence, the use of adjuvant atezolizumab plus bevacizumab improved recurrence-free survival (RFS) but increased toxicity in a phase III trial [138]. This approach, while promising, remains investigational. Further follow-up of RFS and overall survival (OS) are necessary to determine whether adjuvant atezolizumab plus bevacizumab delays or truly prevents disease recurrence. Of note, patients with treated hepatocellular carcinoma at low-risk for recurrence should not be offered adjuvant atezolizumab plus bevacizumab since treatment-related toxicities likely outweigh the potential survival benefits.

In an international, open-label phase III trial (IMbrave050), 668 patients with Child-Pugh Class A hepatocellular carcinoma and no extrahepatic disease who were at high risk for recurrence after curative intent resection or ablation were randomly assigned to either adjuvant therapy with atezolizumab (1200 mg) plus bevacizumab (15 mg/kg) administered intravenously every three weeks for one year (17 cycles), or active surveillance [138]. High-risk features were defined as at least one or more of the following: tumor greater than five cm, more than three tumors, microvascular invasion, minor microvascular invasion Vp1/Vp2, or grade 3 or 4 pathology. In over half (63 percent) of patients, HBV infection was the etiology of the HCC. At median follow-up of 17 months, adjuvant therapy improved RFS relative to active surveillance (one-year RFS 78 versus 65 percent; medians not reached for either arm; HR 0.72, 95% CI 0.53-0.98) with similar overall health-related quality of life and functioning. Overall survival data were immature at first interim analysis and not reported. Grade ≥3 toxicities were higher for adjuvant therapy versus surveillance (41 versus 13 percent), including two therapy-related deaths (esophageal varices hemorrhage and ischemic stroke).

The use of atezolizumab plus bevacizumab for advanced hepatocellular cancer is discussed separately. (See "Systemic treatment for advanced hepatocellular carcinoma", section on 'Atezolizumab plus bevacizumab'.)

Hepatic arterial infusion — The use of hepatic arterial infusion (HAI; adjuvant chemotherapy administered locoregionally via the hepatic arteries) remains investigational, as data are mixed for the efficacy of this approach. Furthermore, few centers have experience performing percutaneous HAI therapy. (See "Systemic treatment for advanced hepatocellular carcinoma", section on 'Systemic chemotherapy'.)

Randomized trials initially suggested limited benefit for adjuvant HAI in resected HCC. As an example, in one meta-analysis of three randomized trials, 108 patients with resected HCC received varying adjuvant chemotherapy regimens. Two trials included HAI with epirubicin, and one trial used intravenous epirubicin [139]. Relative to resection alone, adjuvant chemotherapy failed to improve disease-free survival or overall survival, and was associated with worse survival outcomes in patients with biopsy-proven cirrhosis.

In contrast, a subsequent randomized trial conducted in 315 patients with resected HCC and microvascular invasion evaluated adjuvant HAI using fluorouracil plus leucovorin and oxaliplatin (FOLFOX) versus observation alone [140,141]. HAI with FOLFOX was infused using a percutaneous approach, without an infusion pump. At median follow-up of approximately two years, relative to observation, HAI with FOLFOX improved disease-free survival (median 20 versus 10 months, HR 0.59, 95% CI 0.43-0.81) but not overall survival [141]. However, this trial was conducted almost exclusively in patients from China with HCC and HBV infection, so the ability to generalize these results to populations in other geographic regions with HCC and no HBV infection is unclear.

Other approaches

Transarterial chemoembolization — There is clinical variability in the use of adjuvant TACE following resection of HCC, as studies are inconsistent for the efficacy of this approach. In China, many patients still undergo TACE after hepatic surgery, regardless of the risk profile for recurrence after resection [142,143]. Elsewhere, adjuvant TACE is not standard clinical practice. Further randomized trials are needed to define the appropriate patient populations that may benefit from adjuvant TACE [144].

The available data on the benefits of adjuvant TACE following resection are mixed, likely due to tumor biology and patient selection. Some studies suggest little evidence to support this approach [145-148], while other studies suggest some benefit [149-151]. In a randomized phase III trial, adjuvant TACE improved overall survival over no treatment in 280 patients with an HBV-related resected HCC at intermediate or high risk for recurrence (a single tumor >5 cm without macrovascular invasion, a single tumor with macrovascular invasion, or two or three tumors) [151]. In another randomized trial, postoperative TACE did not improve outcomes compared with traditional herbal medicine in 364 patients at low risk for recurrence (resected small HCC <5 cm) [147].

The use of TACE for locoregional HCC that is not amenable to resection or liver transplantation is discussed separately. (See "Localized hepatocellular carcinoma: Liver-directed therapies for nonsurgical candidates not eligible for local thermal ablation", section on 'TACE and bland particle embolization'.)

Radiolabeled lipiodol — Another locoregional approach involves the intra-arterial infusion of 131I-labeled lipiodol. Lipiodol (Laboratoire Guerbet, France) is a stable fatty acid ethyl ester derived from poppy seed oil that is retained within HCC after intra-arterial injection [152]. The benefits of adjuvant radiolabeled lipiodol have been addressed in the following reports:

●In a trial from Hong Kong in which 43 patients with HCC (mostly related to chronic HBV infection) were randomly assigned to a single dose of 131I-lipiodol or placebo following curative resection, treatment was associated with significantly fewer tumor recurrences (48 versus 64 percent) and significantly higher rates of five-year disease-free and overall survival (67 versus 36 percent) [153,154].

●On the other hand, benefit of a single postoperative injection of lipiodol could not be confirmed in a second trial that randomly assigned 103 patients to resection with or without lipiodol administered four to six weeks later [155]. The small improvement in five-year relapse-free survival in patients receiving lipiodol (45 versus 33 percent, HR 0.75, 95% CI 0.46-1.23) was not statistically significant, and overall survival was similar (54 percent in both groups at five years).

A third randomized trial involving 100 patients has completed accrual and is awaiting data maturation [156]. This approach also needs further evaluation in patients with HCC related to different underlying diseases (such as HCV infection), which may have different tumor biology.

Sorafenib — Sorafenib (Nexavar) is a multitargeted, orally active, small-molecule tyrosine kinase inhibitor that inhibits RAF kinase and also blocks the intracellular portion of the vascular endothelial growth factor receptor (VEGFR). The multicenter, placebo-controlled, European SHARP trial established sorafenib monotherapy as a reference standard systemic treatment for advanced HCC and formed the basis for approval of sorafenib for unresectable HCC in the United States. (See "Systemic treatment for advanced hepatocellular carcinoma", section on 'Sorafenib'.)

A benefit for adjuvant sorafenib could not be shown in the international phase III STORM trial, in which 1114 patients undergoing surgical resection or local ablation for localized HCC were randomly assigned to sorafenib (400 mg twice daily) versus placebo [157]. Patients receiving sorafenib did not have better overall survival (HR 0.99, 95% CI 0.76-1.30), time to recurrence (HR 0.89, 95% CI 0.74-1.08), or recurrence-free survival (HR 0.94, 95% CI 0.78-1.13).

POST-TREATMENT SURVEILLANCE — Patients who undergo a complete resection are at risk for disease recurrence and second primary HCC. Most patients who experience recurrence after resection have recurrent disease confined to the liver. The main goal of post-treatment surveillance is early identification of disease that might be amenable to subsequent local therapy. Several effective treatment modalities can provide disease control after recurrence, including repeat hepatectomy, local ablative therapy, liver transplantation, or transarterial chemoembolization or radioembolization.

The importance of regular postoperative surveillance can be illustrated by a report of 734 Chinese patients who were alive and free of recurrence two years following resection of HCC; of the 303 who had a subsequent recurrence, outcomes were better for those who had received regular post-treatment surveillance [158]. Potentially curative treatments were more often applied (76 versus 36 percent), and median overall survival was significantly higher (67 versus 20 months, 95% CI 0.224-0.418) in this group. The main risk factors for a late recurrence were male sex, cirrhosis, multiple tumors, satellite nodules, tumor size >5 cm, and the presence of vascular invasion. (See 'Patterns of relapse' above.)

There are few data to guide the optimal post-treatment surveillance strategy in patients undergoing locoregional therapy for HCC.

We (and others [68]) suggest the following:

●Imaging (computed tomography [CT] or magnetic resonance imaging [MRI]) every four months for two to three years, then every six months

●Assay of serum alpha-fetoprotein (AFP), if initially elevated, every four months for two to three years, then every six months

These recommendations are consistent with consensus-based guidelines from the National Comprehensive Cancer Network (NCCN) [103].

Some have suggested tailoring the CT/MRI surveillance schedule according to recurrence risk in order to reduce cost and exposure to unnecessary radiation [159]. For those with low-risk (no microvascular invasion and no cirrhosis) or intermediate-risk disease (no microvascular invasion but with cirrhosis, or a solitary tumor with microvascular invasion), it may be possible to extend the surveillance intervals to every 12 months after the initial two years, as recurrence detection rates did not significantly differ with the longer surveillance interval. However, interpretation of these data is limited by the small numbers, the primarily hepatitis B virus (HBV)-infected patient population, the lack of a validation cohort, and possible overfitting of the data.

It is also important that patients with cirrhosis continue to receive liver-related care, including monitoring for esophageal varices, and treatment of their underlying liver disease, which may have a major impact on long-term survival. (See "Surgical resection of hepatocellular carcinoma", section on 'Importance of comprehensive multidisciplinary care'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hepatocellular carcinoma".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Liver cancer (The Basics)")

SUMMARY AND RECOMMENDATIONS

●General principles – Hepatocellular carcinoma (HCC) is an aggressive tumor that often occurs in the setting of chronic liver disease and cirrhosis. Most patients with HCC need comprehensive multidisciplinary care for proper monitoring and assessment of their disease. (See 'Importance of comprehensive multidisciplinary care' above.)

●Surgical management – Partial hepatectomy is one potentially curative treatment for HCC in patients who have adequate liver reserve. (See "Surgical resection of hepatocellular carcinoma".)

●Preoperative evaluation – The preoperative evaluation for resection of HCC should focus on two main issues: the likelihood of disease being confined to the liver, and whether the anatomical constraints of the intrahepatic tumor and underlying liver dysfunction will permit resection. (See 'Preoperative evaluation' above and "Surgical resection of hepatocellular carcinoma", section on 'Preoperative assessment for resectability'.)

•Postoperative outcomes – There is wide variability in outcomes after partial hepatectomy for HCC, mostly attributed to patient selection. The best outcomes (five-year survival rates up to 78 percent) after resection are reported in carefully selected patients with intact liver function who have solitary lesions without intrahepatic metastasis or vascular invasion, tumor diameter ≤5 cm, and a negative surgical margin of >1 cm. (See 'Long-term outcomes' above.)

●Is there a role for neoadjuvant therapy? – Given the high rates of local recurrence after hepatic resection, several types of locoregional neoadjuvant therapy have been evaluated prior to resection, including transarterial chemoembolization (TACE), hepatic arterial infusion of radiolabeled lipiodol, and regional irradiation with or without chemotherapy or TACE. Given the lack of survival benefit in most studies, and the heterogeneity of the populations that have been studied using these approaches, we suggest not pursuing neoadjuvant therapy prior to hepatic resection, unless in the context of a clinical trial (Grade 2B). (See 'Neoadjuvant therapy' above.)

●Adjuvant antiviral therapy for HCC and hepatitis B or C infection

•Hepatitis B – Adjuvant antiviral therapy improves outcomes after potentially curative treatment of hepatitis B virus (HBV)-related HCC. For patients with HBV-related HCC and active HBV-related liver disease, we recommend the use of nucleos(t)ide analogs (Grade 1A). The benefits of nucleos(t)ide analogs on oncologic outcomes in resected patients who do not have active hepatitis and/or a high viral load remain uncertain and require confirmation in large controlled trials with adequate follow-up before this approach can be widely adopted. (See 'HBV-related HCC and nucleoside/nucleotide analogs' above.)

•Hepatitis C – For patients with hepatitis C virus (HCV)-related HCC, we endorse the use of direct-acting antiviral (DAA) agents used for HCV therapy. A major benefit of HCV antiviral treatment among those with active viral infection is a reduction in liver-disease-related morbidity and mortality. (See 'HCV-related HCC' above and "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection", section on 'Hepatocellular carcinoma'.)

•Timing of antiviral therapy – Although postoperative therapy is pursued at many institutions, data comparing preoperative versus postoperative therapy are extremely limited, and clinical practice is variable, with some preferring preoperative antiviral therapy. In our view, either approach is reasonable. (See 'Timing of antiviral therapy' above.)

●Other adjuvant therapies – The use of other adjuvant systemic regimens or hepatic arterial infusion (HAI) therapy remains investigational. Patients interested in these approaches are encouraged to enroll in clinical trials, where available. (See 'Investigational approaches' above.)

●Post-treatment surveillance – In patients undergoing locoregional therapy for HCC, we agree with the consensus-based guidelines from the National Comprehensive Cancer Network (NCCN), which suggest the following after ablation or resection of HCC (see 'Post-treatment surveillance' above):

•Imaging every three to six months for two to three years, then every 6 to 12 months.

•Assay of serum alpha-fetoprotein (AFP), if initially elevated, every three months for two to three years, then every 6 to 12 months.