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Introduction

Hepatocellular carcinoma (HCC), the third leading cause of cancer-associated mortality worldwide, is characterized by poor prognosis and low long-term overall survival (1). Hepatitis B virus (HBV) infection is a well-documented risk factor for hepatocarcinogenesis, and ~90% of patients with HCC in China have chronic HBV infection and concomitant reduced liver function (2,3). Therefore, the prognosis of patients with HBV-associated HCC depends on both tumor status and HBV activity.

Hepatectomy remains the standard curative treatment for HCC, however, postoperative tumor recurrence is notbaly high, with 5 year rates as high as 74% for patients with disease in the intermediate or advanced stages (2). Disease-free survival is similarly low, with 5 year rates of 26% for patients with large/multinodular HCC and 18% for those with macrovascular invasion (3). Tumor recurrence is the most frequent cause of mortality in patients with HCC. Therefore, identifying postoperative therapies that reduce the risk of tumor recurrence is essential.

Risk factors of HCC recurrence

HCC recurrence can be classified as early, occurring <2 years after surgery, and late, occurring >2 years after surgery. Early recurrence is predominantly due to intrahepatic metastasis arising from the primary tumor, while late recurrence results primarily from de novo (multicentric) metastasis. Risk factors of early recurrence are associated with the HCC itself and include tumor size and number, tumor differentiation, vascular invasion, tumor capsule and resection margin (4,5). By contrast, risk factors of late recurrence are associated with remnant liver tissue and include high viral load and hepatic inflammatory activity (4,5).

These different recurrence mechanisms mean that clinicians must carefully consider each patient's risk factor profile following hepatectomy in order to design a treatment strategy that targets both types of recurrence. Although official HCC treatment guidelines do not definitively recommend adjuvant or antiviral therapies for patients with HBV-associated HCC following hepatectomy (6,7), increasing evidence supports their clinical use (8–10).

Indications for adjuvant transarterial chemoembolization

The goal of adjuvant transarterial chemoembolization (TACE) is to destroy small intrahepatic metastases that may not have been detected during surgery, as well as to eliminate tumor cells that may have been released during surgical manipulation of the liver (11). Adjuvant TACE appears to benefit only patients with HCC at high risk of early recurrence, including patients with multiple nodules, large tumors, vascular invasion, poor tumor differentiation, incomplete or absent tumor capsule, or a resection margin <1 cm. The idea that only high-risk patients benefit from adjuvant TACE is supported by retrospective studies (12,13) and a meta-analysis based on randomized studies (14). This meta-analysis, which included six randomized trials involving 659 patients with HCC at a high risk of recurrence, revealed that adjuvant TACE decreased 1- and 3 year mortality, however, not 5 year mortality rates (14). One retrospective study (15) involving 1,924 patients with HCC following curative hepatectomy found that adjuvant TACE improved overall survival in patients with tumors >5 cm, who also had other risk factors, including 2–3 nodules or microvascular invasion. However, adjuvant TACE actually reduced the overall survival of patients with a single tumor <5 cm without microvascular invasion. This lack of clinical benefit was confirmed in a more recent retrospective study (16) involving 229 patients with HCC lacking factors associated with elevated risk of recurrence or reduced overall survival. Adjuvant TACE did not improve the overall survival or reduce recurrence.

Indications for nucleos(t)ide analog (NA) therapy after hepatectomy

Postoperative antiviral therapy with NAs is another therapy commonly used following hepatectomy in patients with HBV-associated HCC (17,18). The goal of postoperative antiviral therapy in HBV-associated HCC is to reduce the viral load of HBV, protect liver function, decrease tumor recurrence, increase overall survival and improve quality of life. The only two randomized trials (19,20) that we identified in literature searches, as well as large cohort studies (18,19,21) examining NA therapy, found that it significantly reduced late HCC recurrence and improved long-term overall survival in patients with HBV-associated HCC following curative hepatectomy. However, the therapy fails to provide obvious clinical benefits for reducing early tumor recurrence or improving short-term overall survival (18–21). This may reflect the fact that the majority of patients in these trials (19,20) were in the early stages of HCC. A longer follow-up of these patients suggested certain clinical benefit. The available evidence, therefore, suggests that postoperative NA therapy affects primarily late recurrence, and it does so by controlling hepatitis activity and reducing chronic inflammation in the remnant liver.

Since numerous patients in advanced stages of HCC exhibit high rates of early recurrence and low long-term overall survival, postoperative NA therapy is likely to be more effective in patients with early-stage HCC following curative hepatectomy. Indeed, this indication is supported by subgroup analyses in retrospective studies (22–24), which showed that postoperative NA therapy can significantly improve disease-free and overall survival in patients in relatively early stages of HCC. However, no significant clinical benefit was observed for those in relatively late stages of HCC (Table I).

Table I. Previous studies evaluating postoperative antiviral therapy and survival, stratified by tumor stage.

Table I.

Previous studies evaluating postoperative antiviral therapy and survival, stratified by tumor stage.

		Disease-free survival		Overall survival
Author	Sample size (T/C)	Liver function (T), A/B	Drug used	Early stage HCC	Late stage HCC	Early stage HCC	Late stage HCC	(Refs.)
Chan et al, 2011	42/94	42/0	Lamivudine (100 mg/d) or entecavir (0.5 mg/d)	P=0.04a or 0.04b	P=0.84c or 0.58d	P=0.02a or 0.004b	P=0.10c or 0.97d	(22)
Ke et al, 2013	141/337	141/0	Lamivudine (100 mg/d)	–	–	BCLC A/B stage: P=0.035	BCLC C stage: P=0.775	(23)
Zhang et al, 2014	40/47	33/6	Entecavir (0.5 mg/d)	Tumor size ≤3: P=0.006	Tumor size >3: P=0.209	Tumor size ≤3: P=0.184	Tumor size >3: P=0.246	(24)

a American joint committee on cancer stage I and II.

b Patients without major vascular invasion.

c American joint committee on cancer stage III.

d Patients with major vascular invasion. BCLC, barcelona clinical liver cancer; C, control group; T, antiviral group. A/B, no. of patients with Child-Pugh A versus Child-Pugh B liver function.

Feasibility of adjuvant TACE combined with NA therapy

These considerations highlight the fact that the indications for adjuvant TACE differ from those for postoperative NA therapy in certain respects. This is important to take into consideration when treating patients with HBV-associated HCC following hepatectomy, particularly since the two therapies are the ones most frequently administered to such patients in HBV-endemic areas (25,26). This raises the question of whether the two therapies can be combined for an improved prognosis. Systematic searches of PubMed, EMBASE, the Cochrane Library revealed two small retrospective studies (27,28) investigating the efficacy of adjuvant TACE combined with antiviral therapy for HBV-associated HCC following hepatectomy. The first retrospective study (27) involved 60 patients, of whom 41 received both therapies and 19 received only TACE. The two groups exhibited similar 1, 2 and 3 year recurrence rates. The other study (28) included 176 patients with Child-Pugh A liver function, of whom 58 received combination therapy and 118 received TACE alone. The two groups exhibited similar disease-free survival (P=0.322), however, the combination group revealed a marginally improved overall survival (P=0.048). However, when analyses were performed with 51 pairs of propensity score-matched patients, the combination group exhibited significantly higher overall survival (P=0.033) and marginally higher disease-free survival (P=0.048). The authors concluded that the combination of adjuvant TACE and NA therapy may prevent HCC recurrence and improve the overall survival following curative hepatectomy (28).

The optimal indications for combined adjuvant TACE and NA therapy remain to be elucidated (29). The two retrospective studies (27,28) mentioned above included patients with advanced-stage HCC, and no subgroup analyses based on tumor stage were performed (27,28). Based on the indications for adjuvant TACE or postoperative NA monotherapy on their own, patients who have HBV-associated, relatively early-stage HCC and who are at high risk of recurrence may be the most suitable candidates for the two therapies combined. Adjuvant TACE is not, however, recommended for patients who have early-stage HBV-associated HCC and who lack risk factors of recurrence (15,16). Combination therapy may also be appropriate for patients with HBV-associated HCC in advanced stages. Although postoperative NA therapy in such patients may not significantly prolong their survival (22–24), it can decrease the rate of HBV reactivation and improve liver function (30,31). Two previous studies suggested that the combination of TACE and NA therapy in such patients can lead to significantly higher overall survival compared with TACE alone (32,33).

Physicians and patients must weigh the pros and cons of treatment options, including associated costs, for managing HBV-associated HCC following hepatectomy. Long-term treatment with NAs will be expensive. Additionally, drug resistance and side effects must also be determined. The most extensive evidence must also be taking into consideration, since future studies may change the picture presented here.

Future perspective

Several international guidelines already recommend antiviral therapy for patients with chronic HBV, however, no standardized international guidelines exist regarding postoperative antiviral therapy for patients with HBV-associated HCC following hepatectomy at present. In general, the clinical practice of antiviral therapy in HBV-associated HCC is based on the management of chronic hepatitis B. The primary goal of antiviral therapy with NAs is to continuously suppress virus replication in order to prevent progression of fibrosis and cirrhosis, and thereby reduce the incidence of liver failure and HCC recurrence. Postoperative antiviral therapy with NAs not only improves liver function, but also reduces the incidence of HBV reactivation and long-term tumor recurrence. The net result is an increase in long-term overall survival. While it is possible that patients at any stage of HBV-associated HCC can benefit from postoperative NA therapy, the precise indications and contradictions of this treatment, as well as the optimal drugs and doses, remain to be clarified. Future studies must elucidate how postoperative NA therapy prevents tumor recurrence and improves overall survival.

No international guidelines definitively recommend adjuvant TACE for patients with HCC following hepatectomy, however, evidence is mounting to suggest a clinical benefit to patients at high risk of recurrence. The present review concluded that, on the basis of existing evidence, the most suitable candidates for adjuvant TACE combined with antiviral NA therapy are patients who exhibit HBV-associated HCC and are at a high risk of recurrence.

References