Adjuvant treatment strategy after curative resection for hepatocellular carcinoma

Abstract

Hepatic resection represents the first-line treatment for patients with resectable hepatocellular carcinoma (HCC). However, the 5-year recurrence rates of HCC after surgery have been reported to range from 50% to 70%. In this review, we evaluated the available evidence for the efficiency of adjuvant treatments to prevent HCC recurrence after curative liver resection. Antiviral therapy has potential advantages in terms of reducing the recurrence rate and improving the overall survival (OS) and/or disease-free survival of patients with hepatitis-related HCC. Postoperative adjuvant transarterial chemoembolization can significantly reduce the intrahepatic recurrence rate and improve OS, especially for patients with a high risk of recurrence. The efficacy of molecular targeted drugs as an adjuvant therapy deserves further study. Adjuvant adoptive immunotherapy can significantly improve the clinical prognosis in the early stage. Randomized controlled trial (RCT) studies evaluating adjuvant immune checkpoint inhibitors are ongoing, and the results are highly expected. Adjuvant hepatic artery infusion chemotherapy might be beneficial in patients with vascular invasion. Huaier granule, a traditional Chinese medicine, has been proved to be effective in prolonging the recurrence-free survival and reducing extrahepatic recurrence. The efficiency of other adjuvant treatments needs to be further confirmed by large RCT studies.

Keywords

hepatocellular carcinoma / adjuvant treatment / hepatic resection / recurrence

Introduction

Hepatocellular carcinoma (HCC) is one of the most common and frequently fatal malignances. HCC is the fourth most frequent cause of cancer-related death and ranks sixth in terms of incident cases worldwide [¹,²]. An estimated 392 868 new HCC cases were recorded in China, with an estimated 368 960 deaths in 2018 [¹]. Approximately half of the new cases and deaths involving HCC worldwide occurred in China [³]. Patients with HCC commonly have underlying chronic liver disease or cirrhosis, caused by hepatitis B or C virus infection, alcohol abuse, or nonalcoholic steatohepatitis cirrhosis [⁴].

At present, the potentially curative options for HCC patients mainly include surgical treatment (liver resection and liver transplantation (LT)) and radiofrequency ablation. Theoretically, LT is the best option because it cures both end stage liver disease and HCC. However, LT is hampered by the severe shortage of donor organs. Moreover, patients with well-preserved liver function or those outside the Milan criteria are not eligible for LT. Ablation is a rational treatment option, but its clinical efficacy is limited by tumor size and location [⁵]. Therefore, surgical resection is still considered as the principal strategy for the treatment of HCC. Unfortunately, the overall survival (OS) of patients with HCC following resection is still very poor because of recurrence and metastasis. The 5-year recurrence rates of HCC following liver resection have been reported to range from 50% to 70% [⁶–⁸].

The prevention and effective management of recurrent HCC are undoubtedly essential to improve long-term survival after liver resection for HCC. In the past few decades, encouraging progress has been made in systemic and locoregional treatment options for HCC and the treatment of viral hepatitis. Published studies have shown some evidence of the efficacy of adjunctive therapies in reducing the risk of tumor recurrence following liver resection. These therapies include antiviral therapy, transarterial chemoembolization (TACE), molecular targeted therapy, immunotherapy, regional or systemic chemotherapy, radiolabeled lipiodol therapy, traditional Chinese medicine, and vitamin K2 (VK2) analogs and retinoids. However, whether these strategies can be used to reduce the risk of recurrence and metastasis following liver resection is unclear. In the present review, we evaluated the available evidence for the efficiency of adjuvant treatments to prevent HCC recurrence after curative liver resection.

Methods

An electronic search was performed to identify all studies that explored the efficacy of adjuvant treatments to prevent HCC recurrence in patients following curative liver resection in PubMed, EMBASE, and Cochrane Library up to August 2020. The following keywords were used: hepatocellular carcinoma, hepatic resection, recurrence, adjuvant therapy, antiviral therapy, nucleoside analogs, interferon, direct antiviral agents, transarterial chemoembolization, molecular targeted therapy, immunotherapy, chemotherapy, hepatic artery infusion chemotherapy, iodine-131, iodine-125, radiation therapy, vitamin K2, retinoids, traditional Chinese medicine, Huaier granule, branched chain amino acids, and PI-88. Both retrospective and prospective studies were considered eligible. Studies published in languages other than English with no translation readily available were excluded. Manual searches of references cited by the published original studies and review articles supplemented the database search strategy. The review focused on the outcomes of OS, recurrence-free survival (RFS), disease-free survival (DFS), and recurrence rates.

Antiviral therapy

Nucleoside analogs (NAs)

Previous studies revealed that high viral load was closely correlated with a high risk of HCC recurrence and metastasis after liver resection [⁹,¹⁰]. Therefore, antiviral therapy plays an important role in preventing postoperative recurrence of hepatitis-related HCC. Five prospective randomized controlled trial (RCT) studies investigated the effect of NA treatment on postoperative prognosis of hepatitis B virus (HBV)-related HCC (Table 1) [¹¹–¹⁵]. For patients who had high preoperative HBV-DNA levels (>2000 IU/mL), Huang et al. [¹¹] found that the administration of adefovir led to significantly longer RFS and OS after 5-year follow-up. Multivariate analysis showed that antiviral therapy was an independent prognostic factor for long-term survival. More recently, Huang et al. [¹²] investigated the effect of antiviral therapy in patients with low (<2000 IU/mL) preoperative viral levels. This study showed that antiviral therapy with telbivudine reduced HBV reactivation and late HCC recurrence and eventually improved survival. Huang et al. [¹³] also found that telbivudine can significantly decrease the perioperative reactivation of viral replication. Yin et al. [¹⁴] reported that lamivudine therapy was associated with significantly improved liver function, decreased HCC recurrence, and longer postoperative survival. By contrast, an RCT from Taiwan, China, which was published as a meeting abstract, demonstrated that adjuvant adefovir did not reduce the postoperative recurrence of HBV-related HCC [¹⁵].

Zhang et al. [¹⁶] conducted a meta-analysis to investigate the prognostic effects of NAs in patients with HBV-related HCC after curative treatment. A total of 21 studies with 8752 patients (2 RCTs and 20 non-RCT studies) were included in the study. The pooled data suggested that NA therapy may reduce the incidence of early recurrence and improve OS. Another meta-analysis of 26 cohort studies, comprising 2546 patients in the antiviral group and 6463 patients in the control group, found that antiviral therapy with NAs confers significant survival benefits, especially in patients with high (≥20 000 IU/mL) preoperative viral levels [¹⁷]. Similar conclusions were obtained in other meta-analyses [¹⁸–²³]. The mechanisms of NA treatment in improving the prognosis after radical hepatectomy for HBV-related HCC may include inhibiting hepatitis activity, decreasing chronic inflammation in the remnant liver, improving liver reserve function, reducing the risk of developing HBV-related HCC, and increasing further therapeutic opportunities following HCC recurrence [²⁴,²⁵].

Interferon

A total of six RCTs of IFN therapy after liver resection for HCC have been reported (Table 2) [²⁶–³¹]. Two focused on HCV-related HCC [²⁶,²⁷], three on HBV- and HCV-related HCC [²⁸,³⁰,³¹], and one on HBV-related HCC [²⁹]. Conflicting conclusions were drawn from these RCT studies. In one study from Taiwan, China with the largest number of subjects, Chen et al. [³¹] found that adjuvant IFNα-2b had no significant effect on the incidence of postoperative recurrence and OS. Mazzaferro et al. [²⁸] also reported that no significant difference in RFS was detected between the IFNα and control groups. However, an obvious benefit on late recurrences was observed in HCV-related HCC patients. Another RCT study from Hong Kong, China found no evidence of a significant effect of adjuvant interferon therapy on the overall recurrence rate for the total patient group, but the incidence of early recurrence in patients with pTNM stage III and IVA tumors was significantly reduced [³⁰]. Sun et al. [²⁹] found that OS was better in the IFN treatment group than in the control group although adjuvant IFN treatment did not significantly improve DFS. Heterogeneity of the underlying liver disease and liver reserve function and differences in interferon types, dose, and treatment duration may be the reasons for the inconsistent results.

Multiple meta-analyses have been published to explore the effect of adjuvant interferon therapy on the prognosis of hepatitis-related HCC after curative therapy [³²–⁴³]. The results of most meta-analyses showed that adjuvant interferon after curative resection or ablation had a significant beneficial effect in terms of survival and tumor recurrence in patients with hepatitis-related HCC. In a recent meta-analysis that only included RCT studies, Xu et al. [⁴²] found that adjuvant IFN can improve OS but has no effect on RFS. Subgroup analysis revealed that adjuvant interferon can reduce the recurrence of patients with tumor less than 3 cm. Xu et al. [⁴⁰] reported that IFN therapy was not associated with decreased postoperative recurrence among patients with HBV-related HCC, but efficiently improved OS and reduced the recurrence rate of HCV-related HCC after surgery. Similar findings have also been observed by other investigators [³⁶,³⁹].

Direct antiviral agents (DAAs)

During the past decades, interferon-based treatment has been considered as the gold standard for chronic hepatitis C. Recently, the development of DAAs (also termed as direct-acting antivirals) has revolutionized the treatment of HCV infection. Multiple studies confirmed that the combined use of two or more of these agents can lead to sustained virological responses (SVRs) up to 95% and is well tolerated [⁴⁴–⁴⁶]. However, DAA treatment might increase the recurrence rates among patients with HCV-related HCC and complete response after resection, ablation, or TACE [⁴⁷]. At the same time, Conti et al. [⁴⁸] also reported that the recurrence rate was surprisingly high (28.8%) among cirrhotic patients with a history of surgical resection or locoregional ablation for HCC after a median follow-up of only 5.7 months. Yang et al. [⁴⁹] investigated the prognostic outcomes in patients listed for LT with HCV-associated HCC who were treated with DAA. The results showed a trend toward a higher risk of HCC recurrence in patients who received pre-LT DAA (5/18, 27.8%) than in untreated patients (6/63, 9.5%) (P = 0.06).

On the other hand, three prospective French multicenter cohorts failed to show an increased risk of HCC recurrence after DAA treatment in patients previously treated for HCC using curative procedures [⁵⁰]. In the largest retrospective study comparing HCC recurrence risk between DAA-treated patients and untreated patients, Singla et al. [⁵¹] found that DAA-based therapy was not associated with overall or early HCC recurrence and recurrence patterns. Of note, DAA therapy was associated with lower recurrence risk in the subgroup of patients who achieved complete response after resection. Recently, in a prospective real-world multicenter observational study, Cabibbo et al. [⁵²] compared the outcomes of 102 patients with BCLC 0/A HCC treated with DAA following curative resection or ablation with 102 DAA-untreated patients. The DAA group showed significantly lower decompensation rate and higher survival rate than the DAA-untreated group. The risk of HCC recurrence was not significantly different between the two groups. In addition, DAA-treated patients who achieved an SVR had better OS and lower risk of tumor recurrence and hepatic decompensation. The available data about the potential risks and benefits of DAA therapy in patients with HCV-related HCC are conflicting. More multicenter prospective studies are needed to provide some insights into this controversial issue.

TACE

TACE is one of the main treatment methods for unresectable HCC, bridging or downstaging therapy before LT. In recent years, TACE is gaining increasing interest as an adjuvant treatment strategy to prevent the recurrence of HCC after surgical resection. The main objective of TACE after liver resection for HCC is to eradicate tumor cells released during surgery due to extrusion and destroy intrahepatic preexisting microscopic carcinomatous foci that preoperative imaging examination failed to detect. Seven RCTs [⁵³–⁵⁹], comprising one from Japan and six from China, investigated the efficacy of adjuvant TACE in preventing the recurrence of HCC (Table 3). All but one study [⁵⁵] concluded that adjuvant postoperative TACE significantly reduces the intrahepatic recurrence rate and improves the OS and/or DFS. A recent meta-analysis involving 11 165 patients showed that patients who received adjuvant TACE had statistically significant improvement in OS and DFS compared with those who received curative resection alone [⁶⁰]. Subgroup analysis revealed that postoperative TACE can improve OS and decrease tumor recurrence for patients with high risk of postoperative recurrence (tumor diameter>5 cm, microvascular invasion (MVI) positive, or multinodular tumor). Liao et al. [⁶¹] conducted a meta-analysis of 8 RCTs and 12 non-RCT studies including 3325 patients. The results also showed that adjuvant TACE was associated with improved OS and RFS. Repeated TACE interventions did not provide a higher survival benefit compared with a single course. Different combinations of TACE antitumor regimes demonstrated similar survival benefits. Several previous meta-analyses have also suggested a beneficial effect of adjuvant TACE on survival [⁶²–⁶⁴].

The management of HCC with portal vein tumor thrombosis (PVTT) or hepatic vein tumor thrombus (HVTT) is complicated and controversial. With the development of treatment modalities, many studies have revealed that surgical resection offers a feasible treatment option for HCC with PVTT or HVTT and may provide a chance for long-term survival [⁶⁵–⁶⁷]. An early RCT involving 51 patients in the TACE group and 53 patients in the control group reported that the estimated survival rates at 1, 3, and 5 years were better in the postoperative TACE group than the control group. Liver resection combined with PVTT removal and postoperative TACE might be beneficial to the survival of HCC patients with PVTT [⁵⁷]. In a large retrospective cohort, Liu et al. [⁶⁸] found that postoperative adjuvant TACE was associated with longer OS. In particular, the benefit of adjuvant TACE seemed to be more pronounced in patients with larger extent of tumor thrombus (type II or III PVTT). For patients with HCC and HVTT, Zhang et al. [⁶⁹] found that the OS and RFS were significantly better for patients in the postoperative TACE group than those in the liver resection alone group. Subgroup analysis showed that postoperative TACE may not provide survival benefits for patients with HVTT that extended to the inferior vena cava.

MVI is one of the most prominent prognostic risk factors of HCC prognosis after surgery. A randomized, open-labeled, phase III trial showed that adjuvant TACE after hepatectomy is effective to prevent recurrence and prolong the survival of patients with a solitary tumor≥5 cm and MVI. Subgroup analysis found that male patients aged<60 years with the presence of cirrhosis, tumor>10 cm, and resection margin<2 cm would benefit most from adjuvant TACE [⁵⁸]. In a recent meta-analysis involving seven studies with 1869 patients, the patients in the postoperative TACE group had longer OS and DFS than those in the hepatectomy alone group. For HCC larger than 5 cm, postoperative TACE prolonged the DFS, but the difference in OS was not statistically significant [⁷⁰]. Another two meta-analyses also suggested that adjuvant TACE could improve PFS and OS for patients with HCC and MVI. Subgroup analysis demonstrated that HCC patients with MVI or tumor diameter>5 cm or multinodular tumors could benefit from adjuvant TACE [⁷¹,⁷²].

Molecular targeted therapy

Sorafenib is regarded as a valuable and standard treatment for patients with advanced and unresectable HCC. Recent opinions that adjuvant sorafenib could benefit patients with HCC after liver resection remain controversial. To date, the STORM trial is the only RCT that investigated the efficacy of sorafenib as an adjuvant therapy in patients with HCC after surgical resection or local ablation with curative intent [⁷³]. It included 1114 patients (556 in the sorafenib group and 558 in the placebo group) across 202 sites in 28 countries. After a median duration of about 12.5 months of treatment, sorafenib had no significant treatment effect on RFS, time to recurrence (TTR), or OS. Another European study also showed that adjuvant sorafenib does not confer any substantial clinical benefit in terms of survival [⁷⁴]. On the contrary, several recent retrospective studies from China demonstrated that sorafenib could reduce recurrence and prolong the survival rate in patients after surgery [⁷⁵–⁸⁰]. Of note, all these studies have included patients with high risk of recurrence after surgery. A retrospective study involving a small sample size from Taiwan, China demonstrated that sorafenib effectively prevents early recurrence after curative liver resection in patients with solitary poorly differentiated tumor and/or satellite nodules and/or MVI [⁷⁵]. Li et al. [⁷⁶] and Xia et al. [⁷⁷] found that adjuvant sorafenib significantly prolonged time to progression, DFS, and OS after curative resection for locally advanced HCC in BCLC stage C patients. For patients with tumors involving a major branch of the portal or hepatic vein, direct invasion of adjacent organs, or tumor ruptures, Liao et al. [⁷⁸] found that patients receiving sorafenib following resection had significantly longer DFS compared with the best supportive care group. Zhuang et al. [⁷⁹] revealed that sorafenib significantly increased OS after hepatectomy in intermediate stage and in advanced stage HCC. Recently, Huang et al. [⁸⁰] evaluated the effect of sorafenib as an adjuvant therapy on the clinical outcomes in HCC patients with MVI. The results indicated that adjuvant sorafenib significantly prolonged both RFS and OS of HCC patients after curative resection. A meta-analysis also found that sorafenib as an adjuvant treatment could improve RFS and reduce the recurrence rate and mortality rate [⁸¹].

Immunotherapy

Immunotherapy has shown to be a promising therapy for HCC by stimulating or adjusting the immune function to kill tumor cells. It includes adoptive immunotherapy (lymphokine-activated killer (LAK) cells, cytokine-induced killer (CIK) cells, natural killer (NK) cells), tumor vaccines, immune checkpoint inhibitors (ICIs), and immunomodulators (cytokines, ILs, chemokines) [⁸²]. To date, seven RCTs from Asia evaluated the efficacy of adjuvant adoptive immunotherapy (AIT) with CIK cells or LAK cells after curative treatments for HCC [⁸³–⁸⁹].

One of the earliest studies by Takayama et al. [⁸⁴] evaluated the therapeutic effect of adjuvant immunotherapy. After a median follow-up of 4.4 years, the patients in the adoptive immunotherapy group had an 18% decreased frequency of recurrence and significantly longer RFS. However, the OS did not differ significantly between groups. Hui et al. [⁸⁵] also found that postoperative immunotherapy with CIK cells may prevent recurrence and metastasis, but it did not affect the OS. For patients with HCC treated by surgical resection, Yu et al. [⁸⁶] found that adjuvant CIK treatment delayed early tumor recurrence, but the 3-year OS and PFS showed no significant differences between the two arms. In 2015, a phase III multicenter RCT study from Korea for the first time demonstrated that adjuvant immunotherapy with commercialized CIK cell agents improves both RFS and OS after potentially curative treatment for HCC [⁸⁷]. The same research team conducted an extended follow-up study [⁸⁸]. The results showed that adjuvant CIK cell immunotherapy significantly improves RFS and OS for up to 5 years. Recently, another RCT also showed that CIK cell treatment significantly prolonged the TTR after curative resection, but the treatment did not affect the DFS and OS [⁸⁹]. The possible explanations for this discrepancy may lie in the differences of the treatment cycle and the durations of AIT therapy. In addition, the length of follow-up and the HCC stage prior to curative treatment varied across the studies. A meta-analysis of the abovementioned RCTs suggested that adoptive immunotherapy can significantly improve the clinical prognosis (recurrence and survival rate) after curative treatment in the early stage (<3 years) but not in the late stage (5 years) [⁹⁰–⁹²]. This may mean that adjuvant AIT can eliminate small intrahepatic metastases, but it may have no effect on liver cirrhosis and cannot prevent multicentric recurrence in remnant liver.

The aim of cancer vaccination is to alter the tumor-suppressing microenvironment and trigger tumor-specific immunological effects by inducing effector T-cells, which can induce immunological memory to control tumor recurrence. Kuang et al. [⁹³] developed an autologous formalin-fixed tumor vaccine. This vaccine significantly reduced early postoperative recurrence and improved OS compared with the no adjuvant control. Dendritic cells (DCs) are professional antigen-presenting cells, which play a crucial role in both innate and adaptive immunity. Several recent prospective studies assessed the efficacy and safety of adjuvant immunotherapy with DC vaccine in patients with HCC after curative treatments. A phase II multicenter clinical study from Korea found that patients who received DC immunotherapy after surgical resection had significantly better RFS than the control group [⁹⁴]. Shimizu et al. [⁹⁵] investigated the efficacy of the combination therapy of DC vaccines and CD3-activated T-cell transfer (ATVAC) for postoperative HCC. The results showed that postoperative ATVAC treatment could succeed in improving RFS and OS in patients with HCC.

Recent advances in cancer immunotherapies using ICIs have brought novel and promising opportunities in cancer treatment. CTLA-4 and PD-1 are the most investigated ICIs in HCC [⁹⁶]. Unfortunately, RCTs assessing the efficacy of ICIs as adjuvant therapy following surgical resection for HCC are lacking. The CheckMate-9DX is an ongoing trial investigating whether nivolumab will improve RFS compared with placebo in patients with HCC who have a high risk of recurrence after hepatic resection or ablation. In a phase III study (KEYNOTE-937), pembrolizumab is being compared with placebo following curative resection or ablation, with RFS as the primary outcome [⁹⁷]. Another phase III study (IMbrave 050) is currently comparing atezolizumab plus bevacizumab with active surveillance in HCC patients at high risk of recurrence following curative treatment. A phase III trial (EMERALD-2) is also looking at the use of durvalumab plus bevacizumab combination or durvalumab alone in the adjuvant setting. The findings of these trials are highly awaited.

Systemic or regional adjuvant chemotherapy

The benefit of adjuvant chemotherapy is to control tumor growth and reduce recurrence, which has been proven in many solid tumors. Four RCT studies have explored the role of adjuvant systemic chemotherapy in reducing recurrence and metastasis after radical resection for HCC. The earliest RCT conducted by Yamamoto et al. [⁹⁸] in 1996 found that the OS and RFS of patients with mild liver dysfunction in the adjuvant oral carmofur group were significantly higher than those of the control group. However, for patients with moderate liver dysfunction, no significant difference was observed. Hasegawa et al. [⁹⁹] found no evidence to support the survival benefit of oral tegafur/uracil for patients who underwent curative hepatic resection and observed that tegafur/uracil might have some potentially undesirable effects on OS. Another RCT from China found that postoperative adjuvant therapy with capecitabine significantly increased the median TTR of HCC patients after curative resection and reduced the risk of tumor recurrence, but did not improve the OS [¹⁰⁰]. A recent RCT involving 117 patients in Japan reported that adjuvant oral tegafur/uracil failed to prolong the OS and RFS compared with surgery alone [¹⁰¹]. A systematic review including the first three RCTs concluded that adjuvant oral systemic chemotherapy did not provide significant benefit regarding OS and DFS [¹⁰²].

Hepatic artery infusion chemotherapy (HAIC) is considered to result in higher tumor drug concentrations and have less systemic toxicity than standard systemic chemotherapy. To reduce early multiple intrahepatic recurrence after surgical resection for patients with PVTT, researchers in some institutions pay more attention to postoperative adjuvant HAIC. Hamada et al. [¹⁰³] reported that HCC patients with portal vein infiltration who were treated with adjuvant HAIC had a higher OS than those without HAI, but not with tumor-free survival. Another retrospective multi-institutional study from Japan involving 400 HCC patients with PVTT in the first branch or main portal trunk found that adjuvant postoperative HAIC was associated with improved DFS and OS in such patients [¹⁰⁴]. For patients with multiple tumors and concomitant MVI, Hsiao et al. [¹⁰⁵] reported that the OS time was better in the HAIC group. Other retrospective studies have also found that adjuvant HAIC might reduce the risk of postoperative recurrence and improve OS in patients with HCC and PVTT [¹⁰⁶–¹⁰⁸]. A meta-analysis based on 11 retrospective cohort studies concluded that the combined treatment of surgical resection and adjuvant HAI therapy had improved OS compared with surgery alone. However, stratified analysis showed that resection with adjuvant HAI therapy failed to improve DFS in tumors≥7 cm [¹⁰⁹].

Radiolabeled lipiodol therapy

Lau et al. [¹¹⁰] proposed for the first time the use of intra-arterial iodine-131(¹³¹I)-labeled lipiodol as an adjuvant treatment after hepatectomy for HCC. The RCT reported that patients who received postoperative intra-arterial ¹³¹I-lipiodol had significantly better DFS and OS than those who received hepatic resection alone. A follow-up study based on all 43 randomized patients found that adjuvant intra-arterial ¹³¹I-lipiodol could significantly improve the long-term DFS and OS up to 7 years [¹¹¹]. Subsequently, two French and one Australian nonrandomized studies also demonstrated favorable outcomes with adjuvant ¹³¹I-lipiodol after resection of HCC [¹¹²–¹¹⁴]. A small case–control study reported that the intrahepatic injection of ¹³¹I-lipiodol was beneficial to prevent early recurrence of HCC following curative surgical resection in the short term up to 15 months [¹¹⁵].

However, a recent multicenter RCT involving 103 patients concluded that adjuvant ¹³¹I-lipiodol therapy did not provide significant clinical benefit [¹¹⁶]. Another retrospective study of the largest sample to date also reached a similar conclusion [¹¹⁷]. The results from meta-analysis showed that adjuvant ¹³¹I-lipiodol significantly reduced the risk of HCC recurrence and improved the DFS and OS [¹¹⁸–¹²⁰]. Only one RCT evaluated the effects of postoperative iodine-125 (¹²⁵I) brachytherapy on the recurrence of HCC. The results indicated that ¹²⁵I brachytherapy could significantly prolong TTR and OS in HCC patients receiving curative resection [¹²¹]. Further larger, multicentered RCTs are warranted to arrive at a conclusive evidence.

Radiation therapy

Radiotherapy (RT) is one of the most important strategies for cancer treatment. Recently, multiple studies have reported positive outcomes of RT with favorable OS and good local control rates in advanced HCC [¹²²,¹²³]. The data on postoperative RT as adjuvant therapy to surgical resection are limited. For centrally located HCC, it is often difficult to gain an adequate resection margin (>1 cm) during liver resection. A prospective randomized study found that adjuvant RT for centrally located HCC did not improve RFS and OS. Subgroup comparison of patients with small HCC (<5 cm) showed that RFS was significantly longer in the adjuvant RT group than in the control group [¹²⁴]. A recent study carried out in HCC patients with MVI and narrow resection margin showed that postoperative RT resulted in significantly superior survival outcomes than in the control group regardless of the degree of MVI classification [¹²⁵]. Some studies have suggested that adjuvant RT might be better than TACE with respect to RFS and OS for HCC patients with MVI [¹²⁶,¹²⁷]. An RCT trial by Sun et al. [¹²⁸] found that postoperative RT significantly improved the DFS and OS outcomes in patients with HCC and PVTT. The survival benefits were limited to patients with HCC and PVTT type I and II.

VK2 analogs and retinoids

VK2 is known as a co-enzyme for γ-carboxylase. VK2 has been shown to induce cell cycle arrest at the G1/S phase, leading to growth inhibition of hepatoma cells, and exert strong anti-angiogenic effects [¹²⁹,¹³⁰]. Six RCTs and one cohort study from Japan investigated the effects of VK2 on recurrence and survival in patients with HCC after curative treatment [¹³¹–¹³⁷]. Three of these RCTs reported that VK2 or combination treatment of VK2 and ACEI may be effective in preventing the recurrence of HCC [¹³¹,¹³³,¹³⁴]. However, other studies found no difference in DFS between treatment and control arms [¹³²,¹³⁵–¹³⁷]. All seven studies suggested that VK2 analogs had no significant effects on OS after hepatic resection or local ablation. A meta-analysis based on these studies found that VK2 analog therapy significantly reduced the 2- and 3-year tumor recurrence rates and improved the 1-, 2-, and 3-year OS [¹³⁸].

Analogues of vitamin A (retinoids) can inhibit chemically induced hepatocarcinogenesis in rats [¹³⁹]. One RCT by Muto et al. [¹⁴⁰] involving 89 patients found that oral polyprenoic acid was effective in reducing the incidence of recurrent or new hepatomas after surgical resection or the percutaneous injection of ethanol. The research group continued to follow up these patients and found that the preventive effect of acyclic vitamin A lasted up to 199 weeks after randomization [¹⁴¹]. All these studies were conducted in Japan where most patients were infected with hepatitis C virus. Therefore, the effect of VK2 analog and retinoid therapy in other patient populations is still unknown.

Traditional Chinese medicine

Traditional Chinese medicine plays an important role in preventing cancer recurrence and metastasis and prolonging the OS of cancer patients in China [¹⁴²]. Perenniporia robiniophila (Murrill) Ryvarden or Huaier is a sandy beige mushroom that grows on hard wood trees and has been used in China for nearly 1600 years [¹⁴³]. Huaier exerts antitumor effects by inducing cell cycle arrest at the G0/G1 phase, inhibiting cell proliferation, inducing cell apoptosis, and inhibiting tumor angiogenesis [¹⁴⁴–¹⁴⁶]. A recent multicenter RCT by our group evaluated the effect of adjuvant application of Huaier granules on long-term prognosis after radical resection of HCC [¹⁴⁷]. A total of 1044 patients were randomly assigned to receive Huaier granules and placebo in a 2:1 ratio. A significant prolongation of RFS and reduced extrahepatic recurrence were observed in the Huaier group. Zhai et al. [¹⁴⁸] conducted a multicenter RCT to compare the clinical efficacy of traditional herbal medicine (THM) treatment and TACE on the recurrence rate of small HCC after radical resection. The results indicated that the RFS and OS in the THM group were significantly superior to those in the TACE group.

Other adjuvant therapies

The administration of branched chain amino acids (BCAAs) is known to correct malnutrition in patients with cirrhosis [¹⁴⁹]. Four RCTs from Japan [¹⁵⁰–¹⁵³], one of which was later republished [¹⁵³], examined the clinical efficiency in terms of tumor recurrence and OS in patients with HCC undergoing hepatic resection. Three of these studies found that BCAA treatment failed to significantly improve OS or reduce tumor recurrence [¹⁵⁰–¹⁵²]. Ichikawa et al. [¹⁵³] found that oral supplementation of BCAA can reduce early recurrence after hepatic resection in patients with HCC.

PI-88 is a compound with antiheparanase activity, which has a direct effect on angiogenic growth factor binding [¹⁵⁴]. A phase II RCT using PI-88 as adjuvant therapy in patients with HCC after curative resection showed that the RFS was marginally higher in the group treated with 160 mg/day PI-88 than the control group (P = 0.07) [¹⁵⁵]. In the observational follow-up study, Liu et al. [¹⁵⁶] reported that PI-88 treatment decreased the 3-year TTR probability by 21.8%. However, no significant increase in RFS or OS was observed.

Conclusions

Adjuvant therapy for preventing recurrence after curative treatment is a critical issue for improving the long-term survival of HCC patients. Antiviral therapy has potential benefits with regard to reducing the recurrence rate and improving the OS and/or DFS of patients with hepatitis-related HCC after curative therapy. Whether direct antiviral drugs will increase the recurrence rate of hepatitis C-related HCC remains to be further investigated. Postoperative adjuvant TACE can significantly reduce the intrahepatic recurrence rate and improve OS, especially for patients with a high risk of recurrence (tumor diameter>5 cm, MVI positive, or multinodular tumors). Although the results of the STROM study did not meet the expected goals, it is too early to believe that molecular targeted drugs are useless in postoperative adjuvant therapy. Based on the recent results of multiple retrospective studies, the efficacy of molecular targeted drugs as an adjuvant therapy deserves further study. Existing evidence suggests that AIT can significantly improve early clinical prognosis (recurrence and survival rate). The long-term efficacy will require further investigation. A number of RCT studies evaluating adjuvant ICI after hepatectomy are ongoing, and the results are highly expected. Current evidence does not support the use of adjuvant chemotherapy to improve survival outcomes. However, adjuvant HAIC might be beneficial in patients with macroscopic or microscopic vascular invasion. The first nationwide multicenter study in China proved the effectiveness of Huaier granule as adjuvant therapy for HCC after liver resection. Other adjuvant treatments such as radiolabeled lipiodol, radiation therapy, VK2 analogs and retinoids, and PI-88 are not routinely used in clinical practices, and further validation from large RCTs is needed.

References

[1] International Agency for Research on Cancer, World Health Organization. Cancer today. accessed May 1, 2020)

[2] Global Burden of Disease Liver Cancer Collaboration; Akinyemiju T, Abera S, Ahmed M, Alam N, Alemayohu MA, Allen C, Al-Raddadi R, Alvis-Guzman N, Amoako Y, Artaman A, Ayele TA, Barac A, Bensenor I, Berhane A, Bhutta Z, Castillo-Rivas J, Chitheer A, Choi JY, Cowie B, Dandona L, Dandona R, Dey S, Dicker D, Phuc H, Ekwueme DU, Zaki MS, Fischer F, Fürst T, Hancock J, Hay SI, Hotez P, Jee SH, Kasaeian A, Khader Y, Khang YH, Kumar A, Kutz M, Larson H, Lopez A, Lunevicius R, Malekzadeh R, McAlinden C, Meier T, Mendoza W, Mokdad A, Moradi-Lakeh M, Nagel G, Nguyen Q, Nguyen G, Ogbo F, Patton G, Pereira DM, Pourmalek F, Qorbani M, Radfar A, Roshandel G, Salomon JA, Sanabria J, Sartorius B, Satpathy M, Sawhney M, Sepanlou S, Shackelford K, Shore H, Sun J, Mengistu DT, Topór-Mądry R, Tran B, Ukwaja KN, Vlassov V, Vollset SE, Vos T, Wakayo T, Weiderpass E, Werdecker A, Yonemoto N, Younis M, Yu C, Zaidi Z, Zhu L, Murray CJL, Naghavi M, Fitzmaurice C. The burden of primary liver cancer and underlying etiologies from 1990 to 2015 at the global, regional, and national level: results from the Global Burden of Disease Study 2015. JAMA Oncol 2017; 3(12): 1683–1691

[3] Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ, He J. Cancer statistics in China, 2015. CA Cancer J Clin 2016; 66(2): 115–132

[4] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin 2017; 67(1): 7–30

[5] O’Leary C, Mahler M, Soulen MC. Curative-intent therapies in localized hepatocellular carcinoma. Curr Treat Options Oncol 2020; 21(4): 31

[6] Asham EH, Kaseb A, Ghobrial RM. Management of hepatocellular carcinoma. Surg Clin North Am 2013; 93(6): 1423–1450

[7] Imamura H, Matsuyama Y, Tanaka E, Ohkubo T, Hasegawa K, Miyagawa S, Sugawara Y, Minagawa M, Takayama T, Kawasaki S, Makuuchi M. Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy. J Hepatol 2003; 38(2): 200–207

[8] Ercolani G, Grazi GL, Ravaioli M, Del Gaudio M, Gardini A, Cescon M, Varotti G, Cetta F, Cavallari A. Liver resection for hepatocellular carcinoma on cirrhosis: univariate and multivariate analysis of risk factors for intrahepatic recurrence. Ann Surg 2003; 237(4): 536–543

[9] Kubo S, Hirohashi K, Tanaka H, Tsukamoto T, Shuto T, Yamamoto T, Ikebe T, Wakasa K, Nishiguchi S, Kinoshita H. Effect of viral status on recurrence after liver resection for patients with hepatitis B virus-related hepatocellular carcinoma. Cancer 2000; 88(5): 1016–1024

[10] Wu JC, Huang YH, Chau GY, Su CW, Lai CR, Lee PC, Huo TI, Sheen IJ, Lee SD, Lui WY. Risk factors for early and late recurrence in hepatitis B-related hepatocellular carcinoma. J Hepatol 2009; 51(5): 890–897

[11] Huang G, Lau WY, Wang ZG, Pan ZY, Yuan SX, Shen F, Zhou WP, Wu MC. Antiviral therapy improves postoperative survival in patients with hepatocellular carcinoma: a randomized controlled trial. Ann Surg 2015; 261(1): 56–66

[12] Huang G, Li PP, Lau WY, Pan ZY, Zhao LH, Wang ZG, Wang MC, Zhou WP. Antiviral therapy reduces hepatocellular carcinoma recurrence in patients with low HBV-DNA levels: a randomized controlled trial. Ann Surg 2018; 268(6): 943–954

[13] Huang L, Li J, Yan J, Sun J, Zhang X, Wu M, Yan Y. Antiviral therapy decreases viral reactivation in patients with hepatitis B virus-related hepatocellular carcinoma undergoing hepatectomy: a randomized controlled trial. J Viral Hepat 2013; 20(5): 336–342

[14] Yin J, Li N, Han Y, Xue J, Deng Y, Shi J, Guo W, Zhang H, Wang H, Cheng S, Cao G. Effect of antiviral treatment with nucleotide/nucleoside analogs on postoperative prognosis of hepatitis B virus-related hepatocellular carcinoma: a two-stage longitudinal clinical study. J Clin Oncol 2013; 31(29): 3647–3655

[15] Chen LT, Jeng LB, Hsiao CF, Wu CC, Lee WC, Wang TE, Lee PH, Chen CL, Chen IS, Lee KT, Hsieh CB, Hwang WS, Yang MD, Yang YS, Lin DY, Chen MF, Chen PJ. Randomized, phase III trial of adjuvant adeforvir vs. therapeutic lamivudine in post-operative BCLC stage 0 or A HBV-related HCC: the Taiwan Cooperative Oncology Group T1206 study. J Clin Oncol 2015; 33(15_suppl): 4101

[16] Zhang G, Yu X, Liu P, Huang X, Jiang X. Efficacy of nucleoside analogs for chronic hepatitis B virus-related hepatocellular carcinoma after curative treatment: a meta-analysis. Dig Dis Sci 2018; 63(12): 3207–3219

[17] Chen XX, Cheng JW, Huang A, Zhang X, Wang J, Fan J, Zhou J, Yang XR. The effect of antiviral therapy on patients with hepatitis B virus-related hepatocellular carcinoma after curative resection: a systematic review and meta-analysis. OncoTargets Ther 2017; 10: 5363–5375

[18] Yuan P, Chen P, Qian Y. Evaluation of antiviral therapy performed after curative therapy in patients with HBV-related hepatocellular carcinoma: an updated meta-analysis. Can J Gastroenterol Hepatol 2016; 2016: 5234969

[19] Liu GM, Huang XY, Shen SL, Hu WJ, Peng BG. Adjuvant antiviral therapy for hepatitis B virus-related hepatocellular carcinoma after curative treatment: a systematic review and meta-analysis. Hepatol Res 2016; 46(1): 100–110

[20] Xia BW, Zhang YC, Wang J, Ding FH, He XD. Efficacy of antiviral therapy with nucleotide/nucleoside analogs after curative treatment for patients with hepatitis B virus-related hepatocellular carcinoma: a systematic review and meta-analysis. Clin Res Hepatol Gastroenterol 2015; 39(4): 458–468

[21] Zhou Y, Zhang Z, Zhao Y, Wu L, Li B. Antiviral therapy decreases recurrence of hepatitis B virus-related hepatocellular carcinoma after curative resection: a meta-analysis. World J Surg 2014; 38(9): 2395–2402

[22] Qu LS, Liu JX, Kuai XL, Xu ZF, Jin F, Zhou GX. Significance of viral status on recurrence of hepatitis B-related hepatocellular carcinoma after curative therapy: a meta-analysis. Hepatol Res 2014; 44(7): 750–760

[23] Wong JS, Wong GL, Tsoi KK, Wong VW, Cheung SY, Chong CN, Wong J, Lee KF, Lai PB, Chan HL. Meta-analysis: the efficacy of anti-viral therapy in prevention of recurrence after curative treatment of chronic hepatitis B-related hepatocellular carcinoma. Aliment Pharmacol Ther 2011; 33(10): 1104–1112

[24] Mo HY, Xiang BD, Zhong JH, Li LQ, You XM. Comment on “Evaluation of Antiviral Therapy Performed after Curative Therapy in Patients with HBV-Related Hepatocellular Carcinoma: An Updated Meta-Analysis”. Can J Gastroenterol Hepatol 2016; 2016: 7625982

[25] Yu LH, Li N, Shi J, Guo WX, Wu MC, Cheng SQ. Does anti-HBV therapy benefit the prognosis of HBV-related hepatocellular carcinoma following hepatectomy? Ann Surg Oncol 2014; 21(3): 1010–1015

[26] Ikeda K, Arase Y, Saitoh S, Kobayashi M, Suzuki Y, Suzuki F, Tsubota A, Chayama K, Murashima N, Kumada H. Interferon β prevents recurrence of hepatocellular carcinoma after complete resection or ablation of the primary tumor—a prospective randomized study of hepatitis C virus-related liver cancer. Hepatology 2000; 32(2): 228–232

[27] Kubo S, Nishiguchi S, Hirohashi K, Tanaka H, Shuto T, Kinoshita H. Randomized clinical trial of long-term outcome after resection of hepatitis C virus-related hepatocellular carcinoma by postoperative interferon therapy. Br J Surg 2002; 89(4): 418–422

[28] Mazzaferro V, Romito R, Schiavo M, Mariani L, Camerini T, Bhoori S, Capussotti L, Calise F, Pellicci R, Belli G, Tagger A, Colombo M, Bonino F, Majno P, Llovet JM;. Prevention of hepatocellular carcinoma recurrence with alpha-interferon after liver resection in HCV cirrhosis. Hepatology 2006; 44(6): 1543–1554

[29] Sun HC, Tang ZY, Wang L, Qin LX, Ma ZC, Ye QH, Zhang BH, Qian YB, Wu ZQ, Fan J, Zhou XD, Zhou J, Qiu SJ, Shen YF. Postoperative interferon alpha treatment postponed recurrence and improved overall survival in patients after curative resection of HBV-related hepatocellular carcinoma: a randomized clinical trial. J Cancer Res Clin Oncol 2006; 132(7): 458–465

[30] Lo CM, Liu CL, Chan SC, Lam CM, Poon RT, Ng IO, Fan ST, Wong J. A randomized, controlled trial of postoperative adjuvant interferon therapy after resection of hepatocellular carcinoma. Ann Surg 2007; 245(6): 831–842

[31] Chen LT, Chen MF, Li LA, Lee PH, Jeng LB, Lin DY, Wu CC, Mok KT, Chen CL, Lee WC, Chau GY, Chen YS, Lui WY, Hsiao CF, Whang-Peng J, Chen PJ; Disease Committee of Adjuvant Therapy for Postoperative Hepatocellular Carcinoma, Taiwan Cooperative Oncology Group, Health Research Institutes, Zhunan, Taiwan, China. Long-term results of a randomized, observation-controlled, phase III trial of adjuvant interferon Alfa-2b in hepatocellular carcinoma after curative resection. Ann Surg 2012; 255(1): 8–17

[32] Breitenstein S, Dimitroulis D, Petrowsky H, Puhan MA, Mullhaupt B, Clavien PA. Systematic review and meta-analysis of interferon after curative treatment of hepatocellular carcinoma in patients with viral hepatitis. Br J Surg 2009; 96(9): 975–981

[33] Miyake Y, Takaki A, Iwasaki Y, Yamamoto K. Meta-analysis: interferon-alpha prevents the recurrence after curative treatment of hepatitis C virus-related hepatocellular carcinoma. J Viral Hepat 2010; 17(4): 287–292

[34] Shen YC, Hsu C, Chen LT, Cheng CC, Hu FC, Cheng AL. Adjuvant interferon therapy after curative therapy for hepatocellular carcinoma (HCC): a meta-regression approach. J Hepatol 2010; 52(6): 889–894

[35] Singal AK, Freeman DH Jr, Anand BS. Meta-analysis: interferon improves outcomes following ablation or resection of hepatocellular carcinoma. Aliment Pharmacol Ther 2010; 32(7): 851–858

[36] Miao RY, Zhao HT, Yang HY, Mao YL, Lu X, Zhao Y, Liu CN, Zhong SX, Sang XT, Huang JF. Postoperative adjuvant antiviral therapy for hepatitis B/C virus-related hepatocellular carcinoma: a meta-analysis. World J Gastroenterol 2010; 16(23): 2931–2942

[37] Jiang S, Liu Y, Wang L, Duan C, Liu M. A meta-analysis and systematic review: adjuvant interferon therapy for patients with viral hepatitis-related hepatocellular carcinoma. World J Surg Oncol 2013; 11(1): 240

[38] Wang J, He XD, Yao N, Liang WJ, Zhang YC. A meta-analysis of adjuvant therapy after potentially curative treatment for hepatocellular carcinoma. Can J Gastroenterol 2013; 27(6): 351–363

[39] Huang TS, Shyu YC, Chen HY, Yuan SS, Shih JN, Chen PJ. A systematic review and meta-analysis of adjuvant interferon therapy after curative treatment for patients with viral hepatitis-related hepatocellular carcinoma. J Viral Hepat 2013; 20(10): 729–743

[40] Xu JB, Qi FZ, Xu G, Chen GF, Huang MD, Zhang JH. Adjuvant interferon therapy after surgical treatment for hepatitis B/C virus-related hepatocellular carcinoma: a meta-analysis. Hepatol Res 2014; 44(2): 209–217

[41] Zhuang L, Zeng X, Yang Z, Meng Z. Effect and safety of interferon for hepatocellular carcinoma: a systematic review and meta-analysis. PLoS One 2013; 8(9): e61361

[42] Xu J, Li J, Chen J, Liu ZJ. Effect of adjuvant interferon therapy on hepatitis B/C virus-related hepatocellular carcinoma after curative therapy—meta-analysis. Adv Clin Exp Med 2015; 24(2): 331–340

[43] Wu J, Yin Z, Cao L, Xu X, Yan T, Liu C, Li D. Adjuvant pegylated interferon therapy improves the survival outcomes in patients with hepatitis-related hepatocellular carcinoma after curative treatment: a meta-analysis. Medicine (Baltimore) 2018; 97(28): e11295

[44] Ioannou GN, Beste LA, Chang MF, Green PK, Lowy E, Tsui JI, Su F, Berry K. Effectiveness of sofosbuvir, ledipasvir/sofosbuvir, or paritaprevir/ritonavir/ombitasvir and dasabuvir regimens for treatment of patients with hepatitis C in the Veterans Affairs National Health Care System. Gastroenterology 2016; 151(3): 457–471.e5

[45] Calleja JL, Crespo J, Rincón D, Ruiz-Antorán B, Fernandez I, Perelló C, Gea F, Lens S, García-Samaniego J, Sacristán B, García-Eliz M, Llerena S, Pascasio JM, Turnes J, Torras X, Morillas RM, Llaneras J, Serra MA, Diago M, Rodriguez CF, Ampuero J, Jorquera F, Simon MA, Arenas J, Navascues CA, Bañares R, Muñoz R, Albillos A, Mariño Z; Spanish Group for the Study of the Use of Direct-acting Drugs Hepatitis C Collaborating Group. Effectiveness, safety and clinical outcomes of direct-acting antiviral therapy in HCV genotype 1 infection: results from a Spanish real-world cohort. J Hepatol 2017; 66(6): 1138–1148

[46] Fox DS, McGinnis JJ, Tonnu-Mihara IQ, McCombs JS. Comparative treatment effectiveness of direct acting antiviral regimens for hepatitis C: data from the Veterans Administration. J Gastroenterol Hepatol 2017; 32(6): 1136–1142

[47] Reig M, Mariño Z, Perelló C, Iñarrairaegui M, Ribeiro A, Lens S, Díaz A, Vilana R, Darnell A, Varela M, Sangro B, Calleja JL, Forns X, Bruix J. Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy. J Hepatol 2016; 65(4): 719–726

[48] Conti F, Buonfiglioli F, Scuteri A, Crespi C, Bolondi L, Caraceni P, Foschi FG, Lenzi M, Mazzella G, Verucchi G, Andreone P, Brillanti S. Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals. J Hepatol 2016; 65(4): 727–733

[49] Yang JD, Aqel BA, Pungpapong S, Gores GJ, Roberts LR, Leise MD. Direct acting antiviral therapy and tumor recurrence after liver transplantation for hepatitis C-associated hepatocellular carcinoma. J Hepatol 2016; 65(4): 859–860

[50] ANRS Collaborative Study Group on Hepatocellular Carcinoma (ANRS CO22 HEPATHER, CO12 CirVir and CO23 CUPILT cohorts). Lack of evidence of an effect of direct-acting antivirals on the recurrence of hepatocellular carcinoma: Data from three ANRS cohorts. J Hepatol 2016; 65(4): 734–740

[51] Singal AG, Rich NE, Mehta N, Branch AD, Pillai A, Hoteit M, Volk M, Odewole M, Scaglione S, Guy J, Said A, Feld JJ, John BV, Frenette C, Mantry P, Rangnekar AS, Oloruntoba O, Leise M, Jou JH, Bhamidimarri KR, Kulik L, Ioannou GN, Huang A, Tran T, Samant H, Dhanasekaran R, Duarte-Rojo A, Salgia R, Eswaran S, Jalal P, Flores A, Satapathy SK, Kagan S, Gopal P, Wong R, Parikh ND, Murphy CC. Direct-acting antiviral therapy for hepatitis C virus infection is associated with increased survival in patients with a history of hepatocellular carcinoma. Gastroenterology 2019; 157(5): 1253–1263.e2

[52] Cabibbo G, Celsa C, Calvaruso V, Petta S, Cacciola I, Cannavò MR, Madonia S, Rossi M, Magro B, Rini F, Distefano M, Larocca L, Prestileo T, Malizia G, Bertino G, Benanti F, Licata A, Scalisi I, Mazzola G, Di Rosolini MA, Alaimo G, Averna A, Cartabellotta F, Alessi N, Guastella S, Russello M, Scifo G, Squadrito G, Raimondo G, Trevisani F, Craxì A, Di Marco V, Cammà C; Rete Sicilia Selezione Terapia – HCV (RESIST-HCV) and Italian Liver Cancer (ITA.LI.CA.) Group. Direct-acting antivirals after successful treatment of early hepatocellular carcinoma improve survival in HCV-cirrhotic patients. J Hepatol 2019; 71(2): 265–273

[53] Izumi R, Shimizu K, Iyobe T, Ii T, Yagi M, Matsui O, Nonomura A, Miyazaki I. Postoperative adjuvant hepatic arterial infusion of Lipiodol containing anticancer drugs in patients with hepatocellular carcinoma. Hepatology 1994; 20(2): 295–301

[54] Li JQ, Zhang YQ, Zhang WZ, Yuan YF, Li GH. Randomized study of chemoembolization as an adjuvant therapy for primary liver carcinoma after hepatectomy. J Cancer Res Clin Oncol 1995; 121(6): 364–366

[55] Li Q, Wang J, Sun Y, Cui YL, Juzi JT, Qian BY, Hao XS. Postoperative transhepatic arterial chemoembolization and portal vein chemotherapy for patients with hepatocellular carcinoma: a randomized study with 131 cases. Dig Surg 2006; 23(4): 235–240

[56] Zhong C, Guo RP, Li JQ, Shi M, Wei W, Chen MS, Zhang YQ. A randomized controlled trial of hepatectomy with adjuvant transcatheter arterial chemoembolization versus hepatectomy alone for Stage III A hepatocellular carcinoma. J Cancer Res Clin Oncol 2009; 135(10): 1437–1445

[57] Peng BG, He Q, Li JP, Zhou F. Adjuvant transcatheter arterial chemoembolization improves efficacy of hepatectomy for patients with hepatocellular carcinoma and portal vein tumor thrombus. Am J Surg 2009; 198(3): 313–318

[58] Wei W, Jian PE, Li SH, Guo ZX, Zhang YF, Ling YH, Lin XJ, Xu L, Shi M, Zheng L, Chen MS, Guo RP. Adjuvant transcatheter arterial chemoembolization after curative resection for hepatocellular carcinoma patients with solitary tumor and microvascular invasion: a randomized clinical trial of efficacy and safety. Cancer Commun (Lond) 2018; 38(1): 61

[59] Wang Z, Ren Z, Chen Y, Hu J, Yang G, Yu L, Yang X, Huang A, Zhang X, Zhou S, Sun H, Wang Y, Ge N, Xu X, Tang Z, Lau W, Fan J, Wang J, Zhou J. Adjuvant transarterial chemoembolization for HBV-related hepatocellular carcinoma after resection: a randomized controlled study. Clin Cancer Res 2018; 24(9): 2074–2081

[60] Chen W, Ma T, Zhang J, Zhang X, Chen W, Shen Y, Bai X, Liang T. A systematic review and meta-analysis of adjuvant transarterial chemoembolization after curative resection for patients with hepatocellular carcinoma. HPB (Oxford) 2020; 22(6): 795–808

[61] Liao M, Zhu Z, Wang H, Huang J. Adjuvant transarterial chemoembolization for patients after curative resection of hepatocellular carcinoma: a meta-analysis. Scand J Gastroenterol 2017; 52(6-7): 624–634

[62] Qi X, Liu L, Wang D, Li H, Su C, Guo X. Hepatic resection alone versus in combination with pre- and post-operative transarterial chemoembolization for the treatment of hepatocellular carcinoma: a systematic review and meta-analysis. Oncotarget 2015; 6(34): 36838–36859

[63] Cheng X, Sun P, Hu QG, Song ZF, Xiong J, Zheng QC. Transarterial (chemo)embolization for curative resection of hepatocellular carcinoma: a systematic review and meta-analyses. J Cancer Res Clin Oncol 2014; 140(7): 1159–1170

[64] Zhong JH, Li LQ. Postoperative adjuvant transarterial chemoembolization for participants with hepatocellular carcinoma: a meta-analysis. Hepatol Res 2010; 40(10): 943–953

[65] Peng ZW, Guo RP, Zhang YJ, Lin XJ, Chen MS, Lau WY. Hepatic resection versus transcatheter arterial chemoembolization for the treatment of hepatocellular carcinoma with portal vein tumor thrombus. Cancer 2012; 118(19): 4725–4736

[66] Yang T, Lin C, Zhai J, Shi S, Zhu M, Zhu N, Lu JH, Yang GS, Wu MC. Surgical resection for advanced hepatocellular carcinoma according to Barcelona Clinic Liver Cancer (BCLC) staging. J Cancer Res Clin Oncol 2012; 138(7): 1121–1129

[67] Chen XP, Qiu FZ, Wu ZD, Zhang ZW, Huang ZY, Chen YF, Zhang BX, He SQ, Zhang WG. Effects of location and extension of portal vein tumor thrombus on long-term outcomes of surgical treatment for hepatocellular carcinoma. Ann Surg Oncol 2006; 13(7): 940–946

[68] Liu S, Guo L, Li H, Zhang B, Sun J, Zhou C, Zhou J, Fan J, Ye Q. Postoperative adjuvant trans-arterial chemoembolization for patients with hepatocellular carcinoma and portal vein tumor thrombus. Ann Surg Oncol 2018; 25(7): 2098–2104

[69] Zhang XP, Liu YC, Chen ZH, Sun JX, Wang K, Chai ZT, Shi J, Guo WX, Wu MC, Lau WY, Cheng SQ. Postoperative adjuvant transarterial chemoembolization improves outcomes of hepatocellular carcinoma associated with hepatic vein invasion: a propensity score matching analysis. Ann Surg Oncol 2019; 26(5): 1465–1473

[70] Shen A, Liu M, Zheng D, Chen Q, Wu Z. Adjuvant transarterial chemoembolization after curative hepatectomy for hepatocellular carcinoma with microvascular invasion: a systematic review and meta-analysis. Clin Res Hepatol Gastroenterol 2020; 44(2): 142–154

[71] Li L, Li B, Zhang M. Postoperative adjuvant transarterial chemoembolization improves the prognosis of hepatocellular carcinoma patients with microvascular invasion: a systematic review and meta-analysis. Acta Radiol 2020; 61(6): 723–731

[72] Chen ZH, Zhang XP, Zhou TF, Wang K, Wang H, Chai ZT, Shi J, Guo WX, Cheng SQ. Adjuvant transarterial chemoembolization improves survival outcomes in hepatocellular carcinoma with microvascular invasion: a systematic review and meta-analysis. Eur J Surg Oncol 2019; 45(11): 2188–2196

[73] Bruix J, Takayama T, Mazzaferro V, Chau GY, Yang J, Kudo M, Cai J, Poon RT, Han KH, Tak WY, Lee HC, Song T, Roayaie S, Bolondi L, Lee KS, Makuuchi M, Souza F, Berre MA, Meinhardt G, Llovet JM; theSTORM investigators. Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol 2015; 16(13): 1344–1354

[74] Antoniou EA, Margonis GA, Amini N, Anastasiou M, Angelou A, Kim Y, Kouraklis G. Sorafenib as an adjuvant therapy for resectable hepatocellular carcinoma: a single center experience. J BUON 2016; 21(5): 1189–1194

[75] Wang SN, Chuang SC, Lee KT. Efficacy of sorafenib as adjuvant therapy to prevent early recurrence of hepatocellular carcinoma after curative surgery: a pilot study. Hepatol Res 2014; 44(5): 523–531

[76] Li J, Hou Y, Cai XB, Liu B. Sorafenib after resection improves the outcome of BCLC stage C hepatocellular carcinoma. World J Gastroenterol 2016; 22(15): 4034–4040

[77] Xia F, Wu LL, Lau WY, Huan HB, Wen XD, Ma KS, Li XW, Bie P. Adjuvant sorafenib after heptectomy for Barcelona Clinic Liver Cancer-stage C hepatocellular carcinoma patients. World J Gastroenterol 2016; 22(23): 5384–5392

[78] Liao Y, Zheng Y, He W, Li Q, Shen J, Hong J, Zou R, Qiu J, Li B, Yuan Y. Sorafenib therapy following resection prolongs disease-free survival in patients with advanced hepatocellular carcinoma at a high risk of recurrence. Oncol Lett 2017; 13(2): 984–992

[79] Zhuang L, Wen T, Xu M, Yang J, Wang W, Wu H, Zeng Y, Yan L, Wei Y, Li B. Sorafenib combined with hepatectomy in patients with intermediate-stage and advanced hepatocellular carcinoma. Arch Med Sci 2017; 13(6): 1383–1393

[80] Huang Y, Zhang Z, Zhou Y, Yang J, Hu K, Wang Z. Should we apply sorafenib in hepatocellular carcinoma patients with microvascular invasion after curative hepatectomy? OncoTargets Ther 2019; 12: 541–548

[81] Li Z, Gao J, Zheng SM, Wang Y, Xiang X, Cheng Q, Zhu J. The efficacy of sorafenib in preventing hepatocellular carcinoma recurrence after resection: a systematic review and meta-analysis. Rev Esp Enferm Dig 2020; 112(3): 201–210

[82] Hong YP, Li ZD, Prasoon P, Zhang Q. Immunotherapy for hepatocellular carcinoma: from basic research to clinical use. World J Hepatol 2015; 7(7): 980–992

[83] Kawata A, Une Y, Hosokawa M, Wakizaka Y, Namieno T, Uchino J, Kobayashi H. Adjuvant chemoimmunotherapy for hepatocellular carcinoma patients. Adriamycin, interleukin 2, and lymphokineactivated killer cells versus adriamycin alone. Am J Clin Oncol 1995; 18(3): 257–262

[84] Takayama T, Sekine T, Makuuchi M, Yamasaki S, Kosuge T, Yamamoto J, Shimada K, Sakamoto M, Hirohashi S, Ohashi Y, Kakizoe T. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet 2000; 356(9232): 802–807

[85] Hui D, Qiang L, Jian W, Ti Z, Da-Lu K. A randomized, controlled trial of postoperative adjuvant cytokineinduced killer cells immunotherapy after radical resection of hepatocellular carcinoma. Dig Liver Dis 2009; 41(1): 36–41

[86] Yu X, Zhao H, Liu L, Cao S, Ren B, Zhang N, An X, Yu J, Li H, Ren X. A randomized phase II study of autologous cytokineinduced killer cells in treatment of hepatocellular carcinoma. J Clin Immunol 2014; 34(2): 194–203

[87] Lee JH, Lee JH, Lim YS, Yeon JE, Song TJ, Yu SJ, Gwak GY, Kim KM, Kim YJ, Lee JW, Yoon JH. Adjuvant immunotherapy with autologous cytokineinduced killer cells for hepatocellular carcinoma. Gastroenterology 2015; 148(7): 1383–1391.e6

[88] Lee JH, Lee JH, Lim YS, Yeon JE, Song TJ, Yu SJ, Gwak GY, Kim KM, Kim YJ, Lee JW, Yoon JH. Sustained efficacy of adjuvant immunotherapy with cytokine-induced killer cells for hepatocellular carcinoma: an extended 5-year follow-up. Cancer Immunol Immunother 2019; 68(1): 23–32

[89] Xu L, Wang J, Kim Y, Shuang ZY, Zhang YJ, Lao XM, Li YQ, Chen MS, Pawlik TM, Xia JC, Li SP, Lau WY. A randomized controlled trial on patients with or without adjuvant autologous cytokineinduced killer cells after curative resection for hepatocellular carcinoma. OncoImmunology 2016; 5(3): e1083671

[90] Zhao H, Zheng M, Wang K, Wang L, He H, Wang M, Shi Y, Huang S, Ji F, Li X, Zhu H, Wang L, Zhang X, Shi X, Zhao S, Fu B, Wu T. A meta-analysis of adoptive immunotherapy in postoperative hepatocellular carcinoma. J Cancer Res Ther 2018; 14(4): 807–814

[91] Mo HY, Liao YY, You XM, Cucchetti A, Yuan BH, Li RH, Zhong JH, Li LQ. Timely meta-analysis on the efficacy of adoptive immunotherapy for hepatocellular carcinoma patients after curative therapy. PLoS One 2017; 12(3): e0174222

[92] Yuan BH, Li RH, Yuan WP, Yang T, Tong TJ, Peng NF, Li LQ, Zhong JH. Harms and benefits of adoptive immunotherapy for postoperative hepatocellular carcinoma: an updated review. Oncotarget 2017; 8(11): 18537–18549

[93] Kuang M, Peng BG, Lu MD, Liang LJ, Huang JF, He Q, Hua YP, Totsuka S, Liu SQ, Leong KW, Ohno T. Phase II randomized trial of autologous formalin-fixed tumor vaccine for postsurgical recurrence of hepatocellular carcinoma. Clin Cancer Res 2004; 10(5): 1574–1579

[94] Lee JH, Tak WY, Lee Y, Heo MK, Song JS, Kim HY, Park SY, Bae SH, Lee JH, Heo J, Kim KH, Bae YS, Kim YJ. Adjuvant immunotherapy with autologous dendritic cells for hepatocellular carcinoma, randomized phase II study. OncoImmunology 2017; 6(7): e1328335

[95] Shimizu K, Kotera Y, Aruga A, Takeshita N, Katagiri S, Ariizumi S, Takahashi Y, Yoshitoshi K, Takasaki K, Yamamoto M. Postoperative dendritic cell vaccine plus activated T-cell transfer improves the survival of patients with invasive hepatocellular carcinoma. Hum Vaccin Immunother 2014; 10(4): 970–976

[96] Harding JJ, El Dika I, Abou-Alfa GK. Immunotherapy in hepatocellular carcinoma: primed to make a difference? Cancer 2016; 122(3): 367–377

[97] Nakano S, Eso Y, Okada H, Takai A, Takahashi K, Seno H. Recent advances in immunotherapy for hepatocellular carcinoma. Cancers (Basel) 2020; 12(4): E775

[98] Yamamoto M, Arii S, Sugahara K, Tobe T. Adjuvant oral chemotherapy to prevent recurrence after curative resection for hepatocellular carcinoma. Br J Surg 1996; 83(3): 336–340

[99] Hasegawa K, Takayama T, Ijichi M, Matsuyama Y, Imamura H, Sano K, Sugawara Y, Kokudo N, Makuuchi M. Uracil-tegafur as an adjuvant for hepatocellular carcinoma: a randomized trial. Hepatology 2006; 44(4): 891–895

[100] Xia Y, Qiu Y, Li J, Shi L, Wang K, Xi T, Shen F, Yan Z, Wu M. Adjuvant therapy with capecitabine postpones recurrence of hepatocellular carcinoma after curative resection: a randomized controlled trial. Ann Surg Oncol 2010; 17(12): 3137–3144

[101] Ishizuka M, Kubota K, Nemoto T, Shimoda M, Kato M, Iso Y, Tago K. Administration of adjuvant oral tegafur/uracil chemotherapy post hepatocellular carcinoma resection: a randomized controlled trial. Asian J Surg 2016; 39(3): 149–154

[102] Zhong J, Xiang B, Ma L, Li L. Conventional oral systemic chemotherapy for postoperative hepatocellular carcinoma: a systematic review. Mol Clin Oncol 2014; 2(6): 1091–1096

[103] Hamada T, Yano K, Wada T, Imamura N, Hiyoshi M, Kondo K, Nanashima A. Increased survival benefit of adjuvant intra-arterial infusion chemotherapy in HCC patients with portal vein infiltration after hepatectomy. World J Surg 2020; 44(8): 2770–2776

[104] Hatano E, Uemoto S, Yamaue H, Yamamoto M; the Japanese Society of Hepato-Biliary-Pancreatic Surgery. Significance of hepatic resection and adjuvant hepatic arterial infusion chemotherapy for hepatocellular carcinoma with portal vein tumor thrombus in the first branch of portal vein and the main portal trunk: a project study for hepatic surgery of the Japanese Society of Hepato–Biliary–Pancreatic Surgery. J Hepatobiliary Pancreat Sci 2018; 25(9): 395–402

[105] Hsiao JH, Tsai CC, Liang TJ, Chiang CL, Liang HL, Chen IS, Chen YC, Chang PM, Chou NH, Wang BW. Adjuvant hepatic arterial infusion chemotherapy is beneficial for selective patients with hepatocellular carcinoma undergoing surgical treatment. Int J Surg 2017; 45: 35–41

[106] Nitta H, Beppu T, Imai K, Hayashi H, Chikamoto A, Baba H. Adjuvant hepatic arterial infusion chemotherapy after hepatic resection of hepatocellular carcinoma with macroscopic vascular invasion. World J Surg 2013; 37(5): 1034–1042

[107] Nagano H, Kobayashi S, Marubashi S, Wada H, Eguchi H, Tanemura M, Tomimaru Y, Umeshita K, Doki Y, Mori M. Combined IFN-a and 5-FU treatment as a postoperative adjuvant following surgery for hepatocellular carcinoma with portal venous tumor thrombus. Exp Ther Med 2013; 5(1): 3–10

[108] Niguma T, Mimura T, Tutui N. Adjuvant arterial infusion chemotherapy after resection of hepatocellular carcinoma with portal thrombosis: a pilot study. J Hepatobiliary Pancreat Surg 2005; 12(3): 249–253

[109] Moran A, Ramos LF, Picado O, Pendola F, Sleeman D, Dudeja V, Merchant N, Yakoub D. Hepatocellular carcinoma: resection with adjuvant hepatic artery infusion therapy vs resection alone. A systematic review and meta-analysis. J Surg Oncol 2019; 119(4): 455–463

[110] Lau WY, Leung TW, Ho SK, Chan M, Machin D, Lau J, Chan AT, Yeo W, Mok TS, Yu SC, Leung NW, Johnson PJ. Adjuvant intra-arterial iodine-131-labelled lipiodol for resectable hepatocellular carcinoma: a prospective randomised trial. Lancet 1999; 353(9155): 797–801

[111] Lau WY, Lai EC, Leung TW, Yu SC. Adjuvant intra-arterial iodine-131-labeled lipiodol for resectable hepatocellular carcinoma: a prospective randomized trial-update on 5-year and 10-year survival. Ann Surg 2008; 247(1): 43–48

[112] Partensky C, Sassolas G, Henry L, Paliard P, Maddern GJ. Intra-arterial iodine 131-labeled lipiodol as adjuvant therapy after curative liver resection for hepatocellular carcinoma: a phase 2 clinical study. Arch Surg 2000; 135(11): 1298–1300

[113] Boucher E, Corbinais S, Rolland Y, Bourguet P, Guyader D, Boudjema K, Meunier B, Raoul JL. Adjuvant intra-arterial injection of iodine-131-labeled lipiodol after resection of hepatocellular carcinoma. Hepatology 2003; 38(5): 1237–1241

[114] Chua TC, Saxena A, Chu F, Butler SP, Quinn RJ, Glenn D, Morris DL. Hepatic resection with or without adjuvant iodine-131-lipiodol for hepatocellular carcinoma: a comparative analysis. Int J Clin Oncol 2011; 16(2): 125–132

[115] Tabone M, Vigano’ L, Ferrero A, Pellerito R, Carbonatto P, Capussotti L. Prevention of intrahepatic recurrence by adjuvant (131)iodine-labeled lipiodol after resection for hepatocellular carcinoma in HCV-related cirrhosis. Eur J Surg Oncol 2007; 33(1): 61–66

[116] Chung AY, Ooi LL, Machin D, Tan SB, Goh BK, Wong JS, Chen YM, Li PC, Gandhi M, Thng CH, Yu SW, Tan BS, Lo RH, Htoo AM, Tay KH, Sundram FX, Goh AS, Chew SP, Liau KH, Chow PK, Tay KH, Tan YM, Cheow PC, Ho CK, Soo KC. Adjuvant hepatic intra-arterial iodine-131-lipiodol following curative resection of hepatocellular carcinoma: a prospective randomized trial. World J Surg 2013; 37(6): 1356–1361

[117] Furtado RV, Ha L, Clarke S, Sandroussi C. Adjuvant iodine (131) lipiodol after resection of hepatocellular carcinoma. J Oncol 2015; 2015: 746917

[118] Gong L, Shi L, Sun J, Yuan WS, Chen JF, Liu P, Gong F, Dong JH. Comparative survival analysis of adjuvant therapy with iodine-131-labeled lipiodol to hepatic resection of primary hepatocellular carcinoma: a meta-analysis. Nucl Med Commun 2014; 35(5): 484–492

[119] Furtado R, Crawford M, Sandroussi C. Systematic review and meta-analysis of adjuvant I¹³¹ lipiodol after excision of hepatocellular carcinoma. Ann Surg Oncol 2014; 21(8): 2700–2707

[120] Hong Y, Wu LP, Ye F, Zhou YM. Adjuvant intrahepatic injection iodine-131-lipiodol improves prognosis of patients with hepatocellular carcinoma after resection: a meta-analysis. Indian J Surg 2015; 77(Suppl 3): 1227–1232

[121] Chen K, Xia Y, Wang H, Xiao F, Xiang G, Shen F. Adjuvant iodine-125 brachytherapy for hepatocellular carcinoma after complete hepatectomy: a randomized controlled trial. PLoS One 2013; 8(2): e57397

[122] Oh D, Lim DH, Park HC, Paik SW, Koh KC, Lee JH, Choi MS, Yoo BC, Lim HK, Lee WJ, Rhim H, Shin SW, Park KB. Early three-dimensional conformal radiotherapy for patients with unresectable hepatocellular carcinoma after incomplete transcatheter arterial chemoembolization: a prospective evaluation of efficacy and toxicity. Am J Clin Oncol 2010; 33(4): 370–375

[123] Yoon SM, Lim YS, Won HJ, Kim JH, Kim KM, Lee HC, Chung YH, Lee YS, Lee SG, Park JH, Suh DJ. Radiotherapy plus transarterial chemoembolization for hepatocellular carcinoma invading the portal vein: long-term patient outcomes. Int J Radiat Oncol Biol Phys 2012; 82(5): 2004–2011

[124] Yu W, Wang W, Rong W, Wang L, Xu Q, Wu F, Liu L, Wu J. Adjuvant radiotherapy in centrally located hepatocellular carcinomas after hepatectomy with narrow margin (<1 cm): a prospective randomized study. J Am Coll Surg 2014; 218(3): 381–392

[125] Wang L, Wang W, Rong W, Li Z, Wu F, Liu Y, Zheng Y, Zhang K, Siqin T, Liu M, Chen B, Wu J. Postoperative adjuvant treatment strategy for hepatocellular carcinoma with microvascular invasion: a non-randomized interventional clinical study. BMC Cancer 2020; 20(1): 614

[126] Wang L, Wang W, Yao X, Rong W, Wu F, Chen B, Liu M, Lin S, Liu Y, Wu J. Postoperative adjuvant radiotherapy is associated with improved survival in hepatocellular carcinoma with microvascular invasion. Oncotarget 2017; 8(45): 79971–79981

[127] Wang L, Chen B, Li Z, Yao X, Liu M, Rong W, Wu F, Lin S, Liu Y, Zheng Y, Li Y, Wang W, Wu J. Optimal postoperative adjuvant treatment strategy for HBV-related hepatocellular carcinoma with microvascular invasion: a propensity score analysis. OncoTargets Ther 2019; 12: 1237–1247

[128] Sun J, Yang L, Shi J, Liu C, Zhang X, Chai Z, Lau WY, Meng Y, Cheng SQ. Postoperative adjuvant IMRT for patients with HCC and portal vein tumor thrombus: an open-label randomized controlled trial. Radiother Oncol 2019; 140: 20–25

[129] Nakamura M, Nagano H, Noda T, Wada H, Ota H, Damdinsuren B, Marubashi S, Miyamoto A, Takeda Y, Doki Y, Umeshita K, Dono K, Sakon M, Monden M. Vitamin K2 has growth inhibition effect against hepatocellular carcinoma cell lines but does not enhance anti-tumor effect of combination treatment of interferon-α and fluorouracil in vitro. Hepatol Res 2006; 35(4): 289–295

[130] Jinghe X, Mizuta T, Ozaki I. Vitamin K and hepatocellular carcinoma: the basic and clinic. World J Clin Cases 2015; 3(9): 757–764

[131] Mizuta T, Ozaki I, Eguchi Y, Yasutake T, Kawazoe S, Fujimoto K, Yamamoto K. The effect of menatetrenone, a vitamin K2 analog, on disease recurrence and survival in patients with hepatocellular carcinoma after curative treatment: a pilot study. Cancer 2006; 106(4): 867–872

[132] Hotta N, Ayada M, Sato K, Ishikawa T, Okumura A, Matsumoto E, Ohashi T, Kakumu S. Effect of vitamin K2 on the recurrence in patients with hepatocellular carcinoma. Hepatogastroenterology 2007; 54(79): 2073–2077

[133] Kakizaki S, Sohara N, Sato K, Suzuki H, Yanagisawa M, Nakajima H, Takagi H, Naganuma A, Otsuka T, Takahashi H, Hamada T, Mori M. Preventive effects of vitamin K on recurrent disease in patients with hepatocellular carcinoma arising from hepatitis C viral infection. J Gastroenterol Hepatol 2007; 22(4): 518–522

[134] Yoshiji H, Noguchi R, Toyohara M, Ikenaka Y, Kitade M, Kaji K, Yamazaki M, Yamao J, Mitoro A, Sawai M, Yoshida M, Fujimoto M, Tsujimoto T, Kawaratani H, Uemura M, Fukui H. Combination of vitamin K2 and angiotensin-converting enzyme inhibitor ameliorates cumulative recurrence of hepatocellular carcinoma. J Hepatol 2009; 51(2): 315–321

[135] Yoshida H, Shiratori Y, Kudo M, Shiina S, Mizuta T, Kojiro M, Yamamoto K, Koike Y, Saito K, Koyanagi N, Kawabe T, Kawazoe S, Kobashi H, Kasugai H, Osaki Y, Araki Y, Izumi N, Oka H, Tsuji K, Toyota J, Seki T, Osawa T, Masaki N, Ichinose M, Seike M, Ishikawa A, Ueno Y, Tagawa K, Kuromatsu R, Sakisaka S, Ikeda H, Kuroda H, Kokuryu H, Yamashita T, Sakaida I, Katamoto T, Kikuchi K, Nomoto M, Omata M. Effect of vitamin K2 on the recurrence of hepatocellular carcinoma. Hepatology 2011; 54(2): 532–540

[136] Ishizuka M, Kubota K, Shimoda M, Kita J, Kato M, Park KH, Shiraki T. Effect of menatetrenone, a vitamin k2 analog, on recurrence of hepatocellular carcinoma after surgical resection: a prospective randomized controlled trial. Anticancer Res 2012; 32(12): 5415–5420

[137] Hosho K, Okano J, Koda M, Murawaki Y. Vitamin K2 has no preventive effect on recurrence of hepatocellular carcinoma after effective treatment. Yonago Acta Med 2008; 51: 95–99

[138] Zhong JH, Mo XS, Xiang BD, Yuan WP, Jiang JF, Xie GS, Li LQ. Postoperative use of the chemopreventive vitamin K2 analog in patients with hepatocellular carcinoma. PLoS One 2013; 8(3): e58082

[139] Moriwaki H, Muto Y, Ninomiya M, Kawai K, Suzuki Y, Seto T. Inhibitory effects of synthetic acidic retinoid and polyprenoic acid on the development of hepatoma in rats induced by 3-methyl-N,N-dimethyl-4-aminoazobenzene. Gastroenterol Jpn 1988; 23(5): 546–552

[140] Muto Y, Moriwaki H, Ninomiya M, Adachi S, Saito A, Takasaki KT, Tanaka T, Tsurumi K, Okuno M, Tomita E, Nakamura T, Kojima T; Hepatoma Prevention Study Group. Prevention of second primary tumors by an acyclic retinoid, polyprenoic acid, in patients with hepatocellular carcinoma. N Engl J Med 1996; 334(24): 1561–1568

[141] Takai K, Okuno M, Yasuda I, Matsushima-Nishiwaki R, Uematsu T, Tsurumi H, Shiratori Y, Muto Y, Moriwaki H. Prevention of second primary tumors by an acyclic retinoid in patients with hepatocellular carcinoma. Updated analysis of the long-term follow-up data. Intervirology 2005; 48(1): 39–45

[142] Liu J, Wang S, Zhang Y, Fan HT, Lin HS. Traditional chinese medicine and cancer: history, present situation, and development. Thorac Cancer 2015; 6(5): 561–569

[143] Li L, Ye S, Wang Y, Tang Z. Progress on experimental research and clinical application of Trametes robiniophila. China Cancer (Zhongguo Zhong Liu) 2007; 16(2): 110–113 (in Chinese)

[144] Bao H, Liu P, Jiang K, Zhang X, Xie L, Wang Z, Gong P. Huaier polysaccharide induces apoptosis in hepatocellular carcinoma cells through p38 MaPK. Oncol Lett 2016; 12(2): 1058–1066

[145] Shan L, Li Y, Jiang H, Tao Y, Qian Z, Li L, Cai F, Ma L, Yu Y. Huaier restrains proliferative and migratory potential of hepatocellular carcinoma cells partially through decreased yes-associated protein 1. J Cancer 2017; 8(19): 4087–4097

[146] Li C, Wu X, Zhang H, Yang G, Hao M, Sheng S, Sun Y, Long J, Hu C, Sun X, Li L, Zheng J. A Huaier polysaccharide restrains hepatocellular carcinoma growth and metastasis by suppression angiogenesis. Int J Biol Macromol 2015; 75: 115–120

[147] Chen Q, Shu C, Laurence AD, Chen Y, Peng BG, Zhen ZJ, Cai JQ, Ding YT, Li LQ, Zhang YB, Zheng QC, Xu GL, Li B, Zhou WP, Cai SW, Wang XY, Wen H, Peng XY, Zhang XW, Dai CL, Bie P, Xing BC, Fu ZR, Liu LX, Mu Y, Zhang L, Zhang QS, Jiang B, Qian HX, Wang YJ, Liu JF, Qin XH, Li Q, Yin P, Zhang ZW, Chen XP. Effect of Huaier granule on recurrence after curative resection of HCC: a multicentre, randomised clinical trial. Gut 2018; 67(11): 2006–2016

[148] Zhai XF, Liu XL, Shen F, Fan J, Ling CQ. Traditional herbal medicine prevents postoperative recurrence of small hepatocellular carcinoma: a randomized controlled study. Cancer 2018; 124(10): 2161–2168

[149] Cabre E, Gonzalez-Huix F, Abad-Lacruz A, Esteve M, Acero D, Fernandez-Bañares F, Xiol X, Gassull MA. Effect of total enteral nutrition on the short-term outcome of severely malnourished cirrhotics. A randomized controlled trial. Gastroenterology 1990; 98(3): 715–720

[150] No authors listed. Long-term oral administration of branched chain amino acids after curative resection of hepatocellular carcinoma: a prospective randomized trial. The San-in Group of Liver Surgery. Br J Surg 1997; 84(11): 1525–1531

[151] Meng WC, Leung KL, Ho RL, Leung TW, Lau WY. Prospective randomized control study on the effect of branched-chain amino acids in patients with liver resection for hepatocellular carcinoma. Aust N Z J Surg 1999; 69(11): 811–815

[152] Okabayashi T, Iyoki M, Sugimoto T, Kobayashi M, Hanazaki K. Oral supplementation with carbohydrate- and branched-chain amino acid-enriched nutrients improves postoperative quality of life in patients undergoing hepatic resection. Amino Acids 2011; 40(4): 1213–1220

[153] Ichikawa K, Okabayashi T, Maeda H, Namikawa T, Iiyama T, Sugimoto T, Kobayashi M, Mimura T, Hanazaki K. Oral supplementation of branched-chain amino acids reduces early recurrence after hepatic resection in patients with hepatocellular carcinoma: a prospective study. Surg Today 2013; 43(7): 720–726

[154] Joyce JA, Freeman C, Meyer-Morse N, Parish CR, Hahahan D. A functional heparan sulphate mimetic implicates both heparanase and heparan sulphate in tumor angiogenesis in a mouse model of multistage cancer. Oncogene 2005; 24(25): 4037–4051

[155] Liu CJ, Lee PH, Lin DY, Wu CC, Jeng LB, Lin PW, Mok KT, Lee WC, Yeh HZ, Ho MC, Yang SS, Lee CC, Yu MC, Hu RH, Peng CY, Lai KL, Chang SS, Chen PJ. Heparanase inhibitor PI-88 as adjuvant therapy for hepatocellular carcinoma after curative resection: a randomized phase II trial for safety and optimal dosage. J Hepatol 2009; 50(5): 958–968

[156] Liu CJ, Chang J, Lee PH, Lin DY, Wu CC, Jeng LB, Lin YJ, Mok KT, Lee WC, Yeh HZ, Ho MC, Yang SS, Yang MD, Yu MC, Hu RH, Peng CY, Lai KL, Chang SS, Chen PJ. Adjuvant heparanase inhibitor PI-88 therapy for hepatocellular carcinoma recurrence. World J Gastroenterol 2014; 20(32): 11384–11393

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