Download PDF
Review  |  Open Access  |  14 Oct 2021

Adjuvant treatment of hepatocellular carcinoma after resection

Views: 2727 |  Downloads: 741 |  Cited:   0
Hepatoma Res 2021;7:68.
10.20517/2394-5079.2021.85 |  © The Author(s) 2021.
Author Information
Article Notes
Cite This Article

Abstract

Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer, and surgical resection offers an opportunity for cure in patients fortunate enough to have tumors amenable to resection. Unfortunately, recurrence rates are as high as 70% five years after resection, and recurrent disease proves to be a major obstacle to improving prognosis. Many adjuvant treatments have been utilized after resection in hopes of improving survival and have failed. This review outlines previous adjuvant strategies for patients with resected HCC and discusses potential steps forward to finding a successful adjuvant therapy.

Keywords

Hepatocellular carcinoma, adjuvant therapy, immunotherapy

INTRODUCTION

Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer and is the third leading cause of cancer death worldwide[1]. Surgical resection offers an opportunity to cure those patients fortunate enough to have tumors amenable to resection with well-preserved liver function[2]. However, patients who undergo “curative” resection have high recurrence rates where up to 70% of patients experience recurrence 5 years after resection[2]. The high rate of HCC recurrence is a major obstacle to improving patient prognosis, where early recurrence, within 2 years, is mainly related to metastasis and tumor dissemination of the primary HCC. In contrast, after 2 years, late recurrence is mostly the result of new tumors arising in the diseased liver[3]. Therefore, adjuvant therapies are in dire need to reduce intrahepatic recurrence rates in patients with resected or ablated HCC. However, many adjuvant strategies have failed to reduce recurrence-free or overall survival (OS).

The past several years have seen advances in the systemic treatment of HCC. For the past decade, sorafenib has not only been the mainstay of systemic treatment but the only drug approved for first-line systemic treatment since 2017. Recently, lenvatinib has been approved in the first-line setting, while regorafenib, cabozantinib, ramucirumab, and the immune checkpoint inhibitor nivolumab are approved as second-line therapy[4]. Despite these recent advances, no therapy has consistently proven effective in the adjuvant setting. Instead, systemic therapy and intra-arterial therapy, as well as several immune-based strategies, have been utilized. Here we will review previous strategies that have been tried and largely failed in the adjuvant treatment of HCC. We will then discuss a potential pathway forward toward achieving success in the adjuvant setting.

SYSTEMIC THERAPIES

The current standard of care for patients with advanced HCC for almost the past decade has been the multi-kinase inhibitor sorafenib which in a clinical trial showed a meager survival advantage of approximately three months over placebo[2,5]. Adjuvant treatment is often derived from studies based on results found to be efficacious in the advanced setting. For example, capecitabine was established as an alternative to the standard bolus fluorouracil as first-line treatment for metastatic colorectal cancer and therefore was evaluated in the adjuvant setting and subsequently found to be an effective alternative to intravenous fluorouracil[6]. However, the same results were not observed with sorafenib in the adjuvant setting. In phase III double-blind study, HCC patients with a complete radiologic response after surgical resection or local ablation were randomized to receive sorafenib or placebo with a primary endpoint of recurrence-free survival (RFS) and a secondary endpoint of OS. Unfortunately, there was no significant difference in median RFS or OS between the groups[7]. Other randomized clinical trials of adjuvant systemic therapies have found broadly similar disappointing results. Based on pre-clinical studies, capecitabine was found to inhibit postoperative recurrence and lung metastasis in mice[8]. In a randomized control trial, capecitabine was found to inhibit post-operative recurrence of HCC but failed to improve OS[9]. Similarly, others have utilized the chemotherapy tegafur/uracil (UFT) in patients who underwent curative hepatic resection and found no difference in RFS or OS compared to surgery alone[10] [Table 1].

Table 1

Systemic (non-arterial) adjuvant therapies for HCC

StudyTreatmentRationale for adjuvantOutcome
Bruix et al.[7] 2015 (STORM)SorafenibSorafenib approved for advanced HCCNo difference in median RFS or OS
Xia et al.[9] 2010Adjuvant capecitabine Capecitabine significantly inhibited postoperative recurrence and lung metastasis in mice[8]Improved DFS and probability of recurrence with no difference in OS
Ishizuka et al.[10] 2016Adjuvant UFT vs. surgery aloneUFT has shown efficacy in some HCC patients with advanced disease[110]No difference in RFS and OS
Hotta et al.[13] 2007Vitamin K2Vitamin K2 has been shown to inhibit the expression of hepatoma-derived growth factors by suppressing the promotor activity of the HDGF protein[11]No difference in HCC recurrence
Yoshida et al.[15] 2011Vitamin K2No improvement of DFS
Ishizuka et al.[14] 2012Vitamin K2No improvement of DFS or OS
Kakizaki et al.[16] 2007Vitamin K2Disease recurrence significantly lower in vitamin K2 group (P = 0.045) but no difference in OS
Mizuta et al.[17] 2006Vitamin K2Disease recurrence lower in vitamin K2 group but no significant difference in OS
Yoshiji et al.[19] 2009Vitamin K2 and ACE inhibitorACE inhibitor and vitamin K2 exert strong anti-angiogenic activities, and the combination showed suppressive effects against the development of HCC in rats[18]Combination of vitamin K2 and ACE inhibitor significantly suppressed recurrence of HCC but no significant difference in cumulative survival
Muto et al.[21] 1996Acyclic retinoid, polyprenoic acidPre-clinical models show polyprenoic acid inhibits hepatocarcinogenesis and induces apoptotis in human hepatoma cell lines[111]Polyprenoic acid prevented recurrent hepatoma after surgical resection or percutaneous injection of ethanol
Liu et al.[25] 2009Heparanase inhibitor PI-88Heparanase is elevated in a wide variety of tumors and is linked to the development of pathological processes such as tumor invasion and metastasis[23]160 mg dosage of PI-88 but not 250 mg dose, improved RFS at 1 year

In addition to traditional chemotherapy, Vitamin K2 has been utilized in the adjuvant setting for patients with HCC. Pre-clinical data demonstrated that Vitamin K2 suppressed the growth of three HCC cell lines through the regulation and suppression of the hepatoma-derived growth factor (HDGF) gene[11]. HDGF is highly expressed in HCC cells stimulating their proliferation with oncogenic and angiogenic activity[11,12]. However, adjuvant trials with Vitamin K2 in HCC have largely disappointing results. Vitamin K2 failed to improve the recurrence of HCC[13-15] or significantly improved the recurrence without an improvement in OS[16,17] [Table 1]. Vitamin K2 has been tested in combination with an angiotensin-converting enzyme (ACE) inhibitor as the combination demonstrated more potent anti-angiogenic and anti-tumor effects than single-agent treatment in rats[18]. However, the combination of vitamin K2 and an ACE inhibitor reduced HCC recurrence without a survival advantage[19].

In addition to vitamin K2, vitamin A derivatives have been utilized in the chemoprevention of HCC as studies have suggested that loss of retinoid activity may be linked to carcinogenesis in HCC[20]. In a prospective randomized control trial, the acyclic retinoid, polyprenoic acid, was found to prevent recurrent HCC after surgical resection or percutaneous injection of ethanol compared to placebo[21]. However, this study has been criticized as the patients in the study had low plasma retinol levels below the level of severe vitamin A deficiency. This has been shown to predispose patients to alterations in differentiation and increased cellular proliferation, and therefore treatment may have restored vitamin A levels, and the broader implication for cancer prevention in patients with normal vitamin A remains unclear[22].

Heparanase has been shown to be elevated in a wide variety of tumors and is linked to the development of pathological processes such as tumor invasion and metastasis[23]. Therefore, heparanase inhibitor PI-88 was studied in patients with HCC in the adjuvant setting [Table 1]. PI-88 demonstrated a benefit of RFS at the 160 mg but not 250 mg dose with no benefit in OS[24,25]. Additionally, in the phase II trial, more than 95% of patients who received PI-88 experienced mild or moderately severe adverse events[25,26].

LOCOREGIONAL THERAPY

Locoregional therapies such as transcatheter arterial chemoembolization (TACE) are a cornerstone of treatment for patients with HCC[1]. These modalities have also been utilized in the adjuvant setting with largely mixed results.

Intra-arterial therapies

Hepatic arterial-based therapies such as TACE, which combines the arterial delivery of beads to restrict tumor blood flow with local administration of chemotherapy, are recommended for patients with the intermediate stage (BCLC stage B) HCC[2]. Chemoembolization with doxorubicin provided a significant survival benefit in stringently selected patients with unresectable HCC[27]. Additionally, chemoembolization with the emulsion of cisplatin in lipiodol displayed improved survival in Asian patients with unresectable HCC[28]. However, results are mixed in the adjuvant setting. Izumi et al.[29] studied the use of TACE with lipiodol containing doxorubicin and mitomycin, finding an improvement in disease-free survival (DFS) but no effect on OS. On the other hand, Li et al.[30] found a significant improvement in intrahepatic recurrence and OS in patients who underwent TACE with lipiodol containing doxorubicin and mitomycin. Additional studies showed improved survival with TACE in patients with resected stage IIIA HCC[31] and patients who required removal of a portal vein tumor thrombus[32]. In addition, the use of TACE with portal vein chemotherapy (PVC) was evaluated. Li et al.[33] noted a significant increase in DFS with TACE + PVC but no difference in DFS with TACE alone. More recent studies have also evaluated the role of TACE in the adjuvant setting for HCC with again largely mixed results[34-36] [Table 2].

Table 2

Adjuvant transcatheter arterial chemoembolization studies for hepatocellular carcinoma

StudyGroupsRationale for adjuvantOutcome
Izumi et al.[29] 1994TACE: lipiodol + doxorubicin + mitomycin + gelatin spongePrevious evidence within the advanced setting[112]Significant improvement of DFS but no effect on OS
Li et al.[30] 1995TACE: lipiodol + doxorubicin + mitomycinSignificant improvement of DFS and OS
Li et al.[33] 2006TACE (lipiodol + Adriamycin + mitomycin + cisplatin or carboplatinum +/- portal vein chemotherapyMicroscopic venous invasion is common and related to post-resection outcome[113]Post-operative TACE + PVC increased DFS. No difference in DFS with TACE alone
Peng et al.[32] 2009TACE: lipiodol + Adriamycin + 5-fluorouracil + gelatin spongeThe study population involved patients with hepatectomy with portal vein tumor thrombus removalTACE improved OS
Zhong et al.[31] 2009TACE: lipiodol + mitomycin + carboplatin + epirubicinSignificantly improved DFS and OS in Stage IIIA HCC
Lai et al.[43] 1998TACE: lipiodol + cisplatin
IV: epirubicin
Regiment and route of administration for adjuvant therapy varied and sought to study in RCTAdjuvant therapy associated with significantly worse DFS and no significance in OS
Li et al.[36] 2017TACE: lipiodol, epirubicin, oxaliplatin, 5-FUUnresectable HCC with benefits of TACE[114]TACE improved RFS and OS
Liu et al.[35] 2016TACE: epirubicin, oxaliplatin, 5-FUUnresectable HCC with benefits of TACE[114]TACE improved 1-year, no difference in 2- or 3-year DFS
Ye et al.[34] 2017TACE: lipiodol, raltitrexed, lobaplatinUnresectable HCC with benefits of TACE[114]TACE improved OS and DFS in patients with HCC with microvascular invasion
Qi et al.[115] 2019TACE: lipiodol, oxaliplatin or lobaplatin, pirarubicin or pharmorubicinUnresectable HCC with benefits of TACE[114]No difference in 1-, 2-, 3-year DFS
Tumor size > 5 cm had improved DFS and OS with TACE

In addition to TACE, several studies have evaluated the use of other arterial-based regiments such as intra-arterial I131 lipiodol or hepatic artery infusion chemotherapy. Trans-arterial I131 lipiodol has largely demonstrated a lack of efficacy[37-39] [Table 3]. Hepatic arterial infusion (HAI) chemotherapy has gained a foothold in the treatment of advanced colorectal liver metastasis, but its role in the treatment in patients with HCC remains limited. Bolus arterial infusion of epirubicin in combination with UFT produced no improvement in RFS over UFT alone[40]. HAI of 5-fluoruracil (5-FU) and cisplatin failed to produce any benefit on recurrence after curative resection of HCC[41]. However, in a retrospective study of 85 patients who underwent radical hepatectomy where 42 received HAI of 5-FU, oxaliplatin, and mitomycin-C, the HAI group demonstrated significantly higher 5-year intrahepatic RFS, DFS, and OS than the control group[42]. However, several studies with trans-arterial therapies did not improve DFS or OS and may have been associated with worse outcomes[43-46].

Table 3

Intra-arterial adjuvant studies for hepatocellular carcinoma

StudyGroupsRationale for adjuvantOutcome
Kim et al.[41] 2011Adjuvant hepatic artery infusion 5-FU and cisplatinRepetitive short course 5-FU and cisplatin showed antitumor effects in advanced HCC[116]No benefit in recurrence rate or median recurrence-free survival at 2 years
Kohno et al.[40] 1996Bolus arterial injection of epirubicin post-op day 28 with UFT vs. UFT aloneBolus injection of epirubicin did not change long-term results
Ono et al.[44] 2001Analysis of three trials of three different post-operative adjuvant therapies: arterial epirubicin with oral tegafur, arterial epirubicin+ IV epirubicin + carmofur, IV epirubicinPre-op transarterial chemoembolization displayed no significant benefit and tried therapy in the adjuvant setting[117]No improvement in DFS or OS with possible worse outcomes for patient receiving adjuvant therapy
Lau et al.[38] 2008Intra-arterial I131 lipiodolI131 lipiodol has active uptake and prolonged retention in hepatoma cellsNo difference in DFS or OS at 8 years
Lau et al.[37] 1999Intra-arterial I131 lipiodolDecrease RFS and increase OS at 3 years
Chung et al.[39] 2013Intra-arterial I131 lipiodolNo difference in RFS or OS
Hirokawa et al.[45] 2020Transarterial catheter infusion of cisplatin three months after surgery then three months later TACE with lipiodol and cisplatinUnresectable HCC with benefits of TACE[114]No difference in relapse-free survival or overall survival
Hamada et al.[46] 2020Hepatic artery infusion: cisplatinHepatic artery infusion chemotherapy may be associated with survival benefits in advanced disease[118]No significant difference in tumor-free or overall survival in HCC patients with portal vein infiltration
Feng et al.[42] 2017Hepatic artery infusion: cisplatinHAI group demonstrated significantly higher 5-year intrahepatic RFS, DFS, and OS
Li et al.[109] 2020Transarterial injection of 131I-metuximab 4-6 weeks after hepatectomyPrevious studies have shown survival benefits of 131I-metuximab in advanced HCC[108]131I-metuximab was associated with improved 5-year RFS in HCC tumors expressing CD147

Brachytherapy

Adjuvant iodine125 brachytherapy has been utilized in patients with resected HCC. In a randomized control trial, 68 HCC patients undergoing curative resection were assigned to receive either iodine125 brachytherapy at the raw surface or resection or best supportive care. Iodine125 brachytherapy was found to improve time to recurrence and OS after curative resection[47]. However, these results have yet to been validated in a larger patient cohort in the adjuvant setting.

Radiation therapy

Although radiation therapy (RT) has traditionally been avoided in the liver due to the risk of radiation-induced liver disease and limited response, recent advances in RT may allow its application as an adjunct to other therapies[48]. In a retrospective study, stereotactic body radiation therapy demonstrated superior efficacy in HCC than sorafenib[49]. A narrow-margin resection (< 1 cm) of HCC has been found to be associated with a significantly higher recurrence rate than patients who underwent wide-margin excision (> 1 cm)[50]. Postoperative RT has been found to be associated with improved recurrence rates in patients who underwent narrow margin hepatectomy[51,52]. In a study comparing conservative therapy, TACE, or radiotherapy in HCC patients with microvascular invasion, adjuvant RT revealed significantly improved RFS and OS compared to TACE and conservative therapy[53]. Additionally, in an analysis of the SEER database, 244 were identified who received preoperative (93 patients) or postoperative (151 patients) RT. Patients who received preoperative RT had improved OS and cancer-specific survival compared to patients who received postoperative RT[54]. The use of RT after hepatectomy remains understudied, and there remains interested in its utilization in both the adjuvant setting and as a bridge to liver transplant[48].

ANTI-VIRAL THERAPY

Chronic viral hepatitis is the greatest risk factor for the development of HCC, where the worldwide incidence of HCC follows that of chronic viral hepatitis[2]. Therefore, anti-viral therapy before and after curative treatment may be crucial in preventing late HCC recurrence[3]. Several groups have evaluated the use of nucleoside analogues in the adjuvant treatment of Hepatitis B virus-related HCC with mixed results [Table 4]. Several randomized control trials found lamivudine not to affect post-operative DFS or OS[55-58]. Other studies demonstrated lamivudine or other nucleoside analogues to improve tumor-free survival in patients with high serum HBV DNA[59,60] or reducing recurrence with prolonged post-operative survival with improved liver function reserve[61]. However, the above studies indicate nucleoside analogues may improve liver function and clearance of HBV in patients with HCC.

Table 4

Anti-viral therapies

StudyGroupsRationale for adjuvantOutcome
Yin et al.[61] 2013Anti-viral medication: lamivudine, adefovir dipivoxil, or entecavirRetrospective studies reported that post-operative treatment conferred postoperative survival[119-122]Improve liver function reserve and reduces HBV-HCC recurrence and prolonged post-operative survival
Huang et al.[123] 2015AdefovirAdefovir reduced late HBV-HCC recurrence and improved OS
Kuzuya et al.[55] 2007LamivudineLamivudine treatment may reduce HBV replication and improve remnant liver function, prevent liver failure and prolong survival[124]No significant difference in cumulative recurrence of survival rates in HBV-HCC
Kubo et al.[59] 2007LamivudineLamivudine improved tumor-free survival rate after curative resection in patients with high serum concentrations of HBV DNA
Li et al.[56] 2010LamivudineNo difference in disease-free survival but promoted post-operative HBV clearance and increased residual liver volume
Piao et al.[57] 2005LamivudineNo difference in HBV-HCC recurrence or survival, but the treatment group was associated with a low death rate due to liver failure
Yoshida et al.[58] 2008LamivudineNo difference in overall survival or recurrence-free survival but did improve liver function for HBV-HCC
Wu et al.[122] 2012Nucleoside analogues: lamivudine, entecavir, and telbivudineAntiviral therapy was associated with a lower risk of HCC recurrence among patients with HBV-related HCC
Yang et al.[60] 2012Nucleoside analogues: lamivudine, entecavir, or adefovirAntiviral therapy was associated with improved RFS for the patient with high HBV viral load
Huang et al.[125] 2018TelbivudineTelbivudine reduced HCC recurrence in patients with low preoperative HBV-DNA levels

STUDIES WITH ADJUVANT IMMUNE-BASED THERAPIES IN HCC

Several randomized clinical trials have been performed utilizing immune-based therapies in the adjuvant setting. This section will discuss the application of immunotherapies in the adjuvant setting focusing on cytokine-based therapy, cell-based therapies, and vaccine-based therapies.

Cytokine based therapy: interferon

The use of interferon (IFN) appeared as a logical first choice for the treatment of HCC as it may show both anti-viral and anti-tumor functions. However, the tumor response rates to IFN therapy were poor in patients with advanced disease, with a partial response rate of 6% (2 of 30 patients) and no benefit in OS. Additionally, IFN therapy was not well tolerated in patients with cirrhosis and HCC, where nearly half of the patients discontinued treatment due to intolerance or adverse events[62].

As with many of the treatment strategies mentioned above in the adjuvant setting for HCC, IFN has been met with mixed results [Table 5]. Several groups found no improvement of RFS or OS in HBV/HCV-HCC patients[63] and HBV-HCC patients[64] after curative resection. Meanwhile, other studies found IFN- improved post-ablation HCC recurrence[65] and preventing late recurrence after resection in HCV-HCC patients but found no improvement in disease-specific survival[66]. Furthermore, several studies found IFN- to not improve HCC recurrence but improved survival after procedures performed for curative intent for HCC[67-70]. Additionally, IFN was shown to improve RFS at 25 months after curative resection or ablation[71]. Pegylated-interferon (PEG-IFN) was associated with a decrease in 1- and 2-year recurrence with a higher survival[72], and the addition of ribavirin was associated with a decreased recurrence and mortality in HCV associated HCC[73].

Table 5

Adjuvant interferon therapy for HCC

StudyTreatmentRationale for adjuvantOutcome
Chen et al.[63] 2012 IFN-αIFN may show both anti-viral and anti-tumor functionNo improvement in RFS or OS in the total patient population of HBV/HCV patients
Sun et al.[70] 2006IFN-αNo improvement in DFS in HBV-related HCC but improved OS in HBV related disease
Lo et al.[64] 2007IFN-αNo improvement in DFS or OS in HBV-related HCC
Shiratori et al.[69] 2003IFN-αNo improvement in RFS but may improve OS in HCV-related disease
Kubo et al.[67] 2002 IFN-αPost-operative IFN did not statistically decrease intrahepatic recurrence but improved cumulative survival in HCV-related HCC
Lin et al.[65] 2004IFN-αPost-ablation IFN reduced the recurrence of HCC recurrence
No survival data were reported
Nishiguchi et al.[68] 2005IFN-αPost-operative IFN group improved cumulative survival but failed to improve intrahepatic recurrence
Mazzaferro et al.[66] 2006IFN-αNo difference in disease-specific survival, but IFN may prevent late recurrence in HCV-HCC
Ikeda et al.[71] 2000 IFN-βImproved RFS at 25 months. OS not reported
Hsu et al.[73] 2013PEG-IFN with ribavirinThe antiviral regimen of IFN-β with ribavirin used to treat HCV-related infection[126]IFN-β with ribavirin was associated with decreased recurrence rate and mortality in patients with HCV-HCC
Lee et al.[72] 2013PEG-IFNPEG-IFN associated with a decrease in 1- and 2-year recurrence and higher survival

Cell and vaccine-based therapy

Adoptive cell transfer (ACT) is a highly personalized form of cancer immunotherapy that involves the transfer of host-derived expanded immune cells[74]. Adoptive transfer of autologous tumor-infiltrating lymphocytes (TIL) has been shown to produce complete and durable tumor regression in patients with metastatic melanoma, and a particular case of metastatic cholangiocarcinoma[75,76]. ACT has been studied in the adjuvant setting for HCC. Wang et al.[77] found that TIL can be expanded and activated in vitro and reduce recurrence rates in patients with HCC compared to patients who did not receive TIL infusion. Meanwhile, adjuvant activated autologous lymphocyte infusions were found to increase RFS but had no impact on OS[78].

Activated T cell transfer has also been applied with adjunctive treatments such as an autologous tumor lysate-pulsed dendritic cell vaccine[79]. Patients who underwent a curative HCC liver resection received an adjuvant dendritic cell vaccine made from a patient’s dendritic cells pulsed with a tumor lysate created from the resected tumor along with activated CD3+ T cells. There was a significant difference in RFS and OS in favor of the combination DC vaccine and ACT vs. no adjuvant therapy[79]. However, other studies have shown mixed results with the use of lymphocyte-activated killer cells along with intra-arterial therapies[80,81]. Tumor associated-antigen pulsed DCs without ACT has also been utilized in the adjuvant setting with no difference in RFS and upon subgroup analysis may have increased the risk of recurrence in patients who were treated with RFA while reducing recurrence in patients who received an operation[82] [Table 6].

Table 6

Immune approaches for adjuvant HCC

StudyTreatmentRationale for adjuvantOutcome
Takayama et al.[78] 2000Adoptive cell transferActivated autologous lymphocyte infusionsIncreased RFS and disease-specific survival but had no impact on OS
Wang et al.[77] 1997ACTReduced recurrence
Lee et al.[87] 2015CIK cellsCIK cells have potent antitumor effects with the dual-functional capability of T cells and NK cellsCIK cell immunotherapy was associated with improved recurrence-free, overall, and cancer-specific survival
Hui et al.[90] 2009CIK cellsCIK cells demonstrated decreased recurrence after radical resection
Kuang et al.[85] 2004Autologous formalin-fixed tumor vaccineHCC vaccine consisted of autologous formalin-fixed tumor tissue fragments, biodegradable microparticles containing GM-CSF, IL2, and tuberculin[127]Vaccine improved RFS and OS
Xie et al.[81] 2000Hepatic artery chemoembolization with lymphocyte-activated killer cells/IL2 after radical surgeryReduced intrahepatic recurrence and improved survival
Shimizu et al.[79] 2014Dendritic call vaccine with activated T-cell transferDendritic cell vaccine was made from a patient’s isolated dendritic cells pulsing with tumor lysate created from the resected tumor and CD3+ activated T cellsSignificant difference in both RFS and OS
Lee et al.[82] 2017TAA-pulsed DC vaccineA previous study demonstrated that IV vaccination with ex vivo DCs showed evidence of antitumor efficacy in advanced HCC[128]No overall difference in RFS. Subgroup analysis with improved RFS in non-RFA patients and increased risk of recurrence in RFA patients
Sawada et al.[83] 2016GPC3 vaccineEarly studies utilizing a GPC3 peptide vaccine found the treatment to be safe and able to induce tumor infiltration of CD8+ T cellsNo statistically significant reduction in recurrence at 2 years
Kawata et al.[80] 1995Intra-arterial Adriamycin, IL-2, lymphocyte-activated killer cellsNo difference in DFS or OS compared to intra-arterial Adriamycin alone

Other vaccine trials have been conducted utilizing a peptide vaccine against the carcinoembryonic antigen glypican-3 (GPC3). GPC3 makes an appealing target for HCC vaccines as it is specifically overexpressed in HCC and often is associated with a poor prognosis. Early studies utilizing a GPC3 peptide vaccine found the treatment to be safe and induce tumor infiltration of CD8+ T cells. The GPC3 vaccine in the adjuvant setting demonstrating a significantly improved recurrence rate in patients treated with surgery plus vaccine compared to surgery alone at 1 year but was found to be no longer statistically significant at 2 years[83]. However, recently, Taniguchi et al.[84] found the GPC3 peptide vaccine decreased 1-year recurrence rate after surgery by 15%, and the 5-year and 8-year survival rates were improved by 10% and 30%, respectively, compared to an unvaccinated group. Additionally, Kuang et al.[85] utilized an autologous formalin-fixed tumor vaccine to improve RFS and OS after curative resection [Table 6].

Another strategy of ACT that has been tried in the adjuvant setting for HCC is through cytokine-induced killer (CIK) cells. CIK cells are autologous cells expanded ex vivo from a patient’s peripheral blood mononuclear cells and cultured with a cytokine cocktail and anti-CD3 antibodies. The resulting cell population has potent antitumor effects with the dual-functional capability of T cells and NK cells[86,87]. CIK cell treatment was found to be an independent prognostic factor for improved OS in patients after HCC resection[88]. In a non-randomized study, Chen et al.[89] found CIK cells improved DFS and OS for patients without microvascular invasion. Furthermore, a randomized controlled trial found CIK cells decreased HCC recurrence after radical resection[90]. Lee et al.[87] studied CIK cells in the adjuvant setting in patients with resected HCC. The primary endpoint of this study was RFS and secondary endpoints, including OS and cancer-specific survival. They found that CIK cell immunotherapy was associated with improved recurrence-free, overall, and cancer-specific survival[87].

Checkpoint inhibition with nivolumab is now a mainstream treatment for patients with sorafenib refractory HCC[91]. Several clinical trials are currently in progress investigating immune checkpoint inhibition for patients with HCC in the adjuvant setting (CheckMate 9DX, nivolumab vs. placebo after resection or ablation; EMERALD-2, adjuvant durvalumab +/- bevacizumab after curative treatment)[92].

FUTURE DIRECTIONS

As the recurrence for HCC after attempted curative ablation or resection remains high, additional studies are required to reduce post-operative recurrence. Many of the treatment strategies mentioned above have been met with largely mixed results. The key to success may be found in selecting patients and pairing them with the appropriate therapy properly[93]. For example, early and late recurrences are linked to different predictive risk factors[94]. Early recurrence is often seen as an intrahepatic metastasis associated with risk factors such as large tumors, incomplete tumor capsules, and venous or microvascular invasion[95-97]. On the other hand, late recurrence is often thought of as the development of a new tumor in a persistently diseased liver with risk factors centered on the extent of the patient’s underlying liver disease and alpha-fetoprotein (AFP) level[95]. Additionally, gene signatures and circulating micro-RNA have been used to predict survival and recurrence[98-101]. Ng et al.[102] investigated a prediction model for early (< 18 months) recurrence following resection. They developed a Recurrent Liver Cancer Score based on four risk factors: AFP, tumor size, multiple tumors or satellite nodules, and microvascular invasion. Low and high-risk groups were at statistically significant risk of recurrence and 5-year survival[102]. The ability to properly select patients may prove vital in achieving success with HCC in the adjuvant setting.

The question remains of what therapy to administer, and we can predict patients who will get a response with potential biomarkers. Pan et al.[103] looked at 48 patients with HCC treated with postoperative adjuvant CIK cell immunotherapy to identify a predictive biomarker for adjuvant CIK cell treatment. They found that there was no association between prognosis and CIK cell phenotype. However, there was a statistically significant improvement in OS and RFS in patients with the high cytotoxic activity of CIK cells compared to the low cytotoxic activity of CIK cells[103]. Additionally, low expression of microRNA miR-26 was found to be a predictor of the worse OS but a better response to IFN therapy[104]. Antiviral-based therapies have not been found to reduce HBV or HCC related recurrence after resection but seem to improve overall liver function which then in turn may improve post-operative survival[61]. Furthermore, with the introduction and application of Harvoni (ledipasvir/sofosbuvir) allowing for the potential cure of HCV, it would be interesting to witness potential changes in HCC recurrence over the next decade. Treating HCV-infected patients before the development of cirrhosis may reduce the risk of HCC[105]. However, data is emerging that treatment of HCV in patients with successfully treated HCC may result in high rates of recurrence, especially within the first six months of treatment[106].

Medicine is becoming more increasingly personalized with the development of targeted therapies aimed at specific molecular alterations. For example, up to 60% of patients with HCC have positive CD147 expression in tumor tissues[107]. CD147 is associated with increased metastatic potential and worse disease outcomes than tumors that are negative for CD147 expression[107]. Blocking CD147 with metuximab, a monoclonal antibody specifically against CD147, has been shown to inhibit HCC cell growth and metastasis[108]. 131I-metuximab was found to be associated with improved 5-year RFS in patients with HCC tumors expressing CD147[109].

CONCLUSION

The past several years have seen advancement in systemic therapies for HCC in the advanced setting. However, patients fortunate enough to undergo resection with intent for cure are plagued by high recurrence rates, and there is currently no approved therapy in the adjuvant setting to help this complex problem. Nevertheless, future success may be found as we continue to learn more about the molecular drivers of tumorigenesis and improved selection of patients, proper therapy, and the development of more targeted therapies.

DECLARATIONS

Authors’ contributions

Conception and drafting of the manuscript: Brown ZJ, Tsung A

Availability of data and materials

Not applicable.

Financial support and sponsorship

None.

Conflicts of interest

Both authors declared that there are no conflicts of interest.

Ethical approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Copyright

© The Author(s) 2021.

REFERENCES

1. Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet 2018;391:1301-14.

2. Llovet JM, Zucman-Rossi J, Pikarsky E, et al. Hepatocellular carcinoma. Nat Rev Dis Primers 2016;2:16018.

3. Du Y, Su T, Ding Y, Cao G. Effects of antiviral therapy on the recurrence of hepatocellular carcinoma after curative resection or liver transplantation. Hepat Mon 2012;12:e6031.

4. Greten TF, Lai CW, Li G, Staveley-O'Carroll KF. Targeted and immune-based therapies for hepatocellular carcinoma. Gastroenterology 2019;156:510-24.

5. Llovet JM, Ricci S, Mazzaferro V, et al. SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378-90.

6. Twelves C, Wong A, Nowacki MP, et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med 2005;352:2696-704.

7. Bruix J, Takayama T, Mazzaferro V, et al. Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol 2015;16:1344-54.

8. Zhou J, Tang ZY, Fan J, et al. Capecitabine inhibits postoperative recurrence and metastasis after liver cancer resection in nude mice with relation to the expression of platelet-derived endothelial cell growth factor. Clin Cancer Res 2003;9:6030-7.

9. Xia Y, Qiu Y, Li J, et al. Adjuvant therapy with capecitabine postpones recurrence of hepatocellular carcinoma after curative resection: a randomized controlled trial. Ann Surg Oncol 2010;17:3137-44.

10. Ishizuka M, Kubota K, Nemoto T, et al. Administration of adjuvant oral tegafur/uracil chemotherapy post hepatocellular carcinoma resection: A randomized controlled trial. Asian J Surg 2016;39:149-54.

11. Yamamoto T, Nakamura H, Liu W, et al. Involvement of hepatoma-derived growth factor in the growth inhibition of hepatocellular carcinoma cells by vitamin K(2). J Gastroenterol 2009;44:228-35.

12. Okuda Y, Nakamura H, Yoshida K, et al. Hepatoma-derived growth factor induces tumorigenesis in vivo through both direct angiogenic activity and induction of vascular endothelial growth factor. Cancer Sci 2003;94:1034-41.

13. Hotta N, Ayada M, Sato K, et al. Effect of vitamin K2 on the recurrence in patients with hepatocellular carcinoma. Hepatogastroenterology 2007;54:2073-7.

14. Ishizuka M, Kubota K, Shimoda M, et al. Effect of menatetrenone, a vitamin k2 analog, on recurrence of hepatocellular carcinoma after surgical resection: a prospective randomized controlled trial. Anticancer Res 2012;32:5415-20.

15. Yoshida H, Shiratori Y, Kudo M, et al. Effect of vitamin K2 on the recurrence of hepatocellular carcinoma. Hepatology 2011;54:532-40.

16. Kakizaki S, Sohara N, Sato K, et al. Preventive effects of vitamin K on recurrent disease in patients with hepatocellular carcinoma arising from hepatitis C viral infection. J Gastroenterol Hepatol 2007;22:518-22.

17. Mizuta T, Ozaki I, Eguchi Y, et al. 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;106:867-72.

18. Yoshiji H, Kuriyama S, Noguchi R, et al. Combination of vitamin K2 and the angiotensin-converting enzyme inhibitor, perindopril, attenuates the liver enzyme-altered preneoplastic lesions in rats via angiogenesis suppression. J Hepatol 2005;42:687-93.

19. Yoshiji H, Noguchi R, Toyohara M, et al. Combination of vitamin K2 and angiotensin-converting enzyme inhibitor ameliorates cumulative recurrence of hepatocellular carcinoma. J Hepatol 2009;51:315-21.

20. Kojima S, Okuno M, Matsushima-Nishiwaki R, Friedman SL, Moriwaki H. Acyclic retinoid in the chemoprevention of hepatocellular carcinoma (review). Int J Oncol 2004;24:797-805.

21. Muto Y, Moriwaki H, Ninomiya M, et al. Prevention of second primary tumors by an acyclic retinoid, polyprenoic acid, in patients with hepatocellular carcinoma. Hepatoma Prevention Study Group. N Engl J Med 1996;334:1561-7.

22. Decensi A, Costa A. Polyprenoic acid in hepatocellular carcinoma. N Engl J Med 1996;335:1461; author reply 1461-2.

23. Miao HQ, Liu H, Navarro E, Kussie P, Zhu Z. Development of heparanase inhibitors for anti-cancer therapy. Curr Med Chem 2006;13:2101-11.

24. Liu CJ, Chang J, Lee PH, et al. Adjuvant heparanase inhibitor PI-88 therapy for hepatocellular carcinoma recurrence. World J Gastroenterol 2014;20:11384-93.

25. Liu CJ, Lee PH, Lin DY, et al. 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;50:958-68.

26. Zhong JH, Ma L, Li LQ. Postoperative therapy options for hepatocellular carcinoma. Scand J Gastroenterol 2014;49:649-61.

27. Llovet JM, Real MI, Montaña X, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet 2002;359:1734-9.

28. Lo CM, Ngan H, Tso WK, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 2002;35:1164-71.

29. Izumi R, Shimizu K, Iyobe T, et al. Postoperative adjuvant hepatic arterial infusion of Lipiodol containing anticancer drugs in patients with hepatocellular carcinoma. Hepatology 1994;20:295-301.

30. 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;121:364-6.

31. Zhong C, Guo RP, Li JQ, et al. 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;135:1437-45.

32. 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;198:313-8.

33. Li Q, Wang J, Sun Y, et al. Postoperative transhepatic arterial chemoembolization and portal vein chemotherapy for patients with hepatocellular carcinoma: a randomized study with 131 cases. Dig Surg 2006;23:235-40.

34. Ye JZ, Chen JZ, Li ZH, et al. Efficacy of postoperative adjuvant transcatheter arterial chemoembolization in hepatocellular carcinoma patients with microvascular invasion. World J Gastroenterol 2017;23:7415-24.

35. Liu C, Sun L, Xu J, Zhao Y. Clinical efficacy of postoperative adjuvant transcatheter arterial chemoembolization on hepatocellular carcinoma. World J Surg Oncol 2016;14:100.

36. Li C, Wen TF, Yan LN, et al. Liver resection versus liver resection plus TACE for patients with hepatocellular carcinoma beyond Milan criteria. J Surg Res 2017;209:8-16.

37. Lau W, Leung T, Ho S, et al. Adjuvant intra-arterial lipiodol-iodine-131 for resectable hepatocellular carcinoma: a prospective randomised trial. Lancet 1999;353:797-801.

38. 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;247:43-8.

39. Chung AY, Ooi LL, Machin D, et al. Adjuvant hepatic intra-arterial iodine-131-lipiodol following curative resection of hepatocellular carcinoma: a prospective randomized trial. World J Surg 2013;37:1356-61.

40. Kohno H, Nagasue N, Hayashi T, et al. Postoperative adjuvant chemotherapy after radical hepatic resection for hepatocellular carcinoma (HCC). Hepatogastroenterology 1996;43:1405-9.

41. Kim DY, Ahn SH, Kim SU, et al. Adjuvant hepatic arterial infusional chemotherapy with 5-fluorouracil and cisplatin after curative resection of hepatocellular carcinoma. Oncology 2011;81:184-91.

42. Feng M, Tang C, Feng W, Bao Y, Zheng Y, Shen J. Hepatic artery-infusion chemotherapy improved survival of hepatocellular carcinoma after radical hepatectomy. Onco Targets Ther 2017;10:3001-5.

43. Lai EC, Lo CM, Fan ST, Liu CL, Wong J. Postoperative adjuvant chemotherapy after curative resection of hepatocellular carcinoma: a randomized controlled trial. Arch Surg 1998;133:183-8.

44. Ono T, Yamanoi A, Nazmy El Assal O, Kohno H, Nagasue N. Adjuvant chemotherapy after resection of hepatocellular carcinoma causes deterioration of long-term prognosis in cirrhotic patients: metaanalysis of three randomized controlled trials. Cancer 2001;91:2378-85.

45. Hirokawa F, Komeda K, Taniguchi K, et al. Is postoperative adjuvant transcatheter arterial infusion therapy effective for patients with hepatocellular carcinoma who underwent hepatectomy? Ann Surg Oncol 2020;27:4143-52.

46. Hamada T, Yano K, Wada T, et al. Increased survival benefit of adjuvant intra-arterial infusion chemotherapy in HCC patients with portal vein infiltration after hepatectomy. World J Surg 2020;44:2770-6.

47. 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:e57397.

48. Akateh C, Black SM, Conteh L, et al. Neoadjuvant and adjuvant treatment strategies for hepatocellular carcinoma. World J Gastroenterol 2019;25:3704-21.

49. Bettinger D, Pinato D, Schultheiss M, et al. Stereotactic body radiation therapy as an alternative treatment for patients with hepatocellular carcinoma compared to sorafenib: a propensity score analysis. Liver Cancer 2019;8:281-94.

50. Liu L, Shui Y, Yu Q, et al. Narrow-margin hepatectomy resulted in higher recurrence and lower overall survival for R0 resection hepatocellular carcinoma. Front Oncol 2020;10:610636.

51. Wang WH, Wang Z, Wu JX, et al. Survival benefit with IMRT following narrow-margin hepatectomy in patients with hepatocellular carcinoma close to major vessels. Liver Int 2015;35:2603-10.

52. Rong W, Yu W, Wang L, et al. Adjuvant radiotherapy in central hepatocellular carcinoma after narrow-margin hepatectomy: a 10-year real-world evidence. Chin J Cancer Res 2020;32:645-53.

53. Wang L, Wang W, Yao X, et al. Postoperative adjuvant radiotherapy is associated with improved survival in hepatocellular carcinoma with microvascular invasion. Oncotarget 2017;8:79971-81.

54. Lin H, Li X, Liu Y, Hu Y. Neoadjuvant radiotherapy provided survival benefit compared to adjuvant radiotherapy for hepatocellular carcinoma. ANZ J Surg 2018;88:E718-24.

55. Kuzuya T, Katano Y, Kumada T, et al. Efficacy of antiviral therapy with lamivudine after initial treatment for hepatitis B virus-related hepatocellular carcinoma. J Gastroenterol Hepatol 2007;22:1929-35.

56. Li N, Lai EC, Shi J, et al. A comparative study of antiviral therapy after resection of hepatocellular carcinoma in the immune-active phase of hepatitis B virus infection. Ann Surg Oncol 2010;17:179-85.

57. Piao CY, Fujioka S, Iwasaki Y, et al. Lamivudine treatment in patients with HBV-related hepatocellular carcinoma--using an untreated, matched control cohort. Acta Med Okayama 2005;59:217-24.

58. Yoshida H, Yoshida H, Goto E, et al. Safety and efficacy of lamivudine after radiofrequency ablation in patients with hepatitis B virus-related hepatocellular carcinoma. Hepatol Int 2008;2:89-94.

59. Kubo S, Tanaka H, Takemura S, et al. Effects of lamivudine on outcome after liver resection for hepatocellular carcinoma in patients with active replication of hepatitis B virus. Hepatol Res 2007;37:94-100.

60. Yang T, Lu JH, Zhai J, et al. High viral load is associated with poor overall and recurrence-free survival of hepatitis B virus-related hepatocellular carcinoma after curative resection: a prospective cohort study. Eur J Surg Oncol 2012;38:683-91.

61. Yin J, Li N, Han Y, et al. 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;31:3647-55.

62. Llovet JM, Sala M, Castells L, et al. Randomized controlled trial of interferon treatment for advanced hepatocellular carcinoma. Hepatology 2000;31:54-8.

63. Chen LT, Chen MF, Li LA, et al. Disease Committee of Adjuvant Therapy for Postoperative Hepatocellular Carcinoma. 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;255:8-17.

64. Lo CM, Liu CL, Chan SC, et al. A randomized, controlled trial of postoperative adjuvant interferon therapy after resection of hepatocellular carcinoma. Ann Surg 2007;245:831-42.

65. Lin SM, Lin CJ, Hsu CW, et al. Prospective randomized controlled study of interferon-alpha in preventing hepatocellular carcinoma recurrence after medical ablation therapy for primary tumors. Cancer 2004;100:376-82.

66. Mazzaferro V, Romito R, Schiavo M, et al. HCC Italian Task Force. Prevention of hepatocellular carcinoma recurrence with alpha-interferon after liver resection in HCV cirrhosis. Hepatology 2006;44:1543-54.

67. 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;89:418-22.

68. Nishiguchi S, Tamori A, Kubo S. Effect of long-term postoperative interferon therapy on intrahepatic recurrence and survival rate after resection of hepatitis C virus-related hepatocellular carcinoma. Intervirology 2005;48:71-5.

69. Shiratori Y, Shiina S, Teratani T, et al. Interferon therapy after tumor ablation improves prognosis in patients with hepatocellular carcinoma associated with hepatitis C virus. Ann Intern Med 2003;138:299-306.

70. Sun HC, Tang ZY, Wang L, et al. 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;132:458-65.

71. Ikeda K, Arase Y, Saitoh S, et al. Interferon beta 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;32:228-32.

72. Lee D, Chung YH, Kim JA, et al. Safety and efficacy of adjuvant pegylated interferon therapy for metastatic tumor antigen 1-positive hepatocellular carcinoma. Cancer 2013;119:2239-46.

73. Hsu YC, Ho HJ, Wu MS, Lin JT, Wu CY. Postoperative peg-interferon plus ribavirin is associated with reduced recurrence of hepatitis C virus-related hepatocellular carcinoma. Hepatology 2013;58:150-7.

74. Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 2015;348:62-8.

75. Rosenberg SA, Yang JC, Sherry RM, et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res 2011;17:4550-7.

76. Tran E, Turcotte S, Gros A, et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science 2014;344:641-5.

77. Wang Y, Chen H, Wu M, Bao J, Cong W, Wang H. Postoperative immunotherapy for patients with hepatocarcinoma using tumor-infiltrating lymphocytes. Chin Med J (Engl) 1997;110:114-7.

78. Takayama T, Sekine T, Makuuchi M, et al. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet 2000;356:802-7.

79. Shimizu K, Kotera Y, Aruga A, et al. Postoperative dendritic cell vaccine plus activated T-cell transfer improves the survival of patients with invasive hepatocellular carcinoma. Hum Vaccin Immunother 2014;10:970-6.

80. Kawata A, Une Y, Hosokawa M, et al. Adjuvant chemoimmunotherapy for hepatocellular carcinoma patients. Adriamycin, interleukin-2, and lymphokine-activated killer cells versus adriamycin alone. Am J Clin Oncol 1995;18:257-62.

81. Xie L, Pang R, Jin Y, Xiang S, Li H. Effects of hepatic artery chemotherapeutic embolization combined with perfusing LAK cells into hepatic artery after radical operation of liver cancer. Zhonghua Gan Zang Bing Za Zhi 2000;8:142-3. (in Chinese).

82. Lee JH, Tak WY, Lee Y, et al. Adjuvant immunotherapy with autologous dendritic cells for hepatocellular carcinoma, randomized phase II study. Oncoimmunology 2017;6:e1328335.

83. Sawada Y, Yoshikawa T, Ofuji K, et al. Phase II study of the GPC3-derived peptide vaccine as an adjuvant therapy for hepatocellular carcinoma patients. Oncoimmunology 2016;5:e1129483.

84. Taniguchi M, Mizuno S, Yoshikawa T, et al. Peptide vaccine as an adjuvant therapy for glypican-3-positive hepatocellular carcinoma induces peptide-specific CTLs and improves long prognosis. Cancer Sci 2020;111:2747-59.

85. Kuang M, Peng BG, Lu MD, et al. Phase II randomized trial of autologous formalin-fixed tumor vaccine for postsurgical recurrence of hepatocellular carcinoma. Clin Cancer Res 2004;10:1574-9.

86. Schmidt-Wolf IG, Lefterova P, Mehta BA, et al. Phenotypic characterization and identification of effector cells involved in tumor cell recognition of cytokine-induced killer cells. Exp Hematol 1993;21:1673-9.

87. Lee JH, Lee JH, Lim YS, et al. Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma. Gastroenterology 2015;148:1383-91.e6.

88. Pan K, Li YQ, Wang W, et al. The efficacy of cytokine-induced killer cell infusion as an adjuvant therapy for postoperative hepatocellular carcinoma patients. Ann Surg Oncol 2013;20:4305-11.

89. Chen J, Lao X, Lin X, et al. Adjuvant cytokine-induced killer cell therapy improves disease-free and overall survival in solitary and nonmicrovascular invasive hepatocellular carcinoma after curative resection. Medicine 2016;95:e2665.

90. Hui D, Qiang L, Jian W, Ti Z, Da-Lu K. A randomized, controlled trial of postoperative adjuvant cytokine-induced killer cells immunotherapy after radical resection of hepatocellular carcinoma. Dig Liver Dis 2009;41:36-41.

91. El-khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 2017;389:2492-502.

92. Huppert LA, Gordan JD, Kelley RK. Checkpoint inhibitors for the treatment of advanced hepatocellular carcinoma. Clin Liver Dis (Hoboken) 2020;15:53-8.

93. Brown ZJ, Greten TF, Heinrich B. Adjuvant treatment of hepatocellular carcinoma: prospect of immunotherapy. Hepatology 2019;70:1437-42.

94. Portolani N, Coniglio A, Ghidoni S, et al. Early and late recurrence after liver resection for hepatocellular carcinoma: prognostic and therapeutic implications. Ann Surg 2006;243:229-35.

95. Cheng Z, Yang P, Qu S, et al. Risk factors and management for early and late intrahepatic recurrence of solitary hepatocellular carcinoma after curative resection. HPB (Oxford) 2015;17:422-7.

96. Imamura H, Matsuyama Y, Tanaka E, et al. Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy. J Hepatol 2003;38:200-7.

97. Poon RT, Fan S, Ng IO, Lo C, Liu C, Wong J. Different risk factors and prognosis for early and late intrahepatic recurrence after resection of hepatocellular carcinoma. Cancer 2000;89:500-7.

98. Borel F, Konstantinova P, Jansen PL. Diagnostic and therapeutic potential of miRNA signatures in patients with hepatocellular carcinoma. J Hepatol 2012;56:1371-83.

99. Budhu A, Jia HL, Forgues M, et al. Identification of metastasis-related microRNAs in hepatocellular carcinoma. Hepatology 2008;47:897-907.

100. Ji J, Eggert T, Budhu A, et al. Hepatic stellate cell and monocyte interaction contributes to poor prognosis in hepatocellular carcinoma. Hepatology 2015;62:481-95.

101. Zhang DY, Goossens N, Guo J, et al. A hepatic stellate cell gene expression signature associated with outcomes in hepatitis C cirrhosis and hepatocellular carcinoma after curative resection. Gut 2016;65:1754-64.

102. Ng KK, Cheung TT, Pang HH, et al. A simplified prediction model for early intrahepatic recurrence after hepatectomy for patients with unilobar hepatocellular carcinoma without macroscopic vascular invasion: an implication for adjuvant therapy and postoperative surveillance. Surg Oncol 2019;30:6-12.

103. Pan QZ, Liu Q, Zhou YQ, et al. CIK cell cytotoxicity is a predictive biomarker for CIK cell immunotherapy in postoperative patients with hepatocellular carcinoma. Cancer Immunol Immunother 2020;69:825-34.

104. Ji J, Shi J, Budhu A, et al. MicroRNA expression, survival, and response to interferon in liver cancer. N Engl J Med 2009;361:1437-47.

105. Tayyab GUN, Rasool S, Nasir B, Rubi G, Abou-Samra AB, Butt AA. Hepatocellular carcinoma occurs frequently and early after treatment in HCV genotype 3 infected persons treated with DAA regimens. BMC Gastroenterol 2020;20:93.

106. Hassany M, Elsharkawy A, Maged A, et al. Hepatitis C virus treatment by direct-acting antivirals in successfully treated hepatocellular carcinoma and possible mutual impact. Eur J Gastroenterol Hepatol 2018;30:876-81.

107. Zhang Q, Zhou J, Ku XM, et al. Expression of CD147 as a significantly unfavorable prognostic factor in hepatocellular carcinoma. Eur J Cancer Prev 2007;16:196-202.

108. Chen ZN, Mi L, Xu J, et al. Targeting radioimmunotherapy of hepatocellular carcinoma with iodine (131I) metuximab injection: clinical phase I/II trials. Int J Radiat Oncol Biol Phys 2006;65:435-44.

109. Li J, Xing J, Yang Y, et al. Adjuvant 131I-metuximab for hepatocellular carcinoma after liver resection: a randomised, controlled, multicentre, open-label, phase 2 trial. Lancet Gastroenterol Hepatol 2020;5:548-60.

110. Ishikawa T, Ichida T, Sugitani S, et al. Improved survival with oral administration of enteric-coated tegafur/uracil for advanced stage IV-A hepatocellular carcinoma. J Gastroenterol Hepatol 2001;16:452-9.

111. Fukutomi Y, Omori M, Muto Y, Ninomiya M, Okuno M, Moriwaki H. Inhibitory effects of acyclic retinoid (polyprenoic acid) and its hydroxy derivative on cell growth and on secretion of alpha-fetoprotein in human hepatoma-derived cell line (PLC/PRF/5). Jpn J Cancer Res 1990;81:1281-5.

112. Okamura J, Horikawa S, Fujiyama T, et al. An appraisal of transcatheter arterial embolization combined with transcatheter arterial infusion of chemotherapeutic agent for hepatic malignancies. World J Surg 1982;6:352-7.

113. Tsai TJ, Chau GY, Lui WY, et al. Clinical significance of microscopic tumor venous invasion in patients with resectable hepatocellular carcinoma. Surgery 2000;127:603-8.

114. Xu L, Peng ZW, Chen MS, et al. Prognostic nomogram for patients with unresectable hepatocellular carcinoma after transcatheter arterial chemoembolization. J Hepatol 2015;63:122-30.

115. Qi YP, Zhong JH, Liang ZY, et al. Adjuvant transarterial chemoembolization for patients with hepatocellular carcinoma involving microvascular invasion. Am J Surg 2019;217:739-44.

116. Park JY, Ahn SH, Yoon YJ, et al. Repetitive short-course hepatic arterial infusion chemotherapy with high-dose 5-fluorouracil and cisplatin in patients with advanced hepatocellular carcinoma. Cancer 2007;110:129-37.

117. Uchida M, Kohno H, Kubota H, et al. Role of preoperative transcatheter arterial oily chemoembolization for resectable hepatocellular carcinoma. World J Surg 1996;20:326-31.

118. Lin CC, Hung CF, Chen WT, Lin SM. Hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma with portal vein thrombosis: impact of early response to 4 weeks of treatment. Liver Cancer 2015;4:228-40.

119. Chan AC, Chok KS, Yuen WK, et al. Impact of antiviral therapy on the survival of patients after major hepatectomy for hepatitis B virus-related hepatocellular carcinoma. Arch Surg 2011;146:675-81.

120. Chuma M, Hige S, Kamiyama T, et al. The influence of hepatitis B DNA level and antiviral therapy on recurrence after initial curative treatment in patients with hepatocellular carcinoma. J Gastroenterol 2009;44:991-9.

121. Huang G, Yang Y, Shen F, et al. Early viral suppression predicts good postoperative survivals in patients with hepatocellular carcinoma with a high baseline HBV-DNA load. Ann Surg Oncol 2013;20:1482-90.

122. Wu CY, Chen YJ, Ho HJ, et al. Association between nucleoside analogues and risk of hepatitis B virus-related hepatocellular carcinoma recurrence following liver resection. JAMA 2012;308:1906-14.

123. Huang G, Lau WY, Wang ZG, et al. Antiviral therapy improves postoperative survival in patients with hepatocellular carcinoma: a randomized controlled trial. Ann Surg 2015;261:56-66.

124. Yao FY, Terrault NA, Freise C, Maslow L, Bass NM. Lamivudine treatment is beneficial in patients with severely decompensated cirrhosis and actively replicating hepatitis B infection awaiting liver transplantation: a comparative study using a matched, untreated cohort. Hepatology 2001;34:411-6.

125. Huang G, Li PP, Lau WY, et al. Antiviral therapy reduces hepatocellular carcinoma recurrence in patients with low HBV-DNA levels: a randomized controlled trial. Ann Surg 2018;268:943-54.

126. Ghany MG, Strader DB, Thomas DL, Seeff LB. American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology 2009;49:1335-74.

127. Peng BG, Liu SQ, Kuang M, et al. Autologous fixed tumor vaccine: a formulation with cytokine-microparticles for protective immunity against recurrence of human hepatocellular carcinoma. Jpn J Cancer Res 2002;93:363-8.

128. Palmer DH, Midgley RS, Mirza N, et al. A phase II study of adoptive immunotherapy using dendritic cells pulsed with tumor lysate in patients with hepatocellular carcinoma. Hepatology 2009;49:124-32.

Cite This Article

Export citation file: BibTeX | RIS

OAE Style

Brown ZJ, Tsung A. Adjuvant treatment of hepatocellular carcinoma after resection. Hepatoma Res 2021;7:68. http://dx.doi.org/10.20517/2394-5079.2021.85

AMA Style

Brown ZJ, Tsung A. Adjuvant treatment of hepatocellular carcinoma after resection. Hepatoma Research. 2021; 7: 68. http://dx.doi.org/10.20517/2394-5079.2021.85

Chicago/Turabian Style

Brown, Zachary J., Allan Tsung. 2021. "Adjuvant treatment of hepatocellular carcinoma after resection" Hepatoma Research. 7: 68. http://dx.doi.org/10.20517/2394-5079.2021.85

ACS Style

Brown, ZJ.; Tsung A. Adjuvant treatment of hepatocellular carcinoma after resection. Hepatoma. Res. 2021, 7, 68. http://dx.doi.org/10.20517/2394-5079.2021.85

About This Article

Special Issue

© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Data & Comments

Data

Views
2727
Downloads
741
Citations
0
Comments
0
45

Comments

Comments must be written in English. Spam, offensive content, impersonation, and private information will not be permitted. If any comment is reported and identified as inappropriate content by OAE staff, the comment will be removed without notice. If you have any queries or need any help, please contact us at support@oaepublish.com.

0
Author's Talk
Download PDF
Cite This Article 13 clicks
Like This Article 45 likes
Share This Article
Scan the QR code for reading!
See Updates
Contents
Figures
Related
Hepatoma Research
ISSN 2454-2520 (Online) 2394-5079 (Print)

Portico

All published articles are preserved here permanently:

https://www.portico.org/publishers/oae/

Portico

All published articles are preserved here permanently:

https://www.portico.org/publishers/oae/