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Publications > Journals > Journal of Clinical and Translational Hepatology > Article Full Text

  • Review Article
  • OPEN ACCESS

Adjuvant Therapy for Hepatocellular Carcinoma After Curative Treatment: Several Unanswered Questions

  • Le Li1,2,#,
  • Zhen-Zhen Li3,#,
  • Li-Xin Pan1,
  • Jia-Yong Su1,
  • Shan Huang1,
  • Liang Ma1,*  and
  • Jian-Hong Zhong1,4,5,* 
 Author information
Journal of Clinical and Translational Hepatology   2024

doi: 10.14218/JCTH.2024.00030

Abstract

Most patients with hepatocellular carcinoma (HCC) have a poor prognosis. Hepatectomy and local ablation are the main curative treatments for HCC. Nevertheless, the recurrence rate after hepatectomy or ablation is up to 70%, which seriously affects patient prognosis. Several adjuvant therapies have been explored to reduce postoperative recurrence. However, although a variety of adjuvant therapies have been shown to reduce the recurrence rate and improve overall survival, a standard consensus of national HCC guidelines for adjuvant treatment is lacking. Therefore, there are significant differences in the recommendations for adjuvant therapy for HCC between the Eastern and Western guidelines. A variety of adjuvant treatment methods, such as antiviral therapy, transarterial chemoembolization or traditional Chinese medicine, are recommended by the Chinese HCC guidelines. However, Western guidelines make few recommendations other than antiviral therapy. Adjuvant immune checkpoint inhibitors are recommended only in the recently updated American Association for the Study of Liver Diseases guidelines. This review summarized the existing adjuvant therapy options after curative hepatectomy or ablation and discusses several important dilemmas of adjuvant treatments.

Graphical Abstract

Keywords

Hepatocellular carcinoma, Adjuvant therapy, Curative hepatectomy, Recurrence, Overall survival, Immune checkpoint inhibitor

Introduction

Hepatocellular carcinoma (HCC) is one of the most common malignancies and the third leading cause of cancer death, with increasing morbidity and mortality in recent years.1 Currently, liver transplantation, hepatectomy or local ablation are the main curative therapies for early HCC. Hepatectomy is recommended in some Asian countries for intermediate or advanced HCC patients with well-preserved liver function.2,3 Theoretically, liver transplantation is the best curative option for HCC but it has limitations in that patients with well-preserved liver function or not satisfying the Milan criteria are not eligible. More important, there is a serious shortage of liver donors. Therefore, hepatectomy and local ablation are still considered to be the main curative treatment options.

In fact, a majority of HCCs are not easy to be detected and diagnosed at the early stage due to a lack of typical symptoms and signs.4–6 Once typical clinical manifestations occur, the disease has usually progressed to an intermediate or advanced stage.7 Even after hepatectomy, the overall survival (OS) of HCC patients remains very poor because of postoperative recurrence and/or metastasis. It has been reported that the 5-year recurrence rate of HCC after curative hepatectomy is not more than 70%.8,9 Even for HCC patients with very early/early stage Barcelona Clinic Liver Cancer (BCLC), the 5-year recurrence rate is 59.3% after hepatectomy and 70.6% after local ablation.10 Therefore, effective preventive measures are urgently needed to reduce recurrence and improve OS after hepatectomy or local ablation.

Many studies have reported the efficacy of various adjuvant therapies in reducing recurrence after hepatectomy or local ablation. Currently, evidence-based medicine in support of adjuvant therapy for HCC is not sufficient, and different countries or regions have different recommendations. In this review, we summarize the existing evidence of adjuvant therapy for HCC after curative hepatectomy or ablation and discuss several urgent dilemmas in adjuvant treatment (Fig. 1).

Follow-up and surveillance, recurrent modality, and adjuvant treatment strategy in patients with hepatocellular carcinoma (HCC) after curative hepatectomy or local ablation.
Fig. 1  Follow-up and surveillance, recurrent modality, and adjuvant treatment strategy in patients with hepatocellular carcinoma (HCC) after curative hepatectomy or local ablation.

ICI, immune checkpoint inhibitor.

Prospective trials, prospective cohort studies, and meta-analyses that explored the efficacy of adjuvant therapies to prevent HCC recurrence in patients following curative hepatectomy or local ablation indexed through December 30, 2023 in the PubMed database (https://pubmed.ncbi.nlm.nih.gov/ ) were identified. The keywords “hepatocellular carcinoma”, “hepatectomy”, “surgery”, “hepatic resection”, “ablation”, “postoperative”, and “adjuvant” were used. Additional papers were identified by manually searching the references of identified studies. Only prospective research and meta-analyses published in English were considered. This review focused on the outcomes of OS and recurrence-free survival (RFS).

Unanswered Questions of Adjuvant Treatment

Who will benefit from adjuvant treatment?

Postoperative adjuvant therapy is necessary because of the high recurrence rate of HCC. However, at present, there is no widely recognized adjuvant treatment modality with clear efficacy. Therefore, it is obviously unreasonable for HCC patients who are tumor-free after curative hepatectomy or local ablation to receive adjuvant therapy. Adjuvant therapy will certainly cause adverse events and increase treatment costs, but it may not significantly reduce the postoperative recurrent rate. Almost all randomized trials that have been published11–13 or are14–16 currently ongoing recruited HCC patients at high risk of recurrence after curative hepatectomy or local ablation. Official guidelines also recommend that HCC patients at high risk of recurrence are eligible to participate in clinical trials and receive adjuvant therapy.2,3,17 Therefore, only patients at high risk of recurrence receive adjuvant therapy.

What are the risk factors for recurrence?

HCC recurrence is generally believed to have two origins. One is the single-center origin in which intrahepatic micro-metastases of the primary tumor or microthrombi before or after hepatectomy. This kind of recurrence usually occurs within 2 years after initial curative treatment, and is termed an early recurrence. The other is the multicenter origin, which occurs late, usually more than 2 years after surgery. Patients with late recurrence have a significantly better prognosis than those with early recurrence, which means that different types of recurrence have different risk factors.18,19 Many studies indicated the main risk factors of early-phase recurrence include tumor size more than 5 cm, multiple tumors, satellites, absence of a tumor capsule, tumor rupture, non-anatomical resection, narrow resection margin (≤2 cm), alpha-fetoprotein ≥400 ng/mL, as well as micro- and macrovascular invasion. In randomized trials, high-risk features for hepatectomy patients included tumor size >5 cm, more than three tumors, microvascular invasion (MVI), macrovascular invasion, and poor tumor differentiation.11–16 Risk factors of late-phase recurrence included liver cirrhosis, higher grade of hepatitis activity, and poor tumor classification.20–22 HCC patients usually have underlying chronic liver disease or cirrhosis caused by chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, alcoholic, or nonalcoholic steatohepatitis.23 They thus always have early and late phase recurrence risk factors.

The existence of high-risk recurrence factors means that the probability of residual tumor in the remanent liver is higher and the possibility of early recurrence is greater, which seriously affects the overall effectiveness of surgical treatment and patient quality of life. Adjuvant therapy after local treatment of HCC aims to reduce the recurrence rate and thus increase RFS and OS. In fact, local (hepatectomy or ablation) and adjuvant treatment can be complementary. On one hand, local treatment reduces tumor burden and induces the release of tumor antigens and pro-inflammatory cytokines. On the other hand, adjuvant immunotherapy and tyrosine kinase inhibitors can boost antitumor immunity. The different risk factors for the two types of recurrence suggest that different targets should be targeted when designing adjuvant therapy. For intrahepatic metastasis, the primary strategy should target disseminated tumor cells that have spread from the primary tumor, just as in transarterial chemoembolization (TACE). For de novo carcinogenesis, the strategy is to control the progression of hepatitis or cirrhosis, as in antiviral treatment.24 The effective elimination of residual tumors or prevention of intrahepatic metastasis with adjuvant therapy can help reduce early recurrence, which may be a reason that adjuvant therapy is more suitable for patients with high-risk factors of recurrence. However, few studies have shown that postoperative antiproliferative and anti-angiogenic therapy reduce latent intrahepatic and extrahepatic spread, which is often associated with the risk of early recurrence.

What are the strategies for adjuvant therapy?

Antiviral therapy

There are multiple goals for antiviral therapy in patients with hepatitis-related HCC. On the basis of comprehensive treatment of HCC, antiviral therapy maximizes long-term inhibition of virus replication, reduces liver damage caused by the virus, prevents disease progression, provides a good basis for liver function, reduces the risk of postoperative recurrence, and ultimately prolongs patient survival.25,26 In HCV-related HCC, sustained viral eradication obtained by interferon-based or interferon-free regimens significantly reduces tumor recurrence without differences associated with the antiviral strategy used.27 However, a meta-analysis showed that recurrence risk and survival were extremely variable in patients with successfully treated HCV-related HCC, providing a useful benchmark for indirect comparison of the benefits of direct-acting antivirals.28 In addition, a high HBV load has been associated with poor RFS and OS in patients with HCC after hepatectomy.21,29 Therefore, antiviral therapy is crucial for preventing postoperative recurrence of HBV- or HCV-related HCC.

Nucleos(t)ide analogs

Several randomized trials reported the positive efficacy of postoperative treatment with nucleos(t)ide analogs for HBV-related HCC, with reduced viral load, decreased tumor recurrence, and improved OS. A meta-analysis of 21 studies including 8,752 patients explored the efficacy of nucleos(t)ide analogs for patients with HBV-related HCC after curative hepatectomy. It found that postoperative nucleos(t)ide analog therapy significantly reduced early recurrence rate and improved OS.30 The use of nucleos(t)ide analogs for postoperative HBV-related HCC is recommended by several HCC treatment guidelines.2,17,31

Nucleos(t)ide analogs include lamivudine, adefovir dipivoxil, entecavir, tenofovir, and others. Previous study found adefovir dipivoxil and lamivudine were associated with similar survival benefits in patients with HBV-related HCC after curative hepatectomy, and that adefovir dipivoxil was more cost-effective.32 Tenofovir has been associated with significantly lower HCC risk than entecavir in patients with chronic HBV infection who are from Asia and/or nucleos(t)ide naïve.33,34 A recent randomized trial including patients with HBV-related HCC after curative hepatectomy, reported that consistent tenofovir therapy was associated with a significantly lower risk of tumor recurrence than entecavir therapy.35 Moreover, when compared with entecavir, tenofovir decreased serum lipoprotein levels in patients with HBV-related HCC.36 Antiviral therapy with tenofovir may thus be the preferred drug for HBV-related HCC after curative treatment.37

Interferon

Many studies reported the safety and efficacy of interferon in the prevention of recurrence after curative hepatectomy for HCC, but with different conclusions. Interferon has various functions such as antiviral replication, antitumor angiogenesis, regulating cell proliferation, immune regulation, and blocking proto-oncogenes. Eight randomized trials reported the safety and efficacy of interferon in preventing postoperative HCC recurrence, of which three enrolled only patients with HCV-related HCC,38–40 one enrolled only HBV-related HCC,41 and the other four included patients with either HBV- or HCV-related HCC.42–45 The reasons for these differences may be heterogeneity of the underlying liver disease and liver reserve function, as well as interferon type, dose, and duration of treatment. A meta-analysis of these eight RCTs concluded that interferon reduced the 2-year recurrence rate and improved the 2-year OS after curative hepatectomy.46 However, another meta-analysis showed that adjuvant interferon was effective in prolonging RFS and OS of HCV-related HCC but not HBV-related HCC, showing that the effectiveness of interferon was different in different populations and viral-related HCC.47 Although adjuvant interferon therapy may be effective, it is associated with many adverse reactions, including fatigue, chills, fever, headache, muscle pain, leukopenia, and thrombocytopenia. Other less common adverse reactions include transaminase elevation and alopecia.

TACE or hepatic arterial infusion chemotherapy

TACE is a key treatment of intermediate-stage HCC. The main purpose of adjuvant TACE is to eradicate tumor cells that may have been released during the intraoperative extrusion and to destroy preexisting microscopic cancer foci that preoperative imaging failed to detect. Randomized trials and retrospective studies with large sample sizes have confirmed that adjuvant TACE reduced the intrahepatic recurrence rate and improved RFS and/or OS after resection.11,12,48 None of these trials included patients who underwent local ablation. A meta-analysis had shown a survival benefit with adjuvant TACE.49 Another meta-analysis including 11,165 patients showed that adjuvant TACE significantly improved RFS and OS compared with curative resection alone. A subgroup analysis showed that adjuvant TACE was more effective in patients with tumor maximum diameters of >5 cm, MVI, and multiple tumors, but had the opposite effects in early HCC patients without MVI, and even decreased RFS.50 The most frequent adverse events of TACE include fever, nausea, ascites, fatigue, leukopenia, and liver function damage. Most patients tolerate it without requiring need symptomatic treatment. All these randomized trials were from China or Japan. The HCC guidelines in Western countries do not recommend adjuvant TACE for HCC.17,51

Hepatic arterial infusion chemotherapy (HAIC) is administered by continuous infusion of chemotherapy drugs into tumor blood vessels with microcatheters. HAIC has the advantages of higher local drug concentration and fewer systemic side effects than systemic chemotherapy. HAIC alone or in combination with immunotherapy or molecular targeted therapy has shown surprising effects in advanced HCC.52–54 A randomized trial enrolled 315 HCC patients with MVI who underwent hepatectomy followed by adjuvant HAIC or routine follow-up. Adjuvant HAIC with FOLFOX significantly improved RFS with acceptable toxicity in HCC patients with MVI.55 However, these findings need to be confirmed by further trials.

During the implementation of TACE and HAIC, digital subtraction angiography (DSA) is required before the drug is injected. DSA can detect residual lesions and determine whether hepatectomy was curative or not. In cases with residual lesions, the purpose of TACE or HAIC is to control residual lesions (so-called recurrence foci). These treatments are not adjuvant therapy. Owing to the absence of DSA detection in the active surveillance group, residual lesions were not found in time. Those who did not achieve genuine curative treatment did not receive TACE or HAIC therapy for residual lesions, and their short-term recurrence rate was significantly higher than that in the treatment group. Although some randomized trials included curative cases, they did not report the specific criteria of “curative”. In addition, those randomized trials did not exclude some cases enrolled after DSA, such as those with residual lesions during imaging. Therefore, the conclusion that adjuvant TACE or HAIC significantly reduced the recurrence rate after curative hepatic resection may not be accurate. If real curative cases were included, positive results might not have been observed. We look forward to RCTs that include genuine curative cases to explore this issue.

Molecular targeted drugs

Whether sorafenib should be used as adjuvant therapy for HCC after curative resection remains controversial. The STORM study explored the safety and efficacy of adjuvant sorafenib treatment of HCC following resection or ablation. The study noted no difference in median RFS in the sorafenib (33.3 months) and placebo groups (33.7 months). Moreover, sorafenib increased the rate of grade 3 or 4 adverse events.13 It is noted that the STORM trial only enrolled a few proportions of patients with a high risk of recurrence. Randomized trials exploring the safety and efficacy of other tyrosine kinase inhibitors (e.g., lenvatinib, apatinib, or donafinib) as adjuvant therapy for HCC after curative hepatectomy are ongoing.

Immunotherapy

Immunotherapy is a therapeutic method of killing tumor cells by stimulating or regulating immune function. Currently, immunotherapy for HCC mainly includes adoptive immunotherapy, immune checkpoint inhibitors (ICIs), tumor vaccines, and others. Several randomized trials have confirmed the safety and efficacy of adjuvant adoptive immunotherapy for patients with HCC after hepatectomy.56–59 These findings were confirmed by meta-analyses.60,61

ICIs are an emerging treatment with great potential for effective treatment of HCC. The success of the IMbrave150 study has laid a solid foundation for the combined use of ICI therapy for advanced HCC.62 A phase II trial with a single arm (n=55) including patients with intermediate or high risk of recurrence who received adjuvant nivolumab had a median RFS of 26 months, but most patients had single tumors with a median diameter of approximately 2.6 cm and no vascular invasion.63 A prospective cohort study included 432 patients receiving no adjuvant therapy (83.6%), 53 (10.2%) who received ICIs alone, and 32 (6.2%) who received adjuvant ICIs plus tyrosine kinase inhibitors. During a median follow-up of 34.0 months, propensity score matching found that RFS and OS were significantly higher in patients who received either type of adjuvant therapy than in those who received no adjuvant therapy. More interestingly, the study found no significant differences in RFS or OS between patients treated with ICIs alone or ICIs with tyrosine kinase inhibitors. The overall study findings imply that ICIs alone or combined with tyrosine kinase inhibitors improved RFS in patients at high risk of HCC recurrence after curative hepatectomy.64 Recently, an interim analysis of IMbrave050 (n=668) reported that at a median follow-up of 17.4 months, adjuvant atezolizumab plus bevacizumab were associated with a significantly lower RFS rate than active surveillance in patients with HCC and a high risk of recurrence (p=0.012). However, the median RFS of both groups had not been reached.65 Longer follow-up is needed to confirm the efficacy of adjuvant atezolizumab plus bevacizumab. Other randomized trials are currently underway, including CheckMate 9DX,14 KEYNOTE-937,15 and EMERALD-216 (Table 1). We are looking forward to the reporting of the trial results.

Table 1

Ongoing phase III clinical trials of adjuvant immune checkpoint inhibitors after hepatectomy or ablation

TrialsClinicalTrials.gov IDSample (n)Tumor statusTreatment armsPrimary endpoint
CheckMate 9DXNCT03383458545High-risk recurrenceNivolumab vs. placeboRFS
EMERALD-2NCT03847428908High-risk recurrenceDurvalumab + bevacizumab vs. durvalumab vs. placeboRFS
IMbrave 050NCT04102098668High-risk recurrenceAtezolizumab + bevacizumab vs. active surveillanceRFS*
KEYNOTE-937NCT03867084950BCLC 0 or APembrolizumab vs. placeboRFS, OS
JUPITER 04NCT03859128402High-risk recurrenceToripalimab vs. placeboRFS
SHR-1210-III-325NCT04639180687High-risk recurrenceCamrelizumab + apatinib vs. active surveillanceRFS

*Interim analysis was reported. BCLC, Barcelona Clinic Liver Cancer; OS, overall survival; RFS, recurrence-free survival.

Systemic chemotherapy

Theoretically, systemic chemotherapy can control tumor growth and reduce recurrence by killing tumor cells in the blood circulation. However, randomized trials did not find carmofur or uracil tegafur significantly improved RFS or OS.66–68 A small randomized trial (n=60) found that postoperative adjuvant capecitabine therapy significantly reduced the risk of tumor recurrence in HCC patients after hepatectomy, but did not improve OS.69 However, a meta-analysis found no significant benefit of adjuvant oral systemic chemotherapy on OS and RFS.70 Moreover, the adverse events of systemic chemotherapy included transaminase elevation, nausea, diarrhea, and bone marrow suppression.

Radiation therapy

Radiotherapy has gradually become one of the main treatment methods for unresectable HCC.71,72 However, the efficacy of adjuvant radiotherapy for HCC after curative hepatectomy remains controversial. A randomized trial (n=119) found that adjuvant radiotherapy was technically feasible and relatively safe for centrally located HCCs after narrow-margin hepatectomy but did not improve RFS and OS.73 A phase II trial included 76 HCC patients who underwent narrow-margin hepatectomy and then received postoperative intensity-modulated radiotherapy. During a median follow-up of 70 months, the 5-year OS and RFS rates were 72.2% and 51.6%, respectively. No marginal recurrence was found. The most common radiation-associated grade-3 toxicity was leukopenia (7.9%).74 A systematic review including 10 studies (three randomized trials, one phase II trial, and six retrospective comparative studies) found adjuvant external beam radiotherapy significantly improved RFS and OS compared with hepatectomy alone.75 Therefore, the current limited evidence showed that adjuvant radiotherapy was a safe and effective measure to prevent HCC recurrence.

A small randomized trial (n=43) found adjuvant intra-arterial iodine-131 labeled significantly improved RFS and OS in patients with HCC after curative hepatectomy.76,77 However, a larger randomized trial (n=103) did not find a clinical benefit of adjuvant iodine-131 for such patients.78 Therefore, the efficacy of adjuvant iodine-131 in HCC needs to be confirmed by more randomized trials with large samples.

Vitamin K2 analogs

Vitamin K2 analogs (VK2) have been shown to induce cell cycle arrest at the G1/S phase leading to growth inhibition of HCC cells and to have potent anti-angiogenic activity, preventing late recurrence.79 Five randomized trials and one cohort study from Japan reported the controversial efficacy of adjuvant oral VK2 in preventing HCC recurrence and improving survival after curative hepatectomy or ablation.80–85 A meta-analysis of. those studies found that adjuvant VK2 analogs reduced short-term tumor recurrence and improved short-term OS.86 It is noted that the included populations were from Japan. The role of VK2 analogs in other countries or regions remains to be explored.

Traditional Chinese medicine

Chen et al.87 performed a multicenter randomized trial of the efficacy of adjuvant Huaier on long-term prognosis after curative hepatectomy. A total of 1,044 patients with HCC after hepatectomy were randomly assigned to receive Huaier or placebo in a 2:1 ratio. RFS was significantly prolonged and extrahepatic recurrence was reduced in the treatment group. The molecular mechanism of Huaier needs further exploration.

When is adjuvant treatment administered?

Although many retrospective or prospective studies have reported the application of adjuvant therapy for HCC, the start time of adjuvant therapy is not uniform. In most randomized trials, the general recommended date of initial adjuvant therapy is 4–8 weeks. The difference between HCC patients and those with other malignant tumors is that HCC develops combined with liver diseases, such as cirrhosis, liver function abnormalities, and others. Therefore, in addition to the recovery of systemic conditions, the date of initial adjuvant therapy for HCC should also be combined with the recovery of postoperative liver function and comorbidities, such as hypertension and diabetes.

Different recommendations for adjuvant therapy in different countries

Although many randomized trials have explored the efficacy of adjuvant therapy, the findings are different, or the same treatment can lead to inconsistent or even opposite findings. Therefore, recommendations for adjuvant therapy differ greatly in the HCC treatment guidelines in different countries (Table 2). There is an East-West consensus regarding the use of nucleos(t)ide analogs for postoperative treatment of patients with HBV-related HCC. The Chinese guidelines recommend adjuvant TACE and Huaier for HCC patients with a high risk of recurrence (Level 1, Strong Recommendation).2 In contrast, the recommendations of HCC guidelines in other countries are conservative. The Korean HCC guidelines recommend adjuvant adoptive immunotherapy after curative hepatectomy88 and the Japanese guidelines only recommend antiviral therapy for patients with viral hepatitis.3 The National Comprehensive Cancer Network guidelines state that no adjuvant therapies have been shown to have benefits but there are ongoing clinical trials.89 The American Association for the Study of Liver Diseases recommends the use of adjuvant ICI-based systemic therapy in patients at a high risk of recurrence after hepatectomy or local ablation (Level 2, Strong Recommendation).17 However, the European Association for the Study of the Liver and the European Society for Medical Oncology do not recommend any adjuvant therapy for HCC.51,90 As medicine evolves and clinical trials are successful, the gaps in the guidelines for adjuvant therapy will be filled.

Table 2

Recommendation of adjuvant therapy for hepatocellular carcinoma in various countries or regions

Treatment optionEASL 2018ESMO 2018AASLD 2023NCCN 2023CNLC 2022JSH 2021KLCA 2022
Nucleoside analogsRoutinely used for hepatitis B virus related hepatocellular carcinoma
InterferonNot recommendedNot recommendedNot recommendedNot recommendedLevel 1, Moderate recommendationNot recommendedNot recommended
TACENot recommendedNot recommendedNot recommendedNot recommendedLevel 1, Strong recommendationNot recommendedNot recommended
HAICNot recommendedNot recommendedNot recommendedNot recommendedExploringNot recommendedNot recommended
TKIsNot recommendedNot recommendedNot recommendedNot recommendedExploringNot recommendedNot recommended
ICIsClinical trialsNot recommendedLevel 2, Strong recommendationClinical trialsExploringNot recommendedNot recommended
Adoptive immunotherapyNot recommendedNot recommendedNot recommendedNot recommendedNot describedNot recommendedCIK cell (Level 2, Strong recommendation)
Systemic chemotherapyNot recommendedNot recommendedNot recommendedNot recommendedNot describedNot recommendedNot recommended
Radiation therapyNot recommendedNot recommendedNot recommendedNot recommendedLevel 2, Moderate/Weak recommendationNot recommendedNot recommended
Vitamin analogs and retinoidsNot recommendedNot recommendedNot recommendedNot recommendedNot describedNot recommendedNot recommended
Heparanase inhibitorsNot recommendedNot recommendedNot recommendedNot recommendedNot describedNot recommendedNot recommended
HuaierNot describedNot describedNot describedNot describedLevel 1, Strong recommendationNot describedNot described

AASLD, American Association for the Study of Liver Diseases; CNLC, China National Liver Cancer; EASL, European Association for the Study of the Liver; ESMO, European Society for Medical Oncology; HAIC, hepatic arterial infusion chemotherapy; ICIs, immune checkpoint inhibitors; JSH, Japan Society of Hepatology; KLCA, Korean Liver Cancer Association; NCCN, National Comprehensive Cancer Network; TACE, transarterial chemoembolization; TKI, tyrosine kinase inhibitor.

There are many reasons why the recommendations of HCC guidelines in different countries or regions may vary greatly. The first is the difference in treatment philosophy. The treatment model recommended by Chinese HCC guidelines presents a multi-treatment model in which one treatment method can be applied to multiple tumor stages. For example, hepatic resection can be applied to stages Ia to IIIa HCC. Tumors of the same stage can receive a variety of treatments. For example, patients with intermediate or advanced HCC can receive transarterial treatment combined with targeting and immunotherapy. In Western guidelines, a combination treatment model is rarely recommended. Second, Western guidelines attach great importance to quality control at the level of evidence. Only high-level evidence-based treatment would be cited in Western guidelines. Finally, most official HCC guidelines, but not those in China, detail each author’s conflict of interest.

Discussion

Although many adjuvant therapies for HCC after hepatectomy or local ablation have been reported, no treatment consensus has been reached. Adjuvant TACE may significantly reduce intrahepatic recurrence and improve OS, but only in patients with a high risk of recurrence, such as tumors >5 cm in diameter, multiple tumors, or those involving micro- or macrovascular invasion.49 It has also been reported that adjuvant HAIC may be beneficial in patients with MVI.55 However, further randomized trials that included genuine curative cases are needed to explore the efficacy of adjuvant TACE or HAIC. A series of randomized trials have shown that antiviral therapy has potential benefits in reducing the recurrence rate and improving RFS and/or OS in patients with viral hepatitis-related HCC after curative hepatectomy or local ablation. Reliable and sufficient high-level evidence has verified this finding. Although the STORM trial reached a negative conclusion, it is not yet possible to conclude that molecular-targeted agents have no role in the adjuvant therapy of HCC. The efficacy of other adjuvant therapies such as radiolabeled lipiodol, radiotherapy, VK2 analogs, retinoids, and heparanase inhibitors has been shown to a certain extent, but they are not routinely used in clinical practice and need to be further verified in large randomized trials. Early trials have found adjuvant immunotherapy has to be effective in HCC. Many randomized trials of adjuvant ICIs in HCC are ongoing, and the results of these trials are worth looking forward to. Although many randomized trials have reported a variety of effective adjuvant treatment options, there are still many open questions worthy of clinical consideration, such as who will benefit most from adjuvant treatment, when adjuvant treatment is administered, which adjuvant treatment options are optimal, how about reliable multiparametric biomarkers of adjuvant therapy response, and so on.91–93 Last but not least, combination regimens, such as TACE or HAIC combined with targeted drugs, ICIs, or radiotherapy, or a combination of targeted agents plus ICIs, is also a direction of adjuvant therapy being explored.94

The purpose of adjuvant therapy is to reduce the risk of postoperative recurrence, thereby reducing the recurrence rate and thus prolonging survival. However, there is no standard stratification of recurrence risk,95,96 and various studies of adjuvant therapy for HCC enrolled populations that differed in recurrence risk. Factors such as viral infection, alpha-fetoprotein level, liver cirrhosis, tumor size, satellite nodules, multiple tumors, and micro- or macrovascular invasion may indicate a high risk of recurrence after hepatectomy or local ablation.22,97 Stratification of high-risk recurrence is also defined differently in different countries, which may lead to significant differences in the effectiveness of different adjuvant treatment regimens and subsequent recommendations in different countries. Integrating these risk factors to identify those at high risk of recurrence and those who could potentially benefit from adjuvant therapy after HCC remains a challenge. In recent years, molecular-targeted drugs and ICIs are emerging and have shown initial efficacy in HCC. In the future, the use of combination therapy such as ICIs combined with molecular targeted drugs and/or TACE will most likely increase.

Abbreviations

BCLC: 

Barcelona Clinic Liver Cancer

HBV: 

chronic hepatitis B virus

HCC: 

hepatocellular carcinoma

HCV: 

hepatitis C virus

HAIC: 

hepatic arterial infusion chemotherapy

ICI: 

immune checkpoint inhibitor

MVI: 

microvascular invasion

OS: 

overall survival

RFS: 

recurrence-free survival

TACE: 

transarterial chemoembolization

VK2: 

vitamin K2 analogs

Declarations

Acknowledgement

We thank the authors of the cited references for their excellent work.

Funding

This work was supported by the Specific Research Project of Guangxi for Research Bases and Talents (GuiKe AD22035057), Guangxi Key Research and Development Plan Project (GuiKe AB24010082), Guangxi TCM appropriate technology development and promotion project (GZSY23-66), and the Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education (GKE-ZZ202217 and GKE-ZZ202311).

Conflict of interest

JHZ has been an Editorial Board Member of Journal of Clinical and Translational Hepatology since 2020. The other authors have no conflict of interests related to this publication.

Authors’ contributions

Conceived the study (JHZ), acquired and analyzed the data (All authors), drafted and revised the manuscript (LL, JHZ), read the manuscript and approved the final version to be published (All authors), and had full access to all the data in the study and serves as guarantor, taking full responsibility for the integrity of the data and the accuracy of the data analysis (JHZ).

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Adjuvant Therapy for Hepatocellular Carcinoma After Curative Treatment: Several Unanswered Questions

Le Li, Zhen-Zhen Li, Li-Xin Pan, Jia-Yong Su, Shan Huang, Liang Ma, Jian-Hong Zhong
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