Postoperative adjuvant management in hepatocellular carcinoma: A review of therapeutic efficacy and prognostic outcomes

Abstract

Primary liver cancer is the sixth most prevalent malignancy worldwide and the third leading cause of cancer-related death. According to the latest data from the National Cancer Center of China, its mortality rate has risen, making it the country’s second-deadliest tumor. Hepatocellular carcinoma (HCC), the predominant histological subtype, remains a substantial therapeutic challenge. Hepatectomy is the treatment of choice for HCC; however, because of its insidious onset and aggressive progression, the global 5-year survival rate is only 14.1%, and up to 70% of patients experience recurrence within five years after surgery. Consequently, reducing postoperative recurrence and prolonging survival have become critical research priorities. Currently, no consensus or guidelines exist regarding the clinical efficacy or potential synergistic effects of diagnostic and therapeutic strategies to prevent postoperative recurrence. In recent years, interest has grown in systemic therapies and combined local modalities - particularly targeted agents and immune checkpoint inhibitors, as adjuvant treatments. This review synthesizes recent advances in targeted and immunotherapeutic adjuvant therapies for postoperative HCC to inform clinical practice and improve patient outcomes.

Key Words: Hepatocellular carcinoma; Recurrence post-surgery; Adjuvant therapy; High risk factors; Molecular targeted therapy; Traditional Chinese medicine; Targeted combination immunotherapy

Core Tip: This article provides a comprehensive evaluation of postoperative adjuvant therapies for hepatocellular carcinoma in patients at high risk of recurrence, detailing the clinical advantages of diverse diagnostic and therapeutic modalities. It highlights the significance and challenges of adjuvant treatment, highlighting the necessity and benefits of multimodal strategies and interdisciplinary collaboration. These insights aim to improve prognosis, extend survival, and inform personalized adjuvant therapy following liver cancer resection.

INTRODUCTION

According to World Health Organization estimates, approximately 900000 new cases of primary liver cancer were diagnosed worldwide in 2020, resulting in about 830000 deaths. China accounted for nearly half of these cases, with 410000 new diagnoses (45.3% of the global total) and 390000 deaths (47.1%), the highest numbers globally[1]. Data from China’s National Cancer Center indicate that hepatocellular carcinoma (HCC) constitutes 7.6% of all cancers, making it the fourth most common malignancy in the country; it is now the second leading cause of cancer related mortality[2]. HCC is the predominant pathological subtype of primary liver cancer, comprising roughly 90% of cases[3]. Surgical resection remains the standard treatment for eligible patients. Although advances in operative technique and perioperative care have improved 5-year survival compared with historical data, the global 5-year survival rate remains only 14.1% because of the tumor’s aggressive biology and late presentation[4]. Postoperative recurrence is also frequent, occurring in up to 70% of patients within five years, with most recurrences arising during the first 2 years after surgery[5]. Wu et al[6] reported similarly unfavorable outcomes, with 27.9% of patients relapsing between years 1 and 3 after resection and 53% experiencing recurrence by year 3. Thus, postoperative recurrence remains the principal barrier to improving HCC prognosis. Strategies that reduce recurrence risk and extend survival are therefore urgent priorities, requiring continued research and clinical innovation.

Postoperative adjuvant therapy seeks to prevent tumor recurrence after curative treatment, thereby improving patient survival[7]. Selecting an appropriate regimen is crucial for reducing recurrence rates and improving long-term outcomes. A Chinese expert consensus recommends individualized adjuvant therapy based on surgical and tumor-related factors to optimize tertiary prevention and improve prognosis[8]. Nevertheless, preventing postoperative HCC recurrence remains a substantial clinical challenge. The efficacy and potential interactions of available adjuvant options have not been fully elucidated, and standardized guidelines are still lacking[9-11].

Recurrence is the principal obstacle to successful HCC management, markedly limiting the benefits of surgery and worsening patient prognosis. Identifying high-risk factors and implementing suitable adjuvant strategies are therefore critical. Recurrence follows a bimodal pattern, peaking at 1-2 years (early recurrence) and again at 4-5 years (late recurrence) after resection[12-14]. Tumor angiogenesis is pivotal in HCC progression and postoperative recurrence (Figure 1) (https://www.cellsignal.cn/). Fukumura et al[15] demonstrated that the vascular endothelial growth factor pathway is central to aberrant tumor angiogenesis and can modulate innate and adaptive immune cell function, leading to immunosuppression. Early recurrence, which accounts for more than 70% of cases, is associated with aggressive disease biology and a poor prognosis[16,17].

Figure 1 Mechanism of tumor angiogenesis. Citation: Ilustration reproduced courtesy of Cell Signaling Technology, Inc. (www.cellsignal.com). The copyright license of Figure 1 is placed in the Supplementary material. Under tumor hypoxia, the hypoxia-inducible factor-1 (HIF-1) dimer remains stable and activates multiple pro-angiogenic genes. This pathway stimulates tumor vascularization and progression through enhanced blood supply formation. Tie2: Tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domains 2; EPH: Erythropoietin-producing hepatocellular; ROBO: Roundabout; FGFR: Fibroblast growth factor receptor; VEGFR2: Vascular endothelial growth factor receptor 2; PDGFR: Platelet-derived growth factor receptor; MMPs: Matrix metalloproteinases; Ets2: E26 transformation-specific 2; HIF-1: Hypoxia-inducible factor-1; Akt: Protein kinase B; Stat3: Signal transducer and activator of transcription 3; Erk: Extracellular signal-regulated kinase; 4E-BP1: Eukaryotic translation initiation factor 4E-binding protein 1; PHD: Prolyl hydroxylase domain-containing protein; CBP: CREB-binding protein; eIF4E1: Eukaryotic translation initiation factor 4E1; HRE: Hypoxia-responsive element; PDGF: Platelet-derived growth factor; SLIT: Slit guidance ligand; VEGF: Vascular endothelial growth factor.

Three broad categories of recurrence risk factors have been identified: Tumor-related characteristics, surgical variables, and patient-specific features. Early recurrence is primarily linked to tumor biology and surgical parameters, whereas late recurrence is more closely associated with the status of the underlying liver disease. Key independent predictors of early recurrence include large tumor diameter (> 5 cm), portal vein thrombosis, microvascular invasion (MVI), and peritumoral infiltration[18-22]. Additional established contributors are multifocal tumors, poor differentiation (Edmondson III/IV), lymphnode metastasis, a narrow surgical margin (≤ 1 cm), and persistently elevated α-fetoprotein levels. Risk factors for late recurrence relate chiefly to hepatic condition and patient demographics: Advanced age (> 60 years); hepatitis B surface antigen positivity; active viral hepatitis; hypoalbuminemia; and advanced fibrosis (Ishak score > 6)[23-29].

POSTOPERATIVE ADJUVANT THERAPY STRATEGIES

To date, convincing evidence that adjuvant therapy can prevent postoperative HCC recurrence or metastasis is lacking. Nonetheless, several modalities are in use, and multiple promising approaches are under active investigation. Current research focuses on systemic antitumor agents - such as targeted drugs and immune checkpoint inhibitors (ICIs) - and localized treatments, including transarterial chemoembolization (TACE) and radiotherapy, evaluated both individually and in combination. When selecting an adjuvant regimen, clinicians should weigh safety, efficacy, adverse event profiles, and real-world data. Muñoz-Martínez et al[30] emphasized that therapeutic choices can vary among physicians, depending on their prioritization of these factors (Figure 2).

Figure 2 Hepatocellular carcinoma treatment options[30]. This schematic illustrates key clinical considerations influencing treatment selection and their relative prioritization among physicians. The left panel depicts decision factors (represented as spheres), with connecting lines indicating individual practitioners’ (P1, P2, ...Pn) priority sequences for hepatocellular carcinoma management. The bottom legend (n^X) denotes the exponential growth of possible therapeutic combinations. The right panel demonstrates how final treatment plans emerge from integrated evaluations of clinical guidelines, patient-specific parameters, local resource availability, and health literacy considerations. Citation: Muñoz-Martínez S, Iserte G, Sanduzzi-Zamparelli M, Llarch N, Reig M. Current pharmacological treatment of hepatocellular carcinoma. Curr Opin Pharmacol 2021; 60: 141-148. Copyright© The Authors 2025. Published by Elsevier Ltd. (https://s100.copyright.com/AppDispatchServlet?publisherName=ELS&contentID=S1471489221001028&orderBeanReset=true).

TACE

TACE is a widely used locoregional therapy for intermediate to advanced stage HCC, yet its efficacy as an adjuvant treatment after curative resection remains uncertain. Large studies suggest that prophylactic TACE may improve disease-free survival (DFS) in high-risk patients, particularly those with MVI or a substantial tumor burden[31]. For example, Wang et al[32] reported that postoperative TACE reduced recurrence by 33% and mortality by 41% in patients with MVI, multiple tumors, or single tumors > 5 cm compared with surgery alone. Likewise, Wei et al[33] found that adjuvant TACE significantly prolonged both median recurrence free survival (RFS) and overall survival (OS) in patients with solitary nodules and concomitant MVI.

Conversely, other evidence calls these benefits into question. In a 2020 prospective randomized controlled trial (RCT), Hirokawa et al[34] allocated 114 resected HCC patients to adjuvant TACE (n = 55) or observation (n = 59) and observed no significant difference in DFS at 1, 3, and 5 years (82%, 55%, and 40% vs 75%, 48%, and 35%; P > 0.05). In contrast, Luo et al[35] analyzed a large retrospective cohort (n = 1505) with propensity score matching (PSM) and showed that TACE significantly improved DFS and OS in patients with MVI (all P < 0.001). Using a similar PSM design, Bai et al[36] confirmed in 2023 that adjuvant TACE is an independent prognostic factor for favorable outcomes after resection.

Growing evidence shows that adjuvant TACE lowers recurrence rates and extends survival in HCC patients with high-risk features, and emerging data suggest that combining TACE with systemic agents may further enhance outcomes in this population.

Hepatic arterial infusion chemotherapy

The 2023 Chinese expert consensus[8] recommends hepatic arterial infusion chemotherapy (HAIC) with a folinic acid, fluorouracil, and oxaliplatin regimen as an effective adjuvant to TACE, reporting significant improvements in RFS among patients with MVI. Folinic acid, fluorouracil, and oxaliplatin - suppresses tumor cell proliferation through the synergistic activity of its three components. Supporting evidence from He et al[37] indicates that HAIC increases surgical resectability and reduces recurrence in early-to-intermediate stage HCC; when combined with resection, HAIC also significantly improves OS. Although these findings are encouraging, the evidence base remains limited because few clinical studies have assessed HAIC in the postoperative setting.

Radiotherapy

Radiofrequency ablation (RFA) is a minimally invasive thermal technique that destroys tumors through localized heating. Approved by the Food and Drug Administration in 1997 for hepatic indications, RFA has become the first-line ablative therapy worldwide for both primary and metastatic liver malignancies[38]. Clinical studies show 5-year survival rates of 60.2%-64% for early-stage HCC (≤ 3 cm), with 10-year survival reaching 27.3%[39,40]. Optimized protocols now extend their use to the management of locally advanced disease[41].

Current evidence for adjuvant postoperative radiotherapy in HCC is limited and inconclusive. Few RCTs have assessed this approach, and results have been inconsistent. A retrospective analysis by Zhu et al[42] indicated that radiotherapy might prolong RFS and OS, but these findings require validation. In a comprehensive meta-analysis, Wang et al[43] pooled data from three RCTs, one phase 2 trial, and six retrospective studies, demonstrating improved DFS and OS, particularly in patients with narrow surgical margins, MVI, or portal vein tumor thrombosis. Although these observations suggest potential value for adjuvant radiotherapy, important knowledge gaps remain.

Paradoxically, some evidence indicates that RFA itself may increase the risk of HCC recurrence. In addition to residual micro metastases, hypoxia-driven pathways triggered after ablation can enhance tumor invasiveness[44,45]. Radiotherapy for HCC has evolved from whole-liver irradiation to precision modalities such as three-dimensional conformal radiotherapy, intensity-modulated radiotherapy, volumetric-modulated arc therapy, and stereotactic body radiotherapy[46,47]. Clinical evidence demonstrates: (1) Three-dimensional conformal radiotherapy: A 52 Gy regimen achieves 73.6%/43.7%/33.3% 1-/3-/5-year OS in ≤ 10 cm advanced HCC[48]; (2) Intensity-modulated radiotherapy enables homogeneous dose distribution for tumors ≤ 7.9 cm in diameter[49]; (3) Volumetric-modulated arc therapy improves target conformality while limiting overdose to surrounding tissue through continuous gantry rotation[50]; and (4) Stereotactic body radiotherapy delivers ablative doses, producing 1 and 2 years progression-free survival rates of 97.4% and 83.8%, respectively, in advanced HCC[51]. Future investigations should refine radiotherapy protocols and establish long term efficacy in rigorously designed clinical trials.

Molecular targeted therapy

The therapeutic landscape of HCC shifted in 2007 with the approval of sorafenib, inaugurating molecular targeted therapy. Subsequent agents - regorafenib, lenvatinib, and cabozantinib - have further expanded treatment options. Llovet et al[52] summarized the mechanisms of these agents and their efficacy in advanced HCC. Although sorafenib, lenvatinib, donafenib, and regorafenib confer survival benefits in unresectable disease[53-57], their value as adjuvant therapy after curative resection remains uncertain.

The phase 3 STORM trial[58] found no significant difference in RFS between sorafenib (33.3 months) and placebo (33.7 months; P = 0.26); however, 92% of participants had single tumors ≤ 3.5 cm, 68% lacked MVI, and median α-fetoprotein was < 6.0 μg/L - features that may account for the negative result (Table 1). Emerging data suggest targeted therapy benefits certain high-risk subgroups. Zhang et al[59] reported longer median OS with sorafenib in MVI-positive patients (32.4 months vs 25.0 months; P = 0.046), though the RFS difference was not significant. In a PSM analysis of 293 MVI positive patients, Bai et al[60] showed that lenvatinib reduced 6 months recurrence (15.9%/43.2% vs 40.1%/57.2%; P = 0.002) and improved survival (85.8%/71.2% vs 69.6%/53.3%; P = 0.009). Apatinib, a selective vascular endothelial growth factor receptor 2 inhibitor, also improved outcomes in patients with portal vein thrombosis[61]. Finally, a single-arm study by Zhou et al[62] demonstrated encouraging lenvatinib activity, with a median RFS of 16.5 months and a 1-year RFS rate of 50.5%, accompanied by acceptable tolerability[62].

Table 1 Adjuvant therapy with molecular targeting and Immunotherapy after hepatocellular carcinoma surgery.

Ref.	Drug	Type of trial	Primary end point	Result
Molecular targeted therapy
Bruix et al[58], 2015	Sorafenib	A phase 3, randomised, double-blind, placebo-controlled trial	RF	mRFS: 33.3 m
Zhang et al[59], 2014	Sorafenib	Single-center retrospective analysis	RFS and OS	RFS: 11.7 m
				OS: 32.4 m
Bai et al[60], 2022	Lenvatinib	A retrospective analysis	Recurrence and survival rates	1-year, 2-year recurrence rate: 15.9%, 43.2%
				1-year, 2-year survival rate: 85.8%, 71.2%
Sun et al[6], 2020	Apatinib	Single-center, open-label, phase II trial	RFS and OS	mRFS: 7.6 m
				1-year RFS and OS: 36.1%, 93.3%
Zhou et al[62], 2022	Lenvatinib	A multi-center, single-arm, prospective clinical trial	RFS	mRFS: 16.5 m
Immunotherapy
Kudo et al[65], 2022	Nivolumab	Multi-center, single-arm clinical trial	1-year RFS	1-year RFS: 78.6%
Zhang et al[66], 2023	Anti-PD-1 antibodies include camrelizumab, toripalimab, sintilimab, and pembrolizumab	Retrospective study	OS and RFS	The 1-year, 2-year, 3-year, and 4-year OS rates: 93.1%, 86.8%, 78.2%, and 51.1%
				The 1-year, 2-year, 3-year, and 4-year RFS rates: 81.7%, 77.0%, 52.3%, and 23.1%
Wang et al[67], 2024	Sintilimab	A multicenter, open-label, randomized, controlled, phase 2 trial.	RFS	mRFS: 27.7 m
Xu et al[68], 2023	Pembrolizumab, tislelizumab, sintilimab, camrelizumab, and toripalimab	A retrospective, multicenter, PSM analysis	RFS and OS	mRFS: 29.6 m mOS: 35.1 m
Targeted combination immunotherapy
Qin et al[74], 2023	Atezolizumab, bevacizumab	A randomised, open - label, multicentre, phase 3 trial	RFS	1-year RFS: 78%
Xia et al[75], 2022	Camrelizumab, apatinib	A single-arm, open label, phase II clinical trial	RFS	1-year RFS: 53.85%
Wang et al[76], 2023	C + A	Retrospective cohort study	RFS and OS	mPFS: C + A: 14.0 m, C + L: 18.0 m, C + S: 12.0 m
	C + L			mOS: C + A: 17.0 m, C + L: 19.0 m, C + S: 15.0 m
	C + S

PD-1: Programmed death 1; PSM: Propensity score matching; RFS: Recurrence free survival time; OS: Overall survival; C + A: Camrelizumab + apatinib; C + L: Camrelizumab + lenvatinib; C + S: Camrelizumab + sorafenib; mRFS: Median recurrence-free survival; mOS: Median overall survival.

However, most available evidence comes from small retrospective series. Although high-quality trials that directly demonstrate a survival benefit are still lacking, the existing data suggest that these agents may offer meaningful clinical value as adjuvant therapy for carefully selected high-risk patients.

Immunotherapy

Immunotherapy, particularly programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors such as nivolumab, pembrolizumab, and atezolizumab, has reshaped HCC treatment by enhancing immune recognition of tumor cells. Clinical trials (CheckMate040, KEYNOTE224) have shown significant survival benefits in advanced disease, and emerging evidence indicates potential in the adjuvant setting. Huang et al[63] reported that ICIs activate effector T cells, promote vascular normalization, reduce immunosuppression within the tumor microenvironment, and further enhance T cell infiltration and function. Chen and Mellman[64] demonstrated that blocking the PD1/PDL1 axis restores antitumor immunity.

In a phase 2 study (UMIN000026648), adjuvant nivolumab achieved a 78.6% 1-year RFS rate and a median RFS of 26.3 months in high-risk patients[65]. In a PSM analysis of 46 patients, Zhang et al[66] showed superior outcomes with PD-1 blockade vs standard care: 1 to 4year OS rates were 93.1%/86.8%/78.2%/51.1% vs 85.3%/70.2%/47.7%/30.0% (P < 0.001), and RFS rates were 81.7%/77.0%/52.3%/23.1% vs 68.4%/47.7%/25.8% (P < 0.001).

Collectively, these findings highlight immunotherapy as a potentially transformative option for both advanced and postoperative HCC management, although further validation in large, randomized trials is warranted.

Wang et al[67] conducted a multicenter, randomized phase 2 trial showing that adjuvant sintilimab nearly doubled the median RFS compared with observation (27.7 vs 15.5 months; P = 0.002). In a prospective, PSM analysis, Xu et al[68] reported superior median RFS with immunotherapy (29.6 vs 19.3 months; P = 0.031); improved OS (35.1 vs 27.8 months; P = 0.036); and multivariate analysis confirmed immunotherapy as an independent prognostic factor for RFS (P = 0.015) and OS (P = 0.013).

The heterogeneous clinical efficacy of ICIs is largely attributed to therapeutic resistance. Primary resistance mechanisms include[69-71]: (1) Tumor-intrinsic upregulation of checkpoint molecules (PD-L1, cytotoxic T-lympocyte antigen-4, lymphocyte-activation gene 3 protein, T cell immunoglobulin domain and mucin domain-3, T cell immunoreceptor with Ig and ITIM domains), enabling immune evasion; and (2) ICI-induced reductions in tumor-infiltrating lymphocytes. In HCC, elevated T cell immunoglobulin domain and mucin domain-3 expression correlates with poor prognosis. The immunosuppressive hepatic tumor microenvironment contains abundant regulatory T cells that suppress CD8+ T-cell activity both directly and through cytokine signaling, thereby fostering tumor progression.

Current evidence indicates that immunotherapy holds promise as an adjuvant strategy for HCC, but most data originate from small retrospective studies. These preliminary findings must be validated in large, multicenter prospective trials to confirm therapeutic efficacy and optimize treatment protocols.

Combination therapy

Targeted combination immunotherapy: Current clinical evidence, exemplified by the ORIENT-32[72] and IMbrave150[73] studies, demonstrates that combining targeted therapy with immunotherapy significantly improves RFS and OS in patients with advanced, unresectable HCC. Nevertheless, data on the efficacy of this approach as postoperative adjuvant therapy for HCC patients at high risk of recurrence remain limited. The landmark IMbrave050 study[74] - the first international trial to evaluate postoperative adjuvant targeted immunotherapy in HCC - yielded encouraging findings. In this trial, high-risk patients received either 12 months of adjuvant atezolizumab plus bevacizumab or observation alone. The combination arm achieved a significantly higher 1-year RFS rate (78%) than the control arm (P = 0.012). Although median survival endpoints were not reached because of limited follow-up, IMbrave050 represents the first positive trial of adjuvant targeted immunotherapy in HCC.

Camrelizumab is an antitumor agent developed independently in China. It belongs to the immunoglobulin CD28/B7 superfamily and comprises 288 amino acids. As a type I transmembrane protein, its extracellular segment contains an extracellular domain, a hydrophobic hinge region, and a cytoplasmic tail, together functioning as an immunosuppressive receptor. Xia et al[75] conducted a phase 2 single-arm study evaluating adjuvant apatinib plus camrelizumab in postoperative HCC patients at high risk of recurrence; the trial reported a 1-year RFS rate of 53.85%. Subgroup analysis indicated greater benefit in patients with smaller tumor diameters. Wang et al[76] performed a comprehensive retrospective analysis comparing four adjuvant regimens: Camrelizumab monotherapy: Objective response rate (ORR): 17.2%; disease control rate%, disease control rate(DCR): 72.0%; median PFS: 11.0 months; median OS: 13.0 months; camrelizumab + apatinib: ORR: 44.6%; DCR: 81.8%; median PFS: 14.0 months; median OS: 17.0 months; camrelizumab + lenvatinib: ORR: 47.9%; DCR: 85.5%; median PFS: 18.0 months; median OS: 19.0 months (most favorable outcomes); and camrelizumab + sorafenib: ORR: 36.3%; DCR: 77.9%; median PFS: 12.0 months; median OS: 15.0 months.

Several multicenter RCTs are investigating combination immunotherapy for HCC patients at high risk of recurrence after radical resection: Ongoing studies include durvalumab plus bevacizumab (EMERALD-2, NCT03847428); sintilimab plus bevacizumab (DaDaLi, NCT04682210); camrelizumab plus apatinib (SHR1210-III-325, NCT04639180); and tislelizumab plus sitravatinib (NCT05564338).

TACE combined with immunotherapy: Recent evidence supports the use of combination adjuvant therapies. Huang et al[77] conducted a PSM retrospective analysis of patients with giant HCC treated with either TACE + PD-1 inhibitor or TACE alone. The combination group showed higher RFS at 1 year: 49.9% (combination) vs 24.7% (TACE alone); 2 years: 35.7% vs 15.5% (P < 0.05); OS: 1 year: 83.6% vs 50.6%; 2 years: 66.9% vs 36.8% (P < 0.05). Liang et al[78] retrospectively compared three adjuvant strategies for HCC with MVI: Lenvatinib monotherapy, TACE alone, and TACE plus Lenvatinib - and found that the combination regimen yielded superior 5 years RFS and OS relative to no adjuvant therapy and to either monotherapy. Although current data suggest clinical benefits from integrating local therapy (TACE) with systemic agents (targeted therapy or immunotherapy) after resection, prospective studies are needed to validate these findings and optimize treatment protocols.

CHEMOTHERAPY

Research on postoperative adjuvant chemotherapy for HCC remains limited. Zhu et al[42] evaluated several chemotherapy regimens, including capecitabine, tegafur/uracil, and epirubicin plus carmofur - across multiple RCTs. Pooled analyses showed that adjuvant chemotherapy did not significantly improve OS. Capecitabine, however, prolonged RFS in patients with hepatitis B virus-associated HCC, whereas the other regimens did not. Overall, adjuvant chemotherapy appears to provide only a modest benefit after HCC resection, highlighting the need for further investigation.

TRADITIONAL CHINESE MEDICINE

Huaier granule, a fungal extract preparation, has demonstrated clinical activity as either monotherapy or combination therapy in several malignancies, including breast, colon, gastric, and lung cancers; HCC; leukemia; and osteosarcoma[79]. Its active proteoglycan fraction consists of 41.5% polysaccharides, 12.93% amino acids, and 8.72% water. Mechanistically, Huaier granule modulates innate immunity by inducing cytokine release and reactive oxygen species/nitric oxide production and exerts antitumor effects by triggering G0/G1 cell cycle arrest and inhibiting angiogenesis[80-82].

Chen et al[83] conducted the first multicenter, randomized, open-label clinical trial in China to evaluate Sophora granules as adjuvant therapy after HCC resection. Participants mixed 20 g of Sophora granules with 100 mL of water and took the preparation orally three times daily for 2 years. The Sophora group achieved a significantly longer mean RFS (75.5 weeks vs 68.5 weeks, P = 0.0001). OS was also higher (95.19% vs 91.46%, P = 0.0207), and the extrahepatic recurrence rate was lower (8.60% vs 13.61%, P = 0.0018). This trial provides the first clinical evidence that Sophora granules can prolong RFS and reduce extrahepatic recurrence after HCC surgery. Supporting these findings, another study[84] reported that Huachansu (a traditional Chinese medicine) likewise improved RFS and OS following resection. Collectively, these preliminary data suggest that traditional Chinese medicine may offer benefits as adjuvant therapy for HCC.

ADOPTIVE IMMUNOTHERAPY

Adoptive immunotherapy (AIT) improves the prognosis of HCC by activating immune responses against tumor cells. Current AIT strategies primarily employ lymphokine-activated killer (LAK) cells and cytokine-induced killer (CIK) cells[85]. These approaches restore cellular immunity and exert antitumor activity. Although AIT is used as an adjuvant therapy after curative treatment for HCC, its clinical efficacy remains controversial.

Evidence on adjuvant LAK therapy is mixed. Kawata et al[86] reported comparable 1-/2-/3-year survival rates (91.7%, 82.9%, and 72.5%, respectively) between LAK-treated patients and controls, concluding that AIT conferred limited postoperative benefit. In contrast, two independent trials demonstrated significant reductions in recurrence and mortality with AIT and documented 100% five-year survival in the treatment groups[87,88]. These studies also found a lower micrometastatic burden in immunotherapy recipients than in controls. A meta-analysis of eight RCTs by Zhao et al[89] showed that AIT significantly decreased 1-/2-/3-year recurrence and mortality rates, although no advantage was seen at five years. Notably, the analysis attributed therapeutic effects mainly to CIK rather than LAK cells.

Two additional investigations confirmed the efficacy of CIK therapy in HCC. In a multicenter phase III trial, Lee et al[90] reported a significantly longer median relapse-free survival in CIK-treated patients than in controls (44.0 months vs 30.0 months; P < 0.05), supporting the role of adjuvant CIK therapy in preventing postoperative recurrence. Similarly, Yu et al[91] prospectively analyzed 132 patients with advanced HCC and observed higher 1-/2-/3-year OS rates in the CIK group than in controls (all P < 0.05), with manageable treatment-related adverse events.

CONCLUSION

Postoperative adjuvant therapy for HCC remains an active field of investigation, but substantial controversies and challenges persist. To date, no universally accepted regimen reliably prevents recurrence and metastasis, and the optimal strategy is still debated. A primary challenge is accurately identifying patients at high risk for relapse - a group most likely to benefit from adjuvant treatment. Emerging evidence suggests that triple-agent combinations may surpass dual-agent regimens; however, adding additional agents does not automatically translate into superior outcomes. Further studies are required to refine such combinations. Future work should prioritize: (1) Individualizing therapy according to each tumor’s molecular and clinical profile; and (2) Discovering biomarkers that predict treatment response. These advances will improve patient selection and enhance the efficacy of perioperative and adjuvant interventions.