INTRODUCTION

It is reported that hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide and the most common cause of death in cirrhotic patients.¹ The recurrence or overall survival (OS) of HCC is closely determined by HCC stage, underscoring the critical importance of early detection.² In contrast to poor prognosis in patients with advanced HCC such as a median survival of 1-3 years, surgical resection or liver transplantation can extend a median survival beyond 5 years in early-stage disease.³ In spite of the curative intent of surgical approaches, recurrence rates remain high up to 60-70% within 5 years, and patients who HCC recurred experience significantly poorer prognosis as compared to those who remain recurrence-free.⁴

In many other types of cancers such as pancreatic,⁵ breast,⁶ lung,⁷ and colorectal cancers,⁸ neoadjuvant therapy has shown significantly better outcomes after resection. Unfortunately, for HCC, neoadjuvant therapy has not yet been proved because of the historically limited efficacy of systemic therapies with adequate safety and efficacy profiles. Furthermore, in the adjuvant setting, the STORM trial in 2015 did not show that sorafenib improved recurrence-free survival (RFS) compared to control the group.⁹ However, in 2019, atezolizumab plus bevacizumab was the first systemic therapy to show better OS compared to sorafenib in the IMBrave150 trial, achieving a median survival of 19 months and an objective response rate (ORR) of 30%, compared to 13.4 months and 11%, respectively, for sorafenib.¹⁰ Similarly, the HIMALAYA trial showed that durvalumab plus tremelimumab significantly improved survival compared to sorafenib with a median OS of 16 months and showed durable responses with 25% of patients surviving beyond 4 years.¹¹ These breakthroughs of systemic therapies have evoked interests in evolving roles of systemic therapies in earlier disease stages such as neoadjuvant, adjuvant, perioperative therapy or down-staging approaches. This review summarizes the rationale, available evidence, ongoing clinical trials, and considerations for incorporating systemic therapies into the neoadjuvant and adjuvant strategies for HCC.

RATIONALES FOR NEOADJUVANT OR ADJUVANT THERAPY

Preclinical investigations across multiple cancer types indicate that administering immunotherapy prior to surgical resection may enhance therapeutic efficacy. This approach leverages the presence of an intact tumor to improve neoantigen presentation, facilitate dendritic cell activation, and promote immune-mediated eradication of both macroscopic and micrometastatic disease.^12-14 Compared to the adjuvant setting, neoadjuvant immunotherapy is hypothesized to elicit a more pronounced and durable immune response, potentially resulting in superior long-term clinical outcomes.

Neoadjuvant immunotherapy offers several advantages that underscore its potential clinical utility. By reducing tumor burden, it may enable less extensive surgical resection, thereby minimizing surgical morbidity and expediting postoperative recovery. Moreover, initiating an antitumor immune response at an earlier stage -when tumor burden is lower and immune competency remains relatively intact- could confer more durable therapeutic benefits. A further key advantage of neoadjuvant therapy is its potential to eliminate micrometastatic disease at an early stage, as undetected malignant clones represent a major driver of postoperative recurrence. Additionally, the neoadjuvant setting presents a unique opportunity to evaluate real-time immune responses to immune checkpoint inhibitors (ICIs), a particularly relevant consideration in HCC, where predictive biomarkers for immunotherapy response remain insufficiently established.

Similar to the rationale underpinning neoadjuvant therapy, adjuvant systemic therapy aims to mitigate recurrence risk following curative-intent treatment.¹⁵ The demonstrated efficacy of cytotoxic chemotherapy in eradicating residual microscopic disease has led to its widespread adoption in malignancies such as breast, lung, and colorectal cancers. Patient selection criteria for adjuvant therapy have been progressively refined based on established oncologic risk factors, including tumor size, histologic differentiation, surgical margin status, and molecular subtypes.

Despite the well-defined predictors of early recurrence in HCC -such as larger tumor size, multiplicity, microvascular invasion, elevated alpha-fetoprotein levels, and poor differentiation- there has historically been a lack of effective adjuvant therapies with proven clinical benefit. The rationale for adjuvant ICI therapy is particularly compelling given the observed correlation between programmed death-ligand 1 (PD-L1) expression, immune evasion mechanisms, and poor postoperative outcomes. The postoperative setting offers distinct advantages for the implementation of immunotherapy, including the confirmation of complete tumor resection and the opportunity to perform histopathologic risk stratification to inform treatment decisions.

POTENTIAL RISKS OF NEOADJUVANT THERAPY

Neoadjuvant therapy is conceptually distinct from the downstaging strategy, as it entails the administration of systemic therapy prior to surgical resection in patients initially deemed resectable. In contrast, down-staging aims to render unresectable cases surgically eligible by reducing tumor burden. A primary concern associated with neoadjuvant therapy is the potential for HCC progression during treatment, which could preclude curative resection in patients who were initially surgical candidates. However, it remains uncertain whether immediate surgical resection would yield superior outcomes in such cases or whether neoadjuvant therapy may instead spare certain patients from highly morbid surgical interventions. Additionally, the risk of immune-related adverse events must be carefully considered, as severe complications could delay surgery or, in some instances, render it unfeasible. Nonetheless, recent neoadjuvant trials have demonstrated promising outcomes, reporting a low disease progression rate of 7% and minimal surgical delays among 86 patients receiving neoadjuvant therapy, suggesting that appropriate patient selection can mitigate these risks.^16-19

Furthermore, patients who develop recurrent HCC following neoadjuvant immunotherapy may harbor immune-resistant tumor clones, complicating subsequent therapeutic strategies. In alignment with these concerns, the American Association for the Study of Liver Diseases recommends transitioning to second-line therapies, including tyrosine kinase inhibitors (TKIs) or combination immunotherapies, for patients who experience early recurrence following treatment with atezolizumab plus bevacizumab.²⁰ These unresolved challenges such as disease progression during neoadjuvant therapy, immune resistance, and therapy-related toxicity, underscore the critical need for further research to refine patient selection criteria, optimize therapeutic regimens, and elucidate the long-term efficacy of neoadjuvant strategies in HCC management.

CLINICAL EVIDENCE SUPPORTING NEOADJUVANT THERAPY IN HCC

Several recent studies have evaluated the safety, feasibility, and efficacy of neoadjuvant immunotherapy in HCC.^16-19 In these investigations, patients underwent programmed death-1 (PD-1)-based therapy for approximately 2-3 months prior to surgical resection. Although definitions of pathological response varied across studies, the reported pathological response rates ranged from 20% to 33%, depending on the therapeutic regimen. These included PD-1 inhibitors combined with TKIs (nivolumab plus cabozantinib), PD-1 monotherapy (nivolumab or cemiplimab), and dual checkpoint blockade targeting PD-1 and cytotoxic T-lymphocyte-associated protein 4 (nivolumab plus ipilimumab). Among these approaches, nivolumab plus ipilimumab demonstrated remarkable OS in the European Society for Medical Oncology (ESMO) Congress 2024.²¹ In this study, 60.5% of the total population (n=43) had Barcelona Clinic Liver Cancer (BCLC) stage C disease, with a median tumor size of 8.7 cm. Three patients exhibited early progression after one cycle of nivolumab plus ipilimumab, while 60% proceeded to surgery following four cycles of treatment. A major pathological response was achieved in 33% of patients, with estimated 2-year progression-free survival and OS rates of 47.1% and 72.0%, respectively.

A key finding across these studies is the ability of neoadjuvant immunotherapy to reshape the tumor immune microenvironment, enhancing immune infiltration and promoting the formation of tertiary lymphoid structures in patients who achieve a pathological response. Notably, the clinical trial investigating nivolumab plus cabozantinib included patients traditionally deemed ineligible for surgical resection due to major vascular invasion or multifocal disease. Despite these high-risk features, patients who exhibited a pathological response demonstrated favorable long-term outcomes, suggesting that neoadjuvant immunotherapy may expand the cohort of patients eligible for curative-intent resection beyond those classified as BCLC stage A.³ The underlying rationale is that a significant pathological response in the primary tumor reflects the successful induction of systemic antitumor immunity and a reduced micrometastatic disease burden, potentially delaying or preventing recurrence.

In a phase II trial, the efficacy of neoadjuvant therapy with TKIs, specifically lenvatinib, was evaluated in patients with advanced HCC (LENS-HCC trial).²² Patients underwent assessment for resectability after 8 weeks of lenvatinib therapy, with resection performed if the tumor was deemed technically resectable. The ORR was 37.5%, and 76.2% of patients underwent surgical resection. The median RFS was 7.2 months.

A prospective, randomized, open-label pilot study (PLENTY trial) examined the efficacy of pembrolizumab plus lenvatinib in patients with HCC exceeding the Milan criteria.²³ With a median follow-up of 37.1 months and a median of four treatment cycles, the 30-month tumor-specific RFS was 37.5% in the pembrolizumab plus lenvatinib group compared to 12.5% in the control group.

Another prospective, single-arm phase II trial investigated the combination of systemic therapy with transarterial chemoembolization (TACE) in 29 patients. In this study, patients underwent a single TACE session on day 1, followed by initiation of tislelizumab and lenvatinib within 7-10 days post-TACE. Surgical resection was performed 8 weeks after treatment. A major pathological response was achieved in 76.9% of patients, with 15.4% exhibiting complete pathological response. At a median follow-up of 8.0 months, the 12-month RFS was 82.5%.²⁴

Similarly, a retrospective multicenter study assessed the efficacy of lenvatinib plus anti-PD-1 antibodies in combination with TACE.²⁵ Patients in this study had large tumors (>10 cm in 74% of cases) and a high incidence of portal vein tumor thrombosis (47%). Among the total population, 81% had BCLC stage B or C disease. TACE was performed initially, followed by the administration of lenvatinib in combination with various anti-PD-1 antibodies. During a median follow-up period of 19.3 months, the 3-year RFS was significantly higher in the triple-therapy group (52%) compared to the control group (30%, P=0.015). Key clinical studies on neoadjuvant therapy for HCC were summarized in Table 1.

While these findings are promising, they are derived from small cohorts, necessitating larger randomized clinical trials to establish the definitive role of neoadjuvant immunotherapy in HCC management. Robust data from phase III trials will be essential to determine whether neoadjuvant approaches should be incorporated into standard clinical practice.

EVALUATION OF ENDPOINTS: RFS vs. OS

Recurrence remains a principal determinant of survival, and therapies that effectively mitigate recurrence risk are anticipated to enhance OS. However, OS outcomes are particularly susceptible to treatment crossover effects, complicating direct comparisons between therapeutic strategies. To quantify the incremental benefit of adjuvant immunotherapy in oncologic outcomes, clinical trials commonly employ surrogate endpoints such as RFS and time to recurrence.²⁶ Although both metrics are utilized to assess therapeutic efficacy, they capture distinct aspects of disease progression. RFS considers both recurrence and all-cause mortality as events, whereas time to recurrence exclusively measures the interval until tumor recurrence, independent of noncancer-related deaths. While RFS is the preferred endpoint in adjuvant therapy trials, its validity as a surrogate for treatment efficacy may be compromised by mortality unrelated to cancer progression, thereby limiting its ability to comprehensively reflect therapeutic benefit.

In unresectable HCC, the OS benefit of systemic therapy can be influenced by crossover to second-line treatment following failure of first-line therapy. However, in patients with resectable HCC who achieve a complete response (CR) after neoadjuvant or adjuvant therapy with surgery, the impact of crossover such as transitioning to subsequent treatments like surgery, RFA, or TACE upon recurrence (i.e., emergence of a new lesion) on OS may differ significantly from situations in patients with unresectable HCC. A more critical consideration is that, in resectable HCC, if OS is used as the primary endpoint following neoadjuvant or adjuvant therapy with surgery, an extended follow-up period is inevitably required. Therefore, RFS is often adopted as a surrogate marker for efficacy evaluation in this context. Notably, the recent European Association for the Study of the Liver (EASL) Clinical Practice Guidelines on the management of HCC identify radiologic response assessed by Response Evaluation Criteria in Solid Tumors (RECIST) as a significant predictor of OS in advanced HCC.²⁷ However, in the neoadjuvant or adjuvant setting for resectable HCC, where the clinical issue centers on whether recurrence occurs after CR, the applicability of RECIST criteria is inherently limited.

CLINICAL EVIDENCE SUPPORTING ADJUVANT THERAPY IN HCC

Historically, antiviral therapy has been the only recommended adjuvant treatment for HCC, demonstrating improvements in OS but failing to significantly reduce tumor recurrence rates.^28,29 Several large-scale clinical trials investigating agents such as uracil-tegafur, peretinoin, interferon, and vitamin K failed to demonstrate meaningful clinical benefits.^30-33 Notably, the STORM trial in 2015 reported no improvement in RFS with adjuvant sorafenib compared to placebo in patients who had undergone surgical resection or radiofrequency ablation.⁹ Conversely, a study from China indicated an RFS advantage with adjuvant hepatic arterial infusion chemotherapy using 5-fluorouracil and oxaliplatin in patients with microvascular invasion (hazard ratio [HR], 0.59; P=0.001).³⁴

At the ESMO Congress 2024, results from the IMbrave050 phase III open-label trial, which compared atezolizumab plus bevacizumab with active surveillance in patients at high risk of recurrence following resection or local ablation, failed to demonstrate a survival benefit.²¹ High-risk criteria were defined as the presence of 1) 1-3 tumors >5 cm, 2) more than three tumors ≤5 cm, or 3) tumors ≤5 cm with vascular invasion or poor differentiation. For patients treated with ablation, risk factors included solitary tumors measuring 2-5 cm or two to four multiple tumors each ≤5 cm. The trial enrolled 668 patients, of whom 88% underwent resection (median tumor size, 5.5 cm), while those in the ablation group had a median tumor size of 2.5 cm. The median treatment duration for atezolizumab plus bevacizumab was 11 months. At 12 months, RFS was 78% in the treatment arm versus 65% in the surveillance group. However, the Kaplan- Meier survival curves appeared to converge at approximately 21 months. The trial did not meet its primary endpoint, as atezolizumab plus bevacizumab failed to demonstrate a statistically significant RFS advantage (HR, 0.90; 95% confidence interval, 0.72-1.12). Moreover, grade 3-4 treatment-related adverse events were reported in 34.9% of patients, and 8.4% required corticosteroid therapy for immune-related adverse effects. Treatment discontinuation due to adverse events occurred in 8.7% of cases, with two treatment-related fatalities (2%).²¹

In contrast, adjuvant sintilimab treatment demonstrated a significant RFS benefit in patients with microvascular invasion.³⁵ This phase II multicenter, open-label, randomized controlled trial in China assigned patients to adjuvant sintilimab (n=99) or active surveillance (n=99). After a median follow-up of 23.3 months, sintilimab significantly prolonged RFS compared to active surveillance (27.7 vs. 15.5 months; HR, 0.534; P=0.002).

Further supporting the role of immunotherapy, a recent propensity score-matched analysis of real-world data found that adjuvant cytokine-induced killer (CIK) cell immunotherapy significantly prolonged RFS in patients (n=49) who had undergone curative resection or radiofrequency ablation.³⁶ During a median follow-up of 19.1 months, CIK cell immunotherapy was associated with significantly improved RFS compared to active surveillance (not reached vs. 29.8 months; adjusted HR, 0.32; P=0.001).

At the 2025 American Society of Clinical Oncology (ASCO) meeting, extended follow-up results from a randomized controlled trial on CIK cell immunotherapy (median follow-up, 115.7 months) were presented. Among 226 patients who underwent curative treatment for stage I or II HCC, those receiving CIK therapy (n=114) exhibited prolonged RFS compared to the control group (n=112) (median RFS, 43.5 vs. 27.4 months; HR, 0.74; P=0.045) over a median follow-up period of 9.6 years.³⁷

A separate cohort study (n=99) evaluated various ICIs, including pembrolizumab, sintilimab, camrelizumab, toripalimab, and tislelizumab, in BCLC stage B or C patients who underwent curative resection.³⁸ ICIs were administered for 12 months, beginning 4-6 weeks post-resection. Over a median follow-up of 24.6 months, adjuvant immunotherapy significantly improved RFS (median RFS, 29.6 months; HR, 0.63; P=0.02) and OS (median OS, 35.1 months; HR, 0.60; P=0.01) compared to active surveillance (median RFS, 19.3 months; median OS, 27.8 months).

Beyond immunotherapy, TKIs have also been investigated as adjuvant strategies. A retrospective propensity score-matched study demonstrated survival benefits with lenvatinib in HCC patients with microvascular invasion post-curative resection.³⁹ Among 43 lenvatinib-treated patients, RFS (HR, 0.52; P=0.016) and OS (HR, 0.46; P=0.001) were significantly improved compared to the matched control group. Similarly, donafenib, another TKI, was evaluated as an adjuvant therapy in patients with high-risk recurrence factors, including 1) single tumor >5 cm or multiple tumors of any size, 2) presence of microvascular invasion, and 3) satellite nodules.⁴⁰ Over a median follow-up of 21.8 months, the donafenib treatment group (n=49) exhibited significantly improved 1-year RFS compared to the active surveillance group (86.6% vs. 64.8%; P=0.004). Key clinical studies on adjuvant therapy for HCC were summarized in Table 1.

Identifying candidates likely to respond to immunotherapy in HCC is crucial for optimizing treatment strategies. In the adjuvant setting, pathological methods and tissue-based biomarkers play a significant role, while in the neoadjuvant setting, liquid biopsy approaches such as circulating tumor cells and cell-free DNA are emerging as valuable tools. In the adjuvant setting, high expression levels of PD-L1, tumor mutational burden, or tumor-infiltrating lymphocytes are associated with better responses to immune checkpoint inhibitors.⁴¹ In the neoadjuvant setting, circulating tumor cells can provide real-time insights into tumor dynamics and treatment response, and analysis of cell-free DNA can reveal genetic alterations and help monitor treatment efficacy.^42,43 While these strategies show promise, challenges such as methodological variability and the need for large-scale validation remain. Conversely, reliance on traditional tissue biopsies may still be necessary due to the current limitations of liquid biopsy technologies in accurately reflecting tumor biology.

Several pivotal clinical trials are currently underway to further refine the role of ICIs in the adjuvant setting (Table 2). Key examples include the CheckMate-9DX trial evaluating nivolumab monotherapy, the KEYNOTE-937 trial assessing pembrolizumab monotherapy, and the EMERALD-2 trial exploring durvalumab with or without bevacizumab. With completion of patient enrollment, the results of these trials are highly anticipated to provide definitive guidance on the clinical utility of adjuvant ICIs in HCC management.

SUMMARY

Advancements in systemic therapies have fueled growing interest in their evolving role in the management of HCC, particularly in neoadjuvant and adjuvant settings. Many studies have recently investigated the feasibility and efficacy of neoadjuvant and adjuvant therapy in HCC treatment. However, the majority of these studies have been constrained by small sample sizes, limiting the ability to draw definitive conclusions. Despite these challenges, accumulating evidence suggests that neoadjuvant and adjuvant therapies confer survival benefits and are progressively expanding their clinical applications (Fig. 1). To optimize the therapeutic impact of these strategies, integration with surgical interventions and other HCC treatment modalities is essential. In this context, appropriate patient selection is critical to maximizing the efficacy of neoadjuvant and adjuvant therapy, emphasizing the indispensable role of a multidisciplinary approach in clinical decision-making. Effective management of HCC necessitates collaboration among specialists from various disciplines, including hepatologists, radiologists, interventional radiologists, hepatobiliary and transplant surgeons, as well as medical and radiation oncologists.⁴⁴ Such multidisciplinary coordination is crucial for accurate disease staging, optimization of treatment selection and sequencing, and ultimately, improving patient outcomes. Additional studies are required to define the subsets of patients most likely to benefit from neoadjuvant or adjuvant therapies.

Article information

Conflicts of Interest

The authors have no conflicts to disclose.

Ethics Statement

This review article is fully based on articles which have already been published and did not involve additional patient participants. Therefore, IRB approval is not necessary.

Funding Statement

This study was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (grant number: 2022R1I1A1A01068809 and 2022R1I1A1A01067589), the National Research Foundation of Korea (NRF) grant funded by the Korea government (Ministry of Science and ICT) (grant number: 2020R1C1C1004112), and The Research Supporting Program of The Korean Association for the Study of the Liver and The Korean Liver Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Data Availability

Not applicable.

Authors Contributions

Conceptualization: HSC, ML

Data curation: ML

Funding acquisition: HSC, ML

Investigation: ML

Methodology: ML

Supervision: ML

Writing - original draft: ML

Writing - review & editing: HSC, ML, THK

Figure 1.

Expanding clinical applications of neoadjuvant and adjuvant therapies. HCC, hepatocellular carcinoma; BCLC, Barcelona Clinic Liver Cancer; Tx, treatment; RFS, recurrence-free survival; OS, overall survival.

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Figure & Data

References

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