Neoadjuvant systemic therapy for hepatocellular carcinoma: challenges and opportunities—a narrative review

Introduction

Primary liver cancer (PLC) is the seventh most common malignant tumor and second most fatal malignancy on a global scale according to the Global Cancer Data (GLOBOCAN) 2020 (1). Notably, China bears the burden of approximately 50% of all liver cancer cases worldwide. Recent data from the National Cancer Center in 2021 revealed that liver cancer has emerged as the fourth most prevalent malignant tumor in China, with the second highest mortality rate (2). Over the past decade, there has been a notable decrease in both incidence rates, dropping from 84.6% to 76.6%, and mortality rates, declining from 86.3% to 79.7% (3). Hepatocellular carcinoma (HCC) stands as the primary histological type of PLC, comprising roughly 85% to 90% of diagnosed cases. The vast majority of HCC cases develop within the context of chronic liver disease, primarily due to chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. Other significant etiologies include metabolic dysfunction-associated steatohepatitis (MASH) and metabolic dysfunction-associated steatotic liver disease (MASLD) related cirrhosis, alcoholic cirrhosis, diabetes, aflatoxin, Wilson’s disease, hemochromatosis, alpha 1-antitrypsin deficiency (4-6).

For selected patients with early-stage HCC, the principal curative methods comprise surgical resection, liver transplantation (LT), and thermal ablation, with a 5-year survival rate of 60–80% (7). Nevertheless, a considerable number of patients are deemed ineligible for surgery due to advanced tumor stage or severe liver disease at the time of diagnosis. Despite eligibility for surgical resection in patients with HCC, the 5-year recurrence rate after hepatectomy can reach as high as 70% (8). Moreover, for recipients meeting the Milan criteria (MC) undergoing LT, the 5-year recurrence rate stands at approximately 20% (9). Therefore, the pivotal aspect in improving the overall outcome of HCC lies in reducing the postoperative recurrence rate.

Neoadjuvant strategies are useful for reducing the risk of recurrence after curative surgeries. In the context of resectable solid organ cancers, neoadjuvant therapy is frequently administered to delay disease progression, ensure appropriate patient selection, reduce tumor burden and potentially eradicate micrometastases prior to surgical procedures (10). In recent years, the advancements in systemic therapy for advanced HCC have significantly contributed to notable improvements in surgical outcomes. While traditional chemotherapy has shown minimal effectiveness in treating HCC, tyrosine-kinase inhibitors (TKIs) have emerged as the standard of care for patients lacking curative treatment options. Studies exploring the inhibition of programmed death receptor 1 (PD-1) or its ligand (PD-L1) in advanced HCC have demonstrated clinically meaningful activity (11). Notably, combining the PD-L1 antibody atezolizumab with the vascular endothelial growth factor (VEGF) inhibitor bevacizumab has shown improved overall survival (OS) and progression-free survival (PFS) compared to the TKI sorafenib (12,13) and has been recommended in some clinical guidelines (14,15). Although the combinations of immune checkpoint inhibitor (ICI) and TKIs as first-line therapy for unresectable HCC have been assessed in a few phase III trials, only camrelizumab plus rivoceranib (also known as apatinib) demonstrated improved PFS and OS over sorafenib in an international phase III study (CARES-310) (16). Recent phase III studies have demonstrated superior performance of the combination therapy involving the PD-L1 inhibitor durvalumab and the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor tremelimumab over sorafenib (17,18). Due to the increasing number of negative studies during the chemotherapy and targeted therapy era, most guidelines do not support the use of systemic therapies in the neoadjuvant or adjuvant setting. However, there are currently numerous ongoing and recently completed clinical trials that are exploring the integration of newer perioperative therapeutic modalities for patients with resectable and potentially resectable HCC (19,20). In this review, we aim to briefly summarize the current available evidence on the safety and efficacy of systemic therapy in neoadjuvant settings designed to improve the outcome of curative-intent liver resection (LR) or LT for patients with resectable HCC. Additionally, we will provide an outlook on future directions of systemic therapy as neoadjuvant treatment in HCC. We present this article in accordance with the Narrative Review reporting checklist (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-175/rc).

Methods

We searched PubMed for the following terms: hepatocellular carcinoma, neoadjuvant, preoperative, chemotherapy, hepatic arterial infusion chemotherapy, targeted therapy, systemic therapy, immunotherapy. The retrieved literature was screened independently by two researchers, and the differences were discussed to reach a consensus. The relevant ongoing clinical trials registered at ClinicalTrials.gov are included. The specific search strategy summary is shown in Table 1.

Potential benefits of neoadjuvant systemic therapy

Similar to the role of neoadjuvant therapy in various other tumor treatments, its application in HCC offers numerous advantages and potential benefits. Initially, neoadjuvant therapy has the potential to prime the immune system, thereby reducing the risk of recurrence. HCC commonly presents as a multiclonal cancer. Preoperatively, tumor cells may have already migrated into the liver and the surrounding region. If only the macroscopic and visible tumor tissues are surgically removed, the patient is likely to experience early postoperative recurrence.

Secondly, neoadjuvant clinical trials provide a distinctive environment for gaining a better understanding of how novel therapies function in HCC patients. This is achieved through comprehensive analysis of pre-treatment and post-treatment tissue from individuals undergoing neoadjuvant therapy. Such studies can contribute valuable insights into biomarkers and help identify optimal combinations of therapeutic approaches. Neoadjuvant systemic therapy can be employed to assess the sensitivity of tumors to anticancer drugs accurately within a relatively short period and assist in determining suitable adjuvant treatment protocols. Whether pathologic response rates (RRs) to neoadjuvant therapy are associated with OS in HCC remains unclear and warrant further investigation (21).

Thirdly, in the scenario of LT for HCC, neoadjuvant therapy serves to prevent patients from dropping out of treatment due to tumor progression during the waiting period, ensuring their eligibility for LT (22). This concept, known as bridging therapy, is strongly advocated in recent European guidelines, recommending neoadjuvant therapies to mitigate the risk of dropout due to tumor progression (7). This strategy is particularly emphasized when the anticipated waiting period exceeds six months.

Lastly, downstaging therapy is undertaken to reduce tumor volume to meet the LT criteria in patients whose HCC stage initially falls outside the criteria (23). In contrast to patients diagnosed with Barcelona Clinic Liver Cancer (BCLC)-0 and BCLC-A disease falling within the MC, those belonging to the heterogeneous BCLC-B category were specifically targeted for downstaging therapies due to their multifocal disease that surpassed the MC. The Organ Procurement and Transplantation Network/United Network for Organ Sharing (UNOS) has adopted a downstaging protocol (UNOS-DS) based on criteria developed at the University of California, San Francisco (UCSF). Inclusion criteria encompass HCC exceeding the MC but meeting one of the following conditions: (I) single tumor size of 5.1–8 cm; (II) 2 to 3 tumors, each <5 cm, with a sum of maximal tumor diameters <8 cm; (III) 4 to 5 tumors, each <3 cm, with a sum of maximal tumor diameter <8 cm. Data show that the application of immunotherapy before LT, whether as bridging therapy or downstaging therapy, can delay tumor progression and even reduce tumor burden, thereby ensuring or increasing the number of patients who meet the criteria for LT (24). However, anti-PD(L)1-based ICIs has the potential to trigger downstream T cell activation, thereby increasing the risk of acute cellular rejection (ACR) and graft rejection. There is a lack of studies evaluating the safety and efficacy of immunotherapy use after transplantation. Consequently, registry trials that led to the approval of ICI use in HCC excluded liver transplant recipients. In clinical practice, immunotherapy is contraindicated for patients who underwent prior LT, although there are clinical trials evaluating it in this setting (25,26).

Neoadjuvant chemotherapy

The utilization of cytotoxic agents in advanced HCC has yielded dismal results, as only a limited number of agents have shown RRs surpassing 20%, and none have exhibited significant survival advantages in phase III trials (27,28). Additionally, a substantial proportion of HCC patients present with underlying chronic liver disease and impaired hepatic function, which amplifies the toxicity of standard drug dosages and complicates the implementation of combination chemotherapy. Consequently, there is a scarcity of research on systemic chemotherapy as a neoadjuvant therapy for patients with resectable HCC. To reduce the systemic side effects associated with chemotherapy, hepatic arterial infusion chemotherapy (HAIC) has emerged as an alternative to systemic chemotherapy. HAIC involves delivering chemotherapy drugs directly into the hepatic artery, the main blood vessel supplying the liver. This approach allows for a higher concentration of the drugs to reach the tumor while minimizing exposure to other tissues.

A retrospective study assessed the impact of neoadjuvant HAIC on 49 patients with HCC exhibiting high malignant potential (29). The treatment protocol involved a 2-week regimen of low-dose 5-fluorouracil and cisplatin. Remarkably, the liver function of the treatment group (undergoing neoadjuvant HAIC and hepatectomy) did not experience adverse effects (AEs) due to the neoadjuvant HAIC. The treatment group achieved significantly superior 1-, 3-, and 5-year disease-free survival (DFS) as well as OS compared to the control group. Further, multivariate analysis identified neoadjuvant HAIC as an independent and favorable prognostic factor for DFS. Recently, a preliminary analysis of a multicenter, phase III, randomized, controlled clinical trial has unveiled more promising evidence (30). In this trial, patients diagnosed with resectable BCLC stage A/B HCC beyond MC were randomly assigned to receive neoadjuvant transarterial infusion (TAI) chemotherapy with FOLFOX regimen (NT group, n=104) before hepatectomy or undergo operation directly (OP group, n=104). The OS and PFS were notably superior in NT group than in OP group. There was no significant difference in recurrence-free survival (RFS) between the two groups. No patients in NT group experienced grade 3 or more severe TAI related adverse events.

The prognosis of HCC patients with portal vein tumor thrombus (PVTT) is generally poor with a median survival time (MST) of 2–4 months with best-supportive care (31). Recent studies have shown that PVTT patients may benefit from surgical resection, the only treatment that may offer long-term survival (32). In a comparative study enrolling 55 patients who underwent hepatectomy alone and 65 patients who received neoadjuvant FOLFOX-HAIC followed by hepatectomy for resectable HCC with PVTT, FOLFOX-HAIC before hepatectomy showed superior survival outcomes and lower recurrence rates compared to hepatectomy alone after matching (33). Subgroup analysis further revealed that the survival benefit was confined to patients who responded to FOLFOX-HAIC and the therapeutic effect of HAIC was more prominent in patients with Vp3/4 (first-order branch/main trunk or contralateral branch invasion) than with Vp1/2 (third-order/second-order branch invasion).

Inferior vena cava tumor thrombus (IVCTT) is a manifestation of advanced hepatic vein invasion with a reported frequency of 1% to 4% (8). According to some treatment guidelines, LR might be an acceptable choice for selected patients (34,35). Kasai et al. (36) retrospectively analyzed the long-term outcomes in 39 operative HCC cases with IVCTT. Among them, eight patients with advanced IVCTT (defined as those patients with suspected extrahepatic metastasis, who will need extracorporeal circulation, or who have marginal liver function and/or multiple bilobar tumors) received neoadjuvant HAIC. Preoperative HAIC was identified as a favorable independent prognostic factor for OS. Among initially advanced IVCTT cases, preoperative HAIC correlated with a better prognosis than no HAIC. Patients with uncontrolled advanced IVCTT had significantly lower OS compared to those without advanced IVCTT or with controlled IVCTT through preoperative HAIC. Hence, operative resection is recommended exclusively for patients lacking advanced IVCTT or those with IVCTT effectively controlled by preoperative HAIC. Despite growing evidence is currently available, neoadjuvant chemotherapy is not recommended by Western clinical guidelines for the following reasons: (I) the relevant studies were mostly small sample studies or case reports; (II) during neoadjuvant therapy, resectable HCC patients may experience disease progression or toxic side effects, thus losing the opportunity for surgery. Therefore, a powerful treatment regimen with a high objective RR and low progressive disease rate is required, but the current efficacy of neoadjuvant chemotherapy is unsatisfactory.

Neoadjuvant targeted therapy

In 2007, two large-scale phase III randomized clinical trials assessed the efficacy of a novel systemic molecular targeted therapy, sorafenib, demonstrating its significant effectiveness in delaying tumor progression among patients with intermediate to advanced-stage HCC (37,38). Subsequently, several TKIs such as regorafenib, cabozantinib, lenvatinib, and donafenib have been approved as either first-line or second-line standard treatment options for HCC. The BIOSPHERE study, an open-label, multicenter phase II trial, investigated sorafenib in the neoadjuvant setting for resectable HCC patients (39). Twenty-five participants received sorafenib 400 mg for 4 weeks pre-surgery. The results exhibited a 32% objective response rate (ORR). Further, 88% achieved R0 tumor resection, and 24% had a pathologic response (>50% necrosis). Neoadjuvant sorafenib demonstrated favorable toxicity and significant efficacy in patients with resectable HCC. Additionally, a multicenter case-matched study examined the intraoperative data and postoperative results of 23 HCC patients who underwent resection after receiving sorafenib treatment, specifically focusing on the recovery of liver function (40). The study affirmed the safety and feasibility of administering sorafenib prior to liver surgery. No adverse consequences associated with sorafenib use during LR were observed. The restoration of liver function was comparable in both groups. Kermiche-Rahali et al. (41) described a patient with a substantial HCC and exhibiting thrombosis in the left intrahepatic portal branch. After nine months of sorafenib, a 15.7-cm HCC shrank by 60% to 6 cm with left portal branch recanalization. Subsequently, a lateral left hepatectomy was performed and pathology showed complete necrosis. No HCC recurrence was observed 14 months post-resection. Despite rare occurrences of substantial tumor regression in some patients following TKI treatment either alone or in combination with cytotoxic chemotherapy before undergoing surgery or other definitive local therapies, the general application of TKIs in the neoadjuvant setting is significantly constrained due to their low objective RRs.

Some case reports or small-sample studies have investigated whether sorafenib alone or in combination with locoregional therapy (LRT) can effectively prevent the progression of HCC beyond the MC while awaiting LT, or promote tumor downstaging to meet the MC. Vagefi et al. (42) described a patient diagnosed with HCC who received sorafenib treatment, which resulted in a notable reduction in tumor burden to allow for liver transplant listing. The first cost-benefit analysis conducted by Vitale et al. (43) demonstrated sorafenib neoadjuvant therapy is cost-effective and had a beneficial effect on survival by comparison with no therapy for T2-HCC patients waiting for LT, especially for those with median waiting times under six months. A study involving a small sample of five patients who underwent sorafenib treatment before LT confirmed that employing a downstaging or bridging strategy involving sorafenib can lead to a significant degree of tumor necrosis and lower rates of recurrence. This targeted therapy was well tolerated and did not seem to affect post-LT mortality (44).

Currently, there is very little information available on the risks or adverse events associated with sorafenib before LT. In a small-scale pilot study, pretransplant exposure to sorafenib was an independent predictor of posttransplant biliary complications (45). One possible reason is that biliary ischemia caused by sorafenib-mediated changes to the peribiliary vascular plexus secondary to VEGF inhibition. Contrary to these findings, Frenette et al. (46) did not observe an elevated incidence of biliary complications or ACR in patients treated with sorafenib before LT. The OS and recurrence rates of HCC were comparable between patients who received sorafenib prior to LT and those in the no-sorafenib group. The substantial contrast in conclusions between these two studies can be primarily attributed to the non-randomized, retrospective nature of the small sample size study. A prospective clinical trial evaluated sorafenib’s viability as neoadjuvant therapy in twelve patients with HCC before LT, focusing on tolerability, toxicity, and post-transplant complications (47). Unfortunately, the study yielded disappointing results on tolerability. Half of the patients discontinued sorafenib due to side effects.

Besides sorafenib, dovitinib, a multi-receptor tyrosine kinase inhibitor, was tested as neoadjuvant therapy prior to locoregional treatment for early/intermediate HCC (48). Among 24 patients, seven underwent LT after dovitinib and locoregional treatment in 11.4 months. Significant reductions in viable tumor size and intratumoral blood flow occurred, but over half of patients developed severe hypertension (grade 3–4). These findings support the use of dovitinib as neoadjuvant strategy, yet underscore the necessity for dose adjustments due to considerable tolerability issues specific to HCC treatment.

Similarly, neoadjuvant targeted therapy is not recommended by clinical guidelines, mainly for the following reasons: (I) there are relatively few studies on the monotherapy application of neoadjuvant targeted therapy, and most of the published studies are small sample studies or conference reports; (II) existing data indicate conflicting findings regarding the efficacy and safety of sorafenib before LT. Additionally, the severe AEs, such as hypertension associated with donafenib, pose significant barriers to the widespread adoption as neoadjuvant therapy.

Neoadjuvant immunotherapy

Over the past decade, immunotherapy has markedly transformed the treatment landscape of solid tumors, including melanoma (49), lung cancers (50,51), renal cancers (52,53), and HCC (54). Immunotherapies encompass various approaches such as ICIs that target PD-1, PD-L1 and CTLA-4, alongside cancer vaccines and adoptive cell therapy (55). Systemic therapy before surgical resection aims to eliminate micrometastases, which could otherwise lead to early recurrence, thereby extending RFS. By introducing ICIs in the neoadjuvant setting, where the tumor burden is greater compared to the postoperative stage, there exists the theoretical potential to evoke a more substantial T-cell response (56). This, in turn, could result in a more profound antitumor effect. Neoadjuvant immunotherapy has been extensively examined in multiple phase Ib/II trials involving patients with initially resectable liver tumors.

The combination or monotherapy of PD-1/PD-L1 inhibitors and CTLA-4 inhibitors exhibits significant promise as a therapeutic approach for perioperative procedures. A phase Ib study (PRIME-HCC) investigated the neoadjuvant therapy combining nivolumab with ipilimumab in seventeen patients undergoing LR for early-stage HCC (57). Following a median follow-up of 6.3 months, one patient experienced relapse 20.8 months after starting treatment. The median time to LR from screening was 2.5 months. Among the 13 patients with available radiological assessments, the ORR was 23%. Pathologically, among the nine evaluable patients, seven (78%) achieved a partial response (PR), including two (22%) with complete response (CR). Additionally, there was one case (7%) of grade 3 alanine aminotransferase/aspartate aminotransferase (ALT/AST) elevation. The combination showed promising evidence of anti-tumour efficacy based on both radiological and pathological responses.

A recent phase II trial, including 27 patients with resectable HCC, evaluated the safety and tolerability of preoperative nivolumab (240 mg Q2W, up to 3 cycles) +/− ipilimumab (1 mg/kg, single dose), followed by an adjuvant therapy of nivolumab (480 mg Q4W, up to 2 years) +/− ipilimumab (1 mg/kg Q4W, up to 4 cycles) (58). Adverse events of grade 3–4 were higher in nivolumab plus ipilimumab (43%) compared to nivolumab alone (23%), yet no surgical delays occurred due to severe adverse events. Median PFS was 9.4 months with nivolumab and 19.53 months with the combination. Notably, achieving a major pathological response (MPR) significantly improved RFS. MPR rates were similar (33% vs. 27%) between nivolumab monotherapy and the combination. Two patients showed pathological complete response (pCR) with nivolumab alone, while three achieved the same with the combination. In both groups, an elevated T-cell infiltrate within the tumor microenvironment was correlated to the pathologic RR. Higher baseline T cell infiltration is necessary for nivolumab monotherapy response, but not for combination therapy since ipilimumab addition results in beneficial immunological alterations in the tumor microenvironment.

Marron et al. (59) conducted the largest phase II trial assessing perioperative cemiplimab (an anti-PD-1 antibody) in 21 patients with resectable HCC. After two cycles of cemiplimab (350 mg Q3W), patients underwent LR followed by an additional eight postoperative cycles of cemiplimab. Among the 20 patients with resected tumors, four (20%) exhibited significant (>70%) tumor necrosis, while seven (35%) displayed 50% or greater tumor necrosis. Patients with higher necrosis exhibited enhanced immune infiltrates in pre-treatment and post-treatment tissue specimens, indicating the potential of immune infiltrates as a predictive biomarker for rapid response to ICI therapy.

Immunotherapy can potentially down-stage tumors for transplantation eligibility, even in advanced cases. However, concerns about severe allograft rejection, adverse events, and treatment-related fatalities have constrained its widespread use (60,61). Several literature case reports discuss immunotherapy as a neoadjuvant treatment preceding LT. The first successful case of downstaging with an ICI was described by Schwacha-Eipper et al. (62). A patient with compensated cirrhosis and a 6.4-cm HCC underwent laparoscopic LR, revealing poorly differentiated HCC. Following HCC recurrence, the patient received systemic therapy, progressing to sorafenib and experiencing intolerance to regorafenib. Subsequently, the patient completed 34 cycles of nivolumab. After a 15-week cessation of nivolumab, the patient successfully underwent LT without any complications. No tumor recurrence or allograft rejection was found after one year of follow-up.

Tabrizian et al. (63) reported a single-center study of nine HCC patients who underwent successful transplantation following neoadjuvant treatment with nivolumab. Among them, 56% had prior HCC resection, and a third exceeded the MC. Nivolumab was administered at 240 mg every two weeks. After a median follow-up of 16 months, no severe allograft rejections, tumor recurrences, or deaths were observed. Analysis of the explant pathology revealed over 90% tumor necrosis in one-third of the cases.

At the Mayo Clinic, a patient with compensated cirrhosis and two HCC lesions within MC received Y-90 radioembolization for downstaging (64). Despite initial response, a year later, advanced disease manifested with new HCC and elevated alpha fetoprotein (AFP) levels (>3,000 ng/mL). Shifting from ineffective sorafenib, the patient underwent nivolumab and ipilimumab therapy, resulting in a significant response after six months. Subsequently, the patient underwent successful LT nine weeks post-discontinuation of ICIs. At the six-month post-transplantation assessment, the patient exhibits excellent graft function without any signs of recurrence or allograft rejection.

Schnickel et al. (65) reported five cases of LT in HCC patients previously treated with nivolumab. The time between the last ICI dose and LT ranged from ten days to six months. Notably, two patients with <3 months from last dose of nivolumab to LT experienced biopsy-proven acute cellular rejection (BPACR) and severe hepatic necrosis, one of whom required retransplantation with recurrent BPACR. However, no BPACR was observed in patients transplanted beyond three months from their last ICI dose. Thus, nivolumab withdrawal three months or more before LT might not increase BPACR risk after LT, suggesting potential safe use in a neoadjuvant setting.

Recognizing the critical role of the washout duration in preventing postoperative rejection after LT, Kuo et al. (66) conducted a review of published case reports or series involving LT for HCC after downstaging or bridge therapy with ICIs. The study involved 28 patients, among whom seven (25%) experienced post-LT rejection episodes. Their findings indicated that a 42-day washout period before LT emerged as the safest timeframe for HCC cases previously treated with ICIs like atezolizumab, nivolumab, or pembrolizumab.

The real-world clinical experiences highlight the risks of a short interval between the last ICIs dose and LT, resulting in acute cellular rejection and graft loss. The antitumor efficacy of ICIs must be carefully weighed against the inherent risk of organ rejection. A multicenter study utilizing a comprehensive database is necessary to assess pre-transplant ICIs usage, its influence on waitlist dropout rates, the most effective immunosuppression strategies, and post-transplant outcomes. Currently, due to the existence of various alternative strategies and the risk of allograft rejection associated with pre-transplant ICIs usage, the use of ICI as a bridging concept is currently not recommended.

Neoadjuvant combined therapy

ICIs plus TKIs

In recent years, the combination of immunotherapy and anti-angiogenesis therapy has garnered significant attention in cancer treatment. Preclinical research has revealed that the combination therapy has a synergistic anticancer impact via modulating several signal pathways (67). A phase II prospective study investigated the efficacy and safety of camrelizumab (an anti-PD-1-antibody) in combination with apatinib as neoadjuvant therapy in 18 patients with resectable HCC (68). The regimen included three doses of camrelizumab (200 mg Q2W) with daily oral apatinib (250 mg) for 21 days pre-resection, followed by eight adjuvant cycles. Results showed an ORR of 16.7% and 33.3% based on Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST (mRECIST) criteria, respectively. Additionally, 17.6% achieved MPR, and one patient (5.9%) reached complete pCR. The 1-year RFS rate was 53.85%, with a trend towards higher RFS in patients with MPR. Grade 3/4 adverse events were observed in 16.7% of patients. Elevated dendritic cells (DCs) indicated greater sensitivity to neoadjuvant therapy, correlating with reduced relapse likelihood.

In a single-arm phase Ib study, Ho and colleagues (69) explored the feasibility of neoadjuvant treatment with cabozantinib and nivolumab in 15 patients with borderline or locally advanced HCC. After the initial two weeks of cabozantinib monotherapy, each patient received four cycles of nivolumab every two weeks along with eight weeks of cabozantinib. Treatment-related adverse events occurred in 93.3% of patients, with grade 3 or higher events in 13.3%. Among the 12 patients who had successful surgical resection, four showed MPRs, and one had a CR. Based on RECIST 1.1, 13 out of 14 had stable disease (SD) (93%) and one had a PR (7%). With a median 1-year follow-up, 5 out of 12 surgical patients experienced recurrence. In-depth biospecimen profiling revealed that responders exhibited a greater abundance of effector T cells, tertiary lymphoid structures, CD138⁺ plasma cells, and a discernible spatial distribution of B cells in comparison to nonresponders.

LRT plus systemic therapy

Transarterial chemoembolization (TACE) effectively manages tumor growth in the targeted HCC nodule. However, TACE induces neo-angiogenic reactions, potentially exacerbating growth in untreated nodules or accelerating new tumor emergence within the cirrhotic liver. Sorafenib has direct inhibitory effects on angiogenesis and cell proliferation in HCC. The combination of local therapy with VEGF-targeted therapy theoretically enhances tumor control in HCC patients awaiting LT. Yet, a multicenter phase III trial revealed similar time-to-progression (TTP), ORR, and disease-control rate (DCR) between neoadjuvant TACE with sorafenib and TACE with placebo before LT, discouraging the recommendation of sorafenib and TACE as a neoadjuvant treatment (70).

Recently, systemic therapy combinations, such as TKIs and ICIs, have shown promise in improving the prognosis of advanced HCC (71,72). In a multicenter retrospective study, surgery alone was compared to neoadjuvant triple therapy (TACE + lenvatinib + PD-1 antibodies) before surgical resection in 100 resectable HCC patients at high recurrence risk (73). The triple therapy demonstrated a notable ORR (83.3%), manageable toxicity and improved DFS and OS compared to surgery alone after matching. Six patients (26.1%) achieved pCR, while four patients (17.4%) exhibited MPR. Furthermore, triple therapy reduces the rate of major vascular invasion and increases the probability of margin-negative resections. The phase III randomized placebo-controlled study, EMERALD-1, revealed that combining TACE with durvalumab plus bevacizumab resulted in statistically significant and clinically meaningful improvements in PFS compared to TACE alone in patients with unresectable and embolization-eligible HCC (74).

Zhu et al. (75) explored neoadjuvant therapy using TACE plus PD-1 inhibitor in intermediate-stage HCC. The ORR and DCR were 75.0% and 100.0%, respectively. Patients treated with this regimen exhibited impressive 1-year and 2-year OS rates of 100.0% and 76.4%, respectively, along with a notable 86.6% 1-year RFS rate. Successful downstaging was observed in 70% of patients undergoing neoadjuvant therapy, correlating with a significantly prolonged RFS compared to those with unsuccessful downstaging. In a retrospective study at our center, outcomes of 41 patients with resectable or borderline resectable HCC receiving neoadjuvant drug-eluting bead TACE (D-TACE) and tislelizumab followed by surgery were compared with those of 41 matched HCC patients undergoing surgery alone (76). In the neoadjuvant group, 87.8% experienced AE, with only one patient having a grade 3/4 ALT elevation. The ORR was 56.1% and 87.8% based on RECIST 1.1 and mRECIST, with a 100% DCR. pCR and MPR were observed in 31.7% and 43.9% of cases, respectively. After matching, patients receiving neoadjuvant therapy showed significantly better prognosis than those undergoing surgery alone.

Yttrium-90 radioembolization (Y90) is an approved intra-arterial therapy for unresectable HCC. Kulik et al. (77) explored the safety of adding sorafenib to Y90 in comparison to Y90 alone for HCC patients awaiting LT. All patients required a permanent half-daily dose reduction of sorafenib, and 50% had to discontinue sorafenib due to side effects. An unexpected observation was an elevated incidence of peri-transplant biliary complications and acute rejection in the combination group. Additional studies are warranted to further investigate the role of sorafenib in the transplant setting.

Radiotherapy has become increasingly utilized in advanced cases of HCC and has shown promising clinical benefits in managing PVTT. Additionally, radiotherapy may induce alterations in the tumor microenvironment that can be exploited by targeting the PD-1/PD-L1 immune checkpoint (78). Wei et al. (79) discovered that neoadjuvant radiotherapy resulted in a reduction in the extent of PVTT and notably improved the postoperative survival. An ongoing phase I trial (NCT05225116) is enrolling HCC patients with portal vein thrombus to assess the safety and efficacy of radiotherapy combined with lenvatinib alongside PD-1 inhibitors as neoadjuvant therapy (80). The primary endpoints include assessing safety (specifically, the number of patients experiencing grade ≥3 TRAE) and determining the number of patients who successfully complete the preoperative treatment and subsequently undergo surgery. In addition, the safety and tolerability of neoadjuvant stereotactic body radiation therapy (SBRT) with atezolizumab and bevacizumab for treating resectable HCC are evaluating (NCT04857684) (81).

Challenges and future direction

The existing evidence discussed above highlight both the promise of systemic therapy in the neoadjuvant setting and the issues that need further clarification prior to widespread adaptation of neoadjuvant therapy for HCC. The selection of an appropriate validated endpoint stands out as a crucial consideration in the trial design for neoadjuvant studies employing ICIs. Currently, OS is the primary clinical endpoint and the gold standard for efficacy evaluation in clinical oncology studies in the context of unresectable or advanced HCC. However, for patients with resectable HCC, the median OS after surgery often exceeds five years. Postoperative RFS could potentially serve as a surrogate endpoint for the neoadjuvant or adjuvant setting, because RFS tend to take less time to follow-up than OS. Two global, open-label, phase III randomized controlled trials (RCTs), STORM and IMbrave050, focused on adjuvant therapy after curative resection or ablation, using RFS as the primary endpoint (82,83). The STORM study, which evaluated sorafenib compared to placebo, found no significant differences in either RFS or OS. In contrast, adjuvant treatment with atezolizumab plus bevacizumab demonstrated a significant improvement in RFS. Cabibbo et al. extracted individual survival data from the Kaplan-Meier RFS and time-to-recurrence (TTR) curves of the placebo arms in both the STORM and IMbrave050 studies. They discovered that the risk of HCC recurrence peaks within the first year of follow-up (84). Data on pathologic response such as pCR or MPR are available immediately after surgical resection or LT. This response has been recognized as a surrogate indicator of long-term efficacy in multiple solid tumors, including breast cancer and non-small cell lung cancer, facilitating a faster assessment of neoadjuvant therapy efficacy. However, the association between pathologic RRs and OS in HCC within the neoadjuvant setting remains unclear. Future maturation of ongoing trials and analysis of accruing trial data may provide further insights into the selection of appropriate endpoints. Furthermore, the definition of MPR varies across trials. Some trials, like those involving nivolumab/cabozantinib (69) and camrelizumab/apatinib (68), consider a pathological response of over 90% tumor necrosis as the threshold, while others, like the cemiplimab (59) and nivolumab/ipilimumab trials (58), set the cutoff at 70% necrosis or even 50% in some cases. Hence, determining a suitable MPR threshold for HCC neoadjuvant therapies requires additional investigation.

Conventional radiologic response assessments may prove inadequate for recording changes within short time intervals, distinguishing between tumor progression and pseudoprogression due to immune infiltration, and accurately estimating the extent of tumor response. Although most MPRs or pCRs align with the CR/PR observed in imaging responses, discrepancies exist. For instance, in the nivolumab/ipilimumab trial, a pathological response was achieved in 78% of cases, whereas the radiologic ORR was only 23% (57). Thus, if immunotherapy is incorporated into a neoadjuvant regimen, further research is needed to determine the appropriate method for assessing efficacy. Immune-related RECIST (iRECIST) is an imaging evaluation method developed based on RECIST/mRECIST specifically for patients receiving ICIs. Unlike traditional RECIST/mRECIST, iRECIST incorporates unique considerations relevant to immunotherapy, such as immune unconfirmed progressive disease (iUPD) and lymph node diameter. It further enhances the imaging evaluation criteria to more accurately reflect the characteristics of immunotherapy. Consequently, iRECIST is anticipated to become widely adopted for assessing the efficacy of immunotherapy (85).

The precise selection of patients who are most likely to benefit from neoadjuvant therapy, along with the identification of the most suitable therapeutic approaches, is fundamental. Over recent years, various models have emerged to predict the risk of recurrence in patients with HCC (86). These models primarily rely on factors such as tumor burden, histological grade, hepatic functional reserve, and patient performance status. Currently, despite their relevance, these data do not provide assurance that the treatment will be personalized (87). How to individually select the beneficiary population of neoadjuvant therapy through molecular markers of HCC, dynamically monitor the effect of preoperative treatment, and predict the surgical prognosis have become the hotspots of future research. Among the serum markers, Zhu et al. (88,89) found that in HCC patients who underwent LT after neoadjuvant treatment with ramucirumab (VEGF-2 inhibitor), AFP levels exceeding 400 µg/L not only indicated a favorable response to ramucirumab but also significantly correlated with early recurrence risk post-transplantation. Finn et al. (90) evaluated the correlations between serum or tissue biomarkers and outcomes from REFLECT trial. Among patients receiving preoperative lenvatinib, those with higher serum fibroblast growth factor (FGF) 19 and FGF23 levels were notably more responsive than their counterparts with lower levels, whereas elevated baseline VEGF, angiopoietin-2 (ANG2), and FGF21 levels were significantly linked to overall postoperative mortality risk. The results from the tissue biopsy showed HCC with high tissue expression of VEGF and/or FGF shows a significantly superior objective response to lenvatinib treatment compared to neoplasms with low or intermediate VEGF and FGF expression. Torrens et al. (91,92) discovered that preoperative application of lenvatinib could enhance the effect of neoadjuvant immunotherapy by blocking fibroblast growth factor receptor 4 (FGFR-4) to reduce the PD-L1 expression and regulatory T-cell differentiation in tumors. Meanwhile, high FGFR-4 expression and regulatory T-cell infiltration in the tumor region can also help to “identify” patients who are more responsive to neoadjuvant lenvatinib + PD-1 inhibitor, which can be used as molecular markers for screening the applicability of neoadjuvant targeted and immunotherapy. The analysis of circulating tumor DNA (ctDNA) can offer crucial genetic insights into tumor cells and holds significant diagnostic and prognostic potential (93). He et al. (94) conducted a study examining mutations in plasma ctDNA across 50 tumor-associated genes in HCC patients. Their findings revealed significantly elevated mutation rates in TP53, RET, FGFR3, and APC among patients with multiple tumors or metastasis compared to those with a single tumor. Though these findings are based on small samples and require further verification, they suggest that patients exhibiting high mutant allele frequency in these genes may derive greater benefit from neoadjuvant therapy.

The optimal duration of preoperative therapy is another key question. Given that the primary objective of neoadjuvant therapy is to stimulate an immune response against micrometastatic disease rather than complete tumor eradication, a shorter intervention period could potentially yield comparable benefits. In addition, appropriate intervention period could reduce the risk of a preoperative immune-related adverse effect (irAE), thereby avoiding diminished efficacy and surgical delay (95). For instance, LR was substantially delayed in one patient enrolled in the cemiplimab trial due to an acute case of pneumonitis that developed just prior to surgery (3). Under certain conditions, such delays may render patients ineligible for surgical intervention. The findings from preclinical mouse models of metastatic malignancies showed that the optimal time between the initial administration of an ICI and surgery was a relatively brief period of 4–5 days. Any shorter or longer delay resulted in reduced efficacy (96). Based on the Chinese expert consensus on neoadjuvant therapy for HCC (2023 edition) (97), it is generally advised that the duration of neoadjuvant therapy for this malignancy not exceed six to twelve weeks, with a maximum extension to 16 weeks. Surgical intervention is to be initiated once the intended therapeutic objective has been met.

In the setting of LT, trials are necessary to determine if combining LT with immunotherapy is more effective than using either treatment alone. It is important to explore the optimal pre-transplantation use of immunotherapy, as well as its effects on graft function after transplantation. Given the considerable risk of allograft organ loss in LT, the timing and duration of preoperative ICI therapy pose significant challenges. Further research is urgently needed to determine the ideal timing for withdrawing ICI therapy in order to prevent ICI-induced rejection. However, the practical application of withdrawal timing is complicated by the unpredictable nature of organ availability and transplantation timing. Additionally, there is an urgent requirement for comprehensive investigations into the management of transplant recipients, including both induction and maintenance immunosuppression. These investigations will facilitate the development of more precise protocols and guidelines to optimize patient outcomes. Currently, there is limited clinical data supporting the use of ICIs before LT. The ongoing ImmunoXXL trial (NCT05879328) is investigating that whether LT, following effective of HCC downstaging with atezolizumab and bevacizumab combination, provides a survival benefit over atezolizumab and bevacizumab maintained treatment alone. A single-arm, open-label, phase II multicenter study (NCT05027425) is recruiting patients to evaluate the safety and efficacy of durvalumab and tremelimumab for HCC patients with cirrhosis or portal hypertension who are eligible for LT listing.

Both neoadjuvant therapy and adjuvant therapy are applicable to HCC patients who are suitable for surgical resection but have a high risk of recurrence and metastasis after surgery (98). Neoadjuvant systemic therapy is often administered to delay disease progression, downstage advanced disease, ensure appropriate patient selection, provide useful information on tumor susceptibility to systemic therapy, and potentially eradicate micro-metastases prior to surgical procedures. Adjuvant systemic therapy, administered after the primary curative treatment, has shown promise in reduce the recurrence rate and increase overall and DFS (99). As the first phase III trial of adjuvant therapy for HCC to yield positive outcomes, IMbrave050 trial evidenced that adjuvant therapy combining atezolizumab and bevacizumab could diminish the risk of postoperative recurrence and metastasis by 28% in comparison to active surveillance among patients presenting high-risk factors for HCC recurrence (83). Recently, a randomized controlled phase II trial demonstrated that sintilimab (PD-1 inhibitor) significantly extended RFS compared to active surveillance (median RFS: 27.7 vs. 15.5 months) in HCC patients with microvascular invasion after hepatectomy (100). Compared with neoadjuvant therapy, postoperative adjuvant therapy can accurately formulate the therapeutic regimen according to the results of postoperative pathology and molecular subtypes. Additionally, the response of the patient to neoadjuvant therapy can provide a reference and basis to ensure the efficacy and safety of adjuvant therapy. Notably, studies have shown that the timing of ICI administration relative to surgery significantly influences patient outcomes, even when the same drugs are used (101). For patients with resectable melanoma, event-free survival was significantly longer for those who received pembrolizumab before and after surgery compared to those who received only adjuvant pembrolizumab. The rationality that neoadjuvant or perioperative treatment therapy may be superior to treatment in the adjuvant setting may lie in: (I) preoperative immunotherapy boosts anti-tumor immunity by priming new T cell responses against tumor neoantigens while the tumor is still present. In the adjuvant setting, only neoantigens from micrometastatic disease remain, leading to less immune priming and activation; (II) postoperative immunosuppression from surgical stress hinders new T cell priming and activation, potentially reducing the effectiveness of adjuvant immunotherapy with checkpoint blockade.

Early (within 2 years of treatment) and late (more than 2 years) recurrences in HCC have different mechanisms, risk factors, and prognoses. Early recurrence results from occult intrahepatic metastases linked to tumor burden. In contrast, late recurrence is generally due to a new neoplasm, with risk factors related to the underlying liver disease, such as cirrhosis and ongoing liver injury. Pre- or postoperative systemic therapies can reduce the risk of early recurrence for patients with high-risk recurrence factors by decreasing occult intra- and extrahepatic dissemination. However, these treatments do not improve liver function or address the underlying cause. De novo tumorigenesis associated with late recurrence remains an issue. Antiviral treatment for chronic HBV infection in post-surgery HCC patients is particularly noteworthy. Distinguishing between intrahepatic metastasis from the primary lesion and de novo tumorigenesis is crucial for determining appropriate individualized treatment strategies.

Conclusions

The management of resectable HCC faces significant challenges due to an unacceptable recurrence rate, particularly early recurrences, and a dismal long-term prognosis following curative hepatectomy or LT. Addressing the imperative issue of preventing recurrence through neoadjuvant treatment strategies is essential to improve the long-term survival of HCC patients. Neoadjuvant therapy involving immunotherapy, particularly ICIs, seems to exhibit the most promising characteristics to signify a groundbreaking shift in HCC treatment, especially when combined with anti-angiogenic therapies and LRT. Ongoing trials will validate the safety and efficacy of systemic therapy in neoadjuvant settings, offering solutions to currently unanswered questions (Table 2). Further research is needed to clarify which HCC patients are suitable candidates for neoadjuvant therapy, to identify biomarkers predicting therapy response, to establish the optimal treatment regimen, and to determine the ideal timing for surgery. These advancements will subsequently change the current practice of resectable tumor in patients with HCC in the near future.

Acknowledgments

None.

Footnote

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