Neoadjuvant therapy: Dawn of reducing the high post-surgery recurrence rate of hepatocellular carcinoma

Abstract

The high postoperative recurrence rate remains a major challenge in the treatment of hepatocellular carcinoma (HCC) following resection. Increasing research has been delved into investigating the role of neoadjuvant therapy on the prognosis of resectable HCC. Recent trends in combination therapy with molecularly targeted agents and immune checkpoint inhibitors have significantly improved the efficacy of systemic antitumor treatments, yielding survival benefits exceeding 40%. Neoadjuvant therapy for HCC, whether based on systemic antitumor treatments, locoregional therapies, or their combination, has emerged as a promising research direction. However, there remains a matter of debate on neoadjuvant therapy. In this review, we summarize and discuss the research progress and challenges of neoadjuvant therapy for HCC over the past five years from the perspective of Chinese guidelines to provide new insights and future directions in this field.

Key Words: Hepatocellular carcinoma; Neoadjuvant therapy; Locoregional therapy; Molecularly targeted drug; Immune checkpoint inhibitor

Core Tip: Currently, numerous articles focus on preoperative antitumor therapy for hepatocellular carcinoma (HCC). Of note, this review uniquely examines neoadjuvant therapy for HCC within the context of combination therapy from the perspective of the China Liver Cancer Stage. Drawing on the Chinese guidelines, it addresses the definition of the neoadjuvant therapy concept, identifies the target population, evaluates the outcomes of various treatment strategies, and discusses the challenges regarding neoadjuvant therapy for HCC.

INTRODUCTION

Primary liver cancer has long been a significant burden on global healthcare, affecting the Western Pacific region, including China, in a disproportionate manner, with approximately 80% of cases being hepatocellular carcinoma (HCC)[1]. The latest data from the World Health Organization indicate that up to 71% of new cases of HCC worldwide are in the Western Pacific region, with 42% of cases in China[2]. Despite surgical resection of the tumor, the 5-year postoperative recurrence rate is still as high as 40%-70%. These findings indicate that HCC is a highly recurrent disease with a poor prognosis[3].

In China, a country with a high incidence of HCC, guidelines for the diagnosis and treatment of HCC emphasize a more aggressive surgical strategy, focusing on the extent of the tumor burden. Hepatic resection for patients with Barcelona Clinic Liver Cancer stage (BCLC) B/C HCC with normal liver function, large isolated tumors, multinodular tumors, macrovascular invasion, or portal hypertension is considered to have a higher long-term survival rate than other nonsurgical treatment modalities. The key to enhancing the prognosis of patients with HCC is to reduce the elevated recurrence rate observed in patients following surgical intervention. This has become a central focus for researchers globally, including those in China.

Consequently, the investigation of neoadjuvant therapy aimed at reducing the incidence of postoperative recurrence is gaining special interest within the field of clinical research. With the combination of molecularly targeted drugs and immune checkpoint inhibitor (ICI) treatment becoming mainstream, neoadjuvant therapy has great potential advantages. Nonetheless, neoadjuvant strategies are still controversial in many aspects, such as patient selection, timing of interventions, and efficacy of therapy. Currently, there is no uniform standard for neoadjuvant therapy for HCC, and issues such as personalized regimens still need to be further explored.

This review offers a comprehensive and systematic overview of HCC neoadjuvant therapy, encompassing key issues such as the conceptualization of the treatment, the population for which it is indicated, neoadjuvant therapy studies in HCC published in the last five years, the current challenges of the therapy and ongoing clinical studies.

THE CONCEPT OF NEOADJUVANT THERAPY AND TARGET POPULATION

Neoadjuvant therapy first emerged in the 1980s[4,5]. Since then, the concept of neoadjuvant therapy and related concepts have undergone continuous improvement. Concurrently, related concepts in the treatment of HCC have also evolved. According to the most recent Chinese guideline for diagnosis and treatment of primary liver cancer (2024 edition), neoadjuvant therapy is defined as the preoperative treatment of patients who are eligible for surgical resection but have high-risk factors for postoperative recurrence[6,7]. Thus, studies on HCC that are not candidates for surgical resection, and studies on antitumor therapy prior to other radical treatments such as ablation and liver transplantation, are excluded.

The independent risk factors of neoadjuvant therapy include the number and size of the tumor the number and size of the tumor, microvascular invasion (MVI), invasive biological characteristics (such as preoperative alpha-fetoprotein level), the severity of chronic liver disease, and surgery-related factors. In accordance with the criteria set forth by the China Liver Cancer Stage (CNLC), surgical resection is a viable option for all stages, from Ia to IIIa[6]. Nevertheless, there is no evidence that patients with stage Ia disease can benefit from neoadjuvant therapy[8]. Furthermore, they may also forfeit the opportunity for surgical intervention due to adverse effects or insensitivity to neoadjuvant therapy; therefore, neoadjuvant therapy is not recommended for patients with stage Ia disease. Furthermore, patients with HCC presenting with CNLC IIb/IIIa have a high tumor load and poor biological behavior compared with patients with early-stage HCC. It is therefore recommended that neo-adjuvant therapy should be carried out with caution following a multidisciplinary discussion and consent process (Figure 1).

Figure 1 Hepatocellular carcinoma patients recommended for neoadjuvant therapy in the Chinese guideline for diagnosis and treatment of hepatocellular carcinoma (2024 edition). CNLC: China Liver Cancer Stage; PS: Performance status. Created by figdraw.com (Supplementary material).

Overall, the overarching objective of neoadjuvant therapy is to facilitate curative transformation in patients, thereby extending their long-term survival prospects. Neoadjuvant therapy is recommended for patients with CNLC Ib/IIa and selected IIb/IIIa HCC that are suitable for surgical resection.

RESEARCH PROGRAMS FOR NEOADJUVANT THERAPY IN THE LAST FIVE YEARS

Locoregional therapy in neoadjuvant therapy

Interventional therapy: Transcatheter arterial chemoembolization (TACE) represents the earliest explored avenue of neoadjuvant therapy for HCC and is currently the most commonly utilized interventional therapy for HCC. In recent years, the clinical value of neoadjuvant TACE has become evident, largely owing to advances in technology, including superselective embolization and drug-loaded microsphere embolization (Table 1)[9,10].

Table 1 Summary of neoadjuvant locoregional therapy studies in hepatocellular carcinoma in the last five years.

Disease	HCC stage/liver function	Treatment arms (n)	Neoadjuvant duration (weeks)	Preoperative stopping time (weeks)	Median follow-up (months)	Primary endpoints findings	Ref.
Resectable HCC	BCLC A/B exceeding the Milan criteria	Neoadjuvant TACE (82) vs direct surgery (82)	4-6	NA	36	1-year OS (97.2% vs 82.4%); 2-year OS (88.4% vs 60.4%); 3-year OS (71.6% vs 45.7%; P = 0.0011)	Fang et al[11]
Resectable HCC (> 5 cm)	NA	Neoadjuvant TACE (60) vs direct surgery (324)	NA	NA	24	DFS (P = 0.935); OS (P = 0.172)	Giannone et al[12]
Resectable HCC (> 5 cm)	Child-Pugh A/B	Neoadjuvant TACE (30) vs Direct surgery (30)	12	NA	24	2-year DFS (P = 0.7045)	Kobayashi et al[13]
Resectable HCC with PVTT	Child-Pugh A	Neoadjuvant HAIC (65) vs direct surgery (55)	9.6	NA	36	1-year OS (94.9% vs 84.6%); 3-year OS (78% vs 47.6%); 5-year OS (66.4% vs 37.2%; P < 0.001)	Hu et al[16]
Centrally located resectable HCC	Child-Pugh A	Neoadjuvant IMRT (41) vs direct surgery (121)	5-6	4-12	45	1-year OS (95% vs 82%); 3-year OS (70% vs 64%); 5-year OS (70% vs 54%; P = 0.0099); 1-year DFS (71% vs 52%); 3-year DFS (53% vs 38%); 5-year DFS (37% vs 34%; P = 0.034)	Wei et al[19]
A single and small (≤ 5 cm) HBV-related resectable HCC	BCLC A	Neoadjuvant IMRT (30) vs direct surgery (30)	NA	4	68	DFS (P = 0.448)	Salem et al[20]

TACE: Transcatheter arterial chemoembolization; HAIC: Hepatic artery infusion chemotherapy; IMRT: Intensity modulated radiotherapy; HCC: Hepatocellular carcinoma; PVTT: Portal vein tumor thrombus; BCLC: Barcelona Clinic Liver Cancer; OS: Overall survival; DFS: Disease-free survival; NA: Not available.

Fang et al[11] conducted a randomized controlled trial of 164 patients with BCLC stage A/B disease beyond the Milan criteria. The overall survival (OS) and progression-free survival (PFS) rates were significantly higher in the neoadjuvant TACE group than in the hepatectomy-only group (HR: 0.3602; 95%CI: 0.1914-0.6779; P = 0.0011). This trial also showed the safety of neoadjuvant TACE therapy since no considerably increased incidence of serious adverse events. Furthermore, a European multicenter retrospective study was conducted to explore the efficacy of neoadjuvant TACE therapy in patients with resectable HCC larger than 5 cm[12]. Compared with the pre-resection group, the neoadjuvant TACE group did not significantly differ in terms of disease-free survival (DFS; HR: 1.017; 95%CI: 0.676-1.530; P = 0.935) or OS (HR: 0.670; 95%CI: 0.373-1.202; P = 0.172). Remarkably, further subgroup analyses revealed TACE improved OS only in patients with HCC larger than 0 cm (HR: 0.258; 95%CI: 0.061-1.093; P = 0.045), whereas it was identified as a critically significant factor in patients with portal vein tumor thrombus (PVTT; HR: 0.523; 95%CI: 0.245-1.118; P = 0.087) and single giant HCC (HR: 0.478; 95%CI: 0.221-1.030; P = 0.052). Japanese scholars have also reached similar conclusions regarding neoadjuvant therapy for resectable HCCs larger than 5 cm[13]. Additionally, a meta-analysis of five studies, including 1556 patients with HCC larger than 5 cm, also indicates that the long-term survival impact of neoadjuvant TACE is contingent upon the specific chemotherapy regimen employed[14]. Compared with single-agent chemotherapy, the combination of chemotherapeutic agents was associated with superior outcomes in terms of OS and DFS. However, the impact on intraoperative bleeding was found to be limited.

In addition to TACE, hepatic arterial infusion chemotherapy (HAIC) is also employed as a neoadjuvant interventional therapy for HCC. Neoadjuvant TACE can result in a severe inflammatory response called postembolization syndrome, which may increase the risk of bleeding in the context of subsequent surgical procedures[15]. In contrast, HAIC avoids this limitation by eschewing embolic agents and producing a lesser degree of inflammatory response.

A team of researchers from Sun Yat-sen University investigated a study to investigate the survival benefit of neoadjuvant HAIC in patients with resectable HCC and PVTT[16]. The OS rates at 5 years (OR: 0.88; 95%CI: 0.47-1.65) and recurrence-free survival (RFS) rates at 5 years (OR: 0.75; 95%CI: 0.28-1.98) were greater in the neoadjuvant HAIC group than in the surgical group. Furthermore, the combination of HAIC and TACE has been demonstrated to increase survival in patients[17]. These data suggested that TACE in conjunction with HAIC therapy is associated with a higher conversion rate and improved PFS in patients with initially unresectable HCC. Additionally, the incidence of grade 3/4 adverse events appeared to be comparable between the two groups. Therefore, TACE-HAIC may be regarded as a more efficacious alternative, paving the way for neoadjuvant interventions.

Taken together, the use of neoadjuvant interventions is more beneficial in patients with larger tumors and high-risk recurrence factors, such as PVTT, who are selected for such therapy. The promotion of refined therapy concepts, such as super-selective embolization, has broadened the scope for benefit among patients undergoing neoadjuvant therapy. Notably, the use of intervention as a standalone neoadjuvant therapy is not a common practice, both domestically and internationally.

Radiotherapy: Neoadjuvant radiotherapy may reduce postoperative recurrence rates and improve postoperative survival (Table 1).

A retrospective study conducted at Peking Union Medical College Hospital examined the long-term survival rates of patients with central HCC who underwent neoadjuvant radiotherapy[18]. The findings of the present study indicated that, in comparison with surgical resection alone, there was a notable distinction in OS (HR: 0.47; 95%CI: 0.24-0.93; P = 0.0099) and DFS (HR: 0.56; 95%CI: 0.34-0.92; P = 0.034) between the neoadjuvant radiotherapy group and the surgical group alone. Another researcher investigated patients with hepatitis B virus-associated small HCC who were at high risk of MVI[19]. The presence of MVI had a significant effect on the survival outcomes of these patients. However, neoadjuvant intensity-modulated radiotherapy has a favorable response rate and minimal toxicity.

Furthermore, internal radiation therapy has the potential to be a valuable addition to HCC therapy as a neoadjuvant radiotherapy option. It is believed to be a viable alternative to TACE in terms of efficacy and safety[20]. Nevertheless, it has not been employed on a significant scale for the treatment of HCC patients in China, largely because of the elevated cost and the paucity of data pertaining to HCC patients in China.

The advent of sophisticated technologies such as 3D conformal radiotherapy and intensity-modulated radiotherapy has enabled the delivery of higher doses of radiation with greater precision to the target area. This has led to an increased tumor response rate and a reduction in the incidence of therapy-related side effects. It is therefore evident that precision radiotherapy represents a key area of ongoing development.

Systemic antitumor treatment in neoadjuvant therapy

Systemic antitumor treatment represents a significant treatment modality for patients with HCC at all stages of disease progression. This approach primarily encompasses the use of molecular targeted drugs and ICI treatment. Particularly the “T-A regimen” (atezolizumab plus bevacizumab), which received approval in 2020, has represented a significant advancement in the field of systemic antitumor treatment for HCC[21]. Subsequent regimens, including sintilimab plus a bevacizumab biosimilar and camrelizumab plus rivoceranib, have demonstrated comparable efficacy[22,23]. At present, this combination therapy is gaining recognition as a standard approach. Another significant advancement in immune drugs was the success of the dual immune combination regimen of tremelimumab plus durvalumab (STRIDE regimen) in 2022. This finding was subsequently validated in further studies in Asian subgroups[24,25]. Nevertheless, the utilization of systemic antitumor treatment in the neoadjuvant therapy of HCC remains an area of ongoing investigation (Table 2).

Table 2 Summary of neoadjuvant systemic antitumor treatment studies in hepatocellular carcinoma in the last five years.

Disease	HCC stage/liver function	Treatment arms (n)	Neoadjuvant duration (weeks)	Preoperative stopping time (weeks)	Median follow-up (months)	Primary endpoints findings	Ref.
Resectable HCC	AJCC stage Ib, II, and IIIb	Neoadjuvant cemiplimab (21)	6	4	NA	Significant tumor necrosis: 20% (4/20)	Marron et al[26]
Locally advanced resectable HCC	Child-Pugh A	Neoadjuvant cabozantinib + nivolumab (15)	8	4	12	AEs: 93.3% (14/15)	Ho et al[27]
Resectable HCC	CNLC IIb/IIIa	Neoadjuvant camrelizumab + apatinib (18)	6	7	12	MPR: 17.6% (3/18); pCR: 5.9% (1/18)	Xia et al[28]
Resectable HCC	Child-Pugh A	Neoadjuvant nivolumab + ipilimumab (14) vs nivolumab (13)	6	NA	24.6	Grade 3 AEs: 43% (6/14) vs 23% (3/13)	Kaseb et al[29]

HCC: Hepatocellular carcinoma; AJCC: American Joint Committee on Cancer; CNLC: China Liver Cancer Stage; AEs: Adverse events; MPR: Major pathological response; NA: Not available.

A single-arm phase II study was conducted to evaluate the efficacy of cemiplimab in patients with neoadjuvant HCC[26]. With the exception of one patient in whom lymph node metastasis was identified intraoperatively and the procedure was therefore aborted, the remaining 20 patients underwent successful surgical resection under the guidance of an external medicine specialist. The disease control rate (DCR) was 100%, with an objective response rate (ORR) of 35%. However, the long-term efficacy of this treatment has not been disclosed because of the limited follow-up period. The feasibility of cabozantinib in combination with nivolumab was evaluated in a study of neoadjuvant therapy for borderline or locally advanced HCC[27]. A major pathological response (MPR) was achieved in 33.33% (5/15) of the patients, and no significant adverse events were observed in any of the patients. This highlights the initial instance of molecularly targeted drugs being employed in conjunction with ICI treatment in the context of neoadjuvant therapy for HCC. The team led by Academician Xue-Hao Wang conducted a phase II clinical study of perioperative treatment with camrelizumab plus rivoceranib[28]. The results demonstrated an ORR of 33.33% (6/18) and a 1-year PFS rate of 53.85% (95%CI: 24.77-75.99%). During the neoadjuvant therapy phase, 16.7% (3/18) of patients reported adverse events of grade 3/4, indicating that the regimen was safe and manageable. Furthermore, the article emphasizes the necessity of postoperative adjuvant therapy to increase the low pathological response rates associated with low-intensity neoadjuvant therapy. The results of a subsequent phase II clinical trial of dual-immunity combination therapy, the nivolumab plus ipilimumab regimen for the perioperative treatment of HCC, demonstrated that the median PFS in the dual-immunity combination group was 19.53 months [95%CI: 2.33-not estimable (NE)], whereas it was 9.4 months (95%CI: 1.47-NE) in the immunological monotreatment group[29]. Additionally, 33% (95%CI: 7.5%-70.1%) of patients in the combination therapy group achieved an MPR. In the combination therapy group, adverse effects were observed, yet overall safety and tolerability were maintained. Concurrently, many neoadjuvant systemic antitumor treatment studies are currently in progress[30-32].

In summary, in current systemic antitumor treatments for HCC, molecularly targeted drugs or ICIs have limited efficacy and are easily tolerated; thus, combination therapy has become mainstream. However, further studies including neoadjuvant therapy with larger samples and longer follow-up periods are needed.

Combined locoregional and systemic antitumor treatment in neoadjuvant therapy

As both local therapies (vascular intervention, radiotherapy) and systemic antitumor therapies (molecular targeted drug treatment, ICI treatment) have their own therapeutic advantages and different antitumor mechanisms, attempting to combine therapeutic approaches to explore potential synergistic effects to improve patient survival is currently an important trend in the treatment of HCC (Table 3).

Table 3 Summary of neoadjuvant locoregional combined with systemic antitumor treatment studies in hepatocellular carcinoma in the last five years.

Disease	HCC stage/liver function	Treatment arms (n)	Neoadjuvant duration (weeks)	Preoperative stopping time (weeks)	Median follow-up (months)	Primary endpoints findings	Ref.
Resectable HCC	BCLC 0-A/CNLC I	Neoadjuvant tislelizumab + SBRT (20)	4	4	60	Delay of surgery: 0; AEs: 100%; Grade 3 AEs: 40% (8/20); Grade 4 or 5 AEs: 0; ORR: 63.2% (12/19); DCR: 100%; pCR: 10.5% (2/19)	Li et al[34]
Resectable HCC	CNLC II	Neoadjuvant TACE + ICIs (20)	8-22	4	24	ORR: 75.0% (15/20); DCR: 100.0%; 1-year DFS: 86.6%; 1-year OS: 100.0%; 2-year OS: 76.4%	Zhu et al[35]
Resectable or borderline Resectable HCC	CNLC Ib/IIa/IIIa	Neoadjuvant TACE + tislelizumab (41) vs direct surgery (41)	6	4	24	AEs: 87.8% (36/41); pCR: 31.7% (13/41); MPR: 43.9% (18/41); incidence of MVI: 4.9%	Zhao et al[36]
Resectable HCC	CNLC Ib-IIIa	Neoadjuvant lenvatinib + ICIs + TACE (24) vs direct surgery (76)	9	3	24	1-year OS (100% vs 92.1%); 2-year OS (100% vs 48.7%; P = 0.003)	Wu et al[37]
Resectable HCC with Cheng’s type I/II PVTT	Child-Pugh A	Neoadjuvant TKIs + ICIs + TACE (33) vs direct surgery (105)	6	4	60	1-year RFS (75.0% vs 55.0%); 3-year RFS (61.3% vs 22.7%); 5-year RFS (61.3% vs 19.9%; P = 0.002)	Hou et al[38]
Resectable HCC with macrovascular invasion	CNLC IIIa	Neoadjuvant TKIs + ICIs + TACE/HAIC/RT (22) vs direct surgery (40)	16	4	24	RFS (P = 0.046)	Wu et al[39]

TACE: Transcatheter arterial chemoembolization; HAIC: Hepatic artery infusion chemotherapy; SBRT: Stereotactic body radiotherapy; HCC: Hepatocellular carcinoma; PVTT: Portal vein tumor thrombus; BCLC: Barcelona Clinic Liver Cancer; CNLC: China Liver Cancer Staging; OS: Overall survival; AEs: Adverse events; DFS: Disease-free survival; ORR: Objective response rate; MPR: Major pathological response; pCR: Pathological complete response; RFS: Recurrence free survival; DCR: Disease control rate; MVI: Microvascular invasion; TKIs: Tyrosine kinase inhibitors; ICIs: Immune checkpoint inhibitors; RT: Radiotherapy.

Radiotherapy has previously been considered to have the advantages of altering the HCC tumor microenvironment and facilitating the synergistic effect of systemic antitumor agents[33]. In a phase Ib clinical trial, 20 patients with BCLC stage 0-A HCC received neoadjuvant therapy with stereotactic body radiotherapy combined with tislelizumab[34]. The ORR was 63.2%, and the DCR was 100%. There were no surgical delays in any of the patients, and there was no increase in surgical difficulty or complications. During neoadjuvant therapy, no grade 4/5 adverse events occurred in any patients. In 2023, Zhu et al[35] reported a study of neoadjuvant therapy in 20 cases of resectable HCC with TACE in combination with camrelizumab/sintilimab. The ORR and DCR in the neoadjuvant group were 75.0% and 100.0%, respectively, with 70.0% of patients successfully downstaged. However, the study revealed a limited survival benefit in the neoadjuvant group compared with the surgery-only group (P > 0.05). In contrast, another protocol involving neoadjuvant TACE and tislelizumab monoclonal antibodies for the treatment of resectable or critically resectable HCC showed a significant survival benefit[36]. Patients receiving neoadjuvant therapy had significantly better PFS (P = 0.041) and OS (P = 0.006) than those receiving surgery alone. The incidence of MVI in the neoadjuvant group was 4.9%, whereas it was greater than 60% in the surgery-alone group. There was only one grade 3/4 event (elevated ghrelin transaminase). A study by Wu et al[37] with HCC treated with neoadjuvant TACE combination with lenvatinib and ICIs (sintilimab/camrelizumab/tislelizumab/pembrolizumab/toripalimab) also supported previous observations. In the neoadjuvant group with the triplet regimen of TACE combined with lenvatinib and ICI, 83.3% of patients achieved an objective response and had significantly longer DFS (P = 0.019) and OS (P = 0.003) than did the surgery-alone group. Another study supporting the survival benefit perspective included 138 patients with resectable HCC with type I/II PVTT treated with a similar regimen and reported that 78.8% of patients achieved an objective response, and neoadjuvant therapy was an independent protective factor for OS (HR: 0.433; 95%CI: 0.195-0.964; P = 0.040) and RFS (HR: 0.458; 95%CI: 0.233-0.897; P = 0.023)[38].

One study focused on the postoperative safety of combined neoadjuvant regimens[39]. A total of 20 multicenter patients receiving different regimens of combined local, targeted drug, and ICI neoadjuvant therapy for HCC were included. The study concluded that neoadjuvant therapy markedly decreased the hazard of tumor recurrence (HR: 0.39; 95%CI: 0.15-0.98; P = 0.046), and in patients with HCC with macrovascular invasion, combined neoadjuvant therapy significantly reduces the rate of tumor recurrence (P = 0.018) and maintains a relatively safe profile in the postoperative period. However, this therapy can also cause chronic liver injury and increase the risk of nontumor-related death (P = 0.036). Therefore, combined neoadjuvant local and systemic antitumor treatment reduces tumor recurrence and achieves survival benefits with overall safety and control.

Some of the ongoing clinical trials are promising. A trial of cadonilimab, the world's first clinical-stage PD-1/CTLA-4 bispecific antibody, in combination with HAIC for neoadjuvant therapy of patients with resectable CNLC Ib/IIa HCC is ongoing[40]. Two other clinical trials of local combined systemic antitumor neoadjuvant therapy from Sichuan University Huaxi Hospital and Tsinghua Changgeng Hospital are also ongoing, and the results of these trials are expected to be published gradually in the future[41,42].

CURRENT CHALLENGES OF NEOADJUVANT THERAPY

Effects on surgery

Neoadjuvant therapy may produce an inflammatory response in the tissue, increasing the probability of tissue fibrosis, which in turn has an impact on the difficulty of maneuvering during surgery. One study revealed that cancer-associated fibroblasts significantly remodel during neoadjuvant therapy, differentiating into new cell subtypes, which may increase the complexity of surgical resection[43]. It has been suggested that significant tissue fibrosis/inflammation may occur within the tumor tissue after neoadjuvant therapy, which may affect the anatomy at the time of surgery and make tumor resection more difficult[44]. However, it has also been suggested that even though intraoperative adhesions are more severe in patients after neoadjuvant therapy, they do not affect the surgical operation, and instead, the median time of surgery can be shortened owing to tumor downstaging[45]. Thus, at this point in time, there is still a lack of conclusive evidence on the impact of neoadjuvant therapy on the difficulty of performing intraoperative operations due to tissue fibrosis, and most of the studies did not analyze in detail the intraoperative challenges faced by the surgeon; thus, there is still some controversy on this issue.

Another effect of neoadjuvant therapy on surgical maneuvers is bleeding. Some molecularly targeted drugs inhibit tumor neovascularization by blocking the VEGF pathway[46]. This blocking effect not only affects the tumor vasculature but also may affect the generation and proliferation of normal vascular endothelial cells, leading to decreased vascular renewal and thus increasing the risk of bleeding. For example, anti-angiogenic targeted drugs such as bevacizumab may lead to increased liver texture fragility, thereby increasing intraoperative bleeding and surgical difficulty. This type of bleeding differs from mucosal bleeding in that its incidence is closely related to the anatomical location of the tumor, the type of histopathology, and the different drugs or doses used[47]. This calls for the surgeon to assess the patient's risk of bleeding carefully before performing the procedure take appropriate preventive measures and choose the right time for intervention. The intraoperative use of new materials is also an option worth considering[48].

Careful timing of interventions

As part of the perioperative treatment, neoadjuvant therapy plays only an auxiliary role, and the core is still subsequent surgery. If the emphasis on neoadjuvant therapy leads to significant delays or even delays in surgery, making HCC patients who could have received surgical resection lose the opportunity for surgery, this is not worth the loss. Therefore, controlling the timing of therapeutic interventions is particularly important. Several important timing points are of great concern. When to start neoadjuvant therapeutic intervention, when to end neoadjuvant therapeutic intervention, and when to perform surgery are all therapeutic interventions whose timing needs to be carefully chosen. With respect to the timing of neoadjuvant therapy, it is generally believed that neoadjuvant therapy should be initiated as soon as possible after the patient is admitted to the hospital and relevant examinations should be completed to avoid delaying the disease. In terms of the length of the neoadjuvant therapy cycle, according to the current consensus of neoadjuvant experts and related studies, the neoadjuvant therapy cycle should usually be given for 6-12 weeks, with a maximum of 16 weeks. The key is not to rely on imaging changes but rather to operate as soon as possible after the therapeutic goal is achieved[8]. Moreover, the timing of drug withdrawal needs to be carefully considered because of concerns about tumor progression and surgical safety. A short withdrawal period increases intraoperative and postoperative risks; a long withdrawal period increases the likelihood of postoperative recurrence. Currently, the minimum recommended discontinuation time is 4 weeks after the last TACE treatment, 2-4 weeks for ICIs, 1 week for small molecule targeted drugs, and 4-6 weeks for bevacizumab monoclonal antibodies to avoid the risk of intraoperative bleeding[7,8].

In future studies, the length of treatment time from the first neoadjuvant therapeutic intervention to the final intervention in HCC patients, the time from admission to surgery in HCC patients, and the time from the final neoadjuvant therapeutic intervention to discontinuation of the drug for surgical resection in HCC patients are worthy of focus as indicators of outcome.

Security concerns

Patients receiving neoadjuvant therapy may experience a decline in physical status, including treatment-related adverse events and increased perioperative liver function. In particular, with the current trend toward combination treatment regimens, the increased intensity of treatment may lead to improved outcomes but is also associated with an increased risk of perioperative complications. Previous studies evaluating TACE combined with targeted and ICI treatment in intermediate to advanced HCC patients compared with TACE alone or TACE targeted alone combined with ICI treatment have shown an increase in adverse events and an acceptable safety profile[49,50]. This emphasizes the complex balance between relevant efficacy and potential complications and the need for broader studies by expanding sample sizes, as well as targeted studies in neoadjuvant therapy.

In clinical practice, it should be noted that both local therapy, systemic antitumor therapy, and a combination of the two have unique advantages and limitations. Different treatments have different characteristics and cutting-edge changes. Standardized and accurate therapeutic decisions should be based on guidelines and high-level evidence-based medical evidence, as well as on the latest advances and research findings in each field. However, a single clinical department may have limitations and lags in other areas of therapeutic approaches, whether in terms of medication experience, timing of treatment, or updating of cutting-edge knowledge. Therefore, another effective initiative to reduce the adverse events and perioperative risks associated with neoadjuvant therapy is to conduct multidisciplinary treatment[51,52]. The communication and cooperation between multidisciplinary teams should be strengthened to ensure appropriate and individualized treatment decisions for patients, and timely assessment and intervention of adverse events are important measures to improve the safety of neoadjuvant therapy and even its efficacy in HCC patients.

Unpredictable efficacy

HCC, a highly heterogeneous malignancy, is resistant to treatment and causes headaches for many physicians[53,54]. Current neoadjuvant treatment regimens, regardless of their type, suffer from limited tumor response rates. Therefore, although the numerous neoadjuvant therapy study protocols vary and there are differences in the setting of study endpoints, the focus on and assessment of treatment response, such as objective remission rates, remains at the core of each study.

Postoperative efficacy is even more difficult to predict, and prognosis-related biomarkers seem to be important options. One study explored the significance of the platelet-lymphocyte ratio in radiotherapy[55]. Platelet-to-lymphocyte ratio (PLR) was found to be correlated with basic tumor characteristics, multiple oncologic factors, treatment outcomes, and toxicity. A high PLR was mostly associated with poor clinical features and prognosis. Similar observations were made in another study on the relevance of the neutrophil-to-lymphocyte ratio to patient survival after lenvatinib treatment[56]. The level of serum alpha-fetoprotein, a classical tumor marker, is still of great value in predicting, among other things, OS and the recurrence rate after resection[57]. Some emerging biomarkers are also popular for research. For example, one study reported that serum CXCL9 and LAG-3 levels were correlated with treatment efficacy and may be markers for predicting the response to the “T-A regimen”[58]. However, large sample studies on combination therapy and specific studies on neoadjuvant therapy are lacking. Moreover, some biomarkers are not routinely measured in clinical practice, and their monitoring may increase the difficulty of testing and the cost to the patient; thus, there is a need to emphasize more readily available biomarkers to increase clinical tractability. In addition, modeling predictive assessment is a promising line of research.

Thus, selecting appropriate study endpoints and identifying reliable biomarkers to predict the response to and prognosis of patients receiving neoadjuvant therapy are essential for guiding regimen selection, optimizing the timing of interventions, and assessing surgical prognosis in patients with HCC.

ONGOING CLINICAL STUDIES

We searched ClinicalTrials.gov for registered clinical trials and screened 43 clinical trials for neoadjuvant treatment of HCC under the CNLC concept (Supplementary Table 1). We found rich applications of neoadjuvant regimens, especially various combination regimens, including the combination of molecularly targeted agents with ICIs, the combination of “the dual immune combination regimen”, and the combination of local therapy with systemic antitumor therapy. It is encouraging that the control group in some studies was also expanded from the previous surgery-only group to the neoadjuvant therapy group without a combination regimen. This means not only the importance and safety of neoadjuvant therapy are recognized, but also that researchers are exploring more effective neoadjuvant options.

CONCLUSION

The advent of the era of combination therapy, represented by the “T-A regimen”, has revolutionized the treatment of HCC and significantly improved survival and prognosis. By integrating the study of neoadjuvant therapy with the study of perioperative treatment and achieving patient-centered, personalized management of the entire disease process, it is possible to further reduce the recurrence and metastasis rates of patients after surgery and improve long-term survival. To improve late-stage efficacy, overcoming the problem of drug resistance is particularly important. In the future, updating drugs with different targets and mechanisms of action, exploring different combinations of combination therapies, and developing new technologies such as oncolytic viruses, cancer vaccines, and gene/cell therapies may help overcome drug resistance[59-61]. Optimization of the original neoadjuvant treatment regimen is as important as the use of the new treatment regimen in subsequent clinical practice. In any country or region, the burden of treatment for oncology patients is still an issue that has to be considered. Anti-tumor treatment options should take into account local policies and health insurance support to identify the most appropriate options for patients. Postoperative recurrence of HCC is still a sword of Damocles that affects the prognosis of patients, and neoadjuvant therapy offers new options for patients to develop individualized treatment plans. The development of neoadjuvant therapy based on clinical trials in advanced HCC still requires continuous research in the selection of patient indications, timing of therapeutic interventions, and specific treatment protocols. Further high-quality basic or clinical studies are expected to provide more in-depth theoretical and clinical guidance for the preoperative and even perioperative management of HCC and to improve the clinical benefit for patients.

ACKNOWLEDGEMENTS

We would further like to extend thanks to Huan-Jun Yan, Jian-Lei Zhang, and Xu-Dong Wu for participating in guided article writing. The illustration was created with help of Figdraw.