Advancing the frontiers of hepatocellular carcinoma treatment: a comprehensive review of past, ongoing, and future clinical trials

Introduction

The incidence of hepatocellular carcinoma (HCC) around the world is increasing, with HCC as the fourth leading cause of cancer-mortality globally (1,2). HCC predominantly occurs in patients with underlying cirrhosis and is the most common cause of primary liver malignancy (3). Risk factors for HCC can vary depending on factors with varying incidences across different geographical locations, but most commonly due to underlying hepatitis B and C. The incidence of non-infective etiologies, such as non-alcoholic fatty liver disease, is noted to be increasing in certain localities and is thought to be partly contributory to the increasing incidence of HCC (1).

The management of HCC is based primarily on the stage of the underlying HCC as well as liver function and performance status, as illustrated by the Barcelona Clinic Liver Cancer (BCLC) guidelines (4). The modern-day treatment of HCC has evolved considerably and encompasses a wide range of management options, including transplantation, surgical resection, systemic therapy, stereotactic body radiotherapy (SBRT), and locoregional therapies (LRTs), such as thermal ablation, transarterial radioembolization (TARE), transarterial embolization (TAE), and transarterial chemoembolization (TACE).

This review outlines treatment options in HCC with a focus on LRTs, SBRT, systemic therapies, and combination approaches based on evidence from past, ongoing, and future clinical trials.

LRTs

The treatment options for patients in whom curative intent is sought include liver transplantation, surgical resection, image-guided ablation, and potentially radiation segmentectomy. Evaluation of evidence for liver transplantation and surgical resection lies beyond the scope of this article.

Image-guided LRTs for HCC include:

• Ablation:
  • Percutaneous ethanol injection (PEI);
  • Radiofrequency ablation (RFA);
  • Microwave ablation (MWA);
  • Cryoablation (Cryo);
  • Irreversible electroporation (IRE);
• Transarterial techniques:
  • TACE;
  • TAE;
  • TARE;
• SBRT.

In this section, each technique will be discussed, and clinical trial evidence for each will be presented. These modalities are summarized in Table 1.

Ablation

Liver ablation is a minimally invasive, image-guided treatment for HCC that destroys tumor tissue using thermal or nonthermal energy sources such as RFA, MWA, or IRE. It is most effective for small tumors (typically ≤3 cm) in patients with preserved liver function who are not surgical candidates. Ablation achieves local control rates comparable to surgical resection in selected cases, with the advantages of lower morbidity, shorter recovery time, and repeatability (37). Treatment success depends on complete tumor coverage and achieving an adequate ablative margin, while follow-up imaging is essential to confirm local tumor control and detect recurrence. A circumferential safety margin of 5 mm is recommended in consensus guidelines and validated in outcome studies, especially for HCC ≤3 cm in size (38). However, there is growing recognition of the need for real-time, intraprocedural assessment of ablation efficacy (39). Emerging evidence highlights the post-ablation safety margin, or minimal ablative margin (MAM), as a critical determinant of local control, with multiple studies indicating that an MAM of less than 5 mm is associated with an increased risk of local recurrence (39,40).

Ablation techniques used to treat HCC include PEI, RFA, MWA, Cryo, and IRE. Previous trials have evaluated ablation vs. surgery and compared various ablation techniques against one another.

RFA vs. surgical resection

RFA has been compared with surgical resection in several randomized controlled trials (RCTs) for the treatment of HCC, including Chen et al. [2006], Huang et al. [2010], Feng et al. [2012], Ng et al. [2017], Xia et al. [2020], Takayama (SURF trial) et al. [2022], Song et al. [2024] (Table 1) (5-11,37). Most trials have shown that RFA is comparable to surgical resection in effectiveness, with no statistically significant difference in overall survival (OS) or recurrence-free survival (RFS) between the two treatments (5-10). In one of the most recent RCTs (SURF trial) from 2022, 308 patients with HCC were treated with either surgical resection vs. RFA (10). This trial reported similar RFS between the two groups (median RFS of 3.5 years in the surgery group and 3.0 years in the RFA group). Surgery group had longer median procedure duration (274 vs. 40 min, P<0.01) and longer median duration of hospital stay (17 vs. 10 days, P<0.01) when compared to the RFA group (10). Most recent RCT from 2024 compared laparoscopic liver resection and RFA in 150 patients and found no significant difference in 5-year OS (74.7% vs. 67.9%) or RFS (51.6% vs. 41.0%) between the two groups (11).

RFA vs. PEI

RFA has been compared to PEI in multiple clinical trials, including Lencioni et al. [2003], Shiina et al. [2005], Lin et al. [2005], and Giorgio et al. [2011] (12-15). RFA demonstrated better outcomes in metrics such as RFS, OS, and local recurrence. The most recent RCT comparing RFA with PEI, was conducted in 2011, comparing 285 patients with single HCC (mean diameter, 2.2 cm) (15). The primary endpoint was 5-year survival. These trials demonstrated that RFA is more effective that PEI, offering improved OS and RFS. Therefore, PEI is almost completely replaced with RFA or other ablation techniques (Table 1).

RFA vs. MWA

At least three RCTs have compared RFA to MWA, all reporting similar OS and RFS, including Yu et al. [2017], Vietti Violi et al. [2018], and Sugimoto et al. [2025] (16-18). However, the most recent study from 2024 evaluated 240 patients with HCC lesions under 4 cm, comparing MWA to single-probe RFA. This study found that MWA was associated with significantly lower local tumor progression (LTP); 16.4% compared to 30.4% with RFA (P=0.007) (Table 1) (18).

RFA vs. Cryo

A multicenter RCL comparing RFA with Cryo showed a statistically significant improvement in LTP at 3 years with Cryo; 7% for Cryo vs. 11% for RFA (P=0.043), indicating slightly lower recurrence with Cryo (19). However, there were no significant differences between the two treatments in OS (at 5 years: 40% for Cryo, 38% for RFA, P=0.747) or tumor-free survival (at 5 years: 35% Cryo vs. 34% RFA, P=0.628) (Table 1) (19).

Summary and conclusion of ablation techniques

As ablation is a targeted, focal therapy, similar to surgical resection, its outcomes are best assessed using measures of technical success and LTP. However, regional (intrahepatic) recurrence is frequent, and the use of varied subsequent treatments can obscure the direct relationship between a specific local intervention and OS.

RFA, MWA, and Cryo have shown comparable OS and RFS. These modalities have largely replaced PEI, which is now reserved for select cases. Among them, MWA has been reported in at least one study to provide superior local tumor control.

TAE techniques

TAE is a technique wherein embolic material is used to occlude the arterial blood supply to the HCC. Similarly, TACE is a technique where chemotherapy (typically doxorubicin) is delivered directly to the arterial supply of the tumor, usually either in emulsion with lipiodol [also known as conventional TACE (cTACE)] or loaded onto particulate embolic material [also known as drug-eluting bead (DEB)-TACE]. TACE has also been delivered using a mixture of gelatin sponge and doxorubicin (20).

TACE

TACE vs. supportive care

TACE (doxorubicin with gelatin sponge) have been shown to be superior to conservative management in patients with unresectable disease in RCT by Llovet et al. [2002] (20). Similarly another RCT, Lo et al. [2002], comparing patients treated with cTACE (cisplatin in lipiodol) with conservative management, demonstrated a statistically significant survival advantage in the cTACE group (Table 1) (21).

cTACE vs. systemic therapy

In a 2009 RCT by Mabed et al., cTACE was compared with systemic chemotherapy in 100 patients with HCC (22). Fifty patients received cTACE using a combination of lipiodol, doxorubicin, and cisplatin, while the other 50 were treated with systemic doxorubicin alone. cTACE was associated with a significantly lower risk of tumor progression, with a median progression-free survival (PFS) of 32 weeks (range, 16–70 weeks) compared to 26 weeks (range, 14–54 weeks) in the systemic therapy group (P=0.03). However, there was no significant difference in median OS between the cTACE group (38 weeks) and the systemic chemotherapy group (32 weeks) (P=0.08), except in patients with serum albumin levels above 3.3 g/dL, where cTACE conferred a significant survival benefit (60 vs. 36 weeks, P=0.003) (Table 1).

cTACE vs. DEB-TACE

Multiple RCTs have compared the efficacy of cTACE vs. DEB-TACE, including Lammer et al. [2010] (PERCISION V study), Sacco et al. [2011], van Malenstein et al. [2011], Golfieri et al. [2014], and Ikeda et al. [2022] (JIVROSG-1302 study) (23-27). Two trials suggested no significant difference in 6-month objective response rate (ORR) (PERCISION V study) and 2-year OS rate, respectively (23,26). One trial has suggested that in patients undergoing selective cTACE, a significant difference was seen in the 3-month complete response rate, compared to the DEB-TACE treatment arm (27). However, studies suggest that DEB-TACE appears to be better tolerated compared to cTACE (23,27). The most recent RCT comparing cTACE and DEB-TACE in HCC is part of the 2025 NCT03778957 trial, the EMERALD-1 trial, which evaluated these modalities alongside a combination therapy durvalumab + bevacizumab + TACE vs. placebo + TACE (41). In this study, 409 patients with HCC were treated with TACE (n=121) or DEB-TACE (n=83) while receiving durvalumab + bevacizumab, compared to 205 patients in the control group that were treated with TACE (n=120) and DEB-TACE (n=85) and receiving placebo (41). In the subgroup analysis, patients treated with durvalumab + bevacizumab + cTACE achieved 19.4 months of PFS vs. 11.1 months in patients treated with durvalumab + bevacizumab + DEB-TACE [hazard ratio (HR) =0.80 vs. 0.74]. With placebo: cTACE had 11.1 months vs. DEB-TACE’s 6.7 months.

TACE with different chemotherapy agents

TACE has been evaluated in two RCTs using different chemotherapy agents, including Ikeda et al. [2018] and Zhu et al. [2022] (42,43). This has included comparative trials between miriplatin and epirubicin as well as dicycloplatin alone, dicycloplatin and epirubicin, or epirubicin alone. No significant difference was seen in OS between the miriplatin and epirubicin groups. However, a significant difference was seen in ORR in the dicycloplatin alone group (compared to the dicycloplatin and epirubicin group). Though not comparable, these studies suggest a potential differential in treatment efficacy depending on the chemotherapy agent(s) used.

TACE vs. transarterial ethanol ablation (TEA)

TACE (using cisplatin) has been evaluated against TEA in one RCT by Yu et al. [2014] (28). This study of 98 patients demonstrated no significant OS difference between the two treatment arms: 25.2 months in TEA vs. 21.5 months in TACE (P=0.32) (28). However, there were improved rates of complete tumor response, greater time to intralesional progression and PFS (TEA =13.1 months vs. TACE =8.7 months, P=0.049) in the TEA arm (28).

TAE

TAE vs. TACE

Three RCTs compared TAE vs. TACE, including Kawai et al. [1992], Chang et al. [1994], and Llovet et al. [2002] (20,29,30). In the pivotal RCT study by Llovet et al., patients were randomized to TACE, TAE, or best supportive care (20). The trial demonstrated a statistically significant survival benefit for TACE over supportive care, but no statistically significant difference was observed between TAE and supportive care.

TAE vs. DEB-TACE

Three RCTs have compared TAE with DEB-TACE, including Malagari et al. [2010], Meyer et al. [2013], and Brown et al. [2016] (31-33). Most recent RCT from Brown et al. treated 101 patients with HCC with TAE or DEB-TACE (150 mg LC beads). No significant difference was seen in PFS or OS between the two treatment arms (33) (Table 1).

TARE

TARE is undertaken by the delivery of radioactive particles (Yttrium-90) in a segmental or lobar fashion in order to treat HCC through localized radiation-induced tumor necrosis.

TARE vs. TACE

Two RCTs have compared TARE to TACE, including Kolligs et al. [2015] and Salem et al. [2016] (34,35). One of the most important clinical trials for TARE in the setting of unresectable HCC was the phase II trial by Salem et al., in which TARE was compared to TACE (PREMIERE trial) (35). Compared to TACE (n=21), TARE (n=26) was associated with a significantly longer time to progression (TTP) (>26 vs. 6.8 months) (35). The REPLACE phase III RCT (NCT04777851) is currently enrolling and will provide more definitive evidence by directly comparing TACE and TARE in intermediate-stage HCC, but results are not yet available.

TARE vs. DEB-TACE

In a recent phase II RCT, TARE was compared with DEB-TACE (TRACE study), with primary endpoints of TTP and OS (36). In this single-center study, 38 patients were treated with TARE and 34 with DEB-TACE. With a comparable safety profile, TARE provided significantly improved both TTP (median TTP of 17.1 months in TARE vs. 9.5 months in DEB-TACE, P=0.002) and OS over DEB-TACE (median OS =30.2 months in TARE group vs. 15.6 months in DEB-TACE group, P=0.006) (36).

Summary and conclusion of embolization techniques

TACE, TAE, and TARE have demonstrated similar OS outcomes. However, more recent clinical trials indicate that TARE offers a longer TTP compared to the other embolization methods.

SBRT

SBRT is a highly targeted external beam radiation technique for treating HCC, capable of achieving local tumor control rates approaching or exceeding 90% in appropriately selected patients (44). SBRT is not included in the current BCLC guidelines; however, it is recommended by the National Comprehensive Cancer Center for unresectable or medically inoperable HCC.

SBRT is primarily employed in individuals who are not suitable candidates for surgery, ablation, or other standard LRTs, and is increasingly being considered as an alternative or complementary option in complex clinical scenarios. SBRT demonstrates the greatest efficacy in HCC lesions measuring less than 6 cm and in patients with well-preserved hepatic function [Child-Pugh (CP) A] (45). Multiple studies, including prospective phase II trials, have reported 1-year local control rates of 82–96% and 1-year OS rates of 36–78% (46). However, long-term tumor control diminishes with increasing lesion size and worsening liver function (CP B/C), where the likelihood of treatment-related toxicity is higher. Additionally, SBRT has shown to be safe and effective in bridging patients with HCC to liver transplant. However, its role in downstaging is limited (47).

SBRT with sorafenib

The RTOGG1112 trial was the most recent randomized phase III study designed to evaluate the efficacy and safety of SBRT combined with sorafenib vs. sorafenib alone in patients with locally advanced, unresectable HCC. Eligible patients had CP A or B7 liver function and no extrahepatic metastases. The trial was a negative, demonstrating no statistically significantly improved OS in the combined group compared with sorafenib alone (48).

Systemic therapy

Systemic therapy for HCC has evolved rapidly, encompassing several therapeutic categories with distinct mechanisms of action. Tyrosine kinase inhibitors (TKIs) such as sorafenib and lenvatinib remain foundational first-line options. These drugs target angiogenic and proliferative signaling pathways (49). Immune checkpoint inhibitors (ICIs), including programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, have transformed the treatment landscape, particularly when used in combination regimens like atezolizumab-bevacizumab or durvalumab-tremelimumab (50,51). Beyond these, non-ICI systemic agents, such as anti-vascular endothelial growth factor (VEGF) antibodies, fibroblast growth factor (FGF) receptor inhibitors, and cytotoxic chemotherapy, are being explored in selected contexts or in combination with LRTs.

Systemic therapy is recommended for patients with intermediate stage disease or in whom surgical or locoregional interventional therapies have been deemed infeasible or have failed (4). The landscape of systemic therapy has evolved considerably in the last two decades. The different classes of systemic therapy and the evidence base supporting their use are considered further below and summarized in Table 2.

TKIs

TKIs are pharmacologic agents that target and block key pathways necessary for proliferation and survival in tumor cells (73,74). Generally, small molecule TKIs interfere with the catalytic domain of tyrosine kinase adenosine triphosphate bindings sites, which inhibit autophosphorylation of its substrate enzyme and prevent downstream activation of intracellular signal transduction cascades responsible for cellular proliferation and tumor angiogenesis (75,76). The introduction of the first Food and Drug Administration (FDA)-approved small molecule TKI, imatinib mesylate, in 2001 for treatment of chronic myeloid leukemia began an era of targeted molecular therapy and since, over 80 small molecular kinase inhibitors have been FDA-approved for cancer treatment (77). Despite significant progress with small molecule kinase inhibitors, high rates of systemic toxicity leading to premature treatment discontinuation and treatment failure associated with the gradual development of acquired drug resistance are challenges requiring further investigation (73).

Key TKIs used in HCC treatment

To date, six small-molecule TKIs have been FDA-approved for the treatment of advanced HCC. These include sorafenib, lenvatinib, donafenib, regorafenib, cabozantinib, and apatinib. Sorafenib, lenvatinib, and donafenib are considered first-line TKI therapies, and regorafenib, cabozantinib, and apatinib are second-line TKI therapies that are administered to patients with progressive disease after initial treatment (78). Sorafenib, the premier FDA-approved systemic therapy for HCC in 2007, is an inhibitor of several kinases primarily targeting Raf kinase isoforms involved in the RAF/MEK/ERK signaling pathway, angiogenic receptor kinases (VEGFR and PDGFR), and tumorigenic receptor kinases (c-Kit, FLT-3, and RET) (79-81). Similar to sorafenib, the subsequently FDA-approved TKIs for HCC have similar molecular structures and demonstrate inhibition of multiple kinases associated with tumor proliferation (81).

First-line TKIs—sorafenib

The landmark clinical trial supporting the use of sorafenib in patients with HCC was the multicenter randomized controlled phase 3 clinical trial (SHARP) based in Europe, North America, South America, and Australia (52). The SHARP trial randomized 602 patients consisting primarily of BCLC C (82%), Eastern Cooperative Oncology Group (ECOG) 0–1 (92%), and CP A (97%). Compared to the control group, patients treated with 400 mg of oral sorafenib twice daily demonstrated nearly 3 months longer median OS (10.7 vs. 7.9 months, P<0.001) and median time to radiologic progression (5.5 vs. 2.8 months, P<0.001). Following the SHARP trial, the ASIA-PACIFIC trial, a multicenter randomized controlled phase 3 clinical trial based in the Asia-Pacific region, demonstrated improved median OS (6.5 vs. 4.2 months, P=0.014) and longer median TTP (2.8 vs. 1.4 months, P=0.0005) in patients treated with sorafenib compared to placebo (53). Similar to the SHARP trial, the 226 randomized patients were primarily BCLC C (96%), ECOG 0–1 (95%), and CP A (97%). In combination, the results of these trials highlighted the clinical benefit of sorafenib for the treatment of HCC in patients across the world.

First-line TKIs—lenavtinib

Lenvatinib is a small molecule, multiple TKI that targets VEGFR1–3, FGFR1–4, PDGFR, RET, and c-KIT (82). Lenvatinib differs in comparison to sorafenib by inhibiting FGFR1–4, which also contributes to tumor tumorigenesis (83). The REFLECT trial was a multicenter, randomized phase 3 clinical study that assessed the non-inferiority of lenvatinib vs. sorafenib in the treatment of unresectable HCC (54). The study consisted of 954 patients with no prior treatments of systemic therapy and advanced disease burden represented primarily by BCLC C (79%), ECOG 0 (63%), and CP A (99%). The median OS was comparable at 12.3 months for lenvatinib and 13.6 months for sorafenib [HR =0.92; 95% confidence interval (CI): 0.79–1.06]. Lenvatinib compared to sorafenib showed improvement in median PFS (7.4 vs. 3.7 months, P<0.0001), TTP (8.9 vs. 3.7 months, P<0.0001), and ORR (24.1% vs. 9.2%, P<0.0001) per modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria. As a result, the REFLECT trial demonstrated that lenvatinib was non-inferior to sorafenib in OS for the treatment of untreated advanced HCC.

First-line TKIs—donafenib

Donafenib, the most recently FDA-approved TKI for HCC, is a novel modified version of sorafenib with a trideuterated N-methyl group with similar antiproliferative potency (84). The ZGDH3 study was an open-label, randomized parallel-controlled phase 2/3 clinical trial based in China that investigated the efficacy and safety of donafenib vs. sorafenib as first-line therapy for systemic therapy-naive patients with unresectable or metastatic HCC (55). A total of 659 patients, consisting primarily of BCLC C (87%), CP A (97%), and ECOG 1 (64%), were randomly assigned and treated with donafenib vs. sorafenib. A significantly longer median OS (12.1 vs. 10.3 months, P=0.0245) and higher 18-month survival rate (35.4% vs. 28.1%, P=0.0460) were seen with donafenib vs. sorafenib. There was no significant difference between the donafenib and sorafenib groups for median PFS (3.7 vs. 3.6 months, P=0.0570), median TTP (3.7 vs. 3.7 months, P=0.1029), and ORR (4.6% vs. 2.7%). As a result, the potential for donafenib as a first-line monotherapy in treating advanced HCC was demonstrated.

Second-line TKIs—regorafenib

Regorafenib is a small molecular multikinase inhibitor that differs molecularly from sorafenib by the addition of a fluorine atom to the central phenyl ring. Due to this change in chemical structure, regorafenib exhibits stronger activity against kinases targeted by sorafenib and additional inhibition of angiopoietin 1 receptor (TIE2) and FGFR1–2 (85). The RESORCE study was a multicenter, randomized phase 3 clinical trial based in North America, South America, Europe, Asia, and Australia that assessed the use of regorafenib in patients with HCC who have failed initial sorafenib treatment (56). The study randomized 573 patients with mostly BCLC C (87%), CP A (98%), and ECOG 0 (66%) into a placebo control and regorafenib group. Statistically significant improvement in median OS (10.6 vs. 7.8 months, P<0.0001), median PFS (3.1 vs. 1.5 months, P<0.0001), and median TTP (3.2 vs. 1.5 months, P<0.0001) with regorafenib compared to placebo was seen, which provided evidence for the use of regorafenib in patients who have failed initial sorafenib therapy for intermediate or advanced HCC.

Second-line TKIs—cabozantinib

Cabozantinib is a small molecule TKI that targets tumorigenic and angiogenic kinases such as VEGFR2, MET, RET, KIT, AXL, and FLT-3, exhibiting a different activity profile from sorafenib (86). In 2018, the CELESTIAL study evaluated the efficacy of cabozantinib compared to placebo for the treatment of patients previously treated with systemic therapy for advanced HCC (57). This international, double-blind, phase 3 clinical trial randomized 707 patients to receive cabozantinib or placebo. All patients had disease progression after prior treatment with sorafenib and were eligible if they had CP A liver function and ECOG performance status 0–1. Cabozantinib showed significantly longer median OS (10.2 vs. 8.0 months, P=0.005) and PFS per RECIST v1.1 (5.2 vs. 1.9 months, P=0.009) compared to placebo. Disease control rate per RECIST v1.1 was achieved in 64% and 33% of the patients in the cabozantinib and placebo group, respectively. The number of high-grade adverse events was increased with cabozantinib compared to placebo (68% vs. 36%). Overall, the CELESTIAL study demonstrated the clinical benefit of cabozantinib in patients previously treated with sorafenib for advanced HCC.

Second-line TKIs—apatinib

Apatinib is a small molecule TKI designed to primarily act as a potent inhibitor of VEGFR-2 and has been reported to have ten times more affinity for VEGFR-2 compared to sorafenib (87). Results of a multicenter, double-blind, randomized controlled phase 3 trial (AHELP study) demonstrated that apatinib significantly improved OS and PFS in patients with advanced HCC that were refractory or intolerant to prior systemic therapy (58). A total of 393 patients, mostly consisting of BCLC C (90%), ECOG 1 (75%), and CP A (95%), were randomly assigned and received apatinib or placebo. The median OS was 8.7 months in the apatinib group vs. 6.8 months in the placebo group (P=0.048). Median PFS was significantly improved with apatinib (4.5 vs. 1.9 months, P<0.0001).

ICIs

As a result of the improved understanding and characterization of immune response regulatory pathways during tumor development and proliferation, the use of ICIs has emerged as a novel therapeutic option for HCC. In addition to its angiogenic activity, tumor cells activate immune checkpoints to prevent immunological surveillance as a key mechanism for survival (88).

The common targets for ICI in HCC are the following surface glycoproteins: PD-1, PD-L1, and CTLA-4. When PD1 interacts with its ligands, a series of immunologic responses triggers apoptosis of antigen-specific T-cells in lymph nodes and reduces apoptosis in regulatory T-cells by signaling of CD28 and blocking T-cell receptors (89). Further, CTLA-4 regulates physiologically unnecessary T-cell activity. In cancer cells, CTLA-4 binds to B7-1 or B7-2 proteins, which prevent T-cells from recognizing and attacking cancer cells (90). Such immunologic pathways in cancer cells are complex and are not yet fully understood. However, inhibition of these pathways has been seen to lead to reactivation of immunologic response to cancer cells and clinical benefit when used as treatment in cancer patients. The clinical trial evidence base for ICIs is considered further.

ICIs—nivolumab

Nivolumab is a monoclonal antibody that binds to and inhibits the PD-1 receptor (91). The CheckMate 040 trial was an open-label, non-comparative, dose escalation and expansion, phase 1/2 trial that assessed the safety and efficacy of nivolumab as a monotherapy for HCC (59). Among the total cohort of 262 patients, the majority of the patients had prior systemic therapies (76%) and sorafenib (70%). The study demonstrated that nivolumab had a manageable safety profile and acceptable tolerability. The ORR was 20% for patients treated with 3 mg/kg nivolumab in the dose-expansion phase and 15% in the dose-escalation phase. At the five-year follow-up, median OS was 26.6 and 15.1 months for the sorafenib-naive and sorafenib-experienced patients, respectively (92). Additionally, the efficacy of nivolumab monotherapy compared to sorafenib was evaluated in an open-label, randomized phase 3 trial (CheckMate 459) (60). The CheckMate 459 trial involved a total of 743 patients with no prior systemic therapy treatment, CP A, and ECOG performance status 0 or 1. The study, however, did not show any improvement in OS between nivolumab vs. sorafenib (15.2 vs. 13.4 months, P=0.075).

ICIs—nivolumab and ipilimumab

The addition of ipilimumab, a CTLA-4 inhibitor, to nivolumab has shown improved clinical benefits in other tumor types (93). In a separate cohort of the CheckMate 040 phase I/II clinical trial, the safety and efficacy of the nivolumab plus ipilimumab were assessed in 148 patients with previously treated advanced HCC (61). All patients had CP A liver function, and ECOG performance status was less than 1. After a median follow-up of 30.7 months, results showed promising ORR of 27–32% across the treatment arms and a manageable safety profile. In a subsequent study, the CheckMate 9DW multi-center phase 3 randomized study is currently investigating the clinical benefit of nivolumab plus ipilimumab vs. standard of care (sorafenib or lenvatinib) as first-line treatment in treatment-naive advanced HCC (62). A total of 668 patients with ECOG performance status less than 1 and CP A liver function were included in the study. In the standard of care group, 85% of the patients received lenvatinib. Preliminary results demonstrated improved median OS in the nivolumab plus ipilimumab group compared to the standard of care group (23.7 vs. 20.6 months, P=0.0180). ORR per RECIST v1.1 was also higher with nivolumab plus ipilimumab than the standard of care group (36% vs. 13%, P<0.0001). The combined nivolumab plus ipilimumab, similar to the prior CheckMate 040 study, had a manageable safety profile. These preliminary results support the use of nivolumab plus ipilimumab as first-line systemic therapy for patients with unresectable HCC. Further findings of this study are pending the final published report.

ICIs—durvalumab and tremelimumab

Durvalumab is a monoclonal antibody that binds to PD-L1 and blocks the interaction between PD-L1 and PD-1 (94). Tremelimumab is a monoclonal antibody that blocks CTLA-4 (95). The key clinical trial for durvalumab and tremelimumab was HIMALAYA, a global, open-label, phase 3 clinical trial that compared the following three regimens: tremelimumab plus durvalumab (STRIDE), durvalumab, and sorafenib (63). A total of 1,171 patients with mostly ECOG 0 (62%), CP A (73%), and BCLC C (81%) were randomly assigned to receive these treatment regimens. One of the study objectives was to assess the noninferiority for OS of durvalumab monotherapy vs. sorafenib. Durvalumab monotherapy was noninferior to sorafenib with median OS of 16.56 vs. 13.77 months (P=0.0674) and PFS of 3.65 vs. 4.07 months and OS HR of 0.86 (95.67% CI: 0.73–1.03; noninferiority margin, 1.08). The HIMALAYA trial demonstrated significantly improved OS with the single dose of tremelimumab in combination with durvalumab (STRIDE) regimen vs. sorafenib. The STRIDE regimen involved one dose of 300 mg tremelimumab plus 1,500 mg of durvalumab every 4 weeks. The OS HR for STRIDE vs. sorafenib was 0.78 (96.02% CI: 0.65–0.93; P=0.0035). The median OS of STRIDE was 16.43 vs. 13.77 months for sorafenib. The findings of the HIMALAYA trial provided support for the survival benefit of durvalumab plus tremelimumab over sorafenib. In addition, results across the treatment groups suggest that the addition of a single dose of tremelimumab may provide long-term clinical benefits when combined with durvalumab therapy.

ICIs—tislelizumab

Tislelizumab is a humanized immunoglobulin G4 (IgG4) monoclonal antibody that binds to PD-1 and has been reported to be effective with a tolerable safety profile in treatment of various tumor types (96,97). Currently, tislelizumab is not FDA-approved for treatment of HCC, but an open-label, multicenter, randomized controlled phase 3 clinical study (RATIONALE-301) demonstrated that tislelizumab monotherapy is noninferior to sorafenib (64). The RATIONALE-301 study compared tislelizumab and sorafenib in a total of 570 patients with BCLC B/C, ECOG performance status less than 1, and CP A. Only patients who had no prior treatment with systemic therapy were included in the study. The median OS was comparable in the tislelizumab and sorafenib groups (15.9 vs. 14.1 months). The OS HR demonstrated noninferiority with tislelizumab vs. sorafenib (HR =0.85; 95.003% CI: 0.71–1.02; noninferior margin, 1.08). The ORR (14.3 vs. 5.4%) and median duration of response (36.1 vs. 11.0 months) were higher in the tislelizumab group compared to sorafenib. However, sorafenib had favorable median PFS (3.4 vs. 2.1 months) and disease control rates (50.3% vs. 44.2%). Overall, these findings suggest that tislelizumab may represent a potential first-line treatment option for advanced HCC.

ICIs—atezolizumab and bevacizumab

Atezolizumab is a monoclonal antibody that binds PD-L1, and bevacizumab is a monoclonal antibody that binds VEGF-A inhibiting angiogenesis (98,99). The IMbrave150 clinical study was a pivotal trial that demonstrated the improved OS and PFS outcomes with atezolizumab plus bevacizumab compared to sorafenib (65). This global, open-label, phase 3 RCT included 336 systemic treatment-naive patients with unresectable HCC. At 12 months, the OS was significantly longer with atezolizumab plus bevacizumab with estimated survival rates at 6 and 12 months of 84.8% and 67.2% in the atezolizumab plus bevacizumab group compared to 72.2% and 54.6% for the sorafenib group. The stratified HR for death was 0.58 (95% CI: 0.42–0.79; P<0.001). The atezolizumab plus bevacizumab group also experienced improved median PFS of 6.8 months compared to 4.3 months for sorafenib (HR =0.59; 95% CI: 0.47–0.76; P<0.001) and higher ORR based on both RECIST v1.1 (27.3% vs. 11.9%, P<0.001) and mRECIST (33.2% vs. 13.3%, P<0.001). Furthermore, updated findings after an additional 12 months of follow-up showed durable long-term clinically meaningful survival benefits of atezolizumab plus bevacizumab over sorafenib (100).

ICIs—atezolizumab and cabozantinib (TKI)

Following the positive results from the IMbrave150 trial with combined ICI plus antiangiogenic agent, the COSMIC-312 study assessed cabozantinib (TKI) plus atezolizumab vs. sorafenib as first-line systemic treatment for advanced HCC (66). COSMIC-312 was an open-label, randomized phase 3 clinical trial that included 837 systemic treatment-naive patients with advanced unresectable HCC. Most patients were ECOG performance status 0 (65%) and BCLC C (67%). All patients had CP A liver function. The participants were randomly assigned to a cabozantinib plus atezolizumab, sorafenib monotherapy, and cabozantinib monotherapy group. The median OS of the cabozantinib plus atezolizumab and sorafenib groups was comparable at 15.4 vs. 15.5 months (HR =0.90; 96% CI: 0.69–1.18; P=0.44), respectively. Despite not showing improvement in OS with the combination of cabozantinib plus atezolizumab therapy, there was an increase in median PFS by 2.6 months with cabozantinib plus atezolizumab compared to sorafenib.

ICIs—pembrolizumab

Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor (101). The use of pembrolizumab monotherapy for previously treated patients with advanced HCC was evaluated by the KEYNOTE-240 trial (67). This study was a randomized, double-blind, global, phase 3 clinical trial of patients with advanced HCC who were previously treated with sorafenib. A total of 413 patients were randomly assigned to receive pembrolizumab monotherapy vs. placebo. Pembrolizumab monotherapy did not meet statistical significance based on the prespecified criteria for median OS (13.8 vs. 10.6 months; HR =0.781; 95% CI: 0.611–0.998; P=0.0238) and PFS (3.0 vs. 2.8 months; HR =0.718; 95% CI: 0.570–0.904; P=0.0022).

The results of a follow-up study (KEYNOTE-394) demonstrated significantly improved OS, PFS, and ORR with pembrolizumab monotherapy vs. placebo in the Asian patient population (68). This study was a double-blind, phase 3 clinical trial including a total of 453 patients with advanced HCC previously treated with sorafenib or oxaliplatin-based chemotherapy. The median OS for the pembrolizumab vs. placebo group was 14.6 and 13.0 months (HR =0.74; 95% CI: 0.63–0.99; P=0.0180), respectively. The PFS (2.6 vs. 2.3 months, P=0.0032) and ORR (12.7% vs. 1.3%, P<0.0001) were also improved in the pembrolizumab group. In combination with the findings of KEYNOTE-240, these results provide support for pembrolizumab for second-line therapy in advanced HCC.

ICIs—pembrolizumab and lenvatinib (TKI)

Further investigation of pembrolizumab for HCC was recently completed in the LEAP-002 trial (69). This study was a randomized, double-blind, phase 3 clinical trial that evaluated the addition of pembrolizumab to lenvatinib for first-line treatment of unresectable HCC (69). A total of 794 patients with unresectable HCC, ECOG performance status less than 1, CP A liver function, and systemic treatment-naive were randomly assigned to the lenvatinib plus pembrolizumab or lenvatinib plus placebo groups. The median OS for the pembrolizumab plus lenvatinib group was 21.2 months compared to 19.0 months for the lenvatinib plus placebo group (HR =0.84; 95% CI: 0.71–1.00; stratified log-rank P=0.023). Median PFS was similar at 8.2 months (pembrolizumab + lenvatinib) and 8.0 months (lenvatinib + placebo) (HR =0.87; 95% CI: 0.73–1.02; stratified log-rank P=0.047). The results of LEAP-002 did not support a change in clinical practice because pembrolizumab plus lenvatinib did not meet the prespecified significance of the study.

ICIs—camrelizumab and rivoceranib (TKI)

Camrelizumab is a monoclonal antibody that binds to PD-1 (102). CARES-310 was a randomized, open-label, international phase 3 clinical trial that evaluated camrelizumab plus rivoceranib (TKI) compared to sorafenib in systemic treatment-naive patients with unresectable HCC (70). A total of 543 patients were 1:1 randomized to camrelizumab plus rivoceranib or sorafenib groups. Median OS was significantly improved with camrelizumab plus rivoceranib compared to sorafenib (22.1 vs. 15.2 months, P<0.0001). Median PFS was also improved at 5.6 and 3.7 months (P<0.0001) for the camrelizumab plus rivoceranib and sorafenib groups, respectively. The CARES-310 trial showed a clinically significant benefit in OS and PFS with camrelizumab plus rivoceranib compared to sorafenib for first-line treatment of patients with unresectable HCC.

ICIs—sintilimab and a bevacizumab biosimilar (IBI305)

Sintilimab is a human IgG4 monoclonal antibody that binds to PD-1 (103). A randomized, open-label, phase 2/3 study (ORIENT-32) trial evaluated sintilimab plus IBI305, a bevacizumab biosimilar, as first-line treatment of patients with unresectable hepatitis B virus (HBV)-associated HCC (71). A total of 595 patients with unrespectable HCC who had no prior systemic therapy, ECOG performance status less than 1, were included and assigned to receive sintilimab plus IBI305 or sorafenib. The sintilimab plus IBI305 group compared to sorafenib had significantly longer median OS (median not reached vs. 10.4 months; HR =0.57; 95% CI: 0.43–0.75; P<0.0001) and PFS (4.6 vs. 2.8 months, P<0.0001). The findings of the ORIENT-32 study showed that sintilimab plus IBI305 provides significantly improved OS and PFS in unresectable HCC and could be a novel treatment option for this patient population. It is important to note that the generalizability of the study findings is limited because the study only included only patients with HBV-associated HCC.

Non-ICI—ramucirumab

Similar to bevacizumab, ramucirumab is a monoclonal antibody that specifically binds to VEGFR2 preventing angiogenesis in tumors (71). The REACH-2 trial was a randomized, double-blind, placebo-controlled, phase 3 study that assessed ramucirumab vs. placebo as a second-line therapy for patients with advanced HCC previously treated with sorafenib (72). Only patients with α-fetoprotein (AFP) greater than 400 ng/mL were included, distinguishing REACH-2 from other previous clinical trials in HCC. A total of 292 patients were treated with either ramucirumab or placebo and had a median follow-up of 7.6 months. Significant improvement in median OS was observed in the ramucirumab group compared to the placebo group (8.5 vs. 7.3 months, P=0.0199), and ramucirumab was well tolerated and had a manageable safety profile. The findings supported the use of ramucirumab in a specific patient population with AFP greater than 400 ng/mL and prior sorafenib treatment.

Ongoing clinical trials and future directions

Since the introduction of sorafenib as the first systemic therapy for the treatment of advanced unresectable HCC, there has been significant advancement contributing to the armamentarium for HCC. Despite this, there are challenges with systemic therapy that warrant further investigation. First, the continued discovery of novel therapeutic agents and combination treatment regimens with improved efficacy, safety, and tolerability is needed. There are many ongoing clinical trials evaluating novel treatment options such as finotonlimab (PD-1 inhibitor) plus bevacizumab biosimilar (NCT04560894), ipilimumab plus atezolizumab-bevacizumab (NCT05665348), and TPST-1120 (PPARα inhibitor) plus atezolizumab-bevacizumab (NCT06680258).

Second, there is a large proportion of patients who do not respond to the available systemic therapeutic options. To date, there are no validated predictive biomarkers for HCC to help clinicians in providing more efficacious and personalized treatment regimens. Further understanding of biomarkers in HCC, as well as clinical trials exploring more niche patient groups, such as the previously discussed REACH-2 trial that investigated patients specifically selected for elevated AFP, is warranted. Furthermore, most clinical trials have excluded patients with CP B or C liver function due to safety and tolerability. There is limited data for the use of systemic therapies within this patient population, and further research is needed to fill this unmet need (104).

Emerging biomarkers in HCC: toward precision immunotherapy

The expanding role of immunotherapy in HCC underscores the urgent need for validated biomarkers that can guide treatment selection, monitor response, and predict outcomes. Despite the success of ICIs and combination regimens in subsets of patients, the absence of reliable predictive biomarkers remains a major limitation to precision oncology in HCC. Emerging evidence suggests that both tumor-intrinsic and circulating biomarkers, such as AFP, circulating tumor DNA (ctDNA), and immune-related gene expression profiles, may hold promise for better patient stratification.

AFP

AFP remains the most widely used serum biomarker in HCC for diagnosis, prognosis, and treatment monitoring. High baseline AFP levels (commonly >400 ng/mL) in HCC patients are associated with more aggressive tumor biology and poorer outcomes following immunotherapy with ICIs (105). Recent studies indicate that dynamic changes in AFP during immunotherapy may reflect tumor burden and treatment response (106). An early “AFP response”, typically defined as a decline of >10–20% from baseline within the first 3 months of ICI therapy, predicts better imaging response, disease control, OS, and PFS (106). However, AFP lacks sufficient specificity and sensitivity to serve as a standalone predictive biomarker. Combining AFP kinetics with other molecular or imaging-based parameters may enhance its predictive value.

ctDNA

ctDNA offers a noninvasive means of real-time molecular profiling and disease monitoring. Circulating DNA, especially circulating ctDNA, is emerging as a promising biomarker and clinical tool in monitoring and guiding LRT, including TACE, TARE, ablation, and SBRT, for treating patients with HCC (107). In HCC, ctDNA can detect tumor-specific mutations, copy number variations, and methylation signatures that may correlate with treatment response or resistance. Concentration and mutation detection rates of ctDNA increase immediately after LRT, reflecting acute tumor cell death and release of tumor-derived DNA fragments (108). Furthermore, ctDNA methylation panels have demonstrated potential in identifying minimal residual disease and predicting recurrence after locoregional or systemic therapy (109). Integration of ctDNA analysis into clinical trials could enable dynamic response assessment and adaptive treatment strategies.

Combination therapies

The role of locoregional interventional therapies in combination with systemically delivered therapies is an area of increasing interest, particularly in combination with ICIs. The principal past, present, and future trials are outlined below and summarized in Table 3.

Combination therapies with ablation

Peng et al. [2013] conducted an RCT comparing RFA with or without TACE (epirubicin and mitomycin) (110). The addition of TACE significantly improved RFS and OS compared to the group treated with RFA alone (1-, 3-, and 4-year OS for the TACE-RFA group =92.6%, 66.6%, and 61.8% vs. 85.3%, 59%, and 45.0%, in the RFA group) (P=0.002) (110). In another trial (phase III HEAT study), an intravenous lyso-thermosensitive liposomal doxorubicin was added to RFA and compared with patients being treated with RFA alone (111). Tak et al. reported no significant difference in PFS or OS (111).

The combination of ablation and immunotherapy has been investigated in two clinical trials (112). In a phase I/II clinical trial of 146 patients with unresectable HCC compared toripalimab (a monoclonal antibody directed against PD-1) with ablation in conjunction with toripalimab (receiving initiation of treatment on day 3 or 14 post-ablation) (113). The study demonstrated a significant difference in ORR, PFS, and OS in patients who received ablation (MWA or RFA) followed by toripalimab compared to patients that did not receive ablation. Additionally, the phase III IMBrave050 RCT (70) demonstrated that RFS was significantly different in patients who received atezolizumab plus bevacizumab vs. active surveillance, following ablation or surgical resection (124).

Combination therapies with TACE/DEB-TACE

TACE, in combination with sorafenib vs. sorafenib alone, has been assessed in several clinical trials (113-117). These trials can be broadly divided into those utilizing cTACE (POST-TACE, TACTICS, and STAH) or DEB-TACE (SPACE and TACE-2) in their respective TACE treatment arms. Of these, the STAH (median PFS, 5.2 vs. 3.6 months; HR =0.73; 90% CI: 0.59–0.91; P=0.010) and TACTICS (median PFS, 25.2 vs. 13.5 months, P=0.006) trials demonstrated improved PFS in the combination treatment group, though neither demonstrated OS benefit (113,115).

TACE has also been evaluated in conjunction with other targeted therapies, including brivanib, orantinib, and lenvatinib in the BRISK-TA, ORIENTAL, and LAUNCH trials, respectively (114,118-120). Of these, only the LAUNCH trial, utilizing lenvatinib, demonstrated an OS benefit in the combination group (TACE + lenvatinib vs. lenvatinib only) (120). In this clinical trial, at median follow-up of 17.0 months, patients treated with TACE plus lenvatinib (LEN-TACE) demonstrated a mean OS of 17.8 vs. 11.5 months in patients that were treated with lenvatinib only (HR =0.45; P<0.001) (120). The median PFS was also longer in the LEN-TACE group (10.6 vs. 6.4 months; HR =0.43; P<0.001).

Combination therapies with TARE

TARE in combination with sorafenib compared to sorafenib alone

TARE combined with sorafenib vs. sorafenib alone was evaluated in three phase III RCTs, including the SARAH trial [2017], SIRveNIB trial [2018], and SORAMIC trial [2019] (121-123). In the 2017 SARAH trial, Vilgrain et al. compared the safety and efficacy of TARE vs. sorafenib in patients with advanced HCC. While no significant differences were observed in OS or PFS, TARE was associated with significantly better treatment tolerance. Treatment-related adverse events occurred twice as often in the sorafenib group (121). In 2018, Chow et al. evaluated the safety and efficacy of TARE vs. sorafenib in 360 patients with locally advanced HCC (SIRveNIB trial) (122). They found no significant differences in OS, TTP, or PFS. However, TARE was better tolerated. Similarly, the SORAMIC trial compared TARE combined with sorafenib to sorafenib alone in 216 patients with advanced HCC (123). The trial failed to demonstrate a significant difference in OS between the two groups; however, a sub-group analysis suggested a survival benefit in the combination arm in patients without cirrhosis. A more recent phase II single-arm trial of 42 patients evaluated the role of TARE in combination with nivolumab (NASIR-HCC trial) (125). This trial demonstrated an acceptable safety profile and evidence of treatment effect, with four patients downstaged to receive partial hepatectomy.

With advancements in personalized dosimetry and multicompartmental modelling in TARE, future studies are warranted to assess optimized dosing strategies in comparison to systemic therapies.

Combination therapies—ongoing and future research

Several clinical trials are ongoing or planned, investigating the role of combining locoregional interventions and systemically administered therapies. These are outlined below and summarized in Table 4.

Future and ongoing trials evaluating the role of TACE

Future and ongoing trials evaluating the role of TACE in combination with ICIs include the phase III EMERALD-1 RCT (TACE with durvalumab ± bevacizumab vs. TACE alone)—with a preliminary analysis demonstrating a meaningful improvement in PFS in the TACE with durvalumab and bevacizumab group compared to the TACE only group (15.0 vs. 8.2 months) (126). An interim analysis of LEAP-012 (TACE + lenvatinib + pembrolizumab vs. TACE only) demonstrated significantly improved PFS in the combination group compared to the TACE alone group (127). Other trials evaluating combination treatments with TACE include TALENTACE phase III RCT (atezolizumab + bevacizumab + TACE vs. TACE), phase III EMERALD-3 RCT (durvalumab + tremelimumab with or without lenvatinib + TACE), phase III ABC-HCC RCT (atezolizumab + bevacizumab vs. TACE), TACE-3 phase II/III RCT (TACE/TAE + nivolumab vs. TACE/TAE), CheckMate 74W (TACE vs. TACE plus nivolumab vs. TACE + nivolumab + ipilimumab), LEN-TAC (TACE + lenvatinib + camrelizumab vs. TACE + lenvatinib), NCT04559607 (TACE + camrelizumab + apatinib vs. TACE), and NCT04981665 (a phase II study postoperative TACE + tislelizumab).

Future and ongoing trials evaluating the role of TARE

Trials evaluating combination treatments with TARE include ROWAN (TARE + durvalumab + tremelimumab vs. TARE), NCT05701488 (TARE + durvalumab + tremelimumab vs. durvalumab + tremelimumab), and phase II EMERALD-Y90 (TARE + durvalumab + bevacizumab).

Future and ongoing trials evaluating the role of ablation

Finally, trials evaluating the role of combination or consecutive therapy following ablation include EMERALD-2 (ablation/resection + durvalumab + bevacizumab + ablation/resection + durvalumab + placebo vs. ablation/resection + placebo vs placebo), KEYNOTE 937 (pembrolizumab + ablation/resection vs. placebo + ablation/resection), CheckMate 9DX (nivolumab + ablation/resection vs. placebo + ablation/resection), and phase II single-arm study, RANT (tislelizumab/sintilimab + lenvatinib/bevacizumab + RFA), which has shown promising initial results (128).

Conclusions

A key limitation of this study is that many of the cited references were conducted predominantly in HBV-endemic regions, which may limit the generalizability of the findings to non-HBV populations, particularly those with hepatitis C virus infection or non-alcoholic fatty liver disease, which are more prevalent in Western cohorts.

As noted in the introduction, the decision between locoregional and systemic therapy is guided by the BCLC staging system. Recent trial data, particularly from studies such as the IMbrave050, HIMALAYA, and LAUNCH trials, are beginning to challenge and refine the traditional BCLC treatment algorithm, especially in the management of intermediate-stage HCC. Traditionally, BCLC has recommended TACE as the standard for intermediate-stage disease; however, emerging evidence suggests that certain subgroups of patients may benefit from combination approaches earlier in the treatment course. For instance, the LAUNCH trial supports the addition of targeted therapy to TACE, demonstrating improved survival outcomes, while the HIMALAYA trial introduces immunotherapy as a viable first-line option in selected patients. These findings prompt a reevaluation of a one-size-fits-all approach, advocating instead for a more nuanced, biology-driven model that considers tumor burden, liver function, and individual response predictors. Incorporating these insights into the BCLC framework would enhance its clinical applicability and allow for more personalized, evidence-based treatment strategies.

Over the last few decades, the availability of treatment options for HCC has significantly expanded with a trend towards treatments centered on targeted systemic therapies or ICIs either alone or in combination with LRTs. A number of ongoing clinical trials aim to definitively determine the precise role of such treatment approaches in the often-complex HCC patient population, who have typically received multiple prior therapies. Nonetheless, the potential for new avenues of treatment has given hope and the results of the numerous aforementioned studies are awaited with hope and much optimism.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-25-53/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-25-53/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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