Pre-transplant downstaging strategies for hepatocellular carcinoma with portal vein tumor thrombus: Current therapies and future challenges

Abstract

Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related mortality worldwide, with approximately 35%-50% of patients presenting concurrent portal vein tumor thrombus (PVTT). Untreated HCC patients with PVTT have a median survival of only 2.5-4 months, posing significant challenges to liver transplantation outcomes. Downstaging therapies play a pivotal role in improving transplant eligibility rates and optimizing post-transplant outcomes. This systematic review summarizes current downstaging therapies, including transarterial chemoembolization, transarterial radioembolization, proton beam therapy, intraportal radiofrequency ablation, and other novel systemic modalities. In-depth analysis of their clinical applications, efficacy, and safety profiles were performed. Furthermore, the review critically evaluates future challenges, including optimized downstaging criteria, personalized and precision medicine approaches, and novel biomaterials for localized therapy for downstaged HCC patients. This review provides comprehensive theoretical and practical insights into pre-transplant downstaging for HCC with PVTT, while highlighting critical avenues for future research and clinical decision-making.

Key Words: Hepatocellular carcinoma; Portal vein tumor thrombus; Liver transplantation; Downstaging therapy; Transarterial chemoembolization

Core Tip: Hepatocellular carcinoma with portal vein tumor thrombus has long been considered a contraindication for liver transplantation due to poor prognosis. However, evolving downstaging strategies, including transarterial chemoembolization, transarterial radioembolization, proton beam therapy, and combination immunotherapies, have shown potential to convert select patients into transplant candidates. This review summarizes current clinical evidence and highlights future directions involving personalized medicine, novel biomaterials, and standardized criteria.

INTRODUCTION

Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer-related mortality globally[1]. Its incidence continues to rise, particularly in regions with high prevalence of chronic hepatitis B virus and hepatitis C virus infections, as well as in populations increasingly affected by non-alcoholic fatty liver disease and cirrhosis[2]. One of the most formidable challenges in HCC is the presence of portal vein tumor thrombus (PVTT), which occurs in approximately 35%-50% of HCC patients at initial diagnosis[3]. PVTT represents a hallmark of aggressive tumor behavior and is classified as macrovascular invasion under the Barcelona Clinic Liver Cancer staging system with advanced stage category[4]. The formation of PVTT not only impairs portal hemodynamics and liver function, but also significantly reduces the efficacy and safety of conventional treatments[5]. Importantly, median overall survival (OS) in untreated HCC patients with PVTT remains dismal, ranging from 2.5 to 4 months, highlighting the urgent need for effective interventions[6].

Liver transplantation (LT) is considered a potentially curative option for selected HCC patients, particularly those within the Milan or UCSF criteria[7]. However, patients with PVTT are typically excluded from transplantation due to high recurrence rates and poor post-transplant outcomes[8]. To address this unmet need, pre-transplant downstaging therapies have been developed with the aim of reducing tumor burden and vascular invasion, thereby enabling patients to meet transplant eligibility criteria and improving long-term survival[9]. Downstaging strategies encompass a broad range of locoregional therapies (Figure 1) such as transarterial chemoembolization (TACE), transarterial radioembolization (TARE), external beam radiotherapy, and more recently, proton beam therapy (PBT) and intraportal radiofrequency ablation (IP-RFA)[10-12]. In addition, systemic therapies, including tyrosine kinase inhibitors (TKIs) (e.g., sorafenib, lenvatinib) and immune checkpoint inhibitors (ICIs) (e.g., atezolizumab plus bevacizumab), have shown potential in reducing tumor size and vascular invasion, either alone or in combination with locoregional approaches[12,13]. Despite promising results from retrospective and early-phase prospective studies, several challenges remain in integrating downstaging therapies into routine clinical practice[14]. This review aims to summarize the current landscape of pre-transplant downstaging therapies for HCC patients with PVTT, critically evaluate their efficacy and safety, and highlight key challenges and opportunities for future clinical and translational research.

Figure 1 Downstaging strategies for hepatocellular carcinoma with portal vein tumor thrombus. TACE: Transarterial chemoembolization; TARE: Transarterial radioembolization; PBT: Proton beam therapy; TKIS: Tyrosine kinase inhibitors; ICIS: Immune checkpoint inhibitors; IP-RFA: Intraportal radiofrequency ablation.

CLASSIFICATION AND PROGNOSTIC IMPACT OF PVTT

PVTT is a critical prognostic factor in HCC, reflecting an advanced disease stage with aggressive biological behavior[15]. Its presence alters liver hemodynamics, accelerates hepatic decompensation, and complicates treatment planning[16]. Accurate classification of PVTT is essential for risk stratification, treatment selection, and evaluating the feasibility of downstaging therapies prior to LT[17]. The Liver Cancer Study Group of Japan (LCSGJ) classification is the most widely used and clinically validated system for categorizing PVTT based on the anatomical extent of portal vein involvement[18]. Patients classified as Vp1-Vp2 often retain better liver function and are more likely to benefit from locoregional therapies such as TACE, PBT, or radioembolization. In contrast, Vp3-Vp4 denotes more advanced disease, often accompanied by worse hepatic reserve, portal hypertension, and increased tumor burden[19]. These patients generally have poor outcomes and are often excluded from surgical or transplant options without prior downstaging[20].

In addition to the LCSGJ system, an alternative and widely adopted classification method, Cheng’s classification system, was developed by Chinese investigators to more precisely reflect the extent of PVTT and guide clinical decision-making in HCC treatment[21,22]. This system categorizes PVTT into four distinct types based on the anatomical location of the tumor thrombus and its extension within the portal venous system[23]. Cheng’s classification is particularly valuable in clinical practice across Asia, where surgical resection remains a central component of HCC treatment[24]. The system not only provides a basis for prognostic stratification but also aids in selecting candidates for aggressive therapies, including downstaging protocols[25]. Generally, patients with Type I and II PVTT are considered suitable for locoregional therapy or surgery, while those with Type III and IV require a multidisciplinary approach, often involving systemic therapy and rigorous assessment for potential downstaging prior to transplant evaluation[26-28]. TACE and TARE show moderate efficacy, but require combination therapies for optimal downstaging. The comparative classification of PVTT is summarized in Table 1.

Table 1 Comparative classification of portal vein tumor thrombus and clinical implications.

System	Grade/type	Anatomical extent	Typical characteristics	Downstaging feasibility
LCSGJ	Vp0	No portal vein invasion	Normal portal flow	Not applicable
	Vp1	Thrombus distal to second-order branches	Peripheral PVTT; limited hepatic impact	High: TACE, TARE, PBT often effective
	Vp2	Thrombus in second-order (segmental) branches	Segmental invasion; localized disease	Moderate to high
	Vp3	Thrombus in first-order (right/Left) portal vein	Major branch occlusion; moderate liver function compromise	Moderate: Requires combination approaches
	Vp4	Thrombus in main trunk or contralateral portal vein	Central occlusion; severe portal hypertension	Low: Systemic + radiation or experimental
Cheng	Type I	Segmental branches of the portal vein	Equivalent to Vp1-Vp2; good prognosis if treated early	High
	Type II	Right or left portal vein	Similar to Vp3; higher recurrence risk post resection	Moderate
	Type III	Main portal vein trunk	Equivalent to Vp4; marked hemodynamic impairment	Low
	Type IV	Extending into superior mesenteric vein	Extensive systemic vascular involvement	Very low: Limited to palliative/systemic care

LCSGJ: The Liver Cancer Study Group of Japan; TACE: Transarterial chemoembolization; TARE: Transarterial radioembolization; PVTT: Portal vein tumor thrombus; PBT: Proton beam therapy.

CURRENT DOWNSTAGING THERAPIES

Downstaging therapies aim to reduce tumor burden and vascular invasion to render HCC patients with PVTT eligible for potentially curative interventions such as LT[29]. These modalities vary in their mechanisms of action, patient selection criteria, and integration with systemic therapy[30].

TACE

TACE is the most frequently applied locoregional therapy for patients with intermediate-stage HCC[31]. Its use in advanced-stage disease, particularly in patients with PVTT, has been controversial due to the potential for hepatic ischemia and subsequent liver decompensation[32]. However, a growing body of evidence suggests that carefully selected patients with segmental or lobar PVTT (e.g., Vp1-Vp2 or Cheng Type I-II) may derive meaningful survival benefit from TACE, either as a standalone modality or in combination with systemic therapy[33]. TACE combines intra-arterial delivery of chemotherapeutic agents (commonly doxorubicin, cisplatin, or epirubicin) with embolic materials such as lipiodol or gelatin sponge particles, leading to both cytotoxic and ischemic necrosis of tumor tissue[34]. In patients with PVTT, tumor regions often receive their primary blood supply via the hepatic artery, allowing for selective embolization despite compromised portal flow, thereby sparing healthy liver parenchyma[35]. The pivotal randomized controlled trial by Lo et al[36] first demonstrated the efficacy of TACE in unresectable HCC. Although patients with main trunk PVTT were excluded, those with segmental PVTT were included. The study reported a significant improvement in median OS in the TACE group (19.4 months vs 7.1 months, P < 0.001), supporting the rationale for TACE in appropriately selected PVTT patients. Further supporting evidence comes from a multi-treatment meta-analysis (2012-2019) involving 4265 PVTT patients across 12 randomized controlled trials[37]. The network analysis compared various treatments including sorafenib, hepatectomy, and TACE, as well as their combinations. Among all strategies, sorafenib combined with TACE was ranked as the most effective, with the highest probability of improving 1-year survival outcomes. Despite its efficacy, TACE is not without risks. The incidence of hepatic decompensation increases substantially in patients with Vp3-Vp4 PVTT or poor liver reserve (Child-Pugh B/C), often limiting its use in advanced cases. TACE, although widely used, may pose significant risks in patients with advanced PVTT (Vp3 and Vp4) due to the potential for hepatic ischemia, especially when portal vein patency is severely compromised. Additionally, TARE, while effective in controlling tumor growth, may not provide adequate results in patients with extensive vascular invasion or those who cannot tolerate the embolic load due to impaired hepatic reserve. Recently reported TACE-based combination therapies for HCC with PVTT were listed in Table 2[5,38-44]. In summary, TACE remains a viable and effective option for downstaging in PVTT patients with preserved liver function and limited PVTT extent[45]. The integration of TACE with systemic agents, particularly sorafenib or ICIs, represents a promising direction for future protocols aiming to improve transplant eligibility and long-term survival[46,47].

Table 2 Transarterial chemoembolization-based combination therapies for hepatocellular carcinoma with portal vein tumor thrombus.

Ref.	Population	Treatment arms	ORR (%)	Median OS (months)	Median PFS (months)	Key findings
Yuan et al[5]	743 HCC with PVTT	TACE + HAIC + TKIs + PD-1 vs TACE	53.7 vs 7.8	Not reached vs 10.4	14.8 vs 2.3	Best surgical conversion and pCR outcomes
You et al[38]	265 HCC with PVTT	IT + TACE vs IT	–	19.0 vs 13.0	12.0 vs 7.3	TACE enhances immune-targeted response
Lu et al[39]	227 Vp2–Vp3 PVTT	TACE + PEI + Lenvatinib vs TACE + Lenvatinib	50.5 vs 25.8	17.1 vs 13.9	8.1 vs 6.5	PEI boosts PVTT regression
Lu et al[40]	105 Vp4 PVTT	125I stent + TACE vs Sorafenib + TACE	–	9.9 vs 6.3	6.6 vs 4.2	125I stent prolongs survival and patency
Zou et al[41]	165 HCC with PVTT	TACE + Lenvatinib + PD-1 vs TACE + Sorafenib + PD-1	41.3 vs 30.6	21.7 vs 15.6	6.3 vs 3.2	Lenvatinib triple better than Sorafenib triple
Lin et al[42]	95 PVTT + APFs	HAIC + Lenvatinib + PD-1 vs TACE + Lenvatinib + PD-1	52.9 vs 27.9	25.0 vs 19.3	21.7 vs 8.7	HAIC favored in APF setting
Zhao et al[43]	58 PVTT + APFs	TACE + 125I vs TACE + Sorafenib	–	12.8 vs 8.0	–	125I improves APF control and OS
Yang et al[44]	116 PVTT	TACE + Lenvatinib vs TACE + Sorafenib	66.8 vs 33.3	18.97 vs 10.77	10.6 vs 5.4	TACE-L significantly outperforms TACE-S in ORR, OS, and PFS

PFS: Progression-free survival; HCC: Hepatocellular carcinoma; TACE: Transarterial chemoembolization; TARE: Transarterial radioembolization; PVTT: Portal vein tumor thrombus; ORR: Objective response rate; OS: Overall survival; HAIC: Hepatic arterial infusion chemotherapy; APF: Atypical portal flow; PEI: Percutaneous ethanol injection; IT: Immunotherapy; TKI: Tyrosine kinase inhibitor.

TARE

TARE, also known as selective internal radiation therapy (SIRT), is an increasingly utilized locoregional therapy in HCC, particularly in patients with PVTT or other forms of macrovascular invasion[48]. Unlike TACE, TARE delivers radioactive microspheres, most commonly yttrium-90 (Y-90), directly into the hepatic artery branches feeding the tumor[49]. These microspheres emit localized beta radiation over approximately two weeks, allowing high-dose radiation to the tumor with minimal embolic effect, making it particularly suitable for PVTT patients who may not tolerate the ischemia induced by TACE[50]. The minimal embolic effect of TARE enables it to preserve portal venous flow, a critical advantage in PVTT patients who often already have impaired portal circulation[51]. Radiation induces DNA damage and apoptosis in tumor cells, including the thrombus within the portal vein, offering both tumor control and potential thrombus regression[52]. Moreover, TARE allows segmental, lobar, or whole-liver treatments, which is advantageous for patients with bilobar disease or PVTT involving major branches[53]. The DOSISPHERE-01 trial demonstrated that personalized SIRT (Y-90) dosing significantly improves downstaging success compared to standard dosing, highlighting the need for tailored treatment protocols. Some clinical studies have validated the role of TARE in HCC (Table 3).

Table 3 Key clinical trials evaluating selective internal radiation therapy (transarterial radioembolization) for hepatocellular carcinoma.

Trial	Phase/design	Comparison	Primary endpoint	Results	Clinical insights
SARAH	Phase III, open-label, randomized controlled trial	SIRT (Y-90) vs Sorafenib	Overall survival (OS)	OS: 8.0 months (SIRT) vs 9.9 months (Sorafenib)- no significant difference. Fewer AEs and better QoL in SIRT group	Comparable efficacy with better safety; viable alternative in select patients
SIRveNIB	Phase III, open-label, randomized controlled trial	SIRT (Y-90) vs Sorafenib	OS	OS: 8.8 months (SIRT) vs 10.0 months (Sorafenib) no significant difference. Grade ≥ 3 AEs: 27.7% (SIRT) vs 50.6% (Sorafenib)	Reinforces safety advantage of SIRT; supports use in selected Asian patient populations
DOSISPHERE-01	Phase II, open-label, randomized controlled trial	Personalized SIRT vs Standard-dose SIRT	OS	OS: 26.6 months (personalized) vs 10.7 months (standard) P = 0.009. Higher response rates; some downstaged to surgery	Personalized dosimetry improves outcomes; highlights need for tailored treatment planning

AE: Adverse events; QoL: Quality of life; SIRT: Selective internal radiation therapy.

A large multicenter retrospective study involving 216 HCC patients with PVTT compared TARE and (TKIs, including sorafenib and Lenvatinib)[54]. The TARE group achieved a significantly superior median OS of 28.2 months vs 7.2 months in the TKI group (P < 0.001). In the matched cohort, TARE demonstrated an objective response rate (ORR) of 53%-56.7%, far exceeding that of TKIs (12.3%-15.0%). A comprehensive network meta-analysis compared 12 treatment strategies in 1623 HCC patients with PVTT[55]. It found that TARE, either alone or combined with other modalities, ranked among the most effective in improving OS, outperforming sorafenib monotherapy in multiple endpoints. TARE is both safe and effective for HCC patients with PVTT with a pooled ORR of 50%-75% and a median OS of approximately 10 months, and a favorable toxicity profile, particularly in patients with Child-Pugh A liver function[56]. A comparison between TACE and TARE has been summarized in Table 4.

Table 4 A comparison between transarterial chemoembolization and transarterial radioembolization.

Therapy	Vp2 PVTT	Vp3 PVTT	ORR (%)	Median OS (months)	Safety profile
TACE	Moderate	Moderate	50-70	18-24	Moderate
TARE	High	Moderate	60-80	22-30	Low

TACE: Transarterial chemoembolization; TARE: Transarterial radioembolization; PVTT: Portal vein tumor thrombus; ORR: Objective response rate; OS: Overall survival.

PBT

PBT is an advanced form of external beam radiation therapy that utilizes the unique physical properties of protons, most notably the Bragg peak, to deliver highly conformal doses of radiation to tumors while sparing surrounding healthy tissues[57]. The Bragg peak in PBT allows for precise tumor irradiation with minimal damage to surrounding healthy tissue, which is particularly crucial in the treatment of PVTT where liver function and vascular integrity are compromised. This characteristic makes PBT particularly well-suited for treating HCC patients with PVTT, especially those with compromised liver function or extensive vascular involvement[58]. Unlike conventional photon-based radiotherapy, PBT allows for precise tumor irradiation with minimal exit dose, thus reducing the risk of radiation-induced liver disease and preserving functional liver parenchyma, critical for patients with underlying cirrhosis or borderline hepatic reserve[59]. PBT, particularly when integrated into a multimodal treatment approach, can effectively downstage HCC with lobar PVTT, potentially expanding the pool of candidates for curative LT[60]. A notable study by Chen et al[61] demonstrates the potential of PBT in downstaging advanced HCC with lobar PVTT to eligibility for living donor LT (LDLT). In this study, two patients with HCC involving lobar PVTT underwent PBT as part of a multimodal treatment strategy. The first patient received PBT at a dose of 72.6 Gy (RBE) in 22 fractions, resulting in complete tumor necrosis and recanalization of the portal vein without residual PVTT, as confirmed by imaging and explant pathology. The second patient underwent a combination of lenvatinib therapy, PBT, and subsequent immunotherapy, leading to significant tumor shrinkage and regression of PVTT, ultimately allowing for successful LDLT. Both cases demonstrated favorable outcomes, with no evidence of residual tumor or PVTT post-transplantation. Therefore, HCC with lobar PVTT, potentially expanding the pool of candidates for curative LT[62].

IP-RFA

IP-RFA is an emerging interventional strategy that applies thermal energy directly to PVTT through the portal venous system. Unlike traditional percutaneous or transarterial RFA, which targets intrahepatic tumors, IP-RFA specifically aims to debulk or ablate intravascular tumor components, particularly thrombi within the main or branch portal vein using a catheter-based approach[63]. The primary rationale for IP-RFA lies in its ability to induce localized tumor necrosis within the portal vein without impairing hepatic arterial flow or inducing significant systemic toxicity. By applying high-frequency alternating current via a radiofrequency electrode catheter inserted into the portal vein, the technique generates heat-induced coagulative necrosis of the thrombus tissue. A compelling clinical case report described a 60-year-old male with HCC-induced PVTT who underwent intraportal RFA combined with stent-assisted recanalization (VesOpen procedure)[64]. No additional systemic or locoregional therapy was administered. At 5-month follow-up, computed tomography imaging showed a significant reduction in tumor size, restored patency of the main and right portal vein, and partial recanalization of the left portal vein. Liver function, appetite, and overall clinical condition had markedly improved. This real-world case illustrates the potential for IP-RFA, particularly when combined with mechanical interventions, to reverse portal hypertension and improve quality of life in end-stage PVTT patients.

TKIs

Systemic therapy has long served as the mainstay treatment for advanced HCC, particularly in patients with PVTT who are ineligible for resection or locoregional therapy[65]. Over the past decade, the landscape of systemic treatment has rapidly evolved, from TKIs such as sorafenib and lenvatinib, to ICIs targeting PD-1/PD-L1 and CTLA-4 pathways[66]. More recently, combination regimens integrating systemic therapy with locoregional modalities (e.g., TACE, TARE, radiotherapy) have shown promise in downstaging advanced HCC to resectability or even liver transplant eligibility[67]. Sorafenib was the first systemic agent approved for advanced HCC following the landmark SHARP trial, which demonstrated modest survival benefit[68]. In PVTT patients, sorafenib has been shown to prolong median OS to 5-6 months; however, response rates remain low (< 10%). Lenvatinib, a multitargeted TKI, showed non-inferiority to sorafenib in the REFLECT trial[69]. Subgroup analysis indicated that lenvatinib may be more effective in patients with macrovascular invasion (including PVTT), yielding higher ORRs approximately 24% and better progression-free survival.

ICIs

The combination of atezolizumab (anti-PD-L1) and bevacizumab (anti-VEGF) has emerged as a transformative systemic therapy for advanced HCC, establishing a new standard of care after the landmark IMbrave150 trial[70]. In this global phase III randomized controlled study, the atezolizumab–bevacizumab combination demonstrated significantly superior clinical outcomes compared to sorafenib, the prior first-line standard[71]. Specifically, the ORR was 27% with atezolizumab–bevacizumab vs 12% with sorafenib, and median OS improved to 19.2 months compared to 13.4 months for sorafenib. Importantly, the IMbrave150 trial included patients with macrovascular invasion, including PVTT, a cohort historically underrepresented in pivotal studies. Subgroup analysis revealed that patients with PVTT still benefited substantially from atezolizumab–bevacizumab in terms of tumor shrinkage, disease stabilization, and vascular invasion control, indicating that immune-anti-angiogenic synergy is not abrogated by the presence of PVTT. Mechanistically, VEGF blockade may enhance T cell infiltration into tumors and normalize abnormal vasculature, thereby improving the efficacy of PD-L1 inhibition even in poorly perfused thrombotic regions[72]. VEGF inhibition reduces tumor vascularization, promoting better immune cell infiltration and enhancing the effects of PD-L1 inhibitors in thrombotic regions, leading to better downstaging outcomes. Building on this success, other ICI-based regimens are under active investigation in the PVTT population. The HIMALAYA trial, a phase III study, evaluated durvalumab (anti-PD-L1) combined with a single priming dose of tremelimumab (anti-CTLA-4) vs sorafenib[73]. Results demonstrated that the dual immune checkpoint blockade significantly improved OS while maintaining a favorable safety profile. Though PVTT-specific data were not fully stratified, subgroup analyses suggest consistent efficacy across macrovascular invasion strata. Similarly, nivolumab, alone or in combination with ipilimumab, has shown durable responses in patients with advanced HCC, including those with vascular invasion, in phase I/II trials (e.g., CheckMate040)[74,75]. In these studies, patients with PVTT achieved partial responses and stable disease, with manageable immune-related adverse events[76].

CHALLENGES AND FUTURE PERSPECTIVES

While downstaging strategies have demonstrated potential to expand the liver transplant candidate pool, a major limitation remains the absence of a globally accepted set of criteria for evaluating downstaging success. Current protocols reference varied benchmarks such as the Milan, UCSF, and Kyoto criteria, each differing in tumor size, number, and biomarker thresholds[77]. This heterogeneity complicates comparative study designs, transplant decision-making, and registry documentation. Moreover, traditional imaging-based criteria (e.g., RECIST, mRECIST) may not fully capture biologic tumor behavior, necessitating the integration of dynamic biomarkers and functional imaging parameters (e.g., PET, gadoxetate-enhanced magnetic resonance imaging) into downstaging assessment frameworks[78].

As molecular oncology advances, there is growing emphasis on tailoring downstaging regimens to individual tumor biology and host factors. Genomic profiling, including TP53, CTNNB1, and TERT mutations, may predict therapeutic resistance or recurrence risk[79]. Recent studies have demonstrated that TP53 mutations are associated with poor prognosis and resistance to conventional therapies, including TACE. CTNNB1 mutations are linked to increased risk of recurrence after downstaging therapies. Liquid biopsies, particularly circulating tumor DNA (ctDNA), have emerged as valuable tools in predicting treatment response and identifying minimal residual disease after therapy. Genomic profiling of TP53 and CTNNB1 mutations can predict resistance to certain therapies, while ctDNA clearance has been shown to correlate with successful downstaging. Similarly, liquid biopsies capturing ctDNA or exosomes can provide real-time insights into tumor burden and clonal evolution[80]. Radiomics and artificial intelligence (AI)-driven imaging analytics offer complementary tools to noninvasively assess tumor aggressiveness and treatment response[81]. Together, these platforms can help stratify patients for intensified, targeted downstaging regimens vs early surgical consideration.

Emerging biomaterials offer new frontiers for localized, sustained drug delivery in downstaging. Bioresponsive hydrogels and nanoscaffolds capable of releasing epigenetic drugs (e.g., decitabine), immune modulators (e.g., PD-1/PD-L1 inhibitors), or chemotherapeutics directly into the tumor microenvironment show promise in preclinical models[82]. For instance, pH- and glutathione-responsive hydrogel systems have demonstrated selective release profiles in the acidic and reductive conditions characteristic of PVTT. Additionally, biomimetic drug carriers (e.g., cell membrane-coated particles) may enable tumor-homing capabilities, thereby enhancing safety and efficacy in patients with compromised liver function[83]. The translation of such systems into clinical trials represents a critical next step. AI and machine learning (ML) can be employed to analyze complex patient data, including clinical, genomic, and imaging information, to predict which downstaging therapies will yield the best outcomes for individual patients. ML algorithms have shown promise in predicting tumor progression, therapeutic response, and even patient survival rates based on pre-treatment characteristics. Besides, real-world data (RWD) from large cohort studies can provide valuable insights into the long-term effectiveness and safety of downstaging therapies across diverse patient populations. Unlike randomized control trials, which often have strict inclusion criteria, RWD includes patients with comorbidities or advanced disease, reflecting the real-world clinical challenges faced by healthcare providers.

Downstaging introduces complex ethical dilemmas regarding organ allocation. Given the organ scarcity and the higher recurrence risk associated with downstaged patients, transparent and objective criteria must be developed to ensure equitable access. Metrics such as duration of radiologic response, biomarker normalization, and absence of vascular invasion on imaging should be validated and integrated into allocation algorithms. Moreover, global transplant networks must collaborate to balance urgency, utility, and equity, ensuring that patients who achieve successful downstaging are not disadvantaged due to procedural variability across institutions. Understanding the differential impacts of these strategies on patient prognosis is crucial for optimizing treatment planning and transplant outcomes. The combination of immunotherapy with locoregional therapies such as TACE or radiation has shown promising results in preclinical studies and early-phase trials. This multimodal approach may enhance the immune response, overcome tumor resistance mechanisms, and significantly improve downstaging efficacy for patients with advanced PVTT.

CONCLUSION

HCC with PVTT represents one of the most challenging clinical scenarios in liver oncology, historically considered a contraindication to LT. However, recent advances in locoregional, systemic, and combination therapies have significantly expanded the potential for effective downstaging, enabling selected patients with PVTT to become eligible for curative LT. Evidence from clinical trials and retrospective studies supports the efficacy of TACE, TARE, PBT, and novel techniques such as IP-RFA, especially when combined with targeted agents and ICIs. Despite these promising developments, major hurdles remain, including the lack of standardized downstaging criteria, variable transplant eligibility thresholds, and insufficient integration of personalized medicine. Furthermore, the emergence of novel biomaterials and biomarker-guided approaches offers exciting prospects for localized, precision therapy but requires rigorous clinical validation. TACE, TARE, and PBT remain the most effective therapies for downstaging PVTT, but future research should focus on standardized downstaging criteria and the integration of personalized treatment approaches, including genomic profiling and novel biomaterials. As the field progresses, multidisciplinary collaboration across oncology, hepatology, transplantation, and bioengineering will be critical.