Radiotherapy, as an important means of treating hepatocellular carcinoma (HCC), has shown unique therapeutic advantages, especially in patients who are unable to undergo surgery or transplantation. It mainly includes external radiotherapy, transarterial radioembolization and intratumoral radioactive particle implantation. However, under the influence of factors such as the hypoxic characteristics of the liver tumor microenvironment and the radioresistance of tumor cells, the effect of radiotherapy may be unstable and may cause side effects, affecting the quality of life of patients. In recent years, with the development of nanotechnology, drug delivery systems based on micro-nanomaterials have provided new solutions for improving the effect of radiotherapy for HCC. Despite this, the application of micro-nano drug delivery systems in the treatment of HCC still faces some challenges, mainly including the in vivo safety and in vivo metabolism of micro-nano materials. This article reviews the latest progress of micro-nano materials in the treatment of HCC, especially their application in radiosensitization and their clinical translation potential. This article systematically analyzes the role of micro-nanomaterials in external or internal radiotherapy sensitization and radioimmunotherapy and explores the advantages of micro-nanomaterials in improving the treatment effect of HCC.

A recent trial has shown that adding transarterial chemoembolization (TACE) to lenvatinib therapy results in enhanced therapeutic efficacy in hepatocellular carcinoma (HCC). We aimed to assess the effectiveness of the lenvatinib and TACE combination in a real-world clinical context for managing HCC and to elucidate the molecular pathways involved.

This retrospective analysis included 199 patients diagnosed with HCC and having intrahepatic lesions between 2018 and 2021. The cohort was divided into those who received lenvatinib plus TACE (n = 62, combination group) and those who received lenvatinib monotherapy (n = 137, monotherapy group). To further explore the underlying mechanisms, Huh-7 cells were exposed to lenvatinib or a vehicle for 48 hours under normoxic or hypoxic conditions.

Propensity score-matched analysis revealed a significant improvement in both overall survival (adjusted HR, 0.38; 95% confidence interval, 0.24-0.59; P < 0.001) and progression-free survival (adjusted HR, 0.41; 95% confidence interval, 0.26-0.64; P < 0.001) in the combination group compared with the monotherapy group. In laboratory experiments, under hypoxic conditions, lenvatinib notably attenuated hypoxia-inducible factor-1α (HIF-1α) protein levels in Huh-7 cells without altering its mRNA levels. Intriguingly, lenvatinib facilitated the mouse double minute 2 homolog-mediated ubiquitination and subsequent degradation of HIF-1α. Additionally, cell viability assays confirmed a significant decrease in Huh-7 cell survival following lenvatinib treatment under hypoxic conditions.

The combination of lenvatinib and TACE significantly improved survival in patients with HCC. The mechanistic foundation seems to be the lenvatinib-triggered degradation of HIF-1α via the mouse double minute 2 homolog-dependent ubiquitination pathway, highlighting a potential therapeutic target in HCC treatment.

The optimal clinical management of unresectable hepatocellular carcinoma (uHCC) is challenging for clinicians. Bayesian network meta-analysis was conducted to compare the efficacy and safety of different interventional strategies for uHCC.

A systematic search was conducted in PubMed, Embase, the Cochrane Library, Web of Science, and CNKI databases. Bayesian network meta-analysis was applied to evaluate the disease control rate (DCR), 1-year survival rate and 2-year survival rate, as well as the incidence of serious adverse events associated with seven interventional strategies. Odds ratios (ORs) were estimated using pairwise and network meta-analysis with random effects. Treatment rankings utilized surface under the cumulative ranking curve (SUCRA), whereas heterogeneity was examined via I-square and meta-regression.

A total of 40 randomized controlled studies were included. Compared with transarterial chemoembolization (TACE) alone, all of the combination treatments, including TACE with radiofrequency ablation (RFA), microwave ablation (MWA), high-intensity focused ultrasound (HIFU), percutaneous ethanol injection (PEI), and radiotherapy (RT), significantly improved the DCR. TACE combined with RFA was observed to be superior to hepatic arterial infusion chemotherapy (HAIC) (OR: 1.91; 95% CI: 1.03-3.81) and TACE (OR: 3.85; 95% CI: 2.66-5.69), with the highest probability (SUCRA 0.836). TACE combined with HIFU ranks highest 1-year survival (SUCRA 0.919) and 2-year survival (SUCRA 0.925) rates, and also exhibited a better 1-year survival rate than HAIC (OR: 2.99; 95% CI: 1.09-9.03). Compared with TACE alone, HAIC exhibited a greater DCR (OR: 2.02; 95% CI: 1.15-3.40) and a potential advantage in 2-year survival (OR: 1.95; 95% CI: 1.02-3.78). No significant differences in serious adverse events were observed across treatments.

Compared with TACE alone, combined treatments for uHCC patients demonstrates better efficacy and survival. Moreover, compared with TACE and HAIC, TACE combined with RFA provides better efficacy, whereas TACE combined with HIFU offers the highest 1-year survival rate. HAIC alone outperforms TACE in DCR and 2-year survival rate.

This meta-analysis and trial sequential analysis (TSA) aimed to evaluate the efficacy and safety of triple therapy with tyrosine kinase inhibitors (TKIs) combined with transcatheter arterial chemoembolization (TACE) plus programmed death 1 (PD-1) inhibitors (T-T-P) and dual therapy with TKIs combined with TACE (T-T) for the treatment of advanced unresectable hepatocellular carcinoma (uHCC).

Literature related to the efficacy of TKIs combined with TACE plus PD-1 inhibitors in uHCC was searched using the Embase, PubMed, and Cocrane libraries. TSA was used to reduce false positive results due to random error.

Seventeen articles were included in this meta-analysis, including 2,561 patients. In the T-T-P group, OS [HR 0.45, 95% confidence interval (CI) 0.39-0.52; p = 0.000], PFS [HR 0.43, 95% CI 0.38 - 0.48; p = 0.000], were significantly prolonged compared to those in the T-T group; ORR (RR 1.59 [95% CI 1.39-1.81]; p = 0.000) and DCR (RR 1.26 [95% CI 1.15-1.37]; p = 0.000) were significantly higher. TSA analysis showed early results without further testing. Prognostic factor analysis demonstrated that portal vein tumor thrombus (PVTT) and extrahepatic metastasis were common independent risk factors for OS and PFS. Regarding grade 3/4 adverse events results showed no statistically significant differences in any of them.

Compared with T-T treatment group, the T-T-P treatment group exhibited a notable improvement in OS and PFS, particularly in cases of PVTT and extrahepatic metastasis. Furthermore, it can markedly enhance the ORR and DCR in patients with uHCC.

Despite some achievements in oxaliplatin-based chemotherapy for the treatment of advanced hepatocellular carcinoma (HCC), the abnormal activation of DNA damage repair pathways in HCC cells remains a major problem, limiting the efficacy of oxaliplatin-based chemotherapy. In a previous study, we found that endonuclease VIII-like protein 3 (NEIL3) is expressed in a high proportion of patients with HCC and associated with an unfavourable prognosis. However, the role of NEIL3 in chemoresistance is still unclear. The aim of this study was to evaluate whether and how NEIL3 regulates oxaliplatin anti-tumour efficacy. Gene expression after oxaliplatin treatment in HCC cell lines was assessed by real-time quantitative PCR, western blot analysis and bioinformatics analysis. The effect of NEIL3 on regulating oxaliplatin efficacy was assessed using cell counting kit-8 assays, colony formation assays, flow cytometry and an in vivo nude mice study. Mechanistic insights into the sensitivity to oxaliplatin mediated by the inhibition of NEIL3 were obtained through immunofluorescence and RNA sequencing analyses. Our findings demonstrated that NEIL3 expression was markedly downregulated after oxaliplatin administration. NEIL3 knockdown impaired cell viability and colony formation and increased apoptosis in HCC cells exposed to oxaliplatin. In addition, NEIL3 inhibition reduced tumour progression and enhanced oxaliplatin efficacy in xenograft nude mice models. Furthermore, knocking down NEIL3 significantly increased the oxaliplatin-mediated inhibition of the Fanconi anaemia pathway. Our results revealed that NEIL3 may be a promising therapeutic target for improving oxaliplatin efficacy in the treatment of HCC.

External beam radiation therapy (RT) has shown promising effects for hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT) in recent studies. However, there is still a lack of consensus on the optimal RT scheme for PVTT treatment. We evaluated the efficacy and safety of image-guided 10-fraction hypofractionated RT in these patients.

Between January 2016 and March 2022, a total of 95 HCC patients with PVTT received 10-fraction hypofractionated image-guided radiation therapy (IGRT) at two institutes, and 69 patients were analyzed. Follow-up imaging was performed at three-month intervals after the completion of RT. The extent of PVTT was described according to the Liver Cancer Study Group of Japan classification: Vp1 = segmental portal vein branch, Vp2 = right/left anterior/posterior portal vein, Vp3 = right/left portal vein, and Vp4 = main portal vein. Response evaluation was performed using Response Evaluation Criteria in Solid Tumors, version 1.1. Freedom from local progression (FFLP), progression-free survival (PFS), and overall survival (OS) were calculated from the start date of RT.

The median prescribed dose of 50 Gy (range: 40-50 Gy; biologically effective dose [BED]: 56-75Gy10) was delivered in 10 fractions. In this cohort, 4.3% of patients had Vp1, 20.3% had Vp2, 37.7% had Vp3, and 37.7% had Vp4. Median Planning target volume was 105.3 cc (interquartile range [IQR], 74.1-179.4 cc). Fifty-two (75.4%) patients received 50 Gy. With a median follow-up of 10.2 months (IQR, 6-21 months), the median OS was 20.3 months, and 1-year FFLP, PFS, and OS rates were 88.7%, 26.9%, and 62.2%, respectively. At 3 months follow-up, 13.0% had a complete response, 36.2% had a partial response, 46.4% had a stable disease and 4.4% had a progressive disease. In the multivariate analysis, alpha-fetoprotein level ≥ 600 IU/ml (hazard ratio [HR] 2.06, p = 0.03), Child-Pugh Class B or C (HR 2.30, p = 0.02), and stage IVA or IVB (4.05, p = 0.02) were significantly related to OS. During the follow-up period, there were 2 (2.9%) cases of grade ≥ 3 toxicity: grade 3 liver enzyme elevation (n = 1), and acute cholangitis (n = 1).

Hypofractionated RT demonstrated promising local PVTT control and OS rates with acceptable toxicity. These data suggest that 10-fraction image-guided hypofractionated RT (BED: 56-75 Gy10) is a feasible treatment option for PVTT in HCC patients.

The primary curative therapies for hepatocellular carcinoma are resection or liver transplantation. For patients requiring downstaging or who are unresectable at presentation, the landscape of local treatment options has vastly changed over the past decades. This change is partly due to the paucity of high-level evidence to guide the selection of liver-directed therapies, where physician preference and treatment patterns have historically resulted in relegating external-beam radiation therapy (EBRT) to a secondary option in the treatment of hepatocellular carcinoma in cases where arterially directed therapies or thermal ablations were not possible. However, technology advancements have substantially improved the ability to treat liver malignancies with high doses of radiation therapy and to minimise doses to uninvolved hepatic parenchyma and other nearby organs. These advancements have enabled safe treatment of hepatocellular carcinoma with EBRT, with low risk of toxicity. Recent randomised trials support the role of EBRT in the treatment of hepatocellular carcinoma from early to advanced stages. These trials identified that EBRT improved several key patient-centred outcomes, including overall survival when using stereotactic body radiotherapy and sorafenib compared with sorafenib alone in unresectable hepatocellular carcinoma, recurrence-free survival with the use of adjuvant EBRT in select patients after hepatocellular carcinoma resection, and quality of life for patients with painful hepatocellular carcinoma masses treated with palliative EBRT. With emerging high-quality evidence, hepatocellular carcinoma therapeutic guidelines should include the growing role of EBRT in improving the quality and quantity of life for patients with liver cancer.

HCC is the fourth leading cause of cancer-related mortality with increasing incidence worldwide. Historically, treatment for early disease includes liver transplantation, surgical resection, and/or other local therapies, such as thermal ablation. As a result of technical advances and high-quality prospective data, the use of definitive external beam radiotherapy with ablative doses has emerged. Intermediate-stage disease has been generally addressed with arterially directed therapies (eg, chemoembolization or radioembolization) and external beam radiotherapy, while advanced stages have been addressed by systemic therapy or best supportive care. The role of each local/locoregional therapy has rapidly evolved in the context of novel pharmacotherapies, including immunotherapies and antiangiogenic agents. The combinations, indications, and timing of treatments vary widely among specialties and geographies. Here, we aim to synthesize the best quality evidence available regarding the efficacy and safety of different liver-directed modalities, with a focus on recent prospective clinical data of external beam radiotherapy within the context of other available liver-directed therapies across Barcelona Liver Classification (BCLC) stages.

The efficacy of adding programmed death-1 (PD-1) inhibitors to transcatheter arterial chemoembolization (TACE) combined with apatinib for advanced hepatocellular carcinoma (HCC) remains controversial. This study aimed to evaluate the efficacy of incorporating PD-1 inhibitors into TACE combined with apatinib.

Relevant literature on TACE combined with apatinib plus PD-1 inhibitors for advanced HCC was searched in PubMed, Cochrane Library, Embase, and Web of Science databases. Trial sequential analysis (TSA) was conducted to minimize randomization errors and assess whether the meta-analysis provided conclusive evidence.

Six studies involving 1,452 patients were included. Compared with the TACE combined with apatinib treatment group (T-A), TACE combined with apatinib plus PD-1 inhibitors (T-A-P) significantly prolonged overall survival (OS) (Hazard Ratio [HR] 2.22, 95% Confidence Interval [CI] 1.93-2.56; p < 0.001) and progression-free survival (PFS) (HR 2.36, 95% CI 2.01-2.77; p < 0.001), while also improving the objective response rate (ORR) (risk ratios [RR] 1.60, 95% CI 1.20-2.14; p < 0.001) and disease control rate (DCR) (RR 1.06, 95% CI 1.00-1.12; p < 0.001). TSA results indicated that additional studies were required to confirm the significance of DCR. Prognostic analysis identified treatment regimen and extrahepatic metastasis as common independent risk factors for OS and PFS. The incidence of adverse events in the T-A-P treatment group was comparable to that in the T-A treatment group.

Adding PD-1 inhibitors to TACE combined with apatinib significantly prolonged OS and PFS, particularly in patients without extrahepatic metastases. It also improved ORR and DCR in patients with HCC.

To evaluate the efficacy, safety, and clinical course following ablative radioembolization with glass microspheres for hepatocellular carcinoma (HCC) with localized portal vein tumor thrombosis (PVTT) in patients with well-preserved liver function.

This is a prospective, open-label, multi-center, single-arm, phase II trial. Key inclusion criteria are unilobar HCC, PVTT confined to the ipsilateral lobe (Vp1-3), no extrahepatic spread, Child-Pugh class A, and a performance status of ≤ 1. Main exclusion criteria are hepatic venous tumor thrombus, bile duct invasion, and massive arterioportal shunting. Depending on the extent of the tumor and PVTT, patients will undergo radiation segmentectomy, modified radiation lobectomy, or ablative lobar treatment, while adhering to dose limits for the non-tumorous liver and lung. The primary outcome measure is overall survival, with the overall survival rate at two years provided as the summary measurement.

This study will enroll 30 patients to explore the efficacy and safety of ablative radioembolization for HCC with localized PVTT. Efficacy will be evaluated by intention-to-treat and per-protocol populations. Safety will be assessed for all patients who received radioembolization at any dose.

This study aims to address the potential of ablative radioembolization as a definitive or effective downstaging treatment for HCC with localized PVTT, where locoregional treatments may be more beneficial than systemic treatments. The results will help establish treatment outcomes that can serve as a standard for future comparative studies and contribute to the standardization of radioembolization approaches for HCC with localized PVTT.

ClinicalTrials.gov ( https://classic.

gov/ct2/show/NCT06166576 ). Identifier: NCT06166576.

Many guidelines for hepatocellular carcinoma (HCC) have been published and are regularly updated worldwide. HCC management involves a broad range of treatment options and requires multidisciplinary care, resulting in significant heterogeneity in management practices across international communities. To support standardized care for HCC, we systematically appraised 13 globally recognized guidelines and expert consensus statements, including five from Asia, four from Europe, and four from the United States. These guidelines share similarities but reveal notable discrepancies in surveillance strategies, treatment allocation, and other recommendations. Geographic differences in tumor biology (e.g., prevalence of viral hepatitis, alcohol-related liver disease, or metabolic dysfunction-associated steatotic liver disease) and disparities in available medical resources (e.g., organ availability, healthcare infrastructure, and treatment accessibility) complicate the creation of universally applicable guidelines. Previously, significant gaps existed between Asian and Western guidelines, particularly regarding treatment strategies. However, these differences have diminished over the years. Presently, variations are often more attributable to publication dates than to regional differences. Nonetheless, Asia-Pacific experts continue to diverge from the Barcelona Clinic Liver Cancer system, particularly with respect to surgical resection and locoregional therapies, which are viewed as overly conservative in Western guidelines. Advancements in systemic therapies have prompted ongoing updates to these guidelines. Given that each set of guidelines reflects distinct regional characteristics, strengths, and limitations, fostering collaboration and mutual complementarity is essential for addressing discrepancies and advancing global HCC care.

Patients with advanced hepatocellular carcinoma (HCC) and macrovascular invasion (MVI) are recommended to receive systemic therapy according to guidelines. Stereotactic body radiotherapy (SBRT) and surgery are increasingly used in this patient population. This study compares outcomes from these local treatments.

Patients diagnosed with HCC with MVI and treated with surgery or SBRT between 1999 and 2022 were included. Propensity score matching minimized bias from confounders. Overall survival (OS) was analyzed using the Kaplan-Meier method,. and local, regional, and distant recurrences were assessed via competing risk methods. Univariable and multivariable analyses adjusted by the Lasso method evaluated OS predictors.

Among 175 patients, 38 underwent surgery and 137 received SBRT. The median age was 61 years, tumor volume was 158.6 cc, and α-fetoprotein level was 197 IU/mL. Most surgical patients had major resection (74%) via an open approach (97%). The median biologically effective dose (BED) for SBRT was 53.7 Gy. After matching, 35 patients per group had a median OS of 16 months. Local failure was higher in the SBRT group (20%) than in the surgery group (12%) at 1 year (p = 0.028). Distant failure was more frequent in surgery (54%) compared with SBRT (17%) [p = 0.003]. Excluding SBRT patients receiving adjuvant systemic therapy did not change the results. In-hospital mortality was 9% post-surgery and 14% experienced post-SBRT liver impairment.

Both surgery and SBRT offer good long-term OS and control. Surgery provides better local control, while SBRT had lower distant relapse. While SBRT has acceptable toxicity, surgery carries a significant mortality risk.

Portal and hepatic vein tumor thrombosis is associated with inferior outcomes in patients with hepatocellular carcinoma (HCC), and systemic treatment alone is often insufficient. This phase II trial evaluated the efficacy and safety of combining sorafenib with radiotherapy in advanced HCC with thrombosis.

Registered at ClinicalTrials.gov (NCT03535259), this phase II single-arm prospective trial targeted patients with HCC with portal or hepatic vein tumor thrombosis, liver minus gross tumor volume >700 ml, and Eastern Cooperative Oncology Group Performance Status scores of 0 or 1. Participants underwent 40-66 Gy radiotherapy for the hepatic primary tumor and vein tumor thrombosis, with concurrent oral sorafenib (400 mg twice daily) until disease progression or unacceptable adverse events. The primary endpoint was median overall survival (mOS) and the secondary endpoints included overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and Modified Response Evaluation Criteria in Solid Tumors (mRECIST), median progression-free survival (mPFS), time to tumor progression (TTP), tumor thrombosis control, and grade ≥3 adverse events.

Between May 2018 and January 2020, 86 patients were enrolled with a median radiotherapy dose of 54 Gy (40-65 Gy). At a median follow-up of 17.2 months, mOS, mPFS, and TTP stood at 16.5, 6.1, and 6.8 months, respectively. ORR reached 47.7% and 52.3% per RECIST and mRECIST, respectively. For the tumor thrombosis, 2-year control rates per mRECIST were 93.1%. No grade 5 adverse events were noted, whereas thrombocytopenia (22.1%) and leukopenia (14.0%) were the main grade 3 adverse events.

Concurrent sorafenib and radiotherapy is an effective and well-tolerated treatment for patients with HCC with portal or hepatic vein tumor thrombosis.

Treatment options for patients with hepatocellular carcinoma (HCC) and vascular tumor thrombus are limited. The efficacy and safety of concurrent sorafenib and radiation for HCC with portal or hepatic vein tumor thrombosis has not been elucidated. This phase II trial shows that concurrent sorafenib and radiotherapy is effective and well-tolerated in the treatment of advanced HCC with portal vein or hepatic vein tumor thrombosis.

This study is registered at ClinicalTrials.gov (NCT03535259).

Transarterial chemoembolization (TACE) is a widely used treatment for hepatocellular carcinoma (HCC), combining targeted chemotherapy and embolization. While effective, TACE can be associated with significant gastrointestinal (GI) side effects, impacting a patient's quality of life.

Quantify the prevalence of key GI complications (diarrhea, nausea, GI toxicity, abdominal pain) following TACE.

Systematic review was performed following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, focusing on studies that reported side effects of TACE. Studies not involving cTACE or drug-eluting bead TACE (DEB-TACE), non-HCC studies, meta-analyses or systematic reviews, and inaccessible publications were excluded.

A PubMed search for clinical and randomized trials was conducted. Extracted data included study identifiers, demographics, TACE details, and GI side effect prevalences. The Mixed Methods Appraisal Tool assessed study quality and bias.

The analysis included data from 81 studies with 121 individual study arms and 9495 patients. Diarrhea was reported in 38 studies, with a mean prevalence of 23.46% (2.5; 95% confidence interval (CI): 18.39-28.544) and a weighted prevalence of 23.5%. Nausea was most frequently reported, mentioned in 67 studies, with a mean prevalence of 34.66% (2.4; 95% CI: 29.89-39.44) and a weighted prevalence of 32.5%. Abdominal pain was reported in 59 studies, with the highest mean prevalence of 48.07% (2.9; 95% CI: 42.20-53.93) and a weighted prevalence of 46.1%. GI toxicity was reported in 32 studies, with a mean prevalence of 8.85% (1.4; 95% CI: 5.99-11.70) and a weighted prevalence of 9.9%. DEB-TACE generally led to slightly higher rates of nausea, diarrhea, abdominal pain, and GI toxicity compared to conventional TACE. The type of chemotherapy agent influenced prevalence of GI-side effects, with high prevalences observed for agents such as zinostatin and cisplatin.

This meta-analysis synthesizes current evidence on managing GI side effects in TACE. Standardizing reporting and developing effective management strategies are crucial to improving patient outcomes.

External-beam radiation (EBRT) is a noninvasive therapeutic alternative to transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC). The objective of this study was to conduct a systematic review and meta-analysis of prospective randomized clinical trials to assess the clinical efficacy of EBRT versus TACE for HCC as either a definitive monotherapy or as a bridge to transplantation/surgery.

A systematic review and meta-analysis were performed to include prospective randomized trials comparing EBRT versus TACE. Data was analyzed with random and fixed-effects models. The inconsistency index (I2) was chosen to assess heterogeneity. Three publications were included with a total of 142 patients. Outcomes included local control (LC), overall survival (OS), progression-free survival (PFS), and occurrences of grade ≥3 toxicity. Comparisons are reported as hazard ratios (HRs) or risk ratios (RRs) with 95% confidence intervals (CIs).

There were three randomized trials that met inclusion criteria. The EBRT was delivered in three to 15 fractions with a total dose between 30 and 75 gray(Gy). EBRT was associated with significantly improved LC (HR, 0.16; 95% CI, 0.08-0.34; I2 = 0%) and PFS (HR, 0.37; 95% CI, 0.23-0.60; I2, 0%) compared with TACE. There was no significant difference between EBRT and TACE in OS (RR, 0.79; 95% CI, 0.51-1.22; I2 = 0%) or grade ≥3 toxicity (RR, 0.86; 95% CI, 0.31-2.37; I2 = 57%). None of the analyses had statistically significant heterogeneity.

Compared with TACE, EBRT yields superior LC and PFS without providing a survival benefit in early and intermediate stage HCC. Additional larger prospective randomized controlled trials should be conducted to further investigate differences in clinical outcomes amongst patients with more advanced disease.

Hepatocellular carcinoma (HCC) persists as a leading cause of cancer-related mortality, often diagnosed at advanced stages with limited treatment options. Locoregional therapies (LRTs) are crucial in HCC management, playing significant roles in neoadjuvant and palliative treatments, among others. However, the unique disease background of HCC necessitates multidisciplinary and integrated treatment strategies. The therapeutic landscape for advanced HCC has been significantly broadened by the advent of combined therapies, presenting multiple approaches aimed at improving long-term survival, which remains a critical challenge. This review offers a comprehensive overview of major LRTs for HCC, highlighting recent technological advancements and exploring the challenges and limitations in their application, and presents the latest developments in combination therapies, including combinations between different LRTs and their integration with systemic treatments. Additionally, we outline future directions for the development of integrated treatment modalities for advanced HCC.

To compare the outcomes of transarterial chemoembolization (TACE) alone with those of TACE combined with external beam radiation therapy (EBRT) in patients with hepatocellular carcinoma (HCC) in a multicenter randomized study.

From 2017 to 2022, 74 HCC patients with tumors confined to the liver without vascular invasion were treated with either TACE only (TACE group, 39 patients) or TACE combined with EBRT (TACE + EBRT group, 35 patients). The primary outcome measured was overall survival (OS). Secondary outcomes included progression-free survival (PFS), local tumor control, and the assessment of treatment-related toxicity.

Due to slow accrual, the trial was closed prematurely after enrolling 74 patients. All patients received 2 cycles of TACE before randomization. The TACE and TACE + EBRT groups showed comparable patient and tumor characteristics. The TACE group underwent a median of 3 TACE cycles, and the TACE + EBRT group received 2 cycles of TACE, and a median of 5500 cGy in 15 fractions. For the TACE group, the median local control (LC) duration was 13.1 months, whereas for the TACE + EBRT group, the median LC was not achieved (P < .001). The PFS was recorded at 11.6 months in the TACE group compared with 15.4 months in the TACE + EBRT group (P = .072). The median OS reached 36.8 months for the TACE group and extended to 47.1 months for the TACE + EBRT group (P = .654). The incidence of toxicity was comparable between both groups.

Although the number of patients enrolled in this clinical trial did not meet expectations. TACE combined with EBRT was shown to be more effective than TACE alone in improving LC without increasing toxicity, whereas PFS and OS were slightly improved. TACE + EBRT can be used as a standard treatment option for patients with inoperable but confined intrahepatic HCC.

Most patients with locally advanced hepatocellular carcinoma (HCC) recur within the liver following systemic therapy.

To determine whether stereotactic body radiation therapy (SBRT) improves outcomes in patients with locally advanced HCC compared with sorafenib alone.

This multicenter phase 3 randomized clinical trial randomized patients with HCC 1:1 to sorafenib or SBRT followed by sorafenib, stratified by performance status, liver function, degree of metastases, and macrovascular invasion. Eligible patients had HCC unsuitable for or refractory to standard local-regional therapies and were candidates for first-line systemic therapy. Data were collected from April 2013 to March 2021, and data were analyzed from July 2022 to August 2023.

Personalized SBRT, 27.5 to 50 Gy in 5 fractions.

The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), adverse events, and quality of life.

Of 193 patients randomized, 177 were eligible. Accrual was stopped early due to a change in standard-of-care systemic therapy. Of 177 included patients, 150 (84.7%) were male, and the median (IQR) age was 66 (60-72) years. Macrovascular invasion was seen in 131 (74.0%). As of July 1, 2022, the median OS was 12.3 months (90% CI, 10.6-14.3) with sorafenib vs 15.8 months (90% CI, 11.4-19.2) following SBRT and sorafenib (hazard ratio [HR], 0.77; 90% CI, 0.59-1.01; 1-sided P = .06). Adjusting for stratification factors, OS was improved with SBRT (HR, 0.72; 95% CI, 0.52-0.99; 2-sided P = .04). Median PFS was improved from 5.5 months (95% CI, 3.4-6.3) with sorafenib to 9.2 months (95% CI, 7.5-11.9) with SBRT and sorafenib (HR, 0.55; 95% CI, 0.40-0.75; 2-sided P < .001). Treatment-related grade 3 or higher adverse events were seen in 37 of 88 (42%) and 39 of 83 (47%) of patients treated with sorafenib vs SBRT and sorafenib, respectively (P = .52). There were 2 treatment-related deaths in the sorafenib group (death not otherwise specified and liver failure) and 1 in the SBRT and sorafenib group (lung infection). At 6 months, improved quality of life was seen in 2 of 20 (10%) and 6 of 17 (35%) of patients treated with sorafenib and SBRT and sorafenib, respectively.

In this phase 3 randomized clinical trial, among patients with locally advanced HCC, SBRT was associated with a clinically important but not statistically significant improved overall survival compared with sorafenib alone.

ClinicalTrials.gov Identifier: NCT01730937.

Promoting the early detection and diagnosis of hepatocellular carcinoma (HCC) is a critical strategy to improve patient outcomes as this can lead to greater access to curative treatments. This review highlights the diagnostic tests for HCC, including the use of the Liver Imaging Reporting and Data System systems and histopathology. Staging is essential for informing prognosis and guiding treatment decisions; this review also covers a widely used and well-validated staging system called the Barcelona-Clinic Liver Cancer (BCLC) algorithm. The BCLC incorporates tumor status, liver function, and patient performance to stage patients with newly diagnosed HCC.

Liver cancer is the third leading cause of cancer-related deaths worldwide, with hepatocellular carcinoma (HCC) accounting for approximately 90% of primary liver cancers. Advances in diagnostic and therapeutic tools, along with improved understanding of their application, are transforming patient treatment. Integrating these innovations into clinical practice presents challenges and necessitates guidance. These clinical practice guidelines offer updated advice for managing patients with HCC and provide a comprehensive review of pertinent data. Key updates from the 2018 EASL guidelines include personalised surveillance based on individual risk assessment and the use of new tools, standardisation of liver imaging procedures and diagnostic criteria, use of minimally invasive surgery in complex cases together with updates on the integrated role of liver transplantation, transitions between surgical, locoregional, and systemic therapies, the role of radiation therapies, and the use of combination immunotherapies at various stages of disease. Above all, there is an absolute need for a multiparametric assessment of individual risks and benefits, considering the patient's perspective, by a multidisciplinary team encompassing various specialties.

Hepatocellular carcinoma (HCC) is a major global burden, ranking as the third leading cause of cancer-related mortality. HCC due to chronic hepatitis B virus (HBV) or C virus (HCV) infection has decreased due to universal vaccination for HBV and effective antiviral therapy for both HBV and HCV, but HCC related to metabolic dysfunction-associated steatotic liver disease and alcohol-associated liver disease is increasing. Biannual liver ultrasonography and serum α-fetoprotein are the primary surveillance tools for early HCC detection among high-risk patients (e.g., cirrhosis, chronic HBV). Alternative surveillance tools such as blood-based biomarker panels and abbreviated magnetic resonance imaging (MRI) are being investigated. Multiphasic computed tomography or MRI is the standard for HCC diagnosis, but histological confirmation should be considered, especially when inconclusive findings are seen on cross-sectional imaging. Staging and treatment decisions are complex and should be made in multidisciplinary settings, incorporating multiple factors including tumor burden, degree of liver dysfunction, patient performance status, available expertise, and patient preferences. Early-stage HCC is best treated with curative options such as resection, ablation, or transplantation. For intermediate-stage disease, locoregional therapies are primarily recommended although systemic therapies may be preferred for patients with large intrahepatic tumor burden. In advanced-stage disease, immune checkpoint inhibitor-based therapy is the preferred treatment regimen. In this review article, we discuss the recent global epidemiology, risk factors, and HCC care continuum encompassing surveillance, diagnosis, staging, and treatments.

To assess the activity and toxicity of hepatic arterial infusion chemotherapy (HAIC)+tislelizumab+lenvatinib (HAIC+tisle+len) in hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) type IV (Vp4 hCC) in a real-world context.

Fifty-five patients, with Vp4 hCC receiving HAIC+tisle+len therapy from April 2021 to December 2022, were analyzed retrospectively. Data on patient characteristics, adverse events (AEs), treatment, and survival were collected. Outcomes were disease control rate (DCR), overall response rate (ORR), overall survival (OS), progression-free survival (PFS), and treatment-related AEs (TRAEs).

As of December 20, 2023, the median follow-up was 17.5 months (95% confidence interval [CI]: 14.7-22.5). The ORR was 52.7% (3 complete response [CR], 26 partial response [PR]) as per RECIST v1.1 and 65.5% (12 CR, 24 PR) as per mRECIST. The DCR was 94.5% using both RECIST v1.1 and mRECIST. The median PFS and the median OS were 8.0 months (95% CI: 6.2-12.3) and 16.7 months (95% CI: 12.0-not reached), respectively. Additionally, PFS was independently predicted only by the best tumor response. In patients with the best tumor response (PR or CR), the median PFS was 11.7 months (95% CI: 8.02-not reached) by mRECIST and 15.4 months (95% CI: 7.39-not reached) by RECIST v1.1. Hypertension (14.5%), decreased albumin levels (10.9%) and anorexia (9.1%) were the most frequently observed grade 3-4 TRAEs.

HAIC+tisle+len regimen demonstrated a promising efficacy and favorable safety for patients with HCC and Vp4, providing valuable real-world evidence to complement the trial data for Vp4 hCC.

Up to half of hepatocellular carcinoma (HCC) cases are diagnosed at an advanced stage, for which effective treatment options are lacking, resulting in a poor prognosis. Over the past few years, the combination of immune checkpoint inhibitors and anti-angiogenic targeted therapy has proven highly efficacious in treating advanced HCC, significantly extending patients' survival and providing a potential for sequential curative surgery. After sequential curative hepatectomy or liver transplantation following conversion therapy, patients can receive long-term survival benefits. In order to improve the long-term survival rate of the overall population with liver cancer and achieve the goal of a 15% increase in the overall 5-year survival rate outlined in the Healthy China 2030 blueprint, the Professional Committee for Prevention and Control of Hepatobiliary and Pancreatic Diseases of Chinese Preventive Medicine Association, Chinese Society of Liver Cancer, and the Liver Study Group of Surgery Committee of Beijing Medical Association organized in-depth discussions among relevant domestic experts in the field. These discussions focused on the latest progress since the release of the Chinese expert consensus on conversion therapy of immune checkpoint inhibitors combined antiangiogenic targeted drugs for advanced hepatocellular carcinoma (2021 Edition) and resulted in a new consensus on the modifications and supplements to related key points. This consensus aims to further guide clinical practice, standardize medical care, and promote the development of the discipline.

Background/Objectives: Combination therapy with atezolizumab and bevacizumab (ATZ/BEV) is extremely effective and yields a high response rate in patients with hepatocellular carcinoma (HCC). In this study, the efficacy of adding locoregional therapy to ATZ/BEV in patients with stable disease (SD) HCC was investigated. Methods: One hundred five HCC patients who were treated with ATZ/BEV or lenvatinib (LEN) as first-line chemotherapy for unresectable HCC were evaluated on the basis of the modified RECIST criteria. SD patients whose initial antitumor effect was achieved received locoregional therapy, and the overall survival (OS) rate was assessed. Results: This study included 58 ATZ/BEV-treated participants and 47 LEN-treated participants. Twenty-eight SD patients (ATZ/BEV) and 20 SD patients (LEN) were identified. OS was significantly greater in ATZ/BEV-treated patients who also received locoregional therapy than in those who did not receive this additional therapy (p = 0.0343), whereas there was no difference between LEN-treated patients who also received locoregional therapy and those who did not. The locoregional therapy consisted of transcatheter arterial chemoembolization (TACE) and/or radiofrequency ablation (RFA). When assessing the add-on effect of TACE and/or RFA in the SD patients treated with ATZ/BEV, five patients were found to achieve CR. Conclusions: The addition of locoregional therapy, such as TACE/RFA, was found to affect SD patients. When a response is limited during ATZ/BEV therapy, it is important to consider the therapeutic option of adding locoregional therapy, as this additional treatment may contribute to improved prognosis via immune modulation.