Search Results (53)

Colorectal cancer frequently metastasizes to the liver, and a substantial proportion of patients present with unresectable colorectal liver metastases (CRLM), which are associated with limited survival. While systemic chemotherapy remains a central component of management, advances in liver-directed therapies and transplantation have significantly expanded therapeutic possibilities in selected patients. This review provides a comprehensive and up-to-date overview of current management strategies for unresectable CRLM, with a focus on systemic chemotherapy, intra-arterial therapies, and liver transplantation. Systemic chemotherapy plays a central role, either as conversion therapy aimed at achieving secondary resectability or as palliative treatment to prolong survival and maintain quality of life. The integration of targeted agents and molecular profiling has enabled increasingly personalized therapeutic strategies. Liver-directed therapies, including hepatic arterial infusion chemotherapy, transarterial chemoembolization, and radioembolization, provide effective local disease control and may facilitate downstaging in selected patients. In parallel, liver transplantation has re-emerged as a promising option for highly selected patients with liver-only disease, demonstrating encouraging long-term survival in recent prospective studies. However, optimal patient selection, timing, and sequencing of these modalities remain key challenges. The management of unresectable CRLM is evolving toward a multidisciplinary and individualized approach that integrates systemic, locoregional, and transplant-based strategies. In selected patients, this paradigm shift may translate into meaningful survival benefit, although further prospective studies are required to refine indications and optimize treatment sequencing. Full article

Background/Objectives: Management of hepatocellular carcinoma (HCC) with main portal vein (MPV) invasion is challenging. We aimed to explore the efficacy and safety of systemic lenvatinib therapy combined with potent locoregional transarterial therapy (e.g., chemoembolisation plus infusion chemotherapy) for the treatment of HCC with MPV invasion. Methods: A direct comparison of different therapeutic regimens through a retrospective matched case—control study was conducted to evaluate the survival benefits of lenvatinib monotherapy versus lenvatinib combined with transarterial chemoembolisation (Len-TACE) versus Len-TACE plus hepatic arterial infusion chemotherapy (Len-TACE-HAIC) with oxaliplatin, fluorouracil, and leucovorin. Between January 2022 and December 2024, consecutive patients with HCC and MPV invasion who received lenvatinib, Len-TACE, or Len-TACE-HAIC from multiple centres in South China were enrolled for this analysis. Overall survival (OS), progression-free survival (PFS), and the objective response rate (ORR) were compared across the treatment groups. Adverse events (AEs) related to treatment were also recorded. Results: A total of 169 patients were included in the study: 48 patients received lenvatinib as systemic treatment, 56 received Len-TACE for locoregional and systemic therapy, and 65 received Len-TACE-HAIC for intensified locoregional and systemic treatment. Patients in the Len-TACE-HAIC group achieved a significantly greater ORR (53.8% vs. 28.6% vs. 6.3%, p < 0.001) than those in the Len-TACE group and the Len group did. Consistently, Len-TACE-HAIC resulted in markedly improved PFS (median, 7.0 vs. 5.0 vs. 2.0 months; p < 0.001) and OS (median, 15.0 vs. 10.0 vs. 7.0 months; p < 0.001). The incidence of grade 3-4 AEs was comparable across the three treatment groups. Conclusions: The results demonstrated that lenvatinib combined with potent locoregional therapy, i.e., the Len-TACE-HAIC regimen, provided superior survival benefits with an acceptable safety profile in patients with HCC and MPV invasion. Full article

Background/Objectives: Patients with unresectable hepatocellular carcinoma (uHCC) refractory or intolerant to immune checkpoint inhibitor (ICI)-based regimens represent a growing yet therapeutically underserved population with limited treatment options. We investigated the efficacy, safety, and mechanistic underpinnings of lenvatinib combined with New FP hepatic arterial infusion chemotherapy (LEN–New FP) in this challenging clinical setting. Methods: We retrospectively analyzed 14 consecutive patients with uHCC treated with LEN–New FP between April 2022 and March 2025. Tumor response was assessed by the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Proper hepatic artery (PHA) diameter was serially measured on angiography as an exploratory assessment of vascular remodeling, and tumor vascularity was semi-quantitatively evaluated using a 4-point angiographic scoring system (Tumor Vascularity Score [TVS]). Results: The cohort comprised BCLC stage B/C (7/7), mALBI grade 1–2b, and 13 of 14 patients with prior ICI-containing therapy. The objective response rate and disease control rate were 85.7% and 100%, including two complete responses. Median overall survival was 22.8 months from LEN–New FP initiation (median follow-up: 15.1 months) and 36.2 months from first-line initiation; median intrahepatic progression-free survival was 10.4 months. A total of 11 of 14 patients (78.6%) transitioned to subsequent therapies, including four curative-intent conversions. PHA narrowing was observed in 10 of 13 evaluable patients (76.9%), with no clear association with hepatic function deterioration. TVS decreased in 10 of 12 evaluable patients (83.3%), with reduction observed in 90.0% of PR/CR cases. Conclusions: LEN–New FP achieved sustained intrahepatic tumor control and encouraging survival in aggressive uHCC, including ICI-refractory or -intolerant disease. The concordant reduction in PHA diameter and tumor vascularity score provides angiographic evidence of VEGFR inhibition-mediated vascular remodeling, offering mechanistic insight into the synergistic antitumor effects of this regimen and supporting LEN–New FP as a promising multimodal strategy within the evolving landscape of HCC treatment. Full article

Background: Most patients with hepatocellular carcinoma (HCC) present with advanced disease and have limited systemic treatment options. Oxaliplatin shows clinical activity in HCC but its effectiveness is frequently curtailed by intrinsic and acquired resistance. We sought to systematically identify genetic vulnerabilities that increase oxaliplatin sensitivity in HCC. Methods: Genome-scale negative-selection CRISPR–Cas9 screens were conducted in two genetically distinct HCC cell lines (Hep3B and MHCC-97H) under low-dose oxaliplatin to discover conserved determinants of sensitivity. Selected DNA damage response (DDR) hits were validated. An oxaliplatin-resistant MHCC-97H subline was generated for transcriptomic profiling to characterize resistance-associated programs. Screen results were integrated with TCGA-LIHC expression and survival data to evaluate clinical relevance. Additionally, we analyzed bulk RNA-seq data from biopsy specimens collected from 36 HCC patients prior to initiation of hepatic arterial infusion chemotherapy (HAIC), comparing expression levels of the DDR genes between patients with objective response and non-responders. Results: Screens in both cell lines converged on DDR pathways, particularly nucleotide excision repair (NER) and the Fanconi anemia/interstrand crosslink repair network; shared sensitizers included ERCC4 (XPF), FANCE and SLX4. Validation experiments showed that disruption of representative DDR factors (POLH and XPA) synergistically increased oxaliplatin efficacy at concentrations as low as 0.5 μM. Transcriptomic analysis of the resistant MHCC-97H subline revealed coordinated upregulation of DNA repair programs, G2/M checkpoint and E2F target signatures, and epithelial–mesenchymal transition features. Integration with TCGA-LIHC data demonstrated frequent overexpression of many screen-identified DDR genes in primary HCC and an association between higher expression of selected factors and poorer patient survival. In the HAIC cohort, several DDR genes, including ATR, BRCA2, CDK7, MUS81, MUTYH, PARG, POLH, POLK and XPA, were significantly lower in the objective response group. Conclusions: DDR components represent candidate biomarkers and therapeutic targets whose inhibition may enhance oxaliplatin efficacy in HCC. Full article

Background: Intrahepatic cholangiocarcinoma (ICC) is an uncommon but increasingly recognized primary liver malignancy with a poor prognosis. Although surgical resection offers the only realistic opportunity for cure, recurrence is common and the optimal integration of surgery with systemic and liver-directed therapies continues to evolve. Summary: This review summarizes contemporary evidence on the diagnosis and multidisciplinary management of ICC with particular emphasis on surgical, systemic, locoregional, and transplant-based strategies. Cross-sectional imaging plays a central role in staging and assessing resectability including evaluation of vascular invasion and the future liver remnant. Upfront resection is appropriate for selected patients with resectable disease and preserved liver function, with margin-negative resection and lymphadenectomy remaining key oncologic goals. Systemic therapy continues to evolve with cytotoxic chemotherapy forming the backbone of treatment for advanced disease and immunotherapy and targeted agents demonstrating promise in biomarker-defined subgroups. Locoregional modalities such as hepatic arterial infusion therapy and radioembolization may provide disease control in liver-dominant ICC and are increasingly used within a multidisciplinary framework. Liver transplantation remains investigational but may offer favorable outcomes in highly selected early-stage disease. Full article

Background/Objectives. Globally, hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and represents the third leading cause of cancer-related mortality. Despite advances in diagnosis and treatment, the overall prognosis of HCC remains poor, largely due to late-stage presentation and high rates of vascular invasion. Portal vein thrombosis constitutes a significant complication of HCC, with an occurrence rate of 35–50%. Portal vein tumour thrombosis (PVTT) represents an aggressive form that is closely linked to decreased patient survival. The incidence of PVTT increases over time, from approximately 21% in the first year after diagnosis to nearly 46% by the third year, highlighting its high prevalence and progressive nature. The introduction of immunotherapy has marked a paradigm shift in the management of HCC. Immune checkpoint inhibitors, particularly those targeting the PD-1/PD-L1 and CTLA-4 pathways, have demonstrated durable responses and significant survival benefits in certain patients with advanced HCC. Furthermore, emerging evidence suggests that combining immunotherapy with local or systemic therapies, such as trans arterial chemoembolization, hepatic arterial infusion chemotherapy, radiotherapy or tyrosine kinase inhibitors, may further enhance antitumor efficacy by modulating the tumour microenvironment and promoting synergistic immune activation. Method: This narrative review provides a comprehensive evaluation of immunotherapy in patients with HCC and PVTT, with a focus on its efficacy as both monotherapy and in combination with other treatment modalities in terms of tumour response, progression-free survival, and overall survival. It also addresses safety, patient selection, and emerging strategies to optimize outcomes in this high-risk population. Conclusions: The combination of multiple therapies could improve the patient’s prognosis by achieving objective response rate of almost 82%, disease control rate of 97% and progression free survival of 12.9 months with quadruple therapy (HAIC-TACE combined with targeted and immunotherapy). Full article

Background: Colorectal liver metastases (CRLM) represent a major determinant of prognosis in patients with metastatic colorectal cancer and account for a substantial proportion of cancer-related mortality worldwide. Over the last decades, survival outcomes have improved significantly as a result of advances in systemic therapies, refinement of surgical techniques, and, most importantly, the widespread implementation of multidisciplinary management strategies. Within this evolving landscape, surgery remains the cornerstone of potentially curative treatment, although its optimal integration with systemic and locoregional therapies requires careful patient selection and individualized treatment planning. Methods: This narrative review explores the contemporary role of surgery within the multidisciplinary management of CRLM, emphasizing how surgical decision-making is integrated with medical oncology, radiology, interventional procedures, and emerging technologies. Results: The pivotal role of multidisciplinary team meetings in defining resectability, treatment sequencing, and therapeutic intent is highlighted. Key technical and oncological criteria guiding upfront resection, neoadjuvant or conversion strategies, and staged approaches are reviewed, including assessment of future liver remnant, optimization of liver volume and function, tumor burden, molecular profile, and dynamic prognostic models. In addition, the review summarizes current evidence supporting parenchyma-sparing liver surgery and the integration of local therapies such as thermal ablation, irreversible electroporation, stereotactic body radiotherapy, selective internal radiation therapy, and hepatic artery infusion chemotherapy within multimodal treatment algorithms. Complex clinical scenarios, including synchronous disease, extensive bilobar metastases, chemotherapy-associated liver injury, and the emerging role of liver transplantation in highly selected patients with liver-only disease, are also addressed. Conclusions: Modern CRLM management has evolved toward a highly individualized, biology-driven approach in which surgery is optimally integrated within a multidisciplinary framework to maximize curative potential and long-term survival. Full article

Background: The combination of hepatic arterial infusion chemotherapy (HAIC) with immune checkpoint inhibitors (ICIs) and anti-angiogenic agents represents a potential therapeutic strategy for advanced hepatocellular carcinoma (HCC). This study aimed to compare the efficacy and safety of triple therapies combining HAIC with ICIs and either bevacizumab or tyrosine kinase inhibitors (TKIs) in these patients. Methods: This retrospective single-center study enrolled 65 consecutive patients with advanced HCC who received HAIC combined with ICIs plus either bevacizumab (bevacizumab group, n = 31) or TKIs (TKIs group, n = 34) between June 2021 and June 2023. Primary endpoints included progression-free survival (PFS), objective response rate (ORR), duration of response (DOR), and safety profiles. Results: The bevacizumab group demonstrated significantly prolonged median PFS (10.9 vs. 7.4 months, p = 0.001) and higher ORR (83.9% vs. 61.8%, p = 0.047) compared with the TKIs group. DOR was longer in the bevacizumab group (7.9 vs. 5.3 months, p = 0.008). Median overall survival (OS) was not reached in the bevacizumab group versus 22.6 months in the TKIs group. Grade 3–4 adverse events occurred in 67.7% of the bevacizumab group and 73.5% of the TKIs group, with distinct toxicity profiles. Gastrointestinal hemorrhage (45.2%) and gastric ulcer (22.6%) predominated in the bevacizumab group, whereas the TKIs group exhibited more hepatic enzyme elevations (aspartate aminotransferase, 67.6%; alanine aminotransferase, 61.8%), proteinuria (29.4%), diarrhea (26.5%), hand-foot syndrome (20.6%), and reactive cutaneous capillary endothelial proliferation (11.8%). Conclusions: Bevacizumab-containing triplet therapy was associated with improved tumor control and delayed progression compared to TKIs-based regimens in advanced HCC. The higher bleeding risk in the bevacizumab group highlights the necessity of standardized baseline evaluation and adequate preventive measures. Full article

Background: Hepatocellular carcinoma (HCC) with portal vein tumour thrombosis (PVTT) has a poor prognosis, and the benefits of neoadjuvant therapy are unclear. This systematic review and meta-analysis aim to evaluate the impact of neoadjuvant treatment (NAT) followed by surgery versus surgery alone on survival outcomes. Methods: A PRISMA-compliant systematic review was conducted by searching the OVID databases Embase, Medline, PubMed, and Scopus for English-language comparative studies of resectable HCC with PVTT, up to 23 January 2025. Two reviewers independently screened, extracted data, and assessed risk of bias (ROBINS-I/ROB2). Hazard ratios (HRs) for overall survival (OS) and recurrence-free survival (RFS) were pooled for meta-analysis. Results: Seven studies (2015–2024, five retrospective cohorts, one non-randomised comparative, one RCT) included 621 patients. The pooled analysis demonstrated that NAT followed by surgery was associated with a significantly improved OS (HR: 0.48, 95% CI: 0.295–0.67, p-value < 0.001, I² = 0.00) and improved RFS (HR: 0.4, 95% CI: 0.2–0.58, p-value < 0.001, I² = 0.00). Conclusions: For patients with HCC and an associated PVTT, neoadjuvant treatment before surgery significantly improves both overall and recurrence-free survival. These findings support a multimodal approach. Current evidence is largely non-randomised and HBV-endemic, warranting prospective validation in aetiologically diverse cohorts, including Western ones. Full article

Purpose: We aimed to study the efficacy and safety of hepatic artery infusion chemotherapy (HAIC) in the treatment of unresectable hepatocellular carcinoma (HCC) with extrahepatic spread (EHS). Materials and Methods: A total of 323 patients with unresectable HCC received HAIC plus lipiodol microvascular embolization. HAIC was performed via puncture of the left subclavian artery with a temporary 4-French angio-catheter placed in the common/proper hepatic artery. The HAIC regimen consisted of a daily infusion of cisplatin (10 mg/m²), mitomycin-C (2 mg/m²), and leucovorin (15 mg/m²), administered over a period of 20–30 min, and then a 5-fluorouracil (5-FU, 100 mg/m²) infusion for the remaining of 22 h of each day, for five consecutive days. Before the temporary catheter was removed, 10 mL of ethiodized oil (Lipiodol, Guerbet, France) was injected to obtain a synergistic effect of chemoinfusion and lipiodol microvascular embolization. Treatment responses were evaluated based on mRECIST criteria. The objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) of patients with EHS were compared to those without. Subgroup analyses of patients with and without major portal vein tumor thrombosis (PVTT) were performed both before and after propensity score matching (PSM). The survival analyses were conducted with the Kaplan–Meier method and compared using the log-rank test. All the statistical analyses were performed by SPSS (version 26.0). Result: The overall ORR was 59.1%. The median OS of the initial cohort and patients positive and negative for EHS were 16.3, 12.0, and 18.0 months, respectively (p = 0.002). In the subgroup analysis, there was no statistical difference in survival in patients with major PVTT between the with-EHS and without-EHS groups (13.0 vs. 15.0 months, p = 0.407). However, the median OS in patients with EHS was significantly shorter than those without EHS (11.4 vs. 19.4 months, p < 0.001) in the subgroup of non-major PVTT patients. After PSM, there were no significant survival differences between the EHS and non-EHS groups in any patient cohort or sub-cohort analysis. Conclusions: For unresectable HCC, controlling intrahepatic tumor progression through HAIC is more important than controlling extrahepatic tumor growth, especially in patients with major PVTT. Personalized locoregional HAIC can be performed in patients with EHS. Full article

Background/Objectives: Advanced hepatocellular carcinoma (HCC) presents limited treatment options; however, immunotherapy demonstrates encouraging outcomes and acceptable adverse reactions in advanced HCC. This study evaluates the efficacy and safety of combining serplulimab, the bevacizumab biosimilar HLX04, and hepatic arterial infusion chemotherapy (HAIC) as a first-line therapy. Methods: This prospective, observational, single-center phase II trial enrolled untreated HCC patients with Barcelona Clinic Liver Cancer (BCLC) stage C. All patients received serplulimab (4.5 mg/kg) and HLX04 (15.0 mg/kg) every 3 weeks, followed by the HAIC-FOLFOX regimen. The primary endpoint was the objective response rate (ORR). Secondary endpoints included the disease control rate (DCR), progression-free survival (PFS), and safety. Results: A total of 32 patients were enrolled. The best outcomes showed an ORR of 53.1%, including 17 partial responses (PR, 53.1%) and 12 stable diseases (SD, 37.5%), resulting in a DCR of 90.6%. Subgroup analysis showed a higher ORR in patients with a single lesion and those receiving ≥3 treatment cycles, with an ORR of 60.7% in the latter group. Additionally, five patients underwent successful hepatectomy after ≥3 treatment cycles, with postoperative pathology confirming extensive tumor necrosis. Kaplan–Meier analysis estimated PFS rates of 89.9% (95% CI: 79.5–100.0%) at 6 months and 70.8% (95% CI: 54.2–92.4%) at 12 months. No deaths related to adverse events (AEs) occurred; four (12.5%) patients experienced grade IV AEs and twelve (37.5%) patients experienced grade III AEs. Conclusions: Serplulimab, HLX04, and HAIC combined as a first-line treatment for advanced HCC have demonstrated promising efficacy, particularly in patients completing ≥3 cycles, with an acceptable safety profile. Further investigation in larger trials is required. Full article

Approximately 90% of liver cancer cases are classified as hepatocellular carcinomas (HCCs), with chemotherapy and immunotherapy being the most recommended treatment options. While conventional chemotherapy specifically targets rapidly dividing cancer cells, it can also impact on healthy cells that are proliferating quickly. This collateral damage to healthy cells, along with the potential for cancer cells to develop resistance, presents significant challenges for conventional chemotherapy in liver cancer patients. Hepatic artery infusion of chemotherapy (HAIC) generally leads to reduced toxicity and fewer side effects. The process of catheter insertion is usually performed under local anesthesia, with lidocaine being the preferred choice to combine with various chemotherapeutics in HCC treatment. In our study, we explored the effects of repurposing lidocaine in combination with cisplatin or 5-fluorouracil (5-FU) on two HCC cell lines, HepG2 and Hep3B. Our cytotoxicity analysis revealed that lidocaine functions as a chemosensitizer for cisplatin and 5-FU in both HepG2 and Hep3B cells. Specifically, we observed an increase in the subG1 population and a reduction in cytosolic reactive oxygen species in cisplatin- or 5-FU-treated HepG2 and Hep3B cells. Interestingly, lidocaine selectively decreased the reduced/oxidized glutathione ratio in cisplatin- or 5-FU-treated HepG2 cells but not in Hep3B cells. Furthermore, lidocaine induced endoplasmic reticulum stress, apoptosis, mitochondrial membrane depolarization, lipid peroxidation, and autophagy while suppressing cellular proliferation HepG2 and Hep3B cells. In conclusion, our study demonstrates the synergistic potential of combining lidocaine with cisplatin or 5-FU for the treatment of HCC, indicating that lidocaine may serve as an effective chemosensitizer. These findings highlight a new clinical advantage of using repurposing lidocaine as a chemosensitizer in the current HAIC procedure, suggesting that this combination warrants further exploration through rigorous clinical trials. In the future, we can better optimize therapeutic regimens, potentially leading to improved patient outcomes in HCCs. Full article

Intermediate- and advanced-stage hepatocellular carcinoma (HCC) continues to present significant therapeutic challenges. Hepatic artery infusion chemotherapy (HAIC), a well-established locoregional treatment for unresectable HCC, has recently demonstrated promising clinical outcomes both as monotherapy and in combination with systemic therapies. This comprehensive review examines recent clinical advances in HAIC for HCC, with particular emphasis on evolving treatment regimens and their therapeutic efficacy. Full article

Optimal curative therapy for intrahepatic cholangiocarcinoma (iCCA) involves hepatic resection; however, due to its insidious nature, iCCA frequently presents at advanced stages. Consequently, 70–80% of patients feature unresectable iCCA at presentation. Recent expansions in therapeutic options for locally advanced unresectable iCCA include immunotherapy, targeted chemotherapeutics, and liver-directed therapies. These have increased progression-free survival, enhanced response rates, and improved downstaging for resection. Liver transplant has also emerged as an alternative for patients whose tumors remain unresectable despite therapeutic response. Here, we explore emerging treatment options included in a multidisciplinary treatment paradigm to prolong survival in patients with initially unresectable locally advanced iCCA. Full article

Objectives: Although systemic chemotherapy (SC) is the mainstay for treating unresectable intrahepatic cholangiocarcinoma (ICC), its efficacy is limited and it causes severe systemic side effects. This study focuses on evaluating the effectiveness and safety of hepatic arterial infusion chemotherapy (HAIC) in combination with lenvatinib plus programmed death-1 (PD-1) inhibitors (HLP), compared to SC in combination with lenvatinib plus PD-1 inhibitors (SCLP) for unresectable ICC. Methods: We analyzed patients initially diagnosed with unresectable ICC at our center between March 2021 and December 2023, classifying them into HLP and SCLP groups according to treatment regimen. This study assessed and compared overall survival (OS), progression-free survival (PFS), tumor response, and safety outcomes across the two treatment groups. Results: This study enrolled 53 subjects in total; 25 were treated with HLP and 28 with SCLP. The two groups showed well-matched baseline characteristics. The HLP group reported an extended median OS (12.8 vs. 11.0 months, p = 0.310) and a prolonged median PFS (8.8 vs. 6.4 months, p = 0.043), compared to the SCLP group. The HLP group had a better objective response rate (ORR) (52% vs. 25%, p = 0.043) and disease control rate (DCR) (96% vs. 78.6%, p = 0.104). Based on OS (p = 0.019) and PFS (p = 0.032) results, those without extrahepatic metastasis seemed to benefit more significantly from the HLP regimen than from the SCLP regimen. The HLP group experienced fewer grade 3–4 adverse events (AEs) than the SCLP group. Conclusions: The HLP regimen for unresectable ICC is an effective and safe strategy and is potentially better suited for patients without extrahepatic metastases. Full article