Advances in the treatment of intrahepatic cholangiocarcinoma: An overview of the current and future therapeutic landscape for clinicians.

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver tumor and remains a fatal malignancy in the majority of patients. Approximately 20%-30% of patients are eligible for resection, which is considered the only potentially curative treatment; and, after resection, a median survival of 53 months has been reported when sequenced with adjuvant capecitabine. For the 70%-80% of patients who present with locally unresectable or distant metastatic disease, systemic therapy may delay progression, but survival remains limited to approximately 1 year. For the past decade, doublet chemotherapy with gemcitabine and cisplatin has been considered the most effective first-line regimen, but results from the recent use of triplet regimens and even immunotherapy may shift the paradigm. More effective treatment strategies, including those that combine systemic therapy with locoregional therapies like radioembolization or hepatic artery infusion, have also been developed. Molecular therapies, including those that target fibroblast growth factor receptor and isocitrate dehydrogenase, have recently received US Food and Drug Administration approval for a defined role as second-line treatment for up to 40% of patients harboring these actionable genomic alterations, and whether they should be considered in the first-line setting is under investigation. Furthermore, as the oncology field seeks to expand indications for immunotherapy, recent data demonstrated that combining durvalumab with standard cytotoxic therapy improved survival in patients with ICC. This review focuses on the current and future strategies for ICC treatment, including a summary of the primary literature for each treatment modality and an algorithm that can be used to drive a personalized and multidisciplinary approach for patients with this challenging malignancy.

Locoregional therapies combined with immune checkpoint inhibitors for liver metastases.

Immune checkpoint inhibitors (ICIs) have achieved remarkable success in clinical research and practice. Notably, liver metastasis is not sensitive to ICIs. Liver locoregional therapies can cause irreversible damage to tumor cells and release tumor antigens, thereby providing a rationale for immunotherapy treatments in liver metastasis. The combination therapy of ICIs with locoregional therapies is a promising option for patients with liver metastasis. Preclinical studies have demonstrated that combining ICIs with locoregional therapies produces a significantly synergistic anti-tumor effect. However, the current evidence for the efficacy of ICIs combined with locoregional therapies remains insufficient. Therefore, we review the literature on the mechanisms of locoregional therapies in treating liver metastasis and the clinical research progress of their combination with ICIs.

Advancements in the Management of Synchronous Colorectal Liver Metastases: A Comprehensive Review of Surgical, Systemic, and Local Treatment Modalities.

PURPOSE OF REVIEW: This review addresses the current landscape of colorectal cancer (CRC) with a focus on liver metastases, the third most common cancer globally. It explores recent findings in treatment strategies, emphasizing the dynamic interplay between surgery, systemic chemotherapy, and local therapies for synchronous colorectal liver metastases (CRLMs). RECENT FINDINGS: Highlighting the role of advanced imaging, the review underscores the significance of contrast-enhanced MRI in surgical planning for CRLMs. Surgical resection remains a primary choice for resectable cases, with considerations for oncologic scoring systems and tumor biology. Perioperative systemic chemotherapy plays a pivotal role, especially in conversion therapy for initially unresectable CRLMs. The review also explores various local therapies, including radiofrequency ablation, microwave ablation, stereotactic body radiotherapy, hepatic arterial infusional chemotherapy, selective internal radiation therapy, and transarterial chemoembolization for unresectable cases. A comprehensive approach, integrating surgery, systemic chemotherapy, and local therapies, is crucial for managing synchronous CRLMs. Surgical resection and perioperative chemotherapy are key players, guided by considerations of tumor biology and scoring systems. For unresectable cases, local therapies offer viable alternatives, emphasizing the need for tailored treatments. Multidisciplinary collaboration among medical oncologists, surgeons, and radiologists is essential. Ongoing research will refine treatment approaches, while emerging technologies hold promise for further advancements in managing colorectal liver metastases.

New insights into mechanisms and interventions of locoregional therapies for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is responsible for a significant number of cancer-related deaths worldwide and its incidence is increasing. Locoregional treatments, which are precision procedures guided by imaging to specifically target liver tumors, play a critical role in the management of a substantial portion of HCC cases. These therapies have become an essential element of the HCC treatment landscape, with transarterial chemoembolization (TACE) being the treatment of choice for patients with intermediate to advanced stages of the disease. Other locoregional therapies, like radiofrequency ablation, are highly effective for small, early-stage HCC. Nevertheless, the advent of targeted immunotherapy has challenged these established treatments. Tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) have shown remarkable efficacy in clinical settings. However, their specific uses and the development of resistance in subsequent treatments have led clinicians to reevaluate the future direction of HCC therapy. This review concentrates on the distinct features of both systemic and novel locoregional therapies. We investigate their effects on the tumor microenvironment at the molecular level and discuss how targeted immunotherapy can be effectively integrated with locoregional therapies. We also examine research findings from retrospective studies and randomized controlled trials on various combined treatment regimens, assessing their validity to determine the future evolution of locoregional therapies within the framework of personalized, comprehensive treatment.

Prospective longitudinal quality of life and survival outcomes in patients with advanced infiltrative hepatocellular carcinoma and portal vein thrombosis treated with Yttrium-90 radioembolization.

BACKGROUND: To determine the effect of Yttrium-90 (Y90) radioembolization on health-related quality of life (HRQOL) and its effect on overall survival advanced, unresectable infiltrative hepatocellular carcinoma (HCC) patients with concurrent portal vein thrombosis (PVT). METHODS: Consecutive patients with unresectable infiltrative HCC and PVT were recruited. The Short-Form 36 (SF-36) questionnaire was used to assess HRQOL for consecutive patients treated with glass-based Y90 based on a prospective phase II trial. MR imaging was used to determine tumor progression every 3 months post-treatment. Overall survival (OS) from treatment and time to progression (TTP) was analyzed using Kaplan-Meier estimation and log-rank test. RESULTS: Thirty patients were treated and followed for 17.4 months; physical and mental component summary scores (PCS & MCS) remained unchanged at one, three, and six months. While no difference was observed in baseline SF-36 scores for patients with prolonged TTP (≥4 months) and OS (≥ 6 months), corresponding 1-month PCS were significantly higher than those with TTP < 4 months and OS < 6 months. At 1 month, patients with normalized Physical Function (PF), Role Physical (RP) and PCS within 2 standard deviations (SD) of US normalized baseline scores had a significantly prolonged median OS (15.7 vs. 3.7 months; p < 0.001) and TTP (12.4 vs. 1.8 mo; p < 0.001) compared those with physical component scores greater than 2SD below normalized US population values. CONCLUSION: Y90 radioembolization for HCC demonstrated long-term preservation of HRQOL. Lower baseline HRQOL scores were predictive of poorer OS. Early (1 month post-treatment) significant decreases in PCS were independent predictors of poorer OS and TTP. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01556282 , registered March 16, 2012.

Remnant vital tissue following locoregional therapy for hepatocellular carcinoma: another player in the game.

The applicability of liver transplantation (LT) as a curative option for patients with hepatocellular carcinoma (HCC) is limited by organ shortage. In addition to tumor size and number, other variables, particularly those that are surrogates of tumor biology should be incorporated into the allocation policies to improve the estimation of post-LT benefit. In this issue of Transplant International, Manzia et al. analyze the role of remnant vital tissue (RVT) of the target lesion after locoregional therapies (LRT) in predicting post-LT HCC recurrence This article is protected by copyright. All rights reserved.

Liver chemoembolization of hepatocellular carcinoma using TANDEM® microspheres.

Transarterial chemoembolization (TACE) combines intra-arterial delivery of a chemotherapeutic agent with selective embolization to obtain a synergistic effect. TACE is recognized as the standard treatment of hepatocellular carcinoma patients at an intermediate stage. If conventional TACE, defined as the injection of an emulsion of a drug with ethiodized oil, still has a role to play, the development of drug-eluting beads has allowed many improvements and optimization of the technique. TANDEM® microspheres are second-generation drug-loadable microspheres. This device raised a special interest due to its tightly calibrated spherical microspheres, with small sizes down to 40 µm available. In this review, we describe the technical characteristics of these microspheres, analyze the scientific literature and hypothesize on the future perspectives.

Do We Have a Winner? Advocating for SBRT in HCC Management.

•Stereotactic body radiotherapy (SBRT) is a safe and effective locoregional therapy for inoperable patients with HCC.•SBRT compares favorably with other local therapies in terms of local control, survival, morbidity, and cost-effectiveness.•SBRT should be considered and discussed in multidisciplinary management of appropriate HCC patients.•Advances in SBRT and novel combinations with systemic therapy may further widen the therapeutic index in HCC.

Liver-Directed Locoregional Therapies for Neuroendocrine Liver Metastases: Recent Advances and Management.

Neuroendocrine tumors (NETs) are a heterogeneous class of cancers, predominately occurring in the gastroenteropancreatic system, which pose a growing health concern with a significant rise in incidence over the past four decades. Emerging from neuroendocrine cells, these tumors often elicit paraneoplastic syndromes such as carcinoid syndrome, which can manifest as a constellation of symptoms significantly impacting patients' quality of life. The prognosis of NETs is influenced by their tendency for metastasis, especially in cases involving the liver, where the estimated 5-year survival is between 20 and 40%. Although surgical resection remains the preferred curative option, challenges emerge in cases of neuroendocrine tumors with liver metastasis (NELM) with multifocal lobar involvement, and many patients may not meet the criteria for surgery. Thus, minimally invasive and non-surgical treatments, such as locoregional therapies, have surfaced. Overall, these approaches aim to prioritize symptom relief and aid in overall tumor control. This review examines locoregional therapies, encompassing catheter-driven procedures, ablative techniques, and radioembolization therapies. These interventions play a pivotal role in enhancing progression-free survival and managing hormonal symptoms, contributing to the dynamic landscape of evolving NELM treatment. This review meticulously explores each modality, presenting the current state of the literature on their utilization and efficacy in addressing NELM.

Effectiveness and safety of computed tomography-guided high-dose-rate brachytherapy in treating recurrent hepatocellular carcinoma not amenable to repeated resection or radiofrequency ablation.

PURPOSE: To assess the efficacy and safety of computed tomography (CT)-guided high-dose-rate HDR) brachytherapy in treating recurrent hepatocellular carcinoma (HCC) not amenable to repeated resection or radiofrequency ablation. MATERIALS AND METHODS: From January 2010 to January 2022, 38 patients (mean age, 70.1 years; SD ± 9.0 years) with 79 nodular and four diffuse intrahepatic HCC recurrences not amenable to repeated resection or radiofrequency ablation underwent CT-guided HDR brachytheapy in our department. Tumor response was evaluated by cross-sectional imaging 6 weeks after CT-guided HDR brachytherapy and every 3 months thereafter. Local tumor control (LTC), progression-free survival (PFS) and overall survival (OS) were assessed using Kaplan-Meier curves (KPCs). Severity of procedure-related complications (PRCs) was classified as recommended by the Society of Interventional Radiology (SIR). RESULTS: Patients were available for MRI evaluation for a mean follow-up of 33.1 months (SD, ±21.6 mm, range 4-86 months; median 29 months). Patients had a mean of 2.3 (SD, ±1.4) intrahepatic tumors. Mean tumor diameter was 43.2 mm (SD, ±19.6 mm). 13 of 38 (34.2%) patients showed local tumor progression after CT-guided HDR brachytherapy. Mean LTC was 29.3 months (SD, ±22.1). Distant tumor progression was seen in 12 patients (31.6%). The mean PFS was 20.8 months (SD, ±22.1). Estimated 1-, 3-, and 5-year PFS rates were 65.1%, 35.1% and 22.5%, respectively. 13 patients died during the follow-up period. Mean OS was 35.4 months (SD, ±21.7). Estimated 1-, 3-, and 5-year OS rates were 91.5%, 77.4% and 58.0%, respectively. SIR grade 1 complications were recorded in 8.6% (5/38) and SIR grade 2 complications in 3.4% (2/58) of interventions. CONCLUSION: CT-guided HDR brachytherapy is a safe and efficient therapeutic option for managing large or critically located HCC recurrences in the remaining liver after prior hepatic resection.

Hepatocellular carcinoma.

An update on the management of Hepatocellular carcinoma (HCC) is provided in the present article for those interested in the UEMS/EBSQ exam in Surgical Oncology. The most recent publications in HCC, including surveillance, guidelines, and indications for liver resection, liver transplantation, and locoregional or systemic therapies, are summarised. The objective is to yield a set of main points regarding HCC that are required in the core curriculum of hepatobiliary oncological surgery.

Management of Hepatocellular Carcinoma in 2024: The Multidisciplinary Paradigm in an Evolving Treatment Landscape.

Liver cancer is the third most common cause of cancer-related deaths worldwide, and hepatocellular carcinoma (HCC) makes up the majority of liver cancer cases. Despite the stabilization of incidence rates in recent years due to effective viral hepatitis treatments, as well as improved outcomes from early detection and treatment advances, the burden of HCC is anticipated to rise again due to increasing rates of metabolic dysfunction-associated steatotic liver disease and alcohol-related liver disease. The treatment landscape is evolving and requires a multidisciplinary approach, often involving multi-modal treatments that include surgical resection, transplantation, local regional therapies, and systemic treatments. The optimal approach to the care of the HCC patient requires a multidisciplinary team involving hepatology, medical oncology, diagnostic and interventional radiology, radiation oncology, and surgery. In order to determine which approach is best, an individualized treatment plan should consider the patient's liver function, functional status, comorbidities, cancer stage, and preferences. In this review, we provide an overview of the current treatment options and key trials that have revolutionized the management of HCC. We also discuss evolving treatment paradigms for the future.

Diagnostic performance of MRI for residual or recurrent hepatocellular carcinoma after locoregional treatment according to contrast agent type: a systematic review and meta­analysis.

PURPOSE: The ideal contrast agent for imaging patients with hepatocellular carcinoma (HCC) following locoregional therapies (LRT) remains uncertain. We conducted a meta-analysis to assess the diagnostic performance of magnetic resonance imaging with extracellular contrast agent (ECA-MRI) and hepatobiliary agent (EOB-MRI) in detecting residual or recurrence HCC following LRT. METHODS: Original studies comparing the diagnostic performance of ECA-MRI and EOB-MRI were systematically identified through comprehensive searches in PubMed, EMBASE, Cochrane Library and Web of Science databases. The pooled sensitivity and specificity of ECA-MRI and EOB-MRI were calculated using a bivariate-random-effects model. Subgroup-analyses were conducted to compare the diagnostic performance of ECA-MRI and EOB-MRI according to different variables. Meta-regression analysis was employed to explore potential sources of study heterogeneity. RESULTS: A total of 15 eligible studies encompassing 803 patients and 1018 lesions were included. Comparative analysis revealed no significant difference between ECA-MRI and EOB-MRI in the overall pooled sensitivity (87% vs. 79%) and specificity (92% vs. 96%) for the detection of residual or recurrent HCC after LRT (P = 0.41), with comparable areas under the HSROC of 0.95 and 0.92. Subgroup analyses indicated no significant diagnostic performance differences between ECA-MRI and EOB-MRI according to study design, type of LRT, most common etiology of liver disease, baseline lesion size, time of post-treated examination and MRI field strength (All P > 0.05). CONCLUSION: ECA-MRI exhibited overall comparable diagnostic performance to EOB-MRI in assessing residual or recurrent HCC after LRT.

The Negative Impact of Sarcopenia on Hepatocellular Carcinoma Treatment Outcomes.

INTRODUCTION: Hepatocellular carcinoma (HCC) represents a major global health concern, characterized by evolving etiological patterns and a range of treatment options. Among various prognostic factors, sarcopenia, characterized by loss of skeletal muscle mass, strength, and function, has emerged as a pivotal contributor to HCC outcomes. Focusing on liver transplantation, surgical resection, locoregional treatments, and systemic therapies, this review aims to analyze the impact of sarcopenia on HCC treatment outcomes, shedding light on an underexplored subject in the pursuit of more personalized management. METHODS: A comprehensive literature review was conducted by searching peer-reviewed articles on sarcopenia and treatment outcomes in patients with HCC from inception up to October 2023. RESULTS: Sarcopenia was found to be prevalent among HCC patients, exhibiting different occurrence, possibly attributable to diverse diagnostic criteria. Notably, despite variations in studies utilizing skeletal muscle indices, sarcopenia independently correlated with lower overall survival (OS), recurrence-free survival (RFS), and progression-free survival (PFS) across surgical (both transplantation and resection), locoregional, and systemic therapies, including tyrosine-kinase inhibitors (TKIs) and immune-checkpoint inhibitors (ICIs). Moreover, a link between sarcopenia and increased rate and severity of adverse events, particularly in surgery and TKIs recipients, and larger tumor size at diagnosis was observed. While baseline sarcopenia negatively influenced treatment outcomes, alterations in muscle mass post-treatment emerged as primary determinants of reduced OS. CONCLUSIONS: Sarcopenia, either present before or after HCC treatment, negatively correlates with response to it, across all etiologies and therapeutic strategies. Although only a few studies have evaluated the impact of supervised physical activity training on muscle mass and OS after HCC treatment, it is crucial to evaluate the presence of sarcopenia before treatment initiation, to better stratify patients' prognosis, thus performing a more tailored approach, and identify therapies able to restore muscle mass in HCC patients. Conversely, the impact of sarcopenia on HCC recurrence and extrahepatic spread remains inadequately explored.

Interventional Treatment Strategies in Intrahepatic Cholangiocarcinoma and Perspectives for Combined Hepatocellular-Cholangiocarcinoma.

cHCC-CCA is an uncommon type of liver cancer that exhibits clinical and pathological characteristics of both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), which are the two main forms of primary liver cancer. The similarity to HCC and CCA makes therapeutical strategies challenging. The poor prognosis of CCA in general, as well as for cHCC-CCA, is mainly attributable to the fact that diagnosis is often at an advanced stage of disease. During the last decade, locoregional therapies usually performed by interventional radiologists and its established role in HCC treatment have gained an increasing role in CCA treatment as well. These comprise a wide range of options from tumor ablation procedures such as radiofrequency ablation (RFA), microwave ablation (MWA), computed tomography high-dose rate brachytherapy (CT-HDRBT), and cryoablation to transarterial chemoembolization (TACE), including the option of intra-arterial administration of radioactive spheres (transarterial radioembolization-TARE), and much attention has focused on the potential of individual concepts in recent years. The purpose of this review is to provide an overview of current radiologic interventions for CCA (excluding options for eCCA), to review and appraise the existing literature on the topic, and to provide an outlook on whether such interventions may have a role as treatment for cHCC-CCA in the future.

Bridging therapies for patients with hepatocellular carcinoma awaiting liver transplantation: A systematic review and meta-analysis on intention-to-treat outcomes.

INTRODUCTION: Locoregional therapies are commonly used as bridging strategies to decrease the drop-out of patients with hepatocellular carcinoma (HCC) awaiting liver transplantation (LT). The present paper aims to assess the outcomes of bridging therapies in patients with HCC considered for LT according to an intention-to-treat (ITT) survival analysis. MATERIAL AND METHODS: Medline and Web of Science databases were searched for reports published before May 2021. Papers assessing adult patients with HCC considered for LT and reporting ITT survival outcomes were included. Two reviewers independently identified, extracted the data, and evaluated the papers according to Newcastle-Ottawa criteria. Outcomes analyzed were: drop-out rate; time on the waiting list; 1-, 3-, and 5-year survival after LT and based on an ITT analysis. RESULTS: The search identified 3106 records; six papers (1043 patients) met the inclusion criteria. Patients with HCC, listed for LT and submitted to bridging therapies presented a longer waiting time before LT (MD 3.77, 95% CI 2.07-5.48) in comparison with the non-interventional group. However, they presented a raised post LT after 1-year (OR 2.00, 95% CI 1.18-3.41), 3-years (OR 1.47, 95% CI 1.01-2.15), and 5-years (OR 1.50, 95% CI 1.06-2.13) survival. CONCLUSION: Patients submitted to bridging procedures, despite having a longer interval on the waiting list, presented better post-LT survival outcomes. Bridging therapies for selected patients at low risk of post-procedural complications and long expected intervals on the waiting list should be encouraged. However, further clinical trials should confirm the survival benefit of bridging therapies in patients with HCC listed for LT.

New Challenges in the Management of Cholangiocarcinoma: The Role of Liver Transplantation, Locoregional Therapies, and Systemic Therapy.

Cholangiocarcinoma (CCA) is a neoplasm with high mortality that represents 15% of all primary liver tumors. Its worldwide incidence is on the rise, and despite important advances in the knowledge of molecular mechanisms, diagnosis, and treatment, overall survival has not substantially improved in the last decade. Surgical resection remains the cornerstone therapy for CCA. Unfortunately, complete resection is only possible in less than 15-35% of cases, with a risk of recurrence greater than 60%. Liver transplantation (LT) has been postulated as an effective therapeutic strategy in those intrahepatic CCA (iCCA) smaller than 3 cm. However, the low rate of early diagnosis in non-resectable patients justifies the low applicability in clinical practice. The evidence regarding LT in locally advanced iCCA is scarce and based on small, retrospective, and, in most cases, single-center case series. In this setting, the response to neoadjuvant chemotherapy could be useful in identifying a subgroup of patients with biologically less aggressive tumors in whom LT may be successful. The results of LT in pCCA are promising, however, we need a very careful selection of patients and adequate experience in the transplant center. Locoregional therapies may be relevant in unresectable, liver-only CCA. In iCCA smaller than 2 cm, particularly those arising in patients with advanced chronic liver disease in whom resection or LT may not be feasible, thermal ablation may become a reliable alternative. The greatest advances in the management of CCA occur in systemic treatment. Immunotherapy associated with chemotherapy has emerged as the gold standard in the first-line treatment. Likewise, the most encouraging results have been obtained with targeted therapies, where the use of personalized treatments has shown high rates of objective and durable tumor response, with clear signs of survival benefit. In conclusion, the future of CCA treatment seems to be marked by the development of new treatment strategies but high-quality, prospective studies that shed light on their use and applicability are mandatory.

Effectiveness of TKI Inhibitors Combined With PD-1 in Patients With Postoperative Early Recurrence of HCC: A Real-World Study.

Objective: To observe the efficacy of TKI inhibitor combined with PD-1 treatment in patients with early recurrence after radical resection of HCC, and to analyze the factors that affect the efficacy. Methods: The baseline demographic and clinical data of 58 patients with early recurrence after radical resection of HCC (including surgical resection and liver transplantation) were collected. Recurrence and metastasis were classified into early (< or =2 years) and late phase (>2 years). After systemic drug treatment (sorafenib, lenvatinib, PD-1), the efficacy was evaluated based on the RECIST 1.1 standard. COX regression model was used to analyze the factors affecting PFS and OS in HCC patients. Survival curves were drawn by Kaplan-Meier method. Results: The study finally included 58 patients who underwent radical resection of HCC, of which 39 were in the TKIs group and 19 were in the TKIs + ICIs combined treatment group. There was no statistical difference in the baseline data of the two groups in HB, PLT, Child-Pugh score and other indicators. Efficacy evaluation results showed that in the 39 TKIs group, 7 patients were PD and 9 patients were PR; while in the 19 TKIs combined with PD-1 group, 2 patients were PD and 6 patients were PR. The median PFS of the TKIs group was 6.2 months, while the median PFS of the TKIs combined PD-1 group was 14.0 months (HR= 0.469, P=0.031). The median OS of the TKIs group was 18.0 months, while the median OS of the TKIs combined with PD-1 group was 35.8 months, an extension of 17.8 months (HR= 0.444, P=0.053). Conclusion: In the first-line treatment of patients with early recurrence after radical resection of HCC, patients treated with TKIs combined with PD-1 therapy has a survival advantage over those treated with TKIs alone. Ascites, HBV DNA positivity, and high levels of AFP often indicate poor efficacy of systemic drug therapy, suggesting that such patients should be closely monitored after surgery and that comprehensive systemic treatment should be administrated in time to improve the prognosis.

Trans-Arterial Chemoembolization Plus Systemic Treatments for Hepatocellular Carcinoma: An Update.

Recent years have seen the advent of novel treatment options for hepatocellular carcinoma (HCC). Given a strong biological rationale supporting this strategy, multiple studies have explored the role of combination treatments including locoregional plus systemic therapies to produce a synergistic effect and enhance antitumor activity. Among locoregional therapies, several clinical trials assessing trans-arterial chemoembolization (TACE) have been recently presented and published. In the current paper, we discuss available evidence and current and future research on combined TACE and systemic treatments, including antiangiogenic agents, immune checkpoint inhibitors, and immune-based combinations for HCC patients.

Systemic Therapy for Hepatocellular Carcinoma: Current Updates and Outlook.

Hepatocellular carcinoma (HCC) has emerged the culprit of cancer-related mortality worldwide with its dismal prognosis climbing. In recent years, ground-breaking progress has been made in systemic therapy for HCC. Targeted therapy based on specific signaling molecules, including sorafenib, lenvatinib, regorafenib, cabozantinib, and ramucirumab, has been widely used for advanced HCC (aHCC). Immunotherapies such as pembrolizumab and nivolumab greatly improve the survival of aHCC patients. More recently, synergistic combination therapy has boosted first-line (atezolizumab in combination with bevacizumab) and second-line (ipilimumab in combination with nivolumab) therapeutic modalities for aHCC. This review aims to summarize recent updates of systemic therapy relying on the biological mechanisms of HCC, particularly highlighting the approved agents for aHCC. Adjuvant and neoadjuvant therapy, as well as a combination with locoregional therapies (LRTs), are also discussed. Additionally, we describe the promising effect of traditional Chinese medicine (TCM) as systemic therapy on HCC. In this setting, the challenges and future directions of systemic therapy for HCC are also explored.