Advanced-stage Hepatocellular Carcinoma Research Articles

An Insight Into the Role of Alpha-Fetoprotein (AFP) in the Development and Progression of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the primary malignancy of hepatocytes and the second most common cause of cancer-related mortality across the globe. Despite significant advancements in screening, diagnosis, and treatment modalities for HCC, the mortality-to-incidence ratio remain unacceptably high. A recent study indicates that a minor population of HCCs are AFP negative or express the normal range of AFP levels. Although it is a gold standard and a more reliable biomarker in the advanced stage of HCC and poorly differentiated tumors, it does not serve as a suitable means for screening HCC. AFP plays a significant role in the development and progression of HCC and understanding its role is crucial. By examining the molecular mechanisms involved in AFP-mediated tumorigenesis, we can better understand HCC pathogenesis and identify potential therapeutic targets. This article details the role of alpha-fetoprotein (AFP) in the carcinogenic transformation of hepatocytes. The article also focuses on information about the structure, biosynthesis, and regulation of AFP at the gene level. Additionally, it discusses the immune evasion, metastasis, and control of gene expression that AFP mediates during HCC.

952P Efficacy and safety of a PRospective, Observational trial of Lenvatinib cOmbined with transarterial chemoembolization (TACE) as initial treatment for advaNced staGe hepatocellular carcinoma (PROLONG): A multicenter, single-armed, real-world study

952P Efficacy and safety of a PRospective, Observational trial of Lenvatinib cOmbined with transarterial chemoembolization (TACE) as initial treatment for advaNced staGe hepatocellular carcinoma (PROLONG): A multicenter, single-armed, real-world study

Combination of transarterial radioembolization with atezolizumab and bevacizumab for intermediate and advanced staged hepatocellular carcinoma: A preliminary report of safety and feasibility

PurposeThe IMbrave150 Phase III trial demonstrated the superiority of atezolizumab and bevacizumab (Atezo/Bev) over sorafenib for unresectable hepatocellular carcinoma (HCC). The present study aims to evaluate the feasibility of TARE in combination with Atezo/Bev for the treatment of intermediate and advanced staged HCC. MethodsA retrospective review at a single institution was performed between May 2021 and December 2022. Patients who received TARE using yttrium-90 (Y90) with concomitant or sequential Atezo/Bev systemic treatment were included. The following outcomes were retrieved: overall survival (OS), radiologic tumor response, progression-free survival, technical adverse events related to TARE, and toxicity based on the National Cancer Institute–Common Terminology Criteria for Adverse Events version 5.0. ResultsTen consecutive patients with intermediate (n ​= ​4) and advanced stage HCC (n ​= ​6) were treated with TARE and sequential/concomitant Atezo/Bev. Tumor control was achieved in all TARE-treated target lesions (100%). Overall disease progression occurred in 4 patients with PFS of 78.8% and 66.7% at 6- and 12- months, respectively. Two patients died at follow-up, with 6-month and 12-month OS rates of 90.0% and 77.1%, respectively. Three (75%) patients with intermediate stage disease were downstaged into Milan criteria. One patient developed grade 3 transaminitis and hypoglobulinemia, while Atezo/Bev was switched to Lenvatinib in another patient due to immunotherapy related myositis. ConclusionThis study demonstrates the initial safety and feasibility of combined TARE with Atezo/Bev for intermediate/advanced stage HCC. Further prospective studies with larger sample sizes are warranted.

Expert consensus on precise diagnosis and management of primary hepatocellular carcinoma in advanced stage (2023 version)

not matching with chinese abstract stage in China. By adopting the "Delphi" consensus formation method, a set of precise staging criteria and corresponding preferred treatment protocols were agreed upon for Chinese patients with hepatocellular carcinoma in advanced stage, taking into account different tumor characteristics, vascular embolism grading, distant metastasis and liver function status, portal hypertension, hepatitis B virus replication status, etc., as well as the prognosis of the patients. This consensus is intended to provide a more detailed, scientific, and reasonable reference basis for the selection of individualized diagnosis and treatment plans for frontline clinicians.

Biomarkers for immunotherapy of hepatocellular carcinoma.

Immune-checkpoint inhibitors (ICIs) are now widely used for the treatment of patients with advanced-stage hepatocellular carcinoma (HCC). Two different ICI-containing regimens, atezolizumab plus bevacizumab and tremelimumab plus durvalumab, are now approved standard-of-care first-line therapies in this setting. However, and despite substantial improvements in survival outcomes relative to sorafenib, most patients with advanced-stage HCC do not derive durable benefit from these regimens. Advances in genome sequencing including the use of single-cell RNA sequencing (both of tumour material and blood samples), as well as immune cell identification strategies and other techniques such as radiomics and analysis of the microbiota, have created considerable potential for the identification of novel predictive biomarkers enabling the accurate selection of patients who are most likely to derive benefit from ICIs. In this Review, we summarize data on the immunology of HCC and the outcomes in patients receiving ICIs for the treatment of this disease. We then provide an overview of current biomarker use and developments in the past 5 years, including gene signatures, circulating tumour cells, high-dimensional flow cytometry, single-cell RNA sequencing as well as approaches involving the microbiome, radiomics and clinical markers. Novel concepts for further biomarker development in HCC are then discussed including biomarker-driven trials, spatial transcriptomics and integrated 'big data' analysis approaches. These concepts all have the potential to better identify patients who are most likely to benefit from ICIs and to promote the development of new treatment approaches.

The efficacy of treatment for hepatocellular carcinoma in elderly patients.

Despite the increasing proportion of elderly patients with hepatocellular carcinoma (HCC) over time, treatment efficacy in this population is not well established. Data collected from the Korean Primary Liver Cancer Registry, a representative cohort of patients newly diagnosed with HCC in Korea between 2008 and 2017, were analyzed. Overall survival (OS) according to tumor stage and treatment modality was compared between elderly and non-elderly patients with HCC. Among 15,186 study patients, 5,829 (38.4%) were elderly. A larger proportion of elderly patients did not receive any treatment for HCC than non-elderly patients (25.2% vs. 16.7%). However, OS was significantly better in elderly patients who received treatment compared to those who did not (median, 38.6 vs. 22.3 months; P<0.001). In early-stage HCC, surgery yielded significantly lower OS in elderly patients compared to non-elderly patients (median, 97.4 vs. 138.0 months; P<0.001), however, local ablation (median, 82.2 vs. 105.5 months) and transarterial therapy (median, 42.6 vs. 56.9 months) each provided comparable OS between the two groups after inverse probability of treatment weighting (IPTW) analysis (all P>0.05). After IPTW, in intermediate-stage HCC, surgery (median, 66.0 vs. 90.3 months) and transarterial therapy (median, 36.5 vs. 37.2 months), and in advanced-stage HCC, transarterial (median, 25.3 vs. 26.3 months) and systemic therapy (median, 25.3 vs. 26.3 months) yielded comparable OS between the elderly and non-elderly HCC patients (all P>0.05). Personalized treatments tailored to individual patients can improve the prognosis of elderly patients with HCC to a level comparable to that of non-elderly patients.

Circulating Tumor Cells as a Promising Tool for Early Detection of Hepatocellular Carcinoma.

Liver cancer is a significant contributor to the cancer burden, and its incidence rates have recently increased in almost all countries. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is the second leading cause of cancer-related deaths worldwide. Because of the late diagnosis and lack of efficient therapeutic modality for advanced stages of HCC, the death rate continues to increase by ~2-3% per year. Circulating tumor cells (CTCs) are promising tools for early diagnosis, precise prognosis, and follow-up of therapeutic responses. They can be considered to be an innovative biomarker for the early detection of tumors and targeted molecular therapy. In this review, we briefly discuss the novel materials and technologies applied for the practical isolation and detection of CTCs in HCC. Also, the clinical value of CTC detection in HCC is highlighted.

Identifying Network Biomarkers in Early Diagnosis of Hepatocellular Carcinoma via miRNA-Gene Interaction Network Analysis.

Hepatocellular carcinoma (HCC) is a highly heterogeneous cancer at the histological level. Despite the emergence of new biological technology, advanced-stage HCC remains largely incurable. The prediction of a cancer biomarker is a key problem for targeted therapy in the disease. We performed a miRNA-gene integrated analysis to identify differentially expressed miRNAs (DEMs) and genes (DEGs) of HCC. The DEM-DEG interaction network was constructed and analyzed. Gene ontology enrichment and survival analyses were also performed in this study. By the analysis of healthy and tumor samples, we found that 94 DEGs and 25 DEMs were significantly differentially expressed in different datasets. Gene ontology enrichment analysis showed that these 94 DEGs were significantly enriched in the term "Liver" with a statistical p-value of 1.71 × 10-26. Function enrichment analysis indicated that these genes were significantly overrepresented in the term "monocarboxylic acid metabolic process" with a p-value = 2.94 × 10-18. Two sets (fourteen genes and five miRNAs) were screened by a miRNA-gene integrated analysis of their interaction network. The statistical analysis of these molecules showed that five genes (CLEC4G, GLS2, H2AFZ, STMN1, TUBA1B) and two miRNAs (hsa-miR-326 and has-miR-331-5p) have significant effects on the survival prognosis of patients. We believe that our study could provide critical clinical biomarkers for the targeted therapy of HCC.

Efficacy of Lenvatinib Combined with Transcatheter Intra-Arterial Therapies for Patients with Advanced-Stage of Hepatocellular Carcinoma: A Propensity Score Matching.

This study aimed to evaluate the effect of lenvatinib (LEN) combined with transcatheter intra-arterial therapy (TIT) for advanced-stage hepatocellular carcinoma (HCC) after propensity score matching (PSM). This retrospective study enrolled 115 patients with advanced-stage HCC who received LEN treatment. The patients were categorized into the LEN combined with TIT group (n = 30) or the LEN monotherapy group (n = 85). After PSM, 38 patients (LEN + TIT group, n = 19; LEN monotherapy group, n = 19) were analyzed. The median overall survival (OS) in the LEN + TIT group was significantly higher than that in the LEN monotherapy group (median survival time (MST): 28.1 months vs. 11.6 months, p = 0.014). The OS in the LEN combined with transcatheter arterial chemoembolization and LEN combined with hepatic arterial infusion chemotherapy groups was significantly higher than that in the LEN monotherapy group (MST 20.0 vs. 11.6 months, 30.2 vs. 11.6 months, p = 0.048, and p = 0.029, respectively). Independent factors associated with OS were alpha-fetoprotein and LEN combined with TIT. The indications for LEN combined with TIT were age <75 years and modified albumin bilirubin (m-ALBI) grade 1. We concluded that LEN combined with TIT may improve prognosis compared with LEN monotherapy in patients with advanced-stage HCC.

Unawareness of hepatitis B infection and lack of surveillance are associated with severity of hepatocellular carcinoma.

Unawareness of hepatitis B virus (HBV) infection and lack of surveillance may serve as major barriers to HBV control and contributors to severe hepatocellular carcinoma (HCC) at presentation. This study evaluated the risk of HBV unawareness and its relationship with HCC severity. This retrospective study was conducted in a tertiary hospital in Taiwan. Patients with HBV-related HCC diagnosed from 2011 to 2021 were enrolled. The demographic, clinical, and HCC characteristics were collected and compared between patients with HBV unawareness and awareness with and without surveillance. Of 501 HBV-related HCC patients enrolled, 105 (21%) patients were unaware of HBV infection at the time of HCC diagnosis. Patients with HBV unawareness were significantly younger and had poorer liver function than those with HBV awareness. Patients with HBV unawareness also had a significantly higher rate of detectable HBV DNA and an advanced stage of HCC. Ninety-one (23%) of the HBV-aware patients did not receive regular surveillance. Patients with HBV unawareness and awareness without surveillance shared similar clinical characteristics with more severe HCC status. Further regression analysis demonstrated that HBV awareness with periodic surveillance was associated with early stage HCC. Meanwhile, we observed that there was no change in the proportion of HBV awareness over the past 10 years. Patients with surveillance also had better HCC survival than patients without surveillance or unawareness. HBV unawareness and lack of regular surveillance correlated with advanced HCC at presentation. Efforts to improve HBV education, disease awareness, and HCC surveillance are needed.

Adverse Event Profile in Advance Hepatocellular Carcinoma treated with Sorafenib Presenting to CMH Rawalpindi

&#x0D; Objective: To look for adverse event profiles in advance of hepatocellular carcinoma treated with Sorafenib presenting to CMH Rawalpindi and study associated socio-demographic factors&#x0D; Study Design: Comparative cross-sectional study&#x0D; Place and Duration of Study: Oncology Department, Combined Military Hospital, Rawalpindi Pakistan, from Dec 2020 to Nov 2021.&#x0D; Methodology: Three hundred patients with diagnosed hepatocellular carcinoma in advanced stage taking Sorafenib chemotherapy for more than three months and less than one year were included in the study. Each patient was assessed for relevant adverse effects in the follow-up outpatient visits by a consultant oncologist. &#x0D; Results: Out of 300 cancer patients using Sorafenib for more than three months and less than one year, 212(70.7%) patients had at least one or more adverse effects, while 88(29.3%) did not experience any adverse effects. Diarrhoea 120(40%) was the most common adverse effect, followed by rash/desquamation 110(36.7%). Advancing age was statistically significantly associated (p-value-0.001) with adverse effects among the target population.&#x0D; Conclusion: A significant number of patients suffering from hepatocellular carcinoma using Sorafenib had mild to moderate adverse effects. Physicians should keep an eye on patients with advancing age for adverse effects of this medication.

Bilobar Radioembolization Carries the Risk of Radioembolization-Induced Liver Disease in the Treatment of Advanced Hepatocellular Carcinoma: Safety and Efficacy Comparison to Systemic Therapy with Atezolizumab/Bevacizumab.

Recommended treatment options for advanced-stage hepatocellular carcinoma (HCC) include systemic therapy (ST) and trans-arterial radioembolization (TARE) with Yttrium-90 (Y90). Before the approval of immune-checkpoint inhibitors, a similar safety profile was reported for TARE and ST with tyrosine kinase inhibitors (TKI). However, whole-liver treatment and underlying cirrhosis were identified as risk factors for potentially lethal radioembolization-induced liver disease (REILD). Therefore, the safety and efficacy of TARE and ST with atezolizumab/bevacizumab were compared in patients with advanced HCC involving at least both liver lobes in a retrospective real-world cohort. In total, 74 patients with new or recurrent advanced-stage HCC (BCLC stage B/C) were included if treated with either bilobar TARE (n = 33) or systemic combination therapy with atezolizumab plus bevacizumab (n = 41). Most patients had compensated liver function (90.5% were classified as Child-Pugh Score A, 73% as ALBI Grade 1) at baseline. Although not significant, patients treated with ST showed a more prolonged overall survival than those treated with Y90 TARE (7.1 months vs. 13.0 months, p = 0.07). While a similar disease control rate could be achieved with bilobar TARE and atezolizumab/bevacizumab, in the TARE group, overall survival was curtailed by the occurrence of REILD. In patients with underlying liver cirrhosis, the liver function at baseline was a predictor for REILD.

Protocol of the RACB study: a multicenter, single-arm, prospective study to evaluate the efficacy of resection of initially unresectable hepatocellular carcinoma with atezolizumab combined with bevacizumab

BackgroundAlthough the standard therapy for advanced-stage hepatocellular carcinoma (HCC) is systemic chemotherapy, the combination of atezolizumab and bevacizumab (atezo + bev) with a high objective response rate may lead to conversion to resection in patients with initially unresectable HCC. This study aims to evaluate the efficacy of atezo + bev in achieving conversion surgery and prolonged progression-free survival (PFS) for initially unresectable HCC.MethodsThe RACB study is a prospective, single-arm, multicenter, phase II trial evaluating the efficacy of combination therapy with atezo + bev for conversion surgery in patients with technically and/or oncologically unresectable HCC. The main eligibility criteria are as follows: (1) unresectable HCC without a history of systemic chemotherapy, (2) at least one target lesion based on RECIST ver. 1.1, and (3) a Child‒Pugh score of 5–6. The definition of unresectable tumors in this study includes macroscopic vascular invasion and/or extrahepatic metastasis and massive distribution of intrahepatic tumors. Patients will be treated with atezolizumab (1200 mg/body weight) and bevacizumab (15 mg/kg) every 3 weeks. If the patient is considered resectable on radiological assessment 12 weeks after initial chemotherapy, the patient will be treated with atezolizumab monotherapy 3 weeks after combination chemotherapy followed by surgery 3 weeks after atezolizumab monotherapy. If the patient is considered unresectable, the patient will continue with atezo + bev and undergo a radiological assessment every 9 weeks until resectable or until disease progression. The primary endpoint is PFS, and the secondary endpoints are the overall response rate, overall survival, resection rate, curative resection rate, on-protocol resection rate, and ICG retention rate at 15 min after atezo + bev therapy. The assessments of safety and quality of life during the treatment course will also be evaluated. The number of patients has been set at 50 based on the threshold and the expected PFS rate at 6 months after enrollment of 40% and 60%, respectively, with a one-sided alpha error of 0.05 and power of 0.80. The enrollment and follow-up periods will be 2 and 1.5 years, respectively.DiscussionThis study will elucidate the efficacy of conversion surgery with atezo + bev for initially unresectable HCC. In addition, the conversion rate, safety and quality of life during the treatment course will also be demonstrated.Trial registrationThis study is registered in the Japan Registry of Clinical Trials (jRCTs051210148, January 7, 2022).

Immunotherapy and Transarterial Radioembolization Combination Treatment for Advanced Hepatocellular Carcinoma.

The efficacy and safety of combined immunotherapy and transarterial radioembolization (TARE) were suggested in preclinical and early-phase trials, but these were limited by small sample sizes. We sought to compare the efficacy of combined therapy and immunotherapy alone in patients with advanced hepatocellular carcinoma (HCC). The National Cancer Database was used to identify patients with advanced HCC diagnosed between January 1, 2017, and December 31, 2019. We included patients who received combined therapy or immunotherapy alone as first-line treatment. Multivariable logistic regression was conducted to determine predictors of combined therapy. Kaplan-Meier and Cox regression approaches were used to identify predictors of overall survival and to compare hazards of mortality between the patients who received combined therapy and immunotherapy alone. Of 1,664 eligible patients with advanced-stage HCC, 142 received combined TARE/immunotherapy and 1,522 received immunotherapy alone. Receipt of combination therapy was associated with care at an academic center and inversely associated with racial/ethnic minority status (Hispanic and Black individuals). The median overall survival was significantly higher in the combination group than in the immunotherapy alone group (19.8 vs 9.5 months). In multivariable analysis, combined therapy was independently associated with reduced mortality (adjusted hazard ratio 0.50, 95% confidence interval: 0.36-0.68, P < 0.001). Results were consistent across subgroups and in sensitivity analyses using propensity score matching and inverse probability of treatment weighting. The combination of TARE and immunotherapy was associated with improved survival compared with immunotherapy alone in patients with advanced-stage HCC. Our findings underly the importance of large clinical trials evaluating combination therapy in these patients.

Long-term outcomes and salvageability in patients undergoing liver resection for intermediate- and advanced-stage hepatocellular carcinoma

BackgroundsThe prognosis of intermediate- and advanced-stage hepatocellular carcinoma after liver resection should be comprehensively analyzed due to the high incidence of tumor recurrence and the availability of salvage therapy. This study evaluated the long-term outcome and salvageability in these patients after liver resection. MethodsData from consecutive patients with intermediate- and advanced-stage hepatocellular carcinoma who underwent initial liver resection from 2000 to 2016 were retrospectively reviewed. Analyses were performed in the setting of the initial liver resection and the recurrence(s). Active salvage therapy for recurrence was defined as the implementation of each therapy with curative intent—repeat surgery, ablative therapy, and liver transplantation. ResultsAmong the 1,013 liver resections for hepatocellular carcinoma, a total of 270 patients were eligible for this study (intermediate hepatocellular carcinoma, n = 134; advanced hepatocellular carcinoma, n = 136). The 5-year overall survival rates for intermediate and advanced-stage hepatocellular carcinoma were 49.7% and 36.8%, respectively; meanwhile, the actual recurrence rates excluding patients who died without recurrence were 94.7% and 90.7%, respectively. Active salvage therapy was performed in 43 (39.8%) patients with intermediate-stage hepatocellular carcinoma and 25 (23.4%) patients with advanced-stage hepatocellular carcinoma. Overall survival after initial liver resection, first active salvage therapy, and second/more active salvage therapy were comparable in both stages. ConclusionsThis study suggests that although liver resection alone may not yield remission in most patients with intermediate and advanced-stage hepatocellular carcinoma, active salvage therapy can potentially prolong survival. Further study to identify approaches to decrease recurrence rates and increase salvageability for these patients would be warranted.

Idarubicin versus epirubicin in drug-eluting beads-transarterial chemoembolization for treating hepatocellular carcinoma: A real-world retrospective study.

The purpose of this study was to compare the efficacy and safety of idarubicin-loaded drug-eluting beads-transarterial chemoembolization (IDA-TACE) and epirubicin-loaded drug-eluting beads-TACE (EPI-TACE) in treating hepatocellular carcinoma (HCC). All patients with HCC treated with TACE in our hospital between June 2020 and January 2022 were screened. The included patients were divided into the IDA-TACE group and EPI-TACE group to compare overall survival (OS), time to progression (TTP), objective response rate (ORR), and adverse events. There were 55 patients each in the IDA-TACE and EPI-TACE groups. Compared with the EPI-TACE group, the median TTP in the IDA-TACE group was not significantly different (10.50 vs. 9.23months; HR 0.68; 95% CI 0.40-1.16; P = 0.154), whereas the survival status in the IDA-TACE group tended to be better (neither achieved; HR 0.47; 95% CI 0.22-1.02; P = 0.055). Based on the Barcelona Clinic Liver Cancer staging system for subgroup analysis, considering stage C patients, the IDA-TACE group performed significantly better in terms of ORR (77.1% vs. 54.3%, P = 0.044), median TTP (10.93 vs. 5.20months; HR 0.46; 95% CI 0.24-0.89; P = 0.021), and median OS (not achieved vs. 17.80months; HR 0.41; 95% CI 0.18-0.93; P = 0.033). Considering stage B patients, there were no significant differences between the IDA-TACE and EPI-TACE groups in terms of ORR (80.0% vs. 80.0%, P = 1.000), median TTP (10.20 vs. 11.2months; HR 1.41; 95% CI 0.54-3.65; P = 0.483), or median OS (neither achieved, HR 0.47; 95% CI 0.04-5.24; P = 0.543). Notably, leukopenia was more common in the IDA-TACE group (20.0%, P = 0.052), and fever was more common in the EPI-TACE group (49.1%, P = 0.010). IDA-TACE was more effective than EPI-TACE in treating advanced-stage HCC and comparable in treating intermediate-stage HCC.

Radiation Therapy With Combination Therapy of Immune Checkpoint Inhibitors and Antiangiogenic Therapy for Hepatocellular Carcinoma

Immune checkpoint inhibitors (ICIs) combined with antiangiogenic therapy have limited efficacy in treating advanced hepatocellular carcinoma (HCC). The synergistic effect of systemic therapy and radiation therapy (RT) might resolve this problem. We aimed to investigate the effect of RT on the treatment outcomes of ICIs and antiangiogenic combination therapy in patients with advanced-stage HCC. This retrospective observational study analyzed the medical records of 194 patients with Barcelona Clinic Liver Cancer stage C HCC who were admitted to our center from August 2018 to June 2022 and received ICIs combined with antiangiogenic therapy as the first-line treatment. Patients who were administered RT for tumor thrombus or symptomatic metastases within 8 weeks of the commencement of combination therapy were allocated to the RT group, whereas those who did not receive RT were assigned to the non-radiation therapy (NRT) group. Propensity score matching was used to mitigate selection bias. The primary endpoints were progression-free survival (PFS) and overall survival (OS). The secondary endpoints included objective response rate, disease control rate (DCR), local PFS, out-of-field PFS, and treatment-related adverse events. A total of 76 patients diagnosed with advanced-stage HCC and treated with ICIs and antiangiogenic therapy were included in the study, with 33 patients in the RT group and 43 patients in the non-RT group. After propensity score matching, 29 matched patient pairs were generated. The median follow-up was 15.5 months, and the RT sites were mainly located on the tumor thrombus (55.2%) and extrahepatic metastatic lesions (48.3%). The median PFS was 8.3 months (95% CI, 5.4-11.3) in the RT group and 4.2 months (95% CI, 3.4-5.0) in the NRT group (P < .001). The median OS was not reached in the RT group and was 9.7 months (95% CI, 4.1-15.3) in the NRT group (P = .002). The objective response rate was 75.9% (95% CI, 56.5-89.7) in the RT group and 24.1% (95% CI, 10.3-43.5) in the NRT group (P < .001). The DCR was 100% in the RT group and 75.9% (95% CI, 56.5-89.7) in the NRT group (P = .005). The median local PFS and out-of-field PFS were 13.2 months (95% CI, 6.3-20.1) and 10.8 months (95% CI, 7.0-14.7), respectively. RT was an independent prognostic factor for PFS (hazard ratio = 0.33; 95% CI, 0.17-0.64; P < .001) and OS (hazard ratio = 0.28; 95% CI, 0.11-0.68; P = .005), respectively. The rates of any grade treatment-related adverse events were similar between the 2 groups. In comparison to the combination of ICIs and antiangiogenic therapy, the inclusion of RT has been observed to improve the DCR and survival outcomes in patients with advanced-stage HCC. The safety profile of this triple therapy was satisfactory.

New Opportunities to Individualize Frontline Therapy in Advanced Stages of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a leading cause of cancer death globally and is rising in incidence. Until recently, treatment options for patients with advanced stages of HCC have been limited to antiangiogenic therapies with modest improvements in overall survival. The emerging role of immunotherapy with immune checkpoint inhibitors (ICI) in oncology has led to a rapid expansion in treatment options and improvements in outcomes for patients with advanced stages of HCC. Recent clinical trials have shown meaningful survival improvement in patients treated with the combination of bevacizumab and atezolizumab, as well as with the combination of tremelimumab with durvalumab, resulting in regulatory approvals of these regimens as frontline therapy. Beyond improvements in overall survival, ICI-based combination regimens achieve higher rates of durable treatment response than multikinase inhibitors and have favorable side effect profiles. With the emergence of doublet anti-angiogenic and immune checkpoint inhibitor (ICI) and dual ICI combinations, individualized therapy is now possible for patients based on co-morbidity profiles and other factors. These more potent systemic therapies are also being tested in earlier stages of disease and in combination with loco-regional therapies such as trans-arterial chemoembolization and stereotactic body radiotherapy. We summarize these advances and emerging therapeutic combinations currently in clinical trials.

Drug-Eluting Porous Embolic Microspheres for Trans-Arterial Delivery of Dual Synergistic Anticancer Therapy for the Treatment of Liver Cancer.

Blockage of blood supply while administering chemotherapy to tumors, using trans-arterial chemoembolization (TACE), is the most common treatment for intermediate and advanced-stage unresectable Hepatocellular carcinoma (HCC). However, HCC is characterized by a poor prognosis and high recurrence rates (≈30%), partly due to a hypoxic pro-angiogenic and pro-cancerous microenvironment. This study investigates how modifying tissue stress while improving drug exposure in target organs may maximize the therapeutic outcomes. Porous degradable polymeric microspheres (MS) are designed to obtain a gradual occlusion of the hepatic artery that nourishes the liver, while enabling efficient drug perfusion to the tumor site. The fabricated porous MS are introduced intrahepatically and designed to release a combination therapy of Doxorubicin (DOX) and Tirapazamine (TPZ), which is a hypoxia-activated prodrug. Liver cancer cell lines that are treated with the combination therapy under hypoxia reveal a synergic anti-proliferation effect. An orthotopic liver cancer model, based on N1-S1 hepatoma in rats, is used for the efficacy, biodistribution, and safety studies. Porous DOX-TPZ MS are very effective in suppressing tumor growth in rats, and induction tissue necrosis is associated with high intratumor drug concentrations. Porous particles without drugs show some advantages over nonporous particles, suggesting that morphology may affect the treatment outcomes.

Introducing yttrium-90 radioembolization to atezolizumab and bevacizumab regimen for intermediate and advanced stage hepatocellular carcinoma: A preliminary report of safety and effectiveness.

e16231 Background: The IMbrave150 Phase III trial demonstrated superiority of atezolizumab and bevacizumab (Atezo/Bev) over sorafenib in unresectable hepatocellular carcinoma (HCC). Combined radiotherapy and immune checkpoint inhibitors have been shown to induce synergistic effects in treatment of HCC and other solid tumors. Barcelona Clinic Liver Cancer 2022 updated guidelines recommend consideration of transarterial radioembolization (TARE) for early stage and very early stage HCC. The present study sims to evaluate the safety and effectiveness of combining TARE and the Atezo/Bev regimen for intermediate and advanced stage HCC. Methods: Retrospective review at a single institution was performed between May 2021 and December 2022. Patients who received TARE using yttrium-90 (Y90) with concomitant or sequential Atezo/Bev systemic treatment were included. The following outcomes were retrieved: overall survival (OS), radiologic tumor response, progression-free survival, technical adverse events related to TARE, and toxicity based on the National Cancer Institute–Common Terminology Criteria for Adverse Events version 5.0. Results: Ten consecutive patients (9 male, 1 female) with unresectable HCC received TARE and Atezo/Bev were included. A total 21 of doses of Y90 were administered with a median target dose of 156 Gy. Tumor control was achieved in all target lesions (100%) based on modified Response Evaluation Criteria in Solid Tumors criteria. Overall disease progression occurred in 4 patients after TARE with a 6- month PFS of 80% (95%CI: 40.9-95.6%) and 12-month PFS of 53.3% (17.3%-79.8%). Two patients died during follow-up, with 6-month and 12-month OS rates of 88.9% (95%CI: 43.3-98.4%) and 76.2% (95%CI: 33.2-93.5%), respectively. One patient developed grade 3 transaminitis and hypoglobulinemia. Atezo/Bev was switched to Lenvatinib in one patient due to myositis. Bevacizumab was held in one patient due to suspected transient ischemic attack. Conclusions: This small patient cohort demonstrated preliminary safety and effectiveness of TARE in combination with Atezo/Bev in treating intermediate and advanced stage HCC. Further prospective and comparative studies with large sample sizes are warranted.