Treatment Of Hepatocellular Carcinoma Research Articles

The efficacy of atezolizumab plus bevacizumab in the treatment of unresectable hepatocellular carcinoma in cirrhotic and non-cirrhotic patients.

e16214 Background: The IMbrave150 trial established that the combination of atezolizumab plus bevacizumab (AB) confers a significant progression-free survival (PFS) benefit when compared with sorafenib in patients with unresectable hepatocellular carcinoma (HCC). However, the nuanced impact of cirrhotic status on treatment response was not established by the study, leaving a critical aspect of patient stratification and outcomes yet to be fully understood. Methods: We conducted a retrospective single-center study of patients with HCC treated with AB between 2020 and 2023. Eligible patients were those who underwent at least one cycle of AB and had a follow-up period of at least three months post-AB initiation. Independent samples T-test and X2 and Fisher’s exact tests were used to evaluate associations between variables. PFS was calculated using the Kaplan-Meier method and compared according to cirrhotic status using the log-rank test. A Cox regression analysis was performed to estimate survival hazard ratios (HR). Results: Among 28 patients, the mean age at diagnosis was 64 years (SD 11), 18 (64%) were male, 26 (93%) had Child-Pugh (CP) class A liver function, and 18 (64%) were cirrhotic. Most patients presented with Barcelona Clinic Liver Cancer stage C disease (61%) and received AB in the first-line setting (93%). Clinicopathological features according to cirrhotic status are detailed in Table 1. With a median follow-up of 14 months (95% CI 8-20) since AB initiation, 16 progression events were recorded, resulting in a median PFS of 12 months (95%CI 6-18) for the entire cohort. Univariate analysis revealed an inferior median PFS in patients with cirrhotic HCC (7 months [95%CI 5-9] vs. not reached [p = 0.038]). However, in a multivariate Cox analysis, only obesity emerged as a significant predictor of an inferior PFS (HR 4.6; 95% CI 1.3 - 16.0, p = 0.018). Conclusions: In our study, cirrhosis was not associated with an inferior PFS. Notably, the majority of cirrhotic patients in this cohort exhibited CP A liver function, so uncertainties persist regarding the impact of cirrhosis on cancer progression in patients with CP B and C liver function. Further investigation is warranted to comprehensively evaluate whether cirrhotic, non-cirrhotic, and obese subgroups respond differently to AB therapy. [Table: see text]

The safety and efficacy of adebelimumab combined apatinib and hepatic artery infusion chemotherapy in the treatment of unresectable hepatocellular carcinoma: A retrospective study.

e16175 Background: The combination of oxaliplatin, fluorouracil, and leucovorin (FOLFOX) used for hepatic arterial infusion chemotherapy (HAIC) has shown promise for advanced hepatocellular carcinoma (HCC) patients. The combined therapy of immune checkpoint inhibitors (ICI) and tyrosine kinase inhibitors (TKI) is now an approved first-line approach for unresectable HCC. This study evaluated the safety and the effect of combining Adebelimumab (a PD-L1 inhibitors) and Apatinib (a tyrosinase kinase inhibitor) with HAIC-FOLFOX for unresectable HCC patients. Methods: The records of patients with unresectable HCC treated with HAIC from March 2023 to November 2023 at our center were retrospectively reviewed. Eligible patients were given a maximum of four cycles of FOLFOX-HAIC, along with Adebelimumab and Apatinib, until either disease progression or intolerable toxicities emerged. The primary outcome measured was the safety and the objective response rate (ORR) based on the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and modify RECIST of combined therapy. Results: Twenty patients were enrolled in the study. The most frequent grade ≥3 or above treatment-related adverse events included elevation of AST (50%) and diminished PLT count (15%). There was no treatment related death. Based on RECIST v1.1 and mRECIST criteria, the confirmed ORR stood at 35% and 70%, with a disease control rate of 85% both. Conclusions: The combination of Adebelimumab, apatinib, and FOLFOX-HAIC demonstrated manageable safety and encouraging results for unresectable HCC.

A real-world experience of hepatic arterial infusion chemotherapy combined with tislelizumab and lenvatinib for unresectable hepatocellular carcinoma with type IV portal vein tumor thrombus.

e16154 Background: Clinical improvement of interventional therapy with PD-(L)1 inhibitors plus molecular targeted therapies in have been confirmed by several studies, such as EMERALD-1, CHANCE001 etc. Limited data of this treatment in unresectable hepatocellular carcinoma (uHCC) patients (pts) with type IV portal vein tumor thrombus (PVTT) is available. This study aims to describe the efficacy and safety in uHCC pts with type IV PVTT (Vp4) who received HAIC combined with tislelizumab and lenvatinib (HAIC+Tisle+Len) in the real-world setting. Methods: This was a single-center, retrospective analysis of Vp4 uHCC pts treated with HAIC+Tisle+Len as first line systemic therapy between Apr 2020 and Dec 2022. Patient characteristics, treatment information, adverse events and survival data were collected. Pts received HAIC of modified FOLFOX (oxaliplatin, 85 mg/m2; leucovorin, 400 mg/m2; 5-fluorouracil bolus, 400 mg/m2 on day 1; 5-fluorouracil infusion, 2400 mg/m2 for 46 h), lenvatinib (8 or 12 mg once daily for body weight, 60 or ≥60 kg), and tislelizumab (200 mg q3w). HAIC was allowed to repeat on demands. Outcomes evaluated included overall survival (OS), progression free survival (PFS), overall response rate (ORR), overall disease control rate (DCR), and treatment-related adverse events (TRAEs). Results: A cohort of 54 pts was identified with a median age of 55 years (range 49-59). Pts characteristics were as follows: male (90.7%), hepatitis B (79.6%), BCLC C stage (100%), Child-Pugh A (88.9%), tumor number [ = 1 (50%), = 2 (7.4%), ≥3 (42.6%)], tumor diameter ≥10 cm (42.6%), extrahepatic metastasis (7.4%), beyond up to steven status (90.7%). As of Dec 20, 2023, the median follow-up duration was 21.3 mo (95% CI, 16.1-26.0), and the median number of HAIC was 3 (range 2-4). The median PFS was 8.1 months (95% CI, 6.8-12.3), while the median OS reached 16.8 months (95% CI:13.1-NR). ORR was 53.7% (3 CR, 26 PR) per RECIST 1.1; ORR was 66.7% (12 CR, 24 PR) per mRECIST. DCR was 96.3% per either RECIST 1.1 or mRECIST. Two pts received surgical treatment after conversion, one of whom underwent liver transplantation and remains tumor-free. The post-PD therapies after first-line treatment were as follows: Tisle+Len (24.1%), TACE+Tisle+Len (18.5%), Tisle+Len+Radiotherapy (7.4%), HAIC+Tisle+Regorafenib (5.6%), others (18.5%). The most common grade 3-4 TRAEs were hypertension (14.8%), decrease in albumin (11.1%), anorexia (9.3%), leukopenia (9.3%), abdominal pain (7.4%) and AST/ALT elevation (7.4%). Conclusions: The combination of HAIC with tislelizumab and lenvatinib represents a promising efficacy and manageable safety for uHCC pts with Vp4, which supplements the trial data for Vp4-HCC with real world outcomes.

Lenvatinib (Lenv) plus tislelizumab (Tis) combined with or without transarterial chemoembolization (TACE) in first-line treatment of unresectable hepatocellular carcinoma (uHCC): A prospective, non-randomized, open-label, phase II cohort study.

e16169 Background: The synergistic potential of programmed death protein-1 inhibitors and tyrosine kinase inhibitors in treating uHCC has been established. TACE, a cornerstone in uHCC therapy, primes the tumor microenvironment for immunotherapy by releasing neoantigens and inducing ischemia. This study explores the efficacy and safety of Lenv plus Tis, combined with or without TACE, in a first-line setting. Methods: This phase II study enrolled patients (pts) with pathologically and/or radiologically diagnosed uHCC eligible for embolization, with at least one measurable lesion, Child-Pugh class A/B, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Pts received Tis (200mg every 3 weeks) and Lenv (oral dose adjusted by weight: 8mg for <60kg and 12mg for ≥60kg) with or without conventional TACE, as determined by the treating physician. The primary endpoint was the objective response rate (ORR), with secondary endpoints including overall survival (OS), progression-free survival (PFS), and disease control rate (DCR). Results: By the data cutoff on January 27, 2024, 37 pts were enrolled: 12 received Lenv+Tis (cohort 1), and 25 received Lenv+Tis+TACE (cohort 2). Median follow-up time was 10.66 months. The ORR was 33.3% in cohort 1 and 68.0% in cohort 2, with DCRs of 100% and 96%, respectively (mRECIST). Median OS was 10.85 months (95% CI, 4.76-16.95) for cohort 1 and 13.61 months (95%CI, NE-NE) for cohort 2. Median PFS was 10.85 months (95% CI, NE-NE) for cohort 1, and 11.86 months (95% CI, 6.49-16.73) for cohort 2. Grade 3-4 treatment-emergent adverse events (teAE) occurred in 50% of cohort 1 and 68% of cohort 2. No fatal adverse event was reported. The most common grade 3-4 teAE (incidence >10%) were anaemia (17%) in cohort 1, and decreased platelet count (16%), hypertension (16%), rash (16%), fatigue (12%), elevated ALT (12%) in cohort 2. Conclusions: Both Lenv+Tis and Lenv+Tis+TACE showed promising efficacy and manageable safety in the first-line treatment of uHCC. More pts were recruiting to further prove these results. Clinical trial information: NCT05842317 . [Table: see text]

Progression pattern and post-progression survival following atezolizumab and bevacizumab treatment in advanced hepatocellular carcinoma.

Although the combination of atezolizumab and bevacizumab (ATZ + BEV) is a standard treatment for advanced hepatocellular carcinoma (HCC), strategies for addressing treatment failure and prognostic factors of post-progression survival (PPS) remain unestablished. We conducted a multicentre retrospective study to evaluate PPS following ATZ + BEV treatment in patients with advanced HCC. We classified the patients into three groups: BCLC stage B and BCLC stage C without or with new extrahepatic lesions (BCLCp-C1 and BCLCp-C2, respectively) at the time of progression. Of the 204 patients who started ATZ + BEV treatment between October 2020 and September 2022, 110 showed disease progression, with 33, 55 and 22 showing the BCLCp-B, BCLCp-C1 and BCLCp-C2 stages of the disease, respectively. Specifically, patients with the BCLCp-B stage of the disease showed better overall survival than those with the BCLCp-C1 and BCLCp-C2 stages (hazard ratios: 1.93 [95% confidence interval, CI, 1.06-3.51] and 2.64 [95% CI, 1.32-5.30] for HCC stages BCLCp-C1 and BCLCp-C2, respectively). Via multivariable analysis, we identified the BCLCp-C1 and BCLCp-C2 stages, as well as performance status, Child-Pugh class and alpha-fetoprotein as poor prognostic factors for PPS. BCLCp-B1 stage was identified as a better prognostic factor for PPS following ATZ + BEV treatment compared with BCLCp-C1 and BCLCp-C2 stages. This may help in making decisions regarding subsequent treatment after ATZ + BEV.

Transarterial chemoembolization (TACE) combined with donafenib as first-line therapy for unresectable hepatocellular carcinoma (uHCC): A real-world clinical study.

e16145 Background: To evaluate the efficacy and safety of TACE combined with Donafenib, which is as a new tyrosine kinase inhibitors therapy recommended by the China liver cancer staging (CNLC) system for the treatment of unresectable hepatocellular carcinoma (uHCC). Methods: We conducted a single-center, retrospective study on patients diagnosed with uHCC treated by TACE plus Donafenib as the first-line therapy between May 2021 and September 2023 at The First Affiliated Hospital of Sun Yat-sen University. The primary outcomes evaluated in this study were progression-free survival (PFS) and overall survival (OS). Local response, one-year survival rate, safety and tolerability were the secondary outcomes. Results: All of 48 eligible patients by August, 2023, with the median age of 59 years. The clinical characteristics were as follows: BCLC stage A:2 (4.2%), B:16 (33.3%), and C:30 (62.5%); Child-Pugh class A:33 (68.8%) and B:15 (31.2%); ECOG PS 0: 27 (56.2%) and 1: 21 (43.7%). In this study, 10 (20.8%) patients had huge intrahepatic lesions, 15 (31.2%) subjects exhibited extrahepatic metastases at multiple sites, 19 (42.2%) patients presented with portal vein tumor thrombus, and 4 patients were diffuse-type HCC.107 TACE sessions were performed. Three patients had liver transplantation as frequent therapy, and histopathological examination of tissue from these subjects revealed complete necrotic foci. The median PFS was 12.8 months (95% CI: 8.66–NA) , mOS was not reached and the one-year OS rate was 87.5% (95% CI: 77%-97%) in the survival results. The tumor objective response rate was 58.3% with 14.5% complete response and 43.7% partial response based on mRECIST assessment. The disease control rate of the study group was 81.3%. The most common treatment-related adverse events (TRAEs) observed were elevated aspartate aminotransferase (AST) levels (75.0%), increase in bilirubin level (72.9%), elevated alanine aminotransferase (ALT) levels (54.2%), hand-foot syndrome (53.1%), diarrhea (29.1%), rashes (22.9%), hair loss (18.4%) and hypertension (12.5%). Twenty-three (46.9%) patients presented with grade 3 or 4 TRAEs including elevated AST levels (22.4%), elevated ALT levels (16.3%), increase in bilirubin level (4%), diarrhea (4%) and hypertension (2%). No Grade 5 TRAEs were observed. Conclusions: The combination of TACE and Donafenib presented good efficacy and tolerability, which could be potentially used as the first-line treatment of Chinese uHCC patients.

Novel engineered regulatory macrophages combined with ICIs for post-transplant recurrence after liver transplantation for HCC.

e14582 Background: Liver transplantation is the most effective treatment for early-stage hepatocellular carcinoma (HCC), but post-transplant recurrence limits the efficacy of surgery and affects the patient prognosis. Most of the current attempts to apply immune checkpoint inhibitors (ICIs) to posttransplant recurrence have resulted in either acute allograft rejection or tumor progression, which may be related to the disruption of the immune balance that maintains immune tolerance and enhances immune activation. Methods: Therefore, we constructed an engineered regulatory macrophages (Mregs) with anti-tumor capacity in the transplant setting using reprogrammed liposomes to precisely regulate the immune microenvironment of post-transplant recurrence, in order to create suitable conditions for the safe use of ICIs. Results: Experimentally, Mregs were shown to prolonged allograft survival without promoting tumor development. Through fusing with the Mregs membrane, reprogrammed liposomes insert an anti-CD47 lipid shell onto the surface, enhancing phagocytosis against tumor. The drug-loaded inner core entered into the cytoplasm to reprogram Mregs. Tomivosertib downregulated the expression of PD-L1 and attenuated the immunosuppressive effect. Pexidartinib inhibited the polarization of the M2 pathway and upregulated the expression of CD80, CD86, and MHC II, enhancing the ability of antigen presentation. Combination with anti-PD-L1 antibodies can enhance anti-tumor effect without accelerating allograft rejection. Both in vivo and in vitro results demonstrate that engineered Mregs provide conditions for the safe use of anti-PD-L1 antibodies in the context of transplantation. Conclusions: Engineered Mregs combined with ICIs enhances immunotherapeutic efficacy and provides a viable therapeutic approach for posttransplant recurrence after liver transplantation for HCC.

Second-line systematic strategy options for the progression of lenvatinib plus tislelizumab treating unresectable hepatocellular carcinoma: A retrospective study.

e16135 Background: Lenvatinib plus Tislelizumab (LEN+TIS) is a first-line systemic treatment for unresectable hepatocellular carcinoma (uHCC) in the real world, however, most uHCC ultimately fail to respond to first-line therapy due to tumor progression or intolerable adverse effects. The progression-free survival (PFS) of Lenvatinib was approximately 8 months in both REFLECT and LEA-002 studies. Therefore, there were doubts about the second-line therapy after progressive disease (PD) of LEN+TIS, and no studies hade reported the specific switching mode. Methods: This study retrospectively analyzed the clinical data of the first-line treatment of uHCC with LEN+TIS in National Cancer Center/Cancer Hospital & Shenzhen Hospital from April 2019 to December 2023. According to the actual use of drugs, Group A changed Lenvatinib to Regorafenib while Tislelizumab was not changed after PD of LEN+TIS; Group B replaced with Regorafenib plus other immune checkpoint inhibitors (including PD-1, PDL-1) after PD of LEN+TIS. The initial dose of Regorafenib was 80 to 160 mg, which could be adjusted according to patient tolerability, with Regorafenib administered orally once daily for the first 3 weeks, every 4 weeks as a cycle; Tislelizumab given 200mg intravenously every 3 weeks. Both group A and B were subdivided into two subgroups based on whether PFS of LEN+TIS had been more than 8 months. Short- and long-term outcomes were assessed by two independent radiologists according to mRESCIST criteria, all statistical analysis was performed using SPSS version 20. Results: After rigorous screening, a total of 446 samples were recruited in this study, including 208 in group A and 238 in group B. The baseline characteristics were comparable between the two groups, all patients were Child-Pugh grade A, and the median follow-up time was 9.8 months. Group A had higher objective response rates (ORR: 31.2%vs26.9%), PFS (7.6vs6.1months), and median overall survival (mOS: 12.8vs11.2months). Subgroup analysis showed that patients in group A who had first-line PFS shorter than 8 months had a better treatment effect than those with first-line PFS longer than 8 months (ORR: 36.9%vs17.7%; DCR:69.2%vs46.8%;PFS: 8.7vs 5.1months; OS: 14.4vs8.9months; P<0.05); patients in group B who were treated with first-line systemic PFS shorter than 8 months was worse than that with first-line PFS longer than 8 months (ORR:12.2%vs38.6%; DCR:45.3%vs68.9%;PFS:5.6vs6.4months;OS:9.1vs12.6months; P<0.05). No new adverse events were observed, no treatment-related deaths occurred in either group. Conclusions: If the PFS of LEN+TIS was shorter than 8 months, Lenvatinib should be changed to Regorafenib, Tislelizumab could be not changed. And if the PFS of LEN+TIS was longer than 8 months, Lenvatinib and Tislelizumab should be changed at the same time, which seemed to achieve better results.

A multi-center retrospective study on the efficacy and safety of regorafenib plus immune checkpoint inhibitors with or without TACE as a second-line treatment for advanced hepatocellular carcinoma.

e16147 Background: At present, there are no definitive optimal treatment options for patients with hepatocellular carcinoma (HCC) following first-line treatment failure. To maximize the survival benefit of patients, we compared the efficacy and safety of regorafenib plus immune checkpoint inhibitors (ICIs) with transarterial chemoem bolization (R+ICIs+TACE) versus regorafenib plus ICIs (R+ICIs) as a second-line treatment for patients with advanced HCC. Methods: This retrospective study included patients with advanced HCC from our multicenter who received R+ICIs+TACE or R+ICIs as a later-line therapy from June 2020 to August 2022.Objective response rate (ORR), disease control rate (DCR), median progression-free survival (m-PFS), and safety were evaluated according to the modified Response Evaluation Criteria in Solid Tumors(m-RECIST). Factors affecting PFS and OS were analyzed using a Cox proportional-hazards regression model. Results: A total of 78 patients were included in the study (regardless of first-line treatment), including 48 who received R+ICIs+TACE and 30 who received R+ICIs. The R+ICIs+TACE group had a significantly higher ORR (31.6% vs. 9.8%, P = 0.021), higher DCR (73.8%vs. 45.7%, P = 0.008), longer PFS (median 8.5 vs.3.6 months, P < 0.0001) and and a longer OS (14.6 vs 8.5 months, P = 0.024) than those who received R+ICIs group. Child-Pugh class A6 and B7, R+ICIs and extrahepatic metastasis were found as independent prognostic factors for poor PFS. R+ICIs, a-fetoprotein > 400 ng/mL and Child-Pugh class were noted as independent prognostic factors for poor OS.There was no notable difference in the total incidence of treatment-related adverse effects (TRAEs) (76.8% vs. 71.3%, P = 0.41) and the incidence of grade 3/4 serious adverse effects (6.2% vs. 16.1%, P = 0.21) between the two group. Conclusions: Regorafenib plus ICIs with TACE showed a promising efficacy with favorable safety in HCC patients with PD-1 inhibitor resistance, especially in the standard second line patients.

Comparing the efficacy and safety of TACE combined with donafenib or lenvatinib in the treatment of unresectable hepatocellular carcinoma.

e16153 Background: For unresectable Intermediate/Advanced-Stage Hepatocellular Carcinoma (uHCC), the efficacy of TACE monotherapy has been unsatisfactory. Studies have shown that TACE combined with molecular targeted drugs exhibits potential synergistic effects, which can prolong the overall survival (OS) of uHCC patients (pts). Donafenib and lenvatinib are small molecule targeted drugs approved as first-line treatments for HCC. The aim of this study is to evaluate the efficacy and safety of TACE combined with donafenib or lenvatinib in the treatment of uHCC. Methods: A retrospective analysis was conducted on the clinical data of uHCC pts treated with donafenib combined with TACE (Dona-TACE) or lenvatinib combined with TACE (Lenva-TACE) at The First Affiliated Hospital of USTC from January 2018 to October 2022. The OS, progression free survival (PFS), objective response rate (ORR), and disease control rate (DCR) of two groups of pts were evaluated according to the mRECIST, and the incidence of adverse events (AEs) was evaluated using CTCAE 5.0. Pts with complete baseline information and at least one follow-up evaluation were incorporated in the final analysis. Results: A total of 105 pts treated with donafenib and 59 pts treated with lenvatinib met the study criteria. After matching with a 1:1 propensity score, 35 pts in the Dona-TACE group and 35 pts in the Lenva-TACE group were included in this study. The baseline characteristics of the two groups are similar (males, 85.7% vs. 85.7%; ECOG PS of 1, 74.3% vs. 71.4%; Exceeding up-to-seven criteria, 74.3% vs. 62.9%; BCLC stage C, 42.9% vs. 40.0%; Combination immunotherapy, 62.9% vs. 54.3%). There was no significant difference in median OS (29.0 vs. 27.3m, P = 0.748) and median PFS (10.5 vs. 10.3m, P = 0.869) in the Dona-TACE and Lenva-TACE groups. The ORR (85.7% vs. 74.3%, P = 0.969) and DCR (94.3% vs. 97.1%, P = 0.280) of the Dona-TACE and Lenva-TACE group were equivalent. Compared with the Lenva-TACE group, pts in the Dona-TACE group had a lower incidence of grade 3-4 adverse events (any grade, 94.3% vs. 91.4%; grade 3 or 4, 34.3% vs. 57.1%, P < 0.05). Among them, pts in the Dona-TACE group had a lower incidence of proteinuria (any grade, 22.9% vs 42.9%; grade 3 or 4, 0 vs17.1%, P < 0.05) and hypertension (any grade, 42.9% vs 71.4%; grade 3 or 4, 2.9% vs 25.7%, P < 0.05) than those in the Lenva-TACE group. Multivariate analysis showed that ECOG PS score, up-to-seven criteria, and tumor blood supply were independent prognostic factors affecting OS (HR, 3.470, 3.619, 3.067; P < 0.05). Conclusions: The efficacy of donafenib and lenvatinib combined with TACE in the treatment of uHCC is equivalent. Furthermore, compared to lenvatinib combined with TACE, donafenib combined with TACE has higher safety.

Efficacy and safety assessment of drug-eluting bead transarterial chemoembolization combined with molecular targeted agents or immunotherapy in unresectable hepatocellullar carcinoma: Real-world evaluation.

e16164 Background: Drug-eluting bead transarterial chemoembolization (DEB-TACE) is established as a safe and effective treatment for advanced hepatocellular carcinoma (HCC). Recent advancements in molecular targeted agents and immunotherapy have led to exploration of combining DEB-TACE with tyrosine kinase inhibitors (TKIs) or immunotherapy. However, real-world evaluations of DEB-TACE in combination with TKIs or immunotherapy are limited. This study aimed to assess the efficacy and safety of DEB-TACE alone, DEB-TACE with TKIs, and DEB-TACE with TKIs and immunotherapy. Methods: This study retrospectively enrolled 124 patients with unresectable HCC treated at Peking University Cancer Hospital from April 2018 to April 2023. Patients were divided into three groups: DEB-TACE alone (DTACE, 45 patients), DEB-TACE plus TKI (DTACE+TKI, 51 patients), and DEB-TACE plus TKI and immunotherapy (DTACE+TKI+IM, 28 patients). Propensity score matching (PSM) was used to compare efficacy and safety between DTACE and DTACE+TKI. Primary endpoints were progression-free survival (PFS), with secondary endpoints including overall survival (OS), objective response rate (ORR), disease control rate (DCR), assessed by RECIST Version 1.1. Adverse events were graded according to CTCAE version 5.0. Results: Among the patients, 99 were male and 25 were female, with 88.7% in BCLC-B or C stage. Before enrollment, 50.8% had received other treatments. In the DTACE+TKI+IM group, mPFS and mOS were higher compared to DTACE or DTACE+TKI alone (mPFS: 15.2 vs 9.2 for DTACE, 8.7 for DTACE+TKI; mOS: 32.3 vs 25.0 for DTACE, 20.9 for DTACE+TKI), though not statistically significant. ORR and DCR were 31.3% and 86.7% in DTACE, 35.3% and 84.3% in DTACE+TKI, and 39.3% and 96.4% in DTACE+TKI+IM, respectively. PSM analysis for DTACE and DTACE+TKI showed slightly better mPFS and mOS in DTACE+TKI (mPFS: 9.5 vs 9.2 months; mOS: 26.2 vs 19.4 months). No treatment-related deaths occurred, and serious adverse events (AEs) were comparable among the groups, with pain being the most common. AE. Notably, the frequency and severity of pain were closely related to the type of drug-eluting beads used, with the incidence of severe pain significantly lower in the HepaSphere DEB-TACE group compared to the CalliSphere or DCB group (0% versus 12.4% versus 19.7%, respectively; p < 0.001). Conclusions: DEB-TACE has been demonstrated as a safe, feasible, and efficacious treatment option for patients with unresectable HCC. There is a notable trend towards prolonged progression-free survival (PFS) and overall survival (OS) when DEB-TACE is combined with TKIs and immunotherapy. Moreover, HepaSphere DEB-TACE shows a lower incidence of severe pain compared to other types of drug-eluting beads, further highlighting its potential advantages in managing HCC.

Surgical resection versus thermal ablation: Comparison of sequential options after successful TACE downstaging therapy for unresectable hepatocellular carcinoma—A long-term multi-institutional study.

e16258 Background: Transarterial chemoembolization (TACE) is an effective and safe treatment for unresectable hepatocellular carcinoma (uHCC). However, the selection of sequential therapeutic modalities after TACE downstaging therapy is still controversial. The aim of this study is to compare the efficacy and safety of surgical resection (SR) and thermal ablation (TA) after successful TACE downstaging therapy for uHCC. Methods: In this real-world multi-institutional study from June 2008 to October 2022, 8,219 consecutive patients with HCC underwent conventional TACE at 12 hospitals. Patients underwent successful TACE downstaging therapy for uHCC beyond Milan criteria, who were assigned into SR group and TA group. The propensity score matching (PSM) was applied to reduce selection bias between groups. Cumulative overall survival (OS) and progression-free survival (PFS) were compared using the Kaplan‒Meier method with the log-rank test. A comparison analysis of major complications was performed using the c2 test. Results: 609 (7.4%) patients received SR or TA after TACE. After PSM 1:1, 185 patients in the SR group were matched with 185 in the TA group. After 4.5 years of median follow-up time, the cumulative 1-, 3-, 5- and 10-year OS rates were 98.8%, 89.3%, 82.9% and 64.4% in the SR group and 99.5%, 88.4%, 75.3% and 53.9% in the TA group, respectively, showing no significant difference ( P = .381). The cumulative 1-, 3-, 5- and 10-year PFS rates were 88.5%, 69.2%, 58.8% and 32.2% in the SR group and 90.6%, 71.4%, 53.1% and 32.0% in the TA group, respectively, showing no significant difference ( P = .855). The incidences of major complications were 6.5% in the SR group and 7.6% in the TA group, showing no significant difference ( P = .684). Conclusions: For uHCC patients beyond the Milan criteria received TACE downstaging therapy, TA might be acceptable as an alternative to SR in first-line sequential treatment scheme.

Impact of the Early COVID-19 Pandemic on Incidence and Outcomes of Hepatocellular Carcinoma in the United States.

Access to hepatocellular carcinoma (HCC) surveillance and treatments were disrupted during the COVID-19 pandemic. We aimed to characterize the impact of the pandemic on HCC incidence and mortality rates, treatment and outcomes in the U.S. Two nationwide databases, the United States Cancer Statistics and the National Vital Statistics System, were used to investigate HCC incidence and mortality between 2001-2020. Trends in age-adjusted incidence (aIR) and mortality (aMR) rates were assessed using joinpoint analysis. The 2020 aIR and aMR were projected based on the pre-pandemic data and compared to actual values to assess the extent of underdiagnosis. We assessed differences in HCC characteristics, treatment and overall survival (OS) between 2020 and 2018-2019. The aIR of HCC in 2020 was significantly reduced compared to 2019 (5.22 vs 6.03/100K PY), representing a 12.2% decrease compared to the predicted aIR in 2020 (5.94/100K PY). The greatest extent of underdiagnosis was observed in Black (-14.87%) and Hispanic (-14.51%) individuals and those with localized HCC (-15.12%). Individuals staged as regional or distant HCC were also less likely to receive treatment in 2020. However, there was no significant difference in short-term OS in 2020 compared to 2018-2019, with HCC mortality rates remaining stable (aMR: 2.76 vs 2.73/100K PY in 2020 vs 2019). The COVID-19 pandemic resulted in underdiagnosis of HCC, particularly early-stage disease and racial ethnic minorities, and underuse of HCC-directed treatment. Longer follow-up is needed to determine the impact of the COVID-19 pandemic on HCC-related mortality.

WDR4 as a potential indicator of clinical prognosis and immunotherapy in hepatocellular carcinoma.

e16275 Background: Immunotherapy has garnered increasing attention in hepatocellular carcinoma (HCC) treatment. However, there remains a pressing need for effective immunological predictive biomarkers. In our previous study, utilizing data extracted from The Cancer Genome Atlas (TCGA) database, we identified a positive correlation between WDR4 expression levels in hepatocellular carcinoma and various clinical parameters, encompassing Stage, T-stage, pathological grade, AFP level, and vascular invasion. Additionally, higher WDR4 expression was linked to poorer prognosis. Leveraging The TIMER and GEPIA databases, we further elucidated a significant association between WDR4 expression levels and the extent of immune cell infiltration, particularly macrophages, B lymphocytes, and myeloid suppressor cells, in hepatocellular carcinoma. These findings propose the potential utility of WDR4 as a biomarker for immune infiltration in hepatocellular carcinoma. As noted in the trial NCT03867084, which hypothesized that adjuvant pembrolizumab might surpass placebo efficacy, there still exists a gap in identifying the specific population benefiting from adjuvant immunotherapy. Methods: Clinical and pathological data from patients who underwent single-agent immunotherapy for HCC were additionally collected from Hunan Provincial People's Hospital between January 1, 2019, and January 31, 2024. These patients participated in the clinical trial (NCT03867084) with informed consent. The relationship between WDR4 expression levels, clinical pathological data, and patient prognosis was assessed using the Kruskal-Wallis test and Kaplan-Meier survival curve analysis. Results: WDR4 displayed significant upregulation in HCC tissues compared to para-carcinoma tissues (P < 0.001) and exhibited robust diagnostic potential. WDR4 expression showed significant associations with various immune cells, including macrophages (r = 0.278, P < 0.001). Kaplan-Meier survival analysis indicated that patients with high WDR4 expression had shorter postoperative progression-free survival in the context of immunotherapy. Data from 37 patients who underwent postoperative single-agent immunotherapy for hepatocellular carcinoma (NCT03867084) revealed a significant correlation between WDR4 expression levels and Disease-Free Survival (DFS), with notable statistical significance (Log-rank P < 0.001). Conclusions: WDR4 demonstrates elevated expression levels within HCC tissues and is associated with immune infiltration, establishing it as a prognostic biomarker in HCC. Furthermore, the positive correlation observed between WDR4 and CD68 as well as PD-L1 underscores its potential as a guiding factor in immunotherapeutic approaches for HCC.

Single-cell transcriptome sequencing to explore the infiltration and disappearance of NK cells in liver cancer.

e14520 Background: The emergence of tumor immunotherapy such as immune checkpoint blocking has greatly promoted the development of Hepatocellular carcinoma (HCC) treatment. However, the response rate of HCC patients to immunotherapy is not high, and the probability of adverse reactions is high. Natural killer (NK) cells play a crucial role in inhibiting the proliferation and metastasis of tumor cells and are expected to become a new hope for tumor therapy. Methods: The HCC single-cell transcriptome atlas was constructed by using the tumor tissues, adjacent tissues, peripheral blood of HCC patients. To emulate the hypoxic state within the tumor, NK cells were treated with rotenone, and the post-rotenone treatment changes of NK cells in transcriptome levels were evaluated using qPCR. The proliferation, apoptosis, and cytotoxicity of NK cells were assessed via flow cytometry. The study also investigated the role of c-Jun N-terminal protein kinase (JNK) in NK cell function by applying the JNK inhibitor tanzisertib (CC-930) in vitro. The impact of JNK inhibition on the tumor-killing potential of NK cells was examined in vivo using tumor-bearing mice NCG (NOD/ShiLtJ-Prkdcem26Cd52Il2rgem26Cd22/Gpt). Results: Analysis of the source of NK cell subsets found that the specific NK cells in tumor tissues were tissue-resident NK cells (trNK). Both RNA velocity analysis and pseudo-time sequence analysis suggested that trNK cells differentiated from PBMC-1 NK cells. Upon treatment of PBMC-1 NK cells with Tanzisertib, we observed inhibition of NK cell apoptosis. Through the subcutaneous tumor formation experiment of NCG mice, Tanzisertib-treated NK cells were transferred into tumor-bearing mice. Notably, we observed a significant reduction in tumor weight (Before treatment: 0.19g, 0.19g, 0.22g, 0.24g, 0.26g, 0.27g; After treatment: 0.16g, 0.17g, 0.17g, 0.19g, 0.21g, 0.23g; P value = 0.049). TUNEL assay confirmed a significant increase number of apoptotic cells within the tumor and an increased number of infiltrated NK cells. Conclusions: The NK cells in HCC tumors are likely derived from the infiltration of NK cells in peripheral blood. Importantly, the inhibition of JNK function can significantly inhibit the apoptosis of NK cells and enhance the killing ability of NK cells against tumor cells in vivo.

Cost-Effectiveness and Budget Impact Analyses of Selective Internal Radiation Therapy versus Atezolizumab Plus Bevacizumab from a German Statutory Health Insurance Perspective.

To compare personalized dosimetry with yttrium-90 (90Y)-loaded glass microspheres (SIRT) vs atezolizumab and bevacizumab (A+B) in hepatocellular carcinoma (HCC) treatment in terms of cost-effectiveness and budget impact from a German statutory health insurance (SHI) perspective. Cost-effectiveness analysis (CEA) and budget impact analysis (BIA) models were developed in MS Excel. The available key studies (IMbrave150 and DOSISPHERE-01) suggest that both strategies are comparable in terms of progression-free survival and overall survival in HCC, but a difference in severe adverse events (SAE) in favor of SIRT was observed. Accordingly, the CEA model investigates the endpoints "cost per SAE avoided" and "cost per quality-adjusted life year (QALY) gained", whereas the BIA simulates the impact of a stepwise re-allocation of current market share to the option which emerges as more cost-effective from the CEA. The model suite estimated a mean annual total per-patient costs of € 29,984 for SIRT, compared to € 75,725 for A+B. SIRT was associated with a lower number of SAE and a higher number of QALYs compared to A+B. Switching additionally 25% of the eligible patients (≈500) from systemic therapy to SIRT could generate annual savings of approximately € 22.6 million Euros to the SHI. SIRT was identified as dominant treatment strategy. SIRT use not only saves SHI expenditure compared to systemic immunotherapy but also yields extra QALYs. This positions SIRT as the dominant and more cost-effective treatment strategy for patients with HCC. The savings to the SHI system, derived from the BIA conducted, become increasingly significant with rising adoption rates of SIRT.

The efficacy and safety study of thymosin α1 combined with PD-1 antibodies as adjuvant therapy in patients with hepatocellular carcinoma with high-risk recurrence factors after radical resection.

e16226 Background: Anti-PD-1 immunotherapy has revolutionized unresectable hepatocellular carcinoma (HCC) treatment. The efficacy of postoperative adjuvant therapy (PAT) using anti-PD-1 in treating HCC is currently the subject of extensive research. This study explored the efficacy and safety of anti-PD-1 antibodies combined with thymosin alpha-1 (Tα1) for patients with HCC and high-risk recurrent factors (HRRFs) post-hepatectomy. Methods: Data from 273 patients with HCC and HRRFs who underwent hepatectomy at Tongji Hospital (January 2019 to July 2022) were prospectively collected. Patients were nonrandomly divided into Tα1+ anti-PD-1 antibodies (65, 23.8%), anti-PD-1 antibodies (84, 30.8%), and control (no adjuvant therapy, 124, 45.4%) groups based on finances and willingness. After propensity score matching (PSM), recurrence-free survival (RFS) and overall survival (OS) were compared. Cox regression analysis identified the RFS- and OS-related prognostic factors, followed by subgroup analysis. Results: After PSM, 65 patients were matched. The anti-PD-1 antibodies + Tα1 group exhibited longer RFS than the anti-PD-1 antibodies (P = 0.014) and control (P < 0.0001) groups. The anti-PD-1 antibodies group had longer RFS than the control group (P < 0.0001). The anti-PD-1 antibodies + Tα1 (P = 0.00049) and anti-PD-1 antibodies groups (P = 0.0041) demonstrated longer OS than the control group. The 1- and 2-year RFS rates in the Tα1 + anti-PD-1 antibodies, anti-PD-1 antibodies, and control groups were 98.4%, 86.2%, and 49.2% (P < 0.001), and 80.2%, 65.8%, and 24.6% (P < 0.001), respectively. The corresponding 1-, 2-, and 3-year OS rates were 100.0%, 100.0%, and 84.6% (P < 0.001), 98.0%, 91.4%, and 69.0% (P < 0.001), and 91.3%, 86.8%, and 57.4% (P < 0.001), respectively. Multivariable analyses suggested that the Tα1 + anti-PD-1 antibodies treatment improved the RFS and OS more than the non-anti-PD-1 antibodies + Tα1 treatment (hazard ratio (HR): 0.174, 95% confidence intervals (CI): 0.089–0.340, P < 0.001 and HR: 0.240, 95% CI: 0.084–0.683, P = 0.008, respectively). Subgroup analysis demonstrated significant RFS and OS benefits for patients with HCC and vascular invasion treated with Tα1 + anti-PD-1 antibodies. Grade 1 and 2 toxicities included rash/pruritus (21.5%), diarrhea (18.5%), and reactive cutaneous capillary endothelial proliferation (RCCEP)(15.4%). Grade 3 toxicities included RCCEP (1.5%), diarrhea (1.5%), rash/pruritus (0.8%), edema (0.8%), hepatitis (0.8%), nausea/vomiting (0.8%), and hypothyroidism (0.8%). No grade 4/5 toxicities or severe adverse events were detected. Conclusions: Combining anti-PD-1 antibodies with Tα1 as adjuvant therapy is safe, improving postoperative prognosis in patients with HCC and HRRFs after hepatectomy, proving more effective than anti-PD-1 antibodies alone.

Ultrastable PLGA-Coated 177Lu-Microspheres for Radioembolization Therapy of Hepatocellular Carcinoma.

Transarterial radioembolization (TARE) is a highly effective localized radionuclide therapy that has been successfully used to treat hepatocellular carcinoma (HCC). Extensive research has been conducted on the use of radioactive microspheres (MSs) in TARE, and the development of ideal radioactive MSs is crucial for clinical trials and patient treatment. This study presents the development of a radioactive MS for TARE of HCC. These MSs, referred to as 177Lu-MS@PLGA, consist of poly(lactic-co-glycolic acid) (PLGA) copolymer and radioactive silica MSs, labeled with 177Lu and then coated with PLGA. It has an extremely high level of radiostability. Cellular experiments have shown that it can cause DNA double-strand breaks, leading to cell death. In vivo radiostability of 177Lu-MS@PLGA is demonstrated by microSPECT/CT imaging. In addition, the antitumor study has shown that TARE of 177Lu-MS@PLGA can effectively restrain tumor growth without harmful side effects. Thus, 177Lu-MS@PLGA exhibits significant potential as a radioactive MS for the treatment of HCC.

Machine learning identification of hypoxia-related genes and prognostic risk-scoring model for effective survival stratification in hepatocellular carcinoma.

e16261 Background: Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related mortality globally, where treatment and prognostic assessment have important implications in clinical practice. Hypoxia, as a common feature within solid tumors, can directly change the tumor microenvironment, which affects the efficacy of cancer treatment and prognosis. In this study, we constructed and validated a hypoxia-based prognostic model using bioinformatics and machine learning. Methods: Two public datasets, GSE14520 and GSE41666, were collected from the Gene Expression Omnibus: (1) HCC tumor tissues compared to adjacent normal tissues (N = 214) and (2) HepG2 cells under normoxic and hypoxic conditions (N = 6). Differential expression analysis was performed to identify HCC characteristic genes and hypoxia-related genes, including their common genes (HCC-Hypoxia Overlap genes, HHOs). Using RNA-seq data of HCC patients (N = 367) from the TCGA Liver Cancer (LIHC) database, univariate Cox regression models were identified, and the Least Absolute Shrinkage and Selection Operator (LASSO) algorithm selected hypoxia-characteristic genes for the multivariate survival model. A hypoxia-related risk score was calculated based on the model of these characteristic genes and dichotomized cases into high-risk (HR) and low-risk (LR) groups. The model was validated using liver cancer cases (N = 232) from the International Cancer Genome Consortium database (ICGC-LIRI-JP). Results: Through differential expression analysis of the two datasets, we identified 52 HHOs. Univariate Cox analysis of these HHOs indicated that 21 genes were significantly associated with HCC patient survival. Through LASSO regression analysis, a total of 9 characteristic genes, including CENPA, KIF20A, DLGAP5, HMMR, UPB1, AFM, CABYR, PHLDA2, and N4BP2L1 were ultimately retained in the survival model. Based on these 9 genes, TCGA-LIHC samples were classified into HR and LR groups, and Kaplan-Meier (KM) analysis revealed significant differences in survival outcomes (p < 0.032). Risk scoring of the ICGC-LIRI-JP validation set classified samples into HR and LR. KM analysis showed that the survival times of patients in the HR group were significantly shorter than those in the LR group (p < 0.0001). Receiver Operating Characteristic Analysis analysis of the survival model showed area under the curve values of 0.815, 0.774, and 0.771 at 1, 2, and 3 years, respectively, demonstrating high performance in risk stratification. Conclusions: This study established a prognostic risk-scoring model based on 9 characteristic genes associated with hypoxia. This model can effectively stratify risks among HCC patients and demonstrate excellent performance in predicting survival. These findings may offer new biomarkers and therapeutic targets for the personalized treatment of HCC.

Recent advances in surgical management strategies for hepatocellular carcinoma

Recent advances in surgical management strategies for hepatocellular carcinoma