Hepatic arterial infusion chemotherapy combined with lenvatinib and PD-1 inhibitors versus lenvatinib and PD-1 inhibitors for HCC refractory to TACE.

BACKGROUND AND AIM: The study aims to investigate the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) combined with lenvatinib and immune checkpoint inhibitors (ICIs) versus lenvatinib and ICIs for hepatocellular carcinoma (HCC) with transarterial chemoembolization (TACE) refractoriness. METHODS: Patients with intermediate or advanced TACE-refractory HCC who received lenvatinib and ICIs with or without HAIC between 2020 and 2022 were retrospectively reviewed. The tumor response, overall survival (OS), progression-free survival (PFS), and treatment-related adverse events (TRAEs) were evaluated and compared between the two groups. Factors affecting OS and PFS were identified with univariate and multivariate Cox regression analyses. RESULTS: A total of 121 patients were enrolled, with 58 patients assigned to the HAIC-Len-ICI group and 63 patients assigned to the Len-ICI group. A higher objective response rate and disease control rate were found in the HAIC-Len-ICI group than in the Len-ICI group (48.30% vs 23.80%, P = 0.005; 87.90% vs 69.80%, P = 0.02, respectively). The median OS was 24.0 months in the HAIC-Len-ICI group and 13.0 months in the Len-ICI group (P = 0.001). The median PFS was 13.0 months in the HAIC-Len-ICI group and 7.2 months in the Len-ICI group (P < 0.001). Multivariable analyses suggested that the presence of cirrhosis, Child-Pugh B stage, and HAIC-Len-ICI therapy option were prognostic factors for OS and PFS. The incidences of any grade and grade 3/4 TRAEs were both comparable between the two groups. CONCLUSIONS: HAIC combined with lenvatinib and ICIs yielded better OS, PFS, ORR, and DCR than lenvatinib-ICI therapy in patients with HCC refractory to TACE, with manageable adverse events.

Real-world efficacy and safety of TACE plus camrelizumab and apatinib in patients with HCC (CHANCE2211): a propensity score matching study.

OBJECTIVES: This study aimed to investigate the efficacy and safety of transarterial chemoembolization (TACE) plus camrelizumab, a monoclonal antibody targeting programmed death-1, and apatinib for patients with intermediate and advanced hepatocellular carcinoma (HCC) in a real-world setting. METHODS: A total of 586 HCC patients treated with either TACE plus camrelizumab and apatinib (combination group, n = 107) or TACE monotherapy (monotherapy group, n = 479) were included retrospectively. Propensity score matching analysis was used to match patients. The overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and safety in the combination group were described in comparison to monotherapy. RESULTS: After propensity score matching (1:2), 84 patients in the combination group were matched to 147 patients in the monotherapy group. The median age was 57 years and 71/84 (84.5%) patients were male in the combination group, while the median age was 57 years with 127/147 (86.4%) male in the monotherapy group. The median OS, PFS, and ORR in the combination group were significantly higher than those in the monotherapy group (median OS, 24.1 vs. 15.7 months, p = 0.008; median PFS, 13.5 vs. 7.7 months, p = 0.003; ORR, 59.5% [50/84] vs. 37.4% [55/147], p = 0.002). On multivariable Cox regression, combination therapy was associated with significantly better OS (adjusted hazard ratio [HR], 0.41; 95% confidence interval [CI], 0.26-0.64; p < 0.001) and PFS (adjusted HR, 0.52; 95% CI, 0.37-0.74; p < 0.001). Grade 3 or 4 adverse events occurred in 14/84 (16.7%) and 12/147 (8.2%) in the combination and monotherapy groups, respectively. CONCLUSIONS: TACE plus camrelizumab and apatinib showed significantly better OS, PFS, and ORR versus TACE monotherapy for predominantly advanced HCC. CLINICAL RELEVANCE STATEMENT: Compared with TACE monotherapy, TACE plus immunotherapy and molecular targeted therapy showed better clinical efficacy for predominantly advanced HCC patients, with a higher incidence of adverse events. KEY POINTS: • This propensity score-matched study demonstrates that TACE plus immunotherapy and molecular targeted therapy have a longer OS, PFS, and ORR compared with TACE monotherapy in HCC. • Grade 3 or 4 adverse events occurred in 14/84 (16.7%) patients treated with TACE plus immunotherapy and molecular targeted therapy compared with 12/147 (8.2%) patients in the monotherapy group, while no grade 5 adverse events were observed in all cohorts.

Optimal time point of response assessment for predicting survival is associated with tumor burden in hepatocellular carcinoma receiving repeated transarterial chemoembolization.

OBJECTIVES: Objective response rate (ORR) under mRECIST criteria after transarterial chemoembolization (TACE) is a well-perceived surrogate endpoint of overall survival (OS). However, its optimal time point remains controversial and may be influenced by tumor burden. We aim to investigate the surrogacy of initial/best ORR in relation to tumor burden. METHODS: A total of 1549 eligible treatment-naïve patients with unresectable hepatocellular carcinoma (HCC), Child-Pugh score ≤ 7, and performance status score ≤ 1 undergoing TACE between January 2010 and May 2016 from 17 academic hospitals were retrospectively analyzed. Based on "six-and-twelve" criteria, tumor burden was graded as low, intermediate, and high if the sum of the maximum tumor diameter and tumor number was ≤ 6, > 6 but ≤ 12, and > 12, respectively. RESULTS: Both initial and best ORRs interacted with tumor burden. Initial and best ORRs could equivalently predict and correlate with OS in low (adjusted HR, 2.55 and 2.95, respectively, both p < 0.001; R = 0.84, p = 0.035, and R = 0.97, p = 0.002, respectively) and intermediate strata (adjusted HR, 1.81 and 2.22, respectively, both p < 0.001; R = 0.74, p = 0.023, and R = 0.9, p = 0.002, respectively). For high strata, only best ORR exhibited qualified surrogacy (adjusted HR, 2.61, p < 0.001; R = 0.70, p = 0.035), whereas initial ORR was not significant (adjusted HR, 1.08, p = 0.357; R = 0.22, p = 0.54). CONCLUSIONS: ORR as surrogacy of OS is associated with tumor burden. For patients with low/intermediate tumor burden, initial ORR should be preferred in its early availability upon similar sensitivity, whereas for patients with high tumor burden, best ORR has optimal sensitivity. Timing of OR assessment should be tailored according to tumor burden. KEY POINTS: • This is the first study utilizing individual patient data to comprehensively analyze the surrogacy of ORR with a long follow-up period. • Optimal timing of ORR assessment for predicting survival should be tailored according to tumor burden. • For patients with low and intermediate tumor burden, initial ORR is optimal for its timeliness upon similar sensitivity with best ORR. For patients with high tumor burden, best ORR has optimal sensitivity.

Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study.

BACKGROUND: China has a high burden of hepatocellular carcinoma, and hepatitis B virus (HBV) infection is the main causative factor. Patients with hepatocellular carcinoma have a poor prognosis and a substantial unmet clinical need. The phase 2-3 ORIENT-32 study aimed to assess sintilimab (a PD-1 inhibitor) plus IBI305, a bevacizumab biosimilar, versus sorafenib as a first-line treatment for unresectable HBV-associated hepatocellular carcinoma. METHODS: This randomised, open-label, phase 2-3 study was done at 50 clinical sites in China. Patients aged 18 years or older with histologically or cytologically diagnosed or clinically confirmed unresectable or metastatic hepatocellular carcinoma, no previous systemic treatment, and a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were eligible for inclusion. In the phase 2 part of the study, patients received intravenous sintilimab (200 mg every 3 weeks) plus intravenous IBI305 (15 mg/kg every 3 weeks). In the phase 3 part, patients were randomly assigned (2:1) to receive either sintilimab plus IBI305 (sintilimab-bevacizumab biosimilar group) or sorafenib (400 mg orally twice daily; sorafenib group), until disease progression or unacceptable toxicity. Randomisation was done using permuted block randomisation, with a block size of six, via an interactive web response system, and stratified by macrovascular invasion or extrahepatic metastasis, baseline α-fetoprotein, and ECOG performance status. The primary endpoint of the phase 2 part of the study was safety, assessed in all patients who received at least one dose of study drug. The co-primary endpoints of the phase 3 part of the study were overall survival and independent radiological review committee (IRRC)-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03794440. The study is closed to new participants and follow-up is ongoing for long-term outcomes. FINDINGS: Between Feb 11, 2019 and Jan 15, 2020, we enrolled 595 patients: 24 were enrolled directly into the phase 2 safety run-in and 571 were randomly assigned to sintilimab-bevacizumab biosimilar (n=380) or sorafenib (n=191). In the phase 2 part of the trial, 24 patients received at least one dose of the study drug, with an objective response rate of 25·0% (95% CI 9·8-46·7). Based on the preliminary safety and activity data of the phase 2 part, in which grade 3 or worse treatment-related adverse events occurred in seven (29%) of 24 patients, the randomised phase 3 part was started. At data cutoff (Aug 15, 2020), the median follow-up was 10·0 months (IQR 8·5-11·7) in the sintilimab-bevacizumab biosimilar group and 10·0 months (8·4-11·7) in the sorafenib group. Patients in the sintilimab-bevacizumab biosimilar group had a significantly longer IRRC-assessed median progression-free survival (4·6 months [95% CI 4·1-5·7]) than did patients in the sorafenib group (2·8 months [2·7-3·2]; stratified hazard ratio [HR] 0·56, 95% CI 0·46-0·70; p<0·0001). In the first interim analysis of overall survival, sintilimab-bevacizumab biosimilar showed a significantly longer overall survival than did sorafenib (median not reached [95% CI not reached-not reached] vs 10·4 months [8·5-not reached]; HR 0·57, 95% CI 0·43-0·75; p<0·0001). The most common grade 3-4 treatment-emergent adverse events were hypertension (55 [14%] of 380 patients in the sintilimab-bevacizumab biosimilar group vs 11 [6%] of 185 patients in the sorafenib group) and palmar-plantar erythrodysaesthesia syndrome (none vs 22 [12%]). 123 (32%) patients in the sintilimab-bevacizumab biosimilar group and 36 (19%) patients in the sorafenib group had serious adverse events. Treatment-related adverse events that led to death occurred in six (2%) patients in the sintilimab-bevacizumab biosimilar group (one patient with abnormal liver function, one patient with both hepatic failure and gastrointestinal haemorrhage, one patient with interstitial lung disease, one patient with both hepatic faliure and hyperkalemia, one patient with upper gastrointestinal haemorrhage, and one patient with intestinal volvulus) and two (1%) patients in the sorafenib group (one patient with gastrointestinal haemorrhage and one patient with death of unknown cause). INTERPRETATION: Sintilimab plus IBI305 showed a significant overall survival and progression-free survival benefit versus sorafenib in the first-line setting for Chinese patients with unresectable, HBV-associated hepatocellular carcinoma, with an acceptable safety profile. This combination regimen could provide a novel treatment option for such patients. FUNDING: Innovent Biologics. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Development of a prognostic score for recommended TACE candidates with hepatocellular carcinoma: A multicentre observational study.

BACKGROUND & AIMS: Previous prognostic scores for transarterial chemoembolization (TACE) were mainly derived from real-world settings, which are beyond guideline recommendations. A robust model for outcome prediction and risk stratification of recommended TACE candidates is lacking. We aimed to develop an easy-to-use tool specifically for these patients. METHODS: Between January 2010 and May 2016, 1,604 treatment-naïve patients with unresectable hepatocellular carcinoma (HCC), Child-Pugh A5-B7 and performance status 0 undergoing TACE were included from 24 tertiary centres. Patients were randomly divided into training (n = 807) and validation (n = 797) cohorts. A prognostic model was developed and subsequently validated. Predictive performance and discrimination were further evaluated and compared with other prognostic models. RESULTS: The final presentation of the model was "linear predictor = largest tumour diameter (cm) + tumour number", which consistently outperformed other currently available models in both training and validation datasets as well as in different subgroups. The thirtieth percentile and the third quartile of the linear predictor, namely 6 and 12, were further selected as cut-off values, leading to the "six-and-twelve" score which could divide patients into 3 strata with the sum of tumour size and number ≤6, >6 but ≤12, and >12 presenting significantly different median survival of 49.1 (95% CI 43.7-59.4) months, 32.0 (95% CI 29.9-37.5) months, and 15.8 (95% CI 14.1-17.7) months, respectively. CONCLUSIONS: The six-and-twelve score may prove an easy-to-use tool to stratify recommended TACE candidates (Barcelona Clinic Liver Cancer stage-A/B) and predict individual survival with favourable performance and discrimination. Moreover, the score could stratify these patients in clinical practice as well as help design clinical trials with comparable criteria involving these patients. Further external validation of the score is required. LAY SUMMARY: There is currently no prognostic model specifically developed for recommended or ideal transarterial chemoembolization (TACE) candidates with hepatocellular carcinoma, despite these patients being frequently identified as the best target population in pivotal randomized controlled trials. The six-and-twelve score provides patient survival prediction, especially in ideal candidates of TACE, outperforming other currently available models in both training and validation sets, as well as different subgroups. With cut-off values of 6 and 12, the score can stratify ideal TACE candidates into 3 strata with significantly different outcomes and may shed light on risk stratification of these patients in clinical practice as well as in clinical trials.

Nomogram and Artificial Neural Network for Prognostic Performance on the Albumin-Bilirubin Grade for Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization.

PURPOSE: To construct the albumin-bilirubin (ALBI) grade and the Child-Turcotte-Pugh (CTP) score based on nomograms, as well as to develop an artificial neural network (ANN) to compare the prognostic performance of the 2 scores for hepatocellular carcinoma (HCC) that has undergone transarterial chemoembolization. MATERIALS AND METHODS: This multicentric retrospective study included patients with HCC who underwent transarterial chemoembolization monotherapy as an initial treatment at 4 institutions between January 2008 and December 2016. In the training cohort, significant risk factors associated with overall survival (OS) were identified by univariate and multivariate analyses. The prognostic nomograms and ANN were established and then validated in 2 validation cohorts. RESULTS: A total of 838 patients (548, 115, and 175 in the training cohort and validation cohorts 1 and 2, respectively) were included. The median OS was 10.4, 15.7, and 9.2 months in the training cohort and validation cohorts 1 and 2, respectively. In the training cohort, both ALBI grade and CTP score were identified as significant risk factors. The ALBI grade and CTP score based on nomograms were established separately and showed similar prognostic performance when assessed externally in validation cohorts (C-index in validation cohort 1: 0.823 vs 0.802, P = .417; in validation cohort 2: 0.716 vs 0.729, P = .793). ANN showed that ALBI grade had higher importance on survival prediction than CTP score. CONCLUSIONS: ALBI grade performs at least no worse than CTP score regarding survival prediction for HCC receiving transarterial chemoembolization. Considering the easy application, ALBI grade has the potential to be regarded as an alternative to CTP score.

Arterial chemotherapy for hepatocellular carcinoma in China: consensus recommendations.

Hepatocellular carcinoma (HCC) is one of the most common malignancies and the third leading cause of cancer-related deaths globally. Hepatic arterial infusion chemotherapy (HAIC) treatment is widely accepted as one of the alternative therapeutic modalities for HCC owing to its local control effect and low systemic toxicity. Nevertheless, although accumulating high-quality evidence has displayed the superior survival advantages of HAIC of oxaliplatin, fluorouracil, and leucovorin (HAIC-FOLFOX) compared with standard first-line treatment in different scenarios, the lack of standardization for HAIC procedure and remained controversy limited the proper and safe performance of HAIC treatment in HCC. Therefore, an expert consensus conference was held on March 2023 in Guangzhou, China to review current practices regarding HAIC treatment in patients with HCC and develop widely accepted statements and recommendations. In this article, the latest evidence of HAIC was systematically summarized and the final 22 expert recommendations were proposed, which incorporate the assessment of candidates for HAIC treatment, procedural technique details, therapeutic outcomes, the HAIC-related complications and corresponding treatments, and therapeutic scheme management.

Immune checkpoint inhibitors and anti-vascular endothelial growth factor antibody/tyrosine kinase inhibitors with or without transarterial chemoembolization as first-line treatment for advanced hepatocellular carcinoma (CHANCE2201): a target trial emulation study.

Background: The role of transarterial chemoembolization (TACE) in the treatment of advanced hepatocellular carcinoma (HCC) is unconfirmed. This study aimed to assess the efficacy and safety of immune checkpoint inhibitors (ICIs) plus anti-vascular endothelial growth factor (anti-VEGF) antibody/tyrosine kinase inhibitors (TKIs) with or without TACE as first-line treatment for advanced HCC. Methods: This nationwide, multicenter, retrospective cohort study included advanced HCC patients receiving either TACE with ICIs plus anti-VEGF antibody/TKIs (TACE-ICI-VEGF) or only ICIs plus anti-VEGF antibody/TKIs (ICI-VEGF) from January 2018 to December 2022. The study design followed the target trial emulation framework with stabilized inverse probability of treatment weighting (sIPTW) to minimize biases. The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), objective response rate (ORR), and safety. The study is registered with ClinicalTrials.gov, NCT05332821. Findings: Among 1244 patients included in the analysis, 802 (64.5%) patients received TACE-ICI-VEGF treatment, and 442 (35.5%) patients received ICI-VEGF treatment. The median follow-up time was 21.1 months and 20.6 months, respectively. Post-application of sIPTW, baseline characteristics were well-balanced between the two groups. TACE-ICI-VEGF group exhibited a significantly improved median OS (22.6 months [95% CI: 21.2-23.9] vs 15.9 months [14.9-17.8]; P < 0.0001; adjusted hazard ratio [aHR] 0.63 [95% CI: 0.53-0.75]). Median PFS was also longer in TACE-ICI-VEGF group (9.9 months [9.1-10.6] vs 7.4 months [6.7-8.5]; P < 0.0001; aHR 0.74 [0.65-0.85]) per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. A higher ORR was observed in TACE-ICI-VEGF group, by either RECIST v1.1 or modified RECIST (41.2% vs 22.9%, P < 0.0001; 47.3% vs 29.7%, P < 0.0001). Grade ≥3 adverse events occurred in 178 patients (22.2%) in TACE-ICI-VEGF group and 80 patients (18.1%) in ICI-VEGF group. Interpretation: This multicenter study supports the use of TACE combined with ICIs and anti-VEGF antibody/TKIs as first-line treatment for advanced HCC, demonstrating an acceptable safety profile. Funding: National Natural Science Foundation of China, National Key Research and Development Program of China, Jiangsu Provincial Medical Innovation Center, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, and Nanjing Life Health Science and Technology Project.

Multi-target lentivirus specific to hepatocellular carcinoma: in vitro and in vivo studies.

BACKGROUND & AIMS: We aimed at investigating the effects of the targeted transduction of the Wtp53-pPRIME-miR30-shRNA gene into liver cancer cells, under the mediation of anti-alpha fetoprotein scFv-directed lentivirus, and the inhibitory effect of this system on liver cancer cells. METHODS: The result of infection was observed by fluorescence microscopy. Polymerase chain reaction and Western blotting were used to demonstrate the successful transduction and transcription of the Wtp53-pPRIME-miR30-shRNA-IGF1R gene. Cell growth was observed via the Cell-Counting Kit-8 Method, and cell apoptosis was detected by terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling. To observe further the effects of AFP-Wtp53-pPRIME-miR30-shRNA-IGF1R therapy in animals, models of BALB-C nude mice bearing subcutaneous human hepatocellular carcinoma were established. The influence of the growth of subcutaneously transplanted tumor, expression of Wtp53 protein, apoptosis, and microvessel formation on the overall level of AFP-Wtp53 pPRIME-miR30-shRNA-IGF1R were also evaluated. RESULTS: Recombinant lentivirus was successfully constructed, and its functional plaque-forming unit titer was determined as 4.58 × 10(9)plaque-forming units/ml. A positive strand was detected by polymerase chain reaction and Western blotting. Lentiviral construction worked effectively in AFP-positive liver cancer cells. In vitro and in vivo experiments showed that the recombinant lentivirus was more efficacious in inhibiting the proliferation of Hep3B cells. CONCLUSIONS: The Wtp53-pPRIME-miR30-shRNA gene can be subjected to targeted transduction into liver cancer cells under the mediation of anti-alpha fetoprotein scFv-directed lentivirus. The Wtp53-pPRIME-miR30-shRNA system has targeting ability and lethal effects on liver cancer cells.

Efficacy and Safety of TACE Combined with Regorafenib Plus PD-1 Inhibitor in the Treatment of Hepatocellular Carcinoma After Sorafenib Resistance.

Purpose: To evaluate the efficacy and safety of TACE combined with regorafenib plus PD-1 inhibitor as a second-line therapy for hepatocellular carcinoma after sorafenib resistance. Materials and Methods: The clinical data of 76 patients with hepatocellular carcinoma who were drug-resistant to sorafenib from September 2018 to May 2022 in the tumor intervention department were collected. Among them, 35 patients used TACE combined with regorafenib plus PD-1 inhibitor (TACE-R-P) as second-line treatment, and the remaining 41 patients used TACE combined with regorafenib (TACE-R) as second-line treatment. The mRECIST (modified Response Evaluation Criteria in Solid Tumors) standard was used to evaluate the therapeutic effect. The progression-free survival (PFS) and overall survival (OS) of the two groups were compared. Blood samples were collected before and after treatment to detect the changes in biochemical indicators, and the adverse events (AEs) related to treatment were recorded. Results: A total of 76 patients were included in the study, including 35 patients receiving TACE-R-P treatment and 41 patients receiving TACE-R treatment. Patients in the TACE-R-P group had longer median OS (19.7months vs 15.2months, HR:0.7716, 95% CI:0.4767-1.2490, P=0.03), longer median PFS (6.3months vs 3.8months, HR:0.6032, 95% CI:0.3727-0.9763, P=0.0029), higher objective response rate (37.14% vs 19.51%, P=0.001) and higher disease control rate (71.43% vs 48.78%, P=0.001) than those in the TACE-R group. Multivariate analysis showed that Child-Pugh grade (B/A; HR=1.283, 95% CI: 0.623-1.707, P=0.014), PVTT (Yes/No, HR=1.455, 95% CI: 0.977-2.038, P=0.018), extrahepatic metastasis (Yes/No, HR=1.766, 95% CI: 1.135-2.302, P=0.022) and treatment option (TACE-R/TACE-R-P, HR=1.930, 95% CI: 1.461-2.850, P=0.017) were independent prognostic factors for OS. There was no significant difference in the incidence and severity of AEs between the two groups. Conclusion: TACE-R-P treatment can be more effective than TACE-R treatment for HCC after sorafenib resistance and can be given priority as a second-line treatment for HCC.

Evaluating the Benefits of TACE Combined with Lenvatinib Plus PD-1 Inhibitor for Hepatocellular Carcinoma with Portal Vein Tumor Thrombus.

INTRODUCTION: This study evaluated the efficacy and safety of transarterial chemoembolization (TACE) combined with lenvatinib plus programmed death (PD)-1 inhibitor (TACE-L-P) versus TACE combined with sorafenib plus PD-1 inhibitor (TACE-S-P) in the treatment of hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT). METHODS: The clinical data of patients with HCC and PVTT treated with TACE-L-P or TACE-S-P from January 2018 to March 2022 were collected. The Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and modified RECIST (mRECIST) standard were used to evaluate the therapeutic effect. The progression-free survival (PFS) and overall survival (OS) of the two groups were compared. Blood samples were collected before and after treatment to detect the changes of biochemical indicators, and the adverse events (AEs) related to treatment were recorded. RESULTS: A total of 165 patients were included in the study, including 80 patients receiving TACE-L-P treatment and 85 patients receiving TACE-S-P. Patients in the TACE-L-P group had longer median OS (21.7 months vs. 15.6 months, P = 0.0027), longer median PFS (6.3 months vs. 3.2 months, P < 0.0001), higher objective response rate (41.25% vs. 30.59%, P = 0.008), and higher disease control rate (86.25% vs. 62.35%, P = 0.008) than those in the TACE-S-P group. Multivariate analysis of the TACE-L-P group showed that VP classification of PVTT, Child-Pugh grade, interleukin-17 (IL-17), vascular endothelial growth factor (VEGF), procalcitonin (PCT), and C-reactive protein (CRP) were independent factors significantly affecting patients' OS (P < 0.05). There was no significant difference in the incidence and severity of AEs between the two groups. CONCLUSION: TACE-L-P treatment can improve the survival of patients with HCC and PVTT with an acceptable safety, but higher inflammatory indicators will affect the therapeutic effect.

Correlation and efficacy of TACE combined with lenvatinib plus PD-1 inhibitor in the treatment of hepatocellular carcinoma with portal vein tumor thrombus based on immunological features.

BACKGROUND: Although the appearance of portal vein tumor thrombus (PVTT) is significantly associated with unfavorable prognosis, there is insufficient evidence to confirm the efficacy and safety of the triple combination of transarterial chemoembolization (TACE), lenvatinib, and programmed cell death-1 (PD-1) inhibitor for patients with hepatocellular carcinoma (HCC) and PVTT. Furthermore, it remains unclear which patient type can obtain the best survival benefit from this combination therapy. METHODS: The data of 160 patients with HCC and PVTT treated with TACE combined with lenvatinib plus PD-1 inhibitor (TACE+LEN + PD-1 group) or TACE combined with lenvatinib (TACE+LEN group) were retrospectively collected and analyzed. To estimate the efficacy and safety of combination therapy for patients with advanced HCC, tumor response, progression-free survival (PFS), overall survival (OS), biochemical indices, and adverse events (AEs) were assessed in this study. More importantly, tumor immune-related cytokines were used to identify biomarkers predicting the therapeutic response of combination therapy. RESULTS: TACE+LEN + PD-1 was superior to TACE+LEN in OS (23.5 vs. 18.3 months, p = 0.0002) and PFS (7.5 vs. 4.3 months, p < 0.0001). Moreover, TACE+LEN + PD-1 achieved more preferable benefits with respect to disease control rate (80.00% vs. 56.67%) and objective response rate (38.57% vs. 24.45%) compared with TACE+LEN in patients with HCC and PVTT (p = 0.025). Multivariate analysis showed that Child-Pugh grade, PVTT classification, treatment option, and interleukin (IL)-6, IL-17, interferon (IFN)-α, and vascular endothelial growth factor (VEGF) levels were independent factors related to OS, whereas PVTT classification, treatment option, and IL-6 and IFN-α levels were independent factors related to PFS. Furthermore, the subgroup analysis illustrated that the inflammatory cytokines VEGF, IL-6, IL-17, and IFN-α might be novel biomarkers for predicting the survival prognosis of patients with advanced HCC and PVTT treated with TACE+LEN + PD-1. The safety in the combination group was acceptable. CONCLUSIONS: Compared with TACE+LEN, the triple combination treatment of TACE+LEN + PD-1 has more promising clinical outcomes and acceptable safety in patients with HCC and PVTT. Child-Pugh grade, PVTT classification, and IL-6, IL-17, IFN-α, and VEGF levels are independent prognostic factors for survival time.

CPEB2 Suppresses Hepatocellular Carcinoma Epithelial-Mesenchymal Transition and Metastasis through Regulating the HIF-1α/miR-210-3p/CPEB2 Axis.

Hepatocellular carcinoma (HCC) is a prevalent and high-mortality cancer worldwide, and its complexity necessitates novel strategies for drug selection and design. Current approaches primarily focus on reducing gene expression, while promoting gene overexpression remains a challenge. In this work, we studied the effect of cytoplasmic polyadenylation element binding protein 2 (CPEB2) in HCC by constructing tissue microarrays (TAMs) from 90 HCC cases and corresponding para-cancerous tissues. Our analysis showed that CPEB2 expression was significantly reduced in HCC tissues, and its low expression was associated with a higher recurrence risk and poorer prognosis in patients with head and neck cancer. CPEB2 was found to regulate HCC epithelial-mesenchymal transition (EMT) and metastasis through the HIF-1α/miR-210-3p/CPEB2 feedback circuit. Using the RNA binding protein immunoprecipitation (RIP) assay, we demonstrated that miR-210 directly governs the expression of CPEB2. The inverse relationship between CPEB2 expression and miR-210-3p in HCC tissues suggested that this regulatory mechanism is directly linked to HCC metastasis, EMT, and clinical outcomes. Moreover, utilizing the SM2miR database, we identified drugs that can decrease miR-210-3p expression, consequently increasing CPEB2 expression and providing new insights for drug development. In conclusion, our findings illustrated a novel HIF-1α/miR-210-3p/CPEB2 regulatory signaling pathway in HCC and highlighted the potential of enhancing CPEB2 expression through targeting miR-210-3p as a novel predictive biomarker and therapeutic strategy in HCC, as it is modulated by the HIF-1α/miR-210-3p/CPEB2 feedback circuit.

Effect of different PD-1 inhibitor combination therapies for unresectable intrahepatic cholangiocarcinoma.

BACKGROUND: Immune checkpoint inhibitor (ICI) combination therapy offers a new option for treatment of unresectable intrahepatic cholangiocarcinoma (uICC). AIM: To compare the effect of different anti-PD-1 combination therapies as the first-line treatments for uICC. METHODS: This study included 318 patients who received chemotherapy alone (Chemo), anti-PD-1 plus chemotherapy (ICI-chemo), anti-PD-1 plus targeted therapy (ICI-target) or anti-PD-1 plus targeted therapy and chemotherapy (ICI-target-chemo) as first line for uICC from 22 centres in China. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR) and safety. RESULTS: Patients with ICI-chemo (median PFS [mPFS], 6.3 months; HR: 0.61, 95% CI: 0.42-0.88; p = 0.008; median OS [mOS], 10.7 months; HR: 0.61, 95% CI: 0.39-0.94; p = 0.026), ICI-target (7.2 months; HR: 0.54, 95% CI: 0.36-0.80; p = 0.002; 15.8 months; HR: 0.54, 95% CI: 0.35-0.84; p = 0.006) or ICI-target-chemo (6.9 months; HR: 0.65, 95% CI: 0.47-0.90; p = 0.009; 14.4 months; HR: 0.47, 95% CI: 0.31-0.70; p < 0.001) achieved better clinical outcomes than those with Chemo (3.8 months; 9.3 months). ICI-target was not inferior to ICI-chemo in survival outcomes (HR for PFS: 0.88, 95% CI: 0.55-1.42; p = 0.614; HR for OS: 0.89, 95% CI: 0.51-1.55; p = 0.680). ICI-target-chemo yielded similar prognoses as ICI-chemo (HR for PFS: 1.07, 95% CI: 0.70-1.62; p = 0.764; HR for OS: 0.77, 95% CI: 0.45-1.31; p = 0.328) and ICI-target (HR for PFS: 1.20, 95% CI: 0.77-1.88; p = 0.413; HR for OS: 0.86, 95% CI: 0.51-1.47; p = 0.583) but resulted in more adverse events (p < 0.001; p = 0.010). Multivariable and propensity score analyses supported these findings. CONCLUSIONS: Among patients with uICC, ICI-chemo or ICI-target provided more survival benefits than Chemo while achieving comparable prognoses and fewer adverse events than ICI-target-chemo.

Irradiation stent with 125 I plus TACE versus sorafenib plus TACE for hepatocellular carcinoma with major portal vein tumor thrombosis: a multicenter randomized trial.

BACKGROUND AND AIM: Treatment strategy for hepatocellular carcinoma (HCC) and Vp4 [main trunk] portal vein tumor thrombosis (PVTT) remains limited due to posttreatment liver failure. We aimed to assess the efficacy of irradiation stent placement with 125 I plus transcatheter arterial chemoembolization (TACE) (ISP-TACE) compared to sorafenib plus TACE (Sora-TACE) in these patients. METHODS: In this multicenter randomized controlled trial, participants with HCC and Vp4 PVTT without extrahepatic metastases were enrolled from November 2018 to July 2021 at 16 medical centers. The primary endpoint was overall survival (OS). The secondary endpoints were hepatic function, time to symptomatic progression, patency of portal vein, disease control rate, and treatment safety. RESULTS: Of 105 randomized participants, 51 were assigned to the ISP-TACE group, and 54 were assigned to the Sora-TACE group. The median OS was 9.9 months versus 6.3 months (95% CI: 0.27-0.82; P =0.01). Incidence of acute hepatic decompensation was 16% (8 of 51) versus 33% (18 of 54) ( P =0.036). The time to symptomatic progression was 6.6 months versus 4.2 months (95% CI: 0.38-0.93; P =0.037). The median stent patency was 7.2 months (interquartile range, 4.7-9.3) in the ISP-TACE group. The disease control rate was 86% (44 of 51) versus 67% (36 of 54) ( P =0.018). Incidences of adverse events at least grade 3 were comparable between the safety populations of the two groups: 16 of 49 (33%) versus 18 of 50 (36%) ( P =0.73). CONCLUSION: Irradiation stent placement plus TACE showed superior results compared with sorafenib plus TACE in prolonging OS in patients with HCC and Vp4 PVTT.

Transarterial chemoembolization with PD-(L)1 inhibitors plus molecular targeted therapies for hepatocellular carcinoma (CHANCE001).

There is considerable potential for integrating transarterial chemoembolization (TACE), programmed death-(ligand)1 (PD-[L]1) inhibitors, and molecular targeted treatments (MTT) in hepatocellular carcinoma (HCC). It is necessary to investigate the therapeutic efficacy and safety of TACE combined with PD-(L)1 inhibitors and MTT in real-world situations. In this nationwide, retrospective, cohort study, 826 HCC patients receiving either TACE plus PD-(L)1 blockades and MTT (combination group, n = 376) or TACE monotherapy (monotherapy group, n = 450) were included from January 2018 to May 2021. The primary endpoint was progression-free survival (PFS) according to modified RECIST. The secondary outcomes included overall survival (OS), objective response rate (ORR), and safety. We performed propensity score matching approaches to reduce bias between two groups. After matching, 228 pairs were included with a predominantly advanced disease population. Median PFS in combination group was 9.5 months (95% confidence interval [CI], 8.4-11.0) versus 8.0 months (95% CI, 6.6-9.5) (adjusted hazard ratio [HR], 0.70, P = 0.002). OS and ORR were also significantly higher in combination group (median OS, 19.2 [16.1-27.3] vs. 15.7 months [13.0-20.2]; adjusted HR, 0.63, P = 0.001; ORR, 60.1% vs. 32.0%; P < 0.001). Grade 3/4 adverse events were observed at a rate of 15.8% and 7.5% in combination and monotherapy groups, respectively. Our results suggest that TACE plus PD-(L)1 blockades and MTT could significantly improve PFS, OS, and ORR versus TACE monotherapy for Chinese patients with predominantly advanced HCC in real-world practice, with an acceptable safety profile.

Immune-related gene signature to predict TACE refractoriness in patients with hepatocellular carcinoma based on artificial neural network.

Background: Transarterial chemoembolization (TACE) is the standard treatment option for intermediate-stage hepatocellular carcinoma (HCC), while response varies among patients. This study aimed to identify novel immune-related genes (IRGs) and establish a prediction model for TACE refractoriness in HCC patients based on machine learning methods. Methods: Gene expression data were downloaded from GSE104580 dataset of Gene Expression Omnibus (GEO) database, differential analysis was first performed to screen differentially expressed genes (DEGs). The least absolute shrinkage and selection operator (LASSO) regression analysis was performed to further select significant DEGs. Weighted gene co-expression network analysis (WGCNA) was utilized to build a gene co-expression network and filter the hub genes. Final signature genes were determined by the intersection of LASSO analysis results, WGCNA results and IRGs list. Based on the above results, the artificial neural network (ANN) model was constructed in the training cohort and verified in the validation cohort. Receiver operating characteristics (ROC) analysis was used to assess the prediction accuracy. Correlation of signature genes with tumor microenvironment scores, immune cells and immune checkpoint molecules were further analyzed. The tumor immune dysfunction and exclusion (TIDE) score was used to evaluate the response to immunotherapy. Results: One hundred and forty-seven samples were included in this study, which was randomly divided into the training cohort (n = 103) and validation cohort (n = 44). In total, 224 genes were identified as DEGs. Further LASSO regression analysis screened out 25 genes from all DEGs. Through the intersection of LASSO results, WGCNA results and IRGs list, S100A9, TREM1, COLEC12, and IFIT1 were integrated to construct the ANN model. The areas under the curves (AUCs) of the model were .887 in training cohort and .765 in validation cohort. The four IRGs also correlated with tumor microenvironment scores, infiltrated immune cells and immune checkpoint genes in various degrees. Patients with TACE-Response, lower expression of COLEC12, S100A9, TREM1 and higher expression of IFIT1 had better response to immunotherapy. Conclusion: This study constructed and validated an IRG signature to predict the refractoriness to TACE in patients with HCC, which may have the potential to provide insights into the TACE refractoriness in HCC and become the immunotherapeutic targets for HCC patients with TACE refractoriness.

Efficacy and safety of camrelizumab plus transarterial chemoembolization in intermediate to advanced hepatocellular carcinoma patients: A prospective, multi-center, real-world study.

Objective: Camrelizumab is a newly developed program-death receptor one inhibitor; the real-world evidence about its application in hepatocellular carcinoma (HCC) treatment is lacking. Therefore, this prospective, multi-center, real-world study evaluated the efficacy and safety of camrelizumab plus transarterial chemoembolization (TACE) in treating intermediate-to-advanced HCC patients. Methods: This study consecutively enrolled 101 intermediate to advanced HCC patients. All patients received camrelizumab-based treatment within 30 days of the perioperative period of the TACE operation. The primary outcome was progression-free survival (PFS), and the secondary effects were overall survival (OS), objective response rate (ORR), disease control rate (DCR), and AEs. Results: Specifically, the median PFS was 9.7 (95% confidence interval: 7.4-12.0) months, with a 1-year PFS rate of 30.6%. Meanwhile, the median OS was not reached (NR) yet, with a 1-year OS rate of 61.9%. Besides, the CR, PR, SD, and PD rates were 12.8%, 44.9%, 29.5%, and 12.8%, respectively. The ORR and DCR were 57.7% and 87.2%, respectively. More cycles of camrelizumab were independently correlated with prolonged PFS (hazard ratio (HR): 0.415, P = 0.002), whereas longer intervals between camrelizumab administration and TACE were independently associated with unfavorable PFS (HR: 1.873, P = 0.032). The incidence of total AEs was 90.1%; most AEs were grade 1 (20.8%), grade 2 (28.7%) and grade 3 (37.6%), while only 3 (3.0%) patients had grade 4 AEs. Conclusion: The camrelizumab plus TACE regimen is effective and safe, indicating its potential to serve as a promising treatment choice for intermediate to advanced HCC patients.

Chinese expert consensus on conversion therapy for hepatocellular carcinoma (2021 edition).

Recent advances in systemic and locoregional treatments for patients with unresectable or advanced hepatocellular carcinoma (HCC) have resulted in improved response rates. This has provided an opportunity for selected patients with initially unresectable HCC to achieve adequate tumor downstaging to undergo surgical resection, a 'conversion therapy' strategy. However, conversion therapy is a new approach to the treatment of HCC and its practice and treatment protocols are still being developed. Review the evidence for conversion therapy in HCC and develop consensus statements to guide clinical practice. Evidence review: Many research centers in China have accumulated significant experience implementing HCC conversion therapy. Preliminary findings and data have shown that conversion therapy represents an important strategy to maximize the survival of selected patients with intermediate stage to advanced HCC; however, there are still many urgent clinical and scientific challenges for this therapeutic strategy and its related fields. In order to summarize and learn from past experience and review current challenges, the Chinese Expert Consensus on Conversion Therapy for Hepatocellular Carcinoma (2021 Edition) was developed based on a review of preliminary experience and clinical data from Chinese and non-Chinese studies in this field and combined with recommendations for clinical practice. Sixteen consensus statements on the implementation of conversion therapy for HCC were developed. The statements generated in this review are based on a review of clinical evidence and real clinical experience and will help guide future progress in conversion therapy for patients with HCC.

Preintervention MCP-1 serum levels as an early predictive marker of tumor response in patients with hepatocellular carcinoma undergoing transarterial chemoembolization.

BACKGROUND: Transarterial chemoembolization (TACE) is a widely accepted treatment for unresectable or intermediate-stage hepatocellular carcinoma (HCC). However, response rates to TACE are heterogeneous and it is not fully understood which patients benefit most from TACE therapy in terms of tumor response. To identify the possible predictive roles of the perioperative monocyte chemoattractant protein-1 (MCP-1) levels in patients of HCC treated with TACE. METHODS: Forty patients of HCC receiving TACE were enrolled in a single center prospective observational study. MCP-1 and miR-210 levels were measured in 40 HCC patients at baseline before TACE and compared with 17 healthy controls by immunoassay and reverse transcriptase quantitative polymerase chain reaction (RT-qPCR). Tumor response assessments were taken after TACE treatment 4-6 weeks. Univariate and multivariate analysis were conducted to analyze factors correlated with tumor response in a Logistic regression model. The predictive roles of the involved variables on tumor response in patients with HCC suffering TACE were examined by receiver operating characteristic (ROC) curve analysis. RESULTS: The serum MCP-1 and miR-210 levels were significantly elevated in HCC patients compared to healthy subjects. Patients with the low preintervention MCP-1 and miR-210 levels attained a higher probability of achieving an objective response (OR) (88.5% vs.42.9%, P=0.007; 76.9% vs. 35.7%, P=0.010, respectively). Pre-TACE MCP-1 level (<816.63 pg/mL) was an independent risk factor associated with OR after TACE by univariate and multivariate analysis while Pre-TACE miR-210 level (<4.43 relative expression) was just positive by univariate analysis. ROC curve analysis showed that a combined index based on those two factors exhibited optimal predictive power of tumor response among all the involved variables (area under the curve =0.823, 95% CI: 0.681-0.965). Additionally, high pre-TACE serum MCP-1 level was correlated with cirrhosis, vascular invasion and Barcelona Clinic Liver Cancer (BCLC) stage. Elevated pre-TACE serum miR-210 level was associated with and BCLC stage. CONCLUSIONS: The study demonstrates that the pre-TACE serum MCP-1 level serves as an effective predictor for tumor response. These findings probably help discriminate HCC patients pre-TACE who specially benefit from TACE regarding OR.