Validation of the CRAFITY score for predicting prognosis in patients with hepatocellular carcinoma undergoing transarterial chemoembolization combined with systemic therapy

Transarterial chemoembolization (TACE) is the standard treatment for hepatocellular carcinoma (HCC); the value of its combination with systemic therapy is worthy of further exploration. This study aimed to investigate the efficacy and safety of TACE combined with tyrosine kinase inhibitor (TKI) and immune checkpoint inhibitor (ICI) in the treatment of unresectable HCC. In this retrospective observational, single-center study, 147 patients with unresectable HCC were divided into a TACE group (n=98) and a non-TACE group (n=49) based on whether TACE was performed during TKI plus ICI therapy. The survival outcomes and adverse events (AEs) of the two groups were compared. Data from patients with unresectable HCC who received TKI plus ICI treatment between July 2017 and April 2020 were collected. The median intrahepatic tumor size was 8.7 cm [interquartile range (IQR), 5.9-12.4 cm]. At data cut-off, overall survival (OS) of the TACE group was significantly longer than that of the non-TACE group (19.5 and 10.8 months, respectively, P=0.005). In the high-risk cohort (with main or contralateral portal vein tumor thrombi and/or bile duct invasion and/or a tumor burden >50% of liver), the OS of the TACE group was still longer than that of the non-TACE group (14.9 and 8.7 months, respectively, P=0.031). Major AEs were tolerated in both groups, and there was no significant difference in their incidence (34.7% and 30.6%, respectively, P=0.621). TACE treatment combined with TKI plus ICI regime resulted in longer OS than treatment with TKI plus ICI alone for patients with unresectable HCC.

In recent years, therapeutic strategies for liver cancer have been continuously evolving, with transarterial chemoembolization (TACE) being widely applied. Although TACE has demonstrated good short-term efficacy, long-term prognosis remains a challenge. This study aimed to investigate the clinical efficacy and safety of TACE combined with tyrosine kinase inhibitors (TKIs) and programmed cell death protein 1 (PD-1) inhibitors versus TACE combined with TKIs alone. Additionally, we explored prognostic factors, constructed a prognostic model, and validated it. A retrospective analysis was conducted on 174 patients with unresectable hepatocellular carcinoma at Lu'an Hospital of Traditional Chinese Medicine Affiliated to Anhui University of Traditional Chinese Medicine from December 21, 2018, to January 15, 2023. Of these, 122 patients were treated with TACE + TKIs + PD-1, and 52 patients with TACE + TKIs. The objective was to compare overall survival (OS) and progression-free survival (PFS) between the two groups, analyze adverse events to assess the safety of the treatment regimen, explore risk factors affecting the prognosis of patients' OS and PFS, construct a prognostic model, and validate it through meta-analysis. The median OS in the TACE + TKIs + PD-1 group was significantly better than that in the TACE + TKIs group {20.8 months [95% confidence interval (CI): 13.6-28.0] vs. 14.7 months (95% CI: 11.6-17.8), P<0.001}. The median PFS in the TACE + TKIs + PD-1 group was also significantly better than that in the TACE + TKIs group [8.6 months (95% CI: 6.6-10.6) vs. 5.2 months (95% CI: 4.8-5.6), P<0.001]. The disease control rate (DCR) and objective response rate (ORR) were 82.8% and 37.7% in the TACE + TKIs + PD-1 group, and 57.7% and 28.9% in the TACE + TKIs group, respectively. The incidence of rash was significantly higher in the TACE + TKIs + PD-1 group than in the TACE + TKIs group. Multifactorial analysis identified treatment options (TACE + TKIs + PD-1 vs. TACE + TKIs) [hazard ratio (HR) =0.311, 95% CI: 0.192-0.503, P<0.001], Barcelona Clinic Liver Cancer (BCLC) stage (B/C) (HR =0.367, 95% CI: 0.235-0.574, P<0.001), and Eastern Cooperative Oncology Group performance status (ECOG PS) (1/0) (HR =1.974, 95% CI: 1.059-3.678, P=0.03) as independent prognostic factors for OS. Treatment options (HR =0.352, 95% CI: 0.221-0.559, P<0.001) and extrahepatic metastasis (yes/no) (HR =2.034, 95% CI: 1.201-3.444, P=0.008) were identified as independent prognostic factors for PFS. The results were confirmed through meta-validation. The area under the curve (AUC) for the 1-, 2-, and 3-year OS nomograms were 0.706, 0.775, and 0.741, respectively, indicating good predictive performance of the model. The TACE + TKIs + PD-1 treatment regimen significantly outperformed TACE + TKIs in terms of OS, PFS, and DCR but increased the incidence of rash. An ECOG PS of 1 and BCLC-C stage were identified as risk factors for OS, while extrahepatic metastasis was an independent risk factor for PFS. The high accuracy of the survival prediction model constructed in this study provides a basis for clinical prognosis.

BackgroundThe evidence of transcatheter arterial chemoembolization (TACE) plus tyrosine kinase inhibitor and immune checkpoint inhibitor in unresectable hepatocellular carcinoma (HCC) was limited. This study aimed to evaluate the role of TACE plus apatinib (TACE + A) and TACE combined with apatinib plus camrelizumab (TACE + AC) in patients with unresectable HCC.MethodsThis study retrospectively reviewed patients with unresectable HCC who received TACE + A or TACE + AC in 20 centers of China from January 1, 2019 to June 31, 2021. Propensity score matching (PSM) at 1:1 was performed to reduce bias. Treatment-related adverse events (TRAEs), overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR) were collected.ResultsA total of 960 eligible patients with HCC were included in the final analysis. After PSM, there were 449 patients in each group, and the baseline characteristics were balanced between two groups. At data cutoff, the median follow-up time was 16.3 (range: 11.9–21.4) months. After PSM, the TACE + AC group showed longer median OS (24.5 vs 18.0 months, p < 0.001) and PFS (10.8 vs 7.7 months, p < 0.001) than the TACE + A group; the ORR (49.9% vs 42.5%, p = 0.002) and DCR (88.4% vs 84.0%, p = 0.003) of the TACE + AC group were also higher than those in the TACE + A group. Fever, pain, hypertension and hand-foot syndrome were the more common TRAEs in two groups.ConclusionsBoth TACE plus apatinib and TACE combined with apatinib plus camrelizumab were feasible in patients with unresectable HCC, with manageable safety profiles. Moreover, TACE combined with apatinib plus camrelizumab showed additional benefit.

Background and AimsRegardless of great progress in early detection of hepatocellular carcinoma (HCC), unresectable HCC (uHCC) still accounts for the majority of newly diagnosed HCC with poor prognosis. With the promising results of a double combination of transarterial chemo(embolization) and tyrosine kinase inhibitors (TKIs), and TKIs and immune checkpoint inhibitors (ICIs), a more aggressive strategy, a triple combination of transarterial chemo(embolization), TKIs, and ICIs has been tried in the recent years. Hence, we aimed to conduct a systematic review to verify the safety and efficacy of the triple therapy for uHCC.MethodsPubMed, MedLine, Embase, the Cochrane Library, and Web of Knowledge were used to screen the eligible studies evaluating the clinical efficacy and safety of triple therapy for patients with uHCC up to April 25th 2022, as well as Chinese databases. The endpoints were the complete response (CR), objective response rate (ORR), disease control rate (DCR), conversion rate, progression-free survival (PFS) rate, overall survival (OS) rate, and the incidence of adverse events (AEs).ResultsA total of 15 studies were eligible with 741 patients receiving transarterial chemoembolization (TACE) or hepatic arterial infusion chemotherapy (HAIC) combined with TKIs and ICIs. The pooled rate and 95% confidence interval (CI) for CR, ORR, and DCR were 0.124 (0.069–0.190), 0.606 (0.528–0.682), and 0.885 (0.835–0.927). The pooled rates for PFS at 0.5 years and 1 year were 0.781 (0.688–0.862) and 0.387 (0.293–0.486), respectively. The pooled rates for OS at 1, 2, and 3 years were 0.690 (0.585–0.786), 0.212 (0.117–0.324), and 0.056 (0.028–0.091), respectively. In addition, the pooled rate and 95%CI for the conversion surgery was 0.359 (0.153–0.595). The subgroup analysis of control studies showed that triple therapy was superior to TACE+TKIs, TKIs+ICIs, and TKIs in CR, ORR, and DCR, conversion rate; PFS; and OS. No fatal AEs were reported, and the top three most common AEs were elevated ALT, elevated AST, and hypertension, as well as severe AEs (grading ≥3).ConclusionWith the current data, we concluded that the triple therapy of TACE/HAIC, TKIs, and ICIs would provide a clinical benefit for uHCC both in short- and long-term outcomes without increasing severe AEs, but the conclusion needs further validation.Systematic Review Registrationhttp://www.crd.york.ac.uk/PROSPERO/, Review registry: CRD42022321970.

Introduction: Standard treatments for intermediate-stage hepatocellular carcinoma (HCC), such as transarterial chemoembolization (TACE), offer limited efficacy, necessitating the exploration of additional therapeutic strategies. Tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) have shown potential to enhance HCC outcomes when combined with TACE. This meta-analysis aimed to evaluate safety and efficacy of TACE, TKIs, and ICIs (TACE + T + I) combination compared to TACE with TKIs alone (TACE + T) in patients with HCC. Methods: A systematic search was performed in “PubMed,” “Google Scholar,” “Cochrane Library,” “Web of Science,” “Scopus,” and “Embase” databases on November 1, 2024. Studies involving patients with HCC comparing TACE + T + I versus TACE + T were included. Efficacy outcomes including objective response rate (ORR), disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and adverse events were extracted. Meta-analysis was conducted using RevMan 5.4. Results: Seventeen studies were included for analysis. Pooled analysis showed a marked improvement in ORR (risk ratio [RR] = 1.57, 95% CI: 1.36–1.80, p < 0.00001) and DCR (RR = 1.13, 95% CI: 1.06–1.20, p = 0.0004) for TACE + T + I regimen over TACE + T. TACE + T + I group also showed a marked benefit in OS (hazard ratio [HR] = 0.37, 95% CI: 0.29–0.48, p < 0.0001) and PFS (HR = 0.44, 95% CI: 0.36–0.53, p < 0.0001). No differences in adverse events were detected between the two groups, indicating comparable tolerability. Conclusion: The findings suggest that the addition of ICIs to TACE and TKI therapy offers substantial efficacy benefits without increasing toxicity for HCC patients. This combination therapy shows potential to improve DCR, ORR, PFS, and OS, underscoring the value of immunotherapy in enhancing outcomes in HCC. However, further randomized trials with standardized treatment protocols are needed to confirm these results and inform clinical guidelines.

Purpose: The aim of this multicenter retrospective study was to evaluate the efficacy and safety of transarterial chemoembolization (TACE) combined with tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (ICI) in treating advanced hepatocellular carcinoma (HCC) compared to treatment with TKI and ICI alone.Methods: The study included 286 patients with advanced HCC, of which 210 were treated with TACE, TKI, and ICI (TACE+T+I group) and 76 with TKI and ICI alone (T+I group). Progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and disease control rate (DCR) were assessed. A nomogram was developed to stratify patients into high-risk and low-risk groups based on their one-year and two-year survival probabilities.Results: Patients in the TACE+T+I group demonstrated significantly longer PFS (8.4 months vs. 4.0 months, Log-rank P = 0.0016) and median OS (14.5 months vs. 10.0 months, Log-rank P < 0.0001) compared to the T+I group. Additionally, the TACE+T+I group had a higher ORR (56.7% vs. 21.1%, P = 0.002) and DCR (84.3% vs. 72.4%, P = 0.023). Both groups exhibited good tolerance to adverse events. A nomogram incorporating factors such as therapeutic strategy, prothrombin time (PT), age, and tumor size effectively categorized patients into low- and high-risk groups with notably different survival outcomes.Conclusion: These findings suggest that TACE combined with TKI and ICI significantly improved survival outcomes and showed good safety compared to TKI and ICI alone in the treatment of advanced HCC.

Immunotherapy improved the efficacy of TACE or TACE plus MTTs in HCC patients: A meta-analysis.

Expanding the immunotherapy roadmap for hepatocellular carcinoma.

To establish and validate a multi-sequence magnetic resonance (MR) imaging-based radiomics model for predicting the objective response rate (ORR) of hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE) in combination with TKI and PD-1 inhibitors, aiming to maximize the efficacy of combination therapy. A total of 151 patients with unresectable HCC who received TACE combined with TKI and PD-1 inhibitors were included from two institutions between January 2019 and November 2022. Of these, 119 patients from Center 1 were randomized into the training group (n = 71) and the test group (n = 48). The 32 patients from Center 2 were used as an external validation set. The region-of-interest (ROI) and feature extraction from preoperative T2-weighted imaging (T2WI), arterial phase, and venous portal phase enhanced MRI images were manually extracted using 3D-slicer software. The most relevant radiomic features were selected using the least absolute shrinkage and selection operator (LASSO) regression. These features were then integrated with predictive clinical features into a logistic regression (LR) model to build a combined model for predicting tumor response. The predictive performance of each model was evaluated using the area under the curve (AUC) of the receiver operating characteristic (ROC). Model performance was further assessed using the calibration curve and the decision curve. Additionally, we also analyzed the relationship between LR-predicted objective response rate (preORR) and progression-free survival (PFS), as well as overall survival (OS) in patients with intermediate and advanced HCC. Univariate and multivariate survival analyses of PFS and OS were conducted to identify independent predictive factors in patients with unresectable HCC. The BCLC stage was identified as an independent factor affecting the ORR in the clinical model (P < 0.05). The AUC values based on the combined model in the training, test, and validation groups was 0.893(95%CI:0.813–0.973),0.862(95%CI: 0.755–0.965), and 0.804(95%CI: 0.614–0.971), respectively. Calibration curves and decision curves demonstrate the good calibration performance and clinical utility of the combined model. In the survival analysis, PFS and OS were significantly different between LR-predicted ORR + and LR-predicted ORR- (P < 0.05). Multivariate survival analysis showed that BCLC stage, tumor size, and radscore were independent predictors of PFS, while BCLC stage and Child-Pugh grade were independent predictors of OS. The combined model based on MRI radiomics can effectively predict the ORR in unresectable HCC with combination therapy.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-18586-7.

ObjectivesTo explore the efficacy and safety of Transarterial chemoembolization (TACE) in combination with immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) in patients with unresectable hepatocellular carcinoma (uHCC).Methods456 patients with HCC receiving either TACE in combination with ICIs and TKIs (combination group, n = 139) or TACE monotherapy (monotherapy group, n = 317) were included from Apr 2016 to Dec 2021 in this retrospective study. We employed propensity score matching (PSM), performed 1:2 optimal pair matching, to balance potential bias.ResultsThe mean follow-up time is 24.7 months (95% CI 22.6–26.8) for matched patients as of March 2022. After matching, the combination group achieved longer OS and PFS (median OS:21.9 vs. 16.3 months, P = 0.022; median PFS: 8.3 vs. 5.1 months, P < 0.0001) than TACE monotherapy group. The combination group had better objective response rate (ORR) and disease control rate (DCR) (ORR: 52.5% vs. 32.8%, P < 0.001; DCR: 82.7% vs. 59.6%, P < 0.001). Subgroup analysis showed that patients who received “TKIs + ICIs” after the first TACE procedure (after TACE group) achieved longer OS than those before the first TACE procedure (before TACE group) (26.8 vs. 19.2 months, P = 0.011). Adverse events were consistent with previous studies of TACE-related trials.ConclusionsTACE plus TKIs and ICIs appeared to deliver longer PFS and OS in HCC patients than TACE monotherapy. “TKIs + ICIs” co-treatment within 3 months after the first TACE procedure might be a better medication strategy.

BackgroundHepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, and advanced-stage disease presents significant therapeutic challenges. Combining transarterial chemoembolization (TACE) with tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) has emerged as a promising strategy to enhance treatment efficacy. This meta-analysis evaluates efficacy and safety of TACE + TKIs + ICIs compared to TKIs + ICIs alone in patients with HCC.MethodsA systematic search was conducted across “PubMed”, “Web of Science”, “Cochrane Library”, “Scopus”, “Google Scholar”, and “Embase” to screen studies up to November 2024. Studies comparing TACE + TKIs + ICIs with TKIs + ICIs alone in advanced HCC were included. Outcomes of interest included objective response rate (ORR), disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and adverse events. Results were reported as relative risk (RR) or hazard ratios (HR) with 95% confidence intervals (CI). Funnel plots was used to assess publication bias.ResultsTen studies comprising 1999 patients were included. The combination of TACE + TKIs + ICIs marked improved ORR (RR = 1.81, 95%CI:1.57–2.09, P < 0.00001) and DCR (RR = 1.32, 95%CI: 1.19–1.46, P < 0.00001) comparing with TKIs + ICIs alone. OS and PFS were also significantly prolonged in combination group, with HR of 0.55 (95%CI:0.48–0.63, P < 0.00001) and 0.73 (95%CI:0.65–0.82, P < 0.00001), respectively. Adverse events such as pain (RR = 3.94, 95%CI:2.40–6.47, P < 0.001) and nausea/vomiting (RR = 2.28, 95% CI:1.56–3.33, P < 0.001) were more frequent in the TACE + TKIs + ICIs group, though rates of hypertension, diarrhea, and rash were similar between groups. Funnel plots indicated minimal publication bias for primary outcomes.ConclusionsThe combination of TACE, TKIs, and ICIs significantly improves ORR, DCR, OS, and PFS compared to TKIs and ICIs alone, demonstrating superior efficacy with an acceptable safety profile. These findings provide evidence for the integration of TACE with systemic therapies in the management of HCC.

The combination of immune checkpoint inhibitors (ICIs) and anti-angiogenic agents has shown promising efficacy in unresectable hepatocellular carcinoma (HCC), but until now no clinical prognostic models or predictive biomarkers have been established. From 2016 to 2021, a total of 258 HCCs treated with ICIs and tyrosine kinase inhibitors (TKIs) were retrospectively enrolled, as the study cohort. Patients' baseline data was extracted by least absolute and shrinkage selection operator (LASSO) and Cox regression. Finally, a prognostic model in the form of nomogram was developed. Model performance was assessed in terms of discrimination, calibration, and clinical utility. A 5-fold cross-validation was used to evaluate the internal repeatability of the model. In addition, the patient cohort was divided into three subgroups according to nomogram scores. Their survivals were estimated by Kaplan-Meier methods and the differences were analyzed using log-rank tests. Seven clinical parameters were selected: Eastern Cooperative Oncology Group performance status (ECOG PS), combination of transarterial chemoembolization (TACE), extrahepatic metastasis (EHM), platelet to lymphocyte ratio (PLR), alanine aminotransferase (ALT), alpha-fetoprotein (AFP), and Child-Pugh score. The model had an area under the curve (AUC) of 0.777 at 1 year and 0.772 at 2 years. Receiver operating characteristic (ROC) curve, calibration curve and decision curve analysis (DCA) showed that the discrimination, consistency and applicability of the model were good. In addition, cross-validation validated the discrimination of the model, and the C index value of the model is 0.7405. The median overall survival (OS) of the high-, medium- and low-risk subgroups was 7.58, 17.50 and 53.17 months, respectively, with a significant difference between the groups (P < 0.0001). We developed a comprehensive and simple prognostic model for the combination of ICIs plus TKIs. And it may predict the efficacy of the combination regimen for unresectable HCC.

To evaluate the impact of pre-treatment hepatitis B virus (HBV) activation on peripheral immune status and treatment response in unresectable hepatocellular carcinoma (uHCC) patients undergoing transarterial chemoembolization (TACE) combined with immune checkpoint inhibitors (ICIs) and anti-vascular endothelial growth factor (anti-VEGF) antibodies or tyrosine kinase inhibitors (TKIs), and to explore the underlying immunological basis. This single-center retrospective study included uHCC patients treated with TACE plus ICIs and anti-VEGF antibodies or TKIs between July 2019 and September 2024. Patients were categorized into inactive and active HBV infection groups based on pre-treatment HBV DNA levels. A 1:2 propensity score matching (PSM) was used to minimize confounding. The primary outcome was overall survival (OS), and secondary outcomes included progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). Peripheral immune markers were assessed at baseline (Cycle0), Cycle2, and Cycle4. Intergroup comparisons and regression analyses were performed to examine associations among HBV activation, immune changes, and objective response (OR). A total of 70 patients were enrolled, and 53 were retained after PSM (26 with inactive and 27 with active HBV infection). Median follow-up was 16.6 months; median OS and PFS were 30.1 and 10.6 months, respectively. At Cycle0, serum IgA levels were higher in the active HBV infection group [3.38 (2.72-4.60) vs 2.70 (2.21-3.32) g/L, P = 0.018], and HBV DNA showed a linear association with baseline IgA (P = 0.042). IgA increased significantly from Cycle0 to Cycle2 in the inactive HBV infection and OR groups but not in their counterparts. ΔIgA (Cycle2-Cycle0) was independently associated with OR (OR = 0.446, P = 0.041), while baseline IgA independently predicted ΔIgA (β = -0.260, P = 0.011). No significant OS or PFS differences were observed between HBV activation groups overall, although a trend toward worse OS appeared in the nOR subgroup (P = 0.058). Pre-treatment HBV activation is linked to altered baseline immune profiles, particularly elevated IgA, and influences early IgA dynamics. Early IgA changes independently predict early treatment response, supporting the integration of IgA-based immune profiling into personalized strategies for HBV-related uHCC.

Introduction: Transarterial chemoembolization (TACE) is the standard treatment for unresectable intermediate-stage hepatocellular carcinoma (HCC), but recurrence after TACE is common. The present phase 2, prospective, multicenter, single-arm trial, the TACTICS-L trial, investigated the efficacy and safety of TACE plus lenvatinib (LEN), a drug that more strongly promotes vascular normalization and has a better objective response rate (ORR) than sorafenib (jRCTs031180074). Methods: Participants were patients with HCC who had not previously received systemic therapy, hepatic arterial infusion chemotherapy, or immunotherapy and who were ineligible for resection or percutaneous ablation therapy. LEN was to be administered 14–21 days before the first TACE, stopped 2 days before TACE, and resumed 3 days after TACE. Key inclusion criteria were unresectable HCC, Child-Pugh A liver function, 0–2 prior TACE sessions, tumor size ≤10 cm, number of tumors ≤10, and ECOG performance status 0–1. Key exclusion criteria were vascular invasion and extrahepatic spread. The primary endpoint was progression-free survival (PFS) by RECICL, and secondary endpoints were time to untreatable progression, ORR, overall survival (OS), and safety. Results: A total of 62 HCC patients were enrolled in this trial. The median age was 72 years, 77.4% of patients were men, and 95.2% had PS 0. The primary endpoint of median PFS was 28.0 months (90% confidence interval [CI] 25.1–31.0) after a minimum 24 months of follow-up. The secondary endpoint of median OS was not reached (90% CI 35.5 months–NR). LEN-TACE achieved a high response rate and high complete response (CR) rate (4 weeks after the first TACE: ORR 79.0%, CR rate 53.2%; best response: ORR 88.7%, CR rate 67.7%) by RECICL. Exploratory subgroup analyses showed that the characteristics of responders/nonresponders (ORR and CR rate) were similar and that LEN-TACE would be effective in all subgroups, including the population in whom TACE alone would be less likely to be curative (e.g., patients with the non-simple nodular type or a high tumor burden). The relative dose intensity of LEN before the first TACE was important for achieving higher CR rate/ORR by LEN-TACE. No new safety concerns were observed. Conclusion: The results of this trial provide encouraging evidence, supporting the efficacy and favorable safety profile of LEN-TACE in patients who are ineligible for locoregional therapy.

Chemoembolization and Radioembolization for Hepatocellular Carcinoma