Transarterial Chemoembolization Refractoriness Research Articles

Predicting Survival Using Whole-Liver MRI Radiomics in Patients with Hepatocellular Carcinoma After TACE Refractoriness.

To develop a model based on whole-liver radiomics features of pre-treatment enhanced MRI for predicting the prognosis of hepatocellular carcinoma (HCC) patients undergoing continued transarterial chemoembolization (TACE) after TACE-resistance. Data from 111 TACE-resistant HCC patients between January2014 and March2018 were retrospectively collected. At a ratio of 7:3, patients were randomly assigned to developing and validation cohorts. The whole-liver were manually segmented, and the radiomics signature was extracted. The tumor and liver radiomics score (TLrad-score) was calculated. Models were trained by machine learning algorithms and their predictive efficacies were compared. Tumor stage, tumor burden, body mass index, alpha-fetoprotein, and vascular invasion were revealed as independent risk factors for survival. The model trained by Random Forest algorithms based on tumor burden, whole-liver radiomics signature, and clinical features had the highest predictive efficacy, with c-index values of 0.85 and 0.80 and areas under the ROC curve of 0.96 and 0.83 in the developing cohort and validation cohort, respectively. In the high-rad-score group (TLrad-score > - 0.34), the median overall survival (mOS) was significantly shorter than in the low-rad-score group (17m vs. 37m, p < 0.001). A shorter mOS was observed in patients with high tumor burden compared to those with low tumor burden (14m vs. 29m, p = 0.007). The combined radiomics model from whole-liver signatures may effectively predict survival for HCC patients continuing TACE after TACE refractoriness. The TLrad-score and tumor burden are potential prognostic markers for TACE therapy following TACE-resistance.

Prognostic Value of Preoperative MRI-derived 3D Quantitative Tumor Arterial Burden in Patients with Hepatocellular Carcinoma Receiving Transarterial Chemoembolization.

Purpose To investigate the association of tumor arterial burden (TAB) on preoperative MRI with transarterial chemoembolization refractoriness (TACER) and progression-free survival (PFS) in patients with hepatocellular carcinoma (HCC). Materials and Methods This retrospective study included patients with HCC who underwent repeated transarterial chemoembolization (TACE) treatments between January 2013 and December 2020. HCC was confirmed with pathology or imaging, and patients with other tumors, lost follow-up, or with a combination of other treatments were excluded. TACER was defined as viable lesions of more than 50% or increase in tumor number after two or more consecutive TACE treatments, continuous elevation of tumor markers, extrahepatic spread, or vascular invasion. TAB assessed with preoperative MRI was divided into high and low groups according to the median. A Cox proportional hazards model was used to determine the predictors of TACER and PFS. Results A total of 355 patients (median age, 61 years [IQR, 54-67]; 306 [86.2%] men, 49 [13.8%] women) were included. During a median follow-up of 32.7 months, the high TAB group had significantly faster TACER and decreased PFS than the low TAB group (all log-rank P < .001). High TAB was the strongest independent predictor of TACER and PFS in multivariable Cox regression analyses (hazard ratio [HR], 2.23 [95% CI: 1.51, 3.29]; HR, 2.30 [95% CI: 1.61, 3.27], respectively), especially in patients with Barcelona Clinic Liver Cancer stage A or a single tumor. The restricted cubic spline plot demonstrated that the HR of TACER and PFS continuously increased with increasing TAB. Conclusion High preoperative TAB at MRI was a risk factor for faster refractoriness and progression in patients with HCC treated with TACE. Keywords: Interventional-Vascular, MR Angiography, Hepatocellular Carcinoma, Transarterial Chemoembolization, Progression-free Survival, MRI Supplemental material is available for this article. © RSNA, 2024.

Rhein‐based Pickering emulsion for hepatocellular carcinoma: Shaping the metabolic signaling and immunoactivation in transarterial chemoembolization

AbstractThe efficacy of transarterial chemoembolization (TACE) has been limited by insufficient embolization and a high incidence of tumor recurrence. Herein, we identified that aberrant metabolic reprogramming and immunosuppression contribute to TACE refractoriness and Rhein, as a potential glycolytic metabolism inhibitor and immunoactivation inducer, was optimized to sensitize tumors to TACE therapy. To achieve efficient embolization, we developed an oil‐in‐water lipiodol embolic emulsion by stabilizing the self‐assembled Rhein nanogel. The assembled Rhein exhibited a nanofiber network, and its integration enhanced the mechanical stability and viscoelasticity of the lipiodol embolic agent. With the synergistic advantages of solid and liquid embolic agents, this carrier‐free Pickering emulsion exhibits efficient embolization and sustained drug release in models of unilateral renal artery embolization, rabbit ear tumor embolization, rabbit orthotopic liver cancer, and rat orthotopic liver cancer. Compared to conventional three‐way catheter mixing methods, multimodal imaging corroborates a marked enhancement in local drug retention and tumor suppression. Importantly, the incorporation of Rhein‐mediated synergistic immunoembolization in this strategy achieved efficient embolization while robustly activating anti‐tumor immune responses, including inducing immunogenic cell death, dendritic cell activation, and major histocompatibility complex class I presentation to CD8+ T cells for tumor killing. Together, these findings reveal a novel strategy for the application of self‐assembled Rhein nanofiber‐stabilized lipiodol emulsion to control metabolic signaling and immunoactivation in TACE.

Efficacy and Safety of TACE Combined with a Tyrosine Kinase Inhibitor for the Treatment of TACE-Refractory Hepatocellular Carcinoma: A Retrospective Comparative Study.

Combining angiogenesis inhibitors may enhance therapeutic efficacy synergistically after TACE refractoriness. The purpose of this study was to compare the outcomes of transarterial chemoembolization (TACE) plus a tyrosine kinase inhibitor (TACE-TKI) with TKI only for patients with TACE-refractory hepatocellular carcinoma (HCC). From January 2019 to March 2022, 101 HCC patients confirmed with TACE-refractory were retrospectively reviewed in the study. Progression-free survival (PFS), overall survival (OS), tumor response, and adverse events (AEs) were evaluated between groups. Fifty-two patients undergoing TACE-TKI, while 32 patients receiving TKI alone were included. The objective response rate (ORR) was higher in the TACE-TKI group compared with the TKI group (55.8% vs. 25.0%, P = 0.006). The median PFS in the TACE-TKI group was significantly longer than that in the TKI group (7.6months vs. 4.9months, P = 0.018). The median OS was non reach to statistical longer than that in the TKI alone group (19.5months vs. 17.7months, P = 0.055). Subgroup analysis showed that TACE-TKI treatment resulted in a significantly longer median PFS and OS for Barcelona Clinic Liver Cancer (BCLC) stage B patients (PFS 11.8months vs. 5.1months, P = 0.017; OS 30.3months vs. 19.4months, P = 0.022). For patients with TACE-refractory HCC, TACE-TKI appeared to be superior to TKI monotherapy with regard to tumor control and PFS. Furthermore, for the BCLC stage B subgroup, TACE-TKI therapy was superior to TKI monotherapy in both OS and PFS.

Development and validation of a clinical factors and body fat distribution-based nomogram to predict refractoriness of transarterial chemoembolization in hepatocellular carcinoma.

Transarterial chemoembolization (TACE) is an important treatment modality for hepatocellular carcinoma (HCC). However, some patients may develop TACE refractoriness during treatment. We aimed to construct a prediction model incorporating computed tomography (CT) body composition and clinical factors to preoperatively predict the risk of developing TACE refractoriness in patients with HCC, enabling the rapid identification of patients at high risk of TACE refractoriness. This study included 128 HCC patients treated with TACE who were randomly assigned to the training (n=89) and validation groups (n=39) in a 7:3 ratio. Multiple body-composition parameters were outlined from CT images of the third lumbar vertebra level of each patient. Standardized values of body-composition parameters were calculated, such as visceral-to-subcutaneous adipose tissue area ratio (VSR). Multifactor logistic regression analysis was performed to identify independent predictors of TACE-refractoriness in patients and to develop predictive models. High- and low-risk subgroup analyses were performed for the predictive model. Alpha-fetoprotein (AFP) level (P=0.041), tumor size (P=0.001), and VSR (P=0.043) were independent risk factors for TACE refractoriness. The combined clinical-body composition model had an area under the curve (AUC) value of 0.875 in the training cohort and an AUC value of 0.837 in the validation cohort. Calibration curves and decision curves revealed the specific optimal performance and clinical utility of the combined model. Subgroup analysis showed differences in predicted TACE refractoriness between the high- and low-risk groups (P<0.001). The combined clinical-body fat distribution model has the good performance in predicting a patient's risk of TACE refractoriness preoperatively and can help clinicians make the best clinical decisions in advance for the treatment of high-risk patients.

Predictive Role of Pretreatment Circulating miR-221 in Patients with Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization.

Aberrantly expressed circulating microRNAs (miRNAs) have been demonstrated to have a crucial role in the diagnosis and prognostication of various cancers, including hepatocellular carcinoma (HCC). This research aimed to examine the role of specific miRNAs in predicting the outcomes for individuals with hepatitis B virus (HBV)-related HCC treated with transarterial chemoembolization (TACE). Stored serum specimens collected prior to the first TACE procedure were employed to determine the expression of serum miR-122, miR-221, and miR-224 using quantitative real-time PCR analysis. The study included 100 HCC patients (84% males, with an average age of 60 years) who were treated with TACE. Throughout the median follow-up spanning 18.5 months (within a range of 3 to 60 months), 42 (42.0%) patients met the criteria of TACE refractoriness. Through multivariate analysis, elevated expressed miR-221 (≥4.0 log10 copies) and advanced HCC staging were identified as independent factors related to TACE refractoriness and short overall survival. However, serum miR-122 and miR-224 levels were not linked to treatment response or overall survival. These findings underscored the potential of incorporating pretreatment levels of serum miR-221 into the established tumor staging to enhance the accurate assessment of TACE responsiveness and prognostic outcome of patients with HCC.

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.

Predictors of Refractoriness and Survival following Transarterial Chemoembolization for Hepatocellular Carcinoma: Outcomes from a Southeast Asian Cohort

Abstract Aim Patients with hepatocellular carcinoma (HCC) become refractory to repeated sessions of transarterial chemoembolization (TACE). The aim of this study was to identify predictors associated with overall survival and refractoriness following repetitive TACE of HCC among patients in Southeast Asia. Materials and Methods The clinical and laboratory characteristics and radiologic response of 39 patients treated with conventional TACE (range 2 to 5) with mitomycin from January 2012 to June 2018 were retrospectively analyzed. Patients were mostly male with a median age of 59 years and belonged to the BCLC B stage with a median tumor size of 7.5 cm. Results The median overall survival was 23.2 months and the overall mortality at 5 years was 36%. Multivariate Cox regression analysis revealed that Child–Pugh (CP) score (hazard ratio [HR] = 3.47, p = 0.044), AST (HR = 7.6, p = 0.021), tumor size (HR = 5.47, p = 0.033), progressive disease on Choi criteria (HR = 5.47, confidence interval [CI] 1.15–25.99, p = 0.033), neutrophil-lymphocyte ratio (HR = 1.25, p = 0.049), and nodular enhancement on follow-up computed tomography (CT; HR = 1.98, p = 0.034) were independent risk factors for poor survival. ALT (p = 0.005), enhancement (p = 0.003), CP score (p = 0.010), and progressive disease on Choi criteria (p = 0.022) were predictive of TACE refractoriness/failure. Conclusion Elevated liver enzymes, CP score, and progressive disease on Choi criteria accurately predict TACE refractoriness and failure, allowing early identification of patients who might benefit from other therapies.

Plasma arginase-1 as a predictive marker for early transarterial chemoembolization refractoriness in unresectable hepatocellular carcinoma.

ObjectiveTo explore the relationship between plasma arginase-1 (ARG1) and early transarterial chemoembolization (TACE) refractoriness in patients with hepatocellular carcinoma (HCC) and develop nomograms for predicting early TACE refractoriness.MethodsA total of 200 patients with HCC, treated with TACE, were included in the study, including 120 in the training set and 80 in the validation set. Pre-treatment enzyme-linked immunosorbent assay was used to detected the plasma ARG1 levels of the patient, and independent predictors of early TACE refractoriness were determined using a multivariate logistic regression model, based on which a predictive model was developed using a nomogram.ResultsRisk of early TACE refractoriness was negatively correlated with plasma ARG1 levels, and multivariate logistic analysis showed tumour size (OR = 1.138, 95% CI = 1.006-1.288, P = 0.041), multiple tumors (OR=4.374, 95% CI = 1.189-16.089, P = 0.026), platelet count (OR = 0.990, 95% CI = 0.980-0.999, P = 0.036), and plasma ARG1 levels (OR = 0.209, 95% CI = 0.079-0.551, P = 0.002) to be independent prognostic factors for early TACE refractoriness.The AUC value for the nomogram of the training cohort was 0.786 (95% CI = 0.702–0.870), and the validation set AUC value was 0.833 (95% CI = 0.791-0.875).The decision curve analysis suggested that the nomogram had good clinical utility.ConclusionHigh plasma ARG1 expression was associated with a lower incidence of early TACE refractoriness. The nomogram constructed based on four independent prognostic factors could facilitate an individualised prediction of the incidence of early TACE refractoriness.

Expert consensus on transarterial chemoembolization refractoriness and subsequent therapies in hepatocellular carcinoma

Transarterial chemoembolization (TACE) is the fundamental method for the treatment of unresectable hepatocellular carcinoma (HCC). Nevertheless, ineffective repeat TACE may lead to damage on liver function and therefore have negative effect on long-term prognosis of HCC. The concept of "TACE failure/refractoriness" was then proposed to avoid ineffective repeat TACE. Nevertheless, whether the existing definitions of "TACE failure/refractoriness" are applicable to Chinese HCCs remains to be discussed. Combining reported clinical evidence with experts' opinion, the Chinese College of Interventionalists (CCI) TACE Refractoriness Collaboration Group proposed the CCI definition and expert consensus on TACE refractoriness in 2021. The CCI definition and expert consensus aims to make the concept of TACE refractoriness more scientific and objective, so as to better guide clinical practice of TACE for patients with HCC in China.

Benefits of step-by-step debulking microwave ablation for huge unresectable hepatocellular carcinoma patients after transcatheter arterial chemoembolization refractoriness

Objectives To compare the safety and efficacy of step-by-step debulking Microwave Ablation (MWA) with Transarterial Chemoembolization (TACE) monotherapy for huge (≥10 cm in diameter) unresectable hepatocellular carcinoma (HCC) after TACE refractoriness. Methods This is a multi-center retrospective study carried out on 599 patients with huge unresectable HCC who received TACE as first-line therapy at five hospitals from January 2009 to December 2018. A total of 103 patients with TACE refractoriness were divided into two cohorts: monthly step-by-step debulking MWA (n = 52) or continued TACE (n = 51). Overall survival (OS) and progression-free survival (PFS) after refractory TACE were evaluated. Residual liver and tumor volume were recorded for the MWA group. Results Median follow-up period was 24.3 months and median OS and PFS were significantly longer in the MWA group than in the TACE group (OS 21.0 vs. 11.7 months, PFS 6.1 vs. 3.0 months, both p < 0.001). The one-, two-, and three-year OS rates in the MWA and TACE groups were 73.1%, 46.6%, and 37.2% versus 43.1%, 15.5%, and 2.9%, respectively. Furthermore, the 0.5-, 1-, and 2-year PFS rates in the MWA and TACE groups were 51.9%, 36.5%, and 25.0% versus 27.5%, 11.8%, and 0, respectively. Multivariate analyses confirmed that switching to debulking MWA treatment was an independent favorable prognostic factor for PFS and OS. In the MWA group, the average additions of residual liver volume/total liver volume were 7.7% ± 6.7%, 7.2% ± 10.2%, and 10.1% ± 8.8% after the first, second, and third MWA procedure. Conclusion Step-by-step debulking MWA can significantly improve long-term OS and PFS in patients with huge unresectable HCCs compared with repeated TACE after TACE refractoriness. Key Point The debulking MWA therapy provides significantly longer OS and PFS than continued TACE for patients with huge unresectable HCCs after TACE-refractory, especially with complete tumor ablation. The most common complications were fever (48.1%) and pain (46.2%) in the MWA group. Two major complications (abdominal infection) were recorded in the MWA group, which recovered after symptomatic treatment. During the course of repeated MWAs, liver hyperplasia appeared mainly after the second MWA procedure and the average maximum increased RLV/TLV rate was 16.3%±12.7%.

Effects of Early TACE Refractoriness on Survival in Patients with Hepatocellular Carcinoma: A Real-World Study.

PurposeTo investigate the effect of early transarterial chemoembolization (TACE) refractoriness on hepatocellular carcinoma (HCC) patient survival and to explore whether viable lesions > 50% after two consecutive TACE treatments negatively affect the prognosis of HCC patients.Patients and MethodsFrom January 2014 to August 2017, 323 HCC patients who received TACE as the initial treatment were analyzed. TACE refractoriness was diagnosed according to the Japan Society of Hepatology 2021 version. Propensity score matching (PSM) was used to create a 1:1 matched group (nonrefractoriness vs refractoriness). To determine survival outcomes and prognostic factors, the Kaplan-Meier method and Cox proportional hazards model were used.ResultsIn total, 51.1% of patients developed early TACE refractoriness (n = 165). After PSM, 120 patients from each group were matched and analyzed. The median overall survival (OS) time of the early TACE refractoriness group was significantly shorter than that of the nonrefractory group [21 months (95% CI: 15.7–26.3) vs 34 months (95% CI: 27.5–40.5), p = 0.002]. Thirty-eight patients with viable lesions >50% after two consecutive TACE procedures were identified and matched with patients of non-refractoriness. No significant difference in median OS was observed [35 months (95% CI: 21.6–48.5) vs 31 months (95% CI: 25.4–36.6), p = 0.611]. Multivariate analysis revealed that the BCLC stage, tumor size, tumor capsule, tumor distribution, α-fetoprotein level (AFP), and early TACE refractoriness were independent risk factors for prognosis in HCC patients.ConclusionEarly TACE refractoriness may shorten the OS of HCC patients. However, viable lesions >50% after two consecutive TACE treatments did not impair the survival of patients. It may be inappropriate to consider these patients as having developed TACE refractoriness.

P-131 Low-dose aspirin in combination with transarterial chemoembolization in treatment of unresectable hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the sixth and fourth common cancer in worldwide and Egypt. Transarterial chemoembolization (TACE) is standard treatment for unresectable HCC. Recent studies showed that TACE refractoriness impairs survival of HCC patients. Various strategies under investigation aim to improve the outcome of TACE, Aspirin demonstrated chemopreventive, antithrombotic and anti-inflammatory properties Moreover, it has been reported that aspirin may reverse apoptosis resistance in HCC cell lines. This study includes 60 patients diagnosed as unresectable HCC indicted for TACE randomized in to two arms; control arm and aspirin arm. All patients have vascular and cellular compensated liver functions; platelets count ≥ 100,000, and normal prothrombin time. We excluded patients with bleeding tendency, gastrointestinal ulcers, portal hypertension, allergy or contraindication to aspirin. Aspirin arm patients received 75 mg of aspirin daily after meal for 3 months; we assessed feasibility, toxicity of aspirin, studied treatment response and disease progression. In this study there was no significant difference between the two arms regarding baseline patients’ characteristics. Regarding compliance to aspirin, 70% of patients were regular; regarding compliance to TACE, 60% of patients were compliant to TACE in aspirin arm versus 56.7% in control arm. Most of side effects of aspirin are of grade 1 gastrointestinal side effect. According to modified RECIST criteria, better responses achieved in aspirin arm; 10% of patients in aspirin arm had complete remission versus 6.7 %in control arm and 30% had partial response in aspirin arm versus 23% in control arm, 30% of patients in aspirin arm had disease progression versus 40% in control arm; however, the difference didn’t reach statistical significant level (p=0.806). 20% of patients in control arm developed portal vein thrombosis versus only 6.7% in aspirin arm. There was an improvement in progression free survival (PFS); the median PFS was not reached for aspirin arm versus 11 months for Control arm (P=0.035). The use of adjuvant aspirin with TACE in patients with HCC is feasible and may be associated with longer PFS and a tendency of better TACE responses; however, larger sample size may yield stronger results.

Hepatic Arterial Infusion of Oxaliplatin, Fluorouracil, and Leucovorin Versus Sorafenib for Hepatocellular Carcinoma Refractory to Transarterial Chemoembolization: Retrospective Subgroup Analysis of 2 Prospective Trials.

Purpose:Sorafenib is recommended for patients with hepatocellular carcinoma refractory to transarterial chemoembolization but with unsatisfactory overall survival and tumor response rate. Previously published studies showed hepatic arterial infusion chemotherapy of oxaliplatin, fluorouracil, and leucovorin was an effective and safe treatment. The aims of this study were to compare the clinical efficacy and safety of oxaliplatin, fluorouracil, and leucovorin-based hepatic arterial infusion chemotherapy with sorafenib in patients with hepatocellular carcinoma refractory to transarterial chemoembolization. Methods: This was a retrospective subgroup analysis of 2 prospective clinical trials, including 114 patients with hepatocellular carcinoma who were confirmed to be transarterial chemoembolization refractoriness. Of these, 55 patients received hepatic arterial infusion chemotherapy of fluorouracil, and leucovorin (FOLFOX-HAIC group, oxaliplatin 85 or 130 mg/m2, leucovorin 400 mg/m2, fluorouracil bolus 400 mg/m2, and 2400 mg/m2 for 23 or 46 h, every 3 weeks), and 59 patients were treated with sorafenib (sorafenib group, 400 mg sorafenib twice daily). Overall survival, progression-free survival, objective response rate, and treatment-related adverse events were compared between the 2 groups. Results: The FOLFOX-HAIC group showed a longer overall survival (17.1 months [95% confidence interval 13.4-20.8] vs 9.1 months [95% confidence interval 7.5-10.6]; hazard ratio 0.35 [95% confidence interval 0.23-0.53]; P < .001), a higher objective response rate (RECIST: 18 [32.7%] vs 1 [1.7%], P < .001), and a longer progression-free survival (7.6 months [95% confidence interval 5.6-9.6] vs 3.9 months [95% confidence interval 2.3-5.4]; hazard ratio 0.49 [95% confidence interval 0.33-0.72]; P < .001) than the sorafenib group. The safety results suggested that both oxaliplatin, fluorouracil, and leucovorin-based hepatic arterial infusion chemotherapy and sorafenib had acceptable treatment-related toxic effects. No significant difference was observed in the overall occurrence of any grade, grade 3/4, or serious adverse events between the 2 groups. Conclusions: Oxaliplatin, fluorouracil, and leucovorin-based hepatic arterial infusion chemotherapy might be a better choice than sorafenib for patients with hepatocellular carcinoma refractory to transarterial chemoembolization.

Development of a Model to Predict Liver Decompensation prior to Transarterial Chemoembolization Refractoriness in Patients with Intermediate-Stage Hepatocellular Carcinoma

Introduction: Transarterial chemoembolization (TACE) is the first-line treatment for patients with intermediate-stage hepatocellular carcinoma (HCC). For patients without an adequate response, current finding suggests that treatment with molecular target agents, approved for advanced stage, might present benefits. However, this requires a preserved liver function. This study aims to evaluate possible predictors of early deterioration of hepatic reserve, prior to TACE refractoriness, in a cohort of patients treated with TACE. Methods: Retrospective analysis of 99 patients withChild-Pugh class A and intermediate-stage HCC who underwent TACE as the first-line treatment. All patients were submitted to a biochemical and medical evaluation prior to initial TACE and every month afterward. Response to initial TACE was evaluated at 1 month. The time to Child-Pugh class deterioration before TACE refractoriness was assessed. Results: Ninety-nine patients were included. Objective response rate (ORR) to initial TACE was assessed as present in 59 (63.4%) and as absent in 34 (36.6%) patients. Liver decompensated before TACE refractoriness in 51 (51.5%) patients, and the median time to liver decompensation was 14 (IQR 8–20) months after first TACE. In multivariate analysis, beyond up-to-7 criteria (HR 2.4, p = 0.031), albumin <35 mg/dL (HR 3.5, p < 0.001) and absence of ORR (HR 2.4, p = 0.020) were associated with decreased overall survival free of liver decompensation. Moreover, beyond up-to-7 criteria, albumin <35 mg/dL and absence of ORR associated negatively with 6-month survival free of liver decompensation. Our model created using those variables was able to predict liver decompensation at 6 months with an AUROC of 0.701 (p = 0.02). Conclusions: The absence of ORR after initial TACE, beyond up-to-7 criteria and albumin <35 mg/dL, was a predictive factor for early liver decompensation before TACE refractoriness in our population. Such patients might benefit from treatment escalation to systemic therapy, in monotherapy or in combination with TACE.

The Impact of Sorafenib in Combination with Transarterial Chemoembolization on the Outcomes of Intermediate-Stage Hepatocellular Carcinoma.

Background:We investigated the treatment outcomes and hepatic reserve of transarterial chemoembolization (TACE)-refractory patients with recurrent advanced hepatocellular carcinoma (HCC) treated with TACE plus sorafenib. Methods:Forty-one patients with intermediate-stage HCC defined as being TACE refractory on imaging were treated with sorafenib and TACE between 2009 and 2012 and comprised the combination treatment group. Twenty-nine patients who received repeated TACE after becoming refractory to TACE between 2005 and 2008 comprised the TACE continuation group. Results:Although the interval between successive rounds of TACE was significantly shorter before the patients developed TACE refractoriness, it was significantly longer after the development of TACE refractoriness, in the combination treatment group compared with the TACE continuation group. The appearance of extrahepatic spread and/or vascular invasion differed significantly between the two groups. The median overall survival was significantly longer in the combination treatment group than in the TACE continuation group (20.5 vs. 15.4 months, respectively; hazard ratio = 2.04; 95% confidence interval = 1.20–3.48). The 3-year overall survival rate was 33.4% in the combination treatment group and 3.5% in the TACE continuation group. Downstaging of the Child–Pugh class was significantly less frequent in the combination treatment group than in the TACE continuation group. In COX proportional hazards analyses, sorafenib plus TACE resulted in a better prognosis compared with repeated TACE. Conclusions:Treatment with sorafenib plus TACE in TACE-refractory patients with intermediate-stage HCC resulted in longer intervals between TACE rounds, better maintenance of hepatic reserve, and significantly longer OS compared with repeated TACE.

Development and Validation of a Predictive Model for Early Refractoriness of Transarterial Chemoembolization in Patients With Hepatocellular Carcinoma.

Objectives: To develop and validate a predictive model for early refractoriness of transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC). Methods: In this multicenter retrospective study, a total of 204 consecutive patients who initially underwent TACE were included. Early TACE refractoriness was defined as patients presented with TACE refractoriness after initial two consecutive TACE procedures. Of all patients, 147 patients (approximately 70%) were assigned to a training set, and the remaining 57 patients (approximately 30%) were assigned to a validation set. Predictive model was established using forward stepwise logistic regression and nomogram. Based on factors selected by logistic regression, a one-to-one propensity score matching (PSM) was conducted to compare progression-free survival (PFS) between patients who were present or absent of early TACE refractoriness. PFS curve was estimated by Kaplan-Meier method and compared by log-rank test. Results: Logistic regression revealed that bilobar tumor distribution (p = 0.002), more than three tumors (p = 0.005) and beyond up-to-seven criteria (p = 0.001) were significantly related to early TACE refractoriness. The discriminative abilities, as determined by the area under the receiver operating characteristic (ROC) curve, were 0.788 in the training cohort and 0.706 in the validation cohort. After PSM, the result showed that patients who were absent of early TACE refractoriness had a significantly higher PFS rate than those of patients who were present (p < 0.001). Conclusion: This study presents a predictive model with moderate accuracy to identify patients with high risk of early TACE refractoriness, and patients with early TACE refractoriness may have a poor prognosis.

Development of a computed tomography-based radiomics nomogram for prediction of transarterial chemoembolization refractoriness in hepatocellular carcinoma

BACKGROUNDSome patients with hepatocellular carcinoma (HCC) are more likely to experience disease progression despite continuous transarterial chemoembolization (TACE), which is called TACE refractoriness. At present, it is still difficult to predict TACE refractoriness, although some models/scoring systems have been developed. At present, radiological-based radiomics models have been successfully applied to predict cancer patient prognosis.AIMTo develop and validate a computed tomography (CT)-based radiomics nomogram for the pre-treatment prediction of TACE refractoriness.METHODSThis retrospective study consisted of a training dataset (n = 137) and an external validation dataset (n = 81) of patients with clinically/pathologically confirmed HCC who underwent repeated TACE from March 2009 to March 2016. Radiomics features were retrospectively extracted from preoperative CT images of the arterial phase. The pre-treatment radiomics signature was generated using least absolute shrinkage and selection operator Cox regression analysis. A CT-based radiomics nomogram incorporating clinical risk factors and the radiomics signature was built and verified by calibration curve and decision curve analyses. The usefulness of the CT-based radiomics nomogram was assessed by Kaplan-Meier curve analysis. We used the concordance index to conduct head-to-head comparisons of the radiomics nomogram with the other four models (Assessment for Retreatment with Transarterial Chemoembolization score; α-fetoprotein, Barcelona Clinic Liver Cancer, Child-Pugh, and Response score; CT-based radiomics signature; and clinical model). All analyses were conducted according to the transparent reporting of a multivariable prediction model for individual prognosis or diagnosis statement.RESULTSThe median duration of follow-up was 61.3 mo (interquartile range, 25.5-69.3 mo) for the training cohort and 67.1 mo (interquartile range, 32.4-71.3 mo) for the validation cohort. The median number of TACE sessions was 4 (range, 3-7) in both cohorts. Eight radiomics features were chosen from 869 candidate features to build a radiomics signature. The CT-based radiomics nomogram included the radiomics score (hazard ratio = 3.9, 95% confidence interval: 3.1-8.8, P < 0.001) and four clinical factors and classified patients into high-risk (score > 3.5) and low-risk (score ≤ 3.5) groups with markedly different prognoses (overall survival: 12.3 mo vs 23.6 mo, P < 0.001). The accuracy of the nomogram was considerably higher than that of the other four models. The calibration curve and decision curve analyses verified the usefulness of the CT-based radiomics nomogram for clinical practice.CONCLUSIONThe newly constructed CT-based radiomics nomogram can be used for the pre-treatment prediction of TACE refractoriness, which may provide better guidance for decision making regarding further TACE treatment.

Prediction of transarterial chemoembolization refractoriness in patients with hepatocellular carcinoma using imaging features of gadoxetic acid-enhanced magnetic resonance imaging.

Repeated transarterial chemoembolization (TACE) can be associated with loss of its efficacy and subsequent tumor progression. To identify features of gadoxetic acid-enhanced magnetic resonance imaging (MRI) associated with TACE refractoriness and to develop a prediction model for estimating the risk of TACE refractoriness. Among 1025 patients with intermediate-stage hepatocellular carcinoma (HCC) who underwent TACE as a first-line treatment during 2010-2017, 427 patients who underwent preoperative gadoxetic acid-enhanced MRI were analyzed. According to the date of initial TACE, patients were divided into the development cohort (n = 211) and the test cohort (n = 216). TACE refractoriness was determined according to the Japan Society of Hepatology guidelines. Univariable and multivariable analyses were performed to investigate the association between clinical/MRI features and TACE refractoriness. The performance of the prediction model was internally and externally assessed using the C-index of discrimination and a Hosmer-Lemeshow goodness-of-fit test for calibration. By analyzing 427 patients, we constructed a prediction model with the following independent features associated with TACE refractoriness: maximum tumor size; tumor number; peritumoral hypointensity on hepatobiliary phase (HBP); and the presence of non-hypervascular hypointense nodule on HBP. This system enabled the prediction of TACE refractoriness in the development cohort (C-index, 0.796) and the test cohort (C-index, 0.738) with good discrimination and calibration abilities. The prediction model based on gadoxetic acid-enhanced MRI features in addition to the known predictors including tumor size and number can be used to estimate the risk of TACE refractoriness in patients with intermediate-stage HCC.

Recent Updates of Transarterial Chemoembolilzation in Hepatocellular Carcinoma.

Transarterial chemoembolization (TACE) is a standard treatment for intermediate-stage hepatocellular carcinoma (HCC). In this review, we summarize recent updates on the use of TACE for HCC. TACE can be performed using two techniques; conventional TACE (cTACE) and drug-eluting beads using TACE (DEB-TACE). The anti-tumor effect of the two has been reported to be similar; however, DEB-TACE carries a higher risk of hepatic artery and biliary injuries and a relatively lower risk of post-procedural pain than cTACE. TACE can be used for early stage HCC if other curative treatments are not feasible or as a neoadjuvant treatment before liver transplantation. TACE can also be considered for selected patients with limited portal vein thrombosis and preserved liver function. When deciding to repeat TACE, the ART (Assessment for Retreatment with TACE) score and ABCR (AFP, BCLC, Child-Pugh, and Response) score can guide the decision process, and TACE refractoriness needs to be considered. Studies on the combination therapy of TACE with other treatment modalities, such as local ablation, radiation therapy, or systemic therapy, have been actively conducted and are still ongoing. Recently, new prognostic models, including analysis of the neutrophil-lymphocyte ratio, radiomics, and deep learning, have been developed to help predict survival after TACE.