Intermediate-stage Hepatocellular Carcinoma Research Articles

Surgical Resection plus Intraoperative Radiofrequency Ablation versus Chemoembolization for the Treatment of Intermediate-Stage (BCLC B) Hepatocellular Carcinoma with Preserved Liver Function: A Propensity Score-Matched Analysis.

Simple SummarySurgical resection plus intraoperative radiofrequency ablation showed better survival outcomes than transarterial chemoembolization in selected patients with intermediate-stage hepatocellular carcinoma and Child–Pugh class A liver function. These findings suggest that surgical resection plus intraoperative radiofrequency ablation may provide an opportunity for curative treatment to selected patients deemed eligible only for palliative treatment.The purpose of this study was to compare the efficacy and safety of surgical resection (SR) plus intraoperative radiofrequency ablation (IORFA) with transarterial chemoembolization (TACE) in patients with intermediate-stage HCC and Child–Pugh class A liver function. Treatment-naïve patients who received SR plus IORFA (n = 104) or TACE (n = 513) were retrospectively evaluated. Patients were subjected to a maximum 1:3 propensity score matching (PSM), yielding 95 patients who underwent SR plus IORFA and 252 who underwent TACE. Evaluation of the entire study population showed that progression-free survival (PFS) and overall survival (OS) were significantly better in the SR plus IORFA than in the TACE group. After PSM, the median PFS (18.4 vs. 15.3 months) and OS (88.6 vs. 56.2 months) were significantly longer, and OS rate significantly higher (HR: 0.65, p = 0.026), in the SR plus IORFA group than in the TACE group. Stratified Cox regression analysis and doubly robust estimation revealed that treatment type was significantly associated with both OS and PFS. Rates of major complications were similar in the SR plus IORFA and TACE groups. In conclusion, SR plus IORFA showed better survival outcomes than TACE. SR plus IORFA may provide curative treatment to patients with intermediate-stage HCC with ≤4 tumors and Child–Pugh class A.

Prediction of hepatocellular carcinoma response to transarterial chemoembolization with intravoxel incoherent motion diffusion-weighted imaging

BackgroundThere are several therapeutic options for hepatocellular carcinoma (HCC). As predicting the treatment response is critical in clinical decision making, we aimed to evaluate the quantitative intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) parameters as potential predictors of treatment response of HCC lesions to transarterial chemoembolization (TACE).ResultsTwelve patients (eight males; mean age, 56.12 ± 7.88) with 26 confirmed HCC lesions were recruited in the study. Thirteen lesions (50%) responded to TACE, and the remaining lesions were categorized as nonresponder. Age > 60 year (p value: 0.018), D (p value: 0.005), D* (p value: 0.005), and f (p value: 0.004) values were significantly different in response and nonresponse group lesions. Logistic multivariate analysis showed that f value (OR: 0.847 (95% CI 0.732–0.98), p value = 0.025) could independently predict tumor response to TACE. The ROC curve analysis showed f value could predict the HCC response to TACE with sensitivity and specificity of 76.9% and 76.9%, respectively.ConclusionsIVIM-DWI parameters, especially the f value, might be useful for predicting the response of the intermediate-stage HCC to TACE.

Real-time automatic prediction of treatment response to transcatheter arterial chemoembolization in patients with hepatocellular carcinoma using deep learning based on digital subtraction angiography videos

BackgroundTranscatheter arterial chemoembolization (TACE) is the mainstay of therapy for intermediate-stage hepatocellular carcinoma (HCC); yet its efficacy varies between patients with the same tumor stage. Accurate prediction of TACE response remains a major concern to avoid overtreatment. Thus, we aimed to develop and validate an artificial intelligence system for real-time automatic prediction of TACE response in HCC patients based on digital subtraction angiography (DSA) videos via a deep learning approach.MethodsThis retrospective cohort study included a total of 605 patients with intermediate-stage HCC who received TACE as their initial therapy. A fully automated framework (i.e., DSA-Net) contained a U-net model for automatic tumor segmentation (Model 1) and a ResNet model for the prediction of treatment response to the first TACE (Model 2). The two models were trained in 360 patients, internally validated in 124 patients, and externally validated in 121 patients. Dice coefficient and receiver operating characteristic curves were used to evaluate the performance of Models 1 and 2, respectively.ResultsModel 1 yielded a Dice coefficient of 0.75 (95% confidence interval [CI]: 0.73–0.78) and 0.73 (95% CI: 0.71–0.75) for the internal validation and external validation cohorts, respectively. Integrating the DSA videos, segmentation results, and clinical variables (mainly demographics and liver function parameters), Model 2 predicted treatment response to first TACE with an accuracy of 78.2% (95%CI: 74.2–82.3), sensitivity of 77.6% (95%CI: 70.7–84.0), and specificity of 78.7% (95%CI: 72.9–84.1) for the internal validation cohort, and accuracy of 75.1% (95% CI: 73.1–81.7), sensitivity of 50.5% (95%CI: 40.0–61.5), and specificity of 83.5% (95%CI: 79.2–87.7) for the external validation cohort. Kaplan-Meier curves showed a significant difference in progression-free survival between the responders and non-responders divided by Model 2 (p = 0.002).ConclusionsOur multi-task deep learning framework provided a real-time effective approach for decoding DSA videos and can offer clinical-decision support for TACE treatment in intermediate-stage HCC patients in real-world settings.

A prospective observational cohort study of lenvatinib as initial treatment in patients with BCLC-defined stage B hepatocellular carcinoma

BackgroundTransarterial chemoembolization (TACE) is the standard treatment for intermediate stage hepatocellular carcinoma (HCC) (Barcelona Clinic Liver Cancer [BCLC] B). However, it often leads to a poor prognosis and decreased hepatic function especially in patients with BCLC substage B2. Lenvatinib (LEN) was demonstrated to be efficacious in these patients in the REFLECT phase 3 trial. We therefore aimed to evaluate the efficacy and safety of LEN as a first-line treatment for the patients with HCC at BCLC substage B2.MethodsThis prospective observational study used LEN in TACE-naïve patients with HCC at BCLC substage B2 and preserved hepatic function. The primary endpoint was overall survival. A one-year survival rate threshold of 60% and an expected survival rate of 78%, based on previous reports of TACE, was assumed for setting the sample size. With a one-sided α-type error of 5% and 70% detection power, 25 patients were required over a 2-year enrollment period and 10-month follow-up period.ResultsThirty-one patients were enrolled in this study from June 2018 to June 2020. The 1-year survival rate was 71.0% (90% confidence interval, 68.4–73.6%). Median overall and progression-free survival periods were 17.0 and 10.4 months, and the objective response rates according to Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1 and modified RECIST criteria were 22.6% and 70.0%, respectively. Common adverse events (AEs) were fatigue (68%), hypertension (65%), anorexia (61%), palmar-plantar erythrodysesthesia (39%), and thrombocytopenia (32%) of any grade; aspartate aminotransferase increased (23%), alanine aminotransferase increased (16%), and grade ≥ 3 proteinuria (13%). Treatment interruption and dose reduction were required in 61% and 81% of patients, respectively. LEN was discontinued in 29 patients due to disease progression (n = 17), AEs (n = 9), conversion to curative treatments (n = 2), and sudden death (n = 1), whereas post-LEN treatments were administered in 18 patients, including systemic chemotherapy (n = 11), TACE (n = 6), transarterial infusion (n = 1) and clinical trial (n = 1).ConclusionsThe results suggest that LEN provides treatment benefits as an initial therapeutic in patients with BCLC substage B2 HCC with a safety profile comparable to that previously reported.

Combination Therapy With Lenvatinib and Radiofrequency Ablation for Patients With Intermediate-Stage Hepatocellular Carcinoma Beyond Up-To-Seven Criteria and Child-Pugh Class A Liver function: A Pilot Study.

BackgroundThe present study aimed to evaluate the efficacy and safety of combined lenvatinib (first-line systemic therapy) and radiofrequency ablation (RFA) therapy in patients with intermediate-stage hepatocellular carcinoma with beyond up-to-seven criteria and Child–Pugh Class A liver function (CP A B2-HCC).MethodsTwenty-two patients with CP A B2-HCC were enrolled in the study. The patients had no history of systemic treatment. For the initial lenvatinib administration in this study, all of the patients had an adequate course of treatment (no less than two weeks) and were administered the recommended dose. Of them, 13 were treated by means of lenvatinib monotherapy (monotherapy group), while the 9 patients with no contraindication to RFA operation and who had consented to RFA received initial lenvatinib plus subsequent RFA (combination group). The clinical outcomes that were considered to evaluate the treatments included tumor response, prognosis (recurrence and survivals), and possible adverse events (serum liver enzymes and clinically visible complications).ResultsThe combination group exhibited a higher object response rate (9/9, 100%) as best tumor response than the monotherapy group (10/13, 76.9%). Longer progression-free survival (PFS) (12.5 months) and overall survival (OS) (21.3) were demonstrated in the combination group than in the monotherapy group (PFS: 5.5 months; OS:17.1 months). The combination group achieved a higher PFS rate (1-year: 74.1%) and OS rate (2-year: 80%) than the monotherapy group (1-year PFS rate: 0%; 2-year OS rate: 25.6%; for PFS, p<0.001; for OS, p=0.022). The treatment strategy was the independent factor for PFS (HR: 18.215 for monotherapy, p =0.010), which was determined by Cox regression analysis, suggesting that a combination strategy may reduce tumor progression when compared to the use of lenvatinib alone. There were no statistically significant intergroup differences that were observed in terms of adverse events, with the exception of ALT elevation (p=0.007) in the combination group.ConclusionOur newly proposed combination therapy may potentially be effective and safe for CP A B2-HCC beyond up-to-seven criteria. A larger scale, multicenter, prospective study is warranted to confirm our findings.

Why does survival of hepatocellular carcinoma patients remain so low? Key stumbling blocks and questions in preclinical and clinical development

ABSTRACT Introduction Hepatocellular carcinoma (HCC) is a complex disease, which involves diverse molecular pathways and etiologies. In recent years, several new systemic treatments have improved survival in advanced stage disease, but numerous significant challenges remain. No significant improvements have been achieved in the intermediate stage disease; this may be attributed to the difficulties in stratification of patients and the broad spectrum of clinical situations in terms of tumor burden and liver function. Areas covered This article considers the recent progress in first- and second-line therapy for advanced HCC. Investigational strategies conducted in intermediate stage HCC, which involve mainly combination therapy with locoregional approaches, and systemic drugs, antiangiogenics, immunotherapies (or both) are then examined. Later, the paper offers insights on the questions and challenges that lie ahead for treating HCC. Expert opinion Clinical and biomolecular markers for the stratification of patients are needed for therapeutic progress. Further molecular profiling data could enhance our knowledge of the molecular pathways underlying this tumor and facilitate the identification of targetable aberrations. This could offer opportunities for precision medicine approaches and improved survival.

Phase I Dose-Escalation Study of Tirapazamine Chemoembolization for Unresectable Early- and Intermediate-Stage Hepatocellular Carcinoma

PurposeTo investigate the safety of replacing doxorubicin with tirapazamine in conventional transarterial chemoembolization (TACE) in an Asian population with hepatocellular carcinoma (HCC), and to determine the optimal tirapazamine dose for phase II studies. Materials and MethodsThis was a phase I, 3 + 3 dose-escalation study for patients with unresectable early- and intermediate-stage HCC who received 5, 10, or 20 mg/m2 of intra-arterial (IA) tirapazamine followed by ethiodized oil/gelatin sponge-based embolization. Key eligibilities included HCCs no more than 10 cm in diameter, prior embolization allowed, Eastern Cooperative Oncology Group performance status of 0 or 1, Child-Pugh score of 5–7, and platelet count of ≥60,000 μL. Dose-limiting toxicity (DLT) was defined as any grade 3 nonhematological or grade 4 hematological toxicity, with the exception of transient elevation of aminotransferase levels after the procedure. ResultsSeventeen patients were enrolled, 59% of whom had progression from a prior HCC therapy and 35% of whom had progression or recurrence after TACE. All patients tolerated the tirapazamine TACE well without any DLT or serious adverse event. Using the modified Response Evaluation Criteria in Solid Tumors, the complete response (CR) rate was 47%, and the CR + partial response rate was 65%. The median duration of response was not reached. The median time to progression was 12.6 months (95% confidence interval, 5.1–not reached). The median overall survival was 29.3 months. The selected phase II dose was set at a fixed dose of 35 mg of IA tirapazamine. ConclusionsIA tirapazamine with transarterial embolization was well tolerated and showed promising efficacy signals in intermediate-stage HCC, justifying pursuit of a phase II study.

Effectiveness and safety of sorafenib 400 mg vs. 800 mg initial dose on survival in patients with advanced and intermediate stage hepatocellular carcinoma: A systematic review and meta-analysis

Effectiveness and safety of sorafenib 400 mg vs. 800 mg initial dose on survival in patients with advanced and intermediate stage hepatocellular carcinoma: A systematic review and meta-analysis

Recent Trends and In-Hospital Mortality of Transarterial Chemoembolization (TACE) in Germany: A Systematic Analysis of Hospital Discharge Data between 2010 and 2019.

Simple SummaryThe minimally invasive procedure of transarterial chemoembolization (TACE) represents a standard oncologic procedure for the treatment of intermediate-stage hepatocellular carcinoma, cholangiocarcinoma, and liver metastases. Up to now, comprehensive data on recent trends and post-interventional in-hospital mortality have been largely lacking. Therefore, the aim of our study was to provide a systematic overview of the different indications and embolization techniques, as well as to identify factors associated with increased in-hospital mortality. For this purpose, we retrospectively examined 49,595 individual cases in Germany, based on standardized hospital discharge data from the German Federal Statistical Office, over the period 2010 to 2019. As a result of our study, we were able to show a correlation of in-hospital mortality with the presence of various complications, the type of embolization used, and the annual case volume. Consequently, our study may help to reduce the mortality of this therapeutic procedure in the future.(1) Background: Transarterial chemoembolization (TACE) is a minimally invasive procedure, characterized by the selective occlusion of tumor-feeding hepatic arteries, via injection of an embolizing agent and an anticancer drug. It represents a standard of care for intermediate-stage hepatocellular carcinoma (HCC), and it is also increasingly performed in cholangiocarcinoma (CCA), as well as in liver metastases. Apart from the original method, based on intra-arterial infusion of a liquid drug followed by embolization, newer particle-based TACE procedures have been introduced recently. As yet, comprehensive data on current trends of TACE, as well as its in-hospital mortality in Germany, which could help to further improve outcome following TACE, are missing. (2) Methods: Based on standardized hospital discharge data, provided by the German Federal Statistical Office from 2010 to 2019, we aimed at systematically evaluating current clinical developments and in-hospital mortality related to TACE in Germany. (3) Results: A total of 49,595 individual cases undergoing TACE were identified within the observation period. The overall in-hospital mortality was 1.00% and significantly higher in females compared to males (1.12 vs. 0.93%; p < 0.001). We identified several post-interventional complications, such as liver failure (51.49%), sepsis (33.87%), renal failure (23.9%), and liver abscess (15.87%), which were associated with a significantly increased in-hospital mortality. Moreover, in-hospital mortality significantly differed between the underlying indications for TACE (HCC: 0.83%, liver metastases: 1.22%, and CCA: 1.40%), as well as between different embolization agents (liquid embolization: 0.80%, loaded microspheres: 0.92%, spherical particles: 1.54%, and non-spherical particles: 2.84%), for which we observed large geographic differences in their frequency of use. Finally, in-hospital mortality was significantly increased in centers with a low annual TACE case volume (<15 TACE/year: 2.08% vs. >275 TACE/year: 0.45%). (4) Conclusion: Our data provide a systematic overview of indications and embolization methods for TACE in Germany. We identified a variety of factors, such as post-interventional complications, the embolization method used, and the hospitals’ annual case volume, which are associated with an increased in-hospital mortality following TACE. These data might help to further reduce the mortality of this routinely performed local-ablative procedure in the future.

Trajectories of serum α-fetoprotein and intermediate-stage hepatocellular carcinoma outcomes after transarterial chemoembolization: A longitudinal, retrospective, multicentre, cohort study

SummaryBackgroundα-fetoprotein (AFP) response has been proven a key tumor marker for hepatocellular carcinoma (HCC), but its definition remains controversial. This study aims to characterize AFP trajectories after transarterial chemoembolization (TACE) and examine its impact on clinical outcomes.MethodsThis longitudinal, multicenter, retrospective, cohort study examined data from the electronic medical record system of four hospitals in China between January 1, 2007 to December 31, 2016. A latent class growth mixed model was applied to distinguish potential AFP dynamic changing trajectories. The multivariable Cox models were used to calculate adjusted hazard ratios (aHRs) and 95% CIs for overall survival. Inverse-probability-of-treatment weighted analyses were performed to eliminate unmeasured confounders through marginal structural models.FindingsA total of 881 patients, who had intermediate-stage HCC with AFP repeatedly measured 3 to 10 times, were included in the study. Three distinct trajectories were identified using the latent class growth mixture model: high-rising (25.7%; n = 226), low-stable (58.7%; n = 517), and sharp-falling (AFP serological response, 15.6%; n = 138). Compared with the low-stable class, the aHRs for death were 5.13 (3.71, 7.10) and 0.52 (0.33, 0.81) for the high-rising and sharp-falling class, adjusted by gender, baseline major tumor size, intrahepatic lesions number, and logAFP(smooth). Furthermore, high-rising class had a significantly higher HR in the subgroup of female patients (10.60, 95%CI: 6.29, 17.86), age<55 (6.78, 95%CI: 4.79, 9.59) and Child-Pugh class B (23.01, 95%CI:8.07, 65.63) (P = 0.014, 0.046 and 0.033 for interaction, respectively). Trajectories of AFP had the highest relative importance of each parameter to survival, including largest tumor size, intrahepatic lesions number, Child-Pugh class, and baseline AFP.InterpretationAFP trajectories were associated with overall survival for intermediate-stage HCC after TACE.FundingThe Natural Science Foundation of Fujian Province (Nos. 2018J01352, 2016J01576 and 2016J01586); the Science and Technology Innovation Joint Foundation of Fujian Province (Nos. 2017Y9125).

Phase I/II Multicenter Trial of a Novel Therapeutic Cancer Vaccine, HepaVac-101, for Hepatocellular Carcinoma

Abstract Purpose: Immunotherapy for hepatocellular carcinoma (HCC) shows considerable promise in improving clinical outcomes. HepaVac-101 represents a single-arm, first-in-human phase I/II multicenter cancer vaccine trial for HCC (NCT03203005). It combines multipeptide antigens (IMA970A) with the TLR7/8/RIG I agonist CV8102. IMA970A includes 5 HLA-A*24 and 7 HLA-A*02 as well as 4 HLA-DR restricted peptides selected after mass spectrometric identification in human HCC tissues or cell lines. CV8102 is an RNA-based immunostimulator inducing a balanced Th1/Th2 immune response. Patients and Methods: A total of 82 patients with very early- to intermediate-stage HCCs were enrolled and screened for suitable HLA haplotypes and 22 put on study treatment. This consisted in a single infusion of low-dose cyclophosphamide followed by nine intradermal coadministrations of IMA970A and CV8102. Only patients with no disease relapse after standard-of-care treatments were vaccinated. The primary endpoints of the HepaVac-101 clinical trial were safety, tolerability, and antigen-specific T-cell responses. Secondary or exploratory endpoints included additional immunologic parameters and survival endpoints. Results: The vaccination showed a good safety profile. Transient mild-to-moderate injection-site reactions were the most frequent IMA970A/CV8102-related side effects. Immune responses against ≥1 vaccinated HLA class I tumor-associated peptide (TAA) and ≥1 vaccinated HLA class II TAA were respectively induced in 37% and 53% of the vaccinees. Conclusions: Immunotherapy may provide a great improvement in treatment options for HCC. HepaVac-101 is a first-in-human clinical vaccine trial with multiple novel HLA class I– and class II–restricted TAAs against HCC. The results are initial evidence for the safety and immunogenicity of the vaccine. Further clinical evaluations are warranted.

Loco-regional treatment of hepatocellular carcinoma: Role of contrast-enhanced ultrasonography.

Hepatocellular carcinoma (HCC) is one of the few cancers for which locoregional treatments (LRTs) are included in international guidelines and are considered as a valid alternative to conventional surgery. According to Barcelona Clinic Liver Cancer classification, percutaneous treatments such as percutaneous ethanol injection, radiofrequency ablation and microwave ablation are the therapy of choice among curative treatments in patients categorized as very early and early stage, while transcatheter arterial chemoembolization is considered the better option for intermediate stage HCC. A precise assessment of treatment efficacy and surveillance is essential to optimize survival rate, whereas residual tumor requires additional treatment. Imaging modalities play a key role in this task. Currently, contrast-enhanced computed tomography/magnetic resonance imaging are considered the standard imaging modalities for this purpose. Contrast enhanced ultrasound (CEUS), using second generation contrast agents, plays an increasingly important role in detecting residual disease after LRTs. CEUS is a straightforward to perform, repeatable and cost-effective imaging modality for patients with renal failure or iodine allergies. Due to the ability to focus on single regions, CEUS can also provide high temporal resolution. Moreover, several studies have reported the same or better diagnostic accuracy as contrast-enhanced computed tomography for assessing tumor vascularity 1 mo after LRTs, and recently three-dimensional (3D)-CEUS has been reported as a promising technique to improve the evaluation of tumor response to therapy. Furthermore, CEUS could be used early after procedures in monitoring HCC treatments, but nowadays this indication is still debated, and data from literature are conflicting, especially after transcatheter arterial chemoembolization procedure.

Transarterial Chemoembolization Combined With Tyrosine Kinase Inhibitors for Intermediate-Stage Hepatocellular Carcinoma, What Else Can We Do?

Transarterial chemoembolization (TACE) has been considered the standard treatment for intermediate-stage hepatocellular carcinoma (HCC). However, intermediate‐stage HCC is highly heterogeneous with a broad population with varying tumour burdens, liver function. This suggests that TACE monotherapy treatment might not be suitable for all patients with intermediate‐stage HCC. The administration of tyrosine kinase inhibitors (TKIs) has become an important treatment option for improving the prognosis of patients with advanced HCC. Over the years, several trials have been conducted to explore the effects of TACE combined with TKIs for intermediate-stage HCC. However, the clinical efficacy is still controversial, and its potential clinical utility needs to be confirmed. This review will focus on the recent progress of TACE combined TKIs for intermediate-stage HCC.

Polyethylene Glycol Drug-Eluting Embolic Microspheres Loaded with Doxorubicin for the Treatment of Hepatocellular Carcinoma: Feasibility, Safety, and Pharmacokinetic Study

PurposePolyethylene glycol drug-eluting microspheres (PEG-DEMs) can be loaded to elute doxorubicin. The current study evaluated the pharmacokinetic profile and safety of PEG-DEMs in the treatment of patients with hepatocellular carcinoma (HCC). Materials and methodsThe current prospective, multicenter, dose-escalation study enrolled 25 patients (68% men) with early or intermediate stage HCC and a performance status of 0. Patients in Cohort I were assigned to receive target doxorubicin doses of 75, 100, or 150 mg. Analyses were performed on the basis of the specific dose of doxorubicin that the patients received because some patients received less than the assigned dose. Patients in Cohort II received the maximum safe tested dose. Adverse events were classified according to the Common Terminology Criteria for Adverse Events version 4.03. The tumor response was evaluated every 3 months according to the European Association for the Study of the Liver criteria and modified Response Evaluation Criteria in Solid Tumors. ResultsThe maximum tested safe dose of doxorubicin was 150 mg. For the groups that received ≤75, 75–100, and 101–150 mg of doxorubicin, the peak plasma concentrations were 286.7 ng/mL ± 220.1, 157.1 ng/mL ± 94.6, and 245.4 ng/mL ± 142.8, respectively; the areas under the curves calculated from 0 to 24 h were 421.7 (ng × h)/mL ± 221.2, 288.1 (ng × h)/mL ± 100.9, and 608.3 (ng × h)/mL ± 319.3, respectively, with almost complete clearance at 24 h. There was no death within 30 d. The best objective response rate was 81%, and the disease control rate was 91%. The median overall survival was 27.2 months (95% confidence interval [CI], 17.5 months to not evaluated [n.e.]); the median progression-free survival was 9.8 months (95% CI, 5.5 months to n.e.). ConclusionsPEG-DEMs demonstrated a favorable safety profile with low systemic concentration of doxorubicin, and promising efficacy.

Effects of Stereotactic Body Radiation Therapy Plus PD-1 Inhibitors for Patients With Transarterial Chemoembolization Refractory.

Background and AimsPatients with intermediate-stage hepatocellular carcinoma (HCC) who are refractory to transarterial chemoembolization (TACE) have a poor prognosis. This study aimed to explore whether stereotactic body radiation therapy (SBRT) combined with PD-1 inhibitors could improve the clinical outcomes of such patients.MethodsThis retrospective cohort study included patients with intermediate-stage HCC who were diagnosed with TACE refractoriness between January 2019 and December 2020 in the Eastern Hepatobiliary Surgery Hospital and the First Affiliated Hospital of Wenzhou Medical University. The patients were divided into two groups: (1) those who switched from TACE to receive stereotactic body radiotherapy (SBRT) combined with PD-1 inhibitors; (2) those who continued TACE treatment and added PD-1 inhibitors. Progression-free survival (PFS), overall survival (OS), and tumour response were assessed in both groups after becoming refractory to TACE treatment.ResultsOf the seventy-six patients included in this study, the median PFS was 19.6 months in the SBRT-IO group (n=31) and 10.1 months in the TACE-IO group (n=45, p<0.05). The SBRT-IO group also had a significantly higher OS than the TACE-IO group (p<0.05). The objective response rate (ORR) and disease control rate (DCR) were also better in the SBRT-IO group (ORR, 71.0% vs. 15.6%, OR=8.483, 95% CI 3.319-21.680, P < 0.001; DCR, 80.6% vs. 31.1%, OR=9.226, 95% CI 3.096-27.493, P < 0.001).ConclusionsSBRT combined with a PD-1 inhibitor improves PFS and OS in TACE-refractory patients with intermediate-stage HCC. Therefore, this therapy is a suitable option in cases of TACE treatment failure.

Combined radiofrequency ablation or microwave ablation with transarterial chemoembolization can increase efficiency in intermediate-stage hepatocellular carcinoma without more complication: a systematic review and meta-analysis

Objectives Radiofrequency ablation (RFA) and microwave ablation (MWA) are widely used in combination with transarterial chemoembolization (TACE) for intermediate-stage hepatocellular carcinoma (HCC) in clinical practice. We aim to compare the efficacy and safety of TACE combined with RFA or MWA versus TACE monotherapy for intermediate-stage HCC. Methods We searched PubMed, Embase, Web of Science, and the Cochrane Library for relevant studies. The outcomes included overall survival (OS), progression-free survival (PFS), local tumor control (LTC) rate, and major complication. Subgroup analysis for different TACE combination therapies was performed. Results Ten studies with 1799 patients with intermediate-stage HCC were included. The pooled hazard ratio (HR) for OS was in favor of TACE combination therapy (HR, 0.50, 95% confidence interval [CI], 0.40–0.62). Specifically, the TACE combination therapy was associated with higher 1-, 3-, and 5-year OS rates. Regarding tumor progression, the TACE combination therapy showed significantly better PFS (HR, 0.47, 95% CI, 0.37–0.61) and higher 1-, 2- and 3-year PFS rates than TACE monotherapy. The pooled odds ratio (OR) for the LTC was also in favor of TACE combination therapy (OR, 0.36, 95% CI, 0.24–0.53). No significant difference was found between the two groups regarding the major complication rate (OR, 1.26, 95% CI, 0.74–2.16). These results were consistent across subgroups of TACE + RFA versus TACE and TACE + MWA versus TACE. Conclusion TACE combined with RFA or MWA can provide significantly better OS, PFS and LTC than TACE monotherapy for patients with intermediate-stage HCC, without increasing the risk of major complications.

Transarterial Chemoembolization for Hepatocellular Carcinoma: Why, When, How?

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. It is principally associated with liver cirrhosis and chronic liver disease. The major risk factors for the development of HCC include viral infections (HBV, HCV), alcoholic liver disease (ALD,) and non-alcoholic fatty liver disease (NAFLD). The optimal treatment choice is dictated by multiple variables such as tumor burden, liver function, and patient’s health status. Surgical resection, transplantation, ablation, transarterial chemoembolization (TACE), and systemic therapy are potentially useful treatment strategies. TACE is considered the first-line treatment for patients with intermediate stage HCC. The purpose of this review was to assess the indications, the optimal treatment schedule, the technical factors associated with TACE, and the overall application of TACE as a personalized treatment for HCC.

Prognostic Value of Postoperative Circulating Tumor DNA in Patients With Early- and Intermediate-Stage Hepatocellular Carcinoma.

Majority of patients with resected early- and intermediate-stage liver cancer will experience postoperative recurrence. This study aimed to investigate the application of ctDNA sequencing in the postoperative period of hepatocellular carcinoma. A total of 96 patients with liver cancer were enrolled in this study. Postoperative peripheral blood samples were collected from all patients after surgery and analyzed using hybridization capture-based next-generation sequencing. Identification of at least one somatic mutation in the peripheral blood was defined as ctDNA+. Five genetic features in tumor tissues were associated with disease-free survival (DFS) using Lasso-Cox model. The area under the receiver operating characteristic curve was 0.813 and 0.882 in training and validation cohorts, respectively. The recurrence rate in ctDNA+ and ctDNA- groups was 60.9% and 27.8%, respectively. Multivariate Cox regression analysis showed that the postoperative ctDNA was an independent prognostic predictor of DFS (HR [hazard ratio]: 6.074, 95% Cl [confidence interval]: 2.648-13.929, P<0.001) and overall survival (OS) (HR: 4.829, 95% CI: 1.508-15.466, P=0.008). Combined ctDNA with AFP improved prediction performance. The median DFS was 2.0, and 8.0 months in ctDNA+/AFP-H and ctDNA+/AFP-L groups, respectively; while ctDNA-/AFP-H and ctDNA-/AFP-L groups had not reached the median time statistically (Log-rank test, P < 0.0001). Furthermore, ctDNA- patients had better prognosis than ctDNA+ patients irrespective of tumor stage. Postoperative ctDNA sequencing has great prognostic value in patients with liver cancer. Patients with positive ctDNA should receive more intensive disease monitoring and more aggressive treatment strategies to improve the survival time.

Randomized Phase 3 LEAP-012 Study: Transarterial Chemoembolization With or Without Lenvatinib Plus Pembrolizumab for Intermediate-Stage Hepatocellular Carcinoma Not Amenable to Curative Treatment

PurposeTransarterial chemoembolization (TACE) is the standard of care for patients with intermediate-stage hepatocellular carcinoma (HCC). Lenvatinib, a multikinase inhibitor, and pembrolizumab, a PD-1 inhibitor, have shown efficacy and tolerability in patients with HCC, and adding this combination to TACE may enhance clinical benefit.ProtocolLEAP-012 is a prospective, double-blind randomized phase 3 study. Adults with confirmed HCC localized to the liver without portal vein thrombosis and not amenable to curative treatment, ≥ 1 measurable tumor per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1), Eastern Cooperative Oncology Group performance status 0 or 1, Child–Pugh class A and no previous systemic treatment for HCC are eligible. Patients will be randomly assigned to lenvatinib once daily plus pembrolizumab every 6 weeks plus TACE or placebos plus TACE. Dual primary endpoints are overall survival and progression-free survival per RECIST 1.1 by blinded independent central review (BICR). Secondary endpoints are progression-free survival, objective response rate, disease control rate, duration of response and time to progression per modified RECIST by BICR; objective response rate, disease control rate, duration of response and time to progression per RECIST 1.1 by BICR; and safety.StatisticsThe planned sample size, 950 patients, was calculated to permit accumulation of sufficient overall survival events in 5 years to achieve 90% power for the overall survival primary endpoint.DiscussionLEAP-012 will evaluate the clinical benefit of adding lenvatinib plus pembrolizumab to TACE in patients with intermediate-stage HCC not amenable to curative treatment.ClinicalTrials.gov NCT04246177.

Efficacy and safety of anlotinib combined with TACE among patients with intermediate and advanced-stage hepatocellular carcinoma (HCC).

454 Background: Given that the onset of hepatocellular carcinoma (HCC) remained insidious, HCC was usually diagnosed of intermediate and advaned stage and surgical resection was not available. Currently, TACE was considered as the standard of care for patients with intermediate and advaned stage HCC, which yielded a complete tumor necrosis rate of 10%̃20% and a median overall survival of 16-20 months. Interestingly, studies had demonstrated that TACE could result in up-regulation of VEGF expression and tumor angiogenesis, thus contributing to tumor recurrence or distant metastasis to some extent. As a novel oral multi-target antiangiogenic TKI, anlotinib could inhibit both tumor angiogenesis and tumor cell proliferation simultaneously. Therefore, anlotinib combined with TACE might play a synergistic action for patients with HCC. Consequently,this retrospective study aimed to investigate the efficacy and safety of anlotinib combined with TACE for patients with intermediate and advaned stage HCC. Methods: This single-center retrospective study involved 75 HCC patients with intermediate and advaned stage BCLC staging B or C and ECOG PS ≤ 2. Enrolled pts was treated with TACE plus anlotinib (12 mg, qd, 2 weeks on 1 week off) until disease progression or unacceptable toxicity. The primary endpoint was overall survival (OS), while the secondary outcomes included safety, objective response rate (ORR), disease control rate (DCR) and progression free survival (PFS) and safety. Both PFS and tumor response were based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Results: By the cutoff date of August, 2021, the median PFS of the 75 pts was 8.0 months (95%CI, 6.3-9.7). The median OS was not yet reached and the 6-month OS rate was 97.3%. In best overall response assessment, there were 13.3% CR (10/75), 45.3% PR (34/75), 34.7% SD (26/75) and 6.7% PD (5/75). Confirmed ORR and DCR was 58.7% (95% CI: 46.7%-69.9%) and 93.3% (95% CI: 85.1%-97.8%) respectively according to mRECIST. Only 5.3% (4/75) of pts had grade 3 treatment-related adverse events (TRAEs). No grade ≥ 4 TRAEs were observed. And the most common TRAEs were hypertension (20%), hand-foot skin reaction (8%), anorexia (6.7%) and diarrhea (6.6%). Conclusions: It was indicated that anlotinib combined with TACE for patients with intermediate and advaned stage HCC demonstrated promising anti-tumor efficacy and a favorable safety profile. The conclusion should be validated in prospective clinical trials subsequently.