Unresectable Hepatocellular Carcinoma Research Articles

Options and survival benefits of conversion therapy for unresectable hepatocellular carcinoma

In the study by Wu et al , patients with unresectable hepatocellular carcinoma were subjected to transarterial chemoembolization (TACE) as a conversion therapy in order to render their tumors suitable for resection. A nomogram was devised and shown to be effective in predicting the survival of these patients. Generalization of the results, however, is questionable since the study subjects consisted of patients who had resection after TACE while excluding patients with the same disease but not suitable for TACE. Immunotherapy can be considered to be an option for conversion therapy. However, markers for determining responses to a conversion therapy and for guiding the decision between TACE and sequential immunotherapy have been lacking. The question of whether effective conversion therapy can truly enhance overall survival remains unanswered.

ASSESSEMENT IN PERFORMANCE OF LI-RADS ALGORITHM IN DETECTING TREATMENT RESPONSE OF HEPATOCELLULAR CARCINOMA AFTER TRANS-ARTERIAL CHEMOEMBOLIZATION

Background:Trans-arterial hemoembolization (TACE) usually indicated for unresectable hepatocellular carcinoma (HCC) on purpose as a bridging, downstaging or palliative treatment. Liver Imaging Reporting and Data Systems Treatment Response (LR-TR) was created to evaluate each lesion post-TACE, which has localized and is suitable for determining whether the tumor is still viable or Non-viable. Purpose: To assess the completion of LI-RADS version 2018 on computer tomography in the evaluation of HCC after TACE. Materials and Methods: A retrospective cross-sectional study involved 58 patients with hepatocellular carcinoma (HCC) who underwent treatment base TACE from June 2021 – September 2022. The clinical situation, AFP levels, and computer tomography (CT) of the patient after treatment were analyzed. The Radiologist evaluated pre- and post-treatment CT findings using LR-TR category, appropriately. The pooled sensitivity, specificity, and accuracy correclated between LR-TR with standard reference. Results: A total 58 patients with HCC (M/F: 13:1, mean age 56.9±11.0 years). For demonstrating the treatment response after first TACE on CT, Non-viable resulted in 32.8%(19/58), and LR-TR Viable was 67.2%(39/58), sensitivity value of 90% (36/40), specificity value of 83.3% (15/18), positive predictor value of 16.7% (3/18), a negative predictor value of 10% (4/40), accuracy value of 87.9% (51/58). The performance status response- AFP response- imaging response correlation was not statistically different, p= 0.552 and p=0.647. Conclusion: Using LR-TR on CT detects treatment response of HCC post-TACE was useful, and high sensitivity, specificity, and accuracy.

Dynamics of the neutrophil‑to‑lymphocyte ratio during lenvatinib treatment for unresectable hepatocellular carcinoma

Dynamics of the neutrophil‑to‑lymphocyte ratio during lenvatinib treatment for unresectable hepatocellular carcinoma

Efficacy and safety of targeted therapy plus immunotherapy combined with hepatic artery infusion chemotherapy (FOLFOX) for unresectable hepatocarcinoma

BACKGROUND The advent of cutting-edge systemic therapies has driven advances in the treatment of hepatocellular carcinoma (HCC), and therapeutic strategies with multiple modes of delivery have been shown to be more efficacious than monotherapy. However, the mechanisms underlying this innovative treatment modality have not been elucidated. AIM To evaluate the clinical efficacy of targeted therapy plus immunotherapy combined with hepatic arterial infusion chemotherapy (HAIC) of FOLFOX in patients with unresectable HCC. METHODS We enrolled 53 patients with unresectable HCC who received a combination of targeted therapy, immunotherapy, and HAIC of FOLFOX between December 2020 and June 2021 and assessed the efficacy and safety of the treatment regimen. RESULTS The objective response rate was 60.4% (32/53), complete response was 24.5% (13/53), partial response was 35.9% (19/53), and stable disease was 39.6% (21/53). The median duration of response and median progression-free survival were 9.1 and 13.9 months, respectively. The surgical conversion rate was 34.0% (18/53), and 1-year overall survival was 83.0% without critical complicating diseases or adverse events (AEs). CONCLUSION The regimen of HAIC of FOLFOX, targeted therapy, and immunotherapy was curative for patients with unresectable HCC, with no serious AEs and a high rate of surgical conversion.

Reply to the letter regarding ‘Impact of Bevacizumab Being Skipped due to Adverse Events of Special Interest for Bevacizumab in Patients with Unresectable Hepatocellular Carcinoma Treated with Atezolizumab plus Bevacizumab: An Exploratory Analysis of the Phase III IMbrave150 Study’

Reply to the letter regarding ‘Impact of Bevacizumab Being Skipped due to Adverse Events of Special Interest for Bevacizumab in Patients with Unresectable Hepatocellular Carcinoma Treated with Atezolizumab plus Bevacizumab: An Exploratory Analysis of the Phase III IMbrave150 Study’

Clinical outcomes of transarterial chemoembolization in Child-Turcotte Pugh class A patients with a single small (≤3cm) hepatocellular carcinoma.

Transarterial chemoembolization (TACE) is one of the standard modalities used to treat unresectable hepatocellular carcinoma (HCC), but the effectiveness of TACE for treating patients with a solitary small (≤3cm) HCC and well-preserved liver function has not been definitively established. This study aimed to determine the therapeutic impact of TACE in patients with these characteristics. This multicenter (four university hospitals) retrospective cohort study analyzed the medical records of 250 patients with a solitary small (≤3cm) HCC and Child-Turcotte-Pugh (CTP) class A liver function diagnosed over 10years. Posttreatment outcomes, including overall survival (OS), recurrence-free survival (RFS), and adverse events, were assessed following TACE therapy. One hundred and thirty-eight of the 250 patients (55.2%) treated with TACE achieved complete remission (CR). Overall median OS was 77.7months, and median OS was significantly longer in the CR group than in the non-CR group (89.1 vs. 58.8months, P=0.001). Median RFS was 19.1months in the CR group. Subgroup analysis identified hypertension, an elevated serum albumin level, and achieving CR as significant positive predictors of OS, whereas diabetes, hepatitis c virus infection, and tumor size (>2cm) were poor prognostic factors of OS. The study demonstrates the effectiveness of TACE as a viable alternative for treating solitary small (≤3cm) HCC in CTP class A patients.

Safety, efficacy, and survival of different transarterial chemoembolization techniques in the management of unresectable hepatocellular carcinoma: a comparative single-center analysis

PurposeTransarterial chemoembolization (TACE) has become the standard of care for the treatment of intermediate-stage hepatocellular carcinoma (HCC). However, current clinical practice guidelines lack consensus on the best selection of a specific TACE technique. This study aims to compare safety, tumor response, and progression-free survival (PFS) of conventional TACE (cTACE), drug-eluting bead TACE (DEB-TACE), and degradable starch microsphere TACE (DSM-TACE).MethodsThis retrospective study included n = 192 patients with HCC who underwent first TACE with unbiased follow-up at 4–6 weeks at our center between 2008 and 2021. Eligibility for TACE was BCLC intermediate stage B, bridging/down-staging (B/D) to liver transplantation (LT), or any other stage when patients were not suitable for resection, LT, local ablation, or systemic therapy. Patients were grouped into three cohorts (n = 45 cTACE, n = 84 DEB-TACE, n = 63 DSM-TACE), and further categorized by TACE indication (B/D or palliative). Liver function and adverse events, response assessed by the modified response evaluation criteria in solid tumors (mRECIST) 4–6 weeks post-TACE and PFS were analyzed.ResultsThere were no significant differences in age, gender distribution, BCLC stage, or etiology of liver disease among the three TACE groups, even in the B/D or palliative subgroups. DEB-TACE induced slight increases in bilirubin in the palliative subgroup and in lactate dehydrogenase in the entire cohort 4–6 weeks post-TACE, and more adverse events in the palliative subgroup. DEB-TACE and DSM-TACE showed significantly higher disease control rates (complete and partial response, stable disease) compared to cTACE, especially in the B/D setting (p < 0.05). There was no significant difference in PFS between the groups [median PFS (months): cTACE, 10.0 vs. DEB, 7.0 vs. DSM, 10.0; p = 0.436].ConclusionOur study provides valuable perspectives in the decision-making for a specific TACE technique: DEB-TACE and DSM-TACE showed improved tumor response. DEB-TACE showed a prolonged impact on liver function and more side effects, so patients with impaired liver function should be more strictly selected, especially in the palliative subgroup.

Efficacy and safety of transarterial chemoembolization combined with targeted therapy and immunotherapy versus with targeted monotherapy in unresectable hepatocellular carcinoma: A systematic review and meta-analysis.

The application of transarterial chemoembolization (TACE) in combination with targeted therapy and immunotherapy (TACE-T-I) for unresectable hepatocellular carcinoma (HCC) has gained increasing attention. However, there are variations in the efficacy and safety outcomes between TACE-T-I versus TACE combined with targeted drugs (TACE-T). This study aims to systematically evaluate the efficacy and safety of TACE-T-I versus TACE-T in unresectable HCC. PubMed, Embase, Cochrane Library, and Web of Science databases were searched from inception to August 21, 2023, for comparative studies on TACE-T-I versus TACE-T for unresectable HCC. Outcome measures included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) and the incidence of treatment-related adverse events (TRAEs). OS was the primary outcome of this study. Weighted mean difference (WMD) or hazard ratio (HR) was used as the pooled statistic for OS and PFS. Relative risk (RR) was employed as the pooled statistic for ORR, DCR and the incidence of TRAEs. And 95% confidence intervals (CIs) were calculated for all effect measures. Data analysis was conducted using Stata 14.0 software. The meta-analysis included 14 studies with 2144 patients. The pooled results showed that compared with patients in the TACE-T group, patients in the TACE-T-I group had higher ORR (RR = 1.61; 95%CI: 1.38-1.89) and DCR (RR = 1.17; 95%CI: 1.09-1.26). Patients in the TACE-T-I group experienced prolonged PFS (WMD = 3.08; 95%CI: 2.63-3.53) and OS (WMD = 5.76; 95%CI: 4.68-6.84). And the risk of disease progression (HR = 0.45; 95%CI: 0.37-0.55) and death (HR = 0.43; 95%CI: 0.38-0.49) was lower in the TACE-T-I group. Common TRAEs included fever, pain, abdominal pain, nausea, vomiting, elevated ALT, elevated AST, hypertension, hand-foot syndrome, proteinuria, and diarrhea. The incidence and severity of TRAEs in the TACE-T-I group were similar to those in the TACE-T group, with no significant differences (P > .05). Current evidence suggests that, on the basis of TACE combined with targeted therapy, the addition of immunotherapy provides better clinical efficacy and survival benefits for unresectable HCC patients, with good tolerability.

Usefulness of atezolizumab plus bevacizumab as second-line therapy for patients with unresectable hepatocellular carcinoma.

To clarify the efficacy of atezolizumab (ATZ) plus bevacizumab (BEV) as the second-line therapy for patients with unresectable hepatocellular carcinoma (HCC). The subjects were 82 patients with HCC receiving ATZ/BEV, including 33 patients with previous therapies with molecular-targeted agents (MTA). Therapeutic efficacy was evaluated using contrast-enhanced CT according to the mRECIST. The Child-Pugh scores were 5, 6,7 and 8 in 40, 35, 5 and 2 patients, respectively, and the extents of HCC progression were BCLC stage A, B and C in 3, 31 and 48 patients, respectively. Early therapeutic efficacy was evaluated in 67 patients, and percentages of patients achieving CR/PR/SD/PD until 12 weeks were 3.0%/29.9%/49.3%/17.9%, respectively, indicating ORR of 32.8% and DCR of 82.1%, The ORR was higher in MTA-naïve patients (40.5%) than in those after discontinuation of lenvatinib due to PD (7.7%, P = 0.0410), while the DCR was equivalent between both patients (83.3% vs 80.0%, P = 0.1184), and the multivariate analysis revealed previous MTA therapies with lenvatinib alone as a factor to deteriorate the ORR (HR of 4.846 (P = 0.0619)). The OS rates at 24 and 48 weeks were 86% and 72%, respectively, and the rates did not differ between MTA-naïve and MTA-experienced patients. Multivariate analyses revealed that achievement of CR, PR or SD and peripheral neutrophil/lymphocyte ratio were associated with a favorable outcome (HR of 0.124, P<0.0001 and 0.351, P = 0.0303). ATZ/BEV merits consideration even for MTA-experienced patients, since the OS was equivalent to those in MTA-naïve patients despite of an unfavorable early therapeutic efficacy.

Hepatic arterial infusion chemotherapy, lenvatinib plus programmed cell death protein-1 inhibitors: A promising treatment approach for high-burden hepatocellular carcinoma.

Hepatic arterial infusion chemotherapy (HAIC) has demonstrated remarkable local therapeutic efficacy in treating patients with large unresectable hepatocellular carcinoma (HCC). Additionally, the combination of lenvatinib and programmed cell death protein-1 (PD-1) inhibitors has demonstrated promising antitumor effects in unresectable HCC. Therefore, we conducted a retrospective analysis to evaluate the efficacy and safety of combining HAIC with lenvatinib and PD-1 inhibitors as a first-line therapeutic approach in high-burden HCC patients. We conducted a retrospective analysis on patients diagnosed with high-burden HCC who had major portal vein tumor thrombosis (Vp3 and Vp4) or tumor occupancy exceeding 50% of the liver. These patients received a first-line treatment consisting of HAIC with a combination of 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX), along with lenvatinib and PD-1 inhibitors between November 2020 and June 2023. The primary endpoints of this study included progression-free survival (PFS) and overall survival (OS), while the secondary endpoints were objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events (TRAEs). Ninety-one patients were enrolled in this study, with a median PFS of 8.8 months (95% confidence interval [CI]: 5.75-11.78) and a median OS of 14.3 months (95% CI: 11.23-17.31). According to RECIST 1.1 criteria, the ORR was 52.7%, and DCR was 95.6%. According to the mRECIST criteria, the ORR was 72.5%, and the DCR was 96.5%. Among all patients, 86 (94.5%) experienced TRAEs, and there were no instances of treatment-related deaths. The combination of HAIC-FOLFOX with lenvatinib and PD-1 inhibitors as a first-line therapy has exhibited notable therapeutic efficacy and well-tolerated adverse events among patients with high-burden HCC.

The Impact of Sequential Therapies after First-Line Systemic Therapies in Unresectable Hepatocellular Carcinoma.

Background: The therapeutic options for hepatocellular carcinoma (HCC) have greatly expanded recently, and current first-line therapies include sorafenib, lenvatinib, and atezolizumab-bevacizumab. The aim of this study was to investigate the therapeutic efficacy of sequential systemic treatments after progressing to the first-line agent in patients with unresectable HCC. Methods: Data were collected from subjects with HCC, BCLC stage B or C, who received first-line sorafenib, lenvatinib, or atezolizumab-bevacizumab from September 2020 to December 2022. The patients who progressed after first-line therapy were evaluated according to individual clinical status in order to decide whether or not to accept sequential therapy. The clinical baseline characteristics and overall survival (OS) of enrolled patients were collected and further analyzed. Results: Among the 127 enrolled patients, percentage of sequential therapy was 67.9%, 21.6%, and 37.5% in those with tumor progression after first-line sorafenib, lenvatinib, or atezolizumab-bevacizumab, respectively. Acceptance of sequential therapy (HR 0.46, p = 0.041) and presentation of ALBI grade I (HR 0.36, p = 0.002) had a significantly positive impact on OS. Pre-treatment ALBI grade had a significant impact on the decision to accept sequential therapy in patients with progressed HCC. Conclusions: The patients who were able to undergo sequential therapy had a better survival outcome compared to those who received only one agent, and the pre-treatment ALBI level might be regarded as a cornerstone tool to assess survival outcomes in patients undergoing treatment for HCC.

[A retrospective study of postoperative adjuvant therapy following immunotherapy combined with targeted therapy and sequential curative surgical procedures for initially unresectable hepatocellular carcinoma].

Objective: To report the clinical efficacy of adjuvant therapy based on pathological results following immunotherapy combined with targeted therapy and sequential curative surgical procedures in patients with initially unresectable hepatocellular carcinoma. Methods: This is a retrospective case series study. Data from 100 patients who underwent adjuvant therapy based on pathological results following immunotherapy combined with targeted therapy and sequential curative surgical procedures with long-term survival were collected from December 2018 to December 2022 at the Faculty of Hepato-Pancreato-Biliary Surgery, First Medical Center, Chinese People's Liberation Army General Hospital. According to inclusion and exclusion criteria, 47 cases were included, among which patients who met the discontinuation criteria and maintained a drug-free tumor-free status. Thirty-nine male and eight female patients were included, with an age of (54.2±18.8)years(range:38 to 73 years) at initial diagnosis. At the time of initial diagnosis, 43 cases (91.5%) were classified as Barcelona Clinic Liver Cancer(BCLC) stage C. Survival curves were made using Kaplan Meier method. Results: Forty-seven patients underwent R0 resection, all achieved a drug-free tumor-free state through postoperative adjuvant therapy based on pathological examination results. Thirty-six patients(76.6%) maintained a drug-free tumor-free survival status for more than 6 months,28 patients(59.6%) for more than 12 months,and 8 patients(17.0%) for more than 24 months. The longest drug-free tumor-free survival in this cohort reached 48 months. The median follow-up time in this study was 32 months. After diagnosis, the overall survival rates at 1- and 3- years were 97.7%(95%CI:93.4% to 100%) and 90.7%(95%CI:82.5% to 99.8%). The postoperative recurrence-free survival rates at 1- and 3- years were 91.0%(95%CI:83.0% to 99.8%) and 71.3%(95%CI:58.7% to 86.5%). Conclusions: The adjuvant therapy based on pathological results following immunotherapy combined with targeted therapy and sequential curative surgical approach provides long-term survival benefits for patients with initially unresectable hepatocellular carcinoma. Standardized adjuvant therapy maybe sustain long-term tumor-free status,and achieve drug-free tumor-free survival.

Higher objective responses by hepatic arterial infusion chemotherapy following atezolizumab and bevacizumab failure than when used as initial therapy in hepatocellular carcinoma: a retrospective study.

Atezolizumab/bevacizumab (atezo-bev) is the first-line chemotherapy for patients with unresectable hepatocellular carcinoma (HCC). However, hepatic artery infusion chemotherapy (HAIC) can be used as an alternative. Our aim was to compare the prognosis of HAIC treatment between newly diagnosed patients and patients treated after failure of atezo-bev. We retrospectively assessed 73 patients with HCC treated with HAIC between January 2022 and September 2023. Fifty-seven patients were treated with HAIC at initial diagnosis, while 16 were treated with HAIC after first-line atezo-bev combination chemotherapy. We evaluated tumor responses, such as overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). No significant difference was observed in either OS or PFS between patients with HCC treated with HAIC at the initial diagnosis and those treated after atezo-bev treatment failure. However, the ORR of the initial HAIC group was 19.6% and that of the HAIC group after atezo-bev therapy failure was 43.6%, which was a statistically significantly difference. Although no significant difference was observed for OS and PFS, the ORR of patients in the HAIC group after the failure of atezo-bev therapy was superior to that of newly diagnosed patients. HAIC may prolong survival in patients with HCC after atezo-bev treatment failure.

Current Roles of Ramucirumab in the Sequential Treatment of Unresectable Hepatocellular Carcinoma.

The treatment algorithm for systemic therapies for advanced hepatocellular carcinoma (HCC) has changed dramatically; however, the therapeutic landscape for sequential second-line or later-line treatments, including ramucirumab, remains controversial. This study aimed to investigate the role of ramucirumab for treating HCC. We retrospectively analyzed data from 17 patients with advanced HCC who received ramucirumab, and 8 of them who received lenvatinib re-administration after ramucirumab treatment failure. The median overall survival of 17 patients treated with ramucirumab was 11.5 months. The median ratios of the 1-month post-treatment α-fetoprotein (AFP) levels and albumin-bilirubin (ALBI) scores to the pre-treatment AFP levels and ALBI scores following ramucirumab treatment were 0.880 and 0.965, respectively. The median ratios of the 1-month post-treatment AFP and ALBI levels to the pre-treatment levels were 1.587 and 0.970 for mALBI grade 1/2a, and 1.313 and 0.936 for mALBI grade 2b/3, respectively. Six of the eight patients who received lenvatinib rechallenge treatment exhibited a decrease in AFP levels one month post-lenvatinib treatment. Deterioration of liver function 3 months post-lenvatinib treatment was noted in five of the eight patients who received lenvatinib rechallenge treatment after ramucirumab. Ramucirumab may be equally useful in patients with unresectable HCC who have poor liver function or whose liver function is aggravated by other therapies. Rechallenge treatment with lenvatinib after ramucirumab may be a valid treatment option for HCC.

Mitochondria-Derived Vesicles, Sterile Inflammation, and Pyroptosis in Liver Cancer: Partners in Crime or Innocent Bystanders?

Alterations in cellular signaling, chronic inflammation, and tissue remodeling contribute to hepatocellular carcinoma (HCC) development. The release of damage-associated molecular patterns (DAMPs) upon tissue injury and the ensuing sterile inflammation have also been attributed a role in HCC pathogenesis. Cargoes of extracellular vesicles (EVs) and/or EVs themselves have been listed among circulating DAMPs but only partially investigated in HCC. Mitochondria-derived vesicles (MDVs), a subpopulation of EVs, are another missing link in the comprehension of the molecular mechanisms underlying the onset and progression of HCC biology. EVs have been involved in HCC growth, dissemination, angiogenesis, and immunosurveillance escape. The contribution of MDVs to these processes is presently unclear. Pyroptosis triggers systemic inflammation through caspase-dependent apoptotic cell death and is implicated in tumor immunity. The analysis of this process, together with MDV characterization, may help capture the relationship among HCC development, mitochondrial quality control, and inflammation. The combination of immune checkpoint inhibitors (i.e., atezolizumab and bevacizumab) has been approved as a synergistic first-line systemic treatment for unresectable or advanced HCC. The lack of biomarkers that may allow prediction of treatment response and, therefore, patient selection, is a major unmet need. Herein, we overview the molecular mechanisms linking mitochondrial dysfunction, inflammation, and pyroptosis, and discuss how immunotherapy targets, at least partly, these routes.

Intestinal Microbiome Associated with Efficacy of Atezolizumab and Bevacizumab Therapy for Hepatocellular Carcinoma.

The combination of atezolizumab and bevacizumab has become the first-line treatment for patients with unresectable hepatocellular carcinoma (HCC). However, no studies have reported on specific intestinal microbiota associated with the efficacy of atezolizumab and bevacizumab. In this study, we analyzed fecal samples collected before treatment to investigate the relationship between the intestinal microbiome and the efficacy of atezolizumab and bevacizumab. A total of 37 patients with advanced HCC who were treated with atezolizumab and bevacizumab were enrolled. Fecal samples were collected from the patients, and they were divided into responder (n = 28) and non-responder (n = 9) groups. We compared the intestinal microbiota of the two groups and analyzed the intestinal bacteria associated with prognosis using QIIME2. The alpha and beta diversities were not significantly different between both groups, and the proportion of microbiota was similar. The relative abundance of Bacteroides stercoris and Parabacteroides merdae was higher in the responder group than in the non-responder group. When the prognosis was analyzed by the presence or absence of those bacteria, patients without both had a significantly poorer prognosis. Differences in intestinal microbiome are involved in the therapeutic effect of atezolizumab and bevacizumab.

Transarterial Chemoembolization Combined with Tyrosine Kinase Inhibitors Plus Immune Checkpoint Inhibitors Versus Tyrosine Kinase Inhibitors Plus Immune Checkpoint Inhibitors in Unresectable Hepatocellular Carcinoma with First- or Lower-Order Portal Vein Tumor Thrombosis.

To compare the efficacy of transarterial chemoembolization (TACE) combined with tyrosine kinase inhibitors (TKIs) plus immune checkpoint inhibitors (ICIs) (TACE-TKI-ICI) versus TKIs plus ICIs (TKI-ICI) for unresectable hepatocellular carcinoma (HCC) with first- or lower-order portal vein tumor thrombosis (PVTT). A retrospective study was performed in HCC patients with first- or lower-order PVTT receiving TKIs (Lenvatinib or sorafenib) plus ICIs (camrelizumab, sintilimab, or atezolizumab) with or without TACE from four institutions between January 2019 and January 2022. Propensity score-based method was performed to minimize bias by confounding factors. Tumor response, progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were evaluated and compared between the two groups. After inverse probability of treatment weighting, two balanced pseudopopulations were created: 106 patients in the TACE-TKI-ICI group and 109 patients in the TKI-ICI group. The objective response rate was higher in the TACE-TKI-ICI group (50.9% vs. 28.4%, P < 0.001). The median PFS and OS were significantly longer in the TACE-TKI-ICI group than in the TKI-ICI group (PFS: 9.1 vs. 5.0months, P = 0.005; OS: 19.1 vs. 12.7months, P = 0.002). In Cox regression, TACE-TKI-ICI treatment was an independent predictor of favorable OS. Treatment-related grade 3/4 AEs were comparable between the two groups (22.6% vs. 17.9%, P = 0.437). TACE-TKI-ICI therapy contributed to better tumor control, PFS and OS than TKI-ICI therapy in unresectable HCC patients with first- or lower-order PVTT.

Efficacy and safety of tislelizumab plus lenvatinib as first-line treatment in patients with unresectable hepatocellular carcinoma: a multicenter, single-arm, phase 2 trial

BackgroundLenvatinib is widely used in treatment of unresectable hepatocellular carcinoma (uHCC), but the benefit of its combination with immunotherapy needs to be verified. This study evaluated the efficacy and safety of tislelizumab plus lenvatinib in systemic treatment-naïve patients with uHCC.MethodsIn this multicenter, single-arm, phase 2 study, systemic treatment-naïve patients with uHCC received tislelizumab 200 mg every three weeks plus lenvatinib (bodyweight ≥ 60 kg: 12 mg; < 60 kg: 8 mg; once daily). Dose-limiting toxicities (DLTs) were evaluated in safety run-in phase to determine whether to enter the expansion phase. The primary endpoint was objective response rate (ORR) assessed by independent review committee (IRC) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1). Based on Simon’s two-stage design, > 6 responders were needed in stage 1 (n = 30) to continue the study, and ≥ 18 responders were needed by the end of stage 2 (n = 60) to demonstrate statistical superiority to a historical control of lenvatinib monotherapy.ResultsSixty-four patients were enrolled. No DLTs were reported. The study achieved statistical superiority (p = 0.0003) with 23 responders assessed by IRC per RECIST v1.1 in the first 60 patients of the efficacy evaluable analysis set (n = 62). After a median follow-up of 15.7 months, confirmed ORR and disease control rate were 38.7% (24/62, 95% confidence interval [CI], 26.6–51.9) and 90.3% (56/62, 95% CI, 80.1–96.4), respectively. Median progression-free survival was 8.2 months (95% CI, 6.8–not evaluable). Overall survival rate at 12 months was 88.6% (95% CI, 77.7–94.4). Grade ≥ 3 treatment-related adverse events occurred in 18 (28.1%) patients.ConclusionsTislelizumab plus lenvatinib demonstrated promising antitumor activity with favourable tolerability as first-line therapy for patients with uHCC.Trial registrationClinicalTrials.gov (NCT 04401800).

Effects of Short-Term Lenvatinib Administration Prior to Transarterial Chemoembolization for Hepatocellular Carcinoma.

Transarterial chemoembolization (TACE) combined with lenvatinib, employing a 4-day lenvatinib administration followed by TACE without an interval (short-term LEN-TACE), was performed for hepatocellular carcinoma (HCC). The aim was to assess tumor hemodynamics following the 4-day lenvatinib and to evaluate the treatment outcomes after the short-term LEN-TACE. 25 unresectable HCC patients received this combined therapy. Lenvatinib (4-12 mg) was administrated for 4 days prior to TACE. Perfusion CT scans were obtained before and after the lenvatinib administration. Either cTACE (76%) or DEB-TACE (24%) were performed. intra-tumor blood flow significantly decreased after the 4-day lenvatinib (p < 0.05). The TACE procedure was successful with no severe adverse events in all patients. The overall complete response (CR) rate was 75% (cTACE 84%, DEB-TACE 40%). The lipiodol-washout ratio between 1 week and 4 months after cTACE correlated with the arterial flow reduction ratio by lenvatinib prior to TACE (r = -0.55). The 12-month progression-free survival (PFS) rate was 75.0%. The short-term LEN-TACE is feasible and safe, demonstrating promising outcomes with a high CR ratio, contributing to lipiodol retention in the tumor after cTACE, and extended PFS. To confirm the advantages of this treatment protocol, a prospective clinical trial is mandatory.

Impact of iodinated oil in proton therapy on relative stopping power of liver post-cTACE

Objective. Conventional transarterial chemoembolization (cTACE) is a common treatment for hepatocellular carcinoma (HCC), often with unsatisfactory local controls. Combining cTACE with radiotherapy shows a promise for unresectable large HCC, with proton therapy preserving healthy liver tissue. However, the proton therapy benefits are subject to the accuracy of tissue relative stopping power (RSP) prediction. The RSP values are typically derived from computed tomography (CT) images using stoichiometric calibration. Lipiodol deposition significantly increases CT numbers in liver regions of post-cTACE. Hence, it is necessary to evaluate the accuracy of RSP in liver regions of post-cTACE. Approach. Liver, water, and iodinated oil samples were prepared. Some liver samples contained iodinated oil. The water equivalent path length (WEPL) of sample was measured through the pullbacks of spread-out Bragg peak (SOBP) depth-dose profiles scanned in a water tank with and without sample in the beam path. Measured RSP values were compared to estimated RSP values derived from the CT number based on the stoichiometric calibration method. Main results. The measured RSP of water was 0.991, confirming measurement system calibration. After removing the RSP contribution from container walls, the pure iodinated oil and liver samples had RSP values of 1.12 and 1.06, while the liver samples mixed with varying oil volumes (5 ml, 10 ml, 15 ml) showed RSP values of 1.05, 1.05 and 1.06. Using the stoichiometric calibration method, pure iodinated oil and liver samples had RSP values of 2.79 and 1.06. Liver samples mixed with iodinated oil (5 ml, 10 ml, 15 ml) had calculated RSP values of 1.21, 1.34, and 1.46. The RSP discrepancy reached 149.1% for pure iodinated oil. Significance. Iodinated oil notably raises CT numbers in liver tissue. However, there is almost no effect on its RSP value. Proton treatment of post-cTACE HCC patients can therefore be overshooting if no proper measures are taken against this specific effect.