Treatment Option For Unresectable Hepatocellular Carcinoma Research Articles

Tislelizumab versus Sorafenib in First-Line Treatment of Unresectable Hepatocellular Carcinoma: Impact on Health-Related Quality of Life in RATIONALE-301 Study

Introduction: RATIONALE-301 (NCT03412773) was a global, phase 3 study comparing the efficacy and safety of tislelizumab with sorafenib as first-line (1L) treatment in adult patients with unresectable hepatocellular carcinoma (HCC) that met its primary endpoint of noninferiority in overall survival (OS). This analysis compared health-related quality-of-life (HRQOL) outcomes between the arms. Methods: Systemic therapy-naive adults with HCC were randomized 1:1 to receive tislelizumab (n = 342) or sorafenib (n = 332). HRQOL was assessed using EORTC QLQ-C30, QLQ-HCC18, and EQ-5D-5L. At cycles 4 and 6, a mixed model for repeated measures was performed using key-prespecified patient-reported outcome (PRO) endpoints of the QLQ-C30 and the QLQ-HCC18. Time to deterioration was analyzed with the Kaplan-Meier method using the PRO endpoints. Results: At cycles 4 and 6, patients in the tislelizumab arm had better HRQOL outcomes than the patients in the sorafenib arm per mean-change difference in GHS/QOL, QLQ-C30 physical functioning and fatigue, and QLQ-HCC18 symptom index; however, no differences for pain were observed. Patients in the tislelizumab arm had lower risk of deterioration in GHS/QOL (HR: 0.68; 95% CI: 0.49–0.94), QLQ-C30 physical functioning (HR: 0.45; 95% CI: 0.32–0.63) and fatigue (HR: 0.47; 95% CI: 0.36–0.61), QLQ-HCC18 symptom index (HR: 0.52; 95% CI: 0.34–0.81), and HCC-specific fatigue (HR: 0.59; 95% CI: 0.45–0.79). For pain, both arms had similar risk of deterioration (HR: 0.78; 95% CI: 0.56–1.09). At cycles 4 and 6, patients in the tislelizumab arm maintained in EQ-5D-5L visual analog scale, whereas scores decreased for the patients in the sorafenib arm. Conclusion: Patients with 1L HCC treated with tislelizumab had favorable HRQOL outcomes compared with patients treated with sorafenib, particularly in fatigue and physical functioning. These results, along with favorable safety profile, better response rate, and OS noninferiority, support tislelizumab as a potential 1L treatment option for unresectable HCC.

Atezolizumab Plus Bevacizumab Versus Lenvatinib for Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis.

Hepatocellular carcinoma (HCC) is often diagnosed in advanced stages. Following sorafenib, lenvatinib (LENV) has been approved as a first-line treatment option for unresectable HCC. In the past few years, at least 9 large-scale cohort studies have examined the efficacy and safety of LENV compared to atezolizumab plus bevacizumab (ATE/BEV) in unresectable HCC, but there is currently no direct meta-analysis conducted for a comprehensive consolidation. To provide the most updated meta-analysis of the clinical efficacy and safety of ATE/BEV versus LENV for patients with unresectable HCC. Our studies comparing the efficacy and safety of ATE/BEV and LENV in unresectable HCC were systematically searched in PubMed, Embase, and Web of Science from inception to February 2023. Outcomes measured were overall survival (OS), progression-free survival (PFS), mortality, complete response (CR), partial response (PR), objective response rate (ORR), disease control rate (DCR), progressive disease (PD), stable disease (SD), and adverse events (AEs). Seven eligible studies involving 4428 patients (1569 in the ATE/BEV group and 2859 in the LENV group) were included in the narrative synthesis. All baseline characteristics were similar between the 2 groups except for Child-Pugh class B. Ultimately, our meta-analysis showed that the LENV group had longer OS and PFS than the ATE/BEV group. Moreover, patients on LENV were more likely to achieve SD, whereas those on ATE/BEV were more likely to achieve PR.

Emphasis on targeted and immunotherapy for liver injury in hepatocellular carcinoma

Treatment with molecular targeted drugs and immune checkpoint inhibitors (ICIs) has become the first-line treatment options for unresectable HCC (hepatocellular carcinoma) and is also one of the anti-recurrence therapies of choice for patients at high risk of recurrence following radical treatment. First-line molecular targeted drugs combined with ICIs or dual-immune therapy significantly increase the median overall survival and objective response rate compared to single-targeted drugs. Targeted therapy and immunotherapy are suitable for HCC patients with Child-Pugh classes A~B. Liver damage caused by targeted drugs includes abnormal transaminases and bilirubin and, in severe cases, hypoproteinemia, ascites, and other occurrences. ICIs-associated immune-mediated hepatitis (IMH) mostly occurs within one to three sessions of treatment (4~12 weeks) and can be treated with glucocorticoids. However, immunosuppressants such as mycophenolate mofetil may be used as necessary.Targeted drugs and ICIs with different mechanisms of action can be selected based on the systemic condition and tumor treatment needs following the restoration of normal liver function.

The Role of TLR4 in the Immunotherapy of Hepatocellular Carcinoma: Can We Teach an Old Dog New Tricks?

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is a leading cause of cancer-related death worldwide. Immunotherapy has emerged as the mainstay treatment option for unresectable HCC. Toll-like receptor 4 (TLR4) plays a crucial role in the innate immune response by recognizing and responding primarily to bacterial lipopolysaccharides. In addition to its role in the innate immune system, TLR4 has also been implicated in adaptive immunity, including specific anti-tumor immune responses. In particular, the TLR4 signaling pathway seems to be involved in the regulation of several cancer hallmarks, such as the continuous activation of cellular pathways that promote cell division and growth, the inhibition of programmed cell death, the promotion of several invasion and metastatic mechanisms, epithelial-to-mesenchymal transition, angiogenesis, drug resistance, and epigenetic modifications. Emerging evidence further suggests that TLR4 signaling holds promise as a potential immunotherapeutic target in HCC. The aim of this review was to explore the multilayer aspects of the TLR4 signaling pathway, regarding its role in liver diseases and HCC, as well as its potential utilization as an immunotherapy target for HCC.

Retrospective Study of the Efficacy and Safety of Chemoembolization with Drug-Eluting Microspheres Combined with Intra-Arterial Infusion of Bevacizumab for Unresectable Hepatocellular Carcinoma.

PurposeTo evaluate the efficacy and safety of chemoembolization with drug-eluting microspheres (DEM-TACE) combined with intra-arterial infusion of bevacizumab in patients with unresectable hepatocellular carcinoma (uHCC) and to identify possible prognostic factors.Patients and MethodsBetween November 2014 and December 2020, 34 patients underwent DEM-TACE combined with intra-arterial infusion of bevacizumab for Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma (HCC) beyond the Up-to-seven criteria or BCLC stage C HCC. Patients with extrahepatic metastasis or inferior vena cava invasion were excluded. The primary endpoint was overall survival (OS). The secondary endpoints were safety (assessed using Common Terminology Criteria for Adverse Events v5.0), the response rate at 1 month, and the identification of prognostic factors. The median OS was calculated using the Kaplan–Meier method. The response rate was evaluated according to the modified Response Evaluation Criteria in Solid Tumors. Prognostic factors were investigated by univariate and multivariable analysis using the Cox proportional hazards model.ResultsThe median OS was 13 months. BCLC stage and presence of portal vein invasion were not significantly associated with OS. There were no grade ≥3 adverse events. The Child–Pugh class did not decline after treatment in 31 of 34 patients. The overall response rate was 14.2% and the disease control rate was 100%. Significant prognostic factors were alcoholic liver disease, Child–Pugh score of ≥8, and microsphere size of 50–100 μm.ConclusionDEM-TACE combined with intra-arterial infusion of bevacizumab is safe and effective, and it could be a treatment option for unresectable HCCs.

P-124 Patient preferences for unresectable hepatocellular carcinoma (HCC) treatments: Balancing overall survival and quality of life

Atezolizumab plus bevacizumab has become the new standard-of-care treatment option for unresectable HCC, replacing oral tyrosine kinase inhibitors (e.g., sorafenib, lenvatinib). As these treatments have varying benefit-risk profiles and routes of administration, we aimed to quantify patients’ benefit-risk preferences for attributes associated with various first-line systemic treatments for unresectable HCC and estimate the minimum acceptable additional months of overall survival (OS) patients would require in exchange for specific treatment-related adverse events. A cross-sectional, web-based discrete-choice experiment (DCE) survey was developed. The survey development was informed by qualitative interviews with patients, published literature and treatment guidelines, expert clinical opinion, and cognitive debriefing interviews. Respondents answered nine DCE questions. Each question offered a choice between two hypothetical treatment profiles created by an experimental design and defined by six attributes with varying levels: OS, number of months to maintain daily function, severity of palmar-plantar syndrome, severity of hypertension, risk of bleeding in the digestive tract, and mode and frequency of administration. Data were analyzed using a random-parameters logit model, and results were used to calculate the minimum number of additional months of OS required to offset worse levels of adverse events. Between August 30, 2021, and October 14, 2021, patients with self-reported unresectable HCC in the United States (N = 200) completed the survey. Mean age was 59 years, 25.0% were White, 41.5% had at least a 4-year college degree, 33.5% reported less than $50,000 annual income, 93.0% were diagnosed less than 5 years ago, 23.0% reported needing help taking care of themselves, 85.5% were currently receiving treatment for their HCC, 51.5% of those currently receiving medicines by intravenous infusion, and 71.3% by oral pills. On average, patients regarded an additional 10 months of maintaining daily function without decline to be as important or more important than an additional 10 months of OS, indicating a willingness to trade off months of maintaining daily function for months of OS. Among the adverse events, respondents placed the most importance on avoiding moderate-to-severe palmar-plantar syndrome and hypertension, requiring an average of more than 10 additional months of OS to offset the increased burden of these two adverse events. Respondents placed the least importance on a 5-percentage-point reduction in the risk of bleeding in the digestive tract (from 2% to 7%), requiring only 1.6 (confidence interval, 0.04-3.17) additional months of OS to offset this change. Additionally, more convenient dosing (e.g., daily oral pill vs. IV infusion every 3 weeks) was less important to respondents than OS, maintenance of daily function, and avoiding severe instances of palmar-plantar syndrome or hypertension. Patients with unresectable HCC prioritized avoiding side effects that would severely impact their quality of life during treatment much more compared with mode and frequency of treatment administration and digestive tract bleeding risk. For patients with unresectable HCC, the ability to maintain quality of life and conduct daily activities is as important or more important than a treatment’s survival benefit.

Usefulness of a novel transarterial chemoinfusion plus external-beam radiation therapy for advanced hepatocellular carcinoma with tumor thrombi in the inferior vena cava and right atrium: Case study.

BackgroundInvasion beyond inferior vena cava (IVC) to right atrium (RA) is a rare complication in patients with advanced hepatocellular carcinoma (HCC), and results in fatal oncologic emergencies, including pulmonary embolism and right heart failure.AimAs there is no gold standard treatment for unresectable HCC with tumor thrombi involving IVC and RA, we considered it valuable to assess safety and efficacy of a combination of hepatic arterial infusion chemoembolization (HAIC) therapy and external‐beam radiation therapy (EBRT).Methods and resultsThe “New FP” was chosen as the HAIC therapy, in which the enhanced permeation and retention effect was achieved using a cisplatin‐Lipiodol suspension combined with continuous infusion of 5‐fluorouracil (5‐FU). Sixteen patients with HCC with tumor thrombi in IVC, RA, and pulmonary arteries were enrolled. modified response evaluation criteria in solid tumors‐based evaluation of response to the combination treatment was as follows: complete response, 6.2% (1 patient); partial response, 81.3% (13 patients); stable disease, 12.5% (2 patients); progressive disease, 0%. The median overall survival time (MST) was 19.0 months. Notably, MST of patients receiving sequential sorafenib monotherapy (39.0 months) was significantly longer than that of the rest (15.3 months).ConclusionThe combination of New FP and EBRT is an efficacious treatment option for unresectable HCC involving IVC and RA, complicated with pulmonary embolism. Sequential administration of molecular‐targeted drugs may prolong survival in such patients.

A systematic literature review and network meta-analysis of first-line treatments for unresectable hepatocellular carcinoma based on data from randomized controlled trials

ABSTRACT Background Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer. First-line treatment options for unresectable HCC include sorafenib, lenvatinib, selective internal radiation therapy (SIRT), and transarterial chemoembolization (TACE). The present study reviewed randomized controlled trials (RCTs) of first-line therapies for unresectable HCC in TACE-ineligible patients. Research design and methods A systematic literature review (SLR) was conducted to identify RCTs of first-line treatments for TACE-ineligible patients with unresectable HCC. Data on overall survival (OS) and progression-free survival were extracted and a contrast-based Bayesian network meta-analysis (NMA) was conducted using Markov Chain Monte Carlo techniques. Results The SLR identified three RCTs: two comparing Y-90 resin microspheres with sorafenib, and one comparing sorafenib with lenvatinib. No RCTs were identified comparing other SIRT technologies with any other approved first-line HCC therapies. The NMA showed no significant OS differences between Y-90 resin microspheres and sorafenib (hazard ratio [HR] 0.92, 95% credible interval [CrI]: 0.79–1.08) or lenvatinib (HR: 0.88, 95% CrI: 0.63–1.22). Conclusions An SLR and NMA showed no significant differences between sorafenib, lenvatinib, and Y-90 resin microspheres in treating unresectable HCC. RCT evidence was not available for any other SIRT technologies and an evaluation of their relative efficacy was therefore not possible.

Immunotherapy in hepatocellular carcinoma: evaluation and management of adverse events associated with atezolizumab plus bevacizumab.

In light of positive efficacy and safety findings from the IMbrave150 trial of atezolizumab plus bevacizumab, this novel combination has become the preferred first-line standard of care for patients with unresectable hepatocellular carcinoma (HCC). Several additional trials are ongoing that combine an immune checkpoint inhibitor with another agent such as a multiple kinase inhibitor or antiangiogenic agent. Therefore, the range of first-line treatment options for unresectable HCC is likely to increase, and healthcare providers need succinct information about the use of such combinations, including their efficacy and key aspects of their safety profiles. Here, we review efficacy and safety data on combination immunotherapies and offer guidance on monitoring and managing adverse events, especially those associated with atezolizumab plus bevacizumab. Because of their underlying liver disease and high likelihood of portal hypertension, patients with unresectable HCC are at particular risk of gastrointestinal bleeding, and this risk may be exacerbated by treatments that include antiangiogenic agents. Healthcare providers also need to be alert to the risks of proteinuria and hypertension, colitis, hepatitis, and reactivation of hepatitis B or C virus infection. They should also be aware of the possibility of rarer but potentially life-threatening adverse events such as pneumonitis and cardiovascular events. Awareness of the risks associated with these therapies and knowledge of adverse event monitoring and management will become increasingly important as the therapeutic range broadens in unresectable HCC.

Treatment options for unresectable HCC with a focus on SIRT with Yttrium-90 resin microspheres.

To identify relevant publications, the PubMed database was queried using one or more of the following search terms alone or in combination with Boolean operators: epidemiology, hepatocellular, hepatocellular cancer, hepatocellular carcinoma, unresectable, radioembolisation, selective internal radiation therapy, SIR-Spheres, yttrium 90, TACE, and sorafenib. The results were sorted or filtered by "Author", "Publication dates" or "Article types" to identify articles relevant to each section of the review. To ensure that information on ongoing clinical trials involving Y-90 resin was included, we conducted a search on "ClinicalTrials.gov", by combining the search terms "HCC" OR "hepatocellular carcinoma" with "Y 90" OR "yttrium 90" OR "radioembo", and screened for studies that involved treatment with Y-90 resin microspheres.

Comparison of transarterial chemo-embolization (TACE) and transarterial radio-embolization (TARE) for the treatment of hepatocellular carcinoma: A systematic review and meta-analysis

Introduction: Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Despite surgery represents the best treatment option, a significant part of malignancies are diagnosed at advanced tumor stage or with a poor liver function. Transhepatic Arterial Chemembolization (TACE) and Transhepatic Arterial Radioembolization (TARE) represent two therapeutic option for unresectable HCC. Aim of this systematic review is to compare the effectiveness of these treatments in patients with unresectable HCC. Methods: Medical databases were searched for potentially relevant publications. Overall survival rate, time to progression, 1-year survival rate, tumor response and complications rate were compared and analysed. Results: Eight studies were included in our systematic review for a total of 1030 and 401 patients treated with TACE and TARE respectively. The data showed a not statistically significant difference in survival and a statistically significant lower incidence in adverse events for TARE. The response analysis was affected by a significant response evaluation methods heterogeneity which substantially reduced our analysis power. Conclusion: Both procedures were useful as treatment options for unresectable HCC, showing a greater tolerability for TARE. However we believe that further studies, with a prospective design and a more comprehensive patients classification, could show more differences in selected patients.

Comparative Study of Living and Deceased Donor Liver Transplantation as a Treatment for Hepatocellular Carcinoma

Living donor liver transplantation (LDLT) is an important treatment option for unresectable hepatocellular carcinoma (HCC), but whether recurrence and survival in LDLT differ from those in deceased donor liver transplantation (DDLT) remains controversial. A retrospective analysis was performed between patients with HCC who underwent LDLT in a Japanese institute (n= 133) and those who underwent DDLT in a United States institute (n= 362). Although there was a difference in patient background characteristics (eg, body mass index, donor age, Model for End-Stage Liver Disease [MELD] score), tumor aggressiveness represented by Milan criteria and microscopic vascular invasion were comparable between the 2 groups. The cumulative 5-year recurrence rates of the LDLT group and the DDLT group were similar (14.8% vs 19.0%, p= 0.638), but overall survival in the LDLT group was significantly better than that in the DDLT group (84.2% vs 63.5%, p < 0.0001). Separate multivariate analysis identified different preoperative predictive factors for HCC recurrence (salvage transplantation and Des-gamma-carboxy prothrombin >300 in the LDLT group, beyond Milan criteria in the DDLT group). Combined multivariate analysis of the 2 groups identified recipient's body mass image >30 kg/m(2) as an independent risk factor for overall survival; the technique of transplantation (LDLT or DDLT) was not found to be a risk factor. When compared between the institutes where LDLT or DDLT were the first treatment choices for unresectable HCC, recurrence rates were comparable. Living donor liver trasplantation is a viable treatment option for unresectable HCC, providing recurrence rates similar to those achieved with DDLT.

Health-related quality of life in unresectable hepatocellular carcinoma (HCC) in patients treated with TACE or 90-Yttrium

8149 Background: Nonsurgical treatment options for unresectable HCC are limited and have modest survival benefits. As a result, health related quality of life (HRQL) has become essential when testing new therapies. The aims of the present study were to test differences in HRQL in HCC patients (pts) treated with 90-Yttrium or transarterial chemoembolization (TACE). Methods: In this prospective, nonrandomized study, 127 pts with biopsy-proven, unresectable HCC, and a prognosis greater than 3 months (mos), were recruited for participation. 79 pts were treated with TACE and 48 pts with 90-Yttrium. HRQL was assessed using the Functional Assessment of Cancer Therapy-Hepatobiliary at diagnosis, 3-, 6-, and 12 mos or until death. Survival was measured in months from diagnosis till death. Results: Using Analyses of Variance (ANOVA), pts referred for treatment with TACE had significantly larger mean tumor size, vascular invasion, and higher bilirubin, WBC, GGTP, and PT at baseline. Using repeated measures Analysis of Covariance (ANCOVA), covarying for significant differences in disease-specific variables at diagnosis, pts treated with 90-Yttrium reported a better functional well-being [F(1,40)=5.7, p=0.02] and overall quality of life [F(1,38)=4.6, p=0.04] at 3-mos follow-up. Pts in both treatment groups reported significant improvement in emotional well-being at 3-mos follow-up [F(1,20)=5.4, p=0.03]. No significant differences in HRQL were observed at 6- or 12-mos follow-up. Conclusions: Treatment of unresectable HCC with Yttrium-90 resulted in better functional well-being and overall HRQL at 3-mos follow-up compared to pts treated with TACE, while covarying for disease-specific differences at diagnosis. It is likely that no differences in HRQL were observed at 6- and 12-months follow-up secondary the high rates of death in pts treated with TACE, compared to 90-Yttrium, at 6-mos (60% vs 40%) and 12-mos (85% vs 65%) and as a result, high levels of attrition in assessment of HRQL were observed due to severe illness and death at 6-mos (N=10 vs 16) and 12-mos follow-up (N=2 vs 7). A randomized control trial assessing HRQL and survival benefits of 90-Yttrium is warranted. No significant financial relationships to disclose.