Real Life Study of Lenvatinib Therapy for Hepatocellular Carcinoma: RELEVANT Study

Introduction: In the REFLECT trial, lenvatinib was found to be noninferior compared to sorafenib in terms of overall survival. Here, we analyze the effects of lenvatinib in the real-life experience of several centers across the world and identify clinical factors that could be significantly associated with survival outcomes. Methods: The study population was derived from retrospectively collected data of HCC patients treated with lenvatinib. The overall cohort included western and eastern populations from 23 center in five countries. Results: We included 1,325 patients with HCC and treated with lenvatinib in our analysis. Median OS was 16.1 months. Overall response rate was 38.5%. Multivariate analysis for OS highlighted that HBsAg positive, NLR >3, and AST >38 were independently associated with poor prognosis in all models. Conversely, NAFLD/NASH-related etiology was independently associated with good prognosis. Median progression-free survival was 6.3 months. Multivariate analysis for progression-free survival revealed that NAFLD/NASH, BCLC, NLR, and AST were independent prognostic factors for progression-free survival. A proportion of 75.2% of patients suffered from at least one adverse effect during the study period. Multivariate analysis exhibited the appearance of decreased appetite grade ≥2 versus grade 0-1 as an independent prognostic factor for worse progression-free survival. 924 patients of 1,325 progressed during lenvatinib (69.7%), and 827 of them had a follow-up over 2 months from the beginning of second-line treatment. From first-line therapy, the longest median OS was obtained with the sequence lenvatinib and immunotherapy (47.0 months), followed by TACE (24.7 months), ramucirumab (21.2 months), sorafenib (15.7 months), regorafenib (12.7 months), and best supportive care (10.8 months). Conclusions: Our study confirms in a large and global population of patients with advanced HCC, not candidates for locoregional treatment the OS reported in the registration study and a high response rate with lenvatinib

Assessment of Macrovascular Invasion in Advanced Hepatocellular Carcinoma: Clinical Implications and Treatment Outcomes with Systemic Therapy

Introduction: Macrovascular invasion (MVI) is a strong prognostic factor for advanced hepatocellular carcinoma (HCC). The current criteria for radiological assessment are unclear in evaluating the impact of MVI on systemic therapy. In this study, we standardized the assessment of MVI and validated its clinical relevance. Methods: Clinical data were collected from patients with advanced HCC and MVI who received first-line systemic therapy at four medical centers in Japan. First, we used macrovascular invasion progression disease (MVI-PD) to track MVI progression, and Response Evaluation Criteria in Solid Tumours version 1.1 progression disease (RECIST v1.1-PD) to evaluate tumor enlargement other than MVI and the appearance of new lesions. Next, we assessed the prognostic value of MVI-PD and RECIST v1.1-PD. Results: Of the 207 advanced HCC patients with MVI, 189 received appropriate imaging evaluation. 40 (21.2%) patients had MVI-PD and RECIST v1.1-PD, 51 (27.0%) had prior MVI-PD, and 61 (32.3%) had prior RECIST v1.1-PD. In a landmark analysis, the prognosis of 163 patients who survived more than three months was analyzed based on the assessment of imaging response during the first three months. The median overall survival (OS) was 5.4 months in those who had MVI-PD and RECIST v1.1-PD, 7.4 months in those who had RECIST v1.1-PD only, 7.2 months in those who had MVI-PD only, and 19.7 months in patients who had neither (p<0.001). The correlation coefficients between progression-free survival and OS in patients with appropriate imaging assessments were similar for MVI-PD (0.515) and RECIST v1.1-PD (0.498). Conclusion: Our findings demonstrate the link between MVI progression and poor OS in systemic therapy for advanced HCC, emphasizing the importance of an accurate method for assessing MVI progression

Sequential therapies after atezolizumab plus bevacizumab or lenvatinib first-line treatments in hepatocellular carcinoma patients

Introduction: The aim of this retrospective proof-of-concept study was to compare different second-line treatments for patients with hepatocellular carcinoma and progressive disease (PD) after first-line lenvatinib or atezolizumab plus bevacizumab.Materials and methods: A total of 1381 patients had PD at first-line therapy. 917 patients received lenvatinib as first-line treatment, and 464 patients atezolizumab plus bevacizumab as first-line.Results: 49.6% of PD patients received a second-line therapy without any statistical difference in overall survival (OS) between lenvatinib (20.6 months) and atezolizumab plus bev-acizumab first-line (15.7 months; p = 0.12; hazard ratio [HR] = 0.80). After lenvatinib first-line, there wasn't any statistical difference between second-line therapy subgroups (p = 0.27; sorafenib HR: 1; immunotherapy HR: 0.69; other therapies HR: 0.85). Patients who under-went trans-arterial chemo-embolization (TACE) had a significative longer OS than patients who received sorafenib (24.7 versus 15.8 months, p < 0.01; HR = 0.64). After atezolizumab plus bevacizumab first-line, there was a statistical difference between second-line therapy subgroups (p < 0.01; sorafenib HR: 1; lenvatinib HR: 0.50; cabozantinib HR: 1.29; other therapies HR: 0.54). Patients who received lenvatinib (17.0 months) and those who under-went TACE (15.9 months) had a significative longer OS than patients treated with sorafenib (14.2 months; respectively, p = 0.01; HR = 0.45, and p < 0.05; HR = 0.46).Conclusion: Approximately half of patients receiving first-line lenvatinib or atezolizumab plus bevacizumab access second-line treatment. Our data suggest that in patients progressed to atezolizumab plus bevacizumab, the systemic therapy able to achieve the longest survival is lenvatinib, while in patients progressed to lenvatinib, the systemic therapy able to achieve the longest survival is immunotherapy

Adverse Events as Potential Predictive Factors of Activity in Patients with Advanced HCC Treated with Atezolizumab Plus Bevacizumab

Background In the context of patients with hepatocellular carcinoma (HCC) treated with systemic therapy, the correlation between the appearance of adverse events (AEs) and reported efficacy outcomes is well-known and widely investigated. From other pathological settings, we are aware of the prognostic and predictive value of the occurrence of immune-related AEs in patients treated with immune-checkpoint inhibitors. Objective This retrospective multicenter real-world study aims to investigate the potential prognostic value of AEs in patients with HCC treated with atezolizumab plus bevacizumab in the first-line setting. Patients and methods The study population consisted of 823 patients from five countries (Italy, Germany, Portugal, Japan, and the Republic of Korea). Results Of the patients, 73.3% presented at least one AE during the study period. The most common AEs were proteinuria (29.6%), arterial hypertension (27.2%), and fatigue (26.0%). In all, 17.3% of the AEs were grade (G) 3. One death due to bleeding was reported. The multivariate analysis confirmed the appearance of decreased appetite G < 2 [versus G >= 2; hazard ratio (HR) 0.60; 95% confidence interval (CI) 0.13-0.90; p < 0.01] and immunotoxicity G < 2 (versus G >= 2; HR: 0.70; 95% CI 0.24-0.99; p = 0.04) as independent prognostic factors for overall survival, and the appearance of decreased appetite G < 2 (versus G >= 2; HR: 0.73; 95% CI 0.43-0.95; p = 0.01), diarrhea (yes versus no; HR: 0.57, 95% CI 0.38-0.85; p = 0.01), fatigue (yes versus no; HR: 0.82, 95% CI 0.65-0.95; p < 0.01), arterial hypertension G < 2 (versus G >= 2; HR: 0.68, 95% CI 0.52-0.87; p < 0.01), and proteinuria (yes versus no; HR: 0.79, 95% CI 0.64-0.98; p = 0.03) as independent prognostic factors for progression-free survival. Conclusions As demonstrated for other therapies, there is also a correlation between the occurrence of AEs and outcomes for patients with HCC for the combination of atezolizumab plus bevacizumab

Regional differences in clinical presentation and prognosis of patients with post-sustained virologic response (SVR) hepatocellular carcinoma.

Background& Amis: Widespread use of direct-acting antivirals (DAAs) for hepatitis C virus (HCV) infection has resulted in increased numbers of patients with hepatocellular carcinoma (HCC) after achieving sustained virologic response ('post-SVR HCC') worldwide. Few data compare regional differences in presentation and prognosis of patients with post-SVR HCC.MethodsWe identified patients with advanced fibrosis (F3/F4) who developed incident post-SVR HCC between March, 2015 and October, 2021 from 30 sites in Europe, North America, South America, Middle East, South Asia, East Asia, and Southeast Asia. We compared patient demographics, liver dysfunction, and tumor burden by region. We compared overall survival by region using Kaplan-Meier analysis and identified factors associated with survival using multivariable Cox regression analysis.ResultsAmong 8,796 patients with advanced fibrosis or cirrhosis who achieved SVR, 583 (6.6%) developed incident HCC. There was marked regional variation in the proportion of detection by surveillance (range: 59.5-100%), median maximum tumor diameter (range: 1.8-5.0 cm), and proportion with multinodular HCC (range: 15.4-60.8%). Prognosis of patients highly varied by region (HR range: 1.82-9.92), with the highest survival in East Asia, North America, and South America, and lowest in the Middle East and South Asia. After adjusting for geographic region, HCC surveillance was associated with early-stage detection (BCLC stage 0/A: 71.0% vs. 21.3%, pConclusionsClinical characteristics, including early-stage detection, and prognosis of post-SVR HCC significantly differed across geographic regions. Surveillance utilization appears to be a high-yield intervention target to improve prognosis among patients with post-SVR HCC globally

Utility of FIB4-T as a Prognostic Factor for Hepatocellular Carcinoma

Background: Most integrated scores for predicting the prognosis of patients with hepatocellular carcinoma (HCC) comprise tumor progression factors and liver function variables. The FIB4 index is an indicator of hepatic fibrosis calculated on the basis of age, aspartate aminotransferase (AST) levels, alanine aminotransferase (ALT) levels, and platelet count, but it does not include variables directly related to liver function. We propose a new staging system, referred to as “FIB4-T,” comprising the FIB4 index as well as tumor progression factors, and examine its usefulness. Method: Subjects included 3800 cases of HCC registered in multiple research centers. We defined grades 1, 2, and 3 as a Fibrosis-4 (FIB4) index of <3.25, 3.26–6.70, and >6.70 as FIB4, respectively, and calculated the FIB4-T in the same manner in which the JIS (Japan Integrated Staging Score) scores and albumin-bilirubin tumor node metastasis (ALBI-T) were calculated. We compared the prognostic prediction ability of FIB4-T with that of the JIS score and ALBI-T. Results: Mean observation period was 37 months. The 5-year survival rates (%) of JIS score (0/1/2/3/4/5), ALBI-T (0/1/2/3/4/5) and FIB4-T (0/1/2/3/4/5) were 74/60/36/16/0, 82/66/45/22/5/0 and 88/75/65/58/32/10, respectively. Comparisons of the Akaike information criteria among JIS scores, ALBI-T, and FIB4-T indicated that stratification using the FIB4-T system was comparable to those using ALBI-T and JIS score. The risk of mortality significantly increased (1.3–2.8 times/step) with an increase in FIB4-T, and clear stratification was possible regardless of the treatment. Conclusions: FIB4-T is useful in predicting the prognosis of patients with HCC from a new perspective

Attempt to establish prognostic predictive system for hepatocellular carcinoma using artificial intelligence for assistance with selection of treatment modality

Background/Aim: Because of recent developments in treatments for hepatocellular carcinoma (HCC), methods for determining suitable therapy for initial or recurrent HCC have become important. This study used artificial intelligence (AI) findings to establish a system for predicting prognosis of HCC patients at time of reoccurrence based on clinical data as a reference for selection of treatment modalities. Material/Methods: As a training cohort, 5701 observations obtained at the initial and each subsequent treatment for recurrence from 1985 HCC patients at a single center from 2000 to 2021 were used. The validation cohort was 5692 observations from patients at multiple centers obtained at the time of the initial treatment. An AI calculating system (PRAID) was constructed based on 25 clinical factors noted at each treatment from the training cohort, then predictive prognostic values for one- and three-year survival in both cohorts were evaluated. Results: After exclusion of patients lacking clinical data regarding albumin-bilirubin grade (ALBI) and/or tumor-node-metastasis stage (TNM), ALBI-TNM (ALBI-T) and modified ALBI-T scores confirmed that prognosis for patients in both cohorts was similar. The area under the curve (AUC) for prediction of both one- and three-year survival in the validation cohort were 0.841 [sensitivity 0.933 (95%CI 0.925-0.940), specificity 0.517 (95%CI 0.484-0.549)] and 0.796 [sensitivity 0.806 (95%CI 0.790-0.821), specificity 0.646 (95%CI 0.624-0.668)], respectively. Conclusion: The present PRAID system might provide useful prognostic information related to short and medium survival for decision making regarding best therapeutic modality for both initial and recurrent HCC cases

Treatment options for solitary hepatocellular carcinoma ≤5 cm: surgery vs. ablation: a multicenter retrospective study

Background/Aim The aim of this study was to compare the therapeutic efficacy of ablation and surgery in solitary hepatocellular carcinoma (HCC) measuring ≤5 cm with a large HCC cohort database. Methods The study included consecutive 2,067 patients with solitary HCC who were treated with either ablation (n=1,248) or surgery (n=819). Th e patients were divided into three groups based on the tumor size and compared the outcomes of the two therapies using propensity score matching. Results No significant difference in recurrence-free survival (RFS) or overall survival (OS) was found between surgery and ablation groups for tumors measuring ≤2 cm or >2 cm but ≤3 cm. For tumors measuring >3 cm but ≤5 cm, RFS was significantly better with surgery than with ablation (3.6 and 2.0 years, respectively, P=0.0297). However, no significant difference in OS was found between surgery and ablation in this group (6.7 and 6.0 years, respectively, P=0.668). Conclusion The study suggests that surgery and ablation can be equally used as a treatment for solitary HCC no more than 3 cm in diameter. For HCCs measuring 3-5 cm, the OS was not different between therapies; thus, ablation and less invasive therapy can be considered a treatment option; however, special caution should be taken to prevent recurrence