Survival In Advanced Hepatocellular Carcinoma Research Articles

CT-based multimodal deep learning for non-invasive overall survival prediction in advanced hepatocellular carcinoma patients treated with immunotherapy

ObjectivesTo develop a deep learning model combining CT scans and clinical information to predict overall survival in advanced hepatocellular carcinoma (HCC).MethodsThis retrospective study included immunotherapy-treated advanced HCC patients from 52 multi-national in-house centers between 2018 and 2022. A multi-modal prognostic model using baseline and the first follow-up CT images and 7 clinical variables was proposed. A convolutional-recurrent neural network (CRNN) was developed to extract spatial-temporal information from automatically selected representative 2D CT slices to provide a radiological score, then fused with a Cox-based clinical score to provide the survival risk. The model’s effectiveness was assessed using a time-dependent area under the receiver operating curve (AUC), and risk group stratification using the log-rank test. Prognostic performances of multi-modal inputs were compared to models of missing modality, and the size-based RECIST criteria.ResultsTwo-hundred seven patients (mean age, 61 years ± 12 [SD], 180 men) were included. The multi-modal CRNN model reached the AUC of 0.777 and 0.704 of 1-year overall survival predictions in the validation and test sets. The model achieved significant risk stratification in validation (hazard ratio [HR] = 3.330, p = 0.008), and test sets (HR = 2.024, p = 0.047) based on the median risk score of the training set. Models with missing modalities (the single-modal imaging-based model and the model incorporating only baseline scans) can still achieve favorable risk stratification performance (all p < 0.05, except for one, p = 0.053). Moreover, results proved the superiority of the deep learning-based model to the RECIST criteria.ConclusionDeep learning analysis of CT scans and clinical data can offer significant prognostic insights for patients with advanced HCC.Critical relevance statementThe established model can help monitor patients’ disease statuses and identify those with poor prognosis at the time of first follow-up, helping clinicians make informed treatment decisions, as well as early and timely interventions.Key PointsAn AI-based prognostic model was developed for advanced HCC using multi-national patients.The model extracts spatial-temporal information from CT scans and integrates it with clinical variables to prognosticate.The model demonstrated superior prognostic ability compared to the conventional size-based RECIST method.Graphical

Predictors of short-term death and long-term survival in advanced hepatocellular carcinoma (HCC) treated with contemporary tyrosine kinase inhibitors (TKI) or immunotherapy: A multicenter analysis from the HCC-CHORD consortium.

4098 Background: Advances in systemic therapy for HCC have increased treatment options, including TKIs and immunotherapy combinations. Variables that predict patient outcomes may be helpful in personalizing treatment decisions. The aim of this study was to identify predictors of short-term death (STD) and long-term survival (LTS) for HCC patients. Methods: Retrospective review of patients with advanced HCC who received a TKI or immunotherapy combinations was conducted between Aug 2018 to Aug 2022 in the Canadian provinces of British Columbia, Alberta, Nova Scotia, Manitoba, as well as from select institutions in Ontario (n = 2). Prior locoregional therapies were permitted. Variables examined were: Barcelona Clinic Liver Cancer (BCLC) stage, Child-Pugh class, albumin-bilirubin (ALBI) grade, alpha fetoprotein (AFP) level, microvascular invasion (MVI), and distant metastases. Multivariate logistic regression was used to determine independent predictors of STD (patient survival &lt; 6 months vs others) and LTS (patient survival &gt; 18 months vs others). Results: 520 patients with the following baseline characteristics were included: median age 66, 84.6% male, 87.4% ECOG performance status 0-1, 69.7% BCLC stage C, and 88.7% Child-Pugh A. First-line treatments were primarily: lenvatinib 57.3%, sorafenib 8.1%, and atezolizumab/bevacizumab 31.7%. Median progression-free survival was 7.4 months (95% CI: 6.2 to 8.4), and overall survival was 17.1 months (95% CI:, 15.1 to 18.8). Independent predictors of STD were (odds ratio): ALBI grade (2.26), MVI (2.13), and distant metastases (2.14). These three factors were also predictive for LTS: ALBI grade (0.45), MVI (0.49), and distant metastases (0.36). Child-Pugh class, AFP, and BCLC stage were not predictive of STD nor LTS (Table). Conclusions: This study supports higher ALBI grade, MVI and distant metastases as predictors of STD, while lower ALBI grade, absence of MVI and lack of distant metastases were predictive of LTS in HCC patients treated with contemporary TKIs or immunotherapy combination regimens. These predictors may help guide treatment decisions in patient populations underrepresented in clinical trials, including patients with Child-Pugh B7 score who are often excluded. [Table: see text]

The Performance of a Survival Nomogram and Albumin-Bilirubin Grade as Prognostic Tools in Advanced Hepatocellular Carcinoma Treated with FOLFOX4.

The ability of the survival nomogram developed in the EACH study and albumin-bilirubin (ALBI) grade to predict the survival of advanced hepatocellular carcinoma (HCC) patients receiving oxaliplatin plus 5-fluorouracil/leucovorin (FOLFOX4) remains unvalidated. Here, we comprehensively evaluated these prognostic tools. The survival nomogram and ALBI grade of each patient were assessed, and the area under the receiver operating curve (AUROC) and Harrell's C-index for the risk classification model were calculated. Overall, 76 HCC patients who received FOLFOX4 between August 2017 and June 2023 were included. The survival nomogram classified patients into low-, intermediate-, and high-risk groups, with a median overall survival (OS) of 9.82, 10.64, and 3.70 months, respectively (p = 0.23). The AUROC was 0.621 and Harrell's C-index was 0.589. However, the ALBI grade categorized all patients into grade 1, 2, and 3, with a median OS of 9.82, 6.83, and 1.58 months, respectively (p = 0.00024). The AUROC was 0.663 and Harrell's C-index was 0.663. The ALBI grade can be a potential prognostic tool. However, the survival nomogram does not provide clear discrimination. Therefore, FOLFOX4 should be an option for patients with ALBI grade 1 who cannot receive immunotherapy or targeted therapy. Additional prospective studies with a larger cohort are warranted to validate the survival nomogram and ALBI grade as prognostic tools.

Predicting survival of patients with advanced hepatocellular carcinoma receiving combination targeted immunotherapy: an evaluation of volumetric imaging parameters.

To evaluate the potential of volumetric imaging in predicting survival of advanced hepatocellular carcinoma (HCC) patients receiving immunotherapy. Retrospective analysis included 40 patients with advanced HCC who received targeted immunotherapy. Baseline and follow-up contrast-enhanced abdominal computed tomography (CT) scans were analyzed. The largest tumor was chosen as the index lesion. Viable tumor volume (qViable) and percentage tumor viability (%Viability) were calculated. Response Evaluation Criteria in Solid Tumors (RECIST) and Tumor volume change after treatment (qRECIST) were measured. Associations with overall survival (OS) were assessed. Cox regression analysis assessed the association between variables and overall survival (OS). A new prognostic stratification system was attempted to categorize patients based on significant predictors of OS. Patients with a baseline %viability > 69% and %viability reduction ≥ 8% were classified as better prognosis. Patients were stratified into better, intermediate and worse prognosis groups based on baseline %viability > 69% and ≥ 8% %viability reduction (better prognosis); baseline %viability ≤ 69% and < 8% %viability reduction (worse prognosis); remainder were intermediate prognosis. Patients with baseline %Viability > 69% and %Viability reduction ≥ 8% showed significantly higher OS. Multivariate analysis confirmed %Viability and %Viability reduction as significant predictors of OS. A prognostic stratification system using these parameters stratified patients into better, intermediate and worse prognosis groups, with the better prognosis showing highest OS. Most patients (97.5%) had stable disease by RECIST while the prognostic model re-classified 47.5% as better prognosis, 37.5% intermediate prognosis, and 15% worse prognosis. Volumetric parameters of %Viability and %Viability reduction predict OS in HCC patients undergoing immunotherapy.

Surrogacy of one-year survival for overall survival in advanced hepatocellular carcinoma

BackgroundThe increasing number of sequential treatments complicates the evaluation of overall survival (OS) in clinical trials for hepatocellular carcinoma (HCC), therefore, reliable surrogate endpoints (SEs) are required. This study aimed to evaluate the surrogacy of progression-free survival (PFS) and one-year (1-yr) milestone survival for OS in HCC trials.MethodsWe systematically searched databases for randomized clinical trials that evaluated systemic treatments for advanced HCC. Individual patient data were reconstructed to calculate the 1-yr survival rate. We adopted a two-stage meta-analytic validation model to evaluate the correlation between SEs and OS, and the correlation between treatment effects on SEs and OS. The hazard ratio (HR) was calculated to assess the treatment effects on PFS and OS, and the 1-yr survival ratio was calculated to evaluate the treatment effects on the 1-yr milestone survival.ResultsThirty-two HCC trials involving 13,808 patients were included. A weak correlation was detected between the median PFS and median OS (R2 = 0.32), whereas the correlation improved between PFS HR and OS HR (R2 = 0.58). We identified strong correlations between the 1-yr survival rate and median OS and between the 1-yr survival ratio and OS HR (R2 = 0.74 and 0.65, respectively). In subgroup analyses, PFS HR strongly correlated with OS HR in trials relevant to immune checkpoint inhibitors (ICIs). Although the correlation remained weak between PFS and OS even in trials with PFS HR ≤ 0.6, the 1-yr survival rate and 1-yr survival ratio were strong surrogates for median OS and OS HR, respectively (R2 = 0.77 and 0.75).ConclusionsOne-year milestone survival outperformed PFS as a SE for OS in HCC, indicating the application of 1-yr survival as a secondary endpoint. In particular, PFS HR was a potential SE for OS HR in the ICI trials.

Surrogate endpoints for overall survival in advanced hepatocellular carcinoma: A meta-analysis.

563 Background: Recent advances in systemic therapies have resulted in improved overall survivals (OS) for patients with advanced hepatocellular carcinoma (aHCC). The most commonly utilized primary endpoint for phase III trials in aHCC is OS. A robust surrogate endpoint (SEP) can reduce time and financial costs of future trials and accelerate regulatory approvals of new therapies. We conducted a literature-based meta-analysis to evaluate SEPs for OS in aHCC. Methods: Randomized controlled trials evaluating systemic therapies in aHCC published 2007 - 2023 were identified through a systemic literature search of Cochrane and Medline databases as well as of abstracts presented at ASCO and ESMO meetings. Hazard ratios (HR) for OS and progression-free survival (PFS) and time to progression (TTP) were extracted. ΔORR was calculated as the difference in overall response rates (ORR) between control and experimental arms. Pearson correlation and mixed-effects meta-regression analyses were performed. Surrogate threshold effect (STE) was determined for each comparison when possible. A p &lt; 0.05 was considered to be statistically significant. Results: 26 trials were identified in the first-line setting with 14,827 patients and 11 trials in the subsequent-line setting with 5,316 patients. In first-line trials, immunotherapy (IO) is associated with higher ORR than other agents (p=0.003). There are statistically significant correlations between HRs of PFS/TTP/ΔORR and OS (Table). The relationship between HR-PFS and HR-OS persists in trials with or without IO, but only in trials enrolling &lt; 30% patients of non-viral aetiologies. In subsequent-line trials, there are statistically significant correlations between HRs of PFS/TTP and OS (Table). STE for HR PFS is 0.68 and 0.87 respectively for 1st and subsequent line trials. Conclusions: There are moderate to strong correlations between PFS and OS in aHCC in first-line and subsequent line trials. STE for HR-PFS of 0.68 in first-line and 0.87 in subsequent-line settings can guide sample size calculation in future clinical trials. [Table: see text]

Overall survival in advanced hepatocellular carcinoma treated with concomitant systemic therapy and stereotactic body radiation therapy or systemic therapy alone

IntroductionFirst-line systemic therapy (ST) options for advanced hepatocellular carcinoma (HCC) include tyrosine kinase inhibitors and immunotherapy (IO). Evolving data suggest prolonged overall survival (OS) when ST is combined with stereotactic body radiation therapy (SBRT), although evidence is significantly limited in HCC populations. We hypothesized that advanced HCC patients in the National Cancer Database (NCDB) would have improved OS when receiving ST+SBRT vs ST alone.MethodsStage III/IV HCC patients diagnosed from 2010-2020 and treated with first-line ST±SBRT were identified from the NCDB. The primary endpoint was OS from date of diagnosis stratified by the receipt of SBRT (ST+SBRT vs ST alone). Survival was estimated using Kaplan-Meier methodology and compared via log-rank. Multivariate analysis (MVA) was performed by Cox regression.ResultsOf 10,505 eligible patients with stage III disease, 115 (1.1%) received ST+SBRT and 10,390 (98.9%) received ST alone. Of 9,617 eligible patients with stage IV disease, 127 (1.3%) received ST+SBRT and 9,490 (98.7%) received ST alone. Median follow-up time was 6.8 months. Baseline characteristics were similar between cohorts. Patients with stage III disease receiving ST+SBRT had improved median OS (12.62 months vs 8.38 months) and higher rates of survival at 1-year (53.0% vs 38.7%) and 2-years (27.0% vs 20.7%) compared to those receiving ST alone (log-rank P=0.0054). Similarly, patients with stage IV disease receiving ST+SBRT had improved median OS (11.79 months vs 5.72 months) and higher rates of survival at 1-year (49.6% vs 26.2%) and 2-years (23.6% vs 12.0%) (log-rank P&amp;lt;0.0001). On MVA, receipt of SBRT predicted improved OS (HR=0.748, 95%CI 0.588-0.951; P=0.0178) and receipt of IO trended towards improved OS (HR=0.859, 95%CI 0.735-1.003; P=0.0538).ConclusionIn advanced HCC, patients receiving ST+SBRT had improved OS compared to those receiving ST alone. Prospective clinical trials are warranted to better identify HCC populations which may benefit from combined modality therapy.

976P Overall survival in advanced hepatocellular carcinoma treated with concomitant systemic therapy and stereotactic radiation therapy or systemic therapy alone

976P Overall survival in advanced hepatocellular carcinoma treated with concomitant systemic therapy and stereotactic radiation therapy or systemic therapy alone

Changing treatment landscape associated with improved survival in advanced hepatocellular carcinoma: a nationwide, population-based study

Background and AimsThe treatment of hepatocellular carcinoma (HCC) is undergoing a historic transformation with the approval of several new systemic therapies in the last few years. This study aimed to examine the impact of this changing landscape on survival and costs in a Western nationwide, real-world cohort. MethodsA nationwide representative claims database (InGef) was screened for HCC cases between 2015 and 2020. Survival in an era with only sorafenib (period A, January 2015 to July 2018) and after approval of lenvatinib and other systemic treatments (period B, August 2018 to December 2020) was analysed. Health care costs were assessed. ResultsWe identified 2876 individuals with HCC in the study period. The proportion of patients receiving systemic therapy increased significantly over time, from 11.8% in 2015 to 15.1% in 2020 (p < 0.0001). The median overall survival in period B was 6.5 months (95% confidence interval [CI]: 4.9–8.9) and in period A was 5.3 months (95% CI: 4.5–6.3; p = 0.046). In period B, the median overall survival with lenvatinib was 9.7 months (95% CI: 6.3–18.4) versus 4.8 months with sorafenib (95% CI: 4.0–7.1, p = 0.008). Costs for prescription drugs per patient increased from €6150 in 2015 to €9049 in 2020 (p < 0.0001), and costs for outpatient care per patient increased from €1646 to €2149 (p = 0.0240). ConclusionThe approval of new systemic therapies resulted in a survival benefit in patients with HCC. The magnitude of the effect is modest and associated with a moderate increase in health costs.

A bibliometric study on the utilization of lenvatinib in hepatocellular carcinoma (2014-2022).

Background: The REFLECT phase-III trial has demonstrated the efficacy of lenvatinib in improving the overall survival of advanced hepatocellular carcinoma (HCC) patients, comparable to sorafenib. The rapidly evolving landscape of hepatocellular carcinoma therapy presents new avenues for lenvatinib. This study aims to provide a scientometric analysis of publications and predict research hotspots in this field. Methods: Relevant publications were sourced from the Web of Science Core Collection (WoSCC) database up until November 2022. The bibliometrix tool in R was employed for scientometric analysis and visualization. Results: A total of 879 publications from 2014 to 2022 were obtained from WoSCC that met the established criteria. These studies involved 4,675 researchers from 40 countries, with an average annual growth rate of 102.5%. The highest number of publications was from Japan, followed by China, Italy, and the United States. The largest proportion of studies, 14.0% (n = 123), was contributed by FUDAN UNIV. The studies were published in 274 journals, with CANCERS (n = 53) being the top journal, followed by FRONTIERS IN ONCOLOGY (n = 51) and HEPATOLOGY RESEARCH (n = 36). The top ten journals accounted for 31.5% of the 879 studies. The most prolific authors were Kudo M (n = 51), Hiraoka A (n = 43), and Tsuji K (n = 38). A total of 1,333 keywords were analyzed, with the present research hotspots being "immune checkpoint inhibitors," "prognosis," and "pd-1." Co-occurrence clustering analysis revealed the top keywords, authors, publications, and journals. Strong collaboration was identified in the field. Conclusion: This scientometric and visual analysis provides a comprehensive summary of the published articles on lenvatinib in HCC during 2014-2022, highlighting the research hotspots, knowledge domain, and frontiers. The results can provide insights into future research directions in this field.

Serum cell division cycle 42 in advanced hepatocellular carcinoma patients: Linkage with clinical characteristics and immune checkpoint inhibitor-related treatment outcomes

ObjectiveCell division cycle 42 (CDC42) facilitates immune escape and drug resistance towards immunotherapy in several malignancies. This prospective study aimed to explore the predictive value of serum CDC42 for immune checkpoint inhibitor (ICI)-treatment response and survival in advanced hepatocellular carcinoma (HCC) patients. MethodsThirty advanced HCC patients scheduled for ICI or ICI-based treatment were enrolled in this prospective study, whose serum CDC42 was determined via enzyme-linked immunosorbent assay before therapy initiation. ResultsThe median (interquartile range) of serum CDC42 level was 766.5 (605.0–1329.5) pg/mL. Serum CDC42 was related to increased tumor size but decreased programmed death-ligand 1 combined positive score (PD-L1 CPS). With respect to ICI or ICI-based treatment outcomes, elevated serum CDC42 was associated with decreased disease control rate, but did not link with objective response rate. Patients with high serum CDC42 (vs. low, cut by its median level) had shortened progression-free survival (PFS), while overall survival (OS) only disclosed a reduced trend (lacked statistical significance) in patients with high serum CDC42 (vs. low). In detail, the median (95%CI) PFS and OS were 3.0 (0.0–6.0) months and 11.7 (2.7–20.7) months in patients with high serum CDC42, while they were 11.1 (6.6–15.6) months and 19.3 (14.5–24.1) months in patients with low CDC42. After adjusted by multivariate cox regression analysis, high serum CDC42 (vs. low) was independently associated with shortened PFS, but not OS. ConclusionsElevated serum CDC42 possesses a potential value in predicting worse ICI or ICI-based treatment outcomes in advanced HCC.

Role of the Prognostic Nutritional Index in Predicting Survival in Advanced Hepatocellular Carcinoma Treated with Atezolizumab Plus Bevacizumab

Introduction: The prognostic nutritional index (PNI) is a multiparametric score introduced by Onodera based on the blood levels of lymphocytes and albumin in patients with gastrointestinal neoplasms. Regarding hepatocellular carcinoma (HCC), its prognostic role has been shown in patients treated with sorafenib and lenvatinib. The aim of this real-world study was to investigate the association between clinical outcomes and PNI in patients being treated with atezolizumab plus bevacizumab. Methods: The overall cohort of this multicentric study included 871 consecutive HCC patients from 5 countries treated with atezolizumab plus bevacizumab in first-line therapy. The PNI was calculated as follows: 10 × serum albumin concentration (g/dL) + 0.005 × peripheral lymphocyte count (number/mm³). Results: Data regarding lymphocyte counts and albumin levels were available for 773 patients; therefore, these patients were included in the final analysis. The cut-off point of the PNI was determined to be 41 by receiver operating characteristic analysis. 268 patients (34.7%) were categorized as the PNI-low group, while the remaining 505 (65.3%) patients as the PNI-high group. At the univariate analysis, high PNI was associated with longer overall survival (OS) (22.5 vs. 10.1 months, HR 0.34, p <0.01) and progression-free survival (PFS) (8.7 vs. 5.8 months, HR 0.63, p <0.01) compared to patients with low PNI. At the multivariate analysis, high versus low PNI resulted as an independent prognostic factor for OS (HR 0.49, p <0.01) and PFS (HR 0.82, p = 0.01). There was no difference in objective response rate between the two groups (high 26.1% vs. low 19.8%, p = 0.09), while disease control rate was significantly higher in the PNI-high group (76.8% vs. 66.4%, p = 0.01). Conclusion: PNI is an independent prognostic factor for OS and PFS in HCC patients on first-line treatment with atezolizumab plus bevacizumab.

108P Role of the prognostic nutritional index in predicting survival in advanced hepatocellular carcinoma treated with atezolizumab plus bevacizumab

The prognostic nutritional index (PNI) is a multiparametric score introduced by Onodera based on the blood levels of lymphocytes and albumin in patients with gastrointestinal neoplasms. Regarding hepatocellular carcinoma (HCC), its prognostic role has been demonstrated in patients treated with sorafenib and lenvatinib. The aim of this real-world study is to investigate the association between clinical outcomes and PNI in patients being treated with atezolizumab plus bevacizumab.

Efficacy and safety of regorafenib alone or in combinations for advanced hepatocellular carcinoma: A multicenter real-world study.

e16122 Background: The earlier randomized phase III RESORCE trial demonstrated that regorafenib improved overall survival in advanced hepatocellular carcinoma (HCC) patients progressing on sorafenib treatment, with a median survival of 10.6 months and a hazard ratio of 0.63 (95% CI 0.50-0.79, p &lt; 0.0001). Meanwhile, more data were published from retrospective studies evaluating the sequence of single drug sorafenib and regorafenib in advanced HCC patients treated in real-world settings [eg, REFINE study (N = 1000; 100 from China)].We aimed to explore the efficacy and safety of regorafenib alone or in combinations in advanced HCC patients in a real-world setting. Methods: This retrospective multicenter study included pathologically or clinically diagnosed advanced HCC patients who received regorafenib alone or in combinations in first to fourth line settings for at least 28 consecutive days. The primary endpoints were objective response rate (ORR, RECIST 1.1 criteria) and progression-free survival (PFS). The secondary endpoints included overall survival (OS) rate at 6-month and 12-month, disease control rate (DCR) and safety. Kaplan-Meier method was used to calculate survival data. Results: A total of 61 advanced HCC patients (55 male vs. 6 female, 2 first-line recipients vs. 47 second-line recipients vs.11 third-line recipients vs. 1 fourth-line recipients, median age of 53.5 years) from 6 Chinese centers were included between January 2018 and June 2021. Most patients had BCLC stage C (96.7%) and a Child-Pugh A or B score in 23% or 57.4% of cases respectively. 23 (37.7%) patients received single drug regorafenib therapy, the remaining patients (62.3%) received different combination therapies, including regorafenib plus immune checkpoint inhibitors (ICIs) (29.5%), regorafenib combined with TACE (14.8%), and triple therapy (TKI, ICI, TACE) (18.0%). The ORR and DCR of 61 recipients were 71.7% and 83.3%, with a median PFS of 12.67 months (range 7.47-13.97). The 6-month, 12-month OS rates were 80.2% and 68.9%. In second-line recipients, the 6-month, and 12-month OS rates were 85.6% and 76.7%, with a PFS of 12.67 months. 36 recipients had treatment-related adverse events (TRAEs); most frequent TEAEs (≥5%) included fatigue (12.4%), abdominal pain (8.5%), anorexia (7%), rash (7%), diarrhea (6.2%), and hand-foot syndrome (6.2%). Conclusions: Regorafenib alone or in combination is effective and safe in advanced HCC patients, with a high response rate as well as long survival, especially in second-line recipients.

Hepatitis C virus eradication ameliorates the prognosis of advanced hepatocellular carcinoma treated with sorafenib.

The risk of hepatocellular carcinoma (HCC) occurrence following hepatitis C virus (HCV) eradication has been previously reported, but the impact of HCV eradication on advanced HCC patient survival remains unclear. Therefore, the present study aimed to evaluate the effect of HCV eradication on the survival outcome of patients with advanced HCC treated with sorafenib. One hundred and three HCV-related advanced HCC patients who were treated with sorafenib were enrolled in this study. Of these, 43 patients were administered antiviral therapy before sorafenib treatment (HCV eradication group), while 60 patients remained HCV-infected (HCV non-eradication group). We analysed the impact of HCV eradication on survival in advanced HCC treated with sorafenib. Median overall survival (OS) was significantly longer in the HCV eradication group than in the HCV non-eradication group (24.0months vs. 14.1 months; p=0.001). Although there was no significant difference in the albumin-bilirubin (ALBI) score at the start of treatment between the HCV eradication group and the non-eradication group (p=0.065), the ALBI score at 2months after initiation of sorafenib treatment was significantly decreased in the HCV non-eradication group (p < 0.001), but not in the HCV eradication group (p=0.121). Multivariate logistic analysis revealed HCV eradication (hazard ratio [HR], 0.5; p=0.006) and ALBI score at the start of treatment (HR, 2.47; p=0.002) as factors that may contribute to OS. HCV eradication may serve an important role in the survival outcome of advanced HCC patients treated with sorafenib.

Knockdown of AKR1C3 Promoted Sorafenib Sensitivity Through Inhibiting the Phosphorylation of AKT in Hepatocellular Carcinoma.

BackgroundSorafenib, which can induce ferroptosis, is a multikinase inhibitor for enhancing survival in advanced hepatocellular carcinoma (HCC). However, a considerable challenge for the treatment of HCC is sorafenib resistance. Therefore, targeting the relationship between sorafenib resistance and ferroptosis genes may provide a novel approach for the treatment of HCC.Materials and MethodsWe analyzed the gene expression and clinicopathological factors from The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC), International Cancer Genome Consortium (ICGC), and Gene Expression Omnibus (GEO) databases (GSE109211/GSE62813). The statistical analysis was conducted in R. Cell proliferation was assayed by MTT, cell colony-forming assay, and wound healing assay. Immunofluorescence assay and Western blot were used to evaluate the expression of AKT.ResultsMany ferroptosis-related genes were upregulated in the sorafenib-resistant group. Aldo-keto reductase 1C3 (AKR1C3) was highly expressed in sorafenib-resistant patients, and the high expression of AKR1C3 was associated with the poor prognosis of patients from the TCGA and ICGC databases. MTT and colony-forming assays showing AKR1C3 overexpression enhanced the proliferation of HCC cells and acute sorafenib resistance. Knockdown of AKR1C3 inhibited the proliferation of HCC cells and increased the drug sensitivity of sorafenib. Immunofluorescence assay and Western blot proved that AKR1C3 promoted the phosphorylation of AKT.ConclusionAKR1C3 can induce sorafenib resistance through promoting the phosphorylation of AKT in HCC. AKR1C3 inhibitors may be used in conjunction with sorafenib to become a better therapeutic target for HCC.

Perioperative nivolumab monotherapy versus nivolumab plus ipilimumab in resectable hepatocellular carcinoma: a randomised, open-label, phase 2 trial

Hepatocellular carcinoma has high recurrence rates after surgery; however, there are no approved standard-of-care neoadjuvant or adjuvant therapies. Immunotherapy has been shown to improve survival in advanced hepatocellular carcinoma; we therefore aimed to evaluate the safety and tolerability of perioperative immunotherapy in resectable hepatocellular carcinoma. In this single-centre, randomised, open-label, phase 2 trial, patients with resectable hepatocellular carcinoma were randomly assigned (1:1) to receive 240 mg of nivolumab intravenously every 2 weeks (for up to three doses before surgery at 6 weeks) followed in the adjuvant phase by 480 mg of nivolumab intravenously every 4 weeks for 2 years, or 240 mg of nivolumab intravenously every 2 weeks (for up to three doses before surgery) plus one dose of 1 mg/kg of ipilimumab intravenously concurrently with the first preoperative dose of nivolumab, followed in the adjuvant phase by 480 mg of nivolumab intravenously every 4 weeks for up to 2 years plus 1 mg/kg of ipilimumab intravenously every 6 weeks for up to four cycles. Patients were randomly assigned to the treatment groups by use of block randomisation with a random block size. The primary endpoint was the safety and tolerability of nivolumab with or without ipilimumab. Secondary endpoints were the proportion of patients with an overall response, time to progression, and progression-free survival. This trial is registered with ClinicalTrials.gov (NCT03222076) and is completed. Between Oct 30, 2017, and Dec 3, 2019, 30 patients were enrolled and 27 were randomly assigned: 13 to nivolumab and 14 to nivolumab plus ipilimumab. Grade 3-4 adverse events were higher with nivolumab plus ipilimumab (six [43%] of 14 patients) than with nivolumab alone (three [23%] of 13). The most common treatment-related adverse events of any grade were increased alanine aminotransferase (three [23%] of 13 patients on nivolumab vs seven [50%] of 14 patients on nivolumab plus ipilimumab) and increased aspartate aminotransferase (three [23%] vs seven [50%]). No patients in either group had their surgery delayed due to grade 3 or worse adverse events. Seven of 27 patients had surgical cancellations, but none was due to treatment-related adverse events. Estimated median progression-free survival was 9·4 months (95% CI 1·47-not estimable [NE]) with nivolumab and 19·53 months (2·33-NE) with nivolumab plus ipilimumab (hazard ratio [HR] 0·99, 95% CI 0·31-2·54); median time to progression was 9·4 months (95% CI 1·47-NE) in the nivolumab group and 19·53 months (2·33-NE) in the nivolumab plus ipilimumab group (HR 0·89, 95% CI 0·31-2·54). In an exploratory analysis, three (23%) of 13 patients had an overall response with nivolumab monotherapy, versus none with nivolumab plus ipilimumab. Three (33%) of nine patients had a major pathological response (ie, ≥70% necrosis in the resected tumour area) with nivolumab monotherapy compared with three (27%) of 11 with nivolumab plus ipilimumab. Perioperative nivolumab alone and nivolumab plus ipilimumab appears to be safe and feasible in patients with resectable hepatocellular carcinoma. Our findings support further studies of immunotherapy in the perioperative setting in hepatocellular carcinoma. Bristol Myers Squibb and the US National Institutes of Health.

Surrogate Indicators of Overall Survival in Advanced Hepatocellular Carcinoma

To the Editor, For more than a decade, the targeted drug sorafenib[1, 2] has been the dominant first-line treatment for patients with advanced hepatocellular carcinoma (HCC). However, due to the low overall response rate and high drug resistance rate, many new targeted drugs have been developed, including sunitinib, brivanib, linifanib, nintedanib, dovitinib, sorafenib plus erlotinib, lenvatinib, and donafenib. On the other hand, with the increasing use of immune checkpoint inhibitors in solid tumors, several trials investigated the efficacy and safety of immune checkpoint inhibitors in advanced HCC. Among these trials, only lenvatinib and donafenib as monotherapy were non-inferior to sorafenib in overall survival in untreated advanced HCC. Most of other trials did not meet their primary end point of overall survival. However, the efficacy of the combination therapy with PD-1 or PD-L1 inhibitor plus bevacizumab (VEGF inhibitor) is amazing.[3, 4] An expert panel convened by the American Association for the Study of Liver Diseases recommended time to progression as the primary endpoint in randomized phase 2 trials and overall survival as the main endpoint to measure effectiveness in phase 3 trials.[5, 6] In real world clinical practice, subsequent antitumor therapies after tumor progression and/or therapies for concurrent liver disease can confound the assessment of clinical benefit. In the recent issue of Journal of Hepatology, on behalf of EASL, Bruix and coworkers updated the recommendations of systemic treatment of HCC.7 This review proposed that “overall survival is the sole robust endpoint to assess the benefit from any intervention in advanced HCC” and “all proposed surrogates lack adequate validation”. Here, we tried to reveal the relationship among objective response rate (ORR), median overall survival (OS) time and median progression-free survival (PFS) time by presenting them in a same curve graph. The potential relationship between PFS and OS is revealed by representing the hazard ratio (with 95% confidence interval) of PFS and OS with a forest plot. We systematically searched PubMed and EMBASE databases and analyzed phase 3 clinical trials with large sample size. A total of 11 trials about first-line systemic therapies for advanced HCC published from 2008 to 2021 were included into analysis. All these 11 trials included a group of patients treated with sorafenib. In addition, 7 trials about second-line systemic therapies published from 2015 to 2021 were also included into analysis. The control group received placebo treatment in all these 7 trials. All these 18 trials reported ORR, median PFS and OS time. The ORR according to RECIST 1.1 in the sorafenib group ranged from 0.7% to 11.9% (median 6.1%). Among patients with sorafenib therapy, the median PFS and OS time was 3.75 (range 2.8 to 5.5) and 10.4 (range 6.5 to 14.7) months, re-spectively. The mean ORR of sorafenib was also calculated. The denominator equals the sum of the sample sizes for each sorafenib group. Percentage was obtained by the sum number of cases with complete or partial response in each trial divided by the denominator. The mean ORR of sorafenib was 6.0%. Actually, atezolizumab plus bevacizumab was associated with the highest ORR (27.3%) while donafenib with the lowest (4.6%). In addition, the median OS time of each trial tended to increase gradually with the increase of ORR and median PFS time (Fig. 1a). However, this trend was not significant in second-line treatment (Fig. 1b). And then, we describe the association between PFS and OS with forest plot (Fig. 1c). We found (1) PD-1 (sintilimab) or PD-L1 (atezolizumab) inhibitor plus bevacizumab was associated with the best survival benefit for patients with advanced HCC;[3, 4] (2) the significant benefit of PFS may not translate into significant benefit of OS (linifanib, lenvatinib, ramucirumab in REACH trial, S-1); (3) similar PFS generally does not translate into OS benefits (sunitinib, brivanib, sorafenib plus erlotinib), except in the ZGDH3 trial (donafenib); (4) a benefit in PFS could predict a benefit in OS when the hazard ratio for PFS is lower than 0.6 in most trials, except ZGDH3[8] (hazard ratio 0.91) and KEYNOTE 240 trial (hazard ratio 0.72).[9] Tumor progression is the leading cause of death in patients with HCC. Increased ORR and PFS may increase OS in firstline setting, but not in second-line therapy. In addition, the optimum cut-off value of hazard ratio for PFS in predicting benefit in OS is still pending.

Objective Response Predicts Survival in Advanced Hepatocellular Carcinoma Treated with Systemic Therapies.

Because of the increased number of sequential treatments used for advanced hepatocellular carcinoma (HCC), there is a need for surrogate endpoints of overall survival (OS). We analyze whether objective response (OR) is an independent predictor and surrogate endpoint of OS. A systematic review of randomized clinical trials (RCT) in advanced HCC published between 2010 and 2020 was conducted to explore OS surrogacy of OR by Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST (mRECIST). In parallel, RCTs exploring the impact of OR on OS in a time-dependent multivariate analysis were integrated in a meta-analysis. Of 65 RCTs identified in advanced HCC, we analyzed 34 studies including 14,056 patients that reported OS and OR by either RECIST (n = 23), mRECIST (n = 5), or both (n = 6). When exploring surrogacy, the trial-level correlation between OR odds ratio and OS HR was R = 0.677 by mRECIST and R = 0.532 by RECIST. Meta-analysis of five RCTs assessing predictors of survival in multivariate analysis found that patients with OR by mRECIST presented a pooled HR for OS of 0.44 (95% confidence interval, 0.27-0.70; P < 0.001) compared with nonresponders. Responses to atezolizumab-bevacizumab had a greater impact on OS than tyrosine kinase inhibitor responses. OR-mRECIST is an independent predictor of OS in patients with advanced HCC. Although correlation of OR-mRECIST and OS is better than with OR-RECIST, the level of surrogacy is modest. Thus, it can be used as endpoint in proof-of-concept phase II trials, but the data do not support its use as a primary endpoint of phase III investigations assessing systemic therapies.

YRDC Mediates the Resistance of Lenvatinib in Hepatocarcinoma Cells via Modulating the Translation of KRAS.

Lenvatinib is the latest and promising agent that has demonstrated a significant improvement of progression-free survival in advanced hepatocellular carcinoma (HCC). However, resistance emerges soon after initial treatment, limiting the clinical benefits of lenvatinib. Therefore, understanding the mechanism of resistance is necessary for improving lenvatinib efficacy. YRDC promotes the proliferation of hepatocarcinoma cells via regulating the activity of the RAS/RAF/MEK/ERK pathway, which was the primary pathway of the anticancer effect of lenvatinib. The purpose of this study is to investigate whether YRDC modulates the sensitivity of lenvatinib in hepatocarcinoma cells. Using the CCK-8 cell viability assay, wound-healing assay and clone formation assay in cell models, and xenograft assay in null mouse, we demonstrated that Huh7 cells with YRDC knockdown showed decreased susceptibility to lenvatinib than their control cells. Furthermore, we found that lenvatinib inhibited the expression of YRDC in a time-dependent manner. This effect may aggravate resistance to lenvatinib in hepatocarcinoma cells and may be an underlying cause of resistance, which emerges soon after lenvatinib initial treatment. To investigate how YRDC modulates the sensitivity of lenvatinib, we assessed the effect of tRNA with different t6A levels on the translation of the KRAS gene by in vitro rabbit reticulocyte translation system and measured the expression levels of the KRAS gene by western blot together with qPCR. We found that YRDC regulates the protein translation of KRAS in cell models, and the tRNA with low t6A modification level reduces the translation of the KRAS in the in vitro translation system. These results suggested that YRDC mediates the resistance of lenvatinib in hepatocarcinoma cells via modulating the translation of the KRAS. In this study, YRDC was confirmed to be a potential novel predictive biomarker of lenvatinib sensitivity in HCC.