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There is a significant discrepancy between the actual choice for initial treatment option for hepatocellular carcinoma (HCC) and recommendations from the currently used BCLC staging system. We develop a machine learning-based clinical decision support system (CDSS) for recommending initial treatment option in HCC and predicting overall survival (OS). From hospital records of 1,021 consecutive patients with HCC treated at a single centre in Korea between January 2010 and October 2010, we collected information on 61 pretreatment variables, initial treatment, and survival status. Twenty pretreatment key variables were finally selected. We developed the CDSS from the derivation set ( N  = 813) using random forest method and validated it in the validation set ( N  = 208). Among the 1,021 patients (mean age: 56.9 years), 81.8% were male and 77.0% had positive hepatitis B BCLC stages 0, A, B, C, and D were observed in 13.4%, 26.0%, 18.0%, 36.6%, and 6.3% of patients, respectively. The six multi-step classifier model was developed for treatment decision in a hierarchical manner, and showed good performance with 81.0% of accuracy for radiofrequency ablation (RFA) or resection versus not, 88.4% for RFA versus resection, and 76.8% for TACE or not. We also developed seven survival prediction models for each treatment option. Our newly developed HCC-CDSS model showed good performance in terms of treatment recommendation and OS prediction and may be used as a guidance in deciding the initial treatment option for HCC.

Introduction/Objective: Lenvatinib demonstrated efficacy and safety in patients with advanced hepatocellular carcinoma (HCC) in the randomized phase III REFLECT trial. Considering the discrepancies in patients between clinical trial data and daily practice, an account of practical experience is needed. Methods: We conducted a multicenter retrospective analysis in which 3 tertiary referral centers participated. A total of 92 patients with advanced HCC treated with lenvatinib between September 2018 and January 2020 were analyzed. Results: Lenvatinib was used as the first-line therapy for 67 (72.8%) patients, and for 25 (27.2%) patients previously treated with other systemic therapy including immune checkpoint inhibitors. At the time of initiation of lenvatinib, 74 (80.4%) and 18 (19.6%) patients were classified as Child-Pugh A and B, respectively. Thirty-five patients (38.0%) had extensive disease that would have excluded them from the REFLECT trial. In the Child-Pugh A group, the response rate graded according to the Response Evaluation Criteria in Solid Tumors v1.1 was 21.1%, median progression-free survival (PFS) was 4.6 (95% confidence interval [CI] 3.1–6.1) months, and overall survival (OS) was 10.7 (95% CI 4.8–16.5) months for patients treated with first-line lenvatinib (n = 57). With second- or later-line lenvatinib (n = 17), median PFS and OS were 4.1 (95% CI 3.1–5.1) and 6.4 (95% CI 5.1–7.7) months, respectively. In the Child-Pugh B group (n = 18), median PFS and OS were 2.6 (95% CI 0.6–4.6) and 5.3 (95% CI 2.0–8.5) months, respectively. The most common grade 3–4 toxicities were hyperbilirubinemia (n = 8; 8.7%), AST elevation (n = 6; 6.5%), and diarrhea (n = 5; 5.4%) across all study patients. Conclusions: In this real-world study, lenvatinib was found to be well tolerated and effective in more heterogeneous HCC patient populations.

To assess the two-year treatment outcomes of chemoembolization with drug-eluting embolics (DEE) for nodular hepatocellular carcinoma (HCC). This study was a prospective, multicenter, registry-based, single-arm trial conducted at five university hospitals in Korea. Patients were recruited between May 2011 and April 2013, with a target population of 200. A DC Bead loaded with doxorubicin was used as the DEE agent. Patients were followed up for two years. Per-patient and per-lesion tumor response analysis, per-patient overall survival (OS) and progression-free survival (PFS) analysis, and per-lesion tumor control analysis were performed. The final study population included 152 patients, with 207 target lesions for the per-lesion analysis. At one-month, six-month, one-year, and two-year per-patient assessments, complete response (CR) rates were 40.1%, 43.0%, 33.3%, and 19.6%, respectively. The objective response (OR) rates were 91.4%, 55.4%, 35.1%, and 19.6%, respectively. The cumulative two-year OS rate was 79.7%. The cumulative two-year PFS rate was 22.4% and the median survival was 9.3 months. In multivariable analysis, the Child-Pugh score ( = 0.019) was an independent predictor of OS, and tumor multiplicity ( < 0.001), tumor size ( = 0.020), and Child-Pugh score ( = 0.006) were independent predictors of PFS. In per-lesion analysis, one-month, six-month, one-year and two-year CR rates were 57.5%, 58.5%, 45.2%, and 33.3%, respectively, and the OR rates were 84.1%, 65.2%, 46.6%, and 33.3%, respectively. The cumulative two-year per-lesion tumor control rate was 36.2%, and the median time was 14.1 months. The Child-Pugh score ( < 0.001) was the only independent predictor of tumor control. Serious adverse events were reported in 11 patients (7.2%). DEE chemoembolization for nodular HCCs in the Korean population showed acceptable survival, tumor response, and safety profiles after a two-year follow-up. Good liver function (Child-Pugh score A5) was a key predictor of per-patient OS, PFS, and per-lesion tumor control.

Background: Cabozantinib, a multiple kinase inhibitor, was recently approved for patients with previously treated unresectable hepatocellular carcinoma (uHCC). We investigated the real-world safety and efficacy profiles of cabozantinib. Methods: This multicenter retrospective study included 110 patients with uHCC who received cabozantinib after progression on other systemic treatments between October 2019 and May 2021. Results: The median age was 58 (range, 20–77) years, and 98 (89.1%) were male. Prior to cabozantinib, all patients were treated with other systemic therapies: sorafenib (n = 104, 94.5%) and regorafenib (n = 91, 82.7%) were the most commonly used agents. Immune checkpoint inhibitors were previously used in 93 patients (84.5%). Cabozantinib was used beyond the third-line of therapy in most patients (n = 90, 81.8%). With a median follow-up duration of 11.9 months [95% confidence interval (CI), 10.8–17.2], the median progression-free survival (PFS) was 3.7 months (95% CI, 3.1–4.9), and the median overall survival (OS) was 7.5 months (95% CI, 5.5–9.5). The disease control rate and overall response rate (ORR) were 66.3% and 3.6%, respectively. In the Child–Pugh A cohort (n = 88), the ORR was 4.5%, and the median PFS and OS were 4.3 months (95% CI, 3.6–5.8) and 9.0 months (95% CI, 7.5–11.7), respectively. Conclusion: Cabozantinib showed consistent efficacy outcomes with a prior phase III trial, although in this study, it was used as later-line therapy for patients who were refractory to multiple systemic treatments, including immune checkpoint inhibitors.

No adjuvant treatment has been established for patients who remain at high risk for hepatocellular carcinoma recurrence after curative-intent resection or ablation. We aimed to assess the efficacy of adjuvant atezolizumab plus bevacizumab versus active surveillance in patients with high-risk hepatocellular carcinoma. In the global, open-label, phase 3 IMbrave050 study, adult patients with high-risk surgically resected or ablated hepatocellular carcinoma were recruited from 134 hospitals and medical centres in 26 countries in four WHO regions (European region, region of the Americas, South-East Asia region, and Western Pacific region). Patients were randomly assigned in a 1:1 ratio via an interactive voice–web response system using permuted blocks, using a block size of 4, to receive intravenous 1200 mg atezolizumab plus 15 mg/kg bevacizumab every 3 weeks for 17 cycles (12 months) or to active surveillance. The primary endpoint was recurrence-free survival by independent review facility assessment in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT04102098. The intention-to-treat population included 668 patients randomly assigned between Dec 31, 2019, and Nov 25, 2021, to either atezolizumab plus bevacizumab (n=334) or to active surveillance (n=334). At the prespecified interim analysis (Oct 21, 2022), median duration of follow-up was 17·4 months (IQR 13·9–22·1). Adjuvant atezolizumab plus bevacizumab was associated with significantly improved recurrence-free survival (median, not evaluable [NE]; [95% CI 22·1–NE]) compared with active surveillance (median, NE [21·4–NE]; hazard ratio, 0·72 [adjusted 95% CI 0·53–0·98]; p=0·012). Grade 3 or 4 adverse events occurred in 136 (41%) of 332 patients who received atezolizumab plus bevacizumab and 44 (13%) of 330 patients in the active surveillance group. Grade 5 adverse events occurred in six patients (2%, two of which were treatment related) in the atezolizumab plus bevacizumab group, and one patient (<1%) in the active surveillance group. Both atezolizumab and bevacizumab were discontinued because of adverse events in 29 patients (9%) who received atezolizumab plus bevacizumab. Among patients at high risk of hepatocellular carcinoma recurrence following curative-intent resection or ablation, recurrence-free survival was improved in those who received atezolizumab plus bevacizumab versus active surveillance. To our knowledge, IMbrave050 is the first phase 3 study of adjuvant treatment for hepatocellular carcinoma to report positive results. However, longer follow-up for both recurrence-free and overall survival is needed to assess the benefit–risk profile more fully. F Hoffmann-La Roche/Genentech.

There is no standard of care for adjuvant therapy for patients with hepatocellular carcinoma. This trial was designed to assess the efficacy and safety of sorafenib versus placebo as adjuvant therapy in patients with hepatocellular carcinoma after surgical resection or local ablation. We undertook this phase 3, double-blind, placebo-controlled study of patients with hepatocellular carcinoma with a complete radiological response after surgical resection (n=900) or local ablation (n=214) in 202 sites (hospitals and research centres) in 28 countries. Patients were randomly assigned (1:1) to receive 400 mg oral sorafenib or placebo twice a day, for a maximum of 4 years, according to a block randomisation scheme (block size of four) using an interactive voice-response system. Patients were stratified by curative treatment, geography, Child-Pugh status, and recurrence risk. The primary outcome was recurrence-free survival assessed after database cut-off on Nov 29, 2013. We analysed efficacy in the intention-to-treat population and safety in randomly assigned patients receiving at least one study dose. The final analysis is reported. This study is registered with ClinicalTrials.gov, number NCT00692770. We screened 1602 patients between Aug 15, 2008, and Nov 17, 2010, and randomly assigned 1114 patients. Of 556 patients in the sorafenib group, 553 (>99%) received the study treatment and 471 (85%) terminated treatment. Of 558 patients in the placebo group, 554 (99%) received the study treatment and 447 (80%) terminated treatment. Median duration of treatment and mean daily dose were 12·5 months (IQR 2·6–35·8) and 577 mg per day (SD 212·8) for sorafenib, compared with 22·2 months (8·1–38·8) and 778·0 mg per day (79·8) for placebo. Dose modification was reported for 497 (89%) of 559 patients in the sorafenib group and 206 (38%) of 548 patients in the placebo group. At final analysis, 464 recurrence-free survival events had occurred (270 in the placebo group and 194 in the sorafenib group). Median follow-up for recurrence-free survival was 8·5 months (IQR 2·9–19·5) in the sorafenib group and 8·4 months (2·9–19·8) in the placebo group. We noted no difference in median recurrence-free survival between the two groups (33·3 months in the sorafenib group vs 33·7 months in the placebo group; hazard ratio [HR] 0·940; 95% CI 0·780–1·134; one-sided p=0·26). The most common grade 3 or 4 adverse events were hand-foot skin reaction (154 [28%] of 559 patients in the sorafenib group vs four [<1%] of 548 patients in the placebo group) and diarrhoea (36 [6%] vs five [<1%] in the placebo group). Sorafenib-related serious adverse events included hand-foot skin reaction (ten [2%]), abnormal hepatic function (four [<1%]), and fatigue (three [<1%]). There were four (<1%) drug-related deaths in the sorafenib group and two (<1%) in the placebo group. Our data indicate that sorafenib is not an effective intervention in the adjuvant setting for hepatocellular carcinoma following resection or ablation. Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals.

ObjectiveSorafenib is the standard systemic therapy for advanced hepatocellular carcinoma (HCC). Survival benefits of resection/local ablation for early HCC are compromised by 70% 5-year recurrence rates. The phase 3 STORM trial comparing sorafenib with placebo as adjuvant treatment did not achieve its primary endpoint of improving recurrence-free survival (RFS). The biomarker companion study BIOSTORM aims to define (A) predictors of recurrence prevention with sorafenib and (B) prognostic factors with B level of evidence.DesignTumour tissue from 188 patients randomised to receive sorafenib (83) or placebo (105) in the STORM trial was collected. Analyses included gene expression profiling, targeted exome sequencing (19 known oncodrivers), immunohistochemistry (pERK, pVEGFR2, Ki67), fluorescence in situ hybridisation (VEGFA) and immunome. A gene signature capturing improved RFS in sorafenib-treated patients was generated. All 70 RFS events were recurrences, thus time to recurrence equalled RFS. Predictive and prognostic value was assessed using Cox regression models and interaction test.ResultsBIOSTORM recapitulates clinicopathological characteristics of STORM. None of the biomarkers tested (related to angiogenesis and proliferation) or previously proposed gene signatures, or mutations predicted sorafenib benefit or recurrence. A newly generated 146-gene signature identifying 30% of patients captured benefit to sorafenib in terms of RFS (p of interaction=0.04). These sorafenib RFS responders were significantly enriched in CD4+ T, B and cytolytic natural killer cells, and lacked activated adaptive immune components. Hepatocytic pERK (HR=2.41; p=0.012) and microvascular invasion (HR=2.09; p=0.017) were independent prognostic factors.ConclusionIn BIOSTORM, only hepatocytic pERK and microvascular invasion predicted poor RFS. No mutation, gene amplification or previously proposed gene signatures predicted sorafenib benefit. A newly generated multigene signature associated with improved RFS on sorafenib warrants further validation.Trial registration number NCT00692770.

Background Post-transplant outcomes for acute liver failure (ALF) are unsatisfactory, and there are debates about the most suitable type of graft. Given the critical shortage of donor organs, accurate assessment of post-transplant outcome in ALF patients is crucial to avoid a futile liver transplantation (LT). Methods A database of 160 consecutive adult ALF patients who underwent primary LT between 2000 and 2009 in a tertiary LT center was analyzed. Results The most common causes of ALF were hepatitis B virus infection (30%) and herbal/folk medicine use (30%). Thirty-six (22.5%) and 124 (77.5%) patients underwent deceased-donor LT (DDLT) and adult-to-adult living-donor LT (LDLT), respectively. During a median follow-up period of 38 (range 1–132) months, the DDLT and LDLT groups showed similar patient ( P  = 0.99) and graft ( P  = 0.97) survival rates. The overall 1- and 3-year patient survival rates were 78.8 and 74.6%, respectively. Five predictors of patient survival were identified by bootstrapping and multivariate analysis: vasopressor requirement, estimated glomerular filtration rate, serum sodium concentration, recipient age, and donor age, at the time of transplant. By summing scores weighted in each of these predictor categories, we designed a prognostic scoring system (scores from −2 to 20) that estimated 1-year post-transplant mortality from 0 to 100% ( c statistic 0.79). Conclusions Long-term outcomes after LDLT and DDLT were comparable in adult patients with ALF. A simple prognostic scoring system that includes 5 predictive variables at the time of LT may help estimate post-transplant survival in ALF patients, regardless of the type of transplant.

The initiation of antiviral treatment in patients with chronic hepatitis B with compensated cirrhosis and low-level viremia (LLV; HBV DNA 15-2,000 IU/mL) remains controversial. We sought to compare the long-term outcomes of these untreated patients according to their viremic status. Six hundred twenty-seven untreated patients with chronic hepatitis B with compensated cirrhosis were analyzed retrospectively. The risk of hepatocellular carcinoma (HCC) and liver-related clinical events, including hepatic decompensation, were compared between patients with LLV and undetectable HBV DNA. Patients who received antiviral treatment were censored during treatment initiation. The mean age of the patients was 54.7 years, 64.4% of whom were male. During the study period, 59 patients developed HCC (20 and 39 in the undetectable and LLV groups, respectively) with an annual incidence of 2.44/100 person-years. Multivariable analysis revealed that the LLV group was associated with a significantly higher risk of HCC (adjusted hazard ratio: 2.36, P = 0.002) than the undetectable group. In the 204 propensity score-matched cohort, the LLV group had a 2.16-fold greater risk of HCC than the undetectable group ( P = 0.014). Liver-related clinical events occurred in 121 patients with an annual incidence of 5.25/100 person-years. Despite not reaching statistical significance, the LLV group tended to have a higher risk of liver-related events in the propensity score-matched cohort (hazard ratio: 1.14, P = 0.50). Compared with patients with undetectable HBV DNA, those with compensated cirrhosis and LLV had a significantly higher risk of HCC. Antiviral treatment should be advised for these patients.

Hepatocellular carcinoma recurs in 70–80% of cases following potentially curative resection or ablation and the immune component of the liver microenvironment plays a key role in recurrence. Many immunosuppressive mechanisms implicated in HCC recurrence are modulated by VEGF and/or immune checkpoints such as PD-L1. Atezolizumab (PD-L1 inhibitor) plus bevacizumab (VEGF inhibitor) has been shown to significantly improve overall survival, progression-free survival and overall response rate in unresectable HCC. Dual PD-L1/VEGF blockade may be effective in reducing HCC recurrence by creating a more immune-favorable microenvironment. We describe the rationale and design of IMbrave 050 (NCT04102098), a randomized, open-label, Phase III study comparing atezolizumab plus bevacizumab versus active surveillance in HCC patients at high-risk of recurrence following curative resection or ablation. The primary end point is recurrence-free survival. NCT04102098