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Introduction: KEYNOTE-240 showed a favorable benefit/risk profile for pembrolizumab versus placebo in patients with sorafenib-treated advanced hepatocellular carcinoma (HCC); however, prespecified statistical significance criteria for overall survival (OS) and progression-free survival (PFS) superiority were not met at the final analysis. Outcomes based on an additional 18 months of follow-up are reported. Methods: Adults with sorafenib-treated advanced HCC were randomized 2:1 to pembrolizumab 200 mg intravenously every 3 weeks or placebo. Dual primary endpoints were OS and PFS assessed per RECIST v1.1 by blinded independent central review (BICR). Secondary endpoints included objective response rate (ORR), assessed per RECIST v1.1 by BICR, and safety. Results: 413 patients were randomized (pembrolizumab, n = 278; placebo, n = 135). As of July 13, 2020, median (range) time from randomization to data cutoff was 39.6 (31.7–48.8) months for pembrolizumab and 39.8 (31.7–47.8) months for placebo. Estimated OS rates (95% CI) were 17.7% (13.4–22.5%) for pembrolizumab and 11.7% (6.8–17.9%) for placebo at 36 months. The estimated PFS rate (95% CI) for pembrolizumab was 8.9% (5.3–13.6%) and 0% for placebo at 36 months. ORR (95% CI) was 18.3% (14.0–23.4%) for pembrolizumab and 4.4% (1.6–9.4%) for placebo. Immune-mediated hepatitis events did not increase with follow-up. No viral hepatitis flare events were reported. Conclusion: With extended follow-up, pembrolizumab continued to maintain improvement in OS and PFS and was associated with a consistent adverse event profile compared with placebo in patients with sorafenib-treated advanced HCC. Although KEYNOTE-240 did not meet prespecified statistical significance criteria at the final analysis, these results together with the antitumor activity of second-line pembrolizumab observed in KEYNOTE-224 and the statistically significant and clinically meaningful OS and PFS benefits of second-line pembrolizumab in patients from Asia observed in KEYNOTE-394 reinforce the clinical activity of pembrolizumab in previously treated patients with advanced HCC. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

• Objective responses and survival were comparable between intent-to-treat (ITT) overall population and Asian cohort. • Median overall survival in Asian patients was similar across HCC aetiologies. • Nivolumab had a manageable safety profile in both the ITT overall population and Asian cohort. Nivolumab, an immune checkpoint inhibitor, is approved in several countries to treat sorafenib-experienced patients with HCC, based on results from the CheckMate 040 study (NCT01658878). Marked differences exist in HCC clinical presentation, aetiology, treatment patterns and outcomes across regions. This analysis assessed the safety and efficacy of nivolumab in the Asian cohort of CheckMate 040. CheckMate 040 is an international, multicentre, open-label, phase I/II study of nivolumab in adults with advanced HCC, regardless of aetiology, not amenable to curative resection or local treatment and with/without previous sorafenib treatment. This analysis included all sorafenib-experienced patients in the intent-to-treat (ITT) overall population and Asian cohort. The analysis cut-off date was March 2018. There were 182 and 85 patients in the ITT population and Asian cohort, respectively. In both populations, most patients were older than 60 years, had BCLC (Barcelona Clinic Liver Cancer) Stage C disease, and had received previous systemic therapy. A higher percentage of Asian patients had HBV infections, extrahepatic metastases and prior therapies. Median follow-up was 31.6 and 31.3 months for the ITT and Asian patients, respectively. Objective response rates were 14% and 15% in the ITT population and Asian cohort, respectively. In the Asian cohort, patients with HBV, HCV or those who were uninfected had objective response rates of 13%, 14% and 21%, respectively. The median duration of response was longer in the ITT (19.4 months) vs. Asian patients (9.7 months). Median overall survival was similar between the ITT (15.1 months) and Asian patients (14.9 months), and unaffected by aetiology in Asian patients. The nivolumab safety profile was similar and manageable across both populations. Nivolumab safety and efficacy are comparable between sorafenib-experienced ITT and Asian patients. The CheckMate 040 study evaluated the safety and efficacy of nivolumab in patients with advanced hepatocellular carcinoma who were refractory to previous sorafenib treatment or chemotherapy. This subanalysis of the data showed that treatment responses and safety in patients in Asia were similar to those of the overall treatment population, providing support for nivolumab as a treatment option for these patients. Clinical trial number: NCT01658878. [ABSTRACT FROM AUTHOR]

Background: 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.Methods: 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.Findings: 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.Interpretation: Our data indicate that sorafenib is not an effective intervention in the adjuvant setting for hepatocellular carcinoma following resection or ablation. [ABSTRACT FROM AUTHOR]

Background & Aims: Hepatocellular carcinoma (HCC) is the second most common cause of cancer deaths worldwide. The global HCC BRIDGE study was a multiregional, large-scale, longitudinal cohort study undertaken to improve understanding of real-life management of patients with HCC, from diagnosis to death., Methods: Data were collected retrospectively from January 2005 to September 2012 by chart reviews of eligible patients newly diagnosed with HCC at participating institutions., Results: Forty-two sites in 14 countries contributed final data for 18 031 patients. Asia accounted for 67% of patients, Europe for 20% and North America for 13%. As expected, the most common risk factor was hepatitis C virus in North America, Europe and Japan, and hepatitis B virus in China, South Korea and Taiwan. The most common Barcelona Clinic Liver Cancer stage at diagnosis was C in North America, Europe, China and South Korea, and A in Taiwan and Japan. Across all stages, first HCC treatment was most frequently transarterial chemoembolization in North America, Europe, China and South Korea, percutaneous ethanol injection or radiofrequency ablation in Japan and resection in Taiwan. Survival from first HCC treatment varied significantly by region, with median overall survival not reached for Taiwan and 60, 33, 31, 24 and 23 months for Japan, North America, South Korea, Europe and China respectively (P < 0.0001)., Conclusions: Initial results from the BRIDGE study confirm previously reported regional trends in patient demographic characteristics and HCC risk factors, document the heterogeneity of treatment approaches across regions/countries and underscore the need for earlier HCC diagnosis worldwide., (© 2015 The Authors. Liver International Published by John Wiley & Sons Ltd.)

Background & Aims: Transarterial chemoembolization (TACE) is used to treat hepatocellular carcinoma (HCC), but it is a challenge to predict patient survival. The hepatic arterial embolization prognostic (HAP) score has been shown to predict which patients will have shorter survival times and should not undergo TACE. We aimed to validate this scoring system in a prospective study of patients in Europe and Asia., Methods: We evaluated the prognostic accuracy of the HAP score in estimating overall survival (OS) of 126 patients with HCC who received TACE in the United Kingdom or Italy (training set) from 2001 through 2013. We also analyzed data from 723 patients treated in Korea and Japan (validation set), including 79 with newly diagnosed HCC, who underwent TACE in Korea or Japan from 2004 through 2013. Response to TACE was determined based on computed tomography analysis. OS was calculated from the time of the first TACE until death or the last follow-up evaluation., Results: OS was associated with hypoalbuminemia, α-fetoprotein level greater than 400 ng/mL, and tumor size greater than 7 cm at diagnosis (P < .01), but not a bilirubin level greater than 17 umol/L (P > .05), in both data sets. The lack of association between OS and bilirubin level was confirmed using receiver operating characteristic analysis. We developed a modified version of the HAP score, based on the level of albumin and α-fetoprotein and tumor size, which predicted OS with increased accuracy in the training and validation cohorts., Conclusions: In a multicenter validation study, we developed a modified version of the HAP that predicts survival of patients with HCC treated with TACE in Europe and Asia. This system might be used to identify patients with HCC most likely to benefit from TACE in clinical practice., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Liver cancer is both common and burdensome in Asia. Effective liver cancer control, however, is hindered by a complex etiology and a lack of coordination across clinical disciplines. We sought to identify strategies for inclusion in a comprehensive liver cancer control for Asia and to compare qualitative and quantitative methods for prioritization., Methods: Qualitative interviews (N = 20) with international liver cancer experts were used to identify strategies using Interpretative Phenomenological Analysis and to formulate an initial prioritization through frequency analysis. Conjoint analysis, a quantitative stated-preference method, was then applied among Asian liver cancer experts (N = 20) who completed 12 choice tasks that divided these strategies into two mutually exclusive and exhaustive subsets. Respondents' preferred plan was the primary outcome in a choice model, estimated using ordinary least squares (OLS) and logistic regression. Priorities were then compared using Spearman's Rho., Results: Eleven strategies were identified: Access to treatments; Centers of excellence; Clinical education; Measuring social burden; Monitoring of at-risk populations; Multidisciplinary management; National guidelines; Public awareness; Research infrastructure; Risk-assessment and referral; and Transplantation infrastructure. Qualitative frequency analysis indicated that Risk-assessment and referral (85%), National guidelines (80%) and Monitoring of at-risk populations (80%) received the highest priority, while conjoint analysis pointed to Monitoring of at-risk populations (p < 0.001), Centers of excellence (p = 0.002), and Access to treatments (p = 0.004) as priorities, while Risk-assessment and referral was the lowest priority (p = 0.645). We find moderate concordance between the qualitative and quantitative methods (rho = 0.20), albeit insignificant (p = 0.554), and a strong concordance between the OLS and logistic regressions (rho = 0.979; p < 0.0001)., Conclusions: Identified strategies can be conceptualized as the ABCs of comprehensive liver cancer control as they focus on Antecedents, Better care and Connections within a national strategy. Some concordance was found between the qualitative and quantitative methods (e.g. Monitoring of at-risk populations), but substantial differences were also identified (e.g. qualitative methods gave highest priority to risk-assessment and referral, but it was the lowest for the quantitative methods), which may be attributed to differences between the methods and study populations, and potential framing effects in choice tasks. Continued research will provide more generalizable estimates of priorities and account for variation across stakeholders and countries.

Background: Hepatocellular carcinoma (HCC) is particularly burdensome in the Asia-Pacific region, however, cross-country comparisons have been limited to somewhat unreliable epidemiological measures. We conducted a comparative needs assessment for HCC control policy to inform HCC control efforts in the Asia-Pacific region. The aims were to identify regional needs, to compare overall competence across the region, and to identify which needs were concordant across the region., Method: Using the self-explicated method, a stated-preference approach, clinical experts from Australia, China, Japan, Korea, Taiwan, and the United States valued ten previously identified dimensions of HCC control: clinical education; risk assessment; HBV strategy; HCV strategy; life-style risk factors; national statistics; funding for screening; funding for treatment; political awareness; and public awareness. Results were normalized and analyzed using Z-scores and ANOVA, with concordance of need across the region tested via the F-test., Results: Seventy-two respondents, equally drawn from the study sites, completed the survey (response rate: 36%). Respondents were hepatologists (39%), oncologists (21%), radiologists (17%), surgeons (17%), and other specialists (7%) who were involved in liver cancer control at local/regional (35%) national (44%) or international (21%) levels. In aggregate, the most significant needs were political awareness, public awareness, and life-style risk factors (all p<0.001). Significant differences in aggregate competence were observed across the region (p<0.001), with better than expected competence reported by respondents from Taiwan (p<0.001), Japan (p=0.006), and Korea (0.041), and close to expected competence reported by respondents from Australia, China, and USA (all p>0.05). There were differences in the extent of needs across the region (p<0.05) on all dimensions except funding for screening, clinical education and life style risk factors., Conclusions: As the first comparative needs assessment for HCC for the Asia-Pacific region, our results can inform national and cross-national priorities for intervention and facilitate the identification of best practices. Regional efforts to control HCC should adopt as objectives the needs for greater political and public awareness and improved management of lifestyle risk factors because these are the most significant needs, and are shared concerns across the region.

Hepatocellular carcinoma is a highly prevalent disease in many Asian countries, accounting for 75-80% of victims worldwide. The incidence of hepatocellular carcinoma varies enormously across Asia, but tends to follow the incidences of hepatitis B infection and liver cirrhosis. The incidence and etiology of hepatocellular carcinoma in Japan are different from the rest of Asia, but similar to that in Western countries because hepatitis C infection is the main etiological factor in Japan. Hepatitis B virus vaccination programs are showing great success in reducing hepatitis B virus-related hepatocellular carcinoma. Screening program improves detection of early hepatocellular carcinoma and has some positive impact on survival, but the majority of hepatocellular carcinoma patients in Asia still present with advanced hepatocellular carcinoma. Long-term outcomes following treatment of even early/intermediate or advanced disease are often unsatisfactory because of a lack of effective adjuvant and systemic therapies. Various clinical practice guidelines for hepatocellular carcinoma have been established and are in use. Clinical diagnosis of hepatocellular carcinoma by imaging diagnosis is replacing diagnosis of hepatocellular carcinoma by pathological confirmation. New imaging and treatment techniques are continuously being developed and guidelines should be updated every 3 or 4 years, incorporating new evidence. New molecularly targeted therapies hold great promise. Sorafenib is the first systemic therapy to demonstrate prolonged survival vs. the placebo in patients with advanced hepatocellular carcinoma. Various other new molecularly targeted agents are currently under investigation.

Hepatocellular carcinoma (HCC) is a heterogeneous condition, with multiple confounding factors making patient assessment extremely complex. Tumor burden, the presence of symptoms, liver function, and comorbidities must all be considered to ensure accurate patient assessment, thereby providing physicians with a common language on which to base treatment decisions and guide research. Although many staging classifications have been developed, there is no consensus on the best classification to use. The Barcelona Clinic Liver Cancer system is a promising candidate for a standard western classification, because it has been externally validated and is endorsed by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases. Similarly, the biomarker-combined Japanese Integrated Staging (JIS) score is the most promising candidate for a standard Asia-Pacific classification, because it has been externally validated and shown to be superior to conventional JIS. Because risk factors vary significantly by region, so too does the predictive power of current staging classifications; any standard global staging classification would need to be validated in both western and Asia-Pacific patients. To date, no such globally validated classification exists. Findings from scientific research have improved our understanding of HCC and enabled us to refine current classifications. The role of tumor markers to predict survival was recently reported, and α-fetoprotein, lens culinaris agglutinin-reactive α-fetoprotein, and des-γ-carboxyprothrombin have now been incorporated into some classifications. Molecular markers have also been linked with poor outcomes and will likely play a role in future classifications. Although more work is required, it is hoped that these and other ongoing research efforts will eventually enable the development of a global staging classification.