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Hepatocellular carcinoma, historically, has had a poor prognosis with very few systemic options. Furthermore, most patients at diagnosis are not surgical candidates. Therefore, locoregional therapy (LRT) has been widely used, with strong data supporting its use. Over the last 15 years, there has been progress in the available systemic agents. This has led to the updated Barcelona Clinic Liver Cancer (BCLC) algorithm's inclusion of these new systemic agents, with advocacy of earlier usage in those who progress on LRT or have tumor characteristics that make them less likely to benefit from LRT. However, neither the adjunct of LRT nor the specific sequencing of combination therapies is addressed directly. This Research Consensus Panel sought to highlight research priorities pertaining to the combination and optimal sequencing of LRT and systemic therapy, assessing the greatest needs across BCLC stages. [Display omitted] [ABSTRACT FROM AUTHOR]

Systemic therapies have improved the management of hepatocellular carcinoma, but there is still a need to further enhance overall survival in first-line advanced stages. This study aimed to evaluate the addition of pembrolizumab to lenvatinib versus lenvatinib plus placebo in the first-line setting for unresectable hepatocellular carcinoma. In this global, randomised, double-blind, phase 3 study (LEAP-002), patients aged 18 years or older with unresectable hepatocellular carcinoma, Child Pugh class A liver disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no previous systemic treatment were enrolled at 172 global sites. Patients were randomly assigned (1:1) with a central interactive voice-response system (block size of 4) to receive lenvatinib (bodyweight <60 kg, 8 mg/day; bodyweight ≥60 kg, 12 mg/day) plus pembrolizumab (200 mg every 3 weeks) or lenvatinib plus placebo. Randomisation was stratified by geographical region, macrovascular portal vein invasion or extrahepatic spread or both, α-fetoprotein concentration, and Eastern Cooperative Oncology Group performance status. Dual primary endpoints were overall survival (superiority threshold at final overall survival analysis, one-sided p=0·019; final analysis to occur after 532 events) and progression-free survival (superiority threshold one-sided p=0·002; final analysis to occur after 571 events) in the intention-to-treat population. Results from the final analysis are reported. This study is registered with ClinicalTrials.gov , NCT03713593 , and is active but not recruiting. Between Jan 17, 2019, and April 28, 2020, of 1309 patients assessed, 794 were randomly assigned to lenvatinib plus pembrolizumab (n=395) or lenvatinib plus placebo (n=399). Median age was 66·0 years (IQR 57·0–72·0), 644 (81%) of 794 were male, 150 (19%) were female, 345 (43%) were Asian, 345 (43%) were White, 22 (3%) were multiple races, 21 (3%) were American Indian or Alaska Native, 21 (3%) were Native Hawaiian or other Pacific Islander, 13 (2%) were Black or African American, and 46 (6%) did not have available race data. Median follow up as of data cutoff for the final analysis (June 21, 2022) was 32·1 months (IQR 29·4–35·3). Median overall survival was 21·2 months (95% CI 19·0–23·6; 252 [64%] of 395 died) with lenvatinib plus pembrolizumab versus 19·0 months (17·2–21·7; 282 [71%] of 399 died) with lenvatinib plus placebo (hazard ratio [HR] 0·84; 95% CI 0·71–1·00; stratified log-rank p=0·023). As of data cutoff for the progression-free survival final analysis (April 5, 2021), median progression-free survival was 8·2 months (95% CI 6·4–8·4; 270 events occurred [42 deaths; 228 progressions]) with lenvatinib plus pembrolizumab versus 8·0 months (6·3–8·2; 301 events occurred [36 deaths; 265 progressions]) with lenvatinib plus placebo (HR 0·87; 95% CI 0·73–1·02; stratified log-rank p=0·047). The most common treatment-related grade 3–4 adverse events were hypertension (69 [17%] of 395 patients in the lenvatinib plus pembrolizumab group vs 68 [17%] of 395 patients) in the lenvatinib plus placebo group), increased aspartate aminotransferase (27 [7%] vs 17 [4%]), and diarrhoea (25 [6%] vs 15 [4%]). Treatment-related deaths occurred in four (1%) patients in the lenvatinib plus pembrolizumab group (due to gastrointestinal haemorrhage and hepatorenal syndrome [n=1 each] and hepatic encephalopathy [n=2]) and in three (1%) patients in the lenvatinib plus placebo group (due to gastrointestinal haemorrhage, hepatorenal syndrome, and cerebrovascular accident [n=1 each]). In earlier studies, the addition of pembrolizumab to lenvatinib as first-line therapy for advanced hepatocellular carcinoma has shown promising clinical activity; however, lenvatinib plus pembrolizumab did not meet prespecified significance for improved overall survival and progression-free survival versus lenvatinib plus placebo. Our findings do not support a change in clinical practice. Eisai US, and Merck Sharp & Dohme, a subsidiary of Merck. [ABSTRACT FROM AUTHOR]

Several breakthroughs in hepatocellular carcinoma (HCC) therapy across tumor stages provide hope to improve its dismal prognosis. Although surgical and local ablative therapies have few significant changes in technique, an improved understanding of tumor biology has facilitated increase numbers of patients who are now eligible to undergo curative-intent procedures. Most notably, acceptable post-transplant outcomes can be achieved in well selected patients whose tumors are downstaged into Milan Criteria. Adjuvant therapy in patients at high risk of recurrence also significantly improves recurrence-free survival after resection or ablation. For patients with liver-localized disease who are not eligible for curative-intent procedures, transarterial chemoembolization (TACE) was historically the treatment modality of choice, regardless of tumor burden; however, there is now increased recognition of patients who are "TACE unsuitable" and may be better treated with systemic therapy. The greatest evolution in HCC treatment options has occurred with systemic therapy, where several new agents are now available in the first- and second-line setting, including immune checkpoint inhibitor combinations. Objective responses are observed in approximately 30% of patients and median survival is approaching 2 years. The availability of immune checkpoint inhibitors has renewed interest in combination therapies for earlier tumor stages, with several phase III trials ongoing. Considering increasing complexities of HCC care, requiring decisions between therapies delivered by different providers, multidisciplinary care is critical and is associated with improved clinical outcomes. In this review, we detail major breakthroughs in HCC therapy, how these breakthroughs can be applied in clinical practice, and remaining areas in need of further research. [ABSTRACT FROM AUTHOR]

Pembrolizumab, a PD-1 inhibitor, demonstrated anti-tumour activity and tolerability in patients treated with sorafenib and with advanced hepatocellular carcinoma in KEYNOTE-224. Longer-term efficacy and safety after ∼2.5 years of additional follow-up are reported. Adults with confirmed hepatocellular carcinoma who experienced progression after or intolerance to sorafenib treatment received pembrolizumab 200 mg every 3 weeks for ≤35 cycles or until confirmed progression, unacceptable toxicity, withdrawal of consent or investigator decision. The primary end-point was objective response rate assessed by blinded independent central review per Response Evaluation Criteria in Solid Tumours v1.1. The secondary end-points included duration of response, disease control rate, time to progression, progression-free survival, overall survival and adverse events. Efficacy and safety were assessed in 104 patients. The median time from first dose to data cutoff was 45.1 months (range, 41.3–49.3). Objective response rate was 18.3% (95% CI: 11.4–27.1), and median duration of response was 21.0 months (range, 3.1 to 39.5+). Disease control rate was 61.5%, and median time to progression was 4.8 months (95% CI: 3.9–7.0). Median progression-free survival was 4.9 months (95% CI: 3.5–6.7) and median overall survival was 13.2 months (95% CI: 9.7–15.3). Of 104 patients, 76 (73.1%) patients reported treatment-related adverse events; most were low grade in severity (grade 3–4, n = 26 [25.0%]; grade 5, n = 1 [1.0%]). Immune-mediated hepatitis occurred in 3 patients (all grade 3). No viral-induced hepatitis flares occurred. After ∼2.5 years of additional follow-up, pembrolizumab continued to provide durable anti-tumour activity and no new safety concerns were identified. NCT02702414. • KEYNOTE-224 was a phase II study involving sorafenib-treated patients with hepatocellular carcinoma. • This post hoc analysis of KEYNOTE-224 evaluated longer-term efficacy and safety. • Pembrolizumab continued to provide durable anti-tumour activity in patients with hepatocellular carcinoma. • After an additional ∼2.5 years of follow-up, no new safety concerns were identified. [ABSTRACT FROM AUTHOR]

Patients with advanced hepatocellular carcinoma (aHCC) and Child-Pugh B liver function are often excluded from clinical trials. In previous studies, overall survival for these patients treated with sorafenib was ∼3–5 months; thus, new treatments are needed. Nivolumab, alone or in combination with ipilimumab, is conditionally approved in the United States to treat patients with aHCC who previously received sorafenib. We describe nivolumab monotherapy outcomes in patients with Child-Pugh B status. This phase I/II, open-label, non-comparative, multicentre trial (27 centres) included patients with Child-Pugh B (B7–B8) aHCC. Patients received intravenous nivolumab 240 mg every 2 weeks until unacceptable toxicity or disease progression. Primary endpoints were objective response rate (ORR) by investigator assessment (using Response Evaluation Criteria in Solid Tumors v1.1) and duration of response. Safety was assessed using National Cancer Institute Common Terminology Criteria for Adverse Events v4.0. Twenty-five sorafenib-naive and 24 sorafenib-treated patients began treatment between November 2016 and October 2017 (median follow-up, 16.3 months). Investigator-assessed ORR was 12% (95% CI 5–25%) with 6 patients responding; disease control rate was 55% (95% CI 40–69%). Median time to response was 2.7 months (interquartile range, 1.4–4.2), and median duration of response was 9.9 months (95% CI 9.7–9.9). Treatment-related adverse events (TRAEs) were reported in 25 patients (51%) and led to discontinuation in 2 patients (4%). The most frequent grade 3/4 TRAEs were hypertransaminasemia (n = 2), amylase increase (n = 2), and aspartate aminotransferase increase (n = 2). The safety of nivolumab was comparable to that in patients with Child-Pugh A aHCC. Nivolumab showed clinical activity and favourable safety with manageable toxicities, suggesting it could be suitable for patients with Child-Pugh B aHCC. In patients with advanced hepatocellular carcinoma, almost all systemic therapies require very good liver function, i.e. Child-Pugh A status. The evidence from this study suggests that nivolumab shows clinical activity and an acceptable safety profile in patients with hepatocellular carcinoma with Child-Pugh B status who have mild to moderate impairment of liver function or liver decompensation that might rule out other therapies. Further studies are warranted to assess the safety and efficacy of nivolumab in this patient population. NCT01658878. [Display omitted] • This is the first report, to our knowledge, of immune checkpoint inhibitor therapy in patients with advanced HCC and Child-Pugh B liver function status. • Median OS with nivolumab was longer than the historical OS rate for patients treated with sorafenib (7.6 months vs. 2.5–5.4 months, respectively). • Clinically meaningful stabilisation of liver function was observed, as evidenced by maintained or improved Child-Pugh scores and albumin-bilirubin scores. • Nivolumab had a favourable safety profile with manageable toxicities when used in patients with Child-Pugh B advanced HCC and was comparable to that seen in patients with Child-Pugh A HCC. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality in Japan. Prognosis is poor, and until recently sorafenib was the only treatment option available for patients with unresectable disease. Lenvatinib is the first therapy to demonstrate noninferiority to sorafenib. An analysis was conducted using clinical data from Japanese patients in the phase III REFLECT trial to assess the cost-effectiveness of lenvatinib versus sorafenib for first-line treatment of unresectable HCC in Japan. A partitioned survival model was implemented adopting the perspective of the Japanese healthcare system, with costs and outcomes modeled over a lifetime horizon and using a discount rate of 2%, as per Japanese guidelines. Population data from the Japanese subpopulation of REFLECT were used to extrapolate outcomes, and costs and resource use were based on Japanese sources. The Japanese tariff was applied to EQ-5D data collected during the REFLECT clinical trial to obtain utility values reflecting the preferences of the Japanese population. Compared with sorafenib, lenvatinib is dominant because it is associated with a reduction in incremental costs of ¥156 799 and incremental quality-adjusted life-years of 0.31. These results were robust to changes in key assumptions, and probabilistic outcomes aligned with deterministic outcomes. Given the use of Japan-specific data in the cost-effectiveness model, it is expected that the use of lenvatinib as a first-line treatment in Japan will be associated with cost savings and improved clinical outcomes versus sorafenib for patients with unresectable HCC. [ABSTRACT FROM AUTHOR]

Kupffer-phase imaging visualized by perfluorobutane (Sonazoid) distribution into normal liver tissues upon phagocytosis by Kupffer cells potentially aids in improving detection of liver metastasis compared with fundamental B-mode EUS (FB-EUS). However, the diagnostic performance of Kupffer-phase imaging in contrast-enhanced harmonic EUS (CH-EUS) remains unclear. Hence, this study aimed to evaluate the usefulness of CH-EUS-based Kupffer-phase imaging for diagnosing liver metastasis from pancreatic cancer. We retrospectively analyzed consecutive patients with pancreatic cancer who underwent contrast-enhanced CT (CE-CT) and FB-EUS, followed by CH-EUS, from 2011 to 2017. The diagnostic ability of CH-EUS against that of CE-CT and FB-EUS for metastasis in the left liver lobe was compared. Subsequently, the influences of CH-EUS on the determination of clinical stage and patient management for pancreatic cancer were assessed. We enrolled 426 patients with pancreatic cancer. Metastasis in the left liver lobe was present in 27.2% of patients. The diagnostic accuracy of CE-CT, FB-EUS, and CH-EUS was 90.6%, 93.4%, and 98.4%, respectively. The sensitivity and diagnostic accuracy of CH-EUS for metastasis in the left liver lobe were significantly higher than those of FB-EUS or CE-CT. The sensitivity of CH-EUS for detecting small liver metastasis (<10 mm) was considerably higher than that of CE-CT or FB-EUS (P <.001). In 2.1% of patients, only CH-EUS could detect a single distant metastasis of the left liver lobe, thereby upgrading the tumor staging and altering the clinical management. CH-EUS-based Kupffer-phase imaging increased the detectability of metastasis in the left liver lobe. This technique could be a reliable pretreatment imaging modality for clinical decision-making in patients with pancreatic cancer. [ABSTRACT FROM AUTHOR]

Data are inconsistent regarding the effects of a wide surgical margin for intrahepatic cholangiocarcinoma on recurrence-free survival and overall survival. This study was performed to investigate the effect of surgical margin width in patients undergoing R0 resection for intrahepatic cholangiocarcinoma, using a nationwide database in Japan. In total, 635 patients with intrahepatic cholangiocarcinoma who were treated by an R0 resection from 2000 to 2007 were identified from the database of a Japanese nationwide survey. Patients were divided into quartiles of the surgical margin width as follows: marginal (<1 mm), narrow (1–4 mm), intermediate (5–9 mm), and wide groups (≥10 mm). Multivariable Cox regression models for recurrence-free survival and overall survival were constructed with adjustment for preoperative and postoperative clinicopathologic factors. Compared with the marginal group, the risk-adjusted hazard ratios (95% confidence intervals) in the narrow, intermediate, and wide groups for recurrence-free survival were 0.92 (0.62–1.37), 0.91 (0.61–1.37), and 0.81 (0.56–1.17), and those for overall survival were 0.79 (0.51–1.24), 0.93 (0.59–1.47), and 0.70 (0.46–1.08), respectively. In 398 patients without lymph node metastasis, the hazard ratios for overall survival were 0.62 (0.34–1.11), 0.63 (0.34–1.17), and 0.51 (0.29–0.90), and those of mass-forming type intrahepatic cholangiocarcinoma were 0.48 (0.21–1.08), 0.43 (0.19–0.96), and 0.40 (0.19–0.82), respectively. Surgical margin width appears to have a limited effect on the prognosis of intrahepatic cholangiocarcinoma except in patients without lymph node metastasis, where a wide surgical margin is associated with favorable outcomes. This survival benefit of a wide surgical margin is especially apparent for the mass-forming type intrahepatic cholangiocarcinoma. [ABSTRACT FROM AUTHOR]

Contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) is used for the diagnosis of pancreatic cancer (PC). Here, we examined the usefulness of CH-EUS for evaluating therapeutic responses in PC. The study included 23 patients with PC who received chemotherapy. Patients underwent contrast-enhanced computed tomography (CE-CT) and CH-EUS before chemotherapy and at the time of evaluation of the therapeutic response. Patients with a ≧50% reduction in serum carbohydrate antigen 19–9 levels after chemotherapy were defined as "super responders". The incidence of an avascular area in the tumor on CH-EUS after chemotherapy was compared between "super responders" and non-super responders. Nine patients were included in the "super responders" group.Tumor reduction rates did not differ significantly between CE-CT and CH-EUS in the "super responders". The appearance of an avascular area was detected in 7 of 9 super responders (77.8%) and in 4 of 14 non-super responders (28.6%), and the difference was significant (P = 0.036). The mean survival time of patients with an avascular area after chemotherapy was longer than that of without an avascular area. Detection of avascular areas by CH-EUS after chemotherapy may predict long-term survival of patients with PC. [ABSTRACT FROM AUTHOR]

Platelet transfusion is used to prevent hemorrhagic events in patients with thrombocytopenia undergoing invasive procedures, but there are many disadvantages. We evaluated the efficacy and safety of lusutrombopag in patients with chronic liver disease and thrombocytopenia undergoing invasive procedures. We performed a double-blind, parallel-group, phase 3 study of 96 patients with chronic liver disease and thrombocytopenia (platelet counts below 50,000/μL) undergoing invasive procedures from October 2013 to May 2014 at 81 centers in Japan. Patients were randomly assigned (1:1) to groups given once-daily lusutrombopag (3 mg) or placebo for up to 7 days. The primary efficacy endpoint was the proportion of patients not requiring platelet transfusion before the invasive procedure. The protocol-defined response (platelet count 50,000/μL or more with an increase of 20,000/μL or more from baseline) and the time course of the change in platelet count were also evaluated. Adverse events were recorded. The proportions of patients who did not require preoperative platelet transfusion were 79.2% (38/48) in the lusutrombopag group and 12.5% (6/48) in the placebo group (P <.0001). A response was observed in 77.1% (37/48) of patients in the lusutrombopag group and 6.3% (3/48) of patients in the placebo group (P <.0001). In the lusutrombopag group without platelet transfusion, the median platelet count was 50,000/μL or more after 5 days; the mean time to reach the maximum platelet count was 13.4 days; and the number of days (adjusted mean) during which the platelet count was 50,000/μL or more was 21.09 days. Adverse drug reactions were reported in 8.3% of patients in the lusutrombopag group and 2.1% of patients in the placebo group. Two patients (1 per group) had a thrombotic event, but neither were associated with an excessive increase in platelet count (200,000/μL or more). In a placebo-controlled trial, lusutrombopag was effective in achieving and maintaining the target platelet count in patients with chronic liver disease and thrombocytopenia undergoing invasive procedures. No significant safety concerns were raised. Japanese clinical trial registration no: JapicCTI-132323 [ABSTRACT FROM AUTHOR]