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Abstract Background & aims The benefit of postoperative adjuvant transcatheter arterial chemoembolization (pTACE) for patients with hepatocellular carcinoma (HCC), especially those with Child-Pugh (CP) B, remains controversial. This study aimed to assess the survival benefit of pTACE for HCC patients with CP B. Methods Data from 297 HCC patients with CP B7 or B8 were analyzed, dividing them into groups with and without pTACE (70, 23.6% vs. 227, 76.4%). Propensity score matching (PSM) was used to control for confounding bias, and competing-risk regression was applied to address bias from non-cancer-specific death (NCSD). Results Preliminary findings suggest that pTACE did not increase the incidence of severe complications in HCC patients with CP B7 or B8. Survival analysis indicated that the group receiving pTACE had better overall survival and recurrence-free survival than the group without pTACE after PSM. Furthermore, competitive risk analysis revealed that pTACE was an independent prognostic factor associated with reduced cancer-specific death incidence (subdistribution hazard ratio [SHR] 0.644, 95%CI: 0.378–0.784, P = 0.011) and recurrence (SHR 0.635, 95% CI: 0.379–0.855, P = 0.001). Importantly, pTACE did not increase NCSD. Subgroup analysis corroborated these results. Conclusion Adjuvant TACE demonstrates the potential to significantly enhance the long-term prognosis of HCC patients with CP B7 or B8 following hepatectomy, particularly those with multiple tumors, large tumor size, macrovascular or microvascular invasion, and narrow resection margin. Hence, pTACE should be considered for patients at high risk of recurrence following thorough evaluation.

Background & aims: The benefit of postoperative adjuvant transcatheter arterial chemoembolization (pTACE) for patients with hepatocellular carcinoma (HCC), especially those with Child-Pugh (CP) B, remains controversial. This study aimed to assess the survival benefit of pTACE for HCC patients with CP B. Methods: Data from 297 HCC patients with CP B7 or B8 were analyzed, dividing them into groups with and without pTACE (70, 23.6% vs. 227, 76.4%). Propensity score matching (PSM) was used to control for confounding bias, and competing-risk regression was applied to address bias from non-cancer-specific death (NCSD). Results: Preliminary findings suggest that pTACE did not increase the incidence of severe complications in HCC patients with CP B7 or B8. Survival analysis indicated that the group receiving pTACE had better overall survival and recurrence-free survival than the group without pTACE after PSM. Furthermore, competitive risk analysis revealed that pTACE was an independent prognostic factor associated with reduced cancer-specific death incidence (subdistribution hazard ratio [SHR] 0.644, 95%CI: 0.378–0.784, P = 0.011) and recurrence (SHR 0.635, 95% CI: 0.379–0.855, P = 0.001). Importantly, pTACE did not increase NCSD. Subgroup analysis corroborated these results. Conclusion: Adjuvant TACE demonstrates the potential to significantly enhance the long-term prognosis of HCC patients with CP B7 or B8 following hepatectomy, particularly those with multiple tumors, large tumor size, macrovascular or microvascular invasion, and narrow resection margin. Hence, pTACE should be considered for patients at high risk of recurrence following thorough evaluation. [ABSTRACT FROM AUTHOR]

The efficacy of systemic therapy for unresectable advanced hepatocellular carcinoma (aHCC) has not been proven in patients with Child-Pugh (C-P) B cirrhosis. Nevertheless, in real-world these patients are treated both with tyrosine kinase inhibitors (TKIs) and with metronomic capecitabine (MC). This study aimed to compare sorafenib and MC outcomes versus best supportive care (BSC) in C-P B patients. Between 2008 and 2020, among 774 C-P B patients with aHCC not amenable/responsive to locoregional treatments, 410 underwent sorafenib, 62 MC, and 302 BSC. The propensity score matching method was used to correct the baseline unbalanced prognostic factors. In the unmatched population, median OS was 9.7 months in patients treated with sorafenib, 8.0 with MC, and 3.9 months with BSC. In sorafenib vs. BSC-matched patients (135 couples), median OS was 7.3 (4.9–9.6) vs. 3.9 (2.6–5.2) months (p <0.001). ECOG-Performance Status, tumor size, macrovascular invasion, AFP, treatment-naive, and sorafenib were independent predictors of survival. In MC vs. BSC-matched patients (40 couples), median OS was 9.0 (0.2–17.8) vs.3.0 (2.2–3.8) months (p <0.001). Median OS did not differ (p = 0.283) in sorafenib vs. MC-matched patients (55 couples). C-P B patients with aHCC undergoing BSC have poor survival. Both Sorafenib and MC treatment improve their prognosis. [ABSTRACT FROM AUTHOR]

Introduction: Systemic therapy is recommended for patients with Child-Pugh A in hepatocellular carcinoma (HCC). We analyzed the outcomes of a cohort of patients with HCC who received either sorafenib (Sor), lenvatinib (Len) or atezolizumab plus bevacizumab (Atezo + Bev) as first-line systemic therapy for HCC, with the aim of identifying prognostic factors for survival. Methods: A total of 825 patients with advanced HCC and Child-Pugh A or B received either Sor, Len or Atezo + Bev as first-line systemic therapy. Liver function was assessed according to the Child-Pugh score and the modified albumin-bilirubin (mALBI) grade. Results: Prognosis was analyzed according to liver function such as Child-Pugh classifications, scores, and mALBI grades that worsened with a decline in liver function (p <0.001 for all). A Child-Pugh score of 7 was a factor significantly associated with OS. In patients with a Child-Pugh score of 7, an mALBI grade of 3 was an independent predictor of OS. In Child-Pugh B patients with HCC, receiving Atezo + Bev was identified as a factor associated with PFS. Conclusion: Determining the hepatic reserve of patients with unresectable HCC might be useful for identifying patents suitable for systemic treatment for HCC. Atezo + Bev might prolong the PFS of patients with a Child-Pugh score of 7. [ABSTRACT FROM AUTHOR]

BACKGROUND: Patients with hepatocellular carcinoma (HCC) and Child-Pugh B liver cirrhosis have poor prognosis and are underrepresented in clinical trials. The CELESTIAL trial, in which cabozantinib improved overall survival (OS) and progression-free survival (PFS) versus placebo in patients with HCC and Child-Pugh A liver cirrhosis at baseline, was evaluated for outcomes in patients who had Child-Pugh B cirrhosis at Week 8. METHODS: This was a retrospective analysis of adult patients with previously treated advanced HCC. Child-Pugh B status was assessed by the investigator. Patients were randomised 2:1 to cabozantinib (60 mg once daily) or placebo. RESULTS: Fifty-one patients receiving cabozantinib and 22 receiving placebo had Child-Pugh B cirrhosis at Week 8. Safety and tolerability of cabozantinib for the Child-Pugh B subgroup were consistent with the overall population. For cabozantinib- versus placebo-treated patients, median OS from randomisation was 8.5 versus 3.8 months (HR 0.32, 95% CI 0.18-0.58), median PFS was 3.7 versus 1.9 months (HR 0.44, 95% CI 0.25-0.76), and best response was stable disease in 57% versus 23% of patients. CONCLUSIONS: These encouraging results with cabozantinib support the initiation of prospective studies in patients with advanced HCC and Child-Pugh B liver function. CLINICAL TRIAL REGISTRATION: NCT01908426.

BackgroundLenvatinib is an approved first-line treatment for unresectable hepatocellular carcinoma (uHCC). We evaluated the safety and efficacy of lenvatinib versus sorafenib in patients with uHCC who deteriorated to Child-Pugh class B (CP-B) on treatment.MethodsWe retrospectively evaluated patients from REFLECT who deteriorated to CP-B versus those who remained Child-Pugh class A (CP-A) within 8 weeks after randomization. Best overall response and objective response rate (ORR) per modified Response Evaluation Criteria In Solid Tumors (mRECIST) were assessed from baseline. Progression-free survival (PFS) per mRECIST and overall survival (OS) were assessed beginning at week 8.ResultsPatients with CP-B versus CP-A classification receiving lenvatinib had ORRs of 28.3 and 42.9%, respectively; patients with CP-B versus CP-A classification receiving sorafenib had ORRs of 8.5 and 12.9%, respectively. Median PFS and OS (landmark analyses beginning at week 8) in patients receiving lenvatinib were 3.7 months [95% confidence interval (CI): 1.8-7.4] and 6.8 months (95% CI: 2.6-10.3) in the CP-B subgroup versus 6.5 months (95% CI: 5.6-7.4) and 13.3 months (95% CI: 11.6-16.1) in the CP-A subgroup, respectively. Median PFS and OS in patients receiving sorafenib were 0.5 months (95% CI: 0.1-3.6) and 4.5 months (95% CI: 2.9-6.1) in the CP-B subgroup versus 3.6 months (95% CI: 2.7-3.7) and 12.0 months (95% CI: 10.2-14.0) in the CP-A subgroup, respectively. The most common treatment-emergent adverse events in the lenvatinib cohort were hypertension (both subgroups) and decreased appetite (CP-B subgroup).ConclusionResults suggest that patients with uHCC whose liver function deteriorates to CP-B after initiation of therapy may continue to receive lenvatinib.Trial registrationClinicalTrials.gov, NCT01761266, https://clinicaltrials.gov/ct2/show/NCT01761266.

Abstract Hepatocellular carcinoma (HCC) is a major cause of death among patients with liver cirrhosis. The rise of immuno‐oncology has revolutionized treatment for advanced HCC. However, most pivotal randomized controlled trials have excluded patients with moderate liver dysfunction (Child–Pugh–Turcotte B), despite the high incidence of liver disease in patients with HCC at the time of diagnosis. Overall survival in patients with HCC and moderate liver dysfunction treated with sorafenib has been found to be only approximately 3–5 months, underlining the need for improved treatment algorithms for this increasingly important subgroup of patients. In this review, we summarize available data on the treatment of patients with HCC and moderate liver dysfunction. Opportunities, as well as clinical challenges, are discussed in detail, highlighting potential changes to the therapeutic landscape.

Abstract Background and Aims Hepatocellular carcinoma (HCC) patients with Child‐Pugh (CP)‐B not eligible for surgery nor other focal therapy options due to impaired liver function, have very limited treatment options. This study aims to retrospectively investigate the toxicity and efficacy of Carbon‐ion radiotherapy (C‐ion RT) on HCC with CP‐B patients. Materials and Methods Patients with CP‐B, no extrahepatic metastasis, and treated with C‐ion RT between May 2000 and March 2020 were retrospectively extracted and included in this study. Results Sixty‐nine lesions of 58 patients were included. The median follow‐up duration was 20.5 (2.7–108) months. During follow‐up, recurrence was observed in 43 patients, including 2 local recurrences and 39 intrahepatic recurrences beyond the irradiation field. A grade 3 acute hepatotoxicity was observed in one patient during the observation period. No acute or late adverse event of grade ≥4 was observed. Overall survival was 80.4% and 46.0% at 1 and 2 years, respectively, and the median survival time was 22.6 months. Local control rate was 96.4% at both 1 and 2 years, and progression‐free survival was 38.6% and 6.9% at 1 and 2 years, respectively, with a median of 9.7 months. Conclusion The C‐ion RT showed low toxicity and good local effect in patients with HCC and CP‐B. Therefore, C‐ion RT could be an appropriate treatment for patients with HCC with poor liver function.

Introduction: Systemic treatment is generally recommended for Child-Pugh (CP) A status patients with an unresectable hepatocellular carcinoma (uHCC). This study aimed to elucidate differences regarding therapeutic efficacy between lenvatinib (LEN), a multi-molecular target agent, and atezolizumab plus bevacizumab (Atez/Bev), a newly developed immune-combined therapeutic regimen for CP-B patients affected by uHCC. Methods: From April 2018 to July 2022, 128 patients with uHCC treated with Atez/Bev (n = 29) or LEN (n = 99) as the initial systemic treatment were enrolled (median age 71 years; males 97; CP score 7:8:9 = 94:28:6; median albumin-bilirubin score −1.71). Therapeutic response was evaluated using RECIST, version 1.1. Clinical features and prognosis were retrospectively examined. Results: There were no significant differences between the Atez/Bev and LEN groups in regard to best response (CR:PR:SD:PD = 0:5:12:7 vs. 5:22:25:20, p = 0.415), progression-free survival (PFS) (median 5.0 [95% CI: 2.4–7] vs. 5.5 [95% CI: 3.4–7.9] months, p = 0.332), or overall survival (OS) (5.8 [95% CI: 4.3–11] vs. 8.8 [95% CI: 6.1–12.9] months, p = 0.178). Adverse events (any grade/≥ grade 3) were observed in 72.4%/17.2% (n = 21/5) of patients treated with Atez/Bev and 78.8%/25.3% (n = 78/25) of those treated with LEN (p = 0.46/0.46). Discussion: This retrospective study found no significant differences regarding PFS or OS between CP-B patients given Atez/Bev or LEN as initial systemic treatment for uHCC. [ABSTRACT FROM AUTHOR]

The A3 adenosine receptor (A3AR) is over-expressed in human hepatocellular carcinoma (HCC) cells. Namodenoson, an A3AR agonist, induces de-regulation of the Wnt and NF-kB signaling pathways resulting in apoptosis of HCC cells. In a phase I healthy volunteer study and in a phase I/II study in patients with advanced HCC, namodenoson was safe and well tolerated. Preliminary evidence of antitumor activity was observed in the phase I/II trial in a subset of patients with advanced disease, namely patients with Child–Pugh B (CPB) hepatic dysfunction, whose median overall survival (OS) on namodenoson was 8.1 months. A phase II blinded, randomized, placebo-controlled trial was subsequently conducted in patients with advanced HCC and CPB cirrhosis. The primary endpoint of OS superiority over placebo was not met. However, subgroup analysis of CPB7 patients (34 namodenoson-treated, 22 placebo-treated) showed nonsignificant differences in OS/progression-free survival and a significant difference in 12-month OS (44% vs 18%, p = 0.028). Partial response was achieved in 9% of namodenoson-treated patients vs 0% in placebo-treated patients. Based on the positive efficacy signal in HCC CPB7 patients and the favorable safety profile of namodenoson, a phase III study is underway. [ABSTRACT FROM AUTHOR]

There is a lack of effective programmed cell death protein 1 (PD-1)‐targeted immunotherapy with good tolerability in patients with advanced hepatocellular carcinoma (HCC) and severely compromised liver function. We assessed patient outcomes after combined camrelizumab and molecular targeted therapy in a multicenter cohort study in China. The study included 99 patients with advanced HCC (58 Child-Pugh A and 41 Child-Pugh B), 84 of them received camrelizumab combined with molecular targeted therapy from January 10, 2019, to March 31, 2021. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) were assessed. The median follow-up was 12.1 months. For patients with Child-Pugh B, the OS probability at 12-months, ORR and DCR were 49.7%, 31.7% and 65.9%, respectively, and the median PFS was 5.1 months [95% confidence interval (CI) 3.0–7.1], which were comparable with Child-Pugh A patients, although median OS was shorter in Child‐Pugh B patients (20.5 vs.13.4 months, P = 0.12). In multivariate analysis, macrovascular infiltration (MVI), but not sex, age, hepatitis B virus etiology, extrahepatic metastasis, Child-Pugh B, or AFP > 400 ng/ml, was associated with 12-months OS [hazard ratio (HR) 2.970, 95% CI 1.276–6.917, P = 0.012] and ORR (HR 2.906, 95% CI 1.18–7.16, P = 0.020). Grade 3/4 immune-related AEs occurred in 26.8% of Child-Pugh B patients, including one potentially treatment-related death. In both groups, the most common AEs were immune thrombocytopenia and hepatotoxicity. Camrelizumab combined with targeted therapy showed favorable effectiveness and tolerability with manageable toxicities in Chinese HCC patients, regardless of Child-Pugh A/B liver function. MVI was associated with suboptimal immunotherapy response and poor prognosis. [ABSTRACT FROM AUTHOR]

Background and Aims: Hepatocellular carcinoma (HCC) patients with Child‐Pugh (CP)‐B not eligible for surgery nor other focal therapy options due to impaired liver function, have very limited treatment options. This study aims to retrospectively investigate the toxicity and efficacy of Carbon‐ion radiotherapy (C‐ion RT) on HCC with CP‐B patients. Materials and Methods: Patients with CP‐B, no extrahepatic metastasis, and treated with C‐ion RT between May 2000 and March 2020 were retrospectively extracted and included in this study. Results: Sixty‐nine lesions of 58 patients were included. The median follow‐up duration was 20.5 (2.7–108) months. During follow‐up, recurrence was observed in 43 patients, including 2 local recurrences and 39 intrahepatic recurrences beyond the irradiation field. A grade 3 acute hepatotoxicity was observed in one patient during the observation period. No acute or late adverse event of grade ≥4 was observed. Overall survival was 80.4% and 46.0% at 1 and 2 years, respectively, and the median survival time was 22.6 months. Local control rate was 96.4% at both 1 and 2 years, and progression‐free survival was 38.6% and 6.9% at 1 and 2 years, respectively, with a median of 9.7 months. Conclusion: The C‐ion RT showed low toxicity and good local effect in patients with HCC and CP‐B. Therefore, C‐ion RT could be an appropriate treatment for patients with HCC with poor liver function. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a major cause of death among patients with liver cirrhosis. The rise of immuno‐oncology has revolutionized treatment for advanced HCC. However, most pivotal randomized controlled trials have excluded patients with moderate liver dysfunction (Child–Pugh–Turcotte B), despite the high incidence of liver disease in patients with HCC at the time of diagnosis. Overall survival in patients with HCC and moderate liver dysfunction treated with sorafenib has been found to be only approximately 3–5 months, underlining the need for improved treatment algorithms for this increasingly important subgroup of patients. In this review, we summarize available data on the treatment of patients with HCC and moderate liver dysfunction. Opportunities, as well as clinical challenges, are discussed in detail, highlighting potential changes to the therapeutic landscape. [ABSTRACT FROM AUTHOR]

Abstract Background Patients with hepatocellular carcinoma (HCC) and Child–Pugh B liver cirrhosis have poor prognosis and are underrepresented in clinical trials. The CELESTIAL trial, in which cabozantinib improved overall survival (OS) and progression-free survival (PFS) versus placebo in patients with HCC and Child–Pugh A liver cirrhosis at baseline, was evaluated for outcomes in patients who had Child–Pugh B cirrhosis at Week 8. Methods This was a retrospective analysis of adult patients with previously treated advanced HCC. Child–Pugh B status was assessed by the investigator. Patients were randomised 2:1 to cabozantinib (60 mg once daily) or placebo. Results Fifty-one patients receiving cabozantinib and 22 receiving placebo had Child–Pugh B cirrhosis at Week 8. Safety and tolerability of cabozantinib for the Child–Pugh B subgroup were consistent with the overall population. For cabozantinib- versus placebo-treated patients, median OS from randomisation was 8.5 versus 3.8 months (HR 0.32, 95% CI 0.18–0.58), median PFS was 3.7 versus 1.9 months (HR 0.44, 95% CI 0.25–0.76), and best response was stable disease in 57% versus 23% of patients. Conclusions These encouraging results with cabozantinib support the initiation of prospective studies in patients with advanced HCC and Child–Pugh B liver function. Clinical Trial Registration: NCT01908426.

Background: Laparoscopic liver resection for hepatocellular carcinoma (HCC) in patients with Child–Pugh A cirrhosis has been shown to be beneficial. However, less is known regarding the outcomes of such treatment in patients with Child–Pugh B cirrhosis. We conducted a retrospective study to evaluate the outcomes of laparoscopic liver resection for HCC in patients with Child–Pugh B cirrhosis, focusing on surgical risks, recurrence, and survival. Methods: 357 patients with HCC who underwent laparoscopic liver resection from 2007 to 2021 were identified from our single-institute database. The patients were divided into three groups by their Child–Pugh score: the Child–Pugh A (n = 280), Child–Pugh B7 (n = 42), and Child–Pugh B8/9 groups (n = 35). Multivariable Cox regression models for recurrence-free survival (RFS) and overall survival (OS) were constructed with adjustment for preoperative and postoperative clinicopathological factors. Results: The Child–Pugh B8/9 group had a significantly higher complication rate, but the complication rates were comparable between the Child–Pugh B7 and Child–Pugh A groups (Child–Pugh A vs. B7 vs. B8/9: 8.2% vs. 9.6% vs. 26%, respectively; P = 0.010). Compared with the Child–Pugh A group, the risk-adjusted hazard ratios (95% confidence intervals) in the Child–Pugh B7 and B8/9 groups for RFS were 1.39 (0.77–2.50) and 3.15 (1.87–5.31), respectively, and those for OS were 0.60 (0.21–1.73) and 1.80 (0.86–3.74), respectively. There were no significant differences in major morbidities (Clavien–Dindo grade > II) (P = 0.117) or the proportion of retreatment after HCC recurrence (P = 0.367) among the three groups. Conclusion: Among patients with HCC, those with Child–Pugh A and B7 cirrhosis can be good candidates for laparoscopic liver resection in terms of complications and recurrence. Despite poor postoperative outcomes in patients with Child–Pugh B8/9 cirrhosis, laparoscopic liver resection is less likely to interfere with retreatment and can be performed as part of multidisciplinary treatment. [ABSTRACT FROM AUTHOR]

Background: Atezolizumab plus bevacizumab (Ate/Bev) demonstrated promising efficacy and safety in patients with advanced hepatocellular carcinoma (HCC) in the phase III IMbrave150 trial. However, patients with Child–Pugh B HCC were excluded in the abovementioned prospective trial. Therefore, we aimed to investigate the efficacy and safety of Ate/Bev in patients with Child–Pugh B HCC. Methods: This multicenter retrospective study included 36 patients with Child–Pugh B advanced HCC who received Ate/Bev at four cancer referral centers between May 2020 and August 2021. Comparative analyses were performed with an independent cohort of patients with Child–Pugh A HCC from the same registry (n = 133). Results: All patients received Ate/Bev as first-line systemic treatment for advanced HCC. The objective response and disease control rates of patients in the Child–Pugh groups B and A were 11.1% and 58.3% and 34.6% and 76.7%, respectively. The median progression-free survival (PFS) and overall survival (OS) were 3.0 months [95% confidence interval (CI), 1.7–4.3) and 7.7 months (95% CI, 4.8–10.6) in the Child–Pugh B group, whereas the median PFS and OS were 9.6 months (95% CI, 5.1–14.2) and not reached (95% CI, not available) in the Child–Pugh A group, respectively. Compared to the Child–Pugh A group, grade 3–4 adverse events (AEs) were more common in the Child–Pugh B group (44.4% versus 15.8, p < 0.001), with the most frequent grade 3–4 AEs being gastrointestinal bleeding (n = 6, 16.7%), neutropenia (n = 5, 13.9%), and thrombocytopenia (n = 4, 11.1%). Conclusions: In the Child–Pugh B subgroup of patients with advanced HCC, Ate/Bev treatment showed modest clinical activity. However, due to the increased frequency of serious AEs, careful evaluation of treatment response and AE management is required in this subgroup of patients. [ABSTRACT FROM AUTHOR]

Introduction: Although many treatment options are available for patients with advanced hepatocellular carcinoma (HCC) and Child-Pugh (CP) class A, those for patients with CP class B remain limited. We aimed to assess the safety and efficacy of hepatic arterial infusion chemotherapy (HAIC) using 5-fluorouracil and cisplatin in patients with advanced HCC and CP class B. Methods: Sixty patients who received HAIC with 5-fluorouracil and cisplatin at Kurume Chuo Hospital between April 2012 and March 2021 were recruited. Cisplatin (30 mg administered over 2 h) and 5-fluorouracil (1,250 mg, 72-h constant infusion) were administered to the tumor-feeding artery every 2 weeks. The primary endpoint was overall survival (OS), while the secondary endpoints were progression-free survival and adverse effects. Results: Among the 60 patients, CP class A and class B were noted in 30 patients each. OS did not significantly differ between the two classes. After 4 weeks of HAIC with 5-fluorouracil and cisplatin, 12 patients in the class B group exhibited improved CP scores (CPSs) relative to those at the start of treatment. There was a significant difference in OS between patients whose CPSs had improved and those whose scores remained unchanged or had worsened. Conclusions: HAIC using 5-fluorouracil and cisplatin is effective and safe for patients with CP class B, and improvements in CPSs after 4 weeks of this therapy may represent a predictive marker of treatment efficacy regardless of pretreatment CPS in patients with CP class B. [ABSTRACT FROM AUTHOR]

Established treatments for advanced hepatocellular carcinoma (HCC) with Child-Pugh cirrhosis B (CPB, moderate hepatic dysfunction) are lacking. A recently published randomized phase 2 study in CPB HCC investigating the safety and efficacy of namodenoson (25 mg BID), an A3 adenosine-receptor agonist vs. placebo, suggested a favorable safety profile and a positive efficacy signal in patients with HCC with a CPB score of 7 (CPB7). The present study reports a 61-year-old woman with CPB7 HCC who received namodenoson for over 6 years through this study and its open-label extension. Computed tomography scans demonstrated partial and complete responses after 7 weeks and 4 years of treatment, respectively. Low albumin levels (31 g/l) and elevated baseline levels of alanine transaminase and aspartate aminotransferase (68 U/l and 44 U/l, respectively) were reported. After 4 weeks of treatment, these levels normalized and were stable for over 6 years. No treatment-emergent adverse events were noted. At the time of reporting, the response is ongoing as manifested by imaging studies and liver function evaluation. [ABSTRACT FROM AUTHOR]

Recent years have seen significant progress in the systemic treatment of hepatocellular carcinoma (HCC), including the advent of immunotherapy. While several large phase III trials have provided the evidence for a multi-line treatment paradigm, they have focused on a highly selected group of patients by excluding potentially confounding comorbidities. As a result, high quality evidence for the systemic treatment of HCC in patients with various comorbidities is missing. This review summarises current knowledge on the use of approved medicines in patients with HIV, autoimmune disease, cardiovascular disease, diabetes, fibrolamellar HCC, mixed HCC-cholangiocarcinoma, decompensated cirrhosis (Child-Pugh B and C), a significant bleeding history, vascular invasion or portal vein thrombosis, as well as the elderly, those on haemodialysis, and those after solid organ transplantation. The article highlights relevant knowledge gaps and current clinical challenges. To improve the safety and efficacy of HCC treatment in these subgroups, future trials should be designed to specifically include patients with comorbidities. [ABSTRACT FROM AUTHOR]

Introduction: Regorafenib is an approved agent in patients with advanced hepatocellular carcinoma (HCC) who progressed on sorafenib, but little is known about its clinical outcomes in Child‐Pugh B patients. We aimed to investigate the safety and effectiveness of regorafenib in Child‐Pugh B HCC patients. Methods: This multicentre retrospective study included 59 patients with Child‐Pugh B HCC who received regorafenib. Comparative analyses were performed with an independent cohort of Child‐Pugh class A patients from the same registry (n = 440). Results: The median age was 58 years (range, 19‐83). All patients had progression on prior sorafenib. Regorafenib was given as 2nd line, and 3rd‐4th line systemic therapy in 37 (62.7%) and 22 (37.3%) patients respectively. Compared to Child‐Pugh A cohort, grade 3‐4 AEs were more common in the Child‐Pugh B cohort (27.1% vs 14.1%, P =.017). The median progression‐free survival (PFS) and overall survival (OS) were 1.8 and 4.6 months, respectively, and these were significantly poorer than the Child‐Pugh A cohort (P =.008 and P <.001 respectively). Child‐Pugh B patients with albumin‐bilirubin (ALBI) grade 3 had a significantly higher frequency of increased bilirubin (P =.01 for any grade and P =.01 for grade 3‐4) and showed significantly poorer OS (P =.021), compared to those with ALBI grade 1 or 2. Conclusion: Regorafenib's poor clinical outcomes and increased frequency of severe adverse events lead us to discourage its use in the Child‐Pugh B population. In particular, regorafenib should not be used in Child‐Pugh B patients with ALBI grade 3. [ABSTRACT FROM AUTHOR]

Purpose: The aim of our study was to evaluate the curative effect and safety of CyberKnife stereotactic body radiation therapy in treating decompensated cirrhosis hepatocellular carcinoma (HCC) patients.Methods: From March 2011 to December 2015, 32 HCC patients who refused or were ineligible for other treatments were treated with CyberKnife stereotactic body radiation therapy. Among these patients, 17 were Child-Pugh score 7 (53.13%), 7 were Child-Pugh score 8 (21.87%), 4 were Child-Pugh score 9 (12.50%), and 4 were Child-Pugh score 10 (12.50%). A total dose of 45–54 Gy in 5–10 fractions was given according to the location of lesions.Results: The median follow-up period was 30 months (8–46 months). By July 2019, the tumors were recurrent or metastasized in 17 patients. The overall survival rates of 1, 2, and 3 years were 84.4, 61.8, and 46.0%, respectively. After 1, 2, and 3 years, the local control rates were 92.9%. The progression-free survival rates of the 1, 2, and 3-year treatments were 73.8, 44.6, and 33.4%, respectively.Conclusions: CyberKnife stereotactic body radiation therapy was an effective option for HCC patients with decompensated cirrhosis. The liver injury occurrence rate was acceptable in our study.

Purpose: The aim of our study was to evaluate the curative effect and safety of CyberKnife stereotactic body radiation therapy in treating decompensated cirrhosis hepatocellular carcinoma (HCC) patients. Methods: From March 2011 to December 2015, 32 HCC patients who refused or were ineligible for other treatments were treated with CyberKnife stereotactic body radiation therapy. Among these patients, 17 were Child-Pugh score 7 (53.13%), 7 were Child-Pugh score 8 (21.87%), 4 were Child-Pugh score 9 (12.50%), and 4 were Child-Pugh score 10 (12.50%). A total dose of 45–54 Gy in 5–10 fractions was given according to the location of lesions. Results: The median follow-up period was 30 months (8–46 months). By July 2019, the tumors were recurrent or metastasized in 17 patients. The overall survival rates of 1, 2, and 3 years were 84.4, 61.8, and 46.0%, respectively. After 1, 2, and 3 years, the local control rates were 92.9%. The progression-free survival rates of the 1, 2, and 3-year treatments were 73.8, 44.6, and 33.4%, respectively. Conclusions: CyberKnife stereotactic body radiation therapy was an effective option for HCC patients with decompensated cirrhosis. The liver injury occurrence rate was acceptable in our study. [ABSTRACT FROM AUTHOR]

• Liver resection for hepatocellular carcinoma in Child-Pugh B cirrhosis should be considered after careful patient selection. • Patient characteristics, tumor pattern, liver function and surgical approach should be considered as selection criteria. • Nomograms to predict surgical risks and survival may help in treatment allocation. Treatment allocation in patients with hepatocellular carcinoma (HCC) on a background of Child-Pugh B (CP-B) cirrhosis is controversial. Liver resection has been proposed in small series with acceptable outcomes, but data are limited. The aim of this study was to evaluate the outcomes of patients undergoing liver resection for HCC in CP-B cirrhosis, focusing on the surgical risks and survival. Patients were retrospectively pooled from 14 international referral centers from 2002 to 2017. Postoperative and oncological outcomes were investigated. Prediction models for surgical risks, disease-free survival and overall survival were constructed. A total of 253 patients were included, of whom 57.3% of patients had a preoperative platelet count <100,000/mm3, 43.5% had preoperative ascites, and 56.9% had portal hypertension. A minor hepatectomy was most commonly performed (84.6%) and 122 (48.2%) were operated on by minimally invasive surgery (MIS). Ninety-day mortality was 4.3% with 6 patients (2.3%) dying from liver failure. One hundred and eight patients (42.7%) experienced complications, of which the most common was ascites (37.5%). Patients undergoing major hepatectomies had higher 90-day mortality (10.3% vs. 3.3%; p = 0.04) and morbidity rates (69.2% vs. 37.9%; p < 0.001). Patients undergoing an open hepatectomy had higher morbidity (52.7% vs. 31.9%; p = 0.001) than those undergoing MIS. A prediction model for surgical risk was constructed (https://childb.shinyapps.io/morbidity/). The 5-year overall survival rate was 47%, and 56.9% of patients experienced recurrence. Prediction models for overall survival (https://childb.shinyapps.io/survival/) and disease-free survival (https://childb.shinyapps.io/DFsurvival/) were constructed. Liver resection should be considered for patients with HCC and CP-B cirrhosis after careful selection according to patient characteristics, tumor pattern and liver function, while aiming to minimize surgical stress. An estimation of the surgical risk and survival advantage may be helpful in treatment allocation, eventually improving postoperative morbidity and achieving safe oncological outcomes. Liver resection for hepatocellular carcinoma in advanced cirrhosis (Child-Pugh B score) is associated with a high rate of postoperative complications. However, due to the limited therapeutic alternatives in this setting, recent studies have shown promising results after accurate patient selection. In our international multicenter study, we provide 3 clinical models to predict postoperative surgical risks and long-term survival following liver resection, with the aim of improving treatment allocation and eventually clinical outcomes. [ABSTRACT FROM AUTHOR]

Purpose There is limited data on radiotherapy (RT) for hepatocellular carcinoma (HCC) in patients with Child-Pugh classification B (CP-B). This study aimed to evaluate the treatment outcomes of fractionated conformal RT in HCC patients with CP-B. Materials and Methods We retrospectively reviewed the data of HCC patients with CP-B treated with RT between 2009 and 2014 at 13 institutions in Korea. HCC was diagnosed by the Korea guideline of 2009, and modern RT techniques were applied. Fraction size was ≤ 5 Gy and the biologically effective dose (BED) ≥ 40 Gy10 (α/β = 10 Gy). A total of 184 patients were included in this study. Results Initial CP score was seven in 62.0% of patients, eight in 31.0%, and nine in 7.0%. Portal vein tumor thrombosis was present in 66.3% of patients. The BED ranged from 40.4 to 89.6 Gy10 (median, 56.0 Gy10). After RT completion, 48.4% of patients underwent additional treatment. The median overall survival (OS) was 9.4 months. The local progression-free survival and OS rates at 1 year were 58.9% and 39.8%, respectively. In the multivariate analysis, non-classic radiation-induced liver disease (RILD) (p < 0.001) and additional treatment (p < 0.001) were the most significant prognostic factors of OS. Among 132 evaluable patients without progressive disease, 19.7% experienced non-classic RILD. Normal liver volume was the most predictive dosimetric parameter of non-classic RILD. Conclusion Fractionated conformal RT showed favorable OS with a moderate risk non-classic RILD. The individual radiotherapy for CP-B could be cautiously applied weighing the survival benefits and the RILD risks. [ABSTRACT FROM AUTHOR]

Introduction: Surgery for Child–Pugh B liver function is considered risky because of its high morbidity rate and the acceptable indication criteria for laparoscopic liver resection (LLR) for Child–Pugh B patients have not been identified. We conducted a retrospective cohort study to determine the optimal introduction of LLR for Child–Pugh B patients based on our single‐institute experience. Methods: A total of 17 Child–Pugh B patients underwent LLR between 2005 and 2017. Their clinical outcomes were compared to those of LLR for Child–Pugh A patients (103 cases), conventional open liver resection for Child–Pugh B patients (19 cases), and radiofrequency ablation (RFA) for Child–Pugh B patients (20 cases) during the same period. Results: LLR for Child–Pugh B patients had a significantly higher conversion rate than LLR for Child–Pugh A patients (Child–Pugh A vs B: 3.9% vs 35.3%, P < 0.01). However, patients who successfully underwent laparoscopic resection (11 cases) had fewer postoperative ascites and shorter postoperative hospital stays compared to patients who underwent conventional open liver resection. In comparison to the RFA group, the LLR group more frequently had lesions in the left lateral segment (LLR vs RFA: 50.0% vs 10.0%, P = 0.02) and exophytic tumor (21.4% vs 0%, P = 0.02) than did the RFA group. Also, compared to the RFA group, the LLR group had a lower local recurrence rate (0% vs 15%, P = 0.25) and a longer recurrence‐free survival (P = 0.049), but the overall survival was similar between the two groups. Conclusions: In the treatment of Child–Pugh B liver malignancy, the minimal invasiveness of LLR was revealed. Our results suggest that lesions in the left lateral segment and exophytic tumors are good indications for LLR for Child–Pugh B. [ABSTRACT FROM AUTHOR]

Sorafenib has been widely used to treat unresectable hepatocellular carcinoma (HCC) but most studies have been done in Child-Pugh A (CP-A) patients with well-preserved liver function. We evaluated the overall survival (OS) and tolerance to sorafenib in a large cohort of Child-Pugh B (CP-B) HCC patients as compared to CP-A HCC patients. We prospectively studied 130 patients with advanced HCC who started sorafenib between January 2011 and December 2015. Patients were classified as CP-A (n = 65) or CP-B (n = 65). The average OS for all 130 patients was 10 months. CP-A patients had a median survival rate significantly longer than CP-B patients: 12 months vs. 6 months. The OS found in our group of CP-B patients was 6.5 months, which is higher than that found in most studies done so far. When stratified, our CP-B patients had better OS than ever reported. The dose of the drug was interrupted due to adverse events (AEs) in 38 (29%) of the patients, of whom 20 (30%) were CP-A patients and 18 (28%) were CP-B patients. This real-life cohort of CP-B HCC patients treated with sorafenib had a higher survival than that described in the literature, with a satisfactory safety profile. Despite the high prevalence of severe AEs in CP-B patients, there were fewer treatment interruptions in this group, indicating that Child-Pugh B patients can tolerate treatment and may benefit from sorafenib. [ABSTRACT FROM AUTHOR]

Background We aimed to evaluate the safety, efficacy and prognostic impact of baseline and early clinical markers in both Child-Pugh A and B patients with advanced hepatocellular carcinoma (HCC). Methods We prospectively studied 89 Japanese patients with HCC (Child-Pugh A, n = 59; Child-Pugh B, n = 30) who were started with sorafenib between May 2010 and July 2013. Results Frequency of sorafenib-related adverse events was almost similar between Child-Pugh score 5, 6, and 7 patients. The rate of liver dysfunction, including any grade encephalopathy, ≥ grade 3 ascites, or ≥ grade 3 bilirubin increased, in Child-Pugh score ≥8 group was significantly higher than that in the other groups. The median overall survival of Child-Pugh score 5, 6, 7 and ≥8 patients were 14.5, 11.1, 8.7 and 4.6 months, respectively. Patients in Child-Pugh score 6 had significantly longer OS than those in Child-Pugh score 7 ( P = 0.049). Multivariate analysis identified macrovascular invasion (MVI), alpha-fetoprotein (AFP), Child-Pugh score and aspartate aminotransferase (AST) as baseline predictors of survival. However, extrahepatic metastasis (EHM) was not a significant prognostic factor. In addition, decrease in AFP level and development of hand-foot skin reaction within 4 weeks after sorafenib initiation were closely associated with favorable survival. Conclusion It is possible that not only Child-Pugh score 5 and 6 but also 7 patients are eligible for future clinical trials with sorafenib or similar drugs. Various survival predictors identified in this study might be considered as stratification factor. Although both MVI and EHM is a phenotype of advanced HCC, MVI should be discriminated from EHM because of the prognostic impact on survival in sorafenib-treated advanced HCC patients. [ABSTRACT FROM AUTHOR]

Purpose To report outcomes in patients with Child-Pugh B or C (CP B/C) hepatocellular carcinoma (HCC) treated with stereotactic body radiotherapy (SBRT). Methods and materials A prospective study of SBRT was developed for patients with CP B7 or B8 unresectable HCC, <10 cm. Selected ineligible patients (e.g. CP > B8, >10 cm) treated off-study from 2004 to July 2012 were also reviewed. Patients were excluded if they were treated as a bridge-to-liver-transplant. Results 29 patients with CP B/C HCC were treated with SBRT (median dose 30 Gy in 6 fractions) from 2004 to December 2012. The majority had CP B7 liver function (69%) and portal vein tumor thrombosis (76%). The median survival was 7.9 months (95% CI: 2.8-15.1). Survival was significantly better in patients with CP = B7 and AFP ≥ 4491 ng/mL. Of 16 evaluable patients, 63% had a decline in CP score by ≥2 points at 3 months. Conclusion SBRT is a treatment option for selected HCC patients with small HCCs and modestly impaired (CP B7) liver function. [ABSTRACT FROM AUTHOR]

BACKGROUND: This study explored the efficacy, tolerability, and survival benefits of using sorafenib in patients with Child-Pugh class B (CPB) cirrhosis. METHODS: Patients with advanced hepatocellular carcinoma who were treated with sorafenib at Queen Mary Hospital, Hong Kong, China, were analyzed retrospectively. Treatment outcomes were analyzed according to their respective Child-Pugh status. Patients with CPB disease were further divided into CPB7 (those with a score of 7) and CPB8-9 (a score of 8 or 9) subgroups. RESULTS: The baseline demographic parameters were comparable between 108 patients with Child-Pugh class A (CPA) disease and 64 CPB patients. Both clinical benefit rate (21.3% vs 32.4% vs 14.8%; P = .23) and progression-free survival (median: 3.2 months vs 3.2 months vs 2.3 months; P = .26) were similar among CPA, CPB7, and CPB8-9 groups, respectively. The overall survival was different among these groups ( P = .002) and showed a trend toward worse outcome in CPB patients: the median was 6.1, 5.4, and 2.7 months among CPA, CPB7, and CPB8-9 patients, respectively. The commonest grade 3/4 adverse events were hand-foot syndrome (13.5%), diarrhea (9.9%), and rash (7.0%). Grade 3/4 leukopenia, thrombocytopenia, and anemia occurred in 2.9%, 5.3%, and 8.8% of the patients, respectively. Overall, the 3 groups of patients experienced similar incidence of most of these adverse events. Nonetheless, CPB patients experienced more anemia ( P = .01), gastrointestinal bleeding ( P = .02), and hepatic encephalopathy ( P = .02). CONCLUSIONS: CPA and CPB patients tolerated sorafenib similarly and derived similar clinical and progression-free survival benefit. Among CPB patients, most benefits were observed in patients with a score of 7. Nevertheless, CPB patients were more susceptible to developing cirrhotic complications, and thus more vigilant surveillance is needed. Cancer 2012. © 2012 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: Lenvatinib is an approved first-line treatment for unresectable hepatocellular carcinoma (uHCC). We evaluated the safety and efficacy of lenvatinib versus sorafenib in patients with uHCC who deteriorated to Child-Pugh class B (CP-B) on treatment., Methods: We retrospectively evaluated patients from REFLECT who deteriorated to CP-B versus those who remained Child-Pugh class A (CP-A) within 8 weeks after randomization. Best overall response and objective response rate (ORR) per modified Response Evaluation Criteria In Solid Tumors (mRECIST) were assessed from baseline. Progression-free survival (PFS) per mRECIST and overall survival (OS) were assessed beginning at week 8., Results: Patients with CP-B versus CP-A classification receiving lenvatinib had ORRs of 28.3 and 42.9%, respectively; patients with CP-B versus CP-A classification receiving sorafenib had ORRs of 8.5 and 12.9%, respectively. Median PFS and OS (landmark analyses beginning at week 8) in patients receiving lenvatinib were 3.7 months [95% confidence interval (CI): 1.8-7.4] and 6.8 months (95% CI: 2.6-10.3) in the CP-B subgroup versus 6.5 months (95% CI: 5.6-7.4) and 13.3 months (95% CI: 11.6-16.1) in the CP-A subgroup, respectively. Median PFS and OS in patients receiving sorafenib were 0.5 months (95% CI: 0.1-3.6) and 4.5 months (95% CI: 2.9-6.1) in the CP-B subgroup versus 3.6 months (95% CI: 2.7-3.7) and 12.0 months (95% CI: 10.2-14.0) in the CP-A subgroup, respectively. The most common treatment-emergent adverse events in the lenvatinib cohort were hypertension (both subgroups) and decreased appetite (CP-B subgroup)., Conclusion: Results suggest that patients with uHCC whose liver function deteriorates to CP-B after initiation of therapy may continue to receive lenvatinib., Trial Registration: ClinicalTrials.gov, NCT01761266, https://clinicaltrials.gov/ct2/show/NCT01761266., Competing Interests: Competing interests: JH: No disclosures. MTC: Eisai: consulting and advisory board. EJ-HK: Eisai: advisory board, speakers bureau; Taiho: advisory board. MR: Employee of Eisai Inc. ZR: Employee of Eisai Inc. AV: Speaker, consultancy, and advisory role: Amgen, Roche, Bayer, Sanofi, BMS, Lilly, Novartis, Eisai, AstraZeneca, Merck, Incyte, Ipsen, PierreFabre, MSD, Sirtex, BTG, Servier, Terumo, GS, (© The Author(s), 2022.)

Simple Summary: We conducted a phase II randomized placebo-controlled trial to investigate namodenoson, an A3 adenosine-receptor agonist, as 2nd-line treatment for advanced hepatocellular carcinoma and moderate hepatic dysfunction (Child–Pugh [CP] scores of 7–9). The study included 50 patients in the namodenoson arm and 28 patients in the placebo arm. No overall survival advantage was observed with namodenoson; however, in patients with CP score of 7 (34 namodenoson-treated, 22 placebo-treated), namodenoson was associated with a significant improvement in 12-month overall survival (44% versus 18%, p = 0.028). Response rates were determined in patients with ≥1 assessment post-baseline (34 namodenoson-treated, 21 placebo-treated). Partial response was achieved by 3 (8.8%) namodenoson-treated and 0 (0%) placebo-treated patients. Namodenoson was well-tolerated, with a safety profile comparable to that of the placebo group. No treatment-related deaths were reported. In conclusion, namodenoson demonstrated a favorable safety profile and a preliminary efficacy signal in the evaluated population. Namodenoson, an A3 adenosine-receptor agonist, showed promising results in advanced hepatocellular carcinoma (HCC) and moderate hepatic dysfunction (Child–Pugh B; CPB) in a phase I/II clinical study. This phase II study investigated namodenoson as second-line therapy in such patients. Patients were randomized 2:1 to twice a day (BID) namodenoson (25 mg; n = 50) or placebo (n = 28). The primary endpoint (overall survival [OS]) was not met. Median OS was 4.1/4.3 months for namodenoson/placebo (hazard ratio [HR], 0.82; 95% confidence interval [CI] 0.49–1.38; p = 0.46). Pre-planned subgroup analysis of CPB7 patients (34 namodenoson-treated, 22 placebo-treated) showed a nonsignificant improvement in OS/progression-free survival (PFS). OS: 6.9 versus 4.3 months; HR, 0.81; 95% CI: 0.45–1.43, p = 0.46. PFS: 3.5 versus 1.9 months; HR, 0.89; 95% CI: 0.51–1.55, p = 0.67 (log-rank test). The difference in 12-month OS was significant (44% versus 18%, p = 0.028). Response rates were determined in patients for whom ≥ 1 assessment post-baseline was available (34 namodenoson-treated, 21 placebo-treated). Partial response was achieved by 3/34 (8.8%) and 0/21 (0%) patients, respectively. Namodenoson was well-tolerated, with a safety profile comparable to that of the placebo group. No treatment-related deaths were reported; no patients withdrew due to toxicity. In conclusion, namodenoson demonstrated a favorable safety profile and a preliminary efficacy signal in HCC CPB. [ABSTRACT FROM AUTHOR]