Summary Transarterial chemoembolization (TACE) is the standard of care for patients with intermediate stage hepatocellular carcinoma (BCLC B). Further improvement of the use of TACE was the subject ...of intense clinical research over the past years. The introduction of DEB-TACE brought more technical standardization and reduction of TACE related toxicity. The use of dynamic radiologic response evaluation criteria (EASL, mRECIST), uncovered the prognostic significance of objective tumor response. Finally, new approaches for better patient selection for initial and subsequent TACE treatment schedules will limit the use of TACE to some extent but have the potential to improve outcome for patients at risk for TACE-induced harm.
Summary
Background
Programmed cell death protein‐1‐targeted immunotherapy has shown promising results in phase II studies of hepatocellular carcinoma.
Aim
To evaluate safety and efficacy of nivolumab ...and pembrolizumab in an international, multicentre, real‐world cohort of patients with advanced hepatocellular carcinoma.
Methods
Sixty‐five patients treated with nivolumab (n = 34) or pembrolizumab (n = 31) between July 10, 2015 and December 31, 2018 (data cut‐off) across six centres in Austria and Germany were retrospectively analysed.
Results
Child‐Pugh class A/B/C was 32 (49%)/28 (43%)/5 (8%). Immunotherapy was used as systemic first‐/second‐/third‐/fourth‐line treatment in 9 (14%)/27 (42%)/26 (40%)/3 (5%) patients. Fifty‐four patients had at least one follow‐up imaging and were, therefore, available for radiological response assessment. The overall response and disease control rates were 12% and 49% respectively. Of 52 evaluable patients, four (8%) had hyperprogressive disease. Median time to progression was 5.5 (95% CI, 3.5‐7.4) months, median progression‐free survival was 4.6 (95% CI, 3.0‐6.2) months, and median overall survival was 11.0 (95% CI, 8.2‐13.8) months. Most common adverse events were infections (n = 7), rash (n = 6), pruritus (n = 3), fatigue (n = 3), diarrhoea (n = 3) and hepatitis (n = 3). Efficacy and safety results were comparable between Child‐Pugh A and B patients; however, median overall survival (OS) was shorter in Child‐Pugh B patients (16.7 vs 8.6 months; P = 0.065). There was no difference in terms of efficacy and adverse events between patients who received immunotherapy as first‐/second‐line and third‐/fourth‐line respectively.
Conclusions
Programmed cell death protein‐1‐targeted immunotherapy with nivolumab or pembrolizumab showed promising efficacy and safety in patients with advanced hepatocellular carcinoma, including subjects with Child‐Pugh stage B and patients with intensive pretreatment.
To compare the efficacies of transarterial chemoembolization (TACE) and sorafenib in patients with advanced-stage hepatocellular carcinoma (HCC).
The retrospective analysis of the data was approved ...by the institutional review board; the requirement to obtain informed consent was waived. Three hundred seventy-two patients with HCC were treated between January 1999 and December 2009. Patients with advanced HCC according to the Barcelona Clinic Liver Cancer (BCLC) staging classification (Child-Pugh class A or B, Eastern Cooperative Oncology Group performance status of 1-2, and/or macrovascular invasion or extrahepatic metastasis) were included in the study (n = 97). Thirty-four patients underwent conventional TACE with doxorubicin plus lipiodol or TACE with drug-eluting beads; 63 patients were treated with sorafenib.
The median duration of sorafenib treatment was 4.6 months (95% confidence interval CI: 3.2, 6.0 months). The median number of TACE sessions per patient was 3 ± 2. Side effects of TACE and sorafenib were comparable to those reported in the literature. The median time to progression was similar between the two treatment groups (P = .737). The median overall survival was 9.2 months (95% CI: 6.1, 12.3 months) for patients treated with TACE and 7.4 months (95% CI: 5.6, 9.2 months) for those treated with sorafenib (P = .377). Only Child-Pugh class was associated with a better overall survival at uni- and multivariate analysis.
TACE achieved a promising outcome in select patients with advanced HCC (BCLC stage C).
Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths and remains a major burden on healthcare systems worldwide. The incidence of HCC continues to rise ...globally, despite preventative efforts being made. Aims: This study aimed to investigate epidemiological changes observed in the etiology and survival outcomes of HCC patients at Klinikum Klagenfurt am Wörthersee between 2012 and 2023. Methods: This was a retrospective, single-center cohort study. Two time-periods (2012–2017 and 2018–2023) were created to enable comparison between the respective intervals. IBM SPSS was used to analyze statistical data. Results: More patients were diagnosed with HCC during the second time period (n = 128, n = 148). The median age of diagnosis was 72.5 years (SD 8.6). Patients were on average 2 years younger in the second time period compared to the first (p = 0.042). Alcohol remained the leading underlying etiology of HCC and no statistically significant change was seen over time (p = 0.353). Nevertheless, a clear upward trend in the number of NASH cases was evident over time (n = 15, n = 28, respectively). Nearly half of the patient population had a normal AFP (<7 µg/L) level at the time of diagnosis (n = 116, 42.6%). The survival time for HCC patients remained similar between time periods, with a median overall survival time of 20.5 months (95% CI 16.8–24.2, p = 0.841), despite improvements in management strategies and the availability of new systemic treatments. More advanced-stage HCC cases were documented in the second period (BCLC-C, n = 23 to n = 46, p = 0.051). An increased number of HCC patients without liver cirrhosis were identified during the second time period (n = 22, n= 47, respectively, p = 0.005). NASH was the most common underlying etiology in patients without liver cirrhosis (50%) compared to alcohol use in being the primary cause in cirrhotic patients (65%, p < 0.001). Conclusion: HCC continues to be an important health concern in our society. The number of HCC patients without liver cirrhosis is steadily increasing, with NAFLD/NASH, due to underlying lifestyle diseases playing an important etiological role. Continued efforts should be made to prevent HCC and to screen at-risk population groups. Preventative strategies and screening techniques should be adjusted in light of the changing epidemiological landscape of HCC, where more focus will have to be placed on detecting HCC in patients without underlying cirrhosis.
Using national registries, we investigated the epidemiological trends of hepatobiliary carcinomas in Austria between 2010 and 2018 and compared them to those reported for the periods of 1990–1999 and ...2000–2009. In total, 12,577 patients diagnosed with hepatocellular carcinoma (n = 7146), intrahepatic cholangiocarcinoma (n = 1858), extrahepatic cholangiocarcinoma (n = 1649), gallbladder carcinoma (n = 1365), and ampullary carcinoma (n = 559), between 2010 and 2018, were included. The median overall survival of all patients was 9.0 months. The best median overall survival was observed in patients with ampullary carcinoma (28.5 months) and the worst median overall survival was observed in patients with intrahepatic carcinoma (5.6 months). The overall survival significantly improved in all entities over the period 2010–2018 as compared with over the periods of 2000–2009 and 1990–1999. Age-adjusted incidence and mortality rates remained stable for most entities in both, men and women; only in gallbladder carcinoma, the incidence and mortality rates significantly decreased in women, whereas, in men, the incidence rates remained stable and mortality rates showed a decreasing trend. We showed that age-adjusted incidence and mortality rates were stable in most entities, except in gallbladder carcinoma. The overall survival improved in almost all entities as compared with those during 1990–2009.
Hypothyroidism has recently been proposed as predisposing factor for HCC development. However, the role of thyroid hormones (TH) in established HCC is largely unclear. We investigated the impact of ...TH on clinical characteristics and prognosis of HCC patients.
Of 838 patients diagnosed with nonsurgical HCC at the Division of Gastroenterology and Hepatology/Medical University of Vienna between 1992 and 2012, 667 patients fulfilled the inclusion criteria. The associations of thyroid function tests with patient, liver, and tumor characteristics as well as their impact on overall survival (OS) were investigated.
Thyroid hormone substitution was more often observed in patients with low thyroid-stimulating hormone (TSH) concentration and in patients with elevated free tetraiodthyronine (fT4). Patients with high TSH (>3.77uU/ml) concentrations had larger tumors, while the opposite was true for patients with low TSH (<0.44uU/ml) concentrations. Subjects with elevated fT4 (>1.66ng/dl) were more likely to have elevated CRP. While TSH was only associated with OS in univariate analysis (≤1.7 vs. >1.7uU/ml, median OS (95%CI), 12.3 (8.9-15.7 months) vs. 7.3 months (5.4-9.2 months); p = 0.003), fT4 (≤1.66 vs. >1.66ng/dl, median OS (95%CI), 10.6 (7.5-13.6 months) vs. 3.3 months (2.2-4.3 months); p = 0.007) remained an independent prognostic factor for OS (HR (95%CI) for fT4>1.66ng/dl, 2.1 (1.3-3.3); p = 0.002) in multivariate analysis.
TSH and fT4 were associated with prognostic factors of HCC (i.e., tumor size, CRP level). Elevated fT4 concentrations were independently associated with poor prognosis in HCC. Further studies are needed to characterize the role of TH in HCC in detail.
Hepatocellular carcinoma (HCC) can have viral or non-viral causes
. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but ...biomarker-based stratification of patients for optimal response to therapy is an unmet need
. Here we report the progressive accumulation of exhausted, unconventionally activated CD8
PD1
T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8
PD1
T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH-HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8
PD1
CXCR6
, TOX
, and TNF
T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8
T cells or TNF neutralization, suggesting that CD8
T cells help to induce NASH-HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8
PD1
T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH-HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment.
We aimed to establish an objective point score to guide the decision for retreatment with transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC). In all, 222 patients ...diagnosed with HCC and treated with multiple TACE cycles between January 1999 and December 2009 at the Departments of Gastroenterology/Hepatology of the Medical Universities of Vienna (training cohort) and Innsbruck (validation cohort) were included. We investigated the effect of the first TACE on parameters of liver function and tumor response and their impact on overall survival (OS, log rank test) and developed a point score (ART score: Assessment for Retreatment with TACE) in the training cohort (n = 107, Vienna) by using a stepwise Cox regression model. The ART score was externally validated in an independent validation cohort (n = 115, Innsbruck). The increase of aspartate aminotransferase (AST) by >25% (hazard ratio HR 8.4; P < 0.001), an increase of Child‐Pugh score of 1 (HR 2.0) or ≥2 points (HR 4.4) (P < 0.001) from baseline, and the absence of radiologic tumor response (HR 1.7; P = 0.026) remained independent negative prognostic factors for OS and were used to create the ART score. The ART score differentiated two groups (0‐1.5 points; ≥2.5 points) with distinct prognosis (median OS: 23.7 versus 6.6 months; P < 0.001) and a higher ART score was associated with major adverse events after the second TACE (P = 0.011). These results were confirmed in the external validation cohort and remained significant irrespective of Child‐Pugh stage and the presence of ascites prior the second TACE. Conclusion: An ART score of ≥2.5 prior the second TACE identifies patients with a dismal prognosis who may not profit from further TACE sessions. (HEPATOLOGY 2013;57:2261–2273)
Background & Aims We aimed to establish an objective point score to guide the decision for the first treatment with transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma ...(HCC). Methods 277 patients diagnosed with HCC and treated with transarterial treatments between 1/2002 and 12/2011 at the Medical Universities of Vienna (training cohort) and Innsbruck (validation cohort) were included. We investigated the impact of baseline liver function and tumour load on overall survival (OS, log-rank test) and developed a point score (STATE-score: Selection for TrAnsarterial chemoembolisation TrEatment) in the training-cohort (n = 131, Vienna) by using a stepwise Cox regression model. The STATE-score was externally validated in an independent validation cohort (n = 146, Innsbruck) and thereafter combined with the Assessment for Retreatment with TACE (ART)-score to identify patients who are (un)suitable for TACE. Results The STATE-score starts with the serum-albumin level (g/L), which is reduced by 12 points each, if the tumour load exceeds the up-to-7 criteria and/or C-reactive protein (CRP) levels are ⩾1 mg/dl (maximum reduction: 24 points). The STATE-score differentiated 2 groups (<18, ⩾18 points) with distinct prognosis (median OS: 5.3 vs. 19.5 months; p <0.001) and a lower STATE-score was associated with short-term harm and increased mortality after TACE-1 (39% vs. 14% p <0.001). Sequential use of the STATE and the ART-score (START-strategy) identified the most (un)suitable patients for TACE. Results were confirmed in the external validation-cohort and were independent from recently proposed baseline selection tools. Conclusion The STATE-score identifies patients who are (un)suitable for the first TACE. The START-strategy identified the best candidates for multiple TACE sessions.
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