Florian Hucke

The ART of decision making: Retreatment with transarterial chemoembolization in patients with hepatocellular carcinoma

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)

Advanced-Stage Hepatocellular Carcinoma: Transarterial Chemoembolization versus Sorafenib

PURPOSE To compare the efficacies of transarterial chemoembolization (TACE) and sorafenib in patients with advanced-stage hepatocellular carcinoma (HCC). MATERIALS AND METHODS 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. RESULTS 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. CONCLUSION TACE achieved a promising outcome in select patients with advanced HCC (BCLC stage C).

The ART-strategy: Sequential assessment of the ART score predicts outcome of patients with hepatocellular carcinoma re-treated with TACE

BACKGROUND & AIMS Recently, we developed the ART score (assessment for re-treatment with TACE) to guide the decision for a second transarterial chemoembolization (TACE-2) in patients with hepatocellular carcinoma (HCC). Patients with an ART score of 0-1.5 points gained benefit from a second TACE session, while patients with an ART score ≥2.5 points did not. Here, we investigated (1) the prognostic significance of the ART score prior to the third (TACE-3) and fourth TACE (TACE-4), and (2) the feasibility of an ART score guided re-treatment strategy by sequential assessment of the ART score in HCC patients treated with multiple TACE sessions. METHODS 109 patients, diagnosed with intermediate stage HCC and treated with ≥3 TACE sessions between January 1999 and December 2009 at the Medical Universities of Vienna and Innsbruck, were included. The ART score prior to each TACE session was assessed in comparison to the TACE naïve liver. The prognostic performance of the ART score before TACE-3 and 4 was evaluated with and without stratification based on the ART score prior to the respective last intervention. RESULTS The pre-TACE-3 ART score discriminated two groups with different prognosis and remained a valid predictor of OS independent of Child-Pugh score (5-7 points), CRP-levels and tumor characteristics. Even in patients with an initially beneficial ART score (0-1.5 points) before TACE-2, repeated ART score assessment before TACE-3 identified a subgroup of patients with dismal prognosis (median OS: 27.8 vs. 10.8 months, p<0.001). Similar results were observed when the ART score was applied before TACE-4. CONCLUSIONS The sequential assessment of the ART score identifies patients with dismal prognosis prior to each TACE session.

Transarterial chemoembolization: Modalities, indication, and patient selection

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.

How to STATE suitability and START transarterial chemoembolization in patients with intermediate stage hepatocellular carcinoma

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.

Clinical characteristics of patients with hepatocellular carcinoma in Austria - is there a need for a structured screening program?

ZusammenfassungHINTERGRUND: Ziel dieser Studie war es, die Unterschiede in der klinischen Erstpräsentation von Patienten mit hepatozellulären Karzinom (HCC) vor und nach der Veröffentlichung der europäischen (EASL) Empfehlungen zu HCC-Vorsorge und Behandlung zu untersuchen. METHODEN: Zwischen 1991 und 2009 wurde an unserer Abteilung bei 907 Patienten ein HCC neu diagnostiziert, wovon 850 in diese Studie aufgenommen wurden. Daten zur Demographie, Leberfunktion und Tumorstadium wurden retrospektiv erhoben. Die Publikation der EASL Empfehlungen im Oktober 2001 diente als Stichtag um klinische Charakteristika und Gesamtüberleben davor (Zeitraum 1) und danach (Zeitraum 2) zu vergleichen. RESULTATE: Im zweiten Untersuchungszeitraum waren Patienten übergewichtiger (BMI: 26,1 vs. 27,5, p = 0,003) litten häufiger an Diabetes (25,4 vs. 37,3 %, p = 0,001) und an einer nicht-alkoholische Fettleberhepatitis (NASH) (0,7 vs. 5,1 %, p < 0,001). Die alkoholische Lebererkrankung löste die Virushepatitis als häufigste Ätiologie ab, jedoch nicht in der wachsenden Gruppe der Patienten mit Migrationshintergrund, bei denen die virale Hepatitis (76,3 %) die Hauptätiologie blieb. Keine Veränderung konnte hinsichtlich der Leberfunktion und Tumorstadien zum Zeitpunkt der Erstdiagnose beobachtet werden. Bei den meisten Patienten wurden überwiegend fortgeschrittene nicht kurativ behandelbare HCCs festgestellt. Allerdings war das mediane Gesamtüberleben aller HCC Patienten in Periode 2 signifikant besser (7 vs. 14 Monate, p < 0,001), was für eine Verbesserung palliativer Therapien spricht. KONKLUSION: Patienten mit HCC werden trotz klarer, seit 9 Jahren bestehender europäischer Screening Empfehlungen überwiegend in nicht kurativ behandelbaren Tumorstadien diagnostiziert. Die Forderung nach einem offiziellen österreichischen HCC-Screeningprogramm für Patienten mit Leberzirrhose scheint gerechtfertigt.SummaryBACKGROUND: We investigated the differences in clinical presentation of patients with hepatocellular carcinoma (HCC) at the time of diagnosis, before and after the publication of the European Association for the study of the Liver (EASL) guidelines of HCC management and screening. METHODS: Between 1991 and 2009, 907 patients were diagnosed with HCC at our department of which 850 were included in this study. Data regarding demography, liver function and tumor stage at the time of diagnosis were retrospectively collected. Differences in clinical characteristics and overall survival (OS) were compared before (period 1) and after (period 2) the publication of the EASL guidelines in 2001. RESULTS: In period 2, patients were more likely to be overweight (BMI: 26.1 vs. 27.5, p = 0.003), suffered more often from diabetes (25.4 vs. 37.3%, p = 0.001) and nonalcoholic steatohepatitis (NASH) (0.7 vs. 5.1%, p < 0.001). Alcoholic liver disease replaced viral hepatitis as the main etiology but not in the increasing number of patients with migration background where viral hepatitis (76.3%) remained the predominant etiology. No change in liver function and tumor stages at the time of HCC diagnosis was observed. Most patients presented with advanced incurable HCC. However, the median OS of all HCC patients increased in period 2 (7 vs. 14 months, p < 0.001) suggesting improvements of palliative therapy. CONCLUSIONS: Patients with HCC are still predominantly diagnosed at incurable tumor stages, despite explicit European screening guidelines existing since 9 years. The implementation of a HCC surveillance program for cirrhotic patients in Austria seems to be warranted.

Incidence and mortality trends for biliary tract cancers in Austria

The epidemiology of biliary tract cancers (BTC) varies between geographical regions and has changed over time globally. We investigated the incidence and mortality trends of patients diagnosed with BTC over a 20‐year period in Austria.

Use of inhibitors of the renin–angiotensin system is associated with longer survival in patients with hepatocellular carcinoma

Background Inhibition of the renin–angiotensin system (RAS) was associated with longer survival in patients with different solid malignancies. Objective The objective of this study was to investigate the effect of RAS inhibitor (RASi) treatment (angiotensin-converting enzyme inhibitors or angiotensin-II-receptor blockers) on survival of patients with hepatocellular carcinoma (HCC). Methods Patients diagnosed with HCC and Child-Pugh A between 1992 and 2013 who received sorafenib, experimental therapy, or best supportive care were eligible for the Vienna cohort. The Mainz cohort included patients with HCC and Child-Pugh A who received sorafenib treatment between 2007 and 2016. The association between RASi and overall survival (OS) was evaluated in univariate and multivariate analyses. Results In the Vienna cohort, 43 of 156 patients received RASi for hypertension. RASi treatment was associated with longer OS (11.9 vs. 6.8 months (mo); p = 0.014) and remained a significant prognostic factor upon multivariate analysis (HR = 0.6; 95% CI 0.4–0.9; p = 0.011). In subgroup analysis, patients treated with sorafenib plus RASi had better median OS (19.5 mo) compared to those treated with either sorafenib (10.9 mo) or RASi (9.7 mo) alone (p = 0.043). The beneficial effect of RASi on survival was confirmed in the Mainz cohort (n = 76). Conclusion RAS inhibition is associated with longer survival in HCC patients with Child-Pugh class A.

Epidemiological Trends of Hepatocellular Carcinoma in Austria

Background/Aims: The heterogeneous epidemiology of hepatocellular carcinoma (HCC) with the highest incidence rates in East Asia, sub-Saharan Africa and Melanesia results from variations in the main risk factors. We investigated epidemiological trends, including incidence and mortality, of patients diagnosed with HCC over a 20-year period in Austria. Methods: Data on age-adjusted incidence rates of HCC were obtained from the Austrian National Cancer Registry, which compiles nationwide data on all newly diagnosed cancers. Data on age-adjusted mortality were obtained from the national death registry (Statistics Austria). Results: Of 24,939 patients diagnosed with hepatobiliary tumors between 1990 and 2009, 8,561 subjects had HCC (m/f ratio 75/25%; mean age 69 years). Lymph node and distant metastases were present in 7.5 and 12.2%, respectively. The age-adjusted incidence rate was significantly higher in men than women (m/f ratio 4.5/1) and markedly increased in men (4.68/5.10) but remained stable in women (1.18/1.11). Similarly, the age-adjusted mortality rate was significantly higher in men than women (m/f ratio 4.5/1), increased in men (4.02/4.98) and remained stable in women (0.92/1.0). The median overall survival was 4.5 months for men and 3.2 months for women with 1-/5-year survival rates of 33/11% and 28/10%, respectively. Conclusion: HCC is the most common hepatobiliary neoplasia in Austria and has a very poor prognosis. The age-adjusted incidence and mortality rates were higher in males, increased over time in men and remained stable in women. Extrahepatic metastases were rarely diagnosed and associated with dismal survival.

Reply to the Letters to the Editor regarding the sequential ART-Score

complete response (CR) and partial response (PR) in this article, quite different from the definition in their previous article, which excluded the complete response (CR)with the reason that patients with complete response (CR) following the first TACE did not receive a further TACE session. We wonder whether the patients with complete response (CR) after TACE-2 or TACE-3 received further TACE sessions in their institutions. We suppose that the distinct definitions of objective tumor response may diminish the credibility of their study. All the above demonstrates that the ART score is not as validated as we previously supposed. All in all, further study is needed to fully validate the clinical practice of ART-score regardless of its remarkable significance in helping distinguish patients who will benefit from repeated TACE.