Matthias Pinter

Sorafenib in Unresectable Hepatocellular Carcinoma from Mild to Advanced Stage Liver Cirrhosis

BACKGROUND Few data are available on the safety and efficacy of sorafenib in patients with multifocal hepatocellular carcinoma (HCC) and advanced liver cirrhosis. METHODS Between May 2006 and December 2007, we treated 59 patients (Child-Pugh class A/B/C, 26/23/10) with unresectable HCC with sorafenib (daily target dose, 400 mg twice daily). Data were collected retrospectively. Survival curves were calculated via the Kaplan-Meier method. RESULTS One patient (Child-Pugh class B) had a partial response, 14 patients (Child-Pugh class A/B/C, 5/7/2) had stable disease, and 32 patients (Child-Pugh class A/B/C, 15/11/6) had progressive disease; 12 patients were not evaluable because they had no follow-up radiologic evaluation. In the intention-to-treat group, the median time to progression and overall survival (OS) time were 2.8 months (range, 1.4-6.5 months) and 6.5 months (range, 0.4-17.4 months), respectively. Well-preserved liver function and lower Barcelona Clinic Liver Cancer stage were associated with a longer OS time on univariate analysis. There were four severe gastrointestinal bleedings (grade 4-5; Child-Pugh class B/C, 2/2). Most drug-related side effects were low grade and manageable irrespective of liver function. CONCLUSIONS Sorafenib is effective and safe in patients with multifocal HCC and Child-Pugh class A cirrhosis. Survival in Child-Pugh class B patients is significantly less than in Child-Pugh class A patients, warranting a prospective randomized trial with a placebo group. Child-Pugh class C patients have a limited life expectancy despite sorafenib treatment because of their severe underlying disease and derive little benefit from sorafenib treatment.

Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic non-response to propranolol

Objective Non-selective β-blockers or endoscopic band ligation (EBL) are recommended for primary prophylaxis of variceal bleeding in patients with oesophageal varices. Additional α-adrenergic blockade (as by carvedilol) may increase the number of patients with haemodynamic response (reduction in hepatic venous pressure gradient (HVPG) of ≥20% or to values <12 mm Hg). Design Patients with oesophageal varices undergoing measurement of HVPG before and under propranolol treatment (80–160 mg/day) were included. HVPG responders were kept on propranolol (PROP group), while non-responders were placed on carvedilol (6.25–50 mg/day). Carvedilol responders continued treatment (CARV group), while non-responders to carvedilol underwent EBL. The primary aim was to assess haemodynamic response rates to carvedilol in propranolol non-responders. Results 36% (37/104) of patients showed a HVPG response to propranolol. Among the propranolol non-responders 56% (38/67) eventually achieved a haemodynamic response with carvedilol, while 44% (29/67) patients were finally treated with EBL. The decrease in HVPG was significantly greater with carvedilol (median 12.5 mg/day) than with propranolol (median 100 mg/day): −19±10% versus −12±11% (p<0.001). During a 2 year follow-up bleeding rates for PROP were 11% versus CARV 5% versus EBL 25% (p=0.0429). Fewer episodes of hepatic decompensation (PROP 38%/CARV 26% vs EBL 55%; p=0.0789) and significantly lower mortality (PROP 14%/CARV 11% vs EBL 31%; p=0.0455) were observed in haemodynamic responders compared to the EBL group. Conclusions Carvedilol leads to a significantly greater decrease in HVPG than propranolol. Using carvedilol for primary prophylaxis a substantial proportion of non-responders to propranolol can achieve a haemodynamic response, which is associated with improved outcome with regard to prevention of variceal bleeding, hepatic decompensation and death.

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).

Obesity-induced inflammation and desmoplasia promote pancreatic cancer progression and resistance to chemotherapy

UNLABELLED It remains unclear how obesity worsens treatment outcomes in patients with pancreatic ductal adenocarcinoma (PDAC). In normal pancreas, obesity promotes inflammation and fibrosis. We found in mouse models of PDAC that obesity also promotes desmoplasia associated with accelerated tumor growth and impaired delivery/efficacy of chemotherapeutics through reduced perfusion. Genetic and pharmacologic inhibition of angiotensin-II type-1 receptor reverses obesity-augmented desmoplasia and tumor growth and improves response to chemotherapy. Augmented activation of pancreatic stellate cells (PSC) in obesity is induced by tumor-associated neutrophils (TAN) recruited by adipocyte-secreted IL1β. PSCs further secrete IL1β, and inactivation of PSCs reduces IL1β expression and TAN recruitment. Furthermore, depletion of TANs, IL1β inhibition, or inactivation of PSCs prevents obesity-accelerated tumor growth. In patients with pancreatic cancer, we confirmed that obesity is associated with increased desmoplasia and reduced response to chemotherapy. We conclude that cross-talk between adipocytes, TANs, and PSCs exacerbates desmoplasia and promotes tumor progression in obesity. SIGNIFICANCE Considering the current obesity pandemic, unraveling the mechanisms underlying obesity-induced cancer progression is an urgent need. We found that the aggravation of desmoplasia is a key mechanism of obesity-promoted PDAC progression. Importantly, we discovered that clinically available antifibrotic/inflammatory agents can improve the treatment response of PDAC in obese hosts. Cancer Discov; 6(8); 852-69. ©2016 AACR.See related commentary by Bronte and Tortora, p. 821This article is highlighted in the In This Issue feature, p. 803.

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.

Single determination of C-reactive protein at the time of diagnosis predicts long-term outcome of patients with hepatocellular carcinoma.

We investigated the prognostic value of C‐reactive protein (CRP) in patients with hepatocellular carcinoma (HCC) not amenable to surgery. A total of 615 patients diagnosed with HCC not amenable to surgery between April 1999 and December 2009 at the Department of Gastroenterology of the Medical Universities of Vienna and Innsbruck were included. We assessed the optimal CRP cutoff by regression spline analysis and tested its impact on median overall survival (OS) by the Kaplan‐Meier method, univariate analysis (log‐rank test), and multivariate analysis (Cox proportional hazard regression model) in a training cohort (n = 466, Vienna) and an independent validation cohort (n = 149, Innsbruck). We found a sigmoid‐shaped association of CRP and the hazard ratio of death upon regression spline analysis and defined a CRP level <1/≥1 mg/dL as optimal cutoff for further survival assessments. Elevated CRP (≥1 mg/dL) at diagnosis was associated with poor OS (CRP‐elevated versus CRP‐normal; 4 versus 20 months; P < 0.001) and remained a significant negative predictor for OS upon multivariate analysis (hazard ratio, 1.7; P < 0.001), which was independent of age, Child‐Pugh class, tumor characteristics, and treatment allocation. Analyses with respect to Barcelona Clinic Liver Cancer (BCLC) stage and Child‐Pugh class supported the relevance of CRP (BCLC‐stage C and Child‐Pugh A: OS for CRP‐elevated versus CRP‐normal, 6 versus 14; P < 0.001; BCLC‐stage C and Child‐Pugh B: OS for CRP‐elevated versus CRP‐normal, 4 versus 15 months; P < 0.001). The prognostic significance of elevated CRP was reproducible at a second CRP determination timepoint and confirmed in the independent validation cohort. Conclusion: Elevated CRP is associated with a dismal prognosis in HCC patients and may become a useful marker for patient selection in HCC management. (HEPATOLOGY 2012)

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.

Osteopontin expression predicts overall survival after liver transplantation for hepatocellular carcinoma in patients beyond the Milan criteria

BACKGROUND & AIMS Microarray data showed that osteopontin overexpression predicts early HCC-recurrence after liver resection. Osteopontin (OPN) expression could serve as a predictor of HCC-recurrence after OLT. METHODS Osteopontin expression was investigated immunohistochemically in a unique population of 125 HCC-patients undergoing OLT between 1982 and 2002, including 81 patients (65%) outside the Milan criteria. Multivariate analysis of factors associated with median overall survival (OS) and time to recurrence (TTR) was performed. RESULTS Osteopontin was expressed in 40/125 (32%) of the HCCs. Overall survival post-OLT at 1, 2, 3, 5 years was 77%, 62%, 52%, and 43% (median survival 37 months). Overall survival was significantly longer without expression of OPN (p < 0.05; (median OS: 56 vs. 23 months). The same was true for median TTR (p = 0.008). Outside Milan criteria, patients without OPN-expression had better prognosis (median OS: 37.8 vs. 19.2 months, p = 0.003). Tumor recurrence in patients transplanted outside Milan criteria occurred in 43% (23 of 54) of patients without and 70% (19 of 27, p = 0.018) of patients with OPN-expression after a median TTR of 83.5 vs. 13.9 months. On multivariate analysis, vascular invasion and OPN-expression were independently associated with OS and TTR in HCC-patients after OLT. CONCLUSIONS Immunohistochemically detectable Osteopontin in HCC is an independent predictor of tumor recurrence and survival in patients beyond Milan criteria undergoing OLT.

Cancer and liver cirrhosis: implications on prognosis and management

Liver cirrhosis, the end-stage of every chronic liver disease, is not only the major risk factor for the development of hepatocellular carcinoma but also a limiting factor for anticancer therapy of liver and non-hepatic malignancies. Liver cirrhosis may limit surgical and interventional approaches to cancer treatment, influence pharmacokinetics of anticancer drugs, increase side effects of chemotherapy, render patients susceptible for hepatotoxicity, and ultimately result in a competitive risk for morbidity and mortality. In this review, we provide a concise overview about the impact of liver cirrhosis on the management and prognosis of patients with primary liver cancer or non-hepatic malignancies.