Claudio Zavaglia

Field-practice study of sorafenib therapy for hepatocellular carcinoma: A prospective multicenter study in Italy

A multicenter randomized controlled trial established sorafenib as a standard of care for patients with advanced hepatocellular carcinoma (HCC). Because the study was prematurely interrupted due to survival benefits in the sorafenib arm, we conducted an observational study to adequately assess risks and benefits of this regimen in field practice. Starting in 2008, all clinically compensated patients with advanced HCC and those with an intermediate HCC who were unfit or failed to respond to ablative therapies were consecutively evaluated in six liver centers in Italy, for tolerability as well as radiologic and survival response to 800‐mg/d sorafenib therapy. Treatment was down‐dosed or interrupted according to drug label. Two hundred ninety‐six patients (88% Child‐Pugh A, 75% Barcelona Clinic Liver Cancer [BCLC]‐C, and 25% BCLC‐B) received sorafenib for 3.8 months (95% CI 3.3‐4.4). Two hundred sixty‐nine (91%) patients experienced at least one adverse event (AE), whereas 161 (54%) had to reduce dosing. Treatment was interrupted in 103 (44%) for disease progression, in 95 (40%) for an AE, and in 38 (16%) for liver deterioration. The median survival was 10.5 months in the overall cohort, 8.4 months in BCLC‐C versus 20.6 months in BCLC‐B patients (P < 0.0001), and 21.6 months in the 77 patients treated for >70% of the time with a half dose versus 9.6 months in the 219 patients treated for >70% of the time with a full dose. At month 2 of treatment, the overall radiologic response was 8%. Eastern Cooperative Oncology Group performance status, macrovascular invasion, extrahepatic spread of the tumor, radiologic response at month 2, and sorafenib dosing were independent predictors of shortened survival. Conclusion: Overall, safety, effectiveness, and generalizability of sorafenib therapy in HCC was validated in field practice. The effectiveness of half‐dosed sorafenib may have implications for tailored therapy. (HEPATOLOGY 2011)

Predictors of Long-Term Survival After Liver Transplantation for Hepatocellular Carcinoma

AIMS:The aim of this study was to identify predictors of both survival and tumor-free survival of a cohort of 155 patients, with hepatocellular carcinoma (HCC) and cirrhosis, who were treated by orthotopic liver transplantation (OLT).METHODS:From January 1989 to December 2002, 603 OLTs were performed in 549 patients. HCC was diagnosed in 116 patients before OLT and in 39 at histological examination of the explanted livers. Eighty-four percent of the patients met “Milan” criteria at histology. Ninety-four patients received anticancer therapies preoperatively.RESULTS:The median follow-up was 49 months (range, 0–178). Overall, 1-, 3-, 5-, and 10-yr survival were 84%, 75%, 72%, and 62%, respectively. Survival was not affected by the patients age or sex, etiology of liver disease, Child score at transplantation, rejection episodes, tumor number, total tumor burden, bilobar tumor, and pathologic Tumor, Nodes, Metastasis (pTNM) stages. There was no statistically significant difference in survival when patients were grouped according to the recently proposed simplified pTNM staging (5-yr survival, 80% in stage I, 69% in stage II, 50% in stage III, p = 0.3) or the United Network for Organ Sharing (UNOS) staging system for HCC. Encapsulation of the tumor and α-fetoprotein levels significantly affect patient survival. Five-year survival of patients with poorly differentiated (G3) HCC was significantly worse than that of patients with moderately (G2) or well-differentiated (G1) HCC (respectively, G3 44%, G2 67%, and G1 97%, p = 0.0015). Patients with micro- or macro-vascular invasion had a worse 5-yr survival than patients without vascular invasion (49% vs 77%, p = 0.04). Multivariate analysis showed that histological grade of differentiation and macroscopic vascular invasion are independent predictors of survival (HR 2.4, 95% CI 1.4–4.1, p = 0.0009 and HR 2.8, 95% CI 1.2–6.8, p = 0.022).CONCLUSION:Histological grade of differentiation and macroscopic vascular invasion, as assessed on the explanted livers, are strong predictors of both survival and tumor recurrence in patients with cirrhosis who received transplants for HCC.

Liver transplantation for HCV cirrhosis: Improved survival in recent years and increased severity of recurrent disease in female recipients: Results of a long term retrospective study

In recent years, a worsening outcome of hepatitis C virus (HCV)‐positive recipients and a faster progression of recurrent disease to overt cirrhosis has been reported. Our aims were to 1) assess patient survival and development of severe recurrent disease (Ishak fibrosis score > 3) in different transplant years; and 2) model the effects of pre‐ and post‐liver transplantation (LT) variables on the severity of recurrent disease. A multicenter retrospective analysis was conducted on 502 consecutive HCV‐positive transplant recipients between January 1990 and December 2002. Protocol liver biopsies were obtained at 1, 3, 5, 7, and 10 yr post‐LT in almost 90% of the patients. All 502 patients were included in the overall survival analysis, while only the 354 patients with a follow‐up longer than 1 yr were considered for the analysis of predictors of disease progression. The overall Kaplan–Meier survival rates were 78.7%, 66.3%, and 58.6%, at 12, 60, and 120 months, respectively, and a trend for a better patient survival over the years emerged from all 3 centers. The cumulative probability of developing HCV‐related recurrent severe fibrosis (Ishak score 4‐6) in the cohort of 354 patients who survived at least 1 yr remained unchanged over the years. Multivariate analysis indicated that older donors (P = 0.0001) and female gender of recipient (P = 0.02) were the 2 major risk factors for the development of severe recurrent disease, while the adoption of antilymphocytic preparations was associated with a less aggressive course (P = 0.03). Two of these prognostic factors, donor age and recipient gender, are easily available before LT and their combination showed an important synergy, such that a female recipient not only had a much higher probability of severe recurrent disease than a male recipient but her risk increased with the increasing age of the donor, reaching almost 100% when the age of the donor was 60 or older. In conclusion, a trend for a better patient survival was observed in more recent years but the cumulative probability of developing severe recurrent disease remained unchanged. The combination of a female recipient receiving an older graft emerged as a strong risk factor for a severe recurrence. Liver Transpl, 2007.

Association between HLA class II alleles and protection from or susceptibility to chronic hepatitis C

BACKGROUND/AIMS Recent studies have suggested that the course of chronic hepatitis C may be influenced by the immunogenetic background of the host. Specifically, HLA-DR11 (5) has been associated with less advanced hepatitis C virus (HCV)-related liver disease. The aim of the present study was to investigate whether HLA-DRB1*11 subtypes or HLA-DQA1 and DQB1 genes might be associated with protection from or susceptibility to chronic HCV infection, histological severity of HCV-induced liver disease and infecting HCV genotype. METHODS Ninety-nine unrelated outpatients with histologically documented chronic hepatitis C were studied and their allele frequencies were compared with those of 179 ethnically matched controls and with those of 41 HCV RNA-positive patients with persistently normal aminotransferase levels (HCV carriers). HLA-DQ types and HLA-DRB1*11 subtypes were determined by polymerase chain reaction gene amplification with sequence specific primers. RESULTS None of 10 DQA1 or 12 DQB1 alleles was significantly associated with susceptibility to or protection from chronic HCV infection or with histological staging or with HCV genotype. However, analysis of DQA1-DQB1 combinations showed that DQA1*0201-DQB1*0201 combination was significantly more frequent in patients compared to controls, both in cis (26.3% vs 16.2%, p = 0.04, odds ratio = 1.8, 95% confidence interval, 0.96-3.5) and in trans (12.1% vs. 1.1%, p = 0.0001, OR = 12.2, 95% CI, 2.6-113.7). HCV carriers did not differ from controls or from patients in the frequency of DQA1-DQB1 combinations. The extended haplotype DRB1*1104, DQA1*0501, DQB1*0301 was seen significantly less frequently in patients than in controls (8% vs 22.3%, p = 0.0025, OR = 0.31, 95% CI, 0.12-0.7) or HCV-RNA carriers (8% vs 26.8%, p = 0.003, OR = 0.24, 95% CI, 0.08-0.73). CONCLUSIONS Immunogenetic factors may play a role in determining both protection from and susceptibility to chronic hepatitis C, the trans-dimer DQA1*0201-DQB1*0201 predisposing to and the DRB1*1104, DQA1*0501, DQB1*0301 haplotype protecting from chronic hepatitis C.

HLA typing in chronic type B, D and C hepatitis

AIMS We aimed to test the hypothesis that susceptibility to chronic HBV, HDV and HCV infections or their pathology is influenced by host genetic factors. METHODS The Human Leukocyte Antigens (HLA) (A, B, DR and DQ) were determined by microlymphocytotoxicity assay in patients with chronic C (n = 117), B (n = 97) or D (n = 27) hepatitis and their frequencies were compared with those of 489 healthy controls. RESULTS No statistically significant association was found between any HLA antigen and chronic B or D hepatitis. A significantly higher frequency of HLA-B14 was observed in patients with chronic persistent or active C hepatitis (16.7% of 90 versus 5.9% of 489, chi(2) = 10.9, pc < 0.05, Relative Risk = 3.17, Etiological Fraction = 0.11). The frequency of HLA-DR5 was lower in HCV positive patients (24.8%) than in controls (45%, chi(2) = 15.1, pc < 0.005, RR = 0.4, EF = -0.37). CONCLUSIONS No correlation could be observed between clearance of HBV or HDV and HLA phenotype. Immunogenetic factors may have a role in determining susceptibility to chronic HCV hepatitis, and in Italian patients HLA-DR5 is a protective factor.

Cost-effectiveness of sorafenib treatment in field practice for patients with hepatocellular carcinoma

The purpose was to assess the cost‐effectiveness of sorafenib in the treatment of hepatocellular carcinoma (HCC) patients incorporating current prices and the results of the recent published field practice SOraFenib Italian Assessment (SOFIA) study. We created a Markov Decision Model to evaluate, in a hypothetical cohort of Caucasian male patients, aged 67 years with Barcelona Clinic Liver Cancer (BCLC) C HCC, or BCLC B HCC who were unfit or failed to respond to locoregional therapies, well compensated cirrhosis, and with performance status 0‐1 according to Eastern Cooperative Oncology Group (ECOG), the cost‐effectiveness of the following strategies: (1) full or dose‐adjusted sorafenib for BCLC B and C patients together; (2) full or dose‐adjusted sorafenib for BCLC B patients; (3) full or dose‐adjusted sorafenib for BCLC C patients. Outcomes include quality‐adjusted life years (QALYs), costs, and incremental cost‐effectiveness ratio (ICER). In the base‐case analysis dose‐adjusted sorafenib was the most effective of the evaluated strategies. For dose‐adjusted sorafenib, QALY was 0.44 for BCLC B and C patients together, 0.44 for BCLC C patients, and 0.38 for BCLC B patients. The ICER of dose‐adjusted sorafenib compared with BSC was €34,534 per QALY gained for BCLC B and C patients together, €27,916 per QALY gained for BCLC C patients, and €54,881 per QALY gained for BCLC B patients. Results were sensitive to BSC survival rate, and sorafenib treatment duration. Conclusion: In daily practice dose‐adjusted, but not full‐dose, sorafenib is a cost‐effective treatment compared to BSC in intermediate and advanced HCC. (HEPATOLOGY 2013)

CYP ENZYME POLYMORPHISMS AND SUSCEPTIBILITY TO HCV-RELATED CHRONIC LIVER DISEASE AND LIVER CANCER

Cancer risk can be influenced by the exposure to endogenous or environmental toxins. Polymorphic enzymes involved in the metabolic activation/detoxification of carcinogens may account for individual variations of risk. We studied the polymorphisms of five enzymes of the P450 superfamily, CYP1A1, CYP1A2, CYP2D6, CYP2E1 and CY3A4, as risk factors for liver disease progression and cancer in hepatitis C virus‐infected patients. CYP genotyping was performed by polymerase chain reaction (PCR) restriction fragment length polymorphism or allele‐specific PCR. Different stages of disease were considered, as follows: 90 asymptomatic carriers and 87 chronic hepatitis, 92 cirrhosis and 91 hepatocellular carcinoma (HCC) cases. Reference allele frequencies were obtained from 99 blood donors. Allele distributions among categories were compared using the χ2 test. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to express relative risks. Independent associations were modeled by correspondence analysis and logistic regression. Frequencies of the CYP1A1 highly inducible alleles, MspI m2 and Val, were increased in liver disease patients compared with carriers; no specific association with HCC was found. The high‐activity CYP2E1 c2 allele was underrepresented among HCC patients with respect to other HCV categories, including cirrhosis. CYP2D6 poor metabolizer (PM) genotypes were significantly more frequent in healthy subjects (7.1%) and carriers (11.1%) than in hepatitis/cirrhosis (4.6%) and HCC (1.2%) patients. This was confirmed by multivariable analysis. PM genotypes protected against progressive disease as ORs reduced proportionally to stage. The age at diagnosis for HCC was anticipated in non‐PM individuals. No differences were seen for CYP1A2 and CYP3A4 genes. Polymorphic variants of CYP genes may contribute to the progression of liver disease and HCC risk in HCV‐infected subjects.

Is the risk of neoplastic recurrence increased after prescribing direct-acting antivirals for HCV patients whose HCC was previously cured?

Variable Total cohort (n = 31) (%) Antitumoral treatment Resection 13 (42%) Resection and percutaneous ablation 1 (3%) Resection and TACE and percutaneous ablation 1 (3%) Resection and TACE 3 (10%) Percutaneous ablation and TACE 3 (10%) Percutaneous ablation 6 (19%) TACE 4 (13%) Worst BCLC stage prior to DAA therapy BCLC-0 8 (26%) BCLC-A1 4 (13%) BCLC-A2 9 (29%) BCLC-A3 2 (6%) BCLC-A4 3 (10%) BCLC-B 4 (13%) BCLC-C 1 (3%) Bilirubin (mean ± SD) 1.1 ± 0.7 Albumin (mean ± SD) 3.7 ± 0.5 Prothrombin time (INR) (mean ± SD) 1.1 ± 0.1 Alanine aminotransferase (mean ± SD) 71 ± 30 Pre-DAA HCV RNA levels (Log10), (median, range) (IU/ml) 5.6 (3.8-7.5) Pre-DAA serum AFP levels (median, range) (ng/ml) 10 (2-278) Treatment regimens SOF/LDV ± RBV for 12 or 24 weeks 15 (48%) SIM/SOF for 12 weeks 6 (19%) SOF/DCV ± RBV for 24 weeks 2 (6%) PrOD or the 3D regimen ± RBV for 12 or 24 weeks 3 (9.6%) SOF/RBV for 24 weeks 3 (9.6%) End of treatment response 31 (100%) Post-DAA serum AFP levels (median, range) (ng/ml) 6 (1-44) Interval between start of DAA therapy and last radiological assessment (months) (median, percentile 25-75) 8 (5-10.9)

Adverse events affect sorafenib efficacy in patients with recurrent hepatocellular carcinoma after liver transplantation: experience at a single center and review of the literature.

Aims The aim of this study was to assess the safety and efficacy of sorafenib, with or without everolimus, in the treatment of recurrent hepatocellular carcinoma (HCC) after an orthotopic liver transplantation (OLT). Methods We reviewed the outcome of our consecutive cohort series of patients. Eleven patients (nine men) with recurrent HCC after OLT were treated. Four patients received cyclosporine plus sorafenib at a starting dose of 400 mg twice daily; seven received the combination of sorafenib (same dosage) and everolimus. Sorafenib was reduced or stopped according to the drug label. Results The median time to recurrence was 12 months (range 2–66). The mean age at the start of treatment was 57±9 years. Sorafenib was withdrawn because of intolerance or side-effects in four (36%) patients. Dose reduction because of adverse events or intolerance was required in 91% of patients after 26±11 days from the start of treatment. The average length of treatment was 68 days (range 15–444). One patient died because of a massive gastrointestinal bleeding while receiving sorafenib and everolimus. The most frequent adverse events were fatigue (54%), skin toxicity (45%), and hypophosphatemia (36%). Two patients (18%) showed a radiological partial response, one (9%) had a stable disease, and six (54%) showed a progressive disease. None of the patients achieved a complete response. Treatment response could not be assessed in two (18%) patients. The overall median survival since the start of treatment was 5 months. One-year survival was 18%. Conclusion Sorafenib, with or without mammalian target of rapamycin inhibitors, is poorly tolerated and rarely effective in the treatment of recurrent HCC after OLT.

Is percutaneous radiofrequency thermal ablation of hepatocellular carcinoma a safe procedure

Aim To assess the safety and efficacy of percutaneous radiofrequency thermal ablation (RFA) in the treatment of nonsurgical hepatocellular carcinoma (HCC) in daily practice. Methods A total of 63 consecutive patients with HCC (solitary nodule ≤5 cm or 2 nodules ≤3 cm) and cirrhosis were treated with RFA. Majority of the patients had a compensated liver disease (73% Child A) and an early tumor stage (87% CLIP 0 or 1). Indications for treatment were primary HCC therapy (30 patients), adjuvant therapy before liver transplantation (15 patients) or palliation in the remaining 18 patients with progression of HCC despite previous antitumoral treatments. RFA was performed by a 100 kW electrical generator connected to an expandable 10-hook electrode. Results Seventy-one lesions were treated in 80 sessions. Sixteen patients required adjuvant chemoembolization. Mean follow-up was 18±12 months. An objective response was achieved in 87% of patients who underwent primary/adjuvant treatment. Complete histological necrosis was found in 38% of patients who underwent liver transplantation. One, 2 and 3-year survival rates were 95, 76 and 72%, respectively in patients who underwent primary/adjuvant therapy and 82, 68 and 51%, respectively in patients who underwent palliative therapy. Major complications (hemoperitoneum, pleuritis, pneumothorax and sepsis) were observed in 6.3% of the patients. Notably, rapid neoplastic progression was observed in two patients within 2 months after a single RFA session (neoplastic portal thrombosis and plurifocal HCC in one patient and cutaneous seeding and lung metastases in another patient). Conclusions Majority of the HCC patients treated by percutaneous RFA can achieve local control of the tumor in HCCs less than or equal to 3 cm. As the procedure can be associated with major complications and cases of rapid neoplastic dissemination may occur, a more accurate selection of candidates to RFA treatment is advisable.