Sorafenib increases cytochrome P450 lipid metabolites in patient with hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a leading cause of cancer death, and medical treatment options are limited. The multikinase inhibitor sorafenib was the first approved drug widely used for systemic therapy in advanced HCC. Sorafenib might affect polyunsaturated fatty acids (PUFA)-derived epoxygenated metabolite levels, as it is also a potent inhibitor of the soluble epoxide hydrolase (sEH), which catalyzes the conversion of cytochrome-P450 (CYP)-derived epoxide metabolites derived from PUFA, such as omega-6 arachidonic acid (AA) and omega-3 docosahexaenoic acid (DHA), into their corresponding dihydroxy metabolites. Experimental studies with AA-derived epoxyeicosatrienoic acids (EETs) have shown that they can promote tumor growth and metastasis, while DHA-derived 19,20-epoxydocosapentaenoic acid (19,20-EDP) was shown to have anti-tumor activity in mice. In this study, we found a significant increase in EET levels in 43 HCC patients treated with sorafenib and a trend towards increased levels of DHA-derived 19,20-EDP. We demonstrate that the effect of sorafenib on CYP- metabolites led to an increase of 19,20-EDP and its dihydroxy metabolite, whereas DHA plasma levels decreased under sorafenib treatment. These data indicate that specific supplementation with DHA could be used to increase levels of the epoxy compound 19,20-EDP with potential anti-tumor activity in HCC patients receiving sorafenib therapy.

Extracellular Vesicles May Predict Response to Radioembolization and Sorafenib Treatment in Advanced Hepatocellular Carcinoma: An Exploratory Analysis from the SORAMIC Trial.

PURPOSE: SORAMIC is a randomized controlled trial in patients with advanced hepatocellular carcinoma (HCC) undergoing sorafenib ± selective internal radiation therapy (SIRT). We investigated the value of extracellular vesicle (EV)-based proteomics for treatment response prediction. EXPERIMENTAL DESIGN: The analysis population comprised 25 patients receiving SIRT+sorafenib and 20 patients receiving sorafenib alone. Patients were classified as responders or nonresponders based on changes in AFP and imaging or overall survival. Proteomic analysis was performed on plasma EVs by LC/MS, followed by bioinformatics analysis. Clinical relevance of candidate EV proteins was validated by survival and receiver-operating characteristic analysis with bootstrap internal sampling validation. Origin of circulating EV was explored by IHC staining of liver and tumor tissues and transcriptomics of blood cells. RESULTS: Proteomic analysis identified 56 and 27 EV proteins that were differentially expressed in plasma EVs between responders and nonresponders receiving SIRT+sorafenib and sorafenib alone, respectively. High EV-GPX3/ACTR3 and low EV-ARHGAP1 were identified as candidate biomarkers at baseline from the 13 responders to SIRT+sorafenib with statistically significant AUC = 1 for all and bootstrap P values 2.23 × 10-5, 2.22 × 10-5, and 2.23 × 10-5, respectively. These patients showed reduced abundance of EV-VPS13A and EV-KALRN 6 to 9 weeks after combined treatment with significant AUC and bootstrap P values. In reverse, low GPX3 and high ARHGAP1 demonstrated better response to sorafenib monotherapy with AUC = 0.9697 and 0.9192 as well as bootstrap P values 8.34 × 10-5 and 7.98 × 10-4, respectively. HCC tumor was the likely origin of circulating EVs. CONCLUSIONS: In this exploratory study, EV-based proteomics predicted response to SIRT+sorafenib and sorafenib-only treatment in patients with advanced HCC of metabolic origin.

Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial.

BACKGROUND: Single-agent nivolumab showed durable responses, manageable safety, and promising survival in patients with advanced hepatocellular carcinoma in the phase 1-2 CheckMate 040 study. We aimed to investigate nivolumab monotherapy compared with sorafenib monotherapy in the first-line setting for patients with advanced hepatocellular carcinoma. METHODS: In this randomised, open-label, phase 3 trial done at medical centres across 22 countries and territories in Asia, Australasia, Europe, and North America, patients at least 18 years old with histologically confirmed advanced hepatocellular carcinoma not eligible for, or whose disease had progressed after, surgery or locoregional treatment; with no previous systemic therapy for hepatocellular carcinoma, with Child-Pugh class A and Eastern Cooperative Oncology Group performance status score of 0 or 1, and regardless of viral hepatitis status were randomly assigned (1:1) via an interactive voice response system to receive nivolumab (240 mg intravenously every 2 weeks) or sorafenib (400 mg orally twice daily) until disease progression or unacceptable toxicity. The primary endpoint was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT02576509. FINDINGS: Between Jan 11, 2016, and May 24, 2017, 743 patients were randomly assigned to treatment (nivolumab, n=371; sorafenib, n=372). At the primary analysis, the median follow-up for overall survival was 15·2 months (IQR 5·7-28·0) for the nivolumab group and 13·4 months (5·7-25·9) in the sorafenib group. Median overall survival was 16·4 months (95% CI 13·9-18·4) with nivolumab and 14·7 months (11·9-17·2) with sorafenib (hazard ratio 0·85 [95% CI 0·72-1·02]; p=0·075; minimum follow-up 22·8 months); the protocol-defined significance level of p=0·0419 was not reached. The most common grade 3 or worse treatment-related adverse events were palmar-plantar erythrodysaesthesia (1 [<1%] of 367 patients in the nivolumab group vs 52 [14%] of patients in the sorafenib group), aspartate aminotransferase increase (22 [6%] vs 13 [4%]), and hypertension (0 vs 26 [7%]). Serious treatment-related adverse events were reported in 43 (12%) patients receiving nivolumab and 39 (11%) patients receiving sorafenib. Four deaths in the nivolumab group and one death in the sorafenib group were assessed as treatment related. INTERPRETATION: First-line nivolumab treatment did not significantly improve overall survival compared with sorafenib, but clinical activity and a favourable safety profile were observed in patients with advanced hepatocellular carcinoma. Thus, nivolumab might be considered a therapeutic option for patients in whom tyrosine kinase inhibitors and antiangiogenic drugs are contraindicated or have substantial risks. FUNDING: Bristol Myers Squibb in collaboration with Ono Pharmaceutical.

Baseline Interleukin-6 and -8 predict response and survival in patients with advanced hepatocellular carcinoma treated with sorafenib monotherapy: an exploratory post hoc analysis of the SORAMIC trial.

PURPOSE: To explore the potential correlation between baseline interleukin (IL) values and overall survival or objective response in patients with hepatocellular carcinoma (HCC) receiving sorafenib. METHODS: A subset of patients with HCC undergoing sorafenib monotherapy within a prospective multicenter phase II trial (SORAMIC, sorafenib treatment alone vs. combined with Y90 radioembolization) underwent baseline IL-6 and IL-8 assessment before treatment initiation. In this exploratory post hoc analysis, the best cut-off points for baseline IL-6 and IL-8 values predicting overall survival (OS) were evaluated, as well as correlation with the objective response. RESULTS: Forty-seven patients (43 male) with a median OS of 13.8 months were analyzed. Cut-off values of 8.58 and 57.9 pg/mL most effectively predicted overall survival for IL-6 and IL-8, respectively. Patients with high IL-6 (HR, 4.1 [1.9-8.9], p < 0.001) and IL-8 (HR, 2.4 [1.2-4.7], p = 0.009) had significantly shorter overall survival than patients with low IL values. Multivariate analysis confirmed IL-6 (HR, 2.99 [1.22-7.3], p = 0.017) and IL-8 (HR, 2.19 [1.02-4.7], p = 0.044) as independent predictors of OS. Baseline IL-6 and IL-8 with respective cut-off values predicted objective response rates according to mRECIST in a subset of 42 patients with follow-up imaging available (IL-6, 46.6% vs. 19.2%, p = 0.007; IL-8, 50.0% vs. 17.4%, p = 0.011). CONCLUSION: IL-6 and IL-8 baseline values predicted outcomes of sorafenib-treated patients in this well-characterized prospective cohort of the SORAMIC trial. We suggest that the respective cut-off values might serve for validation in larger cohorts, potentially offering guidance for improved patient selection.

Liver function after combined selective internal radiation therapy or sorafenib monotherapy in advanced hepatocellular carcinoma.

BACKGROUND & AIMS: SORAMIC is a previously published randomised controlled trial assessing survival in patients with advanced hepatocellular carcinoma who received sorafenib with or without selective internal radiation therapy (SIRT). Based on the per-protocol (PP) population, we assessed whether the outcome of patients receiving SIRT+sorafenib vs. sorafenib alone was affected by adverse effects of SIRT on liver function. METHODS: The PP population consisted of 109 (SIRT+sorafenib) vs. 173 patients (sorafenib alone). Comparisons were made between subgroups who achieved a significant survival benefit or trend towards improved survival with SIRT and the inverse group without a survival benefit: <65 years-old vs. ≥65 years-old, Child-Pugh 5 vs. 6, no transarterial chemoembolisation (TACE) vs. prior TACE, no cirrhosis vs. cirrhosis, non-alcohol- vs. alcohol-related aetiology. The albumin-bilirubin (ALBI) score was used to monitor liver function over time during follow-up. RESULTS: ALBI scores increased in all patient groups during follow-up. In the PP population, ALBI score increases were higher in the SIRT+sorafenib than the sorafenib arm (p = 0.0021 month 4, p <0.0001 from month 6). SIRT+sorafenib conferred a survival benefit compared to sorafenib alone in patients aged <65 years-old, those without cirrhosis, those with Child-Pugh 5, and those who had not received TACE. A higher increase in ALBI score was observed in the inverse subgroups in whom survival was not improved by adding SIRT (age ≥65 years-old, p <0.05; cirrhosis, p = 0.07; Child-Pugh 6, p <0.05; prior TACE, p = 0.08). CONCLUSION: SIRT frequently has a negative, often subclinical, effect on liver function in patients with hepatocellular carcinoma, which may impair prognosis after treatment. Careful patient selection for SIRT as well as prevention of clinical and subclinical liver damage by selective treatments, high tumour uptake ratio, and medical prophylaxis could translate into better efficacy. CLINICAL TRIAL NUMBER: EudraCT 2009-012576-27, NCT01126645 LAY SUMMARY: This study of treatments in patients with hepatocellular carcinoma found that selective internal radiation therapy (SIRT) has an adverse effect on liver function that may affect patient outcomes. Patients should be carefully selected before they undergo SIRT and the treatment technique should be optimised for maximum protection of non-target liver parenchyma.

Impact of combined selective internal radiation therapy and sorafenib on survival in advanced hepatocellular carcinoma.

BACKGROUND & AIMS: Sorafenib is the recommended treatment for patients with advanced hepatocellular carcinoma (HCC). We aimed to compare the efficacy and safety of a combination of sorafenib and selective internal radiation therapy (SIRT) - with yttrium-90 (90Y) resin microspheres - to sorafenib alone in patients with advanced HCC. METHODS: SORAMIC is a randomised controlled trial comprising diagnostic, local ablation and palliative cohorts. Based on diagnostic study results, patients were assigned to local ablation or palliative cohorts. In the palliative cohort, patients not eligible for TACE were randomised 11:10 to SIRT plus sorafenib (SIRT + sorafenib) or sorafenib alone. The primary endpoint was overall survival (OS; Kaplan-Meier analysis) in the intention-to-treat (ITT) population. RESULTS: In the ITT cohort, 216 patients were randomised to SIRT + sorafenib and 208 to sorafenib alone. Median OS was 12.1 months in the SIRT + sorafenib arm, and 11.4 months in the sorafenib arm (hazard ratio [HR] 1.01; 95% CI 0.81-1.25; p = 0.9529). Median OS in the per protocol population was 14.0 months in the SIRT + sorafenib arm (n = 114), and 11.1 months in the sorafenib arm (n = 174; HR 0.86; p = 0.2515). Subgroup analyses of the per protocol population indicated a survival benefit of SIRT + sorafenib for patients without cirrhosis (HR 0.46; 0.25-0.86; p = 0.02); cirrhosis of non-alcoholic aetiology (HR 0.63; p = 0.012); or patients ≤65 years old (HR 0.65; p = 0.05). Adverse events (AEs) of Common Terminology Criteria for AE Grades 3-4 were reported in 103/159 (64.8%) patients who received SIRT + sorafenib, 106/197 (53.8%) patients who received sorafenib alone (p = 0.04), and 8/24 (33.3%) patients who only received SIRT. CONCLUSION: Addition of SIRT to sorafenib did not result in a significant improvement in OS compared with sorafenib alone. Subgroup analyses led to hypothesis-generating results that will support the design of future studies. LAY SUMMARY: Sorafenib given orally is the recommended treatment for patients with advanced hepatocellular carcinoma (HCC). In selective internal radiation therapy (SIRT), also known as radioembolisation, microscopic, radioactive resin or glass spheres are introduced into the blood vessels that feed the tumours in the liver. This study found that the addition of SIRT with 90yttrium-loaded resin microspheres to sorafenib treatment in people with advanced HCC did not significantly improve overall survival compared with sorafenib treatment alone. However, the results give an indication of how future studies using this combination therapy in people with advanced HCC could be designed. STUDY REGISTRATION: EudraCT 2009-012576-27, NCT0112 6645.

Complete response under sorafenib in patients with hepatocellular carcinoma: Relationship with dermatologic adverse events.

The clinical benefit of sorafenib in patients with hepatocellular carcinoma (HCC) has been undervalued due to the absence of complete responses, even though patients who develop early dermatologic reactions have shown to have a positive outcome. In addition, sorafenib is described as an antiangiogenic drug, but it also acts on immunological cells. Thus, the goal of this study was to assess the complete response rate in a retrospective cohort of HCC patients treated with sorafenib and to describe the profile of the patients who achieve complete response for identifying factors related to this event and their connection with the immunological profile of sorafenib. Ten Spanish centers submitted cases of complete response under sorafenib. The baseline characteristics, development of early dermatologic reactions, and cause of treatment discontinuation were annotated. Radiological images taken before starting sorafenib, at first control, after starting sorafenib, at the time of complete response, and at least 1 month after treatment were centrally reviewed. Of the 1119 patients studied, 20 had been classified as complete responders by the centers, but eight of these patients were excluded after central review. Ten patients had complete disappearance of all tumor sites, and two had just a small residual fibrotic scar. Thus, 12 patients were classified as complete responders (58% HCV, median age 59.7 years, 83.4% Child-Pugh class A, Eastern Cooperative Oncology Group performance status 0 91.7%, and Barcelona Clinic Liver Cancer stage C 83.3%). The median overall survival and treatment duration were 85.8 and 40.1 months, respectively. All but one patient developed early dermatologic reactions, and seven patients discontinued sorafenib after achieving complete response due to adverse events, patient decision, or liver decompensation. Conclusion: Complete response affects 1% of patients with HCC who are treated with sorafenib. The association of complete response with early dermatologic reactions supports the role of a specific immune/inflammatory patient profile in the improved response to sorafenib. (Hepatology 2018;67:612-622).

Prevention and treatment of complications of selective internal radiation therapy: Expert guidance and systematic review.

Selective internal radiation therapy (or radioembolization) by intra-arterial injection of radioactive yttrium-90-loaded microspheres is increasingly used for the treatment of patients with liver metastases or primary liver cancer. The high-dose beta-radiation penetrates an average of only 2.5 mm from the source, thus limiting its effects to the site of delivery. However, the off-target diversion of yttrium-90 microspheres to tissues other than the tumor may lead to complications. The most prominent of these complications include radiation gastritis and gastrointestinal ulcers, cholecystitis, radiation pneumonitis, and radioembolization-induced liver disease, which may occur despite careful pretreatment planning. Thus, selective internal radiation therapy demands an expert multidisciplinary team approach in order to provide comprehensive care for patients. This review provides recommendations to multidisciplinary teams on the optimal medical processes in order to ensure the safe delivery of selective internal radiation therapy. Based on the best available published evidence and expert opinion, we recommend the most appropriate strategies for the prevention, early diagnosis, and management of potential radiation injury to the liver and to other organs. (Hepatology 2017;66:969-982).

A comparison of survival in patients with hepatocellular carcinoma and portal vein invasion treated by radioembolization or sorafenib.

BACKGROUND & AIMS: Sorafenib (SOR) is the standard of care for patients with hepatocellular carcinoma (HCC) and portal vein invasion (PVI), based on the results of phase 3 trials. However, radioembolization (RE) using yttrium-90 microspheres has been shown to achieve higher response rates and better survival in large cohorts and phase 2 trials. This study aimed to compare survival of HCC patients with PVI treated by RE or SOR. METHODS: Survival among patients with HCC and PVI treated with RE or SOR in four Spanish hospitals between 2005 and 2013 was analysed retrospectively. Kaplan-Meier survival curves were plotted and baseline variables tested for prognostic value using the log-rank test. A multivariate prognostic model including variables identified in the univariate analysis and adjusted by a propensity score based on factors that may determine the probability of exposure to RE was generated using Cox regression analyses. RESULTS: After a median follow-up of 6 months, 60 deaths had occurred: 38 and 22 in SOR and RE groups respectively. Median survival was 6.7 months (95%CI 5.2-8.1 months) for the entire cohort, and 8.8 months (95%CI 1.8-15.8) in the RE group and 5.4 months (95%CI 2.7-8.1) in the SOR group (P = 0.047). The difference in survival was still statistically significant when 13 patients in the RE group who started SOR after a median time of 8 months were censored from the analysis. CONCLUSIONS: In a cohort of patients with HCC and PVI treatment with RE was associated with a more prolonged survival compared with SOR.

Safety and toxicity of radioembolization plus Sorafenib in advanced hepatocellular carcinoma: analysis of the European multicentre trial SORAMIC.

BACKGROUND & AIMS: The benefits of combined systemic and liver-directed treatments in inoperable intermediate- or advanced-stage hepatocellular carcinoma (HCC) have yet to be defined. This article presents the planned safety analyses for the first 40 patients randomized to radioembolization with yttrium-90 ((90) Y) resin microspheres followed by sorafenib (n = 20) or sorafenib only (n = 20) in the SORAMIC study. METHODS: Patients identified for palliative treatment who were poor candidates for transarterial (chemo)embolization (including those failing TACE) with preserved liver function (Child-Pugh ≤B7) and ECOG performance status <2 were screened. Radioembolization was administered using a sequential lobar approach. On day 3 after the last radioembolization procedure, sorafenib 200 mg twice daily was initiated escalating to 400 mg twice daily 1 week later; a matching sorafenib dose schedule was initiated in the control arm. RESULTS: Patients were followed up for a median of 8.3 months. Median total implanted activity of (90) Y was 1.87 (range: 0.54-2.35) GBq. Patients received a similar intensity and duration of sorafenib in the combination-treatment arm (median daily dose 614 mg over 8.5 months) and control arm (557 mg over 9.6 months). The incidence of total (196 vs. 222) and grade ≥3 (43 vs. 47) adverse events was similar in combination-treatment arm and control arm respectively (P > 0.05). No significant differences in the number of total or grade 3/4 toxicities were recorded for: total bilirubin, albumin, liver enzymes, ascites, Child-Pugh, fatigue, hand-foot skin reaction, blood pressure or diarrhoea. CONCLUSIONS: Radioembolization followed by sorafenib appears to be as well tolerated as sorafenib alone.

Pilot randomized trial of selective internal radiation therapy vs. chemoembolization in unresectable hepatocellular carcinoma.

BACKGROUND & AIMS: To compare selective internal radiation therapy (SIRT) with transarterial chemoembolization (TACE), the standard-of-care for intermediate-stage unresectable, hepatocellular carcinoma (HCC), as first-line treatment. METHODS: SIRTACE was an open-label multicenter randomized-controlled pilot study, which prospectively compared primarily safety and health-related quality of life (HRQoL) changes following TACE and SIRT. Patients with unresectable HCC, Child-Pugh ≤B7, ECOG performance status ≤2 and ≤5 liver lesions (≤20 cm total maximum diameter) without extrahepatic spread were randomized to receive either TACE (at 6-weekly intervals until tumour enhancement was not observed on MRI or disease progression) or single-session SIRT (yttrium-90 resin microspheres). RESULTS: Twenty-eight patients with BCLC stage A (32.1%), B (46.4%) or C (21.4%) received either a mean of 3.4 (median 2) TACE interventions (N = 15) or single SIRT (N = 13). Both treatments were well tolerated. Despite SIRT patients having significantly worse physical functioning at baseline, at week-12, neither treatment had a significantly different impact on HRQoL as measured by Functional Assessment of Cancer Therapy-Hepatobiliary total or its subscales. Both TACE and SIRT were effective for the local control of liver tumours. Best overall response-rate (RECIST 1.0) of target lesions were 13.3% and 30.8%, disease control rates were 73.3% and 76.9% for TACE and SIRT, respectively. Two patients in each group were down-staged for liver transplantation (N = 3) or radiofrequency ablation (N = 1). CONCLUSIONS: Single-session SIRT appeared to be as safe and had a similar impact on HRQoL as multiple sessions of TACE, suggesting that SIRT might be an alternative option for patients eligible for TACE.

Heterogeneity of patients with intermediate (BCLC B) Hepatocellular Carcinoma: proposal for a subclassification to facilitate treatment decisions.

The intermediate stage of hepatocellular carcinoma (HCC) comprises a highly heterogeneous patient population and therefore poses unique challenges for therapeutic management, different from the early and advanced stages. Patients classified as having intermediate HCC by the Barcelona Clinic Liver Cancer (BCLC) staging system present with varying tumor burden and liver function. Transarterial chemoembolization (TACE) is currently recommended as the standard of care in this setting, but there is considerable variation in the clinical benefit patients derive from this treatment.In April 2012, a panel of experts convened to discuss unresolved issues surrounding the application of current guidelines when managing patients with intermediate HCC. The meeting explored the applicability of a subclassification system for intermediate HCC patients to tailor therapeutic interventions based on the evidence available to date and expert opinion. The present report summarizes the proposal of the expert panel: four substages of intermediate HCC patients, B1 to B4.

Efficacy and safety of sorafenib in combination with mammalian target of rapamycin inhibitors for recurrent hepatocellular carcinoma after liver transplantation.

There is currently no consensus on the most suitable treatment for the recurrence of hepatocellular carcinoma (HCC) after liver transplantation. This open, multicenter, retrospective, uncontrolled cohort study was designed to evaluate the safety and preliminary efficacy of the combined use of a mammalian target of rapamycin (mTOR) inhibitor and sorafenib in this setting. In 31 patients who suffered from HCC recurrence after liver transplantation, the immunosuppressive therapy was changed to mTOR inhibitors, and systemic treatment with sorafenib was initiated. This combination was maintained until symptomatic tumor progression, death, hepatic decompensation, or unacceptable toxicity occurred. Primary treatment efficacy was determined by overall survival and progression-free survival, and secondary efficacy was determined by the overall response rate. Toxicity parameters associated with the use of sorafenib and mTOR inhibitors were also analyzed. The overall response rate according to the Response Evaluation Criteria in Solid Tumors was 3.8% (1/26), and there was sustained stabilization of the disease in 13 additional cases (50.0%). The median overall survival was 19.3 months [95% confidence interval (CI) = 13.4-25.1 months], and the median time to progression was 6.77 months (95% CI = 2.3-11.1 months). Only 2 grade 3/4 cases of hyperglycemia and 1 case of grade 3/4 mucositis were reported, and they were possibly related to mTOR inhibitors. The most common severe adverse event probably related to sorafenib was diarrhea (12.9%). In conclusion, the coadministration of sorafenib and an mTOR inhibitor could be effective despite notable toxicity in patients with post-liver transplant HCC recurrence not suitable for radical therapy. The toxicity and efficacy need to be further evaluated in randomized controlled studies for this combination to be considered a valid option.

Consensus on the current use of sorafenib for the treatment of hepatocellular carcinoma.

An expert panel was convened to reach a consensus on the current use of sorafenib in the treatment of hepatocellular carcinoma (HCC). A multinational, multidisciplinary group of experts objectively reviewed clinical data of sorafenib and considered clinical experience to develop statements summarizing our consensus on the current use of sorafenib. Sorafenib is the standard of care for Child-Pugh (CP) A patients with advanced HCC (i.e. not amenable to surgery or locoregional treatment). There is currently insufficient evidence to support the routine clinical use of sorafenib in CP B patients, but sorafenib can be offered as an option for those with compensated liver cirrhosis. Patients with stable performance status who have progressive disease during sorafenib treatment can be maintained on sorafenib, although there are no clear data supporting the continuation of sorafenib in these patients. The effectiveness of the adjuvant use of sorafenib in preventing recurrence after resection or local ablation, or in combination with transarterial chemoembolization, are being evaluated in clinical studies. In conclusion, sorafenib has extended treatment options for patients with HCC, and is now established as the standard of care for CP A patients with HCC not amenable to surgery or locoregional treatment. Based on its multikinase-inhibitor activity and proven efficacy in prolonging survival in HCC, broader use - including a subgroup of patients with CP B (clinically compensated cirrhosis) and earlier disease stages - might be expected dependent on the results of ongoing studies of safety and clinically relevant benefit in these patients.

Gene therapy of cancer based on interleukin 12.

Tumor formation and growth depends mainly on the inability of the organism to elicit a potent immune response, and on the formation of new blood vessels that enable tumor nutrition. Interleukin-12 (IL-12) therapy can target both processes. And IL-12-based gene therapy may restrict IL-12 production to the relevant site in order to obtain enhanced antitumor activity and reduced toxicity. In the clinical setting, IL-12 gene transfer can be used either to improve the pharmacokinetic/pharmacodynamic profile of the cytokine, to transduce dendritic cells or to enhance the efficiency of antitumor vaccination. It can also synergize with other procedures involving the simultaneous transfer of other transgenes or non-gene based strategies. The strong anti-tumoral power shown in many different animal models has not been found in early clinical trials in which cancer patients were treated by peritumoral injections of autologous fibroblasts producing IL-12, intratumoral injections of an adenoviral vector encoding human IL-12 genes, or intratumoral injection of autologous dendritic cells transduced ex vivo with this same adenoviral vector. However, these trials have set the proof-of-concept that local production of IL-12 inside a tumor can stimulate tumor infiltration by effector immune cells and that in some cases it is followed by tumor regression. From the many questions that arise after these disappointing results the most relevant concerns the duration and intensity of transgene expression and the capability to monitor this topics in vivo. New vectors that might achieve regulated, long-term production of this cytokine might have better results and merit clinical testing.