Vaccinia-based oncolytic immunotherapy Pexastimogene Devacirepvec in patients with advanced hepatocellular carcinoma after sorafenib failure: a randomized multicenter Phase IIb trial (TRAVERSE).

Pexastimogene devacirepvec (Pexa-Vec) is a vaccinia virus-based oncolytic immunotherapy designed to preferentially replicate in and destroy tumor cells while stimulating anti-tumor immunity by expressing GM-CSF. An earlier randomized Phase IIa trial in predominantly sorafenib-naïve hepatocellular carcinoma (HCC) demonstrated an overall survival (OS) benefit. This randomized, open-label Phase IIb trial investigated whether Pexa-Vec plus Best Supportive Care (BSC) improved OS over BSC alone in HCC patients who failed sorafenib therapy (TRAVERSE). 129 patients were randomly assigned 2:1 to Pexa-Vec plus BSC vs. BSC alone. Pexa-Vec was given as a single intravenous (IV) infusion followed by up to 5 IT injections. The primary endpoint was OS. Secondary endpoints included overall response rate (RR), time to progression (TTP) and safety. A high drop-out rate in the control arm (63%) confounded assessment of response-based endpoints. Median OS (ITT) for Pexa-Vec plus BSC vs. BSC alone was 4.2 and 4.4 months, respectively (HR, 1.19, 95% CI: 0.78-1.80; p = .428). There was no difference between the two treatment arms in RR or TTP. Pexa-Vec was generally well-tolerated. The most frequent Grade 3 included pyrexia (8%) and hypotension (8%). Induction of immune responses to vaccinia antigens and HCC associated antigens were observed. Despite a tolerable safety profile and induction of T cell responses, Pexa-Vec did not improve OS as second-line therapy after sorafenib failure. The true potential of oncolytic viruses may lie in the treatment of patients with earlier disease stages which should be addressed in future studies. ClinicalTrials.gov: NCT01387555.

Efficacy and safety of combination therapy with everolimus and sorafenib for recurrence of hepatocellular carcinoma after liver transplantation.

BACKGROUND: Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) is still associated with a dismal outcome. Combination therapy with everolimus (EVL) and vascular endothelial growth factor inhibitor sorafenib (SORA) is based on the role of both b-Raf and mammalian target of rapamycin/protein kinase B pathways in the pathogenesis of HCC and is being investigated in clinical practice. METHODS: This was a single-center retrospective analysis on LT recipients with unresectable HCC recurrence and undergoing combination therapy with EVL and SORA. Patients were included if they were switched to EVL+SORA at any time after surgery. Primary endpoint was overall survival (OS) after both LT and recurrence, and response to treatment based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST) in the intention-to-treat (ITT) population. Secondary analysis was safety of combination therapy with EVL and SORA in the population of patients who received ≥1 dose of the study drug. RESULTS: Seven patients (100% male; median age 53 years [interquartile range (IQR) 9 years]) were considered for analysis. HCC recurrence was diagnosed at a median (IQR) interval since LT of 9 (126) months, and patients were administered EVL+SORA at a median interval since LT of 11 (126) months. Baseline immunosuppression was with tacrolimus (TAC) in 2 patients (28.6%), cyclosporine (CsA) in 2 (28.6%), and EVL monotherapy in 3 (42.8%). At a median (IQR) follow-up of 6.5 (14) months, 5 patients (71.4%) were alive, 4 of them (57.1%) with tumor progression according to the mRECIST criteria. Median (IQR) time to progression was 3.5 (12) months. Two patients died at a median (IQR) follow-up of 5 (1) months owing to tumor progression in 1 patient (14.3%) and sepsis in the other (14.3%). EVL monotherapy was achieved in 6 patients (85.7%), whereas 1patient (14.3%) could not withdraw from calcineurin inhibitor owing to acute rejection. Treatment complications were: hand-foot syndrome in 5 patients (71.4%), hypertension in 1 (14.3%), alopecia in 1 (14.3%), hypothyroidism in 1 (14.3%), diarrhea in 2 (28.6%), pruritus in 1 (14.3%), abdominal pain in 1 (14.3%), rash in 1 (14.3%), asthenia in 3 (42.8%), anorexia in 3 (42.8%), and hoarseness in 2 (28.6%). Adverse events led to temporary SORA discontinuation in 2 patients (28.6%) and to SORA dose reduction in 3 (42.8%). CONCLUSIONS: Treatment of HCC recurrence after LT with a combination regimen of EVL+ SORA is challenging because of SORA-related complications. Longer follow-up periods and larger series are needed to better capture the impact of such combination treatment on tumor progression and patient survival.

GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib): second interim analysis.

BACKGROUND: GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma [HCC] and Of its treatment with sorafeNib) is a global, prospective, non-interventional study undertaken to evaluate the safety of sorafenib in patients with unresectable HCC in real-life practice, including Child-Pugh B patients who were excluded from clinical trials. METHODS: Patients with unresectable HCC, for whom the decision to treat with sorafenib, based on the approved label and prescribing guidelines, had been taken by their physician, were eligible for inclusion. Demographic data and disease/medical history were recorded at entry. Sorafenib dosing and adverse events (AEs) were collected at follow-up visits. The second interim analysis was undertaken when ~1500 treated patients were followed up for ≥ 4 months. RESULTS: Of the 1571 patients evaluable for safety, 61% had Child-Pugh A status and 23% Child-Pugh B. The majority of patients (74%) received the approved 800 mg initial sorafenib dose, regardless of Child-Pugh status; however, median duration of therapy was shorter in Child-Pugh B patients. The majority of drug-related AEs were grade 1 or 2, and the most commonly reported were consistent with previous reports. The incidence and nature of drug-related AEs were broadly similar across Child-Pugh, Barcelona Clinic Liver Cancer (BCLC) and initial dosing subgroups, and consistent with the overall population. CONCLUSIONS: Consistent with the first interim analysis, overall safety profile and dosing strategy are similar across Child-Pugh subgroups. Safety findings also appear comparable irrespective of initial sorafenib dose or BCLC stage. Final analyses in > 3000 patients are ongoing.

First interim analysis of the GIDEON (Global Investigation of therapeutic decisions in hepatocellular carcinoma and of its treatment with sorafeNib) non-interventional study.

AIMS: Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib (GIDEON), a global, non-interventional, surveillance study, aims to evaluate the safety of sorafenib in all patients with unresectable hepatocellular carcinoma (uHCC) under real-life practice conditions, particularly Child-Pugh B patients, who were not well represented in clinical trials. METHODS: Treatment decisions are determined by each physician according to local prescribing guidelines and clinical practice. Patients with uHCC who are candidates for systemic therapy, and for whom a decision has been made to treat with sorafenib, are eligible for inclusion. Demographic data and medical and disease history are recorded at entry. Sorafenib dosing and adverse events (AEs) are collected throughout the study. RESULTS: From January 2009 to April 2011, >3000 patients from 39 countries were enrolled. The prespecified first interim analysis was conducted when the initial approximately 500 treated patients had been followed up for ≥4 months; 479 were valid for safety evaluation. Preplanned subgroup analyses indicate differences in patient characteristics, disease aetiology and previous treatments by region. Variation in sorafenib dosing by specialty are also observed; Child-Pugh status did not appear to influence the starting dose of sorafenib. The type and incidence of AEs was consistent with findings from previous clinical studies. AE profiles were comparable between Child-Pugh subgroups. DISCUSSION: The GIDEON study is generating a large, robust database from a broad population of patients with uHCC. First interim analyses have shown global and regional differences in patient characteristics, disease aetiology and practice patterns. Subsequent planned analyses will allow further evaluation of early trends.

Evolving strategies for the management of intermediate-stage hepatocellular carcinoma: available evidence and expert opinion on the use of transarterial chemoembolization.

Transarterial chemoembolization (TACE) is considered the gold standard for treating intermediate-stage hepatocellular carcinoma (HCC). However, intermediate-stage HCC includes a heterogeneous population of patients with varying tumour burdens, liver function (Child-Pugh A or B) and disease aetiology. This suggests that not all patients with intermediate-stage HCC will derive similar benefit from TACE, and that some patients may benefit from other treatment options. Results of an extensive literature review into the treatment of unresectable HCC with TACE were combined with our own clinical experience to identify factors that may predict survival after TACE. We also report contraindications to TACE and propose a treatment algorithm for the repetition of TACE. In addition, we have constructed a number of expert opinions that may be used as a guide to help physicians make treatment decisions for their patients with intermediate-stage HCC. The data included in the literature review related almost exclusively to conventional TACE, rather than to TACE with drug-eluting beads. Therefore, the findings and conclusions of the literature review are only applicable to the treatment of HCC with conventional TACE. Treating physicians may want to consider other treatment options for patients with intermediate-stage HCC who are not suitable for or do not respond to TACE. By distinguishing those patients who represent good candidates for TACE from those where little or no benefit might be expected, it may be possible to make better use of current treatment options and improve outcomes for patients.

Design and rationale for the non-interventional Global Investigation of Therapeutic DEcisions in Hepatocellular Carcinoma and Of its Treatment with Sorafenib (GIDEON) study.

BACKGROUND: Hepatocellular carcinoma (HCC) is a complicated condition influenced by multiple confounding factors, making optimum patient management extremely challenging. Ethnicity, stage at diagnosis, comorbidities and tumour morphology affect outcomes and vary from region to region, and there is no common language to assess patient prognosis and make treatment recommendations. Despite recent efforts to reduce the incidence of HCC, most patients present with unresectable disease. Non-surgical treatments include ablation, transarterial chemoembolisation and the multikinase inhibitor, sorafenib, but their effects in all patient subgroups are not known and further information is needed to optimise the use of these treatments. AIMS: The Global Investigation of Therapeutic DEcisions in Hepatocellular Carcinoma and Of its Treatment with SorafeNib (GIDEON) study (ClinicalTrials.gov identifier NCT00812175; http://clinicaltrials.gov/) is an ongoing global, prospective, non-interventional study of patients with unresectable HCC who are eligible for systemic therapy and for whom the decision has been taken to treat with sorafenib under real-life practice conditions. The aim of this study is to evaluate the safety and efficacy of sorafenib in different subgroups, especially Child-Pugh B where data are limited. DISCUSSION: This study will recruit 3000 patients from > 40 countries and follow them for approximately 5 years to compile a large and robust database of information that will be used to analyse local, regional and global differences in baseline characteristics, disease aetiology, treatment practice patterns and treatment outcomes, with a view to improve the knowledge base used to guide physician treatment decisions and to improve patient outcomes.

Treatment before liver transplantation for HCC.

Liver transplantation (LT) which is currently an established therapy for sma1l, early stage hepatocellular carcinoma (HCC) in patients with cirrhosis requires in most cases long waiting period. Tumor development during the waiting period may be associated with vascular invasion which is a strong factor of postoperative recurrence. Therefore, local treatment of the tumor including trans-arterial chemoembolization (TACE), percutaneous radiofrequency (RF) or partial liver resection can be used before transplantation. In the present paper we reviewed the efficacy of these treatments prior to LT. Although, TACE induced complete tumor necrosis in some patients there is no convincing arguments showing that this treatment reduces the rate of drop out before LT, nor improves the survival after LT. Although, RF can induce complete necrosis in the majority of small tumors (<2.5 cm), there is no data demonstrating that this treatment reduce the rate of drop out before LT, nor improves the survival after LT. It has been showed that both short and long term survival after LT was not compromised by previous partial liver resection of HCC. However, there is no data demonstrating that liver resection before LT, which can be used either as a bridge treatment or as a primary treatment, improves the survival after LT. The current data suggest that there is no role for pre-transplant therapy for HCC within Milano criteria transplanted within six months. On the opposite, if the waiting time is predicted to be prolonged, the risk of tumor progression and either drop-off from the list or interval dissemination with post-transplant tumor recurrence is recognized. In this setting, bridge therapy can reduce that risk but its efficacy has to be determined.

New perspectives for the use of contrast-enhanced liver ultrasound in clinical practice.

The introduction of second-generation microbubble ultrasound contrast agents and the development of contrast specific ultrasound techniques have improved the ability of contrast enhanced ultrasound in detecting and characterising liver lesions, offering new perspectives for its exploitation in clinical hepatology. Indeed, several studies have demonstrated a high diagnostic accuracy in focal lesion characterisation (85-96%) in patients either with or without underlying chronic liver disease. This review article describes the basic principles of contrast enhanced ultrasound, defines the different vascular features of benign and malignant liver lesions, and assesses its clinical impact in different clinical scenarios, according to the guidelines of the European Federation of Societies for Ultrasound in Medicine and Biology, contrast enhanced ultrasound enables the characterisation of focal liver lesions, regardless of the presence or absence of underlying chronic liver disease. Contrast enhanced ultrasound is also useful in staging and follow-up of cancer patients and in monitoring local ablative treatment. Contrast enhanced ultrasound is expected to be considerably increased and replace many computed tomography and magnetic resonance imaging examinations in near future, according to the European Federation of Societies for Ultrasound in Medicine and Biology guidelines. Therefore, it is necessary to take measures in order to meet the demand for an increasing number of these procedures.

Pulmonary radiofrequency ablation in a single lung patient.

Recurrence in the contralateral lung of patients who have undergone pneumonectomy for lung cancer is often not surgically treatable. Percutaneous radiofrequency ablation (RFA) of tumours is an emerging minimally invasive technique which has recently been used in the treatment of lung cancer. The case history is presented of a patient who had previously undergone pneumonectomy in whom recurrence of lung cancer was treated by RFA. The procedure was performed under CT guidance and was uneventful. At follow up 9 months later the tumour appeared to have ablated. To our knowledge, no similar case has previously been reported in the literature.

Percutaneous image-guided radiofrequency ablation in the therapeutic management of hepatocellular carcinoma.

Owing to surveillance programs for detection of hepatocellular carcinoma (HCC) in patients with cirrhosis, more tumors are being detected at an early, asymptomatic stage. Percutaneous ablation is considered the best treatment option for patients with Child-Pugh class A or B cirrhosis and a single, nodular-type HCC smaller than 5 cm or as many as three HCC lesions, each smaller than 3 cm, when surgical resection or liver transplantation is not suitable. Radiofrequency ablation (RFA) has emerged as the most powerful method for percutaneous treatment of early-stage HCC. Recent studies have shown that RFA can achieve more effective local tumor control than ethanol injection and with fewer treatment sessions. In a randomized trial, local recurrence-free survival rates were significantly higher in patients who received RFA than in those treated by ethanol injection, and treatment allocation was confirmed as an independent prognostic factor by multivariate analysis. Due to advances in radiofrequency technology, RFA also has been used to treat patients with more advanced tumors. Preliminary reports have shown that RFA performed after balloon catheter occlusion of the hepatic artery, transarterial embolization, or chemoembolization results in increased volumes of coagulation necrosis, thus enabling successful destruction of large HCC lesions. This report reviews the current status of percutaneous, image-guided RFA in the therapeutic management of HCC.

Radiofrequency thermal ablation of hepatocellular carcinoma: using contrast-enhanced harmonic power doppler sonography to assess treatment outcome.

OBJECTIVE: We evaluated the accuracy of contrast-enhanced harmonic power Doppler sonography in assessing the outcome of radiofrequency thermal ablation of hepatocellular carcinoma. SUBJECTS AND METHODS: Fifty patients with 65 hepatocellular carcinoma nodules (1-5 cm in diameter; mean diameter, 2.5 cm) were studied using unenhanced and contrast-enhanced harmonic power Doppler sonography before and after IV administration of a microbubble contrast agent. The examinations were repeated after treatment of the tumors with radiofrequency ablation. Findings of the Doppler studies were compared with those of dual-phase helical CT, which were used as points of reference for assessing treatment outcome. RESULTS: Before radiofrequency treatment, intratumoral blood flow was revealed by unenhanced power Doppler sonography in 48 (74%) of 65 hepatocellular carcinoma nodules. After injection of the contrast agent, intratumoral enhancement was observed in 61 (94%) of 65 hepatocellular carcinomas (p < 0.01). After radiofrequency treatment, all 51 (84%) of the 61 hepatocellular carcinomas found to be necrotic on helical CT scans failed to show enhancement on power Doppler sonograms. In nine of the 10 lesions that showed a residual viable tumor on helical CT scans, persistent intratumoral enhancement-matching the enhancing areas on helical CT images-was revealed by power Doppler sonography. These nine hepatocellular carcinomas were subjected to repeated radiofrequency thermal ablation with the guidance of contrast-enhanced power Doppler sonography. Complete necrosis was seen after the second treatment session in six of the nine lesions. CONCLUSION: Contrast-enhanced harmonic power Doppler sonography is an accurate technique for assessing the outcome of radiofrequency thermal ablation of hepatocellular carcinoma and may be useful in guiding additional treatment in patients with incomplete response to initial efforts.

Focal liver lesions: MR imaging-pathologic correlation.

Magnetic resonance signal intensity of focal liver lesions is affected by numerous pathologic factors. Lesion histologic features, such as cellularity, vascularity, stromal component, and intratumoral necrosis or hemorrhage, strongly affect T1 and T2 relaxation times. Additionally, intracellular content of certain substances, such as glycogen, fat, melanin, iron, and copper, may also have a substantial role in determining MR signal behavior. In this review we discuss the correlations between MR imaging features and pathologic findings in benign and malignant focal liver lesions. Knowledge of imaging-pathology correlations greatly assist in charac terizing focal lesions. Moreover, in certain tumor histotypes, such as hepatocellular carcinoma, careful analysis of lesion signal intensity may help predict the degree of tumor differentiation.

Assessment of therapeutic effect of liver tumor ablation procedures.

Interventional procedures for percutaneous tumor ablation have gained an increasingly important role in the treatment of liver malignancies. After interventional therapies, diagnostic imaging has the key role in determining if the treated lesion is completely ablated or contains areas of residual viable neoplastic tissue. This is particularly important since in case of incomplete necrosis of the lesion, treatment can be repeated, and tumor ablation can be further pursued. The evaluation of the therapeutic effect of the procedure leads to different problems according to the histotype of the malignancy. In the case of hepatocellular carcinoma, detection of residual viable tumor is facilitated by the typical hypervascular pattern of this neoplasm. Contrast-enhanced color Doppler ultrasonography can be used to monitor tumor response, and, in case of partial necrosis, to target the areas of residual viable tumor. With spiral computed tomography or dynamic magnetic resonance imaging, residual viable hepatocellular carcinoma tissue is reliably depicted as it stands out in the arterial phase images against the unenhanced areas of coagulation necrosis. In the case of hypovascular metastases, a confident diagnosis of successful ablation can be made when an area of thermal necrosis exceeding that of the original lesion is depicted. Peripheral inflammatory reaction following ablation procedures should not be misinterpreted as tumor progression.

Percutaneous ablation of liver malignancies: imaging evaluation of treatment response.

Interventional procedures for percutaneous tumor ablation have gained an increasingly important role in the treatment of liver malignancies. After interventional therapies, diagnostic imaging has the key role to determine if the treated lesion is completely ablated or contains areas of residual viable neoplastic tissue. This is particularly important since in cases of incomplete necrosis of the lesions, treatment can be repeated, and tumor ablation can be further pursued. The evaluation of the therapeutic effect of the procedure arises different problems according to the histotype of the malignancy. In the case of hepatocellular carcinoma (HCC), detection of residual viable tumor is facilitated by the typical hypervascular pattern of this neoplasm. Contrast-enhanced US can be used to monitor tumor response, and, in cases of partial necrosis, to target the areas of residual viable tumor. With spiral CT or dynamic MR imaging, residual viable HCC is reliably depicted as it stands out in the arterial phase images against the unenhanced areas of coagulation necrosis. In the case of hypovascular metastases, a confident diagnosis of successfull ablation can be made when an area of thermal necrosis exceeding that of the original lesion is depicted. Peripheral inflammatory reaction following ablation procedures, that shows itself as an enhancing halo along the necrotic area boundary on spiral CT or dynamic MR images, should not be misinterpreted as tumor progression.

Combination of interventional therapies in hepatocellular carcinoma.

Many interventional techniques aimed at achieving nonsurgical ablation of hepatocellular carcinoma have been developed and clinically tested over the last decade. Percutaneous image-guided therapies such as ethanol injection and radiofrequency thermal ablation provide an effective means for treating hepatocellular carcinoma lesions smaller than 3 cm, but do not ensure successful ablation of larger tumors. In view of the limitations of available interventional therapies, there is currently a focus on a multimodality strategy for the treatment of large hepatocellular carcinomas. Combination of transcatheter arterial chemoembolization and ethanol injection overcomes the weakness of each of the two procedures, enhancing local therapeutic effect and long-term survival. More recently, a new technique for single-session ablation of large hepatocellular carcinoma lesions has been devised by combining transcatheter hepatic arterial balloon occlusion/embolization and radiofrequency treatment. This combined approach substantially increases the thermal necrosis volume that can be created with respect to the conventional radiofrequency technique, as a result of the reduction of heat loss caused by convection. In a pilot multicentric clinical trial performed in 62 patients, successful ablation of hepatocellular carcinoma lesions ranging 3.5-8.5 cm in diameter was achieved in 82% of cases in the absence of major complications. This new technique seems to have the potential to replace other interventional methods for the treatment of large hepatocellular carcinoma.