Riccardo Lencioni

Clinical Management of Hepatocellular Carcinoma. Conclusions of the Barcelona-2000 EASL Conference

Hepatocellular carcinoma (HCC) is a neoplasm the incidence of which is increasing worldwide, but striking geographical differences are observed for both risk factors and occurrence [1]. HCC represents more than 5% of all cancers and the estimated annual number of cases exceeds 500 000. It mostly affects patients with liver cirrhosis and currently represents their most common cause of death. Its clinical relevance and the existence of several diagnostic and therapeutic controversies explain the huge interest raised by this neoplasm. This prompted the European Association for the Study of the Liver (EASL) to organize a Monothematic Conference on Clinical Management of Hepatocellular Carcinoma, which was held in Barcelona in September 2000. During the meeting, a panel of international experts (Appendix A) met to prepare the present document that gives up-dated guidelines for the current clinical practice, and an overview of those aspects that should be the target of future clinical research.

EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma

EASL–EORTC Clinical Practice Guidelines (CPG) on the management of hepatocellular carcinoma (HCC) define the use of surveillance, diagnosis, and therapeutic strategies recommended for patients with this type of cancer. This is the first European joint effort by the European Association for the Study of the Liver (EASL) and the European Organization for Research and Treatment of Cancer (EORTC) to provide common guidelines for the management of hepatocellular carcinoma. These guidelines update the recommendations reported by the EASL panel of experts in HCC published in 2001 [1]. Several clinical and scientific advances have occurred during the past decade and, thus, a modern version of the document is urgently needed. The purpose of this document is to assist physicians, patients, health-care providers, and health-policy makers from Europe and worldwide in the decision-making process according to evidencebased data. Users of these guidelines should be aware that the recommendations are intended to guide clinical practice in circumstances where all possible resources and therapies are available. Thus, they should adapt the recommendations to their local regulations and/or team capacities, infrastructure, and cost– benefit strategies. Finally, this document sets out some recommendations that should be instrumental in advancing the research and knowledge of this disease and ultimately contribute to improve patient care. The EASL–EORTC CPG on the management of hepatocellular carcinoma provide recommendations based on the level of evidence and the strength of the data (the classification of evidence is adapted from National Cancer Institute [2]) (Table 1A) and the strength of recommendations following previously reported systems (GRADE systems) (Table 1B).

Modified RECIST (mRECIST) assessment for hepatocellular carcinoma.

The endpoint in cancer research is overall survival. Nonetheless, other potential surrogate endpoints, such as response rate and time to progression, are currently used. Measurement of response rate in hepatocellular carcinoma (HCC) has become a controversial issue. The World Health Organization (WHO) criteria underestimate the actual response rate; thus, they were amended in 2000 by a panel of experts convened by the European Association for the Study of the Liver (EASL) to take into account treatment-induced tumor necrosis. Applying these guidelines, there was an association between response rate and outcome prediction. More recently, the Response Evaluation Criteria in Solid Tumors (RECIST) guideline was proposed as a method for measuring treatment response based on tumor shrinkage, which is a valuable measure of antitumor activity of cytotoxic drugs. This method was initially adopted by regulatory agencies, such as the U.S. Food and Drug Administration (FDA), for drug approval. However, anatomic tumor response metrics can be misleading when applied to molecular-targeted therapies or locoregional therapies in HCC. In 2008, a group of experts convened by the American Association for the Study of Liver Diseases (AASLD) developed a set of guidelines aimed at providing a common framework for the design of clinical trials in HCC and adapted the concept of viable tumor-tumoral tissue showing uptake in arterial phase of contrast-enhanced radiologic imaging techniques-to formally amend RECIST. These amendments conformed the AASLD-JNCI (Journal of the National Cancer Institute) guidelines and are summarized and clarified in the current article. They are referred to herein as the modified RECIST assessment (mRECIST). Further studies are needed to confirm the accuracy of this measurement compared with conventional gold standards such as pathologic studies of explanted livers.

Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer

Oncolytic viruses and active immunotherapeutics have complementary mechanisms of action (MOA) that are both self amplifying in tumors, yet the impact of dose on subject outcome is unclear. JX-594 (Pexa-Vec) is an oncolytic and immunotherapeutic vaccinia virus. To determine the optimal JX-594 dose in subjects with advanced hepatocellular carcinoma (HCC), we conducted a randomized phase 2 dose-finding trial (n = 30). Radiologists infused low- or high-dose JX-594 into liver tumors (days 1, 15 and 29); infusions resulted in acute detectable intravascular JX-594 genomes. Objective intrahepatic Modified Response Evaluation Criteria in Solid Tumors (mRECIST) (15%) and Choi (62%) response rates and intrahepatic disease control (50%) were equivalent in injected and distant noninjected tumors at both doses. JX-594 replication and granulocyte-macrophage colony-stimulating factor (GM-CSF) expression preceded the induction of anticancer immunity. In contrast to tumor response rate and immune endpoints, subject survival duration was significantly related to dose (median survival of 14.1 months compared to 6.7 months on the high and low dose, respectively; hazard ratio 0.39; P = 0.020). JX-594 demonstrated oncolytic and immunotherapy MOA, tumor responses and dose-related survival in individuals with HCC.

Loco‐regional treatment of hepatocellular carcinoma

Loco‐regional treatments play a key role in the management of hepatocellular carcinoma (HCC). Image‐guided tumor ablation is recommended in patients with early‐stage HCC when surgical options are precluded. Radiofrequency ablation has shown superior anticancer effects and greater survival benefit with respect to the seminal percutaneous technique, ethanol injection, in meta‐analyses of randomized controlled trials, and is currently established as the standard method for local tumor treatment. Novel thermal and nonthermal techniques for tumor ablation—including microwave ablation, irreversible electroporation, and light‐activated drug therapy—seem to have potential to overcome the limitations of radiofrequency ablation and warrant further clinical investigation. Transcatheter arterial chemoembolization (TACE) is the standard of care for patients with asymptomatic, noninvasive multinodular tumors at the intermediate stage. The recent introduction of embolic microspheres that have the ability to release the drug in a controlled and sustained fashion has been shown to significantly increase safety and efficacy of TACE with respect to conventional, lipiodol‐based regimens. The available data for radioembolization with yttrium‐90 suggests that this is a potential new option for patients with HCC, which should be investigated in the setting of randomized controlled trials. Despite the advances and refinements in loco‐regional approaches, the long‐term survival outcomes of patients managed with interventional techniques are not fully satisfactory, mainly because of the high rates of tumor recurrence. The recent addition of molecular targeted drugs with antiangiogenic and antiproliferative properties to the therapeutic armamentarium for HCC has prompted the design of clinical trials aimed at investigating the synergies between loco‐regional and systemic treatments. The outcomes of these trials are eagerly awaited, because they have the potential to revolutionize the treatment of HCC. (HEPATOLOGY 2010;)

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.

Image-guided Tumor Ablation: Standardization of Terminology and Reporting Criteria—A 10-Year Update

Image-guided tumor ablation has become a well-established hallmark of local cancer therapy. The breadth of options available in this growing field increases the need for standardization of terminology and reporting criteria to facilitate effective communication of ideas and appropriate comparison among treatments that use different technologies, such as chemical (eg, ethanol or acetic acid) ablation, thermal therapies (eg, radiofrequency, laser, microwave, focused ultrasound, and cryoablation) and newer ablative modalities such as irreversible electroporation. This updated consensus document provides a framework that will facilitate the clearest communication among investigators regarding ablative technologies. An appropriate vehicle is proposed for reporting the various aspects of image-guided ablation therapy including classification of therapies, procedure terms, descriptors of imaging guidance, and terminology for imaging and pathologic findings. Methods are addressed for standardizing reporting of technique, follow-up, complications, and clinical results. As noted in the original document from 2003, adherence to the recommendations will improve the precision of communications in this field, leading to more accurate comparison of technologies and results, and ultimately to improved patient outcomes. Online supplemental material is available for this article .

The Etiology of Hepatocellular Carcinoma and Consequences for Treatment

Most patients with hepatocellular carcinoma (HCC) have liver cirrhosis, which develops following long periods of chronic liver disease. Cirrhosis is characterized by a decrease in hepatocyte proliferation, indicating an exhaustion of the regenerative capacity of the liver, and results in an increase in fibrous tissue and a destruction of liver cells, which may ultimately lead to the development of cancerous nodules. Half of all cases of HCC are associated with hepatitis B virus infection, with a further 25% associated with hepatitis C virus. Other risk factors for developing HCC include alcoholic liver disease, nonalcoholic steatohepatitis, intake of aflatoxin-contaminated food, diabetes, and obesity. There are multiple factors involved in the etiology of HCC, all of which have a direct impact on patient characteristics and disease course, and although a causative agent can often be identified, HCC remains an extremely complex condition associated with a poor prognosis. Additionally, the geographic variation in etiology means that information from different countries is needed in order to optimize surveillance methods and develop effective chemoprevention strategies. Unfortunately, there are still many gaps in our current understanding, and further research efforts are needed to fully elucidate the diverse mechanisms involved in the pathogenesis of HCC and offer optimal prevention strategies for those at risk.

Local-Regional Treatment of Hepatocellular Carcinoma

Local-regional treatments play a key role in the management of hepatocellular carcinoma (HCC). Image-guided tumor ablation is recommended in patients with early-stage HCC when surgical options are precluded and can replace resection in selected patients. Radiofrequency (RF) ablation has shown superior anticancer effects and greater survival benefit with respect to the seminal percutaneous technique, ethanol injection, in meta-analyses of randomized controlled trials and is currently established as the standard method for local tumor treatment. Novel thermal and nonthermal techniques for tumor ablation, including microwave ablation and irreversible electroporation, seem to have potential to overcome the limitations of RF ablation and warrant further clinical investigation. Transcatheter arterial chemoembolization (TACE) is the standard of care for patients with asymptomatic noninvasive multinodular tumors in intermediate-stage disease. Embolic microspheres that have the ability to release a drug in a controlled and sustained fashion have been shown to substantially increase the safety and efficacy of TACE in comparison to conventional ethiodized oil-based regimens. The available data for radioembolization with yttrium 90 suggest that this is a potential new option for patients with HCC, and future studies should be devoted to assessments of the role of radioembolization in the treatment algorithm for HCC.

Radio-frequency thermal ablation of liver metastases with a cooled-tip electrode needle: results of a pilot clinical trial

Abstract. The aim of this study was to evaluate feasibility, safety, and effectiveness of radio-frequency (RF) thermal ablation, performed by using a cooled-tip electrode needle, in the treatment of liver metastases. Twenty-nine patients (20 males and 9 females; age range 43–77 years) with one to four hepatic metastases 1.1–4.8 cm in diameter (mean 2.9 ± 0.8 cm) from previously resected intra-abdominal primary malignancies were treated. All patients were excluded from surgery and had partial or no response to chemotherapy. Radio-frequency ablation was performed by using a 100-W generator and 17-gauge, dual-lumen, cooled-tip electrode needles with a 2- to 3-cm exposed tip. Exposure time was 12 min for each needle insertion. Findings at spiral CT were used to assess the therapeutic response. A total of 127 insertions were performed (mean 2.4 ± 1.7 insertions/lesion) during 84 treatment sessions (mean 1.6 ± 0.7 sessions/lesion) in absence of major complications. Complete tumor response (i. e., unenhancing area of thermal necrosis larger than the treated tumor) was seen in 41 (77 %) of 53 lesions, including 33 (87 %) of 38 lesions 3 cm or less in diameter. After a mean follow-up period of 6.5 ± 2.1 months (range 3–9 months), recurrence of the treated lesion was seen in 5 (12 %) of the 41 cases. New metastatic lesions appeared in 7 patients. Two patients died after 6 and 8 months, respectively. Of the 27 patients still in follow-up, 14 are currently free of disease. Radio-frequency thermal ablation with a cooled-tip electrode needle is a safe and effective local treatment for hepatic metastases 3 cm or less in greatest dimension.