Josep M. Llovet

Sorafenib in Advanced Hepatocellular Carcinoma

BACKGROUND No effective systemic therapy exists for patients with advanced hepatocellular carcinoma. A preliminary study suggested that sorafenib, an oral multikinase inhibitor of the vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and Raf may be effective in hepatocellular carcinoma. METHODS In this multicenter, phase 3, double-blind, placebo-controlled trial, we randomly assigned 602 patients with advanced hepatocellular carcinoma who had not received previous systemic treatment to receive either sorafenib (at a dose of 400 mg twice daily) or placebo. Primary outcomes were overall survival and the time to symptomatic progression. Secondary outcomes included the time to radiologic progression and safety. RESULTS At the second planned interim analysis, 321 deaths had occurred, and the study was stopped. Median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group (hazard ratio in the sorafenib group, 0.69; 95% confidence interval, 0.55 to 0.87; P<0.001). There was no significant difference between the two groups in the median time to symptomatic progression (4.1 months vs. 4.9 months, respectively, P=0.77). The median time to radiologic progression was 5.5 months in the sorafenib group and 2.8 months in the placebo group (P<0.001). Seven patients in the sorafenib group (2%) and two patients in the placebo group (1%) had a partial response; no patients had a complete response. Diarrhea, weight loss, hand-foot skin reaction, and hypophosphatemia were more frequent in the sorafenib group. CONCLUSIONS In patients with advanced hepatocellular carcinoma, median survival and the time to radiologic progression were nearly 3 months longer for patients treated with sorafenib than for those given placebo. (ClinicalTrials.gov number, NCT00105443.)

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.

Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial

BACKGROUND There is no standard treatment for unresectable hepatocellular carcinoma. Arterial embolisation is widely used, but evidence of survival benefits is lacking. METHODS We did a randomised controlled trial in patients with unresectable hepatocellular carcinoma not suitable for curative treatment, of Child-Pugh class A or B and Okuda stage I or II, to assess the survival benefits of regularly repeated arterial embolisation (gelatin sponge) or chemoembolisation (gelatin sponge plus doxorubicin) compared with conservative treatment. 903 patients were assessed, and 112 (12%) patients were finally included in the study. The primary endpoint was survival. Analyses were by intention to treat. FINDINGS The trial was stopped when the ninth sequential inspection showed that chemoembolisation had survival benefits compared with conservative treatment (hazard ratio of death 0.47 [95% CI 0.25-0.91], p=0.025). 25 of 37 patients assigned embolisation, 21 of 40 assigned chemoembolisation, and 25 of 35 assigned conservative treatment died. Survival probabilities at 1 year and 2 years were 75% and 50% for embolisation; 82% and 63% for chemoembolisation, and 63% and 27% for control (chemoembolisation vs control p=0.009). Chemoembolisation induced objective responses sustained for at least 6 months in 35% (14)of cases, and was associated with a significantly lower rate of portal-vein invasion than conservative treatment. Treatment allocation was the only variable independently related to survival (odds ratio 0.45 [95% CI 0.25-0.81], p=0.02). INTERPRETATION Chemoembolisation improved survival of stringently selected patients with unresectable hepatocellular carcinoma.

The Barcelona Approach: Diagnosis, Staging, and Treatment of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the fifth most common neoplasm in the world, and the third most common cause of cancer‐related death. It affects mainly patients with cirrhosis of any etiology. Patients with cirrhosis are thus usually included in surveillance plans aiming to achieve early detection and effective treatment. Only patients who would be treated if diagnosed with HCC should undergo surveillance, which is based on ultrasonography and α‐fetoprotein every 6 months. Upon diagnosis, the patients have to be staged to define tumor extent and liver function impairment. Thereafter, the best treatment option can be indicated and a prognosis estimate can be established. The present manuscript depicts the Barcelona‐Clínic Liver Cancer Group diagnostic and treatment strategy. This is based on the analysis of several cohort and randomized controlled studies that have allowed the continuous refinement of treatment indication and application. Surgical resection is considered the first treatment option for early stage patients. It is reserved for patients with solitary tumors without portal hypertension and normal bilirubin. If these conditions are not met, patients are considered for liver transplantation (cadaveric or live donation) or percutaneous ablation if at an early stage (solitary ≤ 5 cm or up to 3 nodules ≤ 3 cm). These patients will reach a 5‐year survival between 50 and 75%. If patients are diagnosed at an intermediate stage and are still asymptomatic and have preserved liver function, they may benefit from chemoembolization. Their 3‐year survival will exceed 50%. There is no effective treatment for patients with advanced disease and thus, in such instances, the patients have to be considered for research trials with new therapeutic options. Finally, patients with end‐stage disease should receive only palliative treatment to avoid unnecessary suffering. (Liver Transpl 2004;10:S115–S120.)

Updated treatment approach to hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, and its incidence will further increase, to reach a plateau in 2015–2020. The natural history of the disease is quite well known, except for its early stages, because the majority of patients at this stage are treated with radical approaches. Staging systems are key to predict the prognostics of patients with cancer, to stratify the patients according to prognostic variables in the setting of clinical trials, and to guide the therapeutic approach. The current knowledge of the disease, however, is not sufficient for recommending a staging system to be used worldwide. The conventional staging systems—Okuda stage, and TNM stage—have shown important limitations for classifying patients. Several new systems have been recently proposed, but only three of them have been validated. The Barcelona Clinic Liver Cancer (BCLC) staging classification links the stage of the disease to a specific treatment strategy. The Japan Integrated Staging (JIS) score has been proposed and used in Japan, although it needs Western validation. The Cancer of the Liver Italian Program (CLIP) score is mainly proposed for patients with advanced tumors. Early detection of HCC through surveillance programs allows the application of potentially curative therapies, such as resection, liver transplantation, and percutaneous ablation in patients with early tumors. The applicability of these treatments varies according to geographical distribution: from 50% to 70% of cases in Japan; 25% to 40% of cases in Europe and the United States; and fewer than 10% in Africa. There are no randomized controlled trials (RCTs) comparing any of the three major therapies. These studies are not feasible in the West. Therefore, there is no firm evidence to establish the optimal first-line treatment for small single HCC in patients with well-preserved liver function. Resection and transplantation achieve the best outcomes in well-selected candidates (5-year survival of 60%–70%), and compete as the first option from an intention-to-treat perspective. If surgery is precluded, local, nonsurgical therapies are applied. Percutaneous treatments provide good results (5-year survival of 40%–50%), but are unable to achieve response rates and outcomes comparable to those for surgical treatments, even when applied as the first option. Radiofrequency thermal ablation provides slightly better objective response rates than ethanol injection, but no survival advantages have been fully demonstrated. The remaining treatments have been assessed in the setting of around 70 RCTs conducted during the past 25 years. Chemoembolization has been shown to provide modest survival advantages in two RCTs and a metaanalysis, and is currently the mainstay of treatment in 10% of the whole HCC population. The ideal candidates for this option are patients with well-preserved liver function (Child-Pugh class A) and multinodular asymptomatic tumors without vascular invasion. Further RCTs are needed to assess the best chemotherapeutic agent and the ideal re-treatment schedule. There is no firstline option for patients with advanced HCC (vascular invasion, extrahepatic spread, or cancer-related symptoms). Systemic doxorubicin provides partial responses in 10% of cases, without proven survival advantages, and well-known treatment-related complications. Several other treatments, such as immunotherapy, internal radiation, tamoxifen, or anti-androgen agents, have not shown any relevant anti-tumoral effect or survival benefit. New drugs, such as tyrosine kinase inhibitors and anti-angiogenic agents, are currently being tested in the setting of clinical trials.

Initial response to percutaneous ablation predicts survival in patients with hepatocellular carcinoma

Outcome predictors in patients with hepatocellular carcinoma (HCC) who are treated with percutaneous ablation are ill defined, and it is unknown if successful therapy is associated with improved survival. In our study, 282 cirrhotic patients with early nonsurgical HCC were treated with percutaneous ablation during a 15‐year period. Single tumors were seen in 244 patients, and 2 to 3 nodules were seen in 38 patients. Initial complete response was achieved in 192 patients and was independently related to the size of the main tumor (P = .015) and tumor stage (P = .0001) (≤2 cm, 96%; 2.1‐3 cm, 78%; >3 cm, 56%; 2‐3 nodules, 46%). At the end of follow‐up, 80 patients presented sustained complete response. The 1‐, 3‐, and 5‐year survival rates were 87%, 51%, and 27%, respectively. The independent predictors of survival were Child‐Turcotte‐Pugh class (P = .0001) and initial complete response (P = .006). Child‐Turcotte‐Pugh class A patients with initial complete response achieved 42% survival at 5 years; this figure increased to 63% in patients with tumors 2 cm or smaller. In conclusion, our results demonstrate that initial complete response to percutaneous ablation is associated with an improved survival in both Child‐Turcotte‐Pugh class A and B patients with nonsurgical HCC. Accordingly, initial complete tumor necrosis should be considered a relevant therapeutic target irrespective of tumor size and liver function. (HEPATOLOGY 2004;40:1352–1360.)

High pathological risk of recurrence after surgical resection for hepatocellular carcinoma: An indication for salvage liver transplantation

Surgical resection and liver transplantation offer a 5‐year survival greater than 70% in patients with hepatocellular carcinoma, but the high recurrence rate impairs long‐term outcome after resection. Pathological data such as vascular invasion and detection of additional nodules predict recurrence and divide patients into high and low risk profile. Based on this, we proposed salvage liver transplant to resected patients in whom pathology evidenced high recurrence risk even in the absence of proven residual disease. From January 1995 to August 2003 we have evaluated 1,638 patients. Resection was indicated in 77 patients, but only 17 (22%) (all cirrhotics, 14 hepatitis C virus+) were optimal candidates for both resection and transplantation. Of them, 8 exhibited a high risk profile at pathology and were offered transplantation. Among the 8 high risk patients, 7 presented recurrence, compared with only 2 of the 9 at low risk (P = .012). Two of the high risk patients refused transplant and developed multifocal disease during follow‐up. The other 6 were enlisted and all but 1 had tumor foci in the explant. Only 1 presented extrahepatic dissemination early after transplant and died 4 months later. The others are free of disease after a median follow‐up of 45 months. Two recurrences were detected in low risk patients, 1 of them being transplanted 18 months after surgery. These data in a small series of patients confirm that pathological parameters identify patients at higher risk of recurrence, which allow them to be listed for liver transplantation without proven malignant disease. In conclusion, this policy is clinically effective and could further improve the outcome of resected patients. (Liver Transpl 2004;10:1294–1300.)

Hepatocellular carcinoma: present status and future prospects

Hepatocellular carcinoma (HCC) represents more than 5% of all cancers in the world, and the estimated number of cancer-related deaths exceeds 500,000 per year [1]. Two major epidemiological facts characterize this cancer. It occurs in a previously diseased liver, and the causes of the underlying liver disease differ according to the geographical distribution. Consequently, the mechanisms of hepatocarcinogenesis and the characteristics of the tumour might vary greatly from one part of the world to another. In Africa and Southern Asia, the role of aflatoxin B1 and HBV infection – which is acquired at birth or early in life – is highly predominant. In these patients, HCC develops often at a young age and in the absence of cirrhosis. By contrast, in Japan, Egypt and in Southern Europe, HCV is the main cause of HCC which occurs in older patients, nearly all of them with advanced fibrosis or cirrhosis. In Northern and Central European countries, HCV infection and alcohol are the main causes of cirrhosis. In France, ethanol is still the leading cause of cirrhosis and was responsible for 60% of all HCC cases during the last decade [2]. The incidence of HCC and its clinical presentation are different according to the geographical distribution of risk factors. In parts of Africa or East Asia, where the highest incidence rates are observed, most of the patients are diagnosed with infiltrative or massive tumours. In Western countries, where the underlying liver disease has frequently been detected and the patients are regularly followed, HCC is mostly diagnosed at an asymptomatic stage by routine ultrasonography (US). In a minority of HCV infected or alcoholic patients, HCC appears as a symptomatic disease that decompensates the underlying cirrhosis. Another important epidemiological fact is the rising incidence of HCC in developed countries, where it was a marginal cause of death years ago. In the United States, approximately 15,000 new cases occur each year [3], and in France, where the incidence of HCC has steadily and markedly increased, the estimated number is about 4000 per year [4]. The rising incidence is not only due to a more accurate diagnosis or an increase in the immigration rates from high prevalent countries. Epidemiological data have shown a steady increase in native patients during the last two decades. The reasons advocated for explaining this phenomenon are the increased rate of HCV infection and an improvement of the clinical management of cirrhotic patients. However, the increase incidence of HCC has only been joined by a slight increase in the percentage of cases due to HCV infection. This may favour the hypothesis that enhancing the survival of patients with advanced cirrhosis leads to an increased incidence of HCC. In fact, a decade ago, most of the deaths in cirrhotic patients were due to digestive haemorrhage or bacterial infections, two conditions that are now more efficiently prevented and cured [5]. Therefore, HCC has become the leading cause of death in patients with cirrhosis. Prevention and treatment of this neoplasm are now major concerns.

Hepatitis B virus and hepatocellular carcinoma

The development of hepatocellular carcinoma (HCC) is a major global health problem [1,2]. Its incidence has increased worldwide and nowadays it constitutes the 5th most frequent cancer representing around 5% of all cancers worldwide [2]. More than 500,000 new cases are diagnosed per year and it represents the third cause of cancer-related death and the first cause of death amongst cirrhotic patients [3–5]. HCC incidence has striking geographical differences [1]. In North America, Europe and Australia the ageadjusted incidence is less than 2/100,000 per year. This increases in the South European and Mediterranean countries and reaches the highest scores (.50/100,000) in Sub-Sahara Africa and South East Asia [1]. This geographic pattern overlaps with the distribution of risk factors and probably also reflects genetic characteristics inherited or acquired through oncogenic agents. While in some high risk areas the incidence has decreased as a result of a better health care of the population, the HCC incidence in several areas such as US and South Europe has increased. This may be due both to an increased disease awareness with a higher diagnostic capability, but also to the emergence of risk factors which up to now would have had a minor dissemination and thus, no impact. This is probably the case for hepatitis C virus (HCV)-related HCC that should represent the final step of the HCV epidemic that spread in some Western countries after the second world war, while in Asia it could have appeared decades before. The most relevant oncogenic agent for HCC development is chronic hepatitis B virus (HBV) or HCV infection [1,6]. Their prevalence is known to vary largely among the world population. Not unexpectedly, areas with high prevalence of viral infection have high HCC rates [1]. This association allowed the establishment of the relationship between HBV infection and HCC. Other risk factors such as alcoholism or hemochromatosis are also relevant, but have not yet reached the epidemiological and clinical importance of viral infection. In most cases, HCC development complicates an underlying chronic liver disease, but in all etiological categories the tumor may occur in the absence of cirrhosis or when minimal histologic changes have taken place. The present chapter reviews the evidence that links HCC development with HBV infection, summarizes the mechanisms that may be involved in the HBV carcinogenic pathway and finally provides the guidelines to achieve early diagnosis and effective therapy.

Preoperative evaluation of biliary anatomy in adult live liver donors with volumetric mangafodipir trisodium enhanced magnetic resonance cholangiography

Accurate preoperative depiction of biliary anatomy is not always adequately accomplished by imaging techniques in living donor liver transplantation (LDLT). We present the results of a prospective study designed to evaluate the ability of mangafodipir trisodium (Mn‐DPDP)‐enhanced magnetic resonance (MR) cholangiography (MRC) for this purpose in a series of 25 adult living liver donors (LLDs). We also analyze if a simple or a more complex surgical procedure can be preoperatively suggested for biliary reconstruction in the recipients. Findings on MRC were compared with operative cholangiography (OC). A conventional distribution with a right hepatic duct (RHD) longer than 1 cm anticipated a simple procedure (duct‐to‐duct anastomosis or hepaticojejunostomy [HJ]). A shorter RHD or any variant were predictors of a more complex surgery (bench ductoplasty or multiple anastomoses). Agreement between MRC and OC in assessing the biliary anatomy was measured using the κ statistic, and differences between the kind of surgery predicted at MRC and the biliary anastomosis performed were evaluated with Fishers exact test. Normal variants were present in 16 / 25 donors (64%). MRC was accurate in depicting the pattern of bile duct distribution observed at OC in 22 / 25 (88%) donors (κ = .831), and correctly predicted the complexity of biliary anastomosis in the recipient in 22 / 25 (88%) donors. No significant differences were observed between complexity of biliary surgery proposed at MRC and the final surgery performed (P = .002). In conclusion, Mn‐DPDP‐enhanced MRC is highly accurate in depicting the biliary duct anatomy and can be used preoperatively for surgical planning in LDLT. (Liver Transpl 2004;10:1391–1397.)