Management of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) ranks fifth in frequency worldwide among all malignancies and causes 1 million deaths annually. The management of HCC begins with diagnostic confirmation by radiologic imaging or histology. Staging is essential, as the choice of therapy depends on the functional state of the liver and the extent of tumor growth. Surgery, in the form of either hepatic resection or orthotopic liver transplantation, is the only potentially curative treatment. Transarterial chemoembolization is commonly used as either palliative treatment or adjunctive therapy to surgery, and a survival benefit with this therapy has just recently been demonstrated in a randomized, controlled trial. Patients with inoperable HCC may benefit from local ablative therapy that may still have curative potential in those with sufficiently small lesions and adequate liver function. For patients with advanced HCC, systemic chemotherapy has been widely employed, despite low efficacy and significant complication rate. Tamoxifen did not improve survival in large clinical trials. Gene therapy is an exciting approach to treating HCC but is still largely confined to preclinical and experimental settings.     

Chemoembolisation with lipiodol and doxorubicin: applicability in British patients with hepatocellular carcinoma.

Chemoembolisation has been extensively used as primary treatment for unresectable hepatocellular carcinoma (HCC). In this unit, 185 patients with a new diagnosis of HCC not amenable to surgery were seen between 1988 and 1991. Intended therapy for these patients was chemoembolisation with doxorubicin (60 mg/m2) and lipiodol, repeated at six week intervals until it was technically no longer possible or until complete tumour response had been obtained. Chemoembolisation was possible in 67 of the 185 (37%). Reasons for exclusion were portal vein occlusion (n = 36), decompensated cirrhosis (n = 44), distant metastases (n = 5), diffuse tumour or unsuitable anatomy (tumour or vasculature) (n = 11), patient refusal (n = 11), and other (n = 11). Patients excluded from treatment survived for a median of 10 weeks (range 3 days-19 months). In patients treated, 18 had small HCC (< 4 cm) and 49 had large or multifocal HCC. Chemoembolisation was carried out a median of two sessions for small and three sessions for large tumours. Ten of 18 patients with small HCC showed a 50% or greater reduction in tumour size. Five of 49 patients with large or multifocal tumours showed a response to treatment. Median overall survival for treated patients was 36 weeks (range 3 days-4 years). One patient has subsequently undergone liver transplantation with no recurrence and minimal residual disease at transplantation. Two other patients are alive three years after chemoembolisation, one with no evidence of recurrent disease. No patient was thought suitable for surgery after their response to chemoembolisation. Chemotherapy related complications were seen in 22%. Complications were significantly more common in patients with larger tumours and poor liver reserve. Five patients died as a result of chemotherapy related complications. In conclusion, only one third of UK patients with unresectable HCC are treatable by chemoembolisation. Results with small tumours are encouraging, with a high response rate and the possibility of surgical intervention in previously inoperable disease. Large tumours, however, show a poor response and a significant incidence of side effects, suggesting that this treatment offers little benefit in advanced disease.     

New advances in hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is the leading cause of deaths in cirrhotic patients and the third cause of cancer related deaths.Most HCC are associated withwell known underlying risk factors,in fact,HCC arise in cirrhotic patients in up to 90%of cases,mainly due to chronic viral hepatitis and alcohol abuse.The worldwide prevention strategies are conducted to avoid the infection of new subjects and to minimize the risk of liver disease progression in infected patients.HCC is a condition which lends itself to surveillance as at-risk individuals can readily be identified.The American and European guidelines recommended implementation of surveillance programs with ultrasound every six months in patient atrisk for developing HCC.The diagnosis of HCC can be based on non-invasive criteria(only in cirrhotic patient)or pathology.Accurately staging patients is essential to oncology practice.The ideal tumour staging system in HCC needs to account for both tumour characteristics and liver function.Treatment allocation is based on several factors:Liver function,size and number of tumours,macrovascular invasion or extrahepatic spread.The recommendations in terms of selection for different treatment strategies must be based on evidence-based data.Resection,liver transplant and interventional radiology treatment are mainstays of HCC therapy and achieve the best outcomes in well-selected candidates.Chemoembolization is the most widely used treatment for unresectable HCC or progression after curative treatment.Finally,in patients with advanced HCC with preserved liver function,sorafenib is the only approved systemic drug that has demonstrated a survival benefit and is the standard of care in this group of patients.     

Hepatocellular carcinoma:Surgical perspectives beyond the barcelona clinic liver cancer recommendations

The barcelona clinic liver cancer(BCLC)staging system has been approved as guidance for hepatocellular carcinoma(HCC)treatment guidelines by the main Western clinical liver associations.According to the BCLC classification,only patients with a small single HCC nodule without signs of portal hypertension or hyperbilirubinemia should undergo liver resection.In contrast,patients with intermediate-advanced HCC should be scheduled for palliative therapies,even if the lesion is resectable.Recent studies report good short-term and long-term outcomes in patients with intermediate-advanced HCC treated by liver resection.Therefore,this classification has been criticised because it excludes many patients who could benefit from curative resection.The aim of this review was to evaluate the role of surgery beyond the BCLC recommendations.Safe liver resection can be performed in patients with portal hypertension and well-compensated liver function with a 5-year survival rate of 50%.Surgery also offers good long-term result in selected patients with multiple or large HCCs with a reported 5-year survival rate of over 50%and 40%,respectively.Although macrovascular invasion is associated with a poor prognosis,liver resection provides better long-term results than palliative therapies or best supportive care.Recently,researchers have identified several genes whose altered expression influences the prognosis of patients with HCC.These genes may be useful for classifying the biological behaviour of different tumours.A revision of the BCLC classification should be introduced to provide the best treatment strategy and to ensure the best prognosis in patients with HCC.     

Locoregional treatments for hepatocellular carcinoma

Improvements in diagnostic techniques have enhanced our understanding of the natural history of hepatocellular carcinoma (HCC). This has facilitated a proper evaluation of the available treatment options for this neoplasm through both phase II studies and randomized controlled trials. Surgical resection and liver transplantation constitute the first two radical options, and when they are contra-indicated, patients may benefit from percutaneous ethanol injection or thermal ablation by radiofrequency current. These options may also achieve a complete response and constitute the last potentially radical therapies for small HCC. In contrast, for large multinodular tumours, the available treatment options have not been shown to improve survival. Arterial embolization with or without associated chemotherapy has been widely used. However, randomized controlled trials have failed to show a survival benefit, emphasizing the need to develop new treatment strategies.     

Application of surveillance programs for hepatocellular carcinoma in the Asia–Pacific Region

Hepatocellular carcinoma (HCC) is a potential target for cancer surveillance (or screening) as it occurs in well-defined, at-risk populations and curative therapy is possible only for small tumors. Surveillance has been recommended by regional liver societies and is practiced widely, but its benefits are not clearly established. Hepatic ultrasonography with or without alpha fetoprotein (AFP) performed every 6 months is the preferred program. Surveillance of HCC has been well shown to detect small tumors for curative treatment, which may be translated to improved patient survival. However, most studies are limited by lead-time bias, length bias for early diagnosis of small HCC, different tumor growth rates and poor compliance with surveillance. Cost-effectiveness of surveillance programs depends on the rate of small HCC detected 'accidentally' (routine imaging) in a comparator group, annual incidence of HCC with various etiologies, patient age and the availability of liver transplantation. The incremental cost-effectiveness for 6-monthly AFP and ultrasound has been estimated from approximately $US26 000–74 000/quality adjusted life years (QALY). All cirrhotic patients are therefore recommended for HCC surveillance unless the disease is too advanced for any curative treatment. As chronic hepatitis B can develop into HCC without going through liver cirrhosis, high-risk non-cirrhotic chronic hepatitis B patients are also recommended for HCC surveillance. In conclusion, HCC surveillance could be effective at reducing disease-specific mortality with acceptable cost-effectiveness among selected patient groups, provided it is a well-organized program.     

The evolution of liver transplantation for hepatocellular carcinoma (past, present, and future)

Over the past quarter-century, liver transplantation (LT) has been established as a durable therapy for all forms of end-stage liver disease. LT appears ideally suited for hepatocellular carcinoma (HCC), as it involves complete oncologic resection and correction of the underlying liver dysfunction. Since LT based on the Milan criteria has been shown to provide good diseasefree survival, LT is considered the optimal treatment for small HCC, especially in patients with underlying chronic liver disease. However, because there is a severe shortage of organ donors, not all patients in need can be offered LT. Transplant listing criteria must simultaneously determine the greatest number of suitable candidates for LT while rejecting the smallest number of those who could benefit from LT. The amended model for end-stage liver disease allocation policy has had a positive effect on liver transplant candidates with HCC, and their number has been increasing significantly over the past several years. To minimize dropout from the waiting list, the treatment of HCC with procedures such as chemoembolization, radiofrequency ablation, or ethanol injection in patients awaiting LT have become widespread. It is currently accepted that liver resection is the best option for the treatment of small HCC when liver function is well preserved, and that LT is preferred when liver function is severely impaired (Child-Pugh class B or C). However, the question arises as to what is the best option for Child-Pugh class A patients with early HCC eligible for both resection and LT, especially in Western countries. HCC is a major indication for living donor liver transplantation (LDLT), because the risk of dropout while waiting is negligible. Extension of the Milan criteria in the setting of LDLT may offer more patients a potentially curative treatment without reducing the donor pool of organs for patients on the waiting list with nonmalignant liver disease. However, imprudent expansion of the selection criteria may result in more patients with HCC being cured at the expense of a higher incidence of recurrence.     

Treatment of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and the third cause of cancer-related death. Despite therapeutic advances, the overall survival of patients with HCC has not significantly improved in the last two decades. In the majority of the cases there is underlying cirrhosis, so the prognosis of HCC depends on not only tumor stage but also liver function. There is not a widely accepted HCC staging system. In our group we have developed a new staging classification that stratifies HCC patients into four major categories and simultaneously links staging with treatment. Patients at an early stage are those who present with an asymptomatic single HCC with a maximum diameter of 5cm or up to three nodules each less than 3cm. They will benefit from curative therapies, including resection, liver transplantation (LT), and percutaneous ablation. Patients exceeding these limits, but who are free of cancer-related symptoms and vascular invasion or extrahepatic spread fit into the intermediate stage and may benefit from palliation with chemoembolization. The patients with mild cancer-related symptoms and/or vascular invasion or extrahepatic spread are included in the advanced stage. In this stage there is not effective therapy, and these patients may profit from new therapies in the setting of randomized controlled trials (RCTs). Finally, the patients with severe cancer-related symptoms or great tumor burden belong to the terminal stage and only benefit from symptomatic treatment.     

Hepatic resection beyond barcelona clinic liver cancer indication:When and how

Hepatocellular carcinoma(HCC)is the main common primary tumour of the liver and it is usually associated with cirrhosis.The barcelona clinic liver cancer(BCLC)classification has been approved as guidance for HCC treatment algorithms by the European Association for the Study of Liver and the American Association for the Study of Liver Disease.According to this algorithm,hepatic resection should be performed only in patients with small single tumours of 2-3 cm without signs of portal hypertension(PHT)or hyperbilirubinemia.BCLC classification has been criticised and many studies have shown that multiple tumors and large tumors,as wide as those with macrovascular infiltration and PHT,could benefit from liver resection.Consequently,treatment guidelines should be revised and patients with intermediate/advanced stage HCC,when technically resectable,should receive the opportunity to be treated with radical surgical treatment.Nevertheless,the surgical treatment of HCC on cirrhosis is complex:The goal to be oncologically radical has always to be balanced with the necessity to minimize organ damage.The aim of this review was to analyze when and how liver resection could be indicated beyond BCLC indication.In particular,the role of multidisciplinary approach to assure a proper indication,of the intraoperative ultrasound for intraoperative restaging and resection guidance and of laparoscopy to minimize surgical trauma have been enhanced.     

Liver resection for HCC: Patient's selection and controversial scenarios

Liver resection is a valuable curative option for patients with hepatocellular carcinoma (HCC). Yet, the balance between the operative risk following hepatectomy for HCC occurring on chronic liver disease and the oncologic prognosis of advanced lesions have led treatment recommendations to limiting the place of liver resection to selected patients with preserved liver function harbouring early-stage tumours. However, better understanding of the natural history of both tumour and underlying liver disease, sophisticated assessment of the liver function, improvements in the preoperative management of the patients with the use of liver volume modulation, refinements in surgical technique including anatomic resection and laparoscopic approach along with tailored management of recurrences have led expert centres to better define and extend the indications for liver resection. In this setting, the reported favourable operative results and long-term outcomes following resection of HCC in a number of controversial scenarios support that current guidelines could be refined.     

Is radiofrequency ablation the treatment of choice for patients with small hepatocellular carcinoma?

Liver resection is widely considered the mainstay of curative therapy for small hepatocellular carcinoma (HCC). Radiofrequency ablation (RFA) was initially developed as a treatment for small HCC in patients with considerable cirrhosis and inadequate liver function reserve for liver resection. However, in some centers, RFA is now used for small HCC, as an alternative to liver resection or even as the preferred treatment. This Practice Point commentary discusses the findings and limitations of a retrospective cohort study by Livraghi et al. that analyzed the outcomes of a group of patients with small, single HCC who underwent treatment with RFA. The authors reported a low major complication rate and a local complete response rate similar to that after resection. This commentary highlights the issues to consider when interpreting and generalizing these results, in particular that these findings need to be interpreted in the light of studies that suggest a high rate of local recurrence and incomplete histopathological response after RFA of small HCC.     

Local injection therapy for hepatocellular carcinoma

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world and ranks the third most common cause of cancer-related death. Surgical resection, liver transplantation and percutaneous ablation are generally considered the only curative treatment for early stage HCC. Besides the limitations of insufficient organ donors and a long waiting time for liver transplantation, however, resection is applied only to patients with good hepatic reserve and localized tumors, with a resectability of 30%. DATA SOURCES: Local ablation therapy, which is minimally invasive but contributes to the significant improvement of survival in patients with unresectable tumor, hasbeen widely used in treating small HCC. Among the techniques of local therapy, percutaneous ethanol injection (PEI) with a complete response in 80% of HCCs less than 3 cm has been accepted as an alternative to surgery in patients with small HCC. Moreover, percutaneous hepatic quantified ethanol injection (PHQEI) or PEI according to the standard criteria has been confirmed to benefit patients with HCC, especially when quantified ethanol is given at a short interval (QESI, the interval was 2-3 days). RESULT: Several limitations related to local percutaneous methods may result in incomplete therapeutic effect in case of larger HCC nodules (>3 cm). CONCLUSION: The combined use of different methods according to the clinical status of patients or tumors may be essential to the effective treatment of HCC.     

Complete hepatocellular carcinoma necrosis following sequential porto-arterial embolization

Most patients with hepatocellular carcinoma （HCC） are not eligible for curative treatment, which is resection or transplantation. Two recent series have emphasized the potential benefits of preoperative arterio-portal embolization prior to surgical resection of such tumours. This preoperative strategy offers a better disease free survival rate and a higher rate of total tumor necrosis. In case of non resectable HCC it is now widely accepted that transarterial chemoembolization （TACE） leads to a better survival when compared to conservative treatment. Thus, the question remains whether combined portal vein embolization （PVE） may enhance the proven efficiency of TACE in patients with unresectable HCC. We herein report the case of a 56-year-old cirrhotic woman with a voluminous HCC unsuitable for surgical resection. Yet, complete turnout necrosis and prolonged survival could be achieved a~er a combined porto-arterial embolization. This case emphasizes the potential synergistic effect of a combined arterio-portal embolization and the hypothetical survival benefit of such a procedure, in selected patients, with HCC not suitable for surgery or local ablative therapy.     

Das hepatozellul?re Karzinom aus der Sicht des Internisten und des Chirurgen

Hepatocellular carcinoma (HCC) is the 5th most common cancer in the world and the 3rd cause of cancer-related death. Despite therapeutic advances, the overall survival of patients with HCC has not significantly improved in the last decades. Because in the majority of patients HCCs develop in a cirrhotic liver, the patient’s prognosis depends not only on the tumor stage but also on the liver function. Patients at an early stage with an asymptomatic single HCC with a maximum diameter of 5 cm or up to three nodules each less than 3 cm may benefit from curative therapies, including resection, liver transplantation, and percutaneous ablation. Patients exceeding these limits, but who are free of cancer-related symptoms and vascular invasion or extrahepatic spread, may benefit from palliation with chemoembolization. The advanced stage is characterized by mild cancer-related symptoms and/or vascular invasion or extrahepatic spread. Patients at this stage are eligible for treatment with sorafenib; however, a variety of other new drugs, including small molecules and antibodies, are being tested in randomized controlled trials. The development and evaluation of novel HCC treatment strategies as well as the implementation of existing measures and the development of new ones to prevent HCCs are of utmost importance. A better understanding of the clinical and molecular pathogenesis of HCCs should lead to improved diagnostic, therapeutic, and preventive strategies, with the aim to reduce the incidence of HCC, one of the most devastating malignancies worldwide.     

Treatment of hepatocellular carcinoma

Summary. Treatment of patients with hepatocellular carcinoma (HCC) is largely influenced by local resources and the clinical stage of the disease. Hepatic resection is the treatment of choice for patients with HCC and normal liver. Tumour size and number, and liver status are common guidelines for choosing treatment in patients with cirrhosis. Hepatic resection and liver transplantation offered the best chances of cure in patients with a single small tumour. The 3-year survival of these patients was definitively better than that of historical controls. In the setting of patients with well-preserved liver function, a controlled study comparing the cost-efficacy of resection and transplantation is deemed necessary by many, but it is hardly feasible for both ethical and practical considerations. One major drawback of surgery in patients with a small tumour is early tumour spread to regional lymph-nodes, which favours early tumour recurrence after operation. Patients with more advanced tumour disease were rarely eligible for surgery and had dismal prognoses. For those with small tumours who were not eligible for surgery, percutaneous ethanol injection appeared to be a cost-saving and effective treatment modality. Arterial embolization is the only recom-mendable palliative treatment of patients with large tumours and poor hepatic function.     

Inherited hepatocellular carcinoma

Inherited liver disorders that cause chronic inflammation, fibrosis, and cirrhosis can lead to the development of liver cancer. Because of the rarity and diversity of some of these syndromes, the relative risk of developing HCC in these patients and the age at which tumours typically arise cannot be accurately estimated. Among patients with hereditary hemachromatosis (HH), the annual incidence of HCC is 4% once cirrhosis has been established. Fibrosis and portal hypertension associated with HH can be partially reversed with therapeutic phlebotomy, but it is unclear whether this treatment alters the incidence of HCC in these patients. Importantly, it seems likely that coincidence of these genetic disorders with known HCC risk factors such as alcoholism and viral hepatitis would amplify their oncogenic potential. For this reason, patients with known genetic disorders of the liver should be repeatedly counselled to avoid environmental and toxic injury to the liver. Treatment of HCC in patients with inherited liver disease mirrors that of HCC associated with other etiologies. Unfortunately, there are case series which suggest these patients with inherited liver disease and HCC tend to present at more advanced stages and are therefore not eligible for curative therapies, causing overall decreased survival relative to patients with HCC of viral or other etiologies.     

Hepatocellular carcinoma in patients with HCV.

In most Western countries hepatitis C virus (HCV) is a common risk factor for hepatocellular carcinoma (HCC). Many HCCs are multifocal in origin, but HCC may also grow as a single hepatic nodule for years before generating satellite or distant tumours. HCV may promote cancer through cirrhosis, which is often associated with HCV-related HCC, but it might also have oncogenic properties by interacting with cellular genes that regulate cell growth and differentiation. Treatment of patients with chronic hepatitis C using interferon might attenuate HCC risk, particularly in those who respond to therapy. Many patients whose cancer is detected early have been successfully treated by liver transplantation and have shown significantly prolonged survival. This is less often achieved with hepatic resection or regional therapies, which may indeed destroy small tumours, without affecting the complications of portal hypertension. Screening remains the only realistic approach for improving the treatment of HCC patients, but its cost-effectiveness is uncertain.     

Managing hepatitis B to prevent liver cancer: recent advances

Chronic hepatitis B (CHB) infection is a major cause of human mortality worldwide. The majority of people with CHB are infected early in life, and 20–40% of men and 15% of women with chronic infection will develop hepatocellular carcinoma (HCC). Antiviral therapy is recommended for patients with CHB who have cirrhosis or active disease with the aims of reducing disease progression to cirrhosis, liver failure and liver cancer, thereby preventing death. Evidence that treatment with interferon or with early nucleos(t)ide analogue therapy reduces HCC has been somewhat conflicting, however evidence is emerging to support a significant role in HCC prevention of the more effective antivirals, entecavir and tenofovir. Older patients, those with cirrhosis, and those undergoing curative treatments for HCC derive the greatest medium-term benefit in terms of HCC reduction, but HCC can still occur and long-term surveillance is recommended.     

Management of small hepatocellular carcinoma

In the last years the incidence of hepatocellular carcinoma (HCC) is rising in cirrhotic patients worldwide. Due the importance of early and definite diagnosis of HCC, any nodular lesion detected in patients with chronic liver disease should be considered as suspicious for HCC. The screening and surveillance programs in patients with liver diseases have increased the number of small HCC detected at an early stage, when the therapeutic options available are able to provide benefit. The introduction of new imaging techniques has improved the accuracy of characterizing these nodules. According to the EASL recommendations, contrast-enhanced computed tomography (CT), contrast enhanced ultrasound (US) and magnetic resonance (MR) with different MR-contrast agents are currently used to characterize liver lesions. Imaging guided biopsy is recommended for small nodules or in lesions without typical features (arterial hypervascularization) in at least two imaging techniques. Frequently the differential diagnosis of small nodules is complicated by discordant vascularity and recent studies have also demonstrated the presence of small hypovascular HCC at perfusional US and helical CT. At present, different treatment options can be offered to patients with diagnosis of small HCC at an early stage; percutaneous techniques, surgical resection and liver transplantation can provide benefit in properly selected patients. This review describes some critical points regarding the detection, diagnosis and therapeutic management of small nodules of HCC in cirrhotic patients.