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Treatment of hepatocellular carcinoma

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Hepatocellular carcinoma (HCC) is one of the most common malignant tumours worldwide. The major etiologies and risk factors for HCC development are well defined and some of the multiple steps involved in hepatocarcinogenesis have been elucidated in recent years. Despite these scientific advances and the implementation of measures for early HCC detection in patients at risk, patient survival has not improved during the last three decades. This is due in part to the advanced stage of the disease at the time of clinical presentation, in part due to the limited therapeutic options. These fall into four main categories: (1) surgical interventions, incl. tumour resection and liver transplantation, (2) percutaneous interventions, incl. ethanol injection and radiofrequency thermal ablation, (3) transarterial interventions, incl. embolisation and chemoembolisation and (4) drugs as well as gene and immune therapies. These therapeutic strategies have been evaluated in part in randomised controlled clinical trials that are the basis for therapeutic recommendations. While surgery and percutaneous as well as transarterial interventions are effective in patients with limited disease (1–3 lesions, <5 cm in diameter) and compensated underlying liver disease (cirrhosis Child A), at the time of diagnosis more than 80% patients present with multicentric HCC and advanced liver disease or comorbidities that restrict the therapeutic measures to best supportive care. In order to reduce morbidity and mortality from HCC, therefore, early diagnosis and the development of novel systemic therapies for advanced disease, incl. drugs, gene and immune therapies as well as primary HCC prevention are of paramount importance. Further, secondary HCC prevention after successful therapeutic interventions needs to be improved in order to make an impact on the survival of patients with HCC. New technologies, including gene expression profiling and proteomic analyses, should further elucidate the molecular events underlying HCC development and identify novel diagnostic markers as well as therapeutic and preventive targets.

Section snippets

HCC staging and natural course

For the staging of HCCs five systems have been proposed for the assessment of the extent and of the prognosis of the disease: the Okuda staging system (Table 228), the TNM classification and its modification by the ‘Union International Contre Cancer (UICC)’, the ‘Barcelona Clinic Liver Cancer (BCLC)’ classification (Table 329), and the ‘Cancer of the Liver Italian Program (CLIP)’ score (Table 430). The Okuda staging system is very effective for the identification of a subgroup of patients

Treatment of HCC

Therapies for HCC can be devided into four categories: surgical interventions (tumour resection and liver transplantation), percutaneous interventions (ethanol injection, radiofrequency thermal ablation), transarterial interventions (embolisation, chemoperfusion, or chemoembolisation) and drugs, including gene and immune therapy (Figure 2). Potentially curative therapies are tumour resection, liver transplantation, and percutaneous interventions that can result in complete responses and

Resection

In patients without concomitant liver cirrhosis (5% in Western countries, 40% in Subsahara Africa and Asia) HCC resection is the treatment of choice with low rates of life-threatening complications. By comparison, in the majority of patients with cirrhosis, strict selection is required to avoid resection-related complications, especially postoperative liver failure. Apart from bilirubin and albumin concentration as well as platelet count and indocyanine green clearance,31, 32 a recent study

Percutaneous interventions

Percutaneous interventions are the best options for small unresectable HCCs.44 Tumor ablations can be achieved chemically by percutaneous ethanol injection (PEI) or acetic acid injection (PAI) or thermally by radiofrequency thermal ablation (RFTA), microwave-heat induced thermotherapy (HiTT), laser induced thermotherapy (LiTT), or cryoablation. Apart from percutaneous interventions, these techniques can be applied also laparoscopically or after laparotomy.

Transarterial interventions

Transarterial embolisation and chemoembolisation are the most widely used treatments for HCCs that are unresectable or cannot be effectively treated by percutaneous interventions).51, 52, 53, 54 Embolisation agents may be administered alone (embolisation) or after selective intra-arterial chemotherapy (generally doxorubicin, mitomycin or cisplatin) mixed with lipiodol (chemoembolisation). Transarterial embolisation or chemoembolisation results in partial responses in 15–55% of patients, delays

Drugs

A number of systemic chemotherapies, hormonal and other drugs (Table 5) have been evaluated in clinical trials.56, 57, 58 While most chemotherapeutic agents, tamoxifen,59 octreotide60 and interferon51 have not been shown to be effective in randomised controlled clinical trials, there are a number of substances that may deserve further clinical evaluation, e.g. gemcitabine,61, 62 thymostimulin,63 α-1-thymosin,64 pravastatin,65 thalidomide,66 megestrol acetate,67 several antiangiogenic small

Future treatment strategies

In view of the limited therapeutic options for advanced HCCs a number of experimental strategies are being evaluated (Figure 4), incl. gene and immune therapies based on suicide, cytokine and antiangiogenic genes or DNA vaccination with tumour-specific genes,68, 69 oncolytic viruses70 as well as novel drugs, e.g. 3-bromopyruvate.71

HCC prevention

HCC prevention falls into two categories. Primary prevention that is aimed at the prevention of HCC development in patients with chronic liver diseases of different etiologies and secondary prevention that is aimed at preventing the recurrence and/or the development of new HCC lesions after successful surgical or non-surgical HCC treatment.

Summary and perspectives

HCC is one of the most common malignant tumours in some areas of the world with an extremely poor prognosis. HCC treatment is based on randomised controlled trials and many observational studies. Treatment options fall into four main categories: (1) surgical interventions, incl. tumour resection and liver transplantation, (2) percutaneous interventions, incl. ethanol injection and radiofrequency thermal ablation, (3) transarterial interventions, incl. embolisation and chemoembolisation and (4)

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