Liver Cancer
There are two distinct types of liver cancer. The first is primary liver cancer (the most frequent Hepatocellular Carcinoma) and the second is secondary or metastatic liver cancer. Although these two types of liver cancer are different, they are treated in similar ways although the actual procedures and drugs used in their treatment could differ.
Hepatocellular Carcinoma
Hepatocellular Carcinoma (HCC) is the fifth most common cancer in the world and represents more than 5% of all cancers. Approximately 500 000 cases of HCC are diagnosed each year and it is the third leading cause of cancer-related deaths (Parkin et al, 2001). There are wide geographical variations in the incidence of the disease with the highest rates in the developing countries of Asia and Africa. However, the incidents of HCC are increasing in North America and Europe (El-Serag and Mason, 1999; Nair et al, 2002).
Risk Factors
Hepatocellular Carcinoma is one of the few cancers with well-defined major risk factors (Bosch et al, 1999; Colombo, 2003). It develops within cirrhotic livers in 80% of cases and this pre-neoplastic condition is the strongest predisposing factor (Colombo, 2003).
Other risk factors in the development of HCC include hepatitis infection, aflatoxins and alcoholic cirrhosis. HCC is most often associated with chronic hepatitis B virus (Liaw et al, 1986) in Asia and Africa where it affects younger patients. Worldwide, 380 million individuals have hepatitis B infection, and in endemic areas the carrier rate is up to 10-20% of the population (Bréchot et al, 2001). Chronic hepatitis B carriers have a 100-fold relative risk of developing HCC compared with non carriers, a risk that decreases if the infection was acquired in adulthood and increases in cirrhotic patients (Fatidic et al, 1995).
In North America, Europe and Japan, HCC develops in cirrhotic livers due to hepatitis C (Bruix et al, 1989; Colombo et al, 1991) or alcohol abuse (Tsukuma et al, 1993). Approximately 170 million people worldwide are infected with hepatitis C virus (W.H.O., 1997). There is no available vaccine against hepatitis C and preventing the spread of the virus relies on stopping transmission through blood transfusion and in minimizing the spread in high-risk groups (e.g. drug users).
Aflatoxins are toxic products produced by some molds (Aspergillus flavus) that are found in foods such as peanuts, rice, soybeans and wheat and together with hepatitis B are implicated in the development of HCC is Asia (Sun et al, 1999).
Surveillance and Diagnosis
Surveillance to detect early HCC is highly recommended in patients with cirrhosis (Collier and Sherman, 1998). However, only patients with cirrhosis that can be treated with potentially curative therapies for HCC should have surveillance. These include Child-Pugh A class patients and Child-Pugh B patients if transplantation is available. The European Association for the Study of the Liver (EASL) has endorsed surveillance based on the use of ultrasound and serum alpha-fetoprotein (AFP) every 6 months (Bruix et al, 2001) as shown below.
Surveillance and Recall Strategy for HCC
* Available for curative treatments if diagnosed with HCC
** AFP levels to be defined
*** Pathological confirmation or non-invasive criteria
Improvements in imaging techniques and surveillance have made early diagnosis of HCC possible. However, these diagnostic procedures are expensive and therefore cost effective recall policies are required to accurately diagnose the different types of nodules that may develop in a cirrhotic liver (International working party, 1995; Takayama et al, 1990).
Ultrasound (US) plays a key role in the detection of HCC, but its sensitivity is low (Kim et al, 2001). The best techniques are helical computed tomography (CT) and magnetic resonance imaging (MRI) with contrast enhancement that have an accuracy exceeding 80% (Murakami et al, 2001), however, the sensitivity of both techniques decreases with the extent of the disease. In a recent study, MRI-angiography was found to be more precise than CT in detecting nodules of 1-2cm. However, 20-30% of intrahepatic tumours especially those less than 1cm are not detected with any technique. Spiral CT of the chest and bone scintigraphy is used to rule out extrahepatic spread in candidates for transplantation or inclusion in clinical trials.
Natural History and Prognosis
Until recently, the reported prognosis of HCC was poor and most patients died within 1 year regardless of the treatment they received (Okuda et al, 1985). The introduction of screening programs for high-risk patients enables 30-40% of patients to be diagnosed at the early stages when curative treatments are possible (Bruix and Llovet, 2002). Estimates of outcomes must therefore take into account the stage of the disease at diagnosis.
Very Early HCC
The earliest stage of HCC is known as the Very Early HCC and is defined as patients with well-preserved liver function with the CIS entity (carcinoma in situ). CIS is a very well differentiated HCC that contains bile ducts and portal veins, has ill-defined nodular appearance and has not invaded any structure (Kojiro, 2002; Sakamoto and Hirohasi, 1998; Llovet et al, 1999). These patients have the best outcomes. In Japan these patients are reported to have a 5-year survival rate of 89-93% following resection and 71% following percutaneous treatment (Sakamoto, 1998) and are less prone to recurrence after curative treatments.
Early HCC
The definition of early HCC is a single tumour of 5cm or 3 tumours of 3cm. These patients achieve excellent outcomes with transplantation (Bismuth et al, 1993; Mazzaferro et al, 1996; Llovet et al, 1999). However, treatment response and outcomes of early tumours are variable. For example, complete response rates following percutaneous treatments vary from 90-100% for tumours of 2cm and 50% for 5cm tumours (Livraghi et al, 1995).
Intermediate-Advanced HCC
The majority of patients are diagnosed at the advanced stage of HCC and are therefore precluded from radical treatments. Intermediate stage patients (asymptomatic, with no invasive pattern) show 1, 2 and 3-year survival rates of 80%, 65% and 50% respectively, survival rates in advanced patients (either symptomatic and /or invasive pattern) are 29%, 16% and 8% respectively.
End-Stage HCC
Prognosis for patients with end-stage HCC remains poor. Life expectancy is less than 6 months with no survival benefit from any treatment (Llovet et al, 1999; Villa et al, 2000). Child-Pugh C and Okuda stage III patients are classified as end-stage HCC.
Staging
In general, the prognosis of cancer patients is solely related to tumour stage. However, this is not the case in HCC patients as cirrhosis underlies the neoplasm in most individuals. The outcome is related to both tumour staging and extent of liver cirrhosis, which simultaneously determine the applicability and efficacy of treatments. Accordingly, prognostic modeling in HCC patients has a high complexity and should consider four tightly related aspects: tumour stage, degree of liver function impairment, general patient’s condition, and treatment efficacy (Bruix and Llovet, 2002). Prognostic systems assessing just one of these aspects (Child-Pugh, TNM, Performance status) have a marginal usefulness. Traditionally, HCC has been classified using the TNM staging system (Vauthey et al, 2002) or the Okuda classification (Okuda et al, 1985). The TNM staging is limited as it relies on pathological findings and does not consider liver function. The Okuda staging (Okuda, 1985) based on bilirubin, albumin, ascites and tumour burden has been used for years, but it is unable to distinguish between early and advanced HCC and mostly serves to identify end-stage individuals. Other classification systems have been developed but none has received universal acceptance (Llovet and Beaugrand, 2003; Befeler and Di Bisceglie, 2002). The Barcelona Clinic Liver Cancer (BCLC) staging system (Llovet et al, 1999; Bruix et al, 2002) links tumour stage with treatment strategy and may be applied to the majority of HCC patients (Llovet et al, 1999; Bruix and Llovet, 2002; Llovet et al, 2003). See Figure 2.
Treatment Schedule According to the BCLC Staging Classification
Treatment
Untreated HCC carries a poor prognosis and is directly related to degree of underlying cirrhosis and tumour stage. Early detection offers the only possibility for cure. Patient survival is generally not more than 6 months in patients with large tumour mass and Child C cirrhosis. Patients with small HCC (<5cm diameter) and stable liver function have a better prognosis with 2-year survival rates of 56% (Barbara et al, 1992).
It is generally accepted that surgical resection, liver transplantation and percutaneous ablation are the only curative treatment for patients with early stage HCC. These treatments induce complete response in a high proportion of patients and are expected to improve survival.
Hepatic resection is the treatment of choice in non-cirrhotic patients and can be performed with low rates of life-threatening complications (Bismuth and Majno, 2000; Makuuchi et al, 1992). In cirrhotic patients strict selection criteria are required to avoid life-threatening complications. Five-year survival rates in well-selected patients (asymptomatic with single HCC and well-preserved liver function) may be as high as 70% (Takayama et al, 1998; Llovet et al, 1999; Arii et al, 2000).
Cadaveric liver transplantation (CLT) has been a major breakthrough in the West. With transplantation, a 5-year survival rate of 70% with recurrence rate below 15% is achievable in early HCC patients (Mazzaferro et al, 1996; Llovet et al, 1999; Bismuth et al, 1999; Jonas et al, 2001; Yao et al, 2001). The best candidates for transplantation are those with single HCC 5cm or up to 3 nodules ≤ 3cm. However, liver transplantation is not available to all patients due to a shortage of donors and disease progression as a result of prolonged waiting times (Llovet et al, 1999). Living donor liver transplantation (LDLT) is a feasible alternative to CLT (Gondolesi et al, 2002) but is limited by the 20-40% surgical-related morbidity in recipients and a 0.3 to 0.5% donor mortality (Trotter et al, 2002).
Percutaneous treatments for HCC involve the destruction of neoplastic cells by chemical substances (alcohol or acetic acid) or temperature (radiofrequency, microwave, laser and cryoablation). The aim of each treatment is to create a 1cm ablation ring around the HCC. Percutaneous ethanol injection (PEI) is a well-tolerated treatment with high anti-tumoural efficacy in small (3cm) solitary tumours (Vilana R. et al, 1992). Child Pugh A patients treated by PEI achieve a 50% survival rate at 5 years (Bruix et al, 2001; Arii et al, 2000; Livraghi, 1995). Radiofrequency (RF) ablation may provide superior antitumoural benefits than PEI in tumours larger than 3cm. 5-year estimates for RF ablation range from 33-40% (Rossi et al, 1996; Buscarini et al, 2001). Other ablative techniques are either associated with complications or have no proven advantage.
The majority of HCC patients (approximately 75%) are not candidates for curative treatments either due to poor liver function or the presence of advanced disease. These patients are treated with palliative treatments. Non-surgical treatment for unresectable HCC includes systemic chemotherapy and radiotherapy, but these treatments have not been found to prolong survival in randomized clinical studies. Chemotherapeutic agents (e.g. doxorubicin) can be infused directly into the systemic circulation but patients who receive this treatment suffer serious side effects that may be life threatening (e.g. cardiac toxicity), pain, nausea, vomiting, myelosuppression and alopecia.
Transarterial chemoembolisation (TACE)
Transarterial chemoembolisation involves the periodic injection of a chemotherapeutic agent, mixed with an embolic material, into selected branches of the hepatic arteries feeding the tumour.
Effective embolisation of liver tumours is possible because of 3 circumstances:
- The normal liver receives 75% of its blood supply via the portal vein, and only 25% of the blood required to function is supplied from the hepatic artery (Breedis et al, 1954).
- Hepatic tumours derive 95% of the blood supply from the hepatic artery.
- The development of catheter technology allows super selective placement of catheters for safe and effective delivery of targeted embolisation agents to hepatic tumours. Microcatheters allow safe placement even in the face of aberrant vessels or collateral blood supply.
The rational for TACE is that the infusion of drug such as doxorubicin, mitomycin and cisplatin with a viscous emulsion (e.g. lipiodol) followed by embolisation of the blood vessel with Gelfoam, PVA particles or spherical embolic agents will occlude arterial blood supply to the tumour casing an infarct and subsequent necrosis of the tumour. The advantage of TACE is that higher concentrations of the drug can be delivered to the tumour with decreased systemic exposure compared with systemic chemotherapy.
Arterial embolisation achieves partial response in 15-55% of patients (Lin et al, 1998; Pelletier et al, 1990; Group d’etude, 1995; Bruix et al, 1998; Pelletier et al, 1998; Lo et al, 2002; Llovet et al, 2002) and significantly delays tumour progression and vascular invasion (Group d’etude 1995 and Llovet et al, 2002). Recently two studies have reported survival benefits for chemoembolisation in selected patients. Llovet et al reported 1 and 2 year survival probabilities of 82% and 63% with objective response sustained for at least 6 months in 35% of cases (Llovet et al, 2002). Lo et al found significant improvement in survival for Asian HCC patients treated by chemoembolisation with a lipiodol/cisplatin emulsion and gelatin sponge (Lo et al, 2002). A systematic review and meta-analysis of randomised clinical trials for unresectable HCC has shown a survival benefit of chemoembolisation (Llovet and Bruix, 2003). The best candidates for chemoembolisation are those with preserved liver function and asymptomatic multinodular tumours without vascular invasion or extrahepatic spread.
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