Hepatocellular carcinoma.
Introduction
Hepatocellular carcinoma (HCC) is the fifth most common tumor worldwide, with an incidence equal to the death rate. The incidence of HCC has been rising in Europe and the USA. A recent study showed that because of the lag time between the onset of infection and the development of cirrhosis, the incidence of hepatitis C virus (HCV)-related HCC will continue to increase over the next 20 years. In addition, the improvement in the survival of patients with cirrhosis due to improved specialty care may further increase the number of individuals at risk from developing HCC.
Epidemiology
A landmark study in 1999 showed that the incidence of HCC, thought to be a rare tumor in the USA, was rising to 2.4 per 100 000 people up to 1995. A population study evaluated the risk factors for this increase in the incidence of HCC. The age-adjusted incidence of HCC among those 65 years of age and older significantly increased from 14 per 100 000 in 1993 to 18.1 per 100 000 in 1999. The proportion of HCV-related HCC increased from 11% in 1993 to 21% in 1999 whereas hepatitis B virus (HBV)-related HCC increased from 6 to 11%. The authors concluded that HCV-related HCC accounts for the majority of the increase in incidence seen with this tumor in individuals 65 years and older. Even though this is a population-based study in the USA, an important limitation is that it does not study patients younger than 65 years, which seems to be the majority of patients. These data confirm the projections of an increase in the incidence of HCC over the next two decades.
Risk factors
It has been recognized that the most important risk factor for the development of HCC is cirrhosis. HCV and HBV are the major etiological agents that lead to the development of HCC. Besides etiology of liver disease, other risk factors have been shown to be important in the development of HCC. An association between diabetes mellitus and HCC has been reported, but the temporal relationship remains unknown. A recent population-based case–control study examined the relationship between diabetes and HCC. The authors utilized the surveillance-epidemiology and end-results program-Medicare-linked database to identify patients aged 65 and older who were diagnosed with HCC between 1994 and 1999. They identified 2061 patients with HCC and 6183 non-cancer controls. The proportion of HCC patients with diabetes was 43 compared with 19% with non-cancer controls, and was associated with a 3-fold increase in the risk of HCC. A major problem with this study is the fact that the controls were patients without liver disease and, therefore, at a low risk for developing HCC. A case–control study from the USA, utilizing patients with cirrhosis as controls, evaluated whether alcohol, tobacco, diabetes, and obesity were independent risk factors for HCC. When compared to cirrhotic controls, the independent risk factors for HCC were alcohol exposure of more than 1500 g-years, tobacco more than 20 pack-years, and body mass index more than 30 kg/m2. Importantly, these factors had a synergistic interaction among themselves, indicating a potential common pathophysiological mechanism of carcinogenesis.
Several articles in the last year evaluated coffee intake as a risk for the development of HCC. In a prospective study of 90 452 middle-aged Japanese adults, a total of 334 patients developed HCC (250 men and 84 women) after a 10-year follow-up. The patients who consumed coffee on a daily or almost daily basis (three or four times a week) had a lower risk of HCC than patients who almost never drank coffee. The risk of HCC in those who almost never drank coffee was 547.2 per 100 000 over 10 years but was 214.6 per 100 000 in those who drank coffee on a daily basis. The results were the same after adjusting for alcohol, tobacco, viral hepatitis, age, gender, and previous history of liver disease. These results were replicated in other studies involving an Italian and another Japanese cohort. The results are interesting and should be explored further as a potential chemopreventive agent.
Prevention
Because HCV and HBV are the leading etiological agents that cause HCC, treating these infections may theoretically reduce the development of HCC but the true effectiveness of this approach is unknown. A recent multicenter study in Japan investigated the role of antiviral therapy with interferon-[alpha] in the suppression of HCC over long-term follow-up. A total of 25 centers enrolled 345 patients with HCV-related cirrhosis without HCC (274 underwent antiviral therapy and 74 received no treatment). During a 6-year follow-up, 119 patients developed HCC, of whom 84 (31%) were in the interferon group and 35 (47%) were in the untreated group. The cumulative incidence of HCC was significantly lower in the interferon-treated group than in the untreated group, especially in those with a sustained virological response. Even though this was not a randomized trial and may suffer from selection bias, it shows that this strategy may be important for the prevention of HCV-related HCC among those with cirrhosis. Ongoing randomized studies in the USA and Europe, powered to determine whether interferon can prevent HCC in patients with HCV cirrhosis, may give us definite answers.
Surveillance for hepatocellular carcinoma
Surveillance for HCC, using [alpha]-fetoprotein and ultrasound, is practiced widely and recommended by experts. A recent Markov model showed that surveillance with ultrasound every 6 months was cost-effective and that the impact of surveillance depended on the outcomes and costs of treatment. Finally, a randomized control trial of screening with [alpha]-fetoprotein and ultrasound every 6 months compared with no screening in China was completed and reported. A total of 18 816 patients with chronic hepatitis B or a history of chronic hepatitis were randomized to screening (n = 9373) or no screening (n = 9443). After a total 38 444 person-years in the screening group and 41 077 person-years in the control group, there were 32 deaths from HCC in the screening group and 54 deaths from HCC in the control group, reducing mortality by 37%. This is likely the smallest improvement in survival expected because of the low adherence rates, but it is the first large randomized controlled trial for HCC. However, this is not generalizable to Western populations because the population at risk differs in China.
The new American Association for the Study of Liver Disease (AASLD) guidelines on HCC indicate that surveillance for HCC among patients with cirrhosis should be performed by ultrasonography, that [alpha]-fetoprotein without ultrasonography should not be performed, and that the interval of time for surveillance should be every 6–12 months. A study in 2005 highlighted the poor specificity of [alpha]-fetoprotein, indicating further evidence that it is not a good surveillance test. In addition, the AASLD guidelines state that ‘…new biomarkers to establish the risk of cancer and/or detect its appearance at a preclinical stage are urgently needed’. Two studies utilized surface-enhanced laser desorption ionization time-of-flight mass spectrometry to perform a protein profile of serum that may be able to determine those who have or do not have cancer. Another technique is targeted glycoproteomics to identify serum glycoproteins that correlate with liver cancer. These new methods are exciting and further validation studies are required before they are applied clinically.
Diagnosis
Histological examination of a hepatic mass has long been considered to be the gold standard for the diagnosis of HCC. However, the risks of bleeding and tumor seeding from the biopsy have raised significant concerns about such practice. Therefore, a previous consensus statement provided non-invasive criteria for HCC that included a lesion more than 2 cm on two imaging tests (dynamic ultrasound, magnetic resonance imaging, and computerized tomography scanning) showing hypervascularity or an [alpha]-fetoprotein more than 400 ng/ml and one imaging test showing hypervascularity. A recent study evaluated the impact of arterial hypervascularity in patients with HCC. The authors studied 72 nodules (41 between 1 and 2 cm and 31 between 2.1 and 3 cm) detected by ultrasound in 59 patients. A biopsy of the lesion was performed if the imaging tests did not meet the criteria established by the consensus statement indicated above. Hypervascularity was found in 44 of 72 nodules (44% in those 1–2 cm and 84% in those 2.1–3 cm). Fourteen nodules (19%) had negative results by computerized tomography scan and dynamic ultrasound, and biopsy showed HCC in five hypovascular nodules and 11/14 nodules with hypervascularity on only one technique. Therefore, only 61% of the nodules satisfied the consensus statement criteria and 38% of the cases would have been missed.
Prognosis
Estimating prognosis for patients with HCC is a critical step in their management. The prognosis for most neoplasms is dictated largely by the tumor stage at the time of diagnosis, whereas the situation is more complex in patients with HCC. It is well known that more than 90% of patients with HCC have underlying cirrhosis of the liver, and the functional impairment of the underlying liver has a significant impact on prognosis and on the types of treatment indicated due to the functional reserve of the liver. As a consequence, any staging classification that stratifies patients according to risk should determine hepatic function and tumor staging. There are several staging classifications that have been established in various countries for the prognosis of HCC. An important study in 2005 compared the seven most common staging systems in a cohort from the USA. The authors indicated that the Barcelona Clinic Liver Cancer (BCLC) classification was the best system at stratifying survival for patients at the various staging systems. Studies in other populations have also validated the BCLC classification for prognosis of patients with HCC. Based on these data, the new AASLD guidelines have endorsed the BCLC classification for prognosis and treatment of HCC.
Treatment
The BCLC classification shows that for patients with early-stage tumors, resection, liver transplantation, and radiofrequency ablation (RFA) are curative treatments that potentially lead to 5-year survival rates of about 50%. Recently, various groups have argued that the current criteria for transplantation (single tumor nodule less than 5 cm, or three nodules or fewer, each less than 3 cm in diameter) are too restrictive and some patients with advanced HCC may benefit from liver transplantation or resection. A multicenter study of 1073 resections for HCC investigated the relationship between tumor size and microscopic (occult) vascular invasion. Tumor size and the number of nodules were important factors that predicted vascular invasion. Vascular invasion was present in 55% of patients with tumors of between 5.1 and 6.5 cm compared to 31% for those 5 cm or smaller. The authors concluded that the high prevalence of occult vascular invasion in HCC tumors larger than 5 cm are predictors of poor prognosis and that therefore the criteria for liver transplantation or resection should not be expanded beyond what the BCLC classification indicates. Live-donor liver transplantation has been shown to be an effective strategy for the treatment of patients with liver failure and patients with HCC. A study from four institutions in Korea compared the results of live-donor (n = 237) with cadaveric-donor (n = 75) liver transplantation from 1992 to 2002. There were no differences in tumor characteristics, and the overall 3-year survival rate was 61% for cadaveric donation and 73% for live donation. Thus, live donation is as effective as cadaveric donation for the treatment of HCC when the same criteria are applied. There are no data showing that expanding the established criteria for transplanting HCC by performing live-donor liver transplantation leads to the same outcomes.
There were several papers during the past year that evaluated the efficacy of ablative techniques for the treatment of HCC. There are two main methods for performing tumor ablation: RFA or percutaneous ethanol injection (PEI). An intention-to-treat study of 206 patients who underwent RFA as primary treatment of HCC, who also were excluded as candidates for transplantation or resection, was reported. The study included patients who were Child class A or B, met the criteria for transplantation, and were followed for a mean of 24 months. The overall 1-, 3-, and 5-year probabilities of survival were 97, 67, and 41%, respectively. The authors indicated that RFA was an effective first-line therapy for patients with early-stage HCC but who are not candidates for surgical therapies. Another study from Italy and the USA showed that RFA was also effective as a bridge to liver transplantation. An important study this year evaluated whether percutaneous therapies were associated with an improved overall survival for patients with HCC. A total of 282 patients with early non-surgical HCC were treated with percutaneous ablative techniques, the majority being PEI. The 1-, 3-, and 5-year survival rates were 87, 51, and 27%, respectively. Those who achieve an initial complete response to the ablation achieved a 5-year survival of 42% irrespective of tumor size and hepatic function.
Conclusion
The incidence of HCC continues to rise. Even though patients with cirrhosis are at risk from developing HCC, it is now understood that tobacco, alcohol, diabetes, and obesity interact together in the causation of HCC. Surveillance for HCC leads to an improved overall survival. Triple-phase examination is the best method for the diagnostic evaluation of a hepatic mass, and washout of a hypervascular mass in the delayed phases of contrast appears to be sensitive and specific for HCC. The BCLC classification for HCC offers the best prognostic stratification and the best treatment strategy for patients. RFA seems to lead to an improved survival for patients with early-stage HCC. More studies are needed to determine optimal treatment strategies in patients with advanced HCC.
Hepatocellular carcinoma (HCC) is the fifth most common tumor worldwide, with an incidence equal to the death rate. The incidence of HCC has been rising in Europe and the USA. A recent study showed that because of the lag time between the onset of infection and the development of cirrhosis, the incidence of hepatitis C virus (HCV)-related HCC will continue to increase over the next 20 years. In addition, the improvement in the survival of patients with cirrhosis due to improved specialty care may further increase the number of individuals at risk from developing HCC.
Epidemiology
A landmark study in 1999 showed that the incidence of HCC, thought to be a rare tumor in the USA, was rising to 2.4 per 100 000 people up to 1995. A population study evaluated the risk factors for this increase in the incidence of HCC. The age-adjusted incidence of HCC among those 65 years of age and older significantly increased from 14 per 100 000 in 1993 to 18.1 per 100 000 in 1999. The proportion of HCV-related HCC increased from 11% in 1993 to 21% in 1999 whereas hepatitis B virus (HBV)-related HCC increased from 6 to 11%. The authors concluded that HCV-related HCC accounts for the majority of the increase in incidence seen with this tumor in individuals 65 years and older. Even though this is a population-based study in the USA, an important limitation is that it does not study patients younger than 65 years, which seems to be the majority of patients. These data confirm the projections of an increase in the incidence of HCC over the next two decades.
Even though the incidence of HCC is rising and resource-intensive treatment modalities are increasingly applied, these patients have poor survival. A study examined two national databases, the Multiple Cause of Death file and the Nationwide Inpatient Sample database, to examine trends in mortality and hospital service utilization related to HCC. The authors found that the age-, sex-, and race-specific mortality from HCC increased from 1.54 to 2.58 per 100 000 per year between 1980 and 1998. The estimated national charge in the USA for HCC hospitalizations nationwide increased from $241 million in 1988 to $509 million in 2000 after adjusting for inflation. Given the significant utilization of resources, greater attention to understand the risk factors to implement prevention is urgently warranted.
Risk factors
It has been recognized that the most important risk factor for the development of HCC is cirrhosis. HCV and HBV are the major etiological agents that lead to the development of HCC. Besides etiology of liver disease, other risk factors have been shown to be important in the development of HCC. An association between diabetes mellitus and HCC has been reported, but the temporal relationship remains unknown. A recent population-based case–control study examined the relationship between diabetes and HCC. The authors utilized the surveillance-epidemiology and end-results program-Medicare-linked database to identify patients aged 65 and older who were diagnosed with HCC between 1994 and 1999. They identified 2061 patients with HCC and 6183 non-cancer controls. The proportion of HCC patients with diabetes was 43 compared with 19% with non-cancer controls, and was associated with a 3-fold increase in the risk of HCC. A major problem with this study is the fact that the controls were patients without liver disease and, therefore, at a low risk for developing HCC. A case–control study from the USA, utilizing patients with cirrhosis as controls, evaluated whether alcohol, tobacco, diabetes, and obesity were independent risk factors for HCC. When compared to cirrhotic controls, the independent risk factors for HCC were alcohol exposure of more than 1500 g-years, tobacco more than 20 pack-years, and body mass index more than 30 kg/m2. Importantly, these factors had a synergistic interaction among themselves, indicating a potential common pathophysiological mechanism of carcinogenesis.
Several articles in the last year evaluated coffee intake as a risk for the development of HCC. In a prospective study of 90 452 middle-aged Japanese adults, a total of 334 patients developed HCC (250 men and 84 women) after a 10-year follow-up. The patients who consumed coffee on a daily or almost daily basis (three or four times a week) had a lower risk of HCC than patients who almost never drank coffee. The risk of HCC in those who almost never drank coffee was 547.2 per 100 000 over 10 years but was 214.6 per 100 000 in those who drank coffee on a daily basis. The results were the same after adjusting for alcohol, tobacco, viral hepatitis, age, gender, and previous history of liver disease. These results were replicated in other studies involving an Italian and another Japanese cohort. The results are interesting and should be explored further as a potential chemopreventive agent.
Prevention
Because HCV and HBV are the leading etiological agents that cause HCC, treating these infections may theoretically reduce the development of HCC but the true effectiveness of this approach is unknown. A recent multicenter study in Japan investigated the role of antiviral therapy with interferon-[alpha] in the suppression of HCC over long-term follow-up. A total of 25 centers enrolled 345 patients with HCV-related cirrhosis without HCC (274 underwent antiviral therapy and 74 received no treatment). During a 6-year follow-up, 119 patients developed HCC, of whom 84 (31%) were in the interferon group and 35 (47%) were in the untreated group. The cumulative incidence of HCC was significantly lower in the interferon-treated group than in the untreated group, especially in those with a sustained virological response. Even though this was not a randomized trial and may suffer from selection bias, it shows that this strategy may be important for the prevention of HCV-related HCC among those with cirrhosis. Ongoing randomized studies in the USA and Europe, powered to determine whether interferon can prevent HCC in patients with HCV cirrhosis, may give us definite answers.
Surveillance for hepatocellular carcinoma
Surveillance for HCC, using [alpha]-fetoprotein and ultrasound, is practiced widely and recommended by experts. A recent Markov model showed that surveillance with ultrasound every 6 months was cost-effective and that the impact of surveillance depended on the outcomes and costs of treatment. Finally, a randomized control trial of screening with [alpha]-fetoprotein and ultrasound every 6 months compared with no screening in China was completed and reported. A total of 18 816 patients with chronic hepatitis B or a history of chronic hepatitis were randomized to screening (n = 9373) or no screening (n = 9443). After a total 38 444 person-years in the screening group and 41 077 person-years in the control group, there were 32 deaths from HCC in the screening group and 54 deaths from HCC in the control group, reducing mortality by 37%. This is likely the smallest improvement in survival expected because of the low adherence rates, but it is the first large randomized controlled trial for HCC. However, this is not generalizable to Western populations because the population at risk differs in China.
The new American Association for the Study of Liver Disease (AASLD) guidelines on HCC indicate that surveillance for HCC among patients with cirrhosis should be performed by ultrasonography, that [alpha]-fetoprotein without ultrasonography should not be performed, and that the interval of time for surveillance should be every 6–12 months. A study in 2005 highlighted the poor specificity of [alpha]-fetoprotein, indicating further evidence that it is not a good surveillance test. In addition, the AASLD guidelines state that ‘…new biomarkers to establish the risk of cancer and/or detect its appearance at a preclinical stage are urgently needed’. Two studies utilized surface-enhanced laser desorption ionization time-of-flight mass spectrometry to perform a protein profile of serum that may be able to determine those who have or do not have cancer. Another technique is targeted glycoproteomics to identify serum glycoproteins that correlate with liver cancer. These new methods are exciting and further validation studies are required before they are applied clinically.
Diagnosis
Histological examination of a hepatic mass has long been considered to be the gold standard for the diagnosis of HCC. However, the risks of bleeding and tumor seeding from the biopsy have raised significant concerns about such practice. Therefore, a previous consensus statement provided non-invasive criteria for HCC that included a lesion more than 2 cm on two imaging tests (dynamic ultrasound, magnetic resonance imaging, and computerized tomography scanning) showing hypervascularity or an [alpha]-fetoprotein more than 400 ng/ml and one imaging test showing hypervascularity. A recent study evaluated the impact of arterial hypervascularity in patients with HCC. The authors studied 72 nodules (41 between 1 and 2 cm and 31 between 2.1 and 3 cm) detected by ultrasound in 59 patients. A biopsy of the lesion was performed if the imaging tests did not meet the criteria established by the consensus statement indicated above. Hypervascularity was found in 44 of 72 nodules (44% in those 1–2 cm and 84% in those 2.1–3 cm). Fourteen nodules (19%) had negative results by computerized tomography scan and dynamic ultrasound, and biopsy showed HCC in five hypovascular nodules and 11/14 nodules with hypervascularity on only one technique. Therefore, only 61% of the nodules satisfied the consensus statement criteria and 38% of the cases would have been missed.
Another study evaluated whether washout of contrast in the delayed phases of arterial enhancement was a more specific finding than arterial hypervascularity. A total of 94 patients with cirrhosis and an arterially enhancing mass were followed prospectively. The authors found that washout of contrast in delayed phases had a sensitivity of 89% and specificity of 96% for a diagnosis of HCC, including those with HCC less than 2 cm in diameter. Based on these two studies, the AASLD guidelines have modified the non-invasive criteria for a diagnosis of HCC. If a nodule is more than 2 cm in diameter, only one imaging test (computerized tomography or magnetic resonance imaging) showing a typical pattern, arterial phase hypervascularity and delayed phase washout, is required for the diagnosis of HCC. If a nodule is between 1 and 2 cm in diameter, two imaging tests (computerized tomography or magnetic resonance imaging) showing a typical pattern are required for the diagnosis of HCC. If the nodule exhibits atypical enhancement pattern (any difference from the typical one) then the lesion should be biopsied.
Prognosis
Estimating prognosis for patients with HCC is a critical step in their management. The prognosis for most neoplasms is dictated largely by the tumor stage at the time of diagnosis, whereas the situation is more complex in patients with HCC. It is well known that more than 90% of patients with HCC have underlying cirrhosis of the liver, and the functional impairment of the underlying liver has a significant impact on prognosis and on the types of treatment indicated due to the functional reserve of the liver. As a consequence, any staging classification that stratifies patients according to risk should determine hepatic function and tumor staging. There are several staging classifications that have been established in various countries for the prognosis of HCC. An important study in 2005 compared the seven most common staging systems in a cohort from the USA. The authors indicated that the Barcelona Clinic Liver Cancer (BCLC) classification was the best system at stratifying survival for patients at the various staging systems. Studies in other populations have also validated the BCLC classification for prognosis of patients with HCC. Based on these data, the new AASLD guidelines have endorsed the BCLC classification for prognosis and treatment of HCC.
Treatment
The BCLC classification shows that for patients with early-stage tumors, resection, liver transplantation, and radiofrequency ablation (RFA) are curative treatments that potentially lead to 5-year survival rates of about 50%. Recently, various groups have argued that the current criteria for transplantation (single tumor nodule less than 5 cm, or three nodules or fewer, each less than 3 cm in diameter) are too restrictive and some patients with advanced HCC may benefit from liver transplantation or resection. A multicenter study of 1073 resections for HCC investigated the relationship between tumor size and microscopic (occult) vascular invasion. Tumor size and the number of nodules were important factors that predicted vascular invasion. Vascular invasion was present in 55% of patients with tumors of between 5.1 and 6.5 cm compared to 31% for those 5 cm or smaller. The authors concluded that the high prevalence of occult vascular invasion in HCC tumors larger than 5 cm are predictors of poor prognosis and that therefore the criteria for liver transplantation or resection should not be expanded beyond what the BCLC classification indicates. Live-donor liver transplantation has been shown to be an effective strategy for the treatment of patients with liver failure and patients with HCC. A study from four institutions in Korea compared the results of live-donor (n = 237) with cadaveric-donor (n = 75) liver transplantation from 1992 to 2002. There were no differences in tumor characteristics, and the overall 3-year survival rate was 61% for cadaveric donation and 73% for live donation. Thus, live donation is as effective as cadaveric donation for the treatment of HCC when the same criteria are applied. There are no data showing that expanding the established criteria for transplanting HCC by performing live-donor liver transplantation leads to the same outcomes.
There were several papers during the past year that evaluated the efficacy of ablative techniques for the treatment of HCC. There are two main methods for performing tumor ablation: RFA or percutaneous ethanol injection (PEI). An intention-to-treat study of 206 patients who underwent RFA as primary treatment of HCC, who also were excluded as candidates for transplantation or resection, was reported. The study included patients who were Child class A or B, met the criteria for transplantation, and were followed for a mean of 24 months. The overall 1-, 3-, and 5-year probabilities of survival were 97, 67, and 41%, respectively. The authors indicated that RFA was an effective first-line therapy for patients with early-stage HCC but who are not candidates for surgical therapies. Another study from Italy and the USA showed that RFA was also effective as a bridge to liver transplantation. An important study this year evaluated whether percutaneous therapies were associated with an improved overall survival for patients with HCC. A total of 282 patients with early non-surgical HCC were treated with percutaneous ablative techniques, the majority being PEI. The 1-, 3-, and 5-year survival rates were 87, 51, and 27%, respectively. Those who achieve an initial complete response to the ablation achieved a 5-year survival of 42% irrespective of tumor size and hepatic function.
All the studies showed that RFA was more efficacious in leading to complete necrosis and, more importantly, it lead to better overall survival when compared to PEI. One study compared RFA and PEI with acetic acid injection for ablation, and RFA still had a better overall survival rate. Thus, RFA seems to be the better method of ablation in patients with HCC.
Conclusion
The incidence of HCC continues to rise. Even though patients with cirrhosis are at risk from developing HCC, it is now understood that tobacco, alcohol, diabetes, and obesity interact together in the causation of HCC. Surveillance for HCC leads to an improved overall survival. Triple-phase examination is the best method for the diagnostic evaluation of a hepatic mass, and washout of a hypervascular mass in the delayed phases of contrast appears to be sensitive and specific for HCC. The BCLC classification for HCC offers the best prognostic stratification and the best treatment strategy for patients. RFA seems to lead to an improved survival for patients with early-stage HCC. More studies are needed to determine optimal treatment strategies in patients with advanced HCC.
posted by my-healthcare at 12:56 AM
0 Comments:
Post a Comment
<< Home