Screening for Hepatocellular Carcinoma in Patients with Cirrhosis

Jason D. Huff, HOIII

Case Presentation:Ms. X is a 37-year-old white female who presented to my continuity clinic for a new patient visit.

She came to establish care as she had just moved back to North Carolina from California. Her past medical history is significant for a diagnosis of Hepatitis C in 1997, tobacco and alcohol abuse, and hysterectomy with bilateral oopherectomy for uterine fibroids and endometriosis. While in California, she was being evaluated by a Gastroenterologist for possible treatment of her Hepatitis C and had been scheduled for a liver biopsy prior to her moving to North Carolina. She moved back to North Carolina to be closer to her family because recently her health had been declining. She was unaware of how she contracted hepatitis but thought that it could be from a blood transfusion she got during her hysterectomy. She adamantly denied any IV drug abuse.

She reported having a history of ascites diagnosed by paracentesis, and had recently been prescribed a medicine for “confusion” that possibly had something to do with her liver. Just prior to our visit, she had been discharged from an area hospital for an upper gastrointestinal bleed. Upper endoscopy confirmed grade I esophageal varices. She underwent sclerotherapy for the bleeding and was placed on a medicine to help prevent any further bleeding.

Her current medication list included Lactulose™, propranolol, spironolactone and hormone-replacement therapy. She has no allergies. She reported being abstinent from alcohol for one month prior to our visit, but did report a 1-pack-per-day smoking history. She denied any family history of liver disease, cancer or heart disease. Her examination was significant for palmar erythema, spider angiomata across her upper chest and back, and positive shifting dullness with mild distension notable on abdominal exam. Her liver edge was smooth and non-tender with no noted enlargement. She had no evidence of splenomegaly on exam.

Clinical Questions:The case presentation above clearly describes a patient with many of the features and

complications of cirrhosis. Patients with cirrhosis are at high risk to develop HCC and the incidence in well compensated cirrhosis has been documented at approximately 3% per year.1 With this information I sought to review the current literature on the benefit of screening cirrhotic patients for hepatocellular carcinoma. The questions that I attempted to answer during my search of the literature are as follows:

1. What population of patients deserves screening for HCC?2. Has there been any benefit shown to screening these patients in terms of mortality or disease-free

survival?3. If screening has been shown to improve mortality or disease-free survival, then what are the

appropriate screening tests?

Hepatocellular Carcinoma: Epidemiology Hepatocellular carcinoma (HCC) is the fifth most common malignancy in men, and the eighth

most common in women worldwide.2 It accounts for as many as 1 million deaths annually worldwide. The incidence of HCC, however, varies widely internationally and is more prevalent in areas with a high seroprevalence of chronic hepatitis B virus (HBV) infection. Of the roughly 530,000 new cases of HCC each year worldwide, more than 85% occur in areas such as Taiwan and Southeastern Asia where the incidence of HCC may exceed 30/100,000 compared to 2 to 7/100,000 in Europe and the United States. Recent publications, though, have described an increase of about 80% in the incidence of HCC in the United States over the past 20-30 years and it is estimated that approximately 15,000 new cases occur each year.3

The main risk factors for developing HCC are the hepatitis B and the hepatitis C viruses, which together account for three quarters of all cases worldwide.Error: Reference source not found Other conditions associated with the development of HCC are alcoholic liver disease, aflatoxin exposure, hemochromatosis, tyrosinemia, and alpha-1-antitrypsin deficiency. As was previously alluded to, the attributable risk fraction for each risk factor varies according to the country examined. Whereas HCV has the greatest attributable risk in developed countries such as the United States, Europe and Japan, it is

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responsible for a limited number of cases in most areas of Asia and Africa, where HBV is mainly responsible. Aflatoxin B1 probably does not play a role in developed countries, whereas it is definitely responsible, with a risk, however, not quantifiable, for numerous cases in Africa and Asia.Error: Reference source not found

Hepatitis BWorldwide, HBV is the HCC-determining disease. There is an estimated 350 million people

worldwide who have detectable hepatitis B surface antigen in their peripheral blood. This indicates at least a low level of chronic HBV infection present in these individuals. Most of these infections, occurring in endemic areas such as Asia or Northern Africa, occur early in life, either perinatally or in infancy, and are much less likely to be cleared, unlike HBV exposure in North America, which occurs later in life and is cleared in 90% of cases. The percentage of cases of HCC attributable to HBV worldwide is 52.3% and is higher in these endemic areas where the rates of HBV are higher. One study of a population of Taiwanese patients reported that the relative risk of developing HCC was 102, because among carriers of HBV, 473 cases/100,000 per year developed HCC compared to only 4.6 cases/100,000 per year among noncarriers.Error: Reference source not found Further evidence to support HBV’s role in HCC development comes from a vaccination campaign in Taiwan in the 1980s. After vaccination for HBV, there was an important reduction noted in the incidence of HCC that is still ongoing.

Hepatitis CIn Japan, as well as Europe and North America, the HCC-defining disease is unanimously

hepatitis C virus (HCV) infection. Epidemiologic studies have shown that many patients with HCC (as high as 70%) have anti-HCV antibody in the serum.4 The presence of chronic HCV alone seems to raise a patient’s risk for HCC by about 24-fold. The percentage of cases of HCC worldwide attributable to HCV is around 25% and is more prevalent in Japan, Spain and Italy where the rates of HCV positivity are high. In developed countries, HCV may account for more than 50% of HCCs. HCV therefore represents the most important risk factor for HCC in western countries. The role of HCV genotype and risk of the development of HCC is still up for debate.

CirrhosisHCC is to a large extent a complication of chronic liver disease and cirrhosis. In several large

case series, more than 80% of patients developing HCC are cirrhotic.Error: Reference source not found The constant proliferation of hepatocytes likely represents the key factor of progression to HCC, independent of the etiology. The annual risk of developing HCC in HCV-infected patients seems highly dependent on the presence and severity of the underlying liver disease. Whereas the risk of HCC is rare in carriers of HCV infection, it reaches 1.2-1.7% in patients with underlying chronic hepatitis and can reach 1.4-2.5% in subjects with liver cirrhosis.Error: Reference source not found A few cases of HCC have been reported in HCV infected patients without evidence of cirrhosis, raising the possibility of a mutagenic effect of the virus on liver hepatocytes. In HBV, carriers of the HbsAg rarely develop HCC, but the incidence with increasing severity of liver disease reaches 0.5-0.8% per year in patients with underlying chronic hepatitis and 1.5-6.6% in patients with liver cirrhosis.Error: Reference source not found

Hepatocellular Carcinoma: Diagnosis HCC is most commonly diagnosed incidentally during the asymptomatic phase during evaluation

for a liver transplant or as part of routine screening in those patients with cirrhosis. The classic clinical features of HCC include right upper quadrant pain and weight loss.5 Other clinical scenarios that suggest this diagnosis include worsening liver function in a patient known to have cirrhosis, acute abdominal catastrophe from rupture of a liver tumor with intra-abdominal bleeding, and some rare extrahepatic manifestations such as erythrocytosis, hypoglycemia, watery diarrhea and hypercalcemia.

Serum ά-fetoproteinSerum ά-fetoprotein (AFP) is elevated above 20 ng/ml in more than 70% of patients with

HCC.Error: Reference source not found Nevertheless, AFP elevations from 10-500 ng/ml and even occasionally to 1000 ng/ml may be seen in patients with a high degree of necroinflammatory activity, such as with chronic viral hepatitis, who do not have HCC. In contrast, it has been shown that highly differentiated tumors, or tumors that are severely anaplastic may secrete no AFP at all. In a study performed in France looking at screening patients with cirrhosis for HCC, the sensitivity and specificity for AFP > 15 ng/ml was 50 and 86, respectively.6 When the level of AFP was increased to > 100 ng/ml, the specificity improved to 93 with a sharp decline in the sensitivity to 21. The positive predictive value of

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AFP increases significantly when the AFP > 400 ng/ml but at the expense of poor sensitivity. This makes AFP a better diagnostic tool than screening tool, although it is routinely used, along with ultrasound, to screen those at high risk for HCC. AFP has been found to be useful in monitoring response to treatment and detecting recurrence after treatment if the AFP was elevated prior to treatment.

ImagingImaging studies of the liver play a key role in the diagnosis of HCC. Radiologic modalities such

as ultrasound, CT and MRI have allowed physicians to detect HCC at earlier stages when the malignancy is potentially curable. Ultrasound has been used as a primary screening tool in the past and has been reported to have a relatively high sensitivity and specificity. Studies performed to evaluate the performance characteristics of US as a screening tool have determined its sensitivity to range from 71-78% and its specificity to reach 93%. It is especially good at allowing the clinician to assess potential vascular invasion of the tumor by using real-time color Doppler mode. CT and MRI scanning are primarily being used to verify ultrasound findings and to confirm the diagnosis in patients with an isolated abnormal serum AFP level. The overall sensitivity and specificity of contrast enhanced CT are 68% and 81%, respectively, but the sensitivity decreases for lesions less than 3 cm.7 Smaller tumors are more efficiently detected by MRI, which has 81% sensitivity for tumors less than 2 cm. Spiral CT scanning is even more sensitive, with 87% of tumors less than 1 cm being detected compared to 64% by MRI. Hepatic angiography is an older method of diagnosing liver masses and relies on the neovascularization and hypervascularity of malignant tumors. It’s sensitivity for small tumors has been shown to be poor, so it is mainly reserved for patients undergoing chemoembolization for non-resectable tumors.

HistologyHistologic examination of liver tissue to diagnosis HCC is an important yet controversial subject.

The routine use of percutaneous needle biopsy of suspected tumors in patients with potentially resectable tumors or those potentially cured with transplantation is currently under debate. One possible risk of percutaneous needle biopsy is local spread of HCC along the needle track. Recent evidence suggests that local spread of HCC occurs in as many as 1% of cases after needle biopsy. Certain experts advocate that if a mass is found in the liver, perhaps associated with a markedly elevated serum AFP, the diagnosis is obvious and the biopsy is not needed. If therapies are planned that involve significant risk and are potentially toxic, such as chemoembolization or systemic chemotherapy, consideration should be given to histologic diagnosis prior to initiating treatment.

Hepatocellular Carcinoma: TreatmentThe natural history of HCC is variable and depends on the number and size of neoplastic nodules

at diagnosis and the severity of the underlying chronic liver disease. With advancements in diagnostic modalities, HCC is often found as a single nodule, or nodules of small size that can be potentially treated radically with resection, transplantation or chemoembolization.

TransplantTransplantation would hypothetically be the best treatment for HCC because it results in the

widest possible resection margins for the cancer, removes the remaining liver tissue that is at risk for the development of further cancer, and restores hepatic function. A few case reports have been published showing 5-year survival rates nearing 75%.Error: Reference source not found When compared to patients undergoing orthotopic liver transplant (OLT) without HCC, the survival numbers are nearly identical. Unfortunately, these studies were performed at a time when the average waiting time for a donor liver was less than 6 months. With the average waiting times currently exceeding 1 year, contraindications to transplant or death often develop, usually secondary to progression of disease. With the small number of donor livers available, OLT is not a viable option to most patients with HCC. With the doubling time of a nodule of small dimensions being estimated within a period of 1-19 months, it is easy to see how someone could develop widespread inoperable disease in a matter of months while waiting for a donor liver.

Hepatic ResectionLiver resection treats HCC much in the same way that OLT does, in that it removes the portion of

the liver with cancer. It is unfavorable when compared to OLT in that it does not eliminate the remaining portions of the liver at risk for malignant transformation and neither does it improve hepatic function. Recurrence rates in patients with easily resectable small tumors have been published at exceeding 50%.Error: Reference source not found In addition, the risk for decompensation after surgical resection

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with Child-Pugh class A cirrhosis is up to 50%. It is plausible to treat this group of patients with salvage transplantation, but for the reasons stated previously, this is usually not accomplished.

AblationAblation of the malignant HCC tumors by either chemical means (e.g., absolute alcohol or

trichloroacetic acid) or physical means (e.g., cryoablation, radiofrequency ablation, microwave coagulation or injection of hot saline) have been performed for quite some time, especially in patients whom resection is not possible. Alcohol ablation has historically been the most popular of these treatment modalities and has shown benefit in small trials when compared to resection. One study published 1 and 4 year survival rates of 81% and 44% for surgical resection compared with 83% and 34% for ethanol injection.Error: Reference source not found A point should be made that the study group was small, including 63 patients equally distributed between the two treatment arms.

Radiofrequency ablation has recently become an established method of treatment for HCC. Comparisons between RFA and ethanol injection have shown similar rates in establishing complete tumor necrosis. It is an improvement over ethanol injection in that the number of sessions required to complete tumor ablation is less in RFA. Often times, tumors can be ablated in one sitting with RFA where the patient would have to return for multiple sittings with ethanol injection, increasing the risk of complications.

Chemoembolization and ChemotherapyChemoembolization and chemotherapy are the two remaining treatment options for HCC.

Chemoembolization relies on the fact that HCC derives its blood supply primarily from the hepatic artery, while the surrounding liver receives both portal and arterial blood. The segmental hepatic artery supplying the tumor must be catheterized and an arteriogram must be performed to confirm proper placement. Chemotherapeutic agents are then injected intra-arterially and the hepatic artery is then occluded by injection of material to obstruct flow such as Gelfoam® and Ivalon®. The potential side effects of chemoembolization are not trivial and include hepatic failure, severe pain, and formation of liver abscess.

Chemotherapy is in general considered for use in patients with HCC not amenable to potentially curative therapy and therefore its role is largely palliative. The chemotherapeutic agents shown to have antitumor effects against HCC are listed in the following table.Error: Reference source not found Chemotherapy can be given regionally, much like chemoembolization, or systemically. Systemic administration of chemotherapy is generally associated with low response rates and is often limited by the presence of liver dysfunction and cirrhosis which regularly occurs with HCC. Oral tamoxifen has not been shown to improve mortality in randomized controlled trials and is not recommended.

When symptomatic HCC is diagnosed in a patient with cirrhosis, treatment is usually limited and the prognosis is poor, even when surgery can be considered.Error: Reference source not found Recent publications have suggested that the five-year survival rate for HCC is less than 5 percent.Error: Reference source not found A table outlining median survival among patients with HCC is listed below.Error: Reference source not found The CLIP, Okuda and TNM are all staging systems used to describe the extent of disease with the lower numbers correlating with less advanced disease.

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Some data, though, has suggested that smaller, asymptomatic tumors, when discovered early, have a better prognosis. This would suggest that screening high-risk individuals would be useful in detecting HCC at an early, more treatable stage. More than a decade ago, studies performed in Asia, where HCC is a major cause of death, seemed to show a benefit in screening for HCC. At that time, the annual incidence of HCC was more than 5%, the percentage of small tumors discovered was over 50% and the percentage of operated patients surviving 5 years was over 50% in selected studies.Error: Reference source not found These findings prompted the suggestion that screening should also be performed on at risk patients in the western world. There appear to be characteristic differences between the patients at high risk in North America, Europe and Japan when compared to patients in Asia and Africa. Cirrhotic patients in more developed countries have a greater prevalence of alcoholism, are older and have a smaller number of uninodular encapsulated tumors. With this in mind, the evaluation of screening these high-risk patients looking for improvement in survival was undertaken in the 1990’s and into the twenty-first century.

Identification and Screening of 416 Patients with Chronic Hepatitis at High Risk to Develop Hepatocellular Cancer. Annals of Surgery 1995:The Surgeon’s Perspective

Curley et al. published a study in the Annals of Surgery in 1995 looking prospectively at a group of viral hepatitis patients and their risk for HCC development. From their perspective, the majority of patients diagnosed with HCC were not candidates for potentially curative liver resection at the time of diagnosis because of three factors: (1) large or multicentric liver tumors, (2) the presence of metastatic disease, and (3) insufficient functional hepatic reserve related to chronic hepatocellular injury or cirrhosis.8 For treatment programs to produce long-term survival, therapy would include resection or tumor ablative therapy for small or localized hepatic tumors. Therefore, screening programs aimed at high-risk individuals should be important in the attempt to diagnose liver cancer at an earlier and more treatable stage of disease. For this reason, they prospectively screened a cohort of patients with chronic HBV or HCV infections to determine the incidence of asymptomatic HCC and to identify the subgroups at highest risk to develop HCC.

Materials and MethodsThe study was conducted from July 1, 1993, until December 31, 1994. They looked at patients

from Naples, Italy, and adjoining regions who were seropositive for HBV or HCV infections of at least 5 years duration who were registered and followed at the Cotugno Hospital in Naples. These patients were offered a screening program to detect HCC at the G. Pascale National Cancer Institute in Naples. Chronic HBV was defined as persistently positive sera for hepatitis B surface antigen (HbsAG). Chronic HCV infection was defined as persistently positive sera for HCV on first- and second-generation anti-HCV enzyme-linked immunoassay. Patients excluded from the study were those with Childs’ class B or C cirrhosis, history of hepatic encephlopathy, bleeding gastroesophageal varices, ascites, or a prior diagnosis of any type of malignancy.

A total of 416 patients entered the screening program, 245 men and 171 women. They reported that no patients had any clinical symptoms related to liver dysfunction or hepatocellular cancer. The breakdown of chronic viral hepatitis type was 69 with chronic HBV, 340 with chronic HCV, and 7 with both. The duration of illness was from 5 to 14 years.

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All patients underwent liver biopsy to determine the severity of chronic liver injury. Diagnoses from the liver biopsy were chronic persistent hepatitis, chronic active hepatitis-mild, chronic active hepatitis-severe, or chronic active hepatitis with cirrhosis (all Childs’ class A). Patients then underwent outpatient physical examination, abdominal ultrasound, and serum alpha-fetoprotein (AFP) determination at entry and at 3-month intervals thereafter. When a mass lesion was detected by ultrasound and/or when the serum AFP level exceeded 10ng/ml, further diagnostic evaluation was performed with contrast enhanced computed tomography scans and MRI of the abdomen. The confirmed liver tumor was then biopsied under US or CT guidance and histologic diagnosis was made.

ResultsThe results from the screening

liver biopsy are outlined in the graphic labeled “Table 1”. There was no significant difference between the chronic HBV and HCV viral patients with regard to the severity of chronic liver injury. As Table 1 illustrates, a total of 140 patients had biopsies demonstrating severe liver injury (chronic active hepatitis-severe and chronic active hepatitis with cirrhosis).

Initial screening of the 416 patients revealed asymptomatic hepatocellular carcinoma in 33 or an initial detection rate of 7.9%. The diagnosis was suggested by abnormal US in 5 patients (15.1%), elevated serum AFP in 6 patients (18.2%), or mass lesion on US and elevated AFP in 22 patients (66.7%). Most importantly, three additional cases of HCC were diagnosed in patients with a normal serum AFP level and liver US results at their first screening. These patients had a progressive increase in serum AFP levels at 3-month intervals until 9 to 12 months after entry into the study. All three had a liver tumor of less than 3 cm in diameter, as demonstrated by US. Therefore, 36 patients or 8.6% of the initial 416 screened patients were diagnosed with HCC in the first year of the screening program.

When looking at the cases of HCC compared to the initial liver biopsy histology subtype, a very interesting trend was revealed. Of the 36 cases of HCC, 35 occurred in the 140 patients with chronic active hepatitis-severe or chronic active hepatitis with cirrhosis, compared to one in the other two groups (the author did not specify which group this case fell into). HCC developed in 4 of the 69 patients with chronic HBV, 30 of the 340 with chronic HCV and 2 of the 7 with both HBV and HCV.

Of the 36 cases of HCC, treatment with curative intent was possible in 22: liver resection in 11 patients, and percutaneous ethanol injection (PEI) in the remaining 11 patients. All of the tumors treated with curative intent were solitary and less than 5 cm in diameter. Patients treated with surgery had peripheral lesions that could be resected with at least a 1 cm margin of unaffected liver parenchyma with a wedge or segmental resection. Tumors treated with PEI were centrally located and were thought to be unresectable because of inadequate margins with tumor proximity to major vascular structures or resectable only with a major lobar resection.Error: Reference source not found Of the 14 patients not eligible for possible curative intervention, 10 patients had large (>8 cm in diameter) or multicentric tumors and 4 patients had evidence of distant metastatic disease.

ConclusionsThe authors in this study concluded that patients with severe chronic active hepatitis, cirrhosis or

both are at extremely high risk to develop HCC with their calculated incidence of 25% (35 of the hepatocellular cancers took place in the 140 patients diagnosed with severe liver injury). They also found that a significant number (61.1%) were small, potentially treatable cancers. They recommended screening high risk individuals every 3 months.

Strengths The study group was well defined. All patients were accounted for and documented in the study. The screening program was uniform across the study group. The screening test was evaluated in an appropriate spectrum of patients.

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Weaknesses No long-term follow up, i.e., no determination of effectiveness of screening with regards to

improvement in morbidity/mortality. There was no control group to compare results. The study was not randomized. The study findings are entirely subject to lead time bias.

Outcome of 67 Patients With Hepatocellular Cancer Detected During Screening of 1125 Patients with Chronic Hepatitis. Annals of Surgery 1998: The Surgeon’s Follow up

Izzo et al.9 published a follow up to the study that Curley first authored in the Annals of Surgery in 1998 again looking at the incidence of HCC in patients with chronic viral hepatitis. This time, they included data regarding the resectability and long-term survival rates of these HCC patients. The study again took place in the Campania region of Italy where the incidence of HCC is relatively high, presumably do to high rates of chronic viral hepatitis, especially HCV. They performed this prospective screening trial to determine if routine screening of chronic viral hepatitis patients improves the survival of patients who develop HCC.

MethodsThe study was conducted from July 1, 1993 through June 30, 1996. The inclusion criteria were

the same as the previous study, and again, patients with Child class B or C cirrhosis, a history of hepatic encephalopathy, bleeding gastroesophageal varices, ascites, or a prior diagnosis of any type of malignancy were excluded from the study. All patients involved underwent outpatient physical examination, abdominal US, serum liver function tests (direct and indirect bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transpeptidase, albumin, prothrombin time), and serum alpha-fetoprotein measurements at entry and at 3-month intervals thereafter. Follow up on mass lesions and elevations of serum AFP were performed as in the previous study and all confirmed liver tumors were biopsied under US or CT guidance. Just as before, all patients at entry underwent a percutaneous core liver biopsy to determine the histologic severity of chronic liver injury. They were again placed into the previously described histologic subtypes based on the severity of liver injury.

Patients diagnosed with HCC underwent further clinical evaluation with a chest radiograph and serum laboratory tests (complete blood count, platelet count, blood urea nitrogen, creatinine, glucose and electrolytes). Chest CT scan was performed if there was a question of lung metastases. Patients diagnosed on clinical and radiographic examination with only a solitary liver lesion judged to be resectable (a resection leaving adequate functional hepatic parenchyma) underwent exploratory laparotomy and intraoperative ultrasound. A margin-negative liver resection was performed if there was no evidence of either extrahepatic metastasis or multifocal tumor on intraoperative ultrasound. Patients with only solitary liver lesions judged to be unresectable because of tumor size or intrahepatic location were treated on protocol with percutaneous ethanol injection (PEI). Patients with multifocal liver disease or metastatic disease were treated on protocol with systemic chemotherapy. All HCC patients were followed after resection, PEI or initiation of systemic chemotherapy every 3 months with serum AFP levels, serum liver function tests, abdominal CT scanning and chest radiography.Error: Reference source not found

ResultsThe screening program registered 1125 patients with 672 men and 453 women. No patient had

any clinical symptoms related to liver dysfunction or HCC. Chronic HCV was diagnosed in 804 patients and chronic HBV in 290. A total of 31 patients were co-infected with both HBV and HCV. Registered patients had a duration of chronic viral hepatitis infection of 5 to 17 years with the median being 10.2 years.

At the time of initial screening, asymptomatic HCC was detected in 61 patients, yielding an initial detection rate of 5.4%.Error: Reference source not found An additional six cases were diagnosed during follow up evaluations in patients who on initial evaluation had a normal serum AFP level and no liver tumor by US. All six of these patients developed increasing serum AFP levels 9 to 18 months after entry into the study. In four of the patients, transabdominal US showed a solitary liver tumor < 3 cm in size. In the remaining 2 patients, US did not reveal a mass, but high-resolution CT scanning of the abdomen detected a solitary tumor <3 cm in size.

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Ultrasound was able to demonstrate a liver mass in 58 of the patients (86.6%) while the serum AFP level was elevated in 50 (74.6%). Of the 67 patients diagnosed with HCC, 58 (86.6%) had chronic HCV, 5 (7.5%) had HBV and 4 (5.9%) were co-infected with the two viruses. The percutaneous core liver biopsies were again very revealing in this group. The data is listed below in Table 1. The abbreviations are as follows: CPH, chronic persistent hepatitis, CAH-M, chronic active hepatitis-mild, CAH-S, chronic active hepatitis-severe.

Table 1 Distribution of Patients with HCC by Histologic Subtype

Histologic Subtype Number of Subjects Number with HCC Incidence of HCC

CPH/CAH-M 800 1 0.1%

CAH-S/Cirrhosis 325 66 20.3%

Evaluation of the extent of disease in the 67 patients diagnosed with HCC yielded 28 (42%) patients with disease that appeared resectable. These patients underwent exploratory laparotomy, at which time 4 were found to have extrahepatic nodal metastases and the liver resection was not performed. The 24 that eventually underwent resection with curative intent were resected with at least 1 cm margin of tumor negative hepatic parenchyma. There were no operative or post-operative deaths in these patients. Included in these 24 patients undergoing potentially curative surgery were the 6 people with normal US and serum AFP on initial screen who were later diagnosed with HCC in follow up.

The number of patients with solitary liver lesions deemed unresectable was 14 (21%). These patients were unresectable based on tumor location within the liver that would require a major lobar resection in patients with inadequate functional hepatic reserve or adjacency to a major intrahepatic vascular structure precluding a margin-negative resection. These patients were treated with percutaneous ethanol injection. All tumors were < 5 cm in diameter. The 29 remaining patients (43%) with multifocal or metastatic HCC were treated with one or two active phase II institutional protocols.

With a median follow up of 24 months for the 67 patients with HCC, all 29 patients with multifocal or metastatic HCC had died from their disease. The median survival of the 43 patients with unresectable HCC was 6 months, compared to 26 months for the 24 patients who underwent hepatic resection (p < 0.0001).Error: Reference source not found Of the 14 patients treated with PEI, 9 died of their disease, 2 were alive with disease, and 3 were alive without evidence of recurrent HCC more than 2 years after treatment. Of the 24 patients who underwent resection, 8 (33%) died of recurrent HCC, 1 was alive with hepatic recurrence of HCC, and 15 (62%) were alive without evidence of recurrent HCC. Actuarial survival curves were performed on the 67 patients and the results are presented below.Error: Reference source not found

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Conclusions Patients with histologically severe liver injury from chronic hepatitis virus infection should be

screened every 6 months with transabdominal ultrasonography and serum AFP determination. Chronic hepatitis patients with minimal liver injury are less likely to benefit from long-term screening programs and with a low risk of developing HCC should be followed clinically. Patients with a greater than 20% overall incidence of HCC should be screened.

Strengths The patient population was well defined. The screening test was evaluated in an appropriate spectrum of patients. Patients were followed up for an extended period of time, allowing for survival data to be

calculated. The study had a much larger patient population.

Weaknesses The data is subject to lead time bias. There was no randomization or control group to compare findings. There was no definition of “inadequate functional hepatic reserve” in the unresectable patients.

Prospective study of screening for hepatocellular carcinoma in Caucasian patients with cirrhosis. Journal of Hepatology 1994

Patients and MethodsFrom January 1986 to December 1987, a group of investigators in France prospectively evaluated

the usefulness of screening for HCC in a population of Caucasian patients with cirrhosis of mainly alcoholic origin. All patients with histologically proven cirrhosis, hospitalized in the Hepatogastroenterology Unit of Jean Verdier Hospital were considered for inclusion in the study. At the end of hospitalization, all patients with Child-Pugh’s class A or B cirrhosis without detectable HCC (no focal lesions at US, serum AFP < 15 ng/ml, and plasma des-gamma-carboxyprothrombin [DCP] < 15 mU/mm) were prospectively included if voluntary consent was given and follow up appeared feasible.Error: Reference source not found Included patients were followed up until death or January 1990 (end-point of the study).

The screening protocol consisted of clinical examination, determination of serum AFP and plasma DCP levels and abdominal ultrasonography every 6 months. When an anomaly in test results was detected, additional explorations were performed, in particular infused CT scan. When US showed a focal mass, guided biopsy was performed when possible.

ResultsDuring the inclusion period, 322 patients with cirrhosis were hospitalized in the aforementioned

unit. By the end of the initial hospitalization, a total of 185 survived, were Child-Pugh class A or B and had no detectable HCC. Among the 185 total patients included in the study, 118 were deemed suitable for follow up and were prospectively included in the screening protocol. The characteristics of the patients are as shown in Table 2. The duration of follow up was 35.815 months.

Table 2 Patient Characteristics in 8-year Prospective Screening Trial for HCC

Patient Characteristic # of Patients

SexMaleFemale

6850

Child-Pugh ClassAB

7543

Etiology of CirrhosisAlcohol (>80g/d for >10y)Viral B

865

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Viral non-A, non-BFamilial HemochromatosisPrimary Biliary Cirrhosis

2052

Fourteen HCC were detected during the study, with the annual incidence in years one, two, three and four being 5.4%, 4.4%, 6.6% and 7%, respectively. The clinical features of the 14 patients are listed in Table 3. Patients 3 and 7 had associated liver failure during their follow up, likely contributing more to their overall mortality. The time and cause of death in the total 118 cirrhotic patients submitted to follow up are outlined in Table 4.

Table 3 Characteristics and Outcomes of the 14 patients diagnosed with HCC

Patient Age at Diagnosis

Sex Etiology of Cirrhosis

Test Suggestive

of HCC

Period of follow up

before detection of HCC

Number of

Nodules

Tumor Size (mm)

Treatment Outcome (Months)

1 62 M Alcoholic AFP 38 Diffuse - Chemoembol Died (6)2 63 M Alcoholic US 16 1 35 - Died

(14)3 58 M NonANonB US+AFP 6 1 40 - Died (6)4 69 F NonANonB AFP 41 1 25 Alcoholization Alive

(20)5 61 F Alcoholic US+AFP 5 1 40 - Died (7)6 58 F NonANonB AFP 35 Multiple - - Died

(12)7 61 M NonANonB AFP 6 1 20 - Died (7)8 58 M Alcoholic US+AFP 6 1 20 - Died (4)9 63 F Alcoholic US 15 1 25 Resection +

ChemoembolAlive (31)

10 59 M Alcoholic US 31 1 19 - Died (7)11 66 M Familial

Hemochro.US 38 1 18 Chemoembol Died

(12)12 66 M Alcoholic US 27 Multiple - - Died (3)13 64 M Alcoholic US+DCP 22 2 30;46 Chemoembol Died (8)14 57 F NonANonB US 29 Diffuse - - Died (6)

Table 4 Time and Cause of Death in the 118 Cirrhotic Patients Submitted to Follow Up

Year of follow up 1 2 3 4 Total

No. of patients 118 111 97 55

No. of deaths 2 8 6 5 21

Causes of deathHCCGI hemorrhageHepatic FailureCauses unrelated to the liver

1100

2213

3111

2120

8544

Among the five patients with a single tumor without metastases or other complicating factors, surgery was not performed in four, because of poor clinical status in one, respiratory insufficiency in one and liver failure in two. In the patient who underwent surgery, the tumor recurred 15 months later. No treatment was possible in eight patients for reasons not explained in the study.

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ConclusionsIn this study, regular screening with US, AFP and DCP did not lead to detection of HCC at an

early stage and probably did not modify the prognosis of the disease. Only 3 of the 14 patients diagnosed with HCC had tumors that were less than 3 cm in diameter and isolated without vascular involvement or metastases. As Table 3 illustrates, of the 21 patients who died during follow up, 38% (8 of 21) died of HCC. The notable finding is the high mortality of patients with cirrhosis without HCC. The Kaplan-Meier plot of the survival rate of the 118 patients in this study illustrates the point well. Patients with cirrhosis have a high mortality without a diagnosis of HCC. Clearly in this group of patients, no benefit was seen with regular screening for HCC.

Strengths The long duration of follow up allowed mortality data to be calculated. All patients included in the study were accounted for and exclusion criteria were well defined. The screening test was evaluated in an appropriate spectrum of patients. All patients were followed to end-point.

Weaknesses The study included a small number of patients. There was no randomization to a control group. Inclusion criteria could have been better defined.

Efficacy of a Surveillance Program for Early Detection of Hepatocellular Carcinoma. Cancer 1996

Zoli et al.10 set out to evaluate the efficacy of regular ultrasonographic and laboratory follow up for the early detection of small HCC, and to identify parameters correlated with a higher risk of developing HCC.

Patients and MethodsAll patients with biopsy-proven liver cirrhosis attending the Institute of Clinica Medica Generale e

Terapia Medica of the University of Bologna between January 1989 and December 1991 underwent ultrasound examination of the upper abdomen. Patients who met the following criteria were enrolled in the study: 1) satisfactory or good US visualization of liver parenchyma; 2) no space-occupying liver lesions at US; 3) willing to cooperate by visiting the Institute at scheduled intervals; and 4) living in Emilia Romagna, Italy.

One hundred and sixty four cirrhotic patients (75 males and 89 females) were included in the study. The etiology of their liver disease is outlined in the following table.Error: Reference source not found Those rejected included 42 patients living outside the area defined above, 8 patients with poor US visualization of hepatic parenchyma, and 12 patients with HCC at first US examination.

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At entry, all patients underwent a complete clinical exam and evaluation of specific clinical and biochemical parameters were recorded for statistical purposes. The parameters are as outlined in the following table.Error: Reference source not found

Patients were examined at 6 month intervals by means of physical examination, biochemical assessment and US. The 6-month interval was reduced to a 3-month interval if AFP was greater than 5 times the upper normal limit and if the liver echo-pattern was classified as nonhomogeneous. These patients were observed until the appearance of HCC, death, or until April 1995.

Throughout the study period, patients received treatments to avoid or to treat complications of their liver disease, such as lactulose and/or diuretics.Error: Reference source not found Thirty-four patients received β-blockers or underwent endoscopic sclerotherapy as primary or secondary prophylaxis of GI bleeding.

Patients diagnosed with HCC were treated with hepatic resection, whenever it was considered possible by the surgical team, transcatheter arterial chemoembolization (TACE), or percutaneous ethanol injection (PEI). These patients were observed until death or November 1995.

ResultsThe results of the clinical, biochemical and ultrasound parameters are as outlined in the previous

table, labeled “Table 2”. During the follow up period which ranged from 7 to 77 months, HCC was identified in 34 patients. Among the 34 who developed HCC, 8 patients developed it within 1 year, 11 within 2 years, and 5 within 3 years. The overall incidence of HCC was 4.9% during the first year, 7.7% during the second year, 4.8% during the third year, and 7.4% during the fourth year. The author reported that these values were weighted for the decrease in the number of patients during follow up at the times of evaluation. A total of twenty-eight patients were lost during follow up. All of these patients were accounted for in the study. The clinical features of the patients diagnosed with HCC are outlined in the following table.

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Among the clinical and the biochemical parameters at entry, after univariate analysis, only three variables were significantly associated with the probability of developing HCC. The probability was significantly higher in males, with albumin < 3.5 g/dl and AFP > 20 ng/ml. The etiology of liver disease was not statistically significant, however analyzed (i.e., viral [B+C] vs. not viral, P=0.398; HCV-related vs. all other cases, P=0.2104).Error: Reference source not found After multivariate analysis by means of Cox’s model, male sex together with reduced levels of albumin and increased levels of alkaline phosphatase and AFP were significant independent predictors of the risk of developing HCC.

Treatment and outcome data is described in the following table labeled “Table 6”.Error: Referencesource not found Thirteen of the 34 patients with HCC underwent TACE, 4 underwent PEI, and 2 underwent HR, whereas 14 were not treated or were treated with oral tamoxifen because of poor clinical status or because they refused any aggressive treatment. One patient underwent liver transplantation.

1 Colombo M, de Franchis R, Del Ninno E, et al. Hepatocellular Carcinoma in Italian Patients with Cirrhosis. 1991 NEJM;325(10):675-80.2 Monto A, Wright TL. The Epidemiology and Prevention of Hepatocellular Carcinoma. Seminars in Oncology 2001;28(5):441-9.3 El-Serag HB, Mason AC. Rising Incidence of Hepatocellular Carcinoma in the United States. NEJM March 1999;340(10):745-50.

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By the end of the study observation period, 14 patients with HCC were still alive (41% of the total patients who developed HCC). The cause of death in the remaining patients was related to tumor expansion in 8 patients and complications of liver cirrhosis in 11 patients. One patient died of hemoperitoneum related to the diagnosis of his second cancer originating from the pancreas.

ConclusionsThis study showed that regular screening of patients with AFP and US every 6 months allowed for

28 individuals (82%) to have their HCC diagnosed unifocally with tumor size ranging from 0.8 to 4 cm. Of these patients with unifocal, early stage disease, only 2 underwent potentially curative hepatic resection with 1 patient still alive at follow up 38 months after the start of the study. The patient who died after having hepatic resection did have a larger tumor (3 cm) and ended up dying of liver failure as well as recurrence of HCC. Seventeen patients were able to undergo TACE or PEI and one was treated by transplantation. Eleven patients, though, died before cancer expansion had taken place. Deaths in these patients were do to hepatic failure in 7 and gastrointestinal bleeding in 4.

The authors concluded that US was an effective way to observe cirrhotic patients at risk of HCC and when performed at scheduled intervals, on the basis of risk probability, it is the most cost-effective technique when compared to AFP. They also felt that screening would allow the detection of liver carcinoma at an early stage in a high proportion of patients, possibly improving the prognosis of the disease.

Strengths The screening test was evaluated in an appropriate spectrum of patients. The admission criteria were well defined. The findings are applicable to our patient population.

Weaknesses Not all patients were accounted for in the study. The data is subject to lead time bias. There was no randomization of patients or a control group to make comparisons.

Early Detection of Hepatocellular Carcinoma Increases the Chance of Treatment: Hong Kong Experience. Hepatology 2000

Patients and MethodsAll patients with HCC diagnosed between January 1995 and December 1997 in the University

Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong, were recruited to participate in this study. The diagnosis of HCC was based on AFP levels and imaging techniques including ultrasonography, CT and hepatic angiography and/or liver biopsy. The patients were categorized into two groups: group 1 included patients with subclinical HCC (SCHCC) diagnosed by screening. Group 2 were patients who presented with symptomatic HCC.11

The screening program consisted of AFP levels and liver function biochemistry measured every 3 to 6 months. The program included patients from all Child’s class of liver failure because of the availability of transplantation at this center. The etiology of the HCC was also taken into account and patients were screened for all types of viral hepatitis, history of alcohol intake, and the presence of cirrhosis diagnosed by imaging techniques and/or the presence of cirrhosis-related complications, i.e., esophageal varix, ascites, and encephalopathy before or at the time of diagnosis.

All patients were assessed for surgical resection once HCC was diagnosed. The assessment was based on lobar involvement and liver function analysis. Liver functional reserve was assessed by the indocyanine green clearance test. Exclusion criteria for resection included: 1) bilobar involvement; 2) evidence of main portal vein infiltration/thrombosis; 3) evidence of extrahepatic metastases from chest x-ray and/or CT of the abdomen; 4) poor liver biochemistry suggestive of severe cirrhosis as defined by a

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bilirubin level > 50 μmol/L (normal < 30 μmol/L), a serum albumin of < 25 g/L, and a prolongation of the prothrombin time to 5 seconds over that of the control; 6) Child’s C cirrhosis; 7) poor liver function reserve as indicated by the indocyanine green clearance retention of > 10% at 15 minutes; and 8) poor cardiac and respiratory performance status.Error: Reference source not found Patients not suitable for operation were offered transarterial chemoembolization, unless the main portal vein was thrombosed, the liver function was to poor (bilirubin > 50 μmol/L or the prothrombin time was greater than 5 seconds above the control), or there was severe arterio-venous shunting or extrahepatic metastases.

ResultsDuring the study period, a total of 306 patients were diagnosed with HCC. One hundred forty-two

asymptomatic patients were diagnosed to have HCC under the screening program (group 1), and 164 patients presented with symptomatic HCC (group 2).Error: Reference source not found The median age was 61 years and the male:female ratio was 249:57. The remainder of the patient characteristics are located in Table 5.

Table 5 Characteristics of Patients Diagnosed with HCC

Patient characteristics No. of patients

HBsAg + 243

Anti-HCV + 15

HbsAg + and Anti-HCV + 4

Significant EtOH Hx with negative viral hepatitis

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Unknown etiology for HCC 27

CirrhosisBefore diagnosisAt the time of diagnosis

128126

The prevalence of cirrhosis in group 1 and group 2 was 85.2% and 68.9% respectively. The duration of follow up was shorter in group 2 with median follow up being 4 months vs. 10.5 months in group 1.

The characteristics of the HCC in the two groups as assessed by US, CT, and/or hepatic arteriography are listed in the following table.

From this chart we can see that group 1 had a smaller median tumor size when compared to group 2 that was statistically significant. They also had a larger percentage of < 3 cm and < 5 cm tumors, less bilobar involvement, less multifocal and diffuse HCC and less metastases, all better prognostic factors in survival.

Thirty-eight patients underwent curative resection in group 1, which was significantly higher than group 2 which had 13 patients that were suitable for resection (P < 0.0001). There was also a trend toward a lower cumulative rate of postresection tumor recurrence between the two groups illustrated in the graph below (P = 0.066). For patients with postresection recurrence, the median time of recurrence-free interval was longer in group 1 than in group 2 (11.5 months [3-26 months] vs. 5 months [1-14 months]), though this did not reach statistical significance (P = 0.0698).Error: Reference source not found

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The median survival for all patients was 11 months. When categorized into group 1 or 2 the median survivals were as shown in the following table.

From this data, we can see that for median survival, there was no statistical difference in Child’s C patients between groups 1 and 2, and that Child’s B patients showed a trend towards significance with a P-value equal to 0.0072. Median survival also reached statistical significance in patients receiving TACE. Patients receiving hepatic resection showed a trend towards significance, but at the time of writing, only 3 of the 13 patients in group 2 had died, thus making it impossible to calculate median survival in this group. The cumulative actuarial survival rate was significantly higher in group 1 than in group 2 and is illustrated below. Also illustrated are the cumulative survival rates broken down by Child’s class and by treatment (resection vs. TACE).

ConclusionsThis study was well structured in that they compared high risk patients undergoing active

surveillance who were diagnosed with asymptomatic HCC with patients diagnosed with HCC who had no developed screening program in place. There is a different philosophy in surveillance in this study that is not consistent with other studies that I evaluated. They screened their patients with AFP levels and liver function biochemistry every 3 to 6 months, with no radiographic screening at all. They used US or CT to

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evaluate elevated AFP levels (> 20 ng/ml) that were present in the absence of an elevated ALT, suggestive of hepatitic exacerbation, and/or if the AFP level was either rising or persistently elevated. As was previously stated, the sensitivity of AFP for detecting HCC at this level is not acceptable. They did mention, though that 25% of the patients did have regular US screening performed on their own initiative, independent of AFP levels.

The authors concluded that screening for HCC in chronic HBV and HCV carriers by AFP and/or US can identify tumors at an early stage, resulting in a higher chance of receiving treatment. Whether screening programs can also improve survival can only be studied in prospective, randomized studies.

Strengths The authors took time to point out all the potential weaknesses of the study. All of the patients in the study were accounted for. The screening test was evaluated in an appropriate spectrum of patients.

Weaknesses “Gold standard”, as reported in much of the literature, not used in this study. Data subject to lead time bias. There was no randomization of patients to a control group.

ConclusionsThe general goal of screening for hepatocellular carcinoma is to detect the malignancy when it is

still isolated and small in size, thus eligible for effective therapy, namely surgery. There are 10 criteria for cost-effective screening programs as suggested by the World Health OrganizationError: Reference source not found 1) The condition should be an important health problem; 2) an accepted treatment for diagnosed patients should be available; 3) facilities for diagnosis and treatment should be available; 4) the condition should be recognizable in the latent/early symptomatic stage; 5) suitable tests for screening should be available; 6) the tests available should be acceptable to the population to be tested; 7) the natural history of the condition should be adequately understood; 8) an agreed policy on whom to treat should be established; 9) the cost of diagnosis and treatment should be economically balanced with the whole medical expenditure; and 10) case-finding should be continued. Screening programs for HCC fulfill 9 of the 10 criteria relatively well. Cost effectiveness of screening has not been well studied until recently. A study published in the journal “Gut” looked at the cost effectiveness of surveillance programs for HCC in cirrhotic patients. They prospectively looked at a cohort of patients with cirrhosis and screened them with AFP and US at 6 month intervals. For comparison, they enrolled consecutive patients diagnosed with HCC referred to their center for treatment. These patients were perceived to the the unsurveilled group. Their analysis revealed that the cost of treatable HCC was $17,934 for the surveilled population versus $14555 for the unsurveilled group.12 They did report an overall improved median survival between the two groups (30 months vs. 15 months, surveilled vs. unsurveilled, respectively) that reached statistical significance. With this difference, they calculated that the cost per year life saved was a staggering $112996. This cost did not take into account other incidental costs such as clinic visits, doctors’ time, other costs related to hospitalization, time lost in employment, and travel costs, all of which further increase the cost of surveillance.

Some assumptions are made throughout the literature in reference to screening and resectability of tumors at diagnosis. It has been reported that screening high-risk individuals with US and AFP levels leads to a diagnosis of resectable HCC in 40% to 60% of the HCC patients. Pateron et al. published that in patients with Child-Pugh A or B cirrhosis, screening every 6 months with AFP, US and DCP did not effectively identify potentially resectable tumors in Caucasian patients with cirrhosis of mainly alcoholic origin. In the study published by Zoli et al., of the 34 patients diagnosed with HCC, 2 underwent potentially curative resection of their HCC, with one eventually dying of liver failure and recurrence of the HCC. Twelve of the 34 patients died of other complications of cirrhosis including liver failure and gastrointestinal bleeding, independent of the HCC. I believe that the differences between these findings are a result of the population characteristics from with this data was extracted. Patients in Asia with HCC are generally chronic HBV carriers and are younger, with less incidence of co-morbid causes of liver disease such as alcohol abuse. Most of the encouraging data in the literature describing improved survival with screening comes from this cohort of patients. Over the last decade, researchers in Italy and North America have tried to replicate these findings in a different cohort of patients. As previously described, HCC in these areas tend to occur in older patients with a higher incidence of alcohol abuse and chronic HCV. Clearly, the studies that I have outlined have shown that screened individuals are diagnosed with HCC at an

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earlier stage, but it seems that their co-morbid conditions may negate the screening tests ability to detect these early tumors and thus impart improved survival. Many of the patients in the studies died of complications from their liver disease, possibly independent of their underlying HCC.

The mortality and disease-free survival benefit have yet to be effectively shown for patients undergoing regular screening for HCC. Individual studies have reported statistically significant increases in survival over a 3-year period but none longer than that. Screening for cancer in these patients will find tumors earlier, but any survival benefit noted in studies is subject to lead-time bias, i.e., bias introduced by earlier diagnosis. I believe that long-term survival has not been proven to benefit because we have no well documented treatment that has been shown to effectively improve survival in this group of patients. Screening does allow us to detect tumors at an earlier stage where treatment would theoretically be more beneficial. I believe the problem lies in the substrate from which HCC predominantly arises. Hepatocellular carcinoma preferentially arises in liver tissue that is already diseased. Most patients at risk to develop HCC already have a reduced mortality related to their liver disease. The 1-year mortality for Child-Pugh class A, B, and C cirrhosis is 100%, 80% and 45%, respectively. The natural history of hepatocellular carcinoma is unlikely to be affected by formal surveillance programs in those patients with a greater risk to die from their liver disease. Therefore, if screening is to be performed, the patient population to be screened must be selected very carefully to assure cost effectiveness of the screening and mortality benefit.

In our era of evidence-based medicine, the question must now be asked whether to recommend surveillance for hepatocellular carcinoma in patients at risk to develop the disease. There is a large amount of uncertainty present in the current literature, but after thoroughly reviewing the data, I would recommend surveillance for HCC in high-risk individuals. Patients with biopsy proven severe chronic active hepatitis, cirrhosis or both, were reported to have a HCC incidence of 20% to 25%, making this an extremely high risk group. Since not all patients seen in the outpatient setting will have had a liver biopsy, patients with Child’s A cirrhosis secondary to chronic HBV or HCV infection, alcohol abuse, or cirrhosis secondary to familial hemochromatosis should also be included in HCC surveillance. I would recommend screening with US at 6-month intervals, using high resolution CT or MRI to verify the presence of a liver mass. Although AFP has been used historically to screen, its use is much better suited for following response to treatment in patients with an elevated level at diagnosis.

The debate over surveillance programs for hepatocellular carcinoma will continue until well constructed randomized controlled trials of treatment are published. Any progress in treating HCC will only come from treating small HCC, whether it be by transplantation, local ablation, chemotherapy or some combination of treatments. Therefore, surveillance should be continued and when HCC is found small, well localized and at an early stage, these individuals should be randomized to different forms of therapy. Only with this data will we be truly able to see if there is any benefit to screening for this deadly disease.

4 Montalto G, Cervello M, Giannitrapani L, Dantona F et al. Epidemiology, Risk Factors, and Natural History of Hepatocellular Carcinoma. Annals of New York Academy of Sciences 2002;963:13-20.5 Befeler AS, Di Bisceglie AM. Hepatocellular Carcinoma: Diagnosis and Treatment. Gastroenterology May 2002;122:1609-19.6 Pateron D, Ganne N, Trinchet JC, Aurousseau MH, Mal F, Meicler, C, et al. Prospective study of screening for hepatocellular carcinoma in patients with cirrhosis. Journal of Hepatology 1994;20:65-71.7 Sherman M. Surveillance for Hepatocellular Carcinoma. Seminars in Oncology 2001;28(5):450-9.8 Curley SA, Izzo F, Gallipoli A et al. Identification and Screening of 416 Patients with Chronic Hepatitis at High Risk to Develop Hepatocellular Cancer. Annals of Surgery 1995;222(3):375-83.9 Izzo F, Cremona F, Ruffolo F, Palaia R, Valerio P, Curley S. Outcome of 67 Patients with Hepatocellular Cancer Detected During Screening of 1125 Patients with Chronic Hepatitis. Annals of Surgery 1998;227:513-18.10 Zoli M, Magalotti D, Bianchi G, Gueli C, Marchesini G, Pisi E. Efficacy of a Surveillance Program for Early Detection of Hepatocellular Carcinoma. Cancer 1996;78:199-85.11 Yuen, MF, Cheng CC, Lauder IJ, Lam SK, Ooi CG, Lai CL. Early Detection of Hepatocellular Carcinoma Increases the Chance of Treatment: Hong Kong Experience. Hepatology 2000;31(2):330-35.12 Bolondi L, Sofia S, Siringo S, Gaiani S, Casali A, Zironi G, Piscagalia F, Gramantieri L, Zanetti M, Sherman M. Surveillance programme of cirrhotic patients for early diagnosis and treatment of hepatocellular carcinoma: a cost effective analysis. Gut 2001;48:251-9.

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