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Case Presentation:.doc

  1. 1. Screening for Hepatocellular Carcinoma in Patients with Cirrhosis Jason D. Huff, HOIIICase 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 medicalhistory is significant for a diagnosis of Hepatitis C in 1997, tobacco and alcohol abuse, and hysterectomywith bilateral oopherectomy for uterine fibroids and endometriosis. While in California, she was beingevaluated by a Gastroenterologist for possible treatment of her Hepatitis C and had been scheduled for aliver biopsy prior to her moving to North Carolina. She moved back to North Carolina to be closer to herfamily because recently her health had been declining. She was unaware of how she contracted hepatitisbut thought that it could be from a blood transfusion she got during her hysterectomy. She adamantlydenied any IV drug abuse. She reported having a history of ascites diagnosed by paracentesis, and had recently beenprescribed a medicine for “confusion” that possibly had something to do with her liver. Just prior to ourvisit, she had been discharged from an area hospital for an upper gastrointestinal bleed. Upper endoscopyconfirmed grade I esophageal varices. She underwent sclerotherapy for the bleeding and was placed on amedicine 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 priorto our visit, but did report a 1-pack-per-day smoking history. She denied any family history of liverdisease, cancer or heart disease. Her examination was significant for palmar erythema, spider angiomataacross her upper chest and back, and positive shifting dullness with mild distension notable on abdominalexam. Her liver edge was smooth and non-tender with no noted enlargement. She had no evidence ofsplenomegaly on exam.Clinical Questions: The case presentation above clearly describes a patient with many of the features andcomplications of cirrhosis. Patients with cirrhosis are at high risk to develop HCC and the incidence inwell compensated cirrhosis has been documented at approximately 3% per year.1 With this information Isought to review the current literature on the benefit of screening cirrhotic patients for hepatocellularcarcinoma. 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 eighthmost common in women worldwide.2 It accounts for as many as 1 million deaths annually worldwide. Theincidence of HCC, however, varies widely internationally and is more prevalent in areas with a highseroprevalence of chronic hepatitis B virus (HBV) infection. Of the roughly 530,000 new cases of HCCeach year worldwide, more than 85% occur in areas such as Taiwan and Southeastern Asia where theincidence 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 theUnited States over the past 20-30 years and it is estimated that approximately 15,000 new cases occur eachyear.3 The main risk factors for developing HCC are the hepatitis B and the hepatitis C viruses, whichtogether account for three quarters of all cases worldwide.4 Other conditions associated with thedevelopment of HCC are alcoholic liver disease, aflatoxin exposure, hemochromatosis, tyrosinemia, andalpha-1-antitrypsin deficiency. As was previously alluded to, the attributable risk fraction for each riskfactor varies according to the country examined. Whereas HCV has the greatest attributable risk indeveloped countries such as the United States, Europe and Japan, it is responsible for a limited number of 1
  2. 2. cases in most areas of Asia and Africa, where HBV is mainly responsible. Aflatoxin B1 probably does notplay a role in developed countries, whereas it is definitely responsible, with a risk, however, notquantifiable, for numerous cases in Africa and Asia.4Hepatitis B Worldwide, HBV is the HCC-determining disease. There is an estimated 350 million peopleworldwide who have detectable hepatitis B surface antigen in their peripheral blood. This indicates at leasta low level of chronic HBV infection present in these individuals. Most of these infections, occurring inendemic areas such as Asia or Northern Africa, occur early in life, either perinatally or in infancy, and aremuch less likely to be cleared, unlike HBV exposure in North America, which occurs later in life and iscleared in 90% of cases. The percentage of cases of HCC attributable to HBV worldwide is 52.3% and ishigher in these endemic areas where the rates of HBV are higher. One study of a population of Taiwanesepatients reported that the relative risk of developing HCC was 102, because among carriers of HBV, 473cases/100,000 per year developed HCC compared to only 4.6 cases/100,000 per year among noncarriers.4Further evidence to support HBV’s role in HCC development comes from a vaccination campaign inTaiwan in the 1980s. After vaccination for HBV, there was an important reduction noted in the incidenceof HCC that is still ongoing.Hepatitis C In Japan, as well as Europe and North America, the HCC-defining disease is unanimouslyhepatitis C virus (HCV) infection. Epidemiologic studies have shown that many patients with HCC (ashigh as 70%) have anti-HCV antibody in the serum.4 The presence of chronic HCV alone seems to raise apatient’s risk for HCC by about 24-fold. The percentage of cases of HCC worldwide attributable to HCVis 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 themost important risk factor for HCC in western countries. The role of HCV genotype and risk of thedevelopment of HCC is still up for debate.Cirrhosis HCC is to a large extent a complication of chronic liver disease and cirrhosis. In several largecase series, more than 80% of patients developing HCC are cirrhotic.2 The constant proliferation ofhepatocytes likely represents the key factor of progression to HCC, independent of the etiology. Theannual risk of developing HCC in HCV-infected patients seems highly dependent on the presence andseverity of the underlying liver disease. Whereas the risk of HCC is rare in carriers of HCV infection, itreaches 1.2-1.7% in patients with underlying chronic hepatitis and can reach 1.4-2.5% in subjects with livercirrhosis.4 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 theHbsAg 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.4Hepatocellular Carcinoma: Diagnosis HCC is most commonly diagnosed incidentally during the asymptomatic phase during evaluationfor a liver transplant or as part of routine screening in those patients with cirrhosis. The classic clinicalfeatures of HCC include right upper quadrant pain and weight loss.5 Other clinical scenarios that suggestthis diagnosis include worsening liver function in a patient known to have cirrhosis, acute abdominalcatastrophe from rupture of a liver tumor with intra-abdominal bleeding, and some rare extrahepaticmanifestations such as erythrocytosis, hypoglycemia, watery diarrhea and hypercalcemia.Serum ά-fetoprotein Serum ά-fetoprotein (AFP) is elevated above 20 ng/ml in more than 70% of patients with HCC.5Nevertheless, AFP elevations from 10-500 ng/ml and even occasionally to 1000 ng/ml may be seen inpatients with a high degree of necroinflammatory activity, such as with chronic viral hepatitis, who do nothave HCC. In contrast, it has been shown that highly differentiated tumors, or tumors that are severelyanaplastic may secrete no AFP at all. In a study performed in France looking at screening patients withcirrhosis for HCC, the sensitivity and specificity for AFP > 15 ng/ml was 50 and 86, respectively.6 Whenthe level of AFP was increased to > 100 ng/ml, the specificity improved to 93 with a sharp decline in thesensitivity to 21. The positive predictive value of AFP increases significantly when the AFP > 400 ng/mlbut 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 2
  3. 3. found to be useful in monitoring response to treatment and detecting recurrence after treatment if the AFPwas elevated prior to treatment.Imaging Imaging studies of the liver play a key role in the diagnosis of HCC. Radiologic modalities suchas ultrasound, CT and MRI have allowed physicians to detect HCC at earlier stages when the malignancy ispotentially curable. Ultrasound has been used as a primary screening tool in the past and has been reportedto have a relatively high sensitivity and specificity. Studies performed to evaluate the performancecharacteristics of US as a screening tool have determined its sensitivity to range from 71-78% and itsspecificity to reach 93%. It is especially good at allowing the clinician to assess potential vascular invasionof the tumor by using real-time color Doppler mode. CT and MRI scanning are primarily being used toverify ultrasound findings and to confirm the diagnosis in patients with an isolated abnormal serum AFPlevel. The overall sensitivity and specificity of contrast enhanced CT are 68% and 81%, respectively, butthe 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 oldermethod of diagnosing liver masses and relies on the neovascularization and hypervascularity of malignanttumors. It’s sensitivity for small tumors has been shown to be poor, so it is mainly reserved for patientsundergoing chemoembolization for non-resectable tumors.Histology Histologic 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 resectabletumors or those potentially cured with transplantation is currently under debate. One possible risk ofpercutaneous needle biopsy is local spread of HCC along the needle track. Recent evidence suggests thatlocal spread of HCC occurs in as many as 1% of cases after needle biopsy. Certain experts advocate that ifa mass is found in the liver, perhaps associated with a markedly elevated serum AFP, the diagnosis isobvious and the biopsy is not needed. If therapies are planned that involve significant risk and arepotentially toxic, such as chemoembolization or systemic chemotherapy, consideration should be given tohistologic diagnosis prior to initiating treatment.Hepatocellular Carcinoma: Treatment The natural history of HCC is variable and depends on the number and size of neoplastic nodulesat diagnosis and the severity of the underlying chronic liver disease. With advancements in diagnosticmodalities, HCC is often found as a single nodule, or nodules of small size that can be potentially treatedradically with resection, transplantation or chemoembolization.Transplant Transplantation would hypothetically be the best treatment for HCC because it results in thewidest possible resection margins for the cancer, removes the remaining liver tissue that is at risk for thedevelopment of further cancer, and restores hepatic function. A few case reports have been publishedshowing 5-year survival rates nearing 75%.5 When compared to patients undergoing orthotopic livertransplant (OLT) without HCC, the survival numbers are nearly identical. Unfortunately, these studieswere performed at a time when the average waiting time for a donor liver was less than 6 months. With theaverage 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 aviable option to most patients with HCC. With the doubling time of a nodule of small dimensions beingestimated within a period of 1-19 months, it is easy to see how someone could develop widespreadinoperable disease in a matter of months while waiting for a donor liver.Hepatic Resection Liver resection treats HCC much in the same way that OLT does, in that it removes the portion ofthe liver with cancer. It is unfavorable when compared to OLT in that it does not eliminate the remainingportions 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%.5In addition, the risk for decompensation after surgical resection with Child-Pugh class A cirrhosis is up to50%. It is plausible to treat this group of patients with salvage transplantation, but for the reasons statedpreviously, this is usually not accomplished. 3
  4. 4. Ablation Ablation of the malignant HCC tumors by either chemical means (e.g., absolute alcohol ortrichloroacetic acid) or physical means (e.g., cryoablation, radiofrequency ablation, microwave coagulationor injection of hot saline) have been performed for quite some time, especially in patients whom resectionis not possible. Alcohol ablation has historically been the most popular of these treatment modalities andhas shown benefit in small trials when compared to resection. One study published 1 and 4 year survivalrates of 81% and 44% for surgical resection compared with 83% and 34% for ethanol injection.5 A pointshould be made that the study group was small, including 63 patients equally distributed between the twotreatment 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 tumornecrosis. It is an improvement over ethanol injection in that the number of sessions required to completetumor ablation is less in RFA. Often times, tumors can be ablated in one sitting with RFA where thepatient would have to return for multiple sittings with ethanol injection, increasing the risk ofcomplications.Chemoembolization and Chemotherapy Chemoembolization 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 supplyingthe 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 byinjection of material to obstruct flow such as Gelfoam® and Ivalon®. The potential side effects ofchemoembolization are not trivial and include hepatic failure, severe pain, and formation of liver abscess. Chemotherapy is in general considered foruse in patients with HCC not amenable topotentially curative therapy and therefore its role islargely palliative. The chemotherapeutic agentsshown to have antitumor effects against HCC arelisted in the following table.5 Chemotherapy canbe given regionally, much like chemoembolization,or systemically. Systemic administration ofchemotherapy is generally associated with lowresponse rates and is often limited by the presenceof liver dysfunction and cirrhosis which regularlyoccurs with HCC. Oral tamoxifen has not been shown to improve mortality in randomized controlled trialsand is not recommended. When symptomatic HCC is diagnosed in a patient with cirrhosis, treatment is usually limited andthe prognosis is poor, even when surgery can be considered.7 Recent publications have suggested that thefive-year survival rate for HCC is less than 5 percent.3 A table outlining median survival among patientswith HCC is listed below.5 The CLIP, Okuda and TNM are all staging systems used to describe the extentof disease with the lower numbers correlating with less advanced disease. 4
  5. 5. Some data, though, has suggested that smaller, asymptomatic tumors, when discovered early, havea better prognosis. This would suggest that screening high-risk individuals would be useful in detectingHCC at an early, more treatable stage. More than a decade ago, studies performed in Asia, where HCC is amajor cause of death, seemed to show a benefit in screening for HCC. At that time, the annual incidence ofHCC was more than 5%, the percentage of small tumors discovered was over 50% and the percentage ofoperated patients surviving 5 years was over 50% in selected studies.6 These findings prompted thesuggestion that screening should also be performed on at risk patients in the western world. There appearto be characteristic differences between the patients at high risk in North America, Europe and Japan whencompared to patients in Asia and Africa. Cirrhotic patients in more developed countries have a greaterprevalence of alcoholism, are older and have a smaller number of uninodular encapsulated tumors. Withthis in mind, the evaluation of screening these high-risk patients looking for improvement in survival wasundertaken in the 1990’s and into the twenty-first century.Identification and Screening of 416 Patients with ChronicHepatitis at High Risk to Develop Hepatocellular Cancer. Annalsof Surgery 1995:The Surgeon’s Perspective Curley et al. published a study in the Annals of Surgery in 1995 looking prospectively at a groupof viral hepatitis patients and their risk for HCC development. From their perspective, the majority ofpatients diagnosed with HCC were not candidates for potentially curative liver resection at the time ofdiagnosis because of three factors: (1) large or multicentric liver tumors, (2) the presence of metastaticdisease, and (3) insufficient functional hepatic reserve related to chronic hepatocellular injury or cirrhosis.8For treatment programs to produce long-term survival, therapy would include resection or tumor ablativetherapy for small or localized hepatic tumors. Therefore, screening programs aimed at high-riskindividuals should be important in the attempt to diagnose liver cancer at an earlier and more treatable stageof disease. For this reason, they prospectively screened a cohort of patients with chronic HBV or HCVinfections to determine the incidence of asymptomatic HCC and to identify the subgroups at highest risk todevelop HCC.Materials and Methods The study was conducted from July 1, 1993, until December 31, 1994. They looked at patientsfrom Naples, Italy, and adjoining regions who were seropositive for HBV or HCV infections of at least 5years duration who were registered and followed at the Cotugno Hospital in Naples. These patients wereoffered a screening program to detect HCC at the G. Pascale National Cancer Institute in Naples. ChronicHBV was defined as persistently positive sera for hepatitis B surface antigen (HbsAG). Chronic HCVinfection was defined as persistently positive sera for HCV on first- and second-generation anti-HCVenzyme-linked immunoassay. Patients excluded from the study were those with Childs’ class B or Ccirrhosis, history of hepatic encephlopathy, bleeding gastroesophageal varices, ascites, or a prior diagnosisof any type of malignancy. A total of 416 patients entered the screening program, 245 men and 171 women. They reportedthat no patients had any clinical symptoms related to liver dysfunction or hepatocellular cancer. Thebreakdown of chronic viral hepatitis type was 69 with chronic HBV, 340 with chronic HCV, and 7 withboth. The duration of illness was from 5 to 14 years. All patients underwent liver biopsy to determine the severity of chronic liver injury. Diagnosesfrom the liver biopsy were chronic persistent hepatitis, chronic active hepatitis-mild, chronic activehepatitis-severe, or chronic active hepatitis with cirrhosis (all Childs’ class A). Patients then underwentoutpatient physical examination, abdominal ultrasound, and serum alpha-fetoprotein (AFP) determinationat entry and at 3-month intervals thereafter. When a mass lesion was detected by ultrasound and/or whenthe serum AFP level exceeded 10ng/ml, further diagnostic evaluation was performed with contrastenhanced computed tomography scans and MRI of the abdomen. The confirmed liver tumor was thenbiopsied under US or CT guidance and histologic diagnosis was made.Results The results from the screeningliver biopsy are outlined in the graphiclabeled “Table 1”. There was nosignificant difference between thechronic HBV and HCV viral patientswith regard to the severity of chronic 5
  6. 6. 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 aninitial detection rate of 7.9%. The diagnosis was suggested by abnormal US in 5 patients (15.1%), elevatedserum AFP in 6 patients (18.2%), or mass lesion on US and elevated AFP in 22 patients (66.7%). Mostimportantly, three additional cases of HCC were diagnosed in patients with a normal serum AFP level andliver 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 cmin diameter, as demonstrated by US. Therefore, 36 patients or 8.6% of the initial 416 screened patientswere 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 veryinteresting trend was revealed. Of the 36 cases of HCC, 35 occurred in the 140 patients with chronic activehepatitis-severe or chronic active hepatitis with cirrhosis, compared to one in the other two groups (theauthor did not specify which group this case fell into). HCC developed in 4 of the 69 patients with chronicHBV, 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 11patients, and percutaneous ethanol injection (PEI) in the remaining 11 patients. All of the tumors treatedwith curative intent were solitary and less than 5 cm in diameter. Patients treated with surgery hadperipheral lesions that could be resected with at least a 1 cm margin of unaffected liver parenchyma with awedge or segmental resection. Tumors treated with PEI were centrally located and were thought to beunresectable because of inadequate margins with tumor proximity to major vascular structures or resectableonly with a major lobar resection.8 Of the 14 patients not eligible for possible curative intervention, 10patients had large (>8 cm in diameter) or multicentric tumors and 4 patients had evidence of distantmetastatic disease.Conclusions The authors in this study concluded that patients with severe chronic active hepatitis, cirrhosis orboth are at extremely high risk to develop HCC with their calculated incidence of 25% (35 of thehepatocellular cancers took place in the 140 patients diagnosed with severe liver injury). They also foundthat a significant number (61.1%) were small, potentially treatable cancers. They recommended screeninghigh 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.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 DetectedDuring 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 in1998 again looking at the incidence of HCC in patients with chronic viral hepatitis. This time, theyincluded data regarding the resectability and long-term survival rates of these HCC patients. The studyagain took place in the Campania region of Italy where the incidence of HCC is relatively high, presumablydo to high rates of chronic viral hepatitis, especially HCV. They performed this prospective screening trialto determine if routine screening of chronic viral hepatitis patients improves the survival of patients whodevelop HCC. 6
  7. 7. Methods The study was conducted from July 1, 1993 through June 30, 1996. The inclusion criteria werethe same as the previous study, and again, patients with Child class B or C cirrhosis, a history of hepaticencephalopathy, bleeding gastroesophageal varices, ascites, or a prior diagnosis of any type of malignancywere excluded from the study. All patients involved underwent outpatient physical examination,abdominal US, serum liver function tests (direct and indirect bilirubin, alkaline phosphatase, aspartateaminotransferase, alanine aminotransferase, gamma-glutamyl transpeptidase, albumin, prothrombin time),and serum alpha-fetoprotein measurements at entry and at 3-month intervals thereafter. Follow up on masslesions and elevations of serum AFP were performed as in the previous study and all confirmed livertumors were biopsied under US or CT guidance. Just as before, all patients at entry underwent apercutaneous core liver biopsy to determine the histologic severity of chronic liver injury. They were againplaced 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 andserum laboratory tests (complete blood count, platelet count, blood urea nitrogen, creatinine, glucose andelectrolytes). Chest CT scan was performed if there was a question of lung metastases. Patients diagnosedon clinical and radiographic examination with only a solitary liver lesion judged to be resectable (aresection leaving adequate functional hepatic parenchyma) underwent exploratory laparotomy andintraoperative ultrasound. A margin-negative liver resection was performed if there was no evidence ofeither extrahepatic metastasis or multifocal tumor on intraoperative ultrasound. Patients with only solitaryliver lesions judged to be unresectable because of tumor size or intrahepatic location were treated onprotocol with percutaneous ethanol injection (PEI). Patients with multifocal liver disease or metastaticdisease were treated on protocol with systemic chemotherapy. All HCC patients were followed afterresection, PEI or initiation of systemic chemotherapy every 3 months with serum AFP levels, serum liverfunction tests, abdominal CT scanning and chest radiography.9Results The screening program registered 1125 patients with 672 men and 453 women. No patient hadany clinical symptoms related to liver dysfunction or HCC. Chronic HCV was diagnosed in 804 patientsand chronic HBV in 290. A total of 31 patients were co-infected with both HBV and HCV. Registeredpatients 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 initialdetection rate of 5.4%.9 An additional six cases were diagnosed during follow up evaluations in patientswho on initial evaluation had a normal serum AFP level and no liver tumor by US. All six of these patientsdeveloped 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 notreveal a mass, but high-resolution CT scanning of the abdomen detected a solitary tumor <3 cm in size. Ultrasound was able to demonstrate a liver mass in 58 of the patients (86.6%) while the serumAFP level was elevated in 50 (74.6%). Of the 67 patients diagnosed with HCC, 58 (86.6%) had chronicHCV, 5 (7.5%) had HBV and 4 (5.9%) were co-infected with the two viruses. The percutaneous core liverbiopsies were again very revealing in this group. The data is listed below in Table 1. The abbreviations areas follows: CPH, chronic persistent hepatitis, CAH-M, chronic active hepatitis-mild, CAH-S, chronicactive 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 whichtime 4 were found to have extrahepatic nodal metastases and the liver resection was not performed. The 24that eventually underwent resection with curative intent were resected with at least 1 cm margin of tumornegative hepatic parenchyma. There were no operative or post-operative deaths in these patients. Includedin these 24 patients undergoing potentially curative surgery were the 6 people with normal US and serumAFP on initial screen who were later diagnosed with HCC in follow up. 7
  8. 8. The number of patients with solitary liver lesions deemed unresectable was 14 (21%). Thesepatients were unresectable based on tumor location within the liver that would require a major lobarresection in patients with inadequate functional hepatic reserve or adjacency to a major intrahepaticvascular structure precluding a margin-negative resection. These patients were treated with percutaneousethanol injection. All tumors were < 5 cm in diameter. The 29 remaining patients (43%) with multifocal ormetastatic 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 withmultifocal or metastatic HCC had died from their disease. The median survival of the 43 patients withunresectable HCC was 6 months, compared to 26 months for the 24 patients who underwent hepaticresection (p < 0.0001).9 Of the 14 patients treated with PEI, 9 died of their disease, 2 were alive withdisease, and 3 were alive without evidence of recurrent HCC more than 2 years after treatment. Of the 24patients who underwent resection, 8 (33%) died of recurrent HCC, 1 was alive with hepatic recurrence ofHCC, and 15 (62%) were alive without evidence of recurrent HCC. Actuarial survival curves wereperformed on the 67 patients and the results are presented below.9Conclusions Patients with histologically severe liver injury from chronic hepatitis virus infection should bescreened every 6 months with transabdominal ultrasonography and serum AFP determination. Chronichepatitis patients with minimal liver injury are less likely to benefit from long-term screening programs andwith a low risk of developing HCC should be followed clinically. Patients with a greater than 20% overallincidence 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. 8
  9. 9. Prospective study of screening for hepatocellular carcinoma inCaucasian patients with cirrhosis. Journal of Hepatology 1994Patients and Methods From January 1986 to December 1987, a group of investigators in France prospectively evaluatedthe usefulness of screening for HCC in a population of Caucasian patients with cirrhosis of mainlyalcoholic origin. All patients with histologically proven cirrhosis, hospitalized in theHepatogastroenterology Unit of Jean Verdier Hospital were considered for inclusion in the study. At theend of hospitalization, all patients with Child-Pugh’s class A or B cirrhosis without detectable HCC (nofocal 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.6Included 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 plasmaDCP 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.Results During the inclusion period, 322 patients with cirrhosis were hospitalized in the aforementionedunit. By the end of the initial hospitalization, a total of 185 survived, were Child-Pugh class A or B andhad no detectable HCC. Among the 185 total patients included in the study, 118 were deemed suitable forfollow up and were prospectively included in the screening protocol. The characteristics of the patients areas shown in Table 2. The duration of follow up was 35.8±15 months. Table 2 Patient Characteristics in 8-year Prospective Screening Trial for HCC Patient Characteristic # of Patients Sex Male 68 Female 50 Child-Pugh Class A 75 B 43 Etiology of Cirrhosis Alcohol (>80g/d for >10y) 86 Viral B 5 Viral non-A, non-B 20 Familial Hemochromatosis 5 Primary Biliary Cirrhosis 2 Fourteen HCC were detected during the study, with the annual incidence in years one, two, threeand four being 5.4%, 4.4%, 6.6% and 7%, respectively. The clinical features of the 14 patients are listed inTable 3. Patients 3 and 7 had associated liver failure during their follow up, likely contributing more totheir overall mortality. The time and cause of death in the total 118 cirrhotic patients submitted to followup are outlined in Table 4. 9
  10. 10. Table 3 Characteristics and Outcomes of the 14 patients diagnosed with HCC Patient Age at Sex Etiology of Test Period of Number Tumor Treatment Outcome Diagnosis Cirrhosis Suggestive follow up of Size (Months) of HCC before Nodules (mm) detection of HCC 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 + Alive Chemoembol (31) 10 59 M Alcoholic US 31 1 19 - Died (7) 11 66 M Familial US 38 1 18 Chemoembol Died Hemochro. (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 death HCC 1 2 3 2 8 GI hemorrhage 1 2 1 1 5 Hepatic Failure 0 1 1 2 4 Causes unrelated 0 3 1 0 4 to the liver 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 oneand liver failure in two. In the patient who underwent surgery, the tumor recurred 15 months later. Notreatment was possible in eight patients for reasons not explained in the study.Conclusions In this study, regular screening with US, AFP and DCP did not lead to detection of HCC at anearly stage and probably did not modify the prognosis of the disease. Only 3 of the 14 patients diagnosedwith HCC had tumors that were less than 3 cm in diameter and isolated without vascular involvement ormetastases. As Table 3 illustrates, of the 21 patients who died during follow up, 38% (8 of 21) died ofHCC. The notable finding is the high mortality of patients with cirrhosis without HCC. The Kaplan-Meierplot of the survival rate of the 118 patients in this study illustrates the point well. Patients with cirrhosishave a high mortality without a diagnosis of HCC. Clearly in this group of patients, no benefit was seenwith regular screening for HCC. 10
  11. 11. 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 ofHepatocellular Carcinoma. Cancer 1996 Zoli et al.10 set out to evaluate the efficacy of regular ultrasonographic and laboratory follow up forthe early detection of small HCC, and to identify parameters correlated with a higher risk of developingHCC.Patients and Methods All patients with biopsy-proven liver cirrhosis attending the Institute of Clinica Medica Generale eTerapia Medica of the University of Bologna between January 1989 and December 1991 underwentultrasound examination of the upper abdomen. Patients who met the following criteria were enrolled in thestudy: 1) satisfactory or good US visualization of liver parenchyma; 2) no space-occupying liver lesions atUS; 3) willing to cooperate by visiting the Institute at scheduled intervals; and 4) living in EmiliaRomagna, Italy. One hundred and sixty four cirrhotic patients (75 males and 89 females) were included in thestudy. The etiology of their liver disease is outlined in the following table.10 Those rejected included 42patients living outside the area defined above, 8 patients with poor US visualization of hepatic parenchyma,and 12 patients with HCC at first US examination. At entry, all patients underwent a complete clinical exam and evaluation of specific clinical andbiochemical parameters were recorded for statistical purposes. The parameters are as outlined in thefollowing table.10 11
  12. 12. 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 wasgreater 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 oftheir liver disease, such as lactulose and/or diuretics.10 Thirty-four patients received β-blockers orunderwent endoscopic sclerotherapy as primary or secondary prophylaxis of GI bleeding. Patients diagnosed with HCC were treated with hepatic resection, whenever it was consideredpossible by the surgical team, transcatheter arterial chemoembolization (TACE), or percutaneous ethanolinjection (PEI). These patients were observed until death or November 1995.Results The results of the clinical, biochemical and ultrasound parameters are as outlined in the previoustable, labeled “Table 2”. During the follow up period which ranged from 7 to 77 months, HCC wasidentified in 34 patients. Among the 34 who developed HCC, 8 patients developed it within 1 year, 11within 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 reportedthat these values were weighted for the decrease in the number of patients during follow up at the times ofevaluation. A total of twenty-eight patients were lost during follow up. All of these patients wereaccounted for in the study. The clinical features of the patients diagnosed with HCC are outlined in thefollowing table. 12
  13. 13. Among the clinical and the biochemical parameters at entry, after univariate analysis, only threevariables were significantly associated with the probability of developing HCC. The probability wassignificantly higher in males, with albumin < 3.5 g/dl and AFP > 20 ng/ml. The etiology of liver diseasewas 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).10 After multivariate analysis by means of Cox’s model, male sex together withreduced levels of albumin and increased levels of alkaline phosphatase and AFP were significantindependent predictors of the risk of developing HCC. Treatment and outcome data is described in the following table labeled “Table 6”.10 Thirteen ofthe 34 patients with HCC underwent TACE, 4 underwent PEI, and 2 underwent HR, whereas 14 were nottreated or were treated with oral tamoxifen because of poor clinical status or because they refused anyaggressive treatment. One patient underwent liver transplantation. By the end of the study observation period, 14 patients with HCC were still alive (41% of the totalpatients who developed HCC). The cause of death in the remaining patients was related to tumorexpansion in 8 patients and complications of liver cirrhosis in 11 patients. One patient died ofhemoperitoneum related to the diagnosis of his second cancer originating from the pancreas.Conclusions This study showed that regular screening of patients with AFP and US every 6 months allowed for28 individuals (82%) to have their HCC diagnosed unifocally with tumor size ranging from 0.8 to 4 cm. Ofthese patients with unifocal, early stage disease, only 2 underwent potentially curative hepatic resectionwith 1 patient still alive at follow up 38 months after the start of the study. The patient who died afterhaving hepatic resection did have a larger tumor (3 cm) and ended up dying of liver failure as well asrecurrence of HCC. Seventeen patients were able to undergo TACE or PEI and one was treated bytransplantation. Eleven patients, though, died before cancer expansion had taken place. Deaths in thesepatients 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 HCCand when performed at scheduled intervals, on the basis of risk probability, it is the most cost-effectivetechnique when compared to AFP. They also felt that screening would allow the detection of livercarcinoma at an early stage in a high proportion of patients, possibly improving the prognosis of thedisease.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. 13
  14. 14. 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 theChance of Treatment: Hong Kong Experience. Hepatology 2000Patients and Methods All patients with HCC diagnosed between January 1995 and December 1997 in the UniversityDepartment of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong, were recruited toparticipate in this study. The diagnosis of HCC was based on AFP levels and imaging techniques includingultrasonography, CT and hepatic angiography and/or liver biopsy. The patients were categorized into twogroups: group 1 included patients with subclinical HCC (SCHCC) diagnosed by screening. Group 2 werepatients who presented with symptomatic HCC.11 The screening program consisted of AFP levels and liver function biochemistry measured every 3to 6 months. The program included patients from all Child’s class of liver failure because of theavailability of transplantation at this center. The etiology of the HCC was also taken into account andpatients were screened for all types of viral hepatitis, history of alcohol intake, and the presence of cirrhosisdiagnosed by imaging techniques and/or the presence of cirrhosis-related complications, i.e., esophagealvarix, ascites, and encephalopathy before or at the time of diagnosis. All patients were assessed for surgical resection once HCC was diagnosed. The assessment wasbased on lobar involvement and liver function analysis. Liver functional reserve was assessed by theindocyanine 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 abilirubin level > 50 μmol/L (normal < 30 μmol/L), a serum albumin of < 25 g/L, and a prolongation of theprothrombin time to 5 seconds over that of the control; 6) Child’s C cirrhosis; 7) poor liver function reserveas indicated by the indocyanine green clearance retention of > 10% at 15 minutes; and 8) poor cardiac andrespiratory performance status.11 Patients not suitable for operation were offered transarterialchemoembolization, 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 severearterio-venous shunting or extrahepatic metastases.Results During the study period, a total of 306 patients were diagnosed with HCC. One hundred forty-twoasymptomatic patients were diagnosed to have HCC under the screening program (group 1), and 164patients presented with symptomatic HCC (group 2).11 The median age was 61 years and the male:femaleratio 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 17 hepatitis Unknown etiology for HCC 27 Cirrhosis Before diagnosis 128 At the time of diagnosis 126 14
  15. 15. The prevalence of cirrhosis in group 1 and group 2 was 85.2% and 68.9% respectively. Theduration of follow up was shorter in group 2 with median follow up being 4 months vs. 10.5 months ingroup 1. The characteristics of the HCC in the two groups as assessed by US, CT, and/or hepaticarteriography are listed in the following table. From this chart we can see that group 1 had a smaller median tumor size when compared to group2 that was statistically significant. They also had a larger percentage of < 3 cm and < 5 cm tumors, lessbilobar involvement, less multifocal and diffuse HCC and less metastases, all better prognostic factors insurvival. Thirty-eight patients underwent curative resection in group 1, which was significantly higher thangroup 2 which had 13 patients that were suitable for resection (P < 0.0001). There was also a trend towarda lower cumulative rate of postresection tumor recurrence between the two groups illustrated in the graphbelow (P = 0.066). For patients with postresection recurrence, the median time of recurrence-free intervalwas longer in group 1 than in group 2 (11.5 months [3-26 months] vs. 5 months [1-14 months]), though thisdid not reach statistical significance (P = 0.0698).11 The median survival for all patients was 11 months. When categorized into group 1 or 2 themedian 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’sC patients between groups 1 and 2, and that Child’s B patients showed a trend towards significance with a 15
  16. 16. 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 3of 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 illustratedbelow. Also illustrated are the cumulative survival rates broken down by Child’s class and by treatment(resection vs. TACE).Conclusions This study was well structured in that they compared high risk patients undergoing activesurveillance who were diagnosed with asymptomatic HCC with patients diagnosed with HCC who had nodeveloped screening program in place. There is a different philosophy in surveillance in this study that isnot consistent with other studies that I evaluated. They screened their patients with AFP levels and liverfunction biochemistry every 3 to 6 months, with no radiographic screening at all. They used US or CT toevaluate elevated AFP levels (> 20 ng/ml) that were present in the absence of an elevated ALT, suggestiveof hepatitic exacerbation, and/or if the AFP level was either rising or persistently elevated. As waspreviously stated, the sensitivity of AFP for detecting HCC at this level is not acceptable. They didmention, 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/orUS can identify tumors at an early stage, resulting in a higher chance of receiving treatment. Whetherscreening 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.Conclusions The general goal of screening for hepatocellular carcinoma is to detect the malignancy when it isstill isolated and small in size, thus eligible for effective therapy, namely surgery. There are 10 criteria forcost-effective screening programs as suggested by the World Health Organization11 1) The conditionshould 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 thelatent/early symptomatic stage; 5) suitable tests for screening should be available; 6) the tests availableshould be acceptable to the population to be tested; 7) the natural history of the condition should be 16
  17. 17. adequately understood; 8) an agreed policy on whom to treat should be established; 9) the cost of diagnosisand treatment should be economically balanced with the whole medical expenditure; and 10) case-findingshould be continued. Screening programs for HCC fulfill 9 of the 10 criteria relatively well. Costeffectiveness 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 prospectivelylooked at a cohort of patients with cirrhosis and screened them with AFP and US at 6 month intervals. Forcomparison, 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 oftreatable HCC was $17,934 for the surveilled population versus $14555 for the unsurveilled group.12 Theydid 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, theycalculated that the cost per year life saved was a staggering $112996. This cost did not take into accountother incidental costs such as clinic visits, doctors’ time, other costs related to hospitalization, time lost inemployment, 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 oftumors at diagnosis. It has been reported that screening high-risk individuals with US and AFP levels leadsto a diagnosis of resectable HCC in 40% to 60% of the HCC patients. Pateron et al. published that inpatients with Child-Pugh A or B cirrhosis, screening every 6 months with AFP, US and DCP did noteffectively identify potentially resectable tumors in Caucasian patients with cirrhosis of mainly alcoholicorigin. In the study published by Zoli et al., of the 34 patients diagnosed with HCC, 2 underwentpotentially curative resection of their HCC, with one eventually dying of liver failure and recurrence of theHCC. Twelve of the 34 patients died of other complications of cirrhosis including liver failure andgastrointestinal bleeding, independent of the HCC. I believe that the differences between these findings area result of the population characteristics from with this data was extracted. Patients in Asia with HCC aregenerally chronic HBV carriers and are younger, with less incidence of co-morbid causes of liver diseasesuch as alcohol abuse. Most of the encouraging data in the literature describing improved survival withscreening comes from this cohort of patients. Over the last decade, researchers in Italy and North Americahave tried to replicate these findings in a different cohort of patients. As previously described, HCC inthese 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 anearlier stage, but it seems that their co-morbid conditions may negate the screening tests ability to detectthese early tumors and thus impart improved survival. Many of the patients in the studies died ofcomplications from their liver disease, possibly independent of their underlying HCC. The mortality and disease-free survival benefit have yet to be effectively shown for patientsundergoing regular screening for HCC. Individual studies have reported statistically significant increasesin survival over a 3-year period but none longer than that. Screening for cancer in these patients will findtumors earlier, but any survival benefit noted in studies is subject to lead-time bias, i.e., bias introduced byearlier diagnosis. I believe that long-term survival has not been proven to benefit because we have no welldocumented 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 morebeneficial. 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 riskto develop HCC already have a reduced mortality related to their liver disease. The 1-year mortality forChild-Pugh class A, B, and C cirrhosis is 100%, 80% and 45%, respectively. The natural history ofhepatocellular carcinoma is unlikely to be affected by formal surveillance programs in those patients with agreater risk to die from their liver disease. Therefore, if screening is to be performed, the patient populationto be screened must be selected very carefully to assure cost effectiveness of the screening and mortalitybenefit. In our era of evidence-based medicine, the question must now be asked whether to recommendsurveillance for hepatocellular carcinoma in patients at risk to develop the disease. There is a large amountof uncertainty present in the current literature, but after thoroughly reviewing the data, I would recommendsurveillance 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 highrisk group. Since not all patients seen in the outpatient setting will have had a liver biopsy, patients withChild’s A cirrhosis secondary to chronic HBV or HCV infection, alcohol abuse, or cirrhosis secondary tofamilial hemochromatosis should also be included in HCC surveillance. I would recommend screeningwith 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 totreatment in patients with an elevated level at diagnosis. 17
  18. 18. The debate over surveillance programs for hepatocellular carcinoma will continue until wellconstructed randomized controlled trials of treatment are published. Any progress in treating HCC willonly come from treating small HCC, whether it be by transplantation, local ablation, chemotherapy or somecombination 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. 18
  19. 19. 1 Colombo M, de Franchis R, Del Ninno E, et al. Hepatocellular Carcinoma in Italian Patients with Cirrhosis. 1991NEJM;325(10):675-80.2 Monto A, Wright TL. The Epidemiology and Prevention of Hepatocellular Carcinoma. Seminars in Oncology2001;28(5):441-9.3 El-Serag HB, Mason AC. Rising Incidence of Hepatocellular Carcinoma in the United States. NEJM March1999;340(10):745-50.4 Montalto G, Cervello M, Giannitrapani L, Dantona F et al. Epidemiology, Risk Factors, and Natural History ofHepatocellular Carcinoma. Annals of New York Academy of Sciences 2002;963:13-20.5 Befeler AS, Di Bisceglie AM. Hepatocellular Carcinoma: Diagnosis and Treatment. Gastroenterology May2002;122:1609-19.6 Pateron D, Ganne N, Trinchet JC, Aurousseau MH, Mal F, Meicler, C, et al. Prospective study of screening forhepatocellular 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 toDevelop 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 CancerDetected 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 Detectionof 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 theChance 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 effectiveanalysis. Gut 2001;48:251-9.