The number of papers published in the topic of hepatocellular carcinoma (HCC) increased remarkably from last year. The prevalence of chronic hepatitis C infection has increased the incidence of HCC. However, studies confirm that obesity and nonalcoholic fatty liver disease are important factors for the development of HCC in the United States. Alpha-fetoprotein is the most widely used tumor marker, but has poor diagnostic accuracy and ethnic variability. Using proteonomic genome analysis, new candidate tumor markers have been identified but await validation. Dynamic gadolinium magnetic resonance imaging seems to be more sensitive than spiral computed tomography scan for the identification of HCC, and seems to be modality of choice in most centers. Transplantation offers the best long-term option for patients with HCC, but in a certain group of patients without portal hypertension and well-preserved liver function, surgical resection is an acceptable option. A large study from Europe confirms the utility of resection in some patients with early HCC. However, most patients are not candidates for curative intervention. A meta-analysis and a randomized, controlled trial showed that chemoembolization offers a survival advantage in selected patients (Child class A and B) with nonresectable HCC. Finally, chemoprevention in patients with chronic hepatitis C infection with interferon is a promising strategy to prevent HCC.
Epidemiology
Hepatocellular carcinoma (HCC) is the fourth most common cancer worldwide.[1]
Its incidence rate, however, has been increasing over the last two decades of the 20th century. In the United States, the reported incidence has increased to 4.7/100,000.[2]
In both cases, the male population, both black and white, is primarily affected. However, the incidence of HCC in eastern Asia and middle Africa is more than five times that of North America. Furthermore, from 1981 to 1985 the peak incidence of HCC occurred in patients 80 to 84 years of age, whereas from 1991 to 1995 the peak was noted in persons 74 to 79 years of age. This shift in incidence toward younger persons seen over the last two decades coincides with the prevalence of the hepatitis C infection.[3*, 4]
Risk Factors
A population-based study from China sought to identify risk factors for the development of hepatocellular carcinoma.[5*]
An adult cohort between 25 and 64 years of age was followed between 1992 and 2000. The male cohort included 58,545 men, 15% of whom were hepatitis B (HBV) carriers. The female cohort included 25,340 women, 10.7% of whom were HBV carriers. Using a Cox proportional hazard model, HCC mortality was associated with HBV infection (relative risk (RR) 18.8: 95% CI 15.7-22.5) and a family history of HCC (RR 2.3, 95% CI 1.9-2.7). For women, HCC mortality was associated with HBV infection (RR 33.5: 95% CI 17.1-65.5) and acute hepatitis history (RR 4.7: 95% CI 3-7.5). The HCC risk was not associated with alcohol consumption, water source, or staple foods. An association was seen between tobacco smoking and women with HCC, but this was not seen in men. Another population-based study evaluated families of patients with HCC to determine the number of fatalities and potential risks for developing HCC in these families.[6]
From 1992 to 1997, 15,410 relatives of patients with HCC in three generations were screened for HCC in Taiwan. Using the national citizen identification numbers, the authors searched the total fatalities in the relatives of those with HCC. Of those studied, 37.8% were HBV surface antigen positive, 4.3% anti-HCV positive, and 1.7% had combined HCV and HBV infection. A total of 399 fatalities were detected, including 199 (35%) with HCC, of which most were HBV infected. The authors concluded that the main factor affecting the overall survival of relatives of patients with HCC is chronic viral infection with HBV. These two studies are large population-based but cannot be generalized to western countries, in which the incidence of HBV infection is lower and a higher incidence of cryptogenic liver disease is seen.
The role of hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg) in the development of HCC was also evaluated.[7**]
The authors enrolled 11,893 men without HCC from seven townships in Taiwan. After 92,359 person-years of follow-up, 111 new cases of HCC were diagnosed. The incidence rate was 1169/100,000 cases person-years among those positive for HBsAg and HBeAg, 324/100,000 person-years for those with HBsAg positive only, and 39/100,000 person-years who were negative for both. The relative risk for developing HCC was 60.2 (95% CI 35.5-102) among those positive for both HBeAg and HBsAg, compared with 9.6 (95% CI 6-15.2) among those who were negative for both. The authors concluded that the presence of HBeAg is associated with an increased risk of HCC, indicating that active replication of chronic HBV promotes carcinogenesis among those with chronic HBV infection. Another study evaluated HBV genotypes and the risk of HCC.[8]
A total of 227 patients with chronic HBV infection were studied. Of these, genotype B was predominantly seen in HBV asymptomatic carriers, whereas genotype C was predominant in those with chronic liver disease (49% of chronic hepatitis, 63% in patients with cirrhosis, and 60% of those with HCC). Therefore, the authors conclude that genotype B is associated with a decrease in the likelihood of developing HCC. Further studies are needed to validate the use of genotyping in chronic HBV infection, which may provide a useful tool in differentiating those at risk for developing HCC.
Studies from earlier years indicated that the rise in the incidence of HCC was directly related to the increase in the prevalence of HCV infection.[1]
The role of HCV genotyping on HCC development has been evaluated.[9*]
A total of 593 patients with HCV cirrhosis were followed for 15 years. Genotype 1 was present in 442 or 75% and genotype 2 in 136 or 23%. For those in genotype 1, the development of HCC at 5, 10, and 15 years of follow-up was 32%, 57%, and 71%, respectively. For those in genotype 2, the development of HCC during this time was 26%, 48%, and 71%, respectively. In a multivariate analysis, genotype 1 increased the risk of HCC in those without regular alcohol intake (hazard ratio = 2.57, P = 0.008). The authors concluded that genotype 1 is predictive of developing HCC after a significant follow-up period in patients with cirrhosis caused by HCV. A study from Japan evaluated potential risk factors for the development of HCC in 239 patients with cirrhosis.[10]
They showed a high-titer HBV viral load (> 3.7 log genome equivalents/mL) was the most predictive for the development of HCC in patients with HBV (27%). In those with HCV (70%), male gender, elevated alanine aminotransferase, and high titers of HCV RNA (>1 mEq/mL) were the most important predictors for the development of HCC. Clinical efforts at reducing viral loads in those with chronic viral hepatitis may reduce the risk of HCC, but these results need to be validated in western populations.
Recent epidemiologic observations indicate that obesity might be an independent risk factor for the development of solid organ malignancies (eg, breast cancer, colon cancer, esophageal adenocarcinoma).[11]
Therefore, a group of investigators evaluated whether obesity is a risk for developing HCC.[12*]
The authors examined explanted livers from a national database of patients with HCC. Among 19,271 evaluable patients, the overall incidence of HCC was 3.4%. Obesity was an independent predictor of HCC in patients with alcoholic cirrhosis (OR, 3.2: 95% CI 1.5-6.6) and cryptogenic cirrhosis (OR, 11.1: 95% CI 1.5-87.4). Obesity was not an important predictor for HCC in patients with HCV, HBV, primary biliary cirrhosis, and autoimmune hepatitis. It has been shown that obesity is an important factor in the development of nonalcoholic fatty liver disease (NAFLD) and, furthermore, most patients with cryptogenic cirrhosis appear to have NAFLD as the cause of their chronic liver disease.[13]
A group of investigators from Italy studied whether NAFLD is an important factor for the development of HCC.[14*]
Among 641 patients with HCC, the authors retrospectively evaluated 44 patients with cryptogenic cirrhosis. Patients had higher glucose, cholesterol, and triglyceride levels (all indirect measures of insulin resistance). Therefore, the authors conclude that features suggestive of NAFLD are frequently observed in patients with HCC. These results implicate NAFLD as an important etiological factor in the development of HCC.
Pathology
Data from experimental hepatic carcinogenesis as well as studies in humans suggest that the emergence of HCC is a stepwise progression from cirrhosis to dysplastic nodules to tumors. However, the exact molecular mechanisms are still unclear. HCC nodules obtained after resection or transplantation were analyzed using comparative genomic hybridization.[15]
Of 26 nodules, 16 were classified as regenerative nodules, 4 as low-grade dysplastic nodules, and 6 as high-grade dysplastic nodules. High-grade dysplastic nodules had deletions of chromosome 8p and gains of 1q. The low-grade dysplastic nodules and regenerative nodules did not show these features. The authors conclude that these genetic alterations are important in early hepatocarcinogenesis and suggest a molecular basis for the development of HCC in western countries. Combined HCC and cholangiocarcinoma form about 1% of liver tumors. The diagnostic features have not been established and this has possibly contributed to the variability in its reported clinical outcome. Many of these combination tumors have been considered cholangiocarcinoma in the past based on positivity for biliary-type cytokeratins and lack of HCC markers. Twenty-seven tumors were studied in which positivity for albumin mRNA and cytokeratin immunohistochemical profile confirmed the biphenotypic differentiation.[16]
Interestingly, these combined tumors showed no evidence of cirrhosis in the non-neoplastic liver and only 4 of 27 were positive for HCV or HBV. In addition, these were aggressive tumors with a 3-year survival of 30%. As the incidence of HCC increases, more of these combined tumors will be seen and further characterization of the pathologic characteristics and natural history will be important to appropriately stage these patients.
Tumor Markers
Hepatocellular carcinoma meets most of the standard criteria for instituting a cost-effective surveillance program.[17]
HCC surveillance aims to decrease disease-specific mortality, but this has not been demonstrated in prospective trials. One of the main problems has been the poor sensitivity and specificity of the available tools, -fetoprotein (AFP) and ultrasound of the liver, for the early diagnosis of HCC. Prospective studies evaluating the performance characteristics of AFP for HCC surveillance reported sensitivities of 39% to 64%, specificities of 76% to 91%, and positive predictive values of 9% to 32%.[18*-20**]
A recent study evaluated whether surveillance in patients with cirrhosis improves survival.[21]
The authors retrospectively evaluated 821 patients with HCC to see if their tumor was detected during surveillance and whether it correlated with survival. The authors concluded that semiannual and annual surveillance equally improve survival of cirrhotic patients who go on to develop HCC by increasing the amenability to liver transplantation. However, they showed that the benefit of surveillance was only in those patients with compensated cirrhosis. A study from the United States evaluated the diagnostic value of AFP in patients with chronic HCV infection and whether AFP levels differed according to ethnicity.[22*]
This was a case-control study of 163 patients with HCC and with HCV infection and 149 control HCV cirrhotics. The positive likelihood ratios for AFP levels of 0 to 20, 21 to 50, 51 to 100, and 101 to 200 ng/mL were 0.46, 1.31, 1.15, and 6.90, respectively. The area under the receiving curve was 0.81 for nonblack patients, but only 0.56 for black patients (Fig. 1). The authors conclude that an AFP greater than 200 ng/mL can be used to confirm HCC in patients with HCV-associated cirrhosis and a liver mass; however, only a few patients will meet this criterion. These results clearly indicate the need for a more sensitive and specific marker for HCC.
Figure 1. Receiver operating characteristics curves for -fetoprotein as predictors of hepatocellular carcinoma for each ethnic group. Published with permission.[22*]
Given the importance and widespread use of AFP for the diagnosis of HCC, isoforms of AFP have been developed including the lens culinaris agglutinin-reactive fraction of AFP (AFP-L3) and monosialylated AFP (msAFP). The des-gamma carboxyprothrombin (DCP) is a precursor of normal prothrombin that has been shown to be specific for HCC. A group of investigators from Japan studied the clinical significance of AFP-L3 and DCP levels in 88 patients with HCC.[23]
They showed that those patients with an elevated AFP-L3 had a higher incidence of infiltrative-type and poorly differentiated HCC. Importantly, they showed that patients with only an elevated DCP were more likely to have early HCC. In another study, the significance of msAFP through a novel glycosylation immunoabsorbent assay in 36 patients with HCC and nondiagnostic AFP, and 28 with cirrhosis and no tumor.[24*]
The msAFP was able to discriminate HCC from cirrhosis with an area under the receiver-operating curve of 0.89 (95% CI 0.70-0.92). This is a promising novel tumor marker for the diagnosis of HCC.
The development of HCC is a complex process that involves multiple changes in gene expression that occurs in the presence of chronic liver disease. Identifying proteonomic alterations in those with HCC may provide useful information in the development of diagnostic markers as well as potential therapeutic targets. In one study, proteome alterations were studied from tissue involving HCC, normal, and cirrhotic patients.[25*]
The proteome alterations were observed using two-dimensional polyacrylamide gel electrophoresis and matrix-assisted laser desorption or ionization time-of-flight mass spectrometry. A significant change in expression level was found in 21 proteins. Of these proteins, sarcosine dehydrogenase, liver carboxylesterase, peptidyl-prolyl isomerase A, and laminin B1 were considered novel markers able to differentiate normal and cirrhosis from HCC. These proteins provide a framework for further validation studies. Prior studies have indicated that serum cytokines and growth factors can be useful markers of HCC. In a case-control study from Italy, serum levels of soluble intercellular adhesion molecule-1, soluble interleukin-2 receptor, interleukin 6, and anti-p53 were examined.[26]
The authors concluded that these markers are not useful for the diagnosis and did not correlate with prognosis.
Diagnostic Imaging
Once a liver mass is suspected in patients at risk of developing HCC, further imaging is critical in the evaluation of these patients. Two studies tried to address the issue of which modality, computed tomography (CT) or magnetic resonance imaging (MRI), is more accurate for the diagnosis of HCC. In a study from The Netherlands, the authors performed prospectively compared triple-phase CT and dynamic MRI in 61 patients with HCC.[27*]
Imaging data were compared with the histopathologic examination of surgical specimens. MRI detected more lesions (189 vs 124, P< 0.001) and overall smaller lesions than triple phase CT scanning (1.0 cm vs 1.8 cm, P< 0.001). No difference in accuracy was seen between CT and MRI for lesion characterization. The authors conclude that MRI can detect more and smaller lesions than CT scan, but the techniques are comparable in terms of classification of lesions for management. MRI may be preferred, because of no exposure to radiation and a non-nephrotoxic contrast agent is used. In another study from France, the investigators also prospectively evaluated the accuracy of MRI and triple-phase spiral CT scan for the diagnosis of hepatic nodules in cirrhotic patients compared with histopathology.[28*]
Thirty-four cirrhotic patients awaiting liver transplantation were studied. They showed a sensitivity of MRI and spiral CT for all nodules, HCC, and dysplastic nodules of 44.3% and 32% (P = 0.02), 61% and 52% (P = 0.2), and 27% and 0% (P = 0.04), respectively. MRI is more accurate than spiral CT for the detection of liver nodules but not for HCC nodules. Tumor size is a restricting factor for these two techniques, which were unable to detect small HCC (< 2 cm) in 60% of the cases. Therefore, these techniques are important in the evaluation of patients with liver masses, with MRI slightly more sensitive. However, these techniques have serious tumor size limitations. In the future, it is hoped that the combination of these imaging techniques and novel tumor markers will improve the detection of HCC.
Tumor Staging
The goal of tumor staging is to separate patients into different groups based on their predicted survival to help determine the most appropriate treatment modality. The currently available staging systems for HCC include the pathologic tumor-node-metastasis (pTNM), Okuda, Cancer of the Liver Italian Program (CLIP), and Barcelona Clinic Liver Cancer.[29**]
No one staging system has been shown to be superior. A study from Toronto evaluated the use of CLIP staging in a cohort of patients with HCC and compared it with the Okuda staging system.[30]
A retrospective analysis of 257 patients with HCC found that the overall median survival was 22 months. CLIP stage 0 and Okuda stage 1 had a 5-year survival rate of 67% and 35%, respectively. Patients with a CLIP >/= 4 had a median survival of 3 months. The authors conclude that the CLIP score was easy to implement and more accurate than the Okuda staging, despite having a predominant HBV cohort (compared with the original CLIP cohort that was predominantly HCV infected). In another interesting study from Hong Kong, the investigators examined whether a new staging prognostic index was more discriminant than other staging systems (pTNM, Okuda, and CLIP staging systems).[31]
A total of 926 patients prospectively collected over a 2-year period form the cohort of this study. The Chinese University Prognostic Index (CUPI) was constructed by adding the following factors: total bilirubin, ascites, alkaline phosphatase, AFP, and asymptomatic disease on presentation. The new CUPI characterized three groups with highly significant differences in survival and was more discriminant than the other systems (P< 0.00001). The authors conclude that in this HBV predominant population of patients with HCC, the CUPI was more discriminating than pTNM, Okuda, or CLIP in terms of predicting survival and stratifying into risk groups. All of the known staging systems need to be validated in large western trials of HCV-predominant HCC.
Treatment
Only 10% to 13% of patients diagnosed with HCC are eligible for curative treatments, which include liver transplantation, surgical resection, or tumor ablative therapies. Of these therapies, liver transplantation has the best 1-, 3-, and 5-year survival rates of 78%, 63%, and 57%, respectively.[32]
Liver resection has been demonstrated in Asia to be the best therapeutic option in patients with HCC, but the value of this treatment in western countries is controversial. In a single center in Europe with 328 resections for HCC, the overall survival rates were 81%, 57%, and 37% at 1, 3, and 5 years, respectively.[33]
The 5-year survival rate was higher among patients with normal liver compared with those with chronic liver disease (50% vs 34%, P< 0.05). Therefore, chronic liver disease is a major factor influencing short- and long-term prognosis following surgical resection.
Once HCC is determined not to be resectable, no standard treatment has been shown to be effective. Arterial embolization or chemoembolization is used widely, but evidence of survival benefit is lacking. The group from Barcelona performed a randomized, controlled trial (RCT) of 112 unresectable HCC to assess the survival benefits of repeated arterial embolization (gelatin sponge) or chemoembolization (gelatin sponge plus doxorubicin) versus conservative treatment.[34*]
The trial was stopped early as chemoembolization had survival benefits compared with conservative treatments (hazard ratio of death 0.47 [95% CI 0.25-0.91], P = 0.025). Survival probabilities at 1 and 2 years were 75% and 50% for embolization, 82% and 63% for chemoembolization, and 63% and 27% for control (chemoembolization vs control, P = 0.009). Therefore, chemoembolization improved survival of highly selected (Child class A or B) patients with unresectable HCC. A meta-analysis of RCT evaluating chemoembolization versus conservative treatment was performed.[35*]
5 RCT were identified in which chemoembolization was compared with nonactive treatment, and 13 RCT involving different transarterial modalities. Chemoembolization significantly reduced the overall 2-year mortality rate (OR 0.54, 95% CI 0.33-0.89, P = 0.015) compared with nonactive treatment (Fig. 2). No evidence indicated that chemoembolization was more effective than embolization (OR 1.007, 95% CI 0.79-1.27, P = 0.95), which suggests that the addition of an anticancer drug did not improve the therapeutic benefit.
Figure 2. Seven comparisons of mortality rates. Plot illustrates findings from meta-analysis of the overall 2-year mortality rate in five randomized, controlled trials (seven comparisons) in which chemoembolization was performed for unresectable hepatocellular carcinoma. The bold vertical line represents the equivalence line (odds ratio of 1) between chemoembolization and nonactive treatment. Odds ratios of less than 1 (to the left of the equivalence line) favor chemoembolization, and odds ratios of greater than 1 (to the right of the equivalence line) favor nonactive treatment. When the error bar does not cross the equivalence line, a significant difference exists between treatment and control groups. Data are shown on a logarithmic scale. *Odds ratio for each trial and the overall estimate. The error bars represent the 95% confidence intervals of each estimate. Published with permission.[35*]
In addition to arterial chemoembolization, systemic chemotherapy is also used widely, but survival benefit is lacking. In a trial from France, 21 patients with advanced HCC were treated with epirubicin, cisplatin, and 5-fluorouracil.[36]
The median survival was 10 months. Actuarial survivals (± SD) at 6 months, 1 year, and 2 years were 90% ± 9%, 70% ± 10%, and 24% ± 19%, respectively. Only three patients had objective tumor responses with delay in tumor progression of 5.9 ± 4 months. In conclusion, this regimen gave a poor response and low survival rates. Another study evaluated gemcitabine in 30 patients with advanced HCC.[37]
No complete or partial responses were observed. Only 9 patients had stable disease (median duration 7.4 months, range 2-17). Median survival was 6.9 months (95% CI 4.5-13.5). Although well tolerated, gemcitabine had minimal effect in patients with advanced HCC. Another study evaluated intraarterially delivered cisplatin and etoposide in 26 patients with advanced HCC.[38]
The median survival time was 10 months. In an intention-to-treat analysis, an overall response was seen in 38% of patients. Four treatment-related deaths occurred among the patients. The authors conclude that intraarterial therapy with cisplatin and etoposide seems to have antitumor effects in advanced HCC, but a high-rate of life-threatening complications precludes this form of treatment. Prior studies suggest that long-acting octreotide had antitumor effects in patients with non-resectable HCC. A placebo RCT examined the efficacy of long-acting octreotide (Sandostatin LAR, Sandoz Pharmaceuticals, East Hanover, NJ, USA) for the treatment of advanced HCC.[39]
Patients (N = 70) were randomized to octreotide or control. No difference was seen in the cumulative survival between the octreotide-treated group and controls (median survival 1.93 vs 1.97 months, respectively, P> 0.05). No tumor regression, no reduction in AFP, and no improvement in the quality of life were seen in the octreotide-treated group. Thus, chemotherapy has no therapeutic role in the treatment of advanced HCC. Novel therapies are needed to improve the overall survival and quality of life of those patients with advanced tumors.
The increasing incidence of HCC anticipated over the next 10 to 15 years will lead to a large number of patients who are not candidates for potential curative intervention. Therefore, aims at preventing tumor formation are crucial, especially in those with chronic HCV infection. A study evaluated whether interferon retreatment in previous nonresponders reduces the incidence of HCC in patients with chronic HCV infection.[40]
A total of 309 virologic nonresponders were identified, in whom 99 received interferon alfa and 210 did not, and followed for more than 2 years. The cumulative incidence of HCC was significantly lower in retreated patients. These results suggest that interferon retreatment delays the development of HCC. The result of this study is exciting and we anxiously await the results of the HALT-C trial, a National Institutes of Health-funded trial in the United States investigating whether long-term treatment with pegylated interferon reduces the development of HCC and hepatic decompensation in patients with HCV and advanced fibrosis.
Conclusion
The incidence of HCC is rising and is expected to continue to rise over the next 15 years. Although the increase in the incidence of HCC is related to chronic HCV infection, NALD is an important etiologic factor in patients with HCC. AFP is the most widely used tumor marker for HCC, but its diagnostic accuracy is poor. Proteonomic evaluation is an important tool in the discovery of novel proteins specific to hepatic carcinogenesis, which may lead to novel tumor markers as well as therapeutic targets. Widespread use of tumor surveillance should help identify patients at early stages where curative therapy can be given. Liver transplantation remains the best therapeutic intervention that offers the longest disease-free interval. In selected patients with nonresectable HCC and good hepatic synthetic function, chemoembolization seem to offer a survival advantage versus no treatment. Otherwise, systemic chemotherapy has not been shown to be effective for the treatment of nonresectable HCC. Long-term interferon should be explored as a chemopreventative agent in patients with chronic hepatitis C.
References
Papers of particular interest, published within the annual period of review, have been highlighted as:
* Of special interest
** Of outstanding interest
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4. * An excellent review of the epidemiology and natural history of hepatocellular carcinoma.
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25. * A prospective study of the evaluation of a surveillance program for HCC
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28. ** Conclusions from an international meeting on HCC.
29. Trevisani F, De NS, Rapaccini G, et al.: Semiannual and annual surveillance of cirrhotic patients for hepatocellular carcinoma: effects on cancer stage and patient survival (Italian experience). Am J Gastroenterol 2002, 97:734-744.
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31. * A study of the efficacy of AFP and its ethnic variations in HCV-induced cirrhosis.
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33. Poon TC, Mok TS, Chan AT, et al.: Quantification and utility of monosialylated alpha-fetoprotein in the diagnosis of hepatocellular carcinoma with nondiagnostic serum total alpha-fetoprotein. Clin Chem 2002, 48:1021-1027.
34. * An interesting study that evaluated a new isoform of AFP as a potential tumor marker.
35. Lim SO, Park SJ, Kim W, et al.: Proteonome analysis of hepatocellular carcinoma. Biochem Biophys Res Commun 2002, 291:1031-1037.
36. * The first proteonomic analysis of hepatocellular carcinoma tissue yielding potential new tumor markers.
37. Parasole R, Izzo F, Perrone F, et al.: Prognostic value of serum biologic markers in patients with hepatocellular carcinoma. Clin Cancer Res 2001, 7:3504-3509.
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39. * A prospective study comparing MRI versus CT showing that MRI is more sensitive for detecting HCC in cirrhotics.
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41. * A prospective study comparing MRI and CT in the diagnosis of HCC, which showed an improved sensitivity of MRI for the detection of HCC.
42. Befeler AS, Di Bisceglie AM: Hepatocellular carcinoma: Diagnosis and treatment. Gastroenterology 2002, 122:1609-1616.
43. ** An excellent review of the diagnosis and treatment of HCC.
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49. * A RCT of chemoembolization versus conservative treatment, indicating a survival advantage of chemoembolization.
50. Camma C, Schepis F, Orlando A, et al.: Transarterial chemoembolization for unresectable hepatocellular carcinoma: meta-analysis of randomized controlled trials. Radiology 2002, 224:47-54.
51. * A meta-analysis of RCT of chemoembolization versus no treatment showing shows a survival advantage for chemoembolization in patients with advanced HCC.
52. Boucher E, Corbinais S, Brissot P, et al.: Treatment of hepatocellular carcinoma with systemic chemotherapy combining epirubicin, cisplatinum and infusional 5-fluorouracil. Cancer Chemother Pharmacol 2002, 50:305-308.
53. Fuchs CS, Clark JW, Ryan DP, et al.: A phase II trial of gemcitabine in patients with advanced hepatocellular carcinoma. Cancer 2002, 94:3186-3191.
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Reprint Address
Correspondence to Jorge A. Marrero, MD, Department of Internal Medicine, University of Michigan Medical Center, 3912 Taubman Center, Box 0362, Ann Arbor, MI 48109-0362, USA; e-mail: jmarrero@umich.edu
Abbreviation Notes
AFP, -fetoprotein; CLIP, Cancer of the Liver Italian Program; CT, computed tomography; CUPI, Chinese University Prognostic Index; DCP, des-gamma carboxyprothrombin; HBV, hepatitis B; HbeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HCC, hepatocellular carcinoma; HCV, hepatitis C; MRI, magnetic resonance imaging; msAFP, monosialylated AFP; NADL, nonalcoholic fatty liver disease; PTNM, pathologic tumor-node-metastasis; RCT, randomized, controlled trials
Jorge A. Marrero, MD, Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA
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