Hepatocellular Carcinoma: Targeted Therapy and Multidisciplinary P12 pot

7 Evidence-Based Guidelines for Treatment of Hepatocellular Carcinoma in Japan 95 Revisions of the Guidelines Based on the Latest Knowledge There have been remarkable advances in the management of HCC recently, and the content of parts of the 2005 version of the guidelines, which was based on the literature as of 2002, has become outdated. The work of adding new knowledge and evidence discovered in the period 2003–2007 and revising them is currently under way at present. The widespread adoption of RFA would seem to be the greatest change that can contribute to the treatment algorithm since 2003. RFA enables reliable treat- ment of a larger area via a single puncture and was introduced in Japan around 1999. Since then it has been widely adopted and becoming covered by Japanese national health insurance in April 2004 provided an added boost, so that now it can be said to have replaced PEI. Moreover, the results of RCTs comparing RFA and PEI have been published [14, 15], and the superiority of RFA over PEI appears to have been established as evidence level Ib. Accordingly, not only the answers to the research question group related to percutaneous ablation treatment cited in the 2005 version but the research questions themselves may become the targets of revision. Evaluation of the efficacy of treatment by liver resection and percutaneous abla- tion treatment has also had an impact on the widespread adoption of RFA. The 2005 version of the treatment algorithm is based on the results of treatment by liver resection and PEI, but now that the superiority of RFA over PEI has been established, a comparison between liver resection and percutaneous ablation treat- ment should be performed based on the results of RFA. The results of two RCTs in 2005–2006 have been reported [16, 17], and both of them concluded that the results of liver resection and percutaneous ablation treatment were equivalent. However, there were major problems with both of them, including in their design, and neither of them could be regarded as providing adequate evidence [18]. A paper compar- ing the outcome of liver resection, RFA, and PEI based on a nationwide follow-up survey by the Liver Cancer Study Group of Japan has recently been published [19]. Although the results showed that liver resection was significantly better in cases of recurrence, the differences in survival were not significant; however, the short follow-up period was a problem. The conduct of a high-quality RCT that is able to rigorously evaluate the outcome of RFA and liver resection is awaited in the future. The recommendations of the Japanese guideline about liver transplantation are based on the results of deceased liver transplantation outside Japan. There is a rapid increase in the number of living-donor liver transplantations for HCC in Japan since 1999 [20]. Thus, the recommendations should be amended in an algorithm that reflects their results. Moreover, the results of an RCT that showed the efficacy of a multikinase inhibitor (Sorafenib) against advanced HCC were reported in 2008 [21]. Since there has never been a drug whose efficacy against HCC was demonstrated by a statis- tically significant difference in as sufficient a number of cases as in this study, it generated considerable interest. 96 K. Hasegawa and N. Kokudo Conclusion Because many effective methods are available to treat HCC and the balance between tumor status and liver function status must be taken into consideration, the judgment of skilled specialists is required to make the choice of treatment. On the other hand, the principle of treatment selection based on the hopes and preferences of patients, socioeconomic circumstances, etc., is also important. The treatment algorithm of the Japanese guideline extracts evidence at and above a certain level and reflects it, and it is useful for explaining the complex decision-making process to patients in a way that is easy to comprehend, and for obtaining their understanding in clinical settings, where time is limited. References 1. Makuuchi M, Kokudo N (2006) Clinical practice guidelines for hepatocellular carcinoma: the first evidence based guidelines from Japan. World J Gastroenterol 12:828–829 2. Makuuchi M, Kokudo N, Arii S et al (2008) Development of evidence-based clinical guide- lines for the diagnosis and treatment of hepatocellular carcinoma in Japan. Hepatol Res 38:37–51 3. Liver Cancer Study Group of Japan (1997) Classification of primary liver cancer. Kanehara & Co., Ltd., Tokyo p. 21 4. Makuuchi M, Kosuge T, Takayama T et al (1993) Surgery for small liver cancers. Semin Surg Oncol 9:298–304 5. Llovet JM, Brú C, Bruix J (1999) Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis 19:329–338 6. Bruix J, Sherman M (2005) Management of hepatocellular carcinoma. Hepatology 42: 1208–1236 7. Ishizawa T, Hasegawa K, Aoki T et al (2008) Multiple tumors and concomitant portal hyper- tension are not operative contraindications for hepatocellular carcinoma. Gastroenterology 134:1908–1916 8. Vauthey JN, Lauwers GY, Esnaola NF et al (2002) Simplified staging for hepatocellular carcinoma. J Clin Oncol 20:1527–1536 9. Arii S, Yamaoka Y, Futagawa S et al (2000) Results of surgical and nonsurgical treatment for small-sized hepatocellular carcinomas: a retrospective and nationwide survey in Japan. Hepatology 32:1224–1229 10. Llovet JM, Real MI, Montaña X et al (2002) Arterial embolisation or chemoembolisa- tion versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomized controlled trial. Lancet 359:1734–1739 11. Minagawa M, Makuuchi M, Takayama T et al (2001) Selection criteria for hepatectomy in patients with hepatocellular carcinoma and portal vein tumor thrombus. Ann Surg 233: 379–384 12. Eddy DM (1990) Clinical decision making: from theory to practice. Designing a practice policy. Standards, guidelines, and options. JAMA 263:3077, 3081, 3084 13. Kokudo N, Sasaki Y, Nakayama T et al (2007) Dissemination of evidence-based clinical prac- tice guidelines for hepatocellular carcinoma among Japanese hepatologists, liver surgeons, and primary care physicians. Gut 56:1020–1021 14. Lencioni RA, Allgaier HP, Cioni D et al (2003) Small hepatocellular carcinoma in cirrho- sis: randomized comparison of radio-frequency thermal ablation versus percutaneous ethanol injection. Radiology 228:235–240 7 Evidence-Based Guidelines for Treatment of Hepatocellular Carcinoma in Japan 97 15. Shiina S, Teratani T, Obi S et al (2005) A randomized controlled trial of radiofrequency abla- tion with ethanol injection for small hepatocellular carcinoma. Gastroenterology 129:122–130 16. Huang GT, Lee PH, Tsang YM et al (2005) Percutaneous ethanol injection versus surgical resection for the treatment of small hepatocellular carcinoma: a prospective study. Ann Surg 242:36–42 17. Chen MS, Li JQ, Zheng Y et al (2006) A prospective randomized trial comparing percuta- neous local ablative therapy and partial hepatectomy for hepatocellular carcinoma. Ann Surg 243:321–328 18. Hasegawa K, Kokudo N, Makuuchi M (2008) Surgery or ablation for hepatocellular carci- noma? Ann Surg 247:557–558 19. Hasegawa K, Makuuchi M, Takayama T, et al. for the Liver Cancer Study Group of Japan (2008) Surgical resection vs. percutaneous ablation for hepatocellular carcinoma: a preliminary report of the Japanese nationwide survey. J Hepatol 49:589–594 20. Todo S, Furukawa H, Tada M; Japanese Liver Transplantation Study Group (2007) Extending indication: role of living donor liver transplantation for hepatocellular carcinoma. Liver Transpl 13(11 Suppl 2): S48–S54 21. Llovet JM, Ricci S, Mazzaferro V, et al. for SHARP Investigators Study Group (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378–390 Chapter 8 Hepatocellular Carcinoma Arising in the Non-viral, Non-alcoholic Liver Charles E. Woodall, Robert C.G. Martin, Kelly M. McMasters, and Charles R. Scoggins Keywords HCC risk factors · HCC in the non-fibrotic liver · Non-cirrhotic hepatoma · Fibrolamellar carcinoma (FLC) · Hereditary hemochromatosis (HH) · Non-alcoholic fatty liver disease (NAFLD) Hepatocellular carcinoma is one of the five most common cancers worldwide and is one of the top three in regard to annual mortality. Greater than 80% occur in either sub-Saharan Africa or East Asia, and most of these cases are attributed to viral hepatitis. Increased public awareness and educational campaigns have led to decreasing incidences in these endemic areas. However, the rate of HCC in a number of areas with traditionally low rates of viral hepatitis, including Australia, the United States, Canada, and the United Kingdom, has increased significantly. This rising incidence cannot be easily explained by changes in immigration, hepatitis C virus, or ethanol. Risk Factors for Hepatocellular Carcinoma It is widely known that chronic hepatitis B and C virus infection remains the most dominant risk factor in HCC incidence. Other well-known hepatocellular carci- noma risk factors include alcoholic cirrhosis and carcinogen exposure. The universal belief has always been that cirrhosis precedes the development of HCC, even in the United States where continued reports state that approximately 95% of HCC arises in the background of cirrhosis [1]. Indeed, most cases of HCC occur in the setting of cirrhosis, thus impacting the treatment modalities available. However, some cases of HCC arise in a normal liver in patients with no history of alcoholism and negative viral serologies. A certain proportion of these cases are R.C.G. Martin (B) Division of Surgical Oncology, Department of Surgery, University of Louisville School of Medicine, Louisville, KY, USA 99 K.M. McMasters, J N. Vauthey (eds.), Hepatocellular Carcinoma, DOI 10.1007/978-1-60327-522-4_8, C  Springer Science+Business Media, LLC 2011 100 C.E. Woodall et al. associated with rare etiologies such as non-alcoholic fatty liver disease, hemochro- matosis, aflatoxin exposure, or variant subtypes of hepatoma not associated with cirrhosis. Recently, epidemiologic research has generated data demonstrating the emergence of HCC in the absence of underlying liver disease. These data may par- tially explain why there has been a two-fold increase in the age-adjusted incident rate of HCC in the United States between 1985 and 2002 [2]. This incidence has caused an increase of 1.3 per 100,000 during 1978–1980 to 3.3 per 100,000 during 1999–2001 [3]. Interestingly, the largest increase during this period has occurred in Caucasians (including Hispanics) while the lowest increase has been within the Asian population. More recent reports have demonstrated that as many as 40% of the HCC diagnosed in the United States is of unknown cause (i.e., no alcohol, hepatitis, or cirrhosis) [3] (Fig. 8.1). Aflatoxin Alcohol Chronic HBV Genetic disease e.g. hemochromatosis HCV Cirrhosis (Genetic Alterations) Unknown Environmental Exposure Genetic Polymorphisms Unknown Viral Exposure HCC Age and Gender Fig. 8.1 Potential causes of non-cirrhotic hepatocellular cancer 8 Hepatocellular Carcinoma Arising in the Non-viral, Non-alcoholic Liver 101 HCC in the Non-fibrotic Liver The etiology of HCC in patients without chronic hepatitis infection or chronic cir- rhosis from other causes remains unclear. To date, because of the overwhelming data demonstrating that most cases of HCC arise in the cirrhotic liver (either associated with viral hepatitis or alcohol-related damage), there has been little attention on the increasing incidence of HCC in patients who lack fibrosis. Recent data from centers in the central United States have shed some light onto the rising incidence of HCC in the absence of fibrosis. It is quite possible that national increase in the incidence of HCC reflects similar increases in HCC among patients without hepatitis or cir- rhosis in other regions [4]. Why some patients with apparently normal liver tissue would develop HCC is poorly understood. One reason for the increased incidence of HCC may be related to changes in the diagnostic criteria used in epidemiologic databases. In the 1970s and early 1980s, the SEER database only recorded histologically confirmed cases of HCC. While this is highly specific, it may underestimate the true incidence of HCC. The average yearly age-adjusted incidence rates of all HCC captured by the SEER database irre- spective of the method of diagnosis have increased approximately 30%. Because the diagnosis of HCC now can occur without histologic confirmation, based on the pres- ence of underlying cirrhosis, nodular mass seen CT or MRI, and an elevated AFP level, the corresponding increased incidence in the SEER database may be partially related to these changes in diagnostic criteria. Similarly, with the rapid rise in hepatic resections now being performed at all age groups, some patients who were initially diagnosed and treated for cancer of unknown primary are now being appropriately being diagnosed as having HCC. Perhaps the true incidence of HCC is not rising as quickly as previously described; instead, there might be some shift in the diagnosis, with the incidence of carci- noma of unknown primary decreasing as our ability to appropriately diagnose these patients as having either HCC or intrahepatic cholangiocarcinoma improves. A more liberal policy of resection in appropriate patients who were initially diagnosed as unknown primary cancers has led to more precise diagnoses, some of which are HCC. This type of policy may also contribute to the higher regional incidence of the non-cirrhotic hepatoma [4]. Other potential etiologies for the increasing incidence of the non-cirrhotic hep- atoma may include the ever-increasing age of the US population. The elderly (defined as people aged 65 years or older) will account for over 61% of all new cancer cases and 70% of all annual cancer deaths [5]. It has been recently estimated that the elderly patient population has 11 times the cancer risk of people under the age of 65 years. It has also been estimated that in 2030 approximately 20% of the US population will be older than 65 years of age [6]. These changes alone coupled with environmental exposure and potential genetic effects along with other potential causes are the reason for these rising incidence rates. This reasoning is further solidified by the significant differences in the clini- cal, radiologic, and pathologic features of the patients with non-cirrhotic hepatoma (Table 8.1) when compared to the common cirrhotic patient with HCC (Fig. 8.2). 102 C.E. Woodall et al. Table 8.1 Features of the non-cirrhotic hepatoma Patient – Advanced age – Higher incidence of women – Non-alcohol related – Generally tolerate major hepatectomy well Liver – No fibrosis – Large, solitary tumor Serum – Low to normal AFP level – Absence of evidence for viral hepatitis – Preserved hepatic synthetic function AFP, alpha fetoprotein Fig. 8.2 Radiologic presentation of a cirrhotic HCC (left) with shrunken liver, ascites, and invasive lesion and non-cirrhotic HCC (right) with normal size liver, sharp liver borders, and non-evidence of nodularity The non-cirrhotic hepatoma patients are significantly older, more commonly female, less often smokers, have a greater incidence of a normal alpha-fetoprotein level, larger sized tumors, and a smaller number of tumors (most commonly a single liver tumor). These more favorable features have led to an ability to be more surgically aggressive in these patients because of their underlying normal hepatic parenchyma. This variant histology responds well to aggressive surgical resection with a lower risk for hepatic failure postoperatively [4]. In a review of Kentucky’s patients with HCC, we have seen a fourfold increase i n age-specific HCC diagnosis, with the most rapid increase seen in the 60- to 69-year- old age group. We also have frequently observed the phenomenon in older patients, without hepatitis or cirrhosis, who have large solitary tumors and normal AFP levels. We have described these as “Kentucky hepatomas” because of the unique disease presentation that differs from most other regions with a greater endemic hepatitis population. In the University of Louisville database of hepatobiliary cancer, 60% of HCC patients were without hepatitis or cirrhosis (Fig. 8.3). These non-cirrhotic, hepatitis-free patients were found to be significantly older (70 vs. 55 years; P = 0.001), to be more often female (40.3 vs. 24.4%; P = 0.01), to have a larger tumor size (6.5 vs. 3.9 cm; P = 0.004), to have fewer liver lesions (median 1 vs. 3; P = 0.22), and to more frequently undergo surgical therapy (75.6 vs. 53.8%; P = 0.01) than the patients with cirrhosis or hepatitis. Furthermore, the non-cirrhotic, 8 Hepatocellular Carcinoma Arising in the Non-viral, Non-alcoholic Liver 103 Fig. 8.3 Age-specific increase in incidence of HCC in t he state of Kentucky. Y-axis is percent of patients in each of the age groups specified non-hepatitis patients had a median AFP level of 16 vs. 320 in the group with hep- atitis or cirrhosis (P = 0.02). We found that there was a similar increase in HCC incidence across all 5 regions of Kentucky. Whether this phenomenon is specific to Kentucky (and other regions of the Midwest) is not known; however, others have seen a similar rise in HCC without cirrhosis. In a comparison of other studies that have presented the incidence of this variant non-cirrhotic HCC, the data from the University of Louisville demonstrate the single largest incidence rate. A recent report from Reichman demonstrated an incidence of 26%; however, it also noted a worse overall survival when compared to the cirrhotic population [7]. Similar high incidence (31%) was reported from Fong et al., with- out a difference in overall survival [8]. Both of these reports were from the United States, i n New Jersey and New York, which has a higher incidence of Asian immi- grants and thus probable higher incidence of hepatitis. Other reports have detailed the incidence of this variant HCC in Europe and Asia [9–11] to be much lower, most likely due to etiologic influences. Fibrolamellar Carcinoma Fibrolamellar carcinoma (FLC) was first described by Edmonson in 1956 [12]. It is a rare hepatic malignancy, comprising less than 1% of primary liver malignancies in a US population-based study [13]. The histologic appearance of FLC is distinc- tive, consisting of deeply eosinophilic malignant hepatocytes surrounded by thick fibrous bands arranged in a lamellar-like fashion [14]. Radiographically, the tumors are hyper-vascular and tend to be large, be calcified, and have a central scar [15], all distinct differences from conventional HCC (Table 8.2). Many consider it a variant of HCC, though the epidemiology, clinicopathologic factors, and prognosis differ widely from HCC. FLC is largely tumors of youth and young adulthood. The median age of patients with FLC is on the order of 25 years [16–18], far younger than conventional HCC. 104 C.E. Woodall et al. Table 8.2 Differences between fibrolamellar carcinoma and traditional HCC Fibrolamellar Traditional HCC Patient related Young age Lack fibrosis Better survival Patient related Older age Cirrhotic Worse survival Tumor related Central scar Typically solitary Higher resection rate Tumor related No scar Often multifocal Lower resection rate FLC is not associated with an underlying history of cirrhosis [19–21], and this fact may account for the differences in age distribution, given that a background of fibrosis is not common in younger populations. There also does not appear to be any connection with viral hepatitis, ethanol, or estrogen use, all factors commonly considered in association with conventional HCC [19]. There are conflicting data comparing the survival of patients with FLC with traditional HCC. Some authors have reported no survival benefit for FLC patients who have undergone resection (when compared to traditional HCC), although the number of cases was too small to draw firm conclusions [22]. These data are sim- ilar to that published by others, although the rate of resectability for patients with FLC might be higher [23]. In contrast to these data are reports demonstrating an improved survival for patients with FLC, including one report of a 56% 5-year sur- vival for resected patients [24]. Further data suggesting a more favorable biologic behavior for FLC include high resectability rates and improved survival following resection [17, 19, 20, 23]. Like traditional HCC, FLC is prone to recurrence following resection. The most common site for recurrence appears to be in the liver remnant. Unlike traditional HCC, however, recurrent FLC might fare better following recurrence. Data demon- strate that patients with recurrent FLC survive longer than those patients with recurrent traditional HCC [25, 26]. Furthermore, patients with recurrent FLC might be amenable to re-resection, with data demonstrating a survival advantage to this aggressive approach [27]. FLC might have a higher risk for nodal metastasis upon presentation, and the rate of metastatic lymph nodes has been reported to be as high as 30% [28]. This raises the question of the role of routine portal lymphadenectomy at the time of initial hepatectomy. Hereditary Hemochromatosis Hereditary hemochromatosis (HH) is an autosomal recessive syndrome of iron overload. It is characterized by increased absorption of iron in the intestines with deposition in organs such as the heart, skin, pancreas, pituitary, and liver [29]. It is an under-recognized congenital condition caused by missense mutations at the HFE gene; some authors report HH is 10 times more common than cystic fibrosis [30], . and above a certain level and reflects it, and it is useful for explaining the complex decision-making process to patients in a way that is easy to comprehend, and for obtaining their understanding. small hepatocellular carcinoma: a prospective study. Ann Surg 242:36–42 17. Chen MS, Li JQ, Zheng Y et al (2006) A prospective randomized trial comparing percuta- neous local ablative therapy and. unresectable hepatocellular carcinoma: a randomized controlled trial. Lancet 359:1734–1739 11. Minagawa M, Makuuchi M, Takayama T et al (2001) Selection criteria for hepatectomy in patients with hepatocellular