2009 Practice Guidelines for the Management of Hepatocellular Carcinoma

Transcription

1 <Special Contribution> 2009 Practice Guidelines for the Management of Hepatocellular Carcinoma Korean Liver Cancer Study Group and National Cancer Center, Korea Introduction In Korea, over 14,000 (11,264 males and 3,643 females, year 2005) patients with newly developed primary liver cancer (liver cancer) were annually reported. It is the fourth prevalent cancer preceded by gastric cancer, lung cancer and colon cancer. 1 Recently, as the occurrence of Western-style malignancies have rapidly increased in Korea, the ranking of liver cancer has relatively been lowered. However, the number of occurrences of liver cancer has steadily increased and the incidences of liver cancer development are on the rise in the world as well. 1,2 Liver cancer is the major cause of mortality of Korean males in their 50s. There are 22.7 liver cancer deaths (34.1 male, 11.2 female) per a population of 100,000 people annually. 3 Hepatocellular carcinoma (HCC) takes up about 75% of the Korean liver cancer cases. 4 The five-year survival rate of liver cancer shows a poor prognosis of 18.9% 1 The cause of poor prognosis of HCC was suggested as follows: First, it causes micro- and macro-vascular invasion eventhough early and small cancer, and has an aggressive biologic characteristic. Second, most HCC is accompanied by chronic hepatitis or liver cirrhosis, which interferes with cancer treatment. Third, most HCC does not have specific symptoms and may lead to a very advanced state in absence of periodic checkups, making it difficult to arrive at a cure. 5 Fortunately, however, ever since the cancer survival rate report which began in 2002, the five-year survival rate has shown a steady improvement in Korea. 1 This progress owes to various promotions of early detection of liver disease including the National Screening Program for Cancer and to the result of generalized antiviral treatment against the underlying chronic hepatitis B of HCC patients. Concerns and efforts to increase the survival rate by having early diagnosis of HCC and optimal treatments are keenly needed. Western guideline for the management of HCC were developed, but these guidelines were somewhat unsuitable for Korean patiens. Thus, the Korean Liver Cancer Study Group (KLCSG) and the *Annotation: These guidelines are organized opinions for which specialists reviewed medical evidence available up to now so that they may actually be used as references for clinical practice, research and education of hepatocellular carcinoma. These guidelines are intended to be flexible, in contrast to standards of care, which are inflexible policies to be followed in every cases. These guidelines were prepared by a joint collaboration of the Korean Liver Cancer Study Group (KLCSG) and the National Cancer Center, Korea (NCC, Korea). This may not be revised, changed or assumed without prior consent from these two institutions. **Corresponding author: Joong-Won Park, ; jwpark@ncc.re.kr; phone: ; fax: ; address: 111 Jungbalsan-ro, Ilsandong-gu, Goyang, Gyeonggi , South Korea ***Acknowledgement: This work was supported by National Cancer Center, Korea (grant # , # ) and a fund from Korean Liver Cancer Study Group

2 National Cancer Center (NCC), Korea jointly reported the Clinical Practice Guidelines for HCC for the first time in Korea in It established the validity of clinical diagnosis for HCC and suggested treatment approaches and indications. Thus, it provided guidelines and references to front-line clinicians, residents and students in association with clinical practice of HCC. Owing to medical advances for the last six year after that, there were considerable changes in the diagnosis and treatment of HCC. As more national and foreign data are accumulated, KLCSG-NCC, Korea newly revised the Clinical Practice Guidelines for HCC. For selection of a treatment method of HCC, cancer staging and the extent of underlying liver functions should be considered. Furthermore, fast advances in radical treatment methods and the appearance of various new treatment modalities have led to confusion largely in the selection of HCC treatment. Thus, an organized referencing data for clinical practice of the management of HCC should be necessary. Accordingly, since the summer of 2008, in several Revsion Committee meetings, for which forty or more specialists in the field of hepatology, surgery, radiology and radiation oncology participated, they meticulously reviewed national and global papers, collected opinions based on evidences, and prepared revised guidelines through advisory committee conferences and a public forum (Appendix 1, 2). The guidelines would never be inflexible standards of care for patients with HCC. However, it was prepared for use as references to diagnosis, education and research of HCC in Korea. The guidelines reflected evidence-based medical knowledge 7,8 as top priority and made references to opinions of specialists. It would require continuous supplementations and revisions pertaining to advancing medical information in the days ahead (Table 1). Diagnosis of Hepatocellular Carcinoma HCC is diagnosed through liver biopsy and non invasive methods such as imaging and tumor marker tests. Most HCC has an obvious etiologic factor, and a surveillance test is necessary for early detection of liver cancer in a high risk group. In Korea, the causes of HCC are chronic hepatitis and liver cirrhosis due to hepatitis B and C viruses and alcohol, which take up almost 90% of entire patients. Thus, surveillance tests for HCC [abdominal ultrasonography and serum alpha-fetoprotein (AFP) test] for the high risk group (positive for hepatitis B or C virus or liver cirrhosis) should be performed every six to twelve months. 9,10 This assessment was made in consideration of tumor doubling time and expense-efficacy ratio, and the data based on the fact that the survival rate of patients diagnosed early as having HCC under the surveillance test was higher than that of patients without such surveillance test. 8,9 In the screening or surveillance tests of cases where HCC is suspected, serum AFP should be confirmed and the state of hepatitis B and C viruses Table 1. Levels of evidence according to study design* Level I Evidence obtained from at least one properly designed randomized controlled trial. Level II-1 Evidence obtained from well-designed controlled trials without randomization. Level II-2 Evidence obtained from well-designed cohort or case-control analytic studies, preferably from more than one center or research group. Level II-3 Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled trials might also be regarded as this type of evidence. Level III Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees. *Agency for Healthcare Research Quality USPSTF: Ranking evidence about the effectiveness of treatments or screening - 2 -

3 KLCSG-NCC, Korea. Practice guidelines for management of hepatocellular carcinoma 2009 must also be verified. Alcohol intake and duration, accompaniment of toxic hepatitis and other factors relating to HCC should be grasped through history taking. Radiologic tests first implemented to patients suspicious of HCC are dynamic contrast-enhanced CT or MRI. Also, gastric endoscopy may be performed to get the state of portal hypertension. Other tumor markers (des-gamma-carboxy prothrombin (DCP) or protein induced by vitamin K absence-ii, PIVKA II) may also be conducted in case where serum AFP level is not high. In confirmation of HCC, a tissue biopsy would give a definite diagnosis, but histologic tests may not be performed in the practice due to hemorrhage and ascites secondary to compromised liver function, having the risk of carcinoma seeding and complexity of tumor targeting. Histologic tests for hepatic nodules in patients with liver cirrhosis include fine needle aspiration cytology, fine needle aspiration biopsy and needle core biopsy. The sensitivity for HCC varies with a range of 67~93%, and that of small-sized HCC of 2 cm or less is even lower. 11 Furthermore, the difficulty of tumor targeting in the test may even decrease the sensitivity. Cancer cell seeding through tissue biopsy was reported in 0.6~5.1%, and so necessity of tissue biopsy would be in question in cases where surgery may provide a cure. Also, the false negative rate of histologic tests is reported to be about 30% in past data 12 and in actual clinical practices, most patients are diagnosed in a noninvasive approach depending on clinical diagnostic standard. Noninvasive methods of HCC diagnosis involve radiologic tests and tumor marker tests in patients with chronic liver diseases or liver cirrhosis. Anyhow, the reality is that, clinically, there still is no clear-cut diagnostic standard for HCC. Serum AFP level is the most commonly used test among tumor markers, and the AFP value of 200 ng/ml or higher among high-risk patients would mean a high likelihood of existing HCC. 13 Nevertheless, approximately 35% of small-sized HCC is associated with a normal AFP level. 14 Apart from HCC, rise in the AFP level also occurs in nonspecific cases such as in time of hepatitis exacerbation or in an active regeneration phase of the hepatic tissues. Thus, it would be difficult to diagnose HCC merely with a serum AFP test. In addition, glycosylated AFP/total AFP ratio (AFP-L3), 1,2 DCP (PIVKA-II), 3,4 a-l-fucosidase, 5,6 and Glypican-3 7 are used for the diagnosis of HCC. However, no tumor marker provided definitive diagnosis of HCC up to now, and there is no evidence that any other tumor marker provides a higher diagnostic value than that of AFP. A proper combination of these tumor marker tests would provide better diagnostic results than a single tumor marker test could. Recently, in cases of any one of 1) AFP>200 ng/ml, 2) AFP-L3>15% or 3) PIVKA-II>40 mau/ ml, dynamic contrast-enhanced CT/MRI was recommended for the diagnosis of HCC in Japanese recommendations. 22,23 There have also been several Korean reports on the clinical validity of tumor markers, but more sufficient studies would be necessary. Meanwhile, in patients with liver cirrhosis for whom a nodule was verified under ultrasonography, a continuous rise in the AFP level for a set period of three to six months should provide suspicion of HCC and dynamic contrast-enhanced CT or MRI should be considered, even if serum AFP test shows a value less than 200 ng/ml. 22 Radiologic imaging patterns along with a tumor marker are also important in noninvasive diagnosis of HCC. With respect to sensitivity and specificity of radiologic imaging tests for the diagnosis of HCC, angiography or a specimen of hepatic resection was largely reported as the basis in the past, but recently a pathologic test of the entire liver excised from liver transplantation became the basis. Therefore, the accuracy is reported to be lower than that of the past eventhough progression of imaging techniques. In the examples of liver transplantation of HCC, the diagnostic sensitivity of HCC in dynamic contrast enhanced CT was 75.0%. The sensitivity of dynamic contrast enhanced MRI was 100% for the lesion of 2 cm or larger, but was 52% for smaller sized HCC of - 3 -

4 less than 2 cm The overall sensitivity of radiologic diagnosis for HCC was reported 61~67% for ultrasonography; 68~91%, dynamic contrast enhanced CT; and 81~100%, dynamic contrast enhanced MRI. 23,30,31 If hepatic nodules were discovered incidentally or during a surveillance test among patients with chronic liver disease, dynamic contrast enhanced CT or MRI should be performed for the differential diagnosis of the nodule. In the dynamic radiologic test, nodule(s) with typical findings of HCC, namely, contrast enhancement in the arterial phase and washed-out in the portal phase in comparison with liver parenchyma, may be diagnosed as HCC. In an imaging diagnosis of HCC, the size of nodule should be considered. Regenerated nodules engendered by the result of chronic inflammation lead to dysplastic nodule, early HCC, small HCC, and advanced HCC via multi-step hepatocercinogenesis with gradual increase of the nodule size. 32,33 In general, if the size of HCC were grown to 2 cm or greater, histologic differentiation grade would get worse. As malignant differentiation of a tumor gradually becomes worse, the tumor would have high vascularity and the portal blood flow would largely be lost, showing characteristic findings of HCC. 31,33 Thus, if the serum AFP level were 200 ng/ml or higher in high-risk patients, where hepatic nodule(s) was also verified by ultrasonography, any finding characteristic of HCC in either dynamic contrast enhancement CT or MRI would lead to the diagnosis of HCC. If the serum AFP level were less than 200 ng/ml, two or more positive findings of 1) dynamic contrast enhancement CT, 2) dynamic contrast enhancement MRI or 3) hepatic arterial angiography would be nessessary to establish the diagnosis of HCC. On the other hand, when a tumor of 2 cm or larger in patients with liver cirrhosis has any typical characteristics of HCC in dynamic imaging techniques, one could diagnose it as HCC regardless of the serum AFP levels (Table 2). In the event where it neither satisfies the above criteria nor shows typical characteristics of HCC, a tissue biopsy should be performed for the diagnosis. If the size of a nodule is larger than 1 cm in a high risk group and it shows atypical findings in radiologic or histologic tests, follow-up study with a tumor marker test, dynamic contrast enhancement CT or MRI should be performed in order to clarify the possibility of being HCC. If the size of the nodule is less than 1 cm, which could not be verified by a radiologic or histologic examination in a high risk group, a tumor marker test and ultrasonography should be performed repeatedly in an interval of three to six months, monitoring for any increase in the size and tumor marker. The previous diagnostic criteria of HCC in 2003 KLCSG-NCC, Korea guide- Table 2. Diagnosis of hepatocellular carcinoma 1. Clinical Diagnosis While having the risk factor(s) (HBV +, HCV +, Liver cirrhosis), and if serum AFP 200 ng/ml, typical characteristic finding* of HCC in either one of dynamic contrast enhancement CT or MRI if serum AFP <200 ng/ml, typical characteristic finding* of HCC in 2 or more radiologic studies below. radiologic study: dynamic contrast enhancement CT or MRI, or hepatic artery angiography If liver cirrhosis patients have a tumor 2 cm, typical characteristic finding* of HCC in either one of dynamic contrast enhancement CT or MRI, regardless of serum AFP level. 2. Histologic diagnosis Biopsy should be performed for the diagnosis of HCC, in cases where the lesion does not satisfy the above criteria, or it shows atypical radiologic finding of HCC. *In comparison with liver parenchyma, contrast enhancement in the arterial phase and washout in the portal/venous phase

5 KLCSG-NCC, Korea. Practice guidelines for management of hepatocellular carcinoma 2009 lines was based on the serum AFP level of 400 ng/ml. It showed 95.1% sensitivity and 93.7% positive predictability in the retrospective study. 34 The revised guidelines lowered the diagnostic standard for the serum AFP level to 200 ng/ml based on recent studies. 8,13 Recently, various radiologic and molecular biologic techniques in association with diagnosis of HCC have progressed, but accurate diagnosis of small HCC of less than 2 cm still remains to be elucidated. PET-CT would not be recommended for the diagnosis of small HCC. 35 Histologic tests would not be easy for HCC discovered in patients with liver cirrhosis due to an intrinsic problem, and noninvasive radiologic methods such as dynamic contrast enhanced CT or MRI take up the key role. In this guideline, the radiologic diagnosis for HCC specified contrast enhancement in the arterial phase and wash-out in the portal phase, in comparison with hepatic parenchyma. In actual clinical practice, however, various findings relating to HCC are observed in accordance with tumor staging and size. Thus, comprehensive decisions and follow-ups by specialists in radiology and hepatology would be essential for the definitive diagnosis of HCC. Various countries suggested general staging classifications for HCC such as anatomically-classified TNM (tumor node metastasis) Staging as well as hepatic function and capability-considered Okuda, CLIP, BCLC (AASLD) and JIS. Nevertheless, there is no unified staging method in the world. 8 These guidelines take into account the 2003 Guidelines by KLCSG-NCC, Korea 6 and the Modified UICC Staging 36 of Japanese Liver Cancer Study Group, adopted by the stipulated provisions of KLCSG (Table 3). Recommendations [1] When nodules are detected in ultrasound surveillance in a high risk group for HCC (positive for hepatitis B or C virus, or liver cirrhosis), dynamic contrast enhancement CT or MRI should be performed for the diagnosis (evidence level II). [2] If the serum AFP level is 200 ng/ml or higher in high-risk patients, for whom hepatic nodule(s) was also verified by ultrasonography, typical characteristic (hypervascular with washout in the portal/venous phase) of HCC in either dynamic contrast enhancement CT or dynamic contrast enhancement Table 3. Modified UICC stage* Stage T N M I T1 N0 M0 II T2 N0 M0 III T3 N0 M0 IV A T4 T1~3 N0 N1 M0 M0 IV B T1~4 N0~N1 M1 1 Number 1 2 Size <2 cm 3 Vascular invasion (-) T1 (3/3) T2 (2/3) T3 (1/3) T4 (0/3) *Adopted from Liver Cancer Study Group of Japan: Ueno S, et al. Hepatol Res 2002;24:

6 Figure 1. Treatment plan for hepatocellular carcinoma. MRI lead to the diagnosis of HCC. If the serum AFP level is less than 200 ng/ml, two or more positive findings of 1) dynamic contrast enhancement CT, 2) dynamic contrast enhancement MRI or 3) hepatic arterial angiography would lead to the diagnosis of HCC. On the other hand, when a tumor of 2 cm or larger in patients with liver cirrhosis has typical characteristic of HCC in dynamic contrast enhancement CT or MRI, one could diagnose it as HCC regardless of the serum AFP levels. However, the lesion does not satisfy the above criteria or shows atypical findings of HCC, biopsy should be performed for the diagnosis (Table 2) (evidence level II). [3] If nodules of high risk patients are smaller than 1 cm, which diagnosis may not be verified by a radiologic or histologic examination, a tumor marker test and ultrasonography should be performed several times repeatedly in an interval of three to six months, monitoring for any increase in the size and level of tumor marker (evidence level III). Hepatic Resection Hepatic resection is the primary treatment method for HCC patients without liver cirrhosis, for whom hepatic resection is possible. 37 In the premise that the remaining liver functions are sufficient, hepatic resection is preferentially considered for patients with liver cirrhosis (Fig. 1). 38,39 Recently, thanks to to advances in preoperative tests, surgical technique, and improvement of postoperative management, the mortality rate of hepatic resection at Korean special institutions decreased to less than 1~3%, and the 5-year survival rate increased by 50% or more. 40,41 As a preoperative test for the assessment of safety of hepatic resection, the Child-Pugh Classification has been used for a long time (Table 4). 42 Presently, most hepatic resection is performed in patients with a Child-Pugh class A who have a Grade 0~2 of an ECOG performance stage (Table 5). However, cases with quite advanced liver cirrhosis may belong to Child-Pugh class A. Thus, the Child-Pugh Classification would - 6 -

7 KLCSG-NCC, Korea. Practice guidelines for management of hepatocellular carcinoma 2009 Table 4. Child-Pugh Classification Albumin(g/dl) > ~3.5 <2.8 Bilirubin(mg/dl) < ~3.0 >3.0 Prothrombin time prolonged(s) 0~4 4~6 >6 Ascites none slight moderate Encephalopathy (grade) none 1~2 3~4 Class A 6 points Class B =7~9 points Class C 10 points. Table 5. Eastern Cooperative Oncology Group (ECOG) performance stage* Grade ECOG 0 Fully active, able to carry on all pre disease performance without restriction 1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 2 50% of waking hours 3 Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours 4 Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 5 Dead *Oken, M.M., et al. Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5: , not be a sufficient test method for the assessment of safety of hepatic resection. Therefore, the Indocyanine Green 15 minutes Retention Rate (ICG-R15), suggested in Japan, is performed in various Korean institutions as a preoperative test for the prediction of remaining liver functions. 43 On the other hand, portal hypertension and serum bilirubin level were suggested as important indices for the assessment of resectability in Europe and the U.S.A. Having any one of 1) a hepatic venous pressure gradient of 10 mmhg or higher, 2) esophagel varix or 3) thrombocytopenia (less than 100,000/mm 3 ) accompanied by splenomegaly was defined as a clinically significant portal hypertension. 44 It was reported home and abroad that the incidence rate of complications of hepatic resection was high and long-term prognosis was poor in cases of portal hypertension. 44,45 However, the extent of resection may be different depending on the size, number, and location of a tumor. Accordingly, the dimension of the remaining liver and remaining liver functions may also be dissimilar. Unlike in Western countries, liver transplantation using the liver from a deceased donor would not be frequent in Korea. In patients of Child-Pugh A and B, and in the presence of mild portal hypertension and hyperbilirubinemia, surgical resection could selectively be considered. As preoperative radiologic studies, conducted to examine the possibility of resection, dynamic contrast enhancement CT is the basic test utilized while the MRI test has increased its validity owing to development of a hepatic cell-specific contrast medium. 46 For the purpose of finding the lesions of extrahepatic metastasis, lung CT, bone scan and 18 F-FDG PET-CT test may be performed as needed Ultrasonography during surgery is advantageous in the diagnosis of small tumors not discovered in preoperative tests. 49,50 Transcatheter arterial chemoembolization (TACE), performed before hepatic resection for the purpose of improving prognosis after surgery, is not recommended. 51,52 There were reports asserting that portal vein embo

8 lization, performed before undertaking extensive hepatic resection, might induce compensatory hypertrophy of the remaining liver and reduce the risk of surgery especially in cases with liver cirrhosis, but these are largely debatable. 53,54 The reason that hepatic resection has recently become safer is the reduction in the amount of hemorrhage during surgery and minimization of the amount of blood transfusion required. Blood transfusion compromises anticancer immunologic mechanism, and increases recurrence after hepatic resection in HCC patients with hypoalbuinemia in particular, 55 and is a risk factor for developing complications in case of repeated hepatic resection due to recurrence. 56 Owing to selective hepatic blood flow occlusion, maintaining low central venous pressure, and precise transection of the hepatic parenchyma, the recent rate of transfusion in hepatic resection is 10% or less. 57 As a recommendation, anatomical resection has theoretical advantages for reducing recurrences by securing resection margin and removing micro-metastasis. However, the advantages in the recurrent state, survival rate or recurrence rate, in comparison with non-anatomical resection, have not been well demonstrated. The extent of surgery is affected by underlying disease such as liver cirrhosis. Thus, seeking for the most appropriate surgical approach for each individual case depends on the patient status which may be more important for the postoperative outcome Performing surgery not having any malignant cells infiltrated in the resection plane would be absolutely important for the long-term prognosis, and there are reports that securing the resection margin could reduce recurrences. 61,62 Ultrasonography may be performed during surgery in order to decide on the accurate extent of liver resection and to verify the location of the vessels adjacent to the resection plane. 63 Laparoscopic hepatic resection has advanced rapidly and its indications have been extended, and, including an extensive hepatic resection, which has been safely carried out among selected patients Thus, cases of laparoscopic hepatic resection for HCC have increased. However, studies comparing it with open hepatic resection would be necessary for the long-term prognosis in the days ahead. 64 The best prognosis for hepatic resection was generally shown in cases involving one or two smallsized tumor(s), but good prognosis has been reported in some limited patients with a large-sized or multiple tumor(s) or aged patients as well It was reported that performing hepatic resection first would be an effective method in patients with ruptured HCC and good liver functions. 71 However, with hemodynamically unstable cases, bring about hemostasis with TACE and performing elective surgery after an accurate assessment of remaining liver functions would be more effective with respect to longterm survival rate. 72,73 In the event of malignant infiltration of the main hepatic vein or main portal vein, generally hepatic resection is contraindicated. Nevertheless, in patients with either less hepatic fibrosis or a low Edmondson-Steiner grading of malignant differentiation, the 5-year survival rate of 20% or more was reported after hepatic resection. Hence, needed are studies on surgical indication of HCC which infiltrated the main vasculature. The 5-year survival rate of HCC after hepatic resection is about 58~81%, but about 80~95% of these cases recur within the liver. 75 Various risk factors relating to recurrences after surgery were reported. Among them, the presence of microvascular invasion(s) and satellite nodule(s) is associated with frequent recurrences, requiring meticulous care Recently, epochal advances in the molecular technique have led to introductions of various tumor markers for the early discovery of mulitple tumor markers, 79 but there are still limitations in clinical applications. The serum AFP measurement is the most commonly used tumor marker test after surgery of liver cancer, but the serum PIVKA-II is also a useful marker for follow-ups of recurrences if there is sufficient preoperative increase. 80 It is recommended that tumor marker tests and radiologic tests should be - 8 -

9 KLCSG-NCC, Korea. Practice guidelines for management of hepatocellular carcinoma 2009 performed in certain intervals in order to have early detection of recurrences after hepatic resection. 81 Recently, there have been numerous clinical studies on methods of follow up after surgery, but up to now, there are no concrete evidence supporting which method is most efficious. 82 The 5-year survival rate for patients, who underwent repeated hepatic resection after a recurrence in the liver after initial hepatic resection, was reported to be 37~70%. In cases where a relapse is at least one year or more away from initial operation or in cases of a focal recurrence, repeated hepatic resection is recommended. 75,83 In cases of a recurrence occurring within the liver, salvage liver transplantation could be considered. 84 After hepatic resection, recurrences in the area other than the liver occur in 15~37% of cases, which may commonly be seen in the lung, abdomen and the bones. 85 In the event where the liver function is maintained and the intrinsic malignancy in the liver is controllable, metastatectomy may be considered. 86,87 Recommendations [1] HCC patients who have a single lesion located in the liver should be considered if they have well preserved liver function (Child-Pugh class A) without portal hypertension nor hyperbilirubinemia (evidence level II). [2] In HCC patients with Child-Pugh class A or superb B accompanied by mild portal hypertension or mild hyperbilirubinemia, restricted surgical resection less than hemihepatectomy could selectively be considered (evidence level II). [3] In cases of focal HCC recurrence within the liver after hepatic resection, accompanied by a long period of disease free survival, repeated hepatic resection may be considered (evidence level III). Liver Transplantation Liver transplantation involves a complete removal of a diseased liver including HCC and transplanting of a new liver. Theoretically, it is the most ideal treatment method. 8,88 However, liver transplantation in cases of advanced HCC showed very poor prognosis, and there was a time that liver transplantation was relatively contraindicated. Recently, as an excellent disease free survival rate was reported for liver transplantation in patients with early HCC, liver transplantation has been recognized as the most effective treatment method for certain HCC patients. The Milan Group of Italy reported an excellent result after liver transplantation, showing that patients of HCC with 1) no extrahepatic metastasis and no vascular infiltration in the radiologic study before transplantation, 2) a single nodule of 5 cm or less, 3) three or less nodules in cases of having multiple nodules and each nodule of 3 cm or less, had the 4-year survival rate of 75% and the disease free survival rate of 83%. They suggested the criteria of liver transplantation for patients with HCC by reporting such an excellent result. 89 Since then, the Milan criteria as it is called has widely been used for liver transplantation in patients with HCC in various countries. Such a stringent criteria isused because socially the optimum gain should be achieved from the livers from the limited cadaveric donors. Thus, it has a disadvantage that some patients with advanced HCC, which may show an excellent result after liver transplantion, would be excluded from the benefit. Accordingly, there are yet many debates on the criteria of liver transplantation for patients with HCC. Particularly, there is no standard criteria in cases of living donor liver transplantation. If the optimum level of a cure should be 50% or more for the 5-year survival rate after liver transplantation in patients with HCC, the indication for liver transplantation could be expanded beyond the Milan criteria For instance, the University of California, San Francisco (UCSF) Group reported the 5-year survival rate of 75% for patients with 1) a single tumor of 6.5 cm or less, 2) less than three nodules in multiple cases, the longest diameter of - 9 -

10 less than 4.5 cm and the sum of each diameter less than 8 cm. 94 However, it should be considered that the UCSF criteria were a retrospective study based on the pathologic report of an extracted liver. In South Korea, the causative disease of most patients with HCC requiring liver transplantation is HBV-associated chronic hepatitis, and is different from that of the Western territories. In consideration of the circumstances in South Korea, where living donor liver transplantation has largely been performed for patients with HCC, 92,93 in particular, it would be unreasonable to apply the Western criteria generally With respect to liver transplantation using a liver from the brain-dead donor, donor organs are always in shortage. Thus, many patients are waiting for liver transplantation. Especially, the problem for patients with HCC is the long waiting period from registration to liver transplantation. The United Network for Organ Sharing (UNOS) of the U.S. introduced the MELD scoring system in order to decide on the priority order for liver transplantation. Patients with HCC of T2 Stage get the MELD score of 22 points, and also get additional points of 10% every three months of waiting for transplantation, making efforts to shorten the waiting time in these patients. 92,93 However, the National Organ Transplantation Management Center in Korea operates the Korean Network for Organ Sharing (KONOS) grading system. 93 There are no additional points for patients with HCC. The provision about patients with HCC in the KONOS grading specifies that cases with the Child-Turcott- Pugh score of 7 points or higher and belonging to the Milan criteria at the same time belong to KONOS grade 2B. Patients with KONOS grade 2B are pushed back in the priority order, and will not be able to undergo transplantation in a short time. Before transplantation, patients with HCC undergo tests for staging HCC, in addition to general wholebody examination for liver transplantation. 8,14 Dynamic contrast enhancement CT or MRI is performed as a radiologic test for the liver itself. Contrast enhanced brain, lung,and pelvis CT and bone scan are performed for the confirmation of metastasis. In addition to the general selection purpose of the decision of tumor metastasis, 18 F-FDG PET-CT may help in deciding for the biologic characteristics of HCC. 96 Serum AFP, PIVKA II, and tumor markers are performed.. The drop out rate, the proportion of patients who could not undergo liver transplantation due to a progressed tumor during the waiting period of liver transplantation is 15% in six months and 25% in one year. 97 A local treatment such as TACE or radiofrequency ablation may be performed in order to prevent tumor progression In cases beyond the Milan or UCSF criteria, downstaging may be attempted before transplantation. Downstaging of HCC by TACE may be possible in 24~63%. 90,100, Downstaging is more effective in cases where a tumor size is less than 7 cm or the number of tumors is three or less. 104 Downstaging is possible with either radiofrequency ablation or hepatic resection, and the efficacy may not yet be concluded. 105 Salvage liver transplantation In HCC patients who first underwent hepatic resection and have tumor recurrence or decompensated liver function, liver transplantation could be performed and this is referred to as salvage liver transplantation. Most patients (70~80%) experiencing recurrence after hepatic resection due to HCC meeting the Milan criteria, may encounter recurrence again within the Milan criteria. 106,107 Surgical complication associated with salvage liver transplantation or the tumor recurrence rate are similar to that of primary liver transplantation. 108,109 Thus, the criteria for the selection of salvage liver transplantation are similar to that of primary liver transplantation. 108,109 Living donor liver transplantation In South Korea where organs from the brain-dead donor are absolutely lacking, living donor liver transplantation is mainly performed. In 2007, six hundred twenty cases of living donor liver transplantations

11 KLCSG-NCC, Korea. Practice guidelines for management of hepatocellular carcinoma 2009 and one hundred twenty-eight cases of brain-dead donor liver transplantation were performed, and the number of patients waiting for brain-dead donor liver transplantation is 2,108 in South Korea. 93 The number of livers from the brain-dead donors is small in Korea, and 50~60% of these patients were categorized as emergency patients (KONOS Grading 1, 2A). Thus, the possibility of undergoing brain-dead donor liver transplantation in a timely manner for patients with HCC is quite low. 110 In the premise that the waiting period of brain-dead donor liver transplantation is longer than seven months, living donor liver transplantation is reported to be cost-effective compared to that of brain-dead donor liver transplantation. 111,112 The 5-year survival rate of living donor liver transplantation meeting the Milan criteria is 76~80%, and that of living donor liver transplantation beyond the Milan criteria is 45~60%. They are similar to the survival rate of brain-dead donor liver transplantation. 93, Accordingly, it is valid to apply the selection criteria of brain-dead donor liver transplantation for patients with HCC even for living donor liver transplantation. However, even beyond the Milan criteria, there is special circumstances where the recipient of the living donor liver transplantation is in a special relation with the donor, and transplantation may be performed for some cases in spite of high recurrence risk Nevertheless, the safety of the donor must be considered in living donor liver transportation. The frequency rate of surgical complications for the donors of living donor liver transplantation was reported to be in wide range of 8~78% The frequency rate of serious complications is low,about 1-3% at liver transplantation centers where much experience has been accummulated. However, in East Asia, at least three healthy donors died of complications associated with donation Thus, it is essential to strictly apply the selection criteria for the healthy donors, and to decide the appropriate extent of donor hepatectomy Recurrence and its associated factors The recurrence rate of HCC after liver transplantation in cases of meeting the Milan criteria is 10~20% in the five year period. However, the recurrence rate for cases beyond the Milan criteria is high showing 50% or more. 13,15-18 The period of recurrence of HCC after transplantation is 8~14 months on the average and largely within two years. However, about 20% recur three years after transplantation and long-term follow-up is needed With respect to the recurrence site, extrahepatic metastasis was most frequent taking up more than half of recurrences (53%), extrahepatic metastasis accompanied by intrahepatic recurrence was 31%, and intrahepatic recurrences were 16%. The extrahepatic metastases include lung (43%) and bone (33%). In addition, it is metastasized to the adjacent lymph nodes, adrenal gland, and brain. 126,127 There is yet no effective way of preventing HCC recurrences after liver transplantation. Factors that predict recurrences of HCC include: vascular infiltration, size and number, tumor differentiation, serum AFP and PIVKA-II as well as HCC positivity in 18 F-FDG PET-CT. 91,96, ,136 Among them, the most predictive factor is the vascular infiltration of the tumor, verified grossly or microscopically. As the size and number of the tumor increases or differentiation worsens, the frequency of vascular infiltration increases. 123,137,138 However, findings of microvascular infiltration and differentiation of the tumor may only be attained by histologic tests. Hence, it is a disadvantage since they may not be utilized as prognostic factors before surgery. Immunosuppresive and anti-viral treatment No standard immunosuppressant has been established yet after liver transplantation in patients with HCC. However, an immunosuppressant, based on calcineurine inhibitor, is generally used. 139 Recently, it was reported that Sirolimus suppressed recurrence of HCC by having an antiproliferation effect, but it was not clearly elucidated yet. Also, hepatitis B, the

12 underlying disease, may recur during recurrence of HCC. Thus, an antiviral treatment against hepatitis B is necessary Recommendations [1] In patients with HCC, having neither vascular infiltration nor distant metastasis radiologically, a single tumor <5 cm, or up to three nodules <3 cm (the Milan criteria), liver transplantation is an effective treatment method (evidence level II). [2] While other effective treatment methods are not applicable, in the cases of HCC having no infiltration of major vessels and no extrahepatic metastasis, living donor liver transplantation, for which the safety of the donor should be preferentially considered, may be applicable to the extended criteria beyond that of Milan (evidence level III). [3] In cases where patients with HCC may not predict the time of liver transplantation during the waiting period, local treatment and TACE may be considered (evidence level III). [4] Certain patients of liver transplantation, for whom downstaging using TACE is possible, may expect the similar survival rate as that of liver transplantation performed under the UCSF criteria (evidence level II). [5] If recurrent HCC after hepatic resection is within the Milan criteria, salvage liver transplantation is largely possible. The survival rate may be similar to that of primary liver transplantation (evidence level II). Local Ablation Therapies Local ablation therapies are relatively easy to perform, and cause less destructive changes to the liver parenchymal tissue around the tumors. Due to this minimal invasiveness, local ablation therapies have widely been used as a non-surgical treatment modality for HCC. At present, the standard local ablation therapies include radiofrequency ablation (RFA) and percutaneous ethanol injection therapy (PEIT). All the other treatment methods such as microwave coagulation therapy, laser interstitial thermal ablation, cryoablation, percutaneous acetic acid injection and high intensity focused ultrasound (HIFU) are classified as clinical trials. According to the researcher or treatment modality, indications for local ablation therapies may be different, but are usually as follows: 1) single tumor with a diameter of 5 cm or less or 2) multiple tumor of three or less with a diameter of 3 cm or less. The success rate of local treatment is closely related to the size of a tumor. In general, the local tumor control rate becomes lower as the tumor size becomes larger. A 80% or more initial complete ablation rate can be obtained for a tumor less than or equal to 3 cm. 146 Currently, efforts are being made to widen the indications so that local ablation therapy may be applicable to larger tumors. The ideal indication of a local ablation therapy is a Child-Pugh class A patient with a solitary small HCC less than or equal to 2 cm. At present, the treatment of choice for such a patient is surgical resection or transplantation. 8,147 However, based upon the fact that local treatments can also show favorable clinical outcomes comparable to that of surgical resection, some investigators asserted that local treatment should be considered as a primary treatment for such tumors. 148 Independently significant factors related to the survival after local ablation therapies include initial complete ablation, Child-Pugh score, number and size of tumor(s) and pretreatment serum AFP level. In cases of adjusted platelet count of 50,000/mm 3 or less or prothrombin time of 50% or less, treatment is avoided due to a high risk of hemorrhage during the procedure. Radiofrequency ablation Currently, RFA is the most widely practiced ablation method for HCC. The RFA technique allows a very fast radiofrequency current (460 to 500 khz) to flow in the vicinity of an electrode inserted within a tumor, inducing inter-molecular friction and subsequent internal heating of the tumor and its nearby tissues. The application of heat energy at 60 can

13 KLCSG-NCC, Korea. Practice guidelines for management of hepatocellular carcinoma 2009 cause an almost immediate protein denaturation and necrosis of the cell membranes, leading to coagulative necrosis, while the application of heat energy at 45~50 for three minutes or longer can also lead to similar necrotic effects. Compared to PEIT, the major advantage of RFA is that complete tumor necrosis can be obtained with few sessions of treatment, and that the results are more predictable. In cases of HCC larger than 2 cm, RFA shows a higher rate of local tumor response compared to PEIT In general, a percutaneous approach is ususally resorted, but laparoscopic or open surgical approach can be considered also depending on the location of the tumor. The initial complete ablation rates for small tumors were reported to be 96% or higher It was reported that additional sessions of RFA might raise the rate of complete ablation up to 100%. 153 Although a consensus does not exist for the definition of local recurrence, the rates of recurrence following initial complete ablation are reported to range from 0.9% to 14%. 148,155,156 The long-term survival outcomes of patients with HCC treated with RFA can be variable according to the tumor size. For compensated cirrhotic patients with a HCC less than or equal to 2 cm, the 3-year and 5-year overall survival rates were known to be approximately 90% and 65~70%, respectively, 148,155,156 while the 3-year and 5-year survival rates for 2~5 cm were known to be approximately 65~75% and 50% respectively. 155,156 Despite these favorable outcomes, RFA has some disadvantages as follows: 1) Compared to PEIT, there is a higher risk of major adverse effects in cases where the tumors are located near the liver hilum or a major organ such as colon or gall bladder. 150,157,158 2) A heat sink effect may cause insufficient heat transmission in cases where the tumor is located adjacent to relatively large intrahepatic vessels, which may hinder effective transmission of heat energy to the tumor. Mortality rate due to RFA complication was reported to be 0.1~0.5% and major complication rate of RFA was less than 5%. 148,157,158 In several randomized controlled trials (RCTs) between RFA versus PEIT for patients with HCC, ,153,154 patients treated with RFA showed better local tumor response and overall survival outcomes compared to PEIT. A meta-analysis on the recent four RCTs demonstrated that the 3-year overall survival rate of RFA was significantly higher than that of PEIT. 159 Nevertheless, for patients with small HCC less than 2 cm, there was no definite difference in the survival between these two treatment methods, and further prospective controlled studies are needed. Several observational studies and suboptimal RCTs reported that the long-term survival rate of RFA was similar to that of surgical resection It may promise an extension of the indication of RFA for HCC in the future. However, most studies are not randomized trials and the data is still inadequate to draw a definite conclusion as yet. A recently reported RCT between RFA and resection included a total of 180 patients with a solitary HCC less than or equal to 5 cm. 160 There were no differences in the baseline tumor characteristics between the two groups in this study. 160 The results showed that there were no significant differences in the 1-, 2-, 3- and 4-year overall and disease-free survival rates between RFA and surgical resection. However, it is not feasible to draw a definite conclusion from only a single study performed in only one institution, and the results must be verified by well-designed prospective multi-center clinical trials. Percutaneous ethanol injection therapy Percutaneous ethanol injection therapy (PEIT) has been widely used in the treatment of HCC, because it is relatively easy to perform and adverse reactions are not frequent. However, recently, PEIT is being replaced by RFA. The reasons are that, as opposed to RFA, PEIT should be performed repetitively and it is difficult to obtain complete necrosis for a tumor larger than 3 cm. Thus, PEIT is largely used for patients with three or less nodules while the maximal diameter is less than or equal to 3 cm. The reported rates

14 of tumor necrosis using PEIT are variable depending on the researchers, ranging between 66% and 100% The therapeutic efficacy of PEIT largely depends on the tumor size. As the size increases, the rate of tumor necrosis drops down. Ninety percent (90%) or higher rate of tumor necrosis was reported for tumors less than or equal to 2 cm. However, the rate drop to approximtely 50% for a tumor with the diameter ranging between 3 cm and 5 cm The local recurrence rate of PEIT was reported to range between 24% and 34%, although there is no consensus for the definition of local recurrence. 151,152 For patients with Child-Pugh class A and a solitary tumor less than or equal to 2 cm, the 3-year and 5-year overall survival rates were reported to be 70~80% and 50% or more, respectively. 151,152,158,169 For tumors of 2-3 cm in the diameter, the 3-year overall survival rate was reported to be 47~64%. 155,156 For patients with Child-Pugh class A or B and a solitary tumor of 3 cm or less, several comparative studies between PEIT and surgical resection showed no definite difference in survival between the two treatment groups Especially, a recent RCT between PEIT and surgical resection, targeting on 76 patients who had one or two HCC nodule(s) of 3 cm or less in the diameter, reported that there were no difference in the survival rate and local recurrence rate between the two treatment groups. 170 However, it is very difficult to reach a definite conclusion with only one RCT. Furthermore, the sample size of the RCT was calculated based on the tumor recurrence rate, not on the survival rate. Even though there was no statistical difference in the survival rates of the two treatments, the 5-year survival rates were much different as 46% and 81.8% for PEIT and resection group, respectively. Thus, future well-designed prospective controlled studies are necessary to reach a definite conclusion. Other local ablation therapies in clinical trials In addition to RFA and PEIT, there are other local ablation treatment methods, including microwave coagulation therapy, laser interstitial thermal ablation, cryoablation, percutaneous acetic acid injection and high intensity focused ultrasound (HIFU), and holmium injection. However, little comparative studies with standard treatment methods have been reported as yet, and no clinical trials showed better outcomes than RFA. Therefore, it is difficult to suggest clinical indications for these modalities at this stage. Recommendations [1] Radiofrequency ablation is applicable as a curative treatment for a single HCC with a diameter of 3 cm or less (evidence level I). [2] Radiofrequency ablation is superior to percutaneous ethanol injection therapy with regards to the tumor necrosis and the survival rate (evidence level I). However, the therapeutic efficacies of these two treatment modalities are equivalent for a HCC with a diameter of 2 cm or less (evidence level II-I). [3] Other local ablation methods in clinical trials do not have controlled studies in comparison with standard treatments, and have insufficient data. They are generally not applicable to HCC patients, for whom standard treatments can be applied (evidence level II-3). Transarterial Chemoembolization (TACE) Most patients diagnosed as unresectable HCC have one of the followings: 1) multiple intrahepatic nodules, 2) inability to secure sufficient area of resection in the periphery of the tumor, 3) infiltration into the portal vein, or 4) compromised liver functions. 173 Transarterial chemoembolization (TACE) is the most commonly used treatment method for these patients, while tumor necrosis can be achieved by the combined effects of antitumoral chemotherapy and selective ischemia for tumoral tissue. This procedure involves mixing of chemotherapeutic agents such as doxorubin, cisplatin or mitomcycin with iodized oil and injection of the mixture into the feeding artery