Surgical Treatment for Hepatocellular Carcinoma

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1 Review Article Jpn J Clin Oncol 2011;41(4) doi: /jjco/hyr016 Advance Access Publication 16 March 2011 Surgical Treatment for Hepatocellular Carcinoma Tadatoshi Takayama * Department of Digestive Surgery, Nihon University School of Medicine, Tokyo, Japan *For reprints and all correspondence: Tadatoshi Takayama, Department of Digestive Surgery, Nihon University School of Medicine, Oyaguchikami-machi, Itabashi-ku, Tokyo , Japan. tadtak@med.nihon-u.ac.jp Received September 7, 2010; accepted January 24, 2011 Surgery is the most important therapeutic approach for patients with hepatocellular carcinoma. We have reviewed patients survival after resection for hepatocellular carcinoma in 17 series since 2000, each including more than 100 patients. Median survival rates were 80% (range 63 97%) at 1 year, 70% (34 78%) at 3 years and 50% (17 69%) at 5 years. Such wide ranges of survival rates are attributed mainly to differences in the hepatocellular carcinoma stage among studies, but the survival rate is obviously much better for early hepatocellular carcinomas. Today, liver resection is an established treatment for hepatocellular carcinoma owing to minimal surgical mortality and improved survival. Liver transplantation is one of the best treatments for hepatocellular carcinoma in patients who meet the selection criteria. Further studies are needed to establish suitable criteria for transplantation in patients with hepatocellular carcinoma. For patients who are not candidates for liver resection or transplantation, percutaneous ablation is the best treatment option. However, no randomized controlled clinical trial has compared the results of ablation with those of surgical therapy for hepatocellular carcinoma, and none of the ablation techniques have been shown to offer a definitive survival advantage. A treatment algorithm based on published evidence is now available, which helps us to select the most suitable therapeutic option for individual patients, depending on tumor characteristics and liver functional reserve. This review paper summarizes the current status of the surgical management of hepatocellular carcinoma. Key words: hepatocellular carcinoma liver resection liver transplantation guideline INTRODUCTION Hepatocellular carcinoma (HCC) is one of the most common malignancies in Asia and Africa, and its incidence is rising in Western countries (1). Chronic infection with hepatitis C virus and hepatitis B virus or alcoholism plays a major role in its etiology. The tumor is usually advanced when the patient presents with clinical symptoms. Screening for HCC in high-risk patients is thus justified. Early detection of HCC allows the application of potentially curative treatments, such as liver resection and transplantation. HCC is unique, in that both the tumor stage and the degree of liver damage must be simultaneously considered when selecting the optimal treatment strategy (1). For an individual patient, the most appropriate therapeutic option needs to be selected from among multiple approaches, including liver resection, percutaneous ablation, transarterial embolization (TAE) and transplantation, but few evidencebased guidelines for decision-making are available (2 7). Surgery still remains the most important treatment for patients with HCC. Over the past few decades, considerable progress has been made in the diagnosis and surgical therapy of HCC. In fact, tumors are now often identified at an early stage (8), surgery has an acceptable operative mortality rate (even in cirrhotic patients,,5%) with good long-term survival (9,10) and the results of transplantation have steadily improved because of careful patient selection (11). However, HCC is still associated with high mortality as a result of cancer recurrence, and outcomes remain poor even after potentially curative treatment (12). This paper summarizes the current status of surgical treatment for HCC. # The Author (2011). Published by Oxford University Press. All rights reserved.

2 448 Surgical treatment for hepatocellular carcinoma LIVER RESECTION Hepatic resection is the treatment of choice for HCC especially in non-cirrhotic patients. Major resections can be done with low rates of life-threatening complications (13). Conversely, among patients who have cirrhosis, strict selection criteria are required to avoid treatment-related complications. To avoid post-operative liver failure, a careful assessment of the liver functional reserve is important, because most patients with HCC have underlying cirrhosis. PROCEDURES Routine operative procedures essential for liver resection include intraoperative ultrasonography, vascular occlusion, hepatic parenchymal transection and drainage after transection. Intraoperative ultrasonography is essential for the safe performance of liver resection. Makuuchi et al. reported that tumors and anatomic structures could not be correctly located before this diagnostic technique became available. Ultrasonography allows liver resection to be done safely, without injuring major vessels, and facilitates the detection of occult tumors, which cannot be identified on pre-operative imaging, during both primary and repeat liver resection (14). It has also enabled the development of procedures such as inferior right hepatic vein-preserving hepatectomy (15) and ultrasonically guided subsegmentectomy (16). Recent retrospective studies of HCC have shown that anatomic resection is superior to non-anatomic resection (17). Another factor related to the safety of liver resection is intermittent inflow occlusion. Inflow occlusion methods, such as hemihepatic vascular occlusion and Pringle s maneuver, do not adversely affect post-operative liver function and markedly reduce blood loss, as confirmed by a randomized controlled trial (RCT) (18). Total hepatic vascular exclusion, or occlusion of both the inflow and outflow tracts of the whole liver, has been tried, but is now used only in a limited number of patients because the procedure is complex and carries an increased risk of perioperative morbidity, including post-operative liver dysfunction (19). Clavien et al. (20) reported that ischemic preconditioning by inflow occlusion for 10 min significantly improved post-operative liver function. Imamura et al. (21) found that a combination of preconditioning and intermittent inflow occlusion ameliorated the post-operative increase in serum aminotransferase levels, even during the recovery period after liver transplantation. The superiority of intermittent inflow occlusion over continuous or total occlusion is now widely accepted. OUTCOMES We have reviewed survival after resection for HCC in 17 series reported since 2000, each of which included more than 100 patients (Table 1) (22 38). Median survival rates were 80% (range 63 97%) at 1 year, 70% (34 78%) at 3 years and 50% (17 69%) at 5 years. Such wide ranges of Table 1. Survival after resection of hepatocellular carcinoma Author Year n Survival rate at 1 year 3 years 5 years Arii et al. (22) 2000 HCC, 2 cm, CP-A % NA 72% HCC, 2 cm, CP-B % NA 56% HCC, 2 5 cm, CP-A % NA 58% HCC, 2 5 cm, CP-B % NA 45% Zouh et al. (23) % 61% 50% Poon et al. (24) % 62% 36% Nagasue et al. (25) % 61% 50% Kanematsu et al. (26) % 67% 51% Belghiti et al. (27) % 57% 37% Chen et al. (28) % 54% 34% Wayne et al. (29) % NA 41% Yeh et al. (30) % 42% 32% Ercolani et al. (31) % 63% 43% Chen et al. (32) NA 34% 17% Capussotti et al. (33) NA 51% 34% Hasegawa et al. (34) Anatomic resection % 84% 66% Non-anatomic resection 54 93% 66% 35% Sasaki et al. (35) Hepatitis B-positive 67 NA 80% 62% Hepatitis C-positive 351 NA 78% 69% John et al. (36) % 37% 22% Nathan et al. (37) NA NA 39% Yang et al. (38) % 56% 38% HCC, hepatocellular carcinoma; CP, Child Pugh classification; NA, not assessed. survival rates are attributed mainly to differences in the HCC stage among the studies, but the survival rate is obviously much better for early-stage HCCs (39). Today, liver resection is an established treatment for HCC owing to minimal surgical mortality and improved survival. Although early diagnosis and treatment improve survival, HCC frequently recurs after curative liver resection. The postoperative 5-year recurrence rate is %, and median survival after recurrence is 7 28 months (40). Micrometastases from HCC can be detected by molecular techniques in 88% of the patients at the time of surgery and probably lead to post-surgical recurrence (41). About 80% of recurrent tumors develop exclusively within the liver, and only 20% of such tumors are resectable. As a treatment option, repeat liver resection has played an important role in selected patients, yielding results similar to those after primary resection, with a 5-year survival rate of about 50%. We have proposed that

3 Jpn J Clin Oncol 2011;41(4) 449 repeat resection is indicated for the treatment of recurrence in patients with a single HCC at the first resection, a disease-free interval longer than 1 year and recurrent HCC with no portal invasion (42). In patients who met these criteria, the 5-year survival rate was 86% after the second resection. Predictors of poor outcomes in HCC are common to all therapeutic approaches and include more than three tumors, a tumor size larger than 5 cm, portal vein invasion, intrahepatic metastases, absence of a tumor pseudocapsule, advanced TNM stage (III or IV), and a Child Pugh class of C. The most important factors appear to be vascular invasion and liver function (43). Pre-operative TAE in surgical candidates aims to reduce tumor mass, facilitates resection and decreases recurrence after resection. One small study reported that TAE significantly improved survival (44), but most studies have found no evidence of a survival benefit or reduced recurrence (45). Two RCTs have suggested that pre-operative TAE does not contribute to better survival (46,47). A world review of laparoscopic liver resection demonstrated that the procedure by experienced hands carries an acceptable morbidity and mortality with comparable survival rates in HCC (48). This becomes a procedure of choice in a selected group of HCC patients, because Japanese National Health Insurance system has recently covered the costs. LIVER TRANSPLANTATION Liver transplantation is one of the best therapeutic approaches for HCC in patients who fulfill the selection criteria, such as the Milan criteria (solitary tumors of,5 cm in diameter and up to three tumor nodules, each of which is,3 cm)(11). First, it removes the tumor with the widest margin, together with any intrahepatic metastasis. Second, it cures the underlying cirrhosis that is responsible for both hepatic decompensation and metachronous tumors after partial hepatectomy. Finally, it allows the histological examination of the entire liver, resulting in the most accurate pathologic staging. Therefore, transplantation is theoretically ideal because it eliminates not only the existing HCC, but also the precancerous damaged liver itself. SELECTION CRITERIA HCC is the only solid neoplasm in which transplantation has a relevant role in treatment. Liver transplantation has revolutionized the therapeutic strategy for HCC. Patients must be carefully screened to identify candidates most likely to benefit from transplantation. The most crucial problem associated with transplantation for HCC is recurrence. It is fatal almost without exception because of the recurrence by metastases and the effect of immunosuppressant therapy. Thus, the indications in patients with HCC should be limited by tumor-related factors. The risk of recurrence is mainly related to the following variables: vascular invasion, the size Table 2. Selection criteria for transplantation in hepatocellular carcinoma Author n Selection criteria Survival rate at 5 years Mazzaferro et al. (11) 48 Milan criteria: single HCC 5 cm or up to 3 nodules 3cm Yao et al. (49) 70 UCSF criteria: a maximum tumor size of 6.5 cm or 2 lesions,4.5 cm in diameter with a total tumor diameter of,8 cm 75% (4 years) 75% Kwon et al. a cm and AFP 400 ng/ml 87% (50) Ito et al. a (51) tumors 5 cm in diameter and PIVKAII 400 mau/ml 87% Sugawara et al. a (52) Soejima et al. a (53) Lee et al. (54) Yang et al. a (55) Jonas et al. (56) Mazzaferro et al. (57) 72 Up to 5 nodules with a maximum diameter of 5 cm 60 Without extrahepatic spread and macroscopic vascular invasion 186 Up to 6 nodules with a maximum diameter of 5 cm 63 Scoring criteria involving tumor size, number and AFP levels 21 A maximum diameter of,6 cm, and a total tumor diameter,15 cm 283 Up to 7 criteria: 7 as the sum of the largest tumor size (cm) and the number of tumors 79% (3 years) 69% (3 years) 76% 67% (3 years) 68% (3 years) 71% UCSF, University of California, San Francisco; AFP, a-fetoprotein; PIVKAII, proteins induced by vitamin K absence II. a Living-donor liver transplantation. and number of nodules, serum a-fetoprotein levels and tumor differentiation (11,49 53). The Milan criteria have been empirically defined, which are most widely accepted for selecting candidates for transplantation among patients with HCC (11). The long-term results of transplantation in patients who met the Milan criteria were close to those obtained in patients without malignancy, with a 4-year survival rate of 85%. However, it has been argued that the Milan criteria may be too restrictive and that an appreciable proportion of patients who do not meet the criteria could derive an acceptable benefit from transplantation. In recent years, efforts have been made to extend the criteria for liver transplantation. The University of California, San Francisco (UCSF)-expanded criteria have been proposed as a less restrictive alternative to the Milan criteria. The 5-year posttransplantation survival rate in patients fulfilling the UCSF criteria was 75%. Besides the number and sizes of nodules, serum a-fetoprotein levels, and proteins induced by vitamin K absence were shown to have a significant impact on posttransplantation survival. Various other groups have published expanded criteria, with results not dissimilar to the original Milan criteria (11,49 57) (Table 2). Even if the selection criteria and indications for transplantation in patients with HCC could be expanded, the current shortage of liver grafts

4 450 Surgical treatment for hepatocellular carcinoma and the lack of data defining new limits for transplantation in patients with HCC would make efforts to expand the listing criteria very controversial. Expanded listing criteria would lead to the inclusion of patients with more advanced cancer, potentially resulting in higher dropout rates accompanied by poorer survival rates on intent-to-treat analysis (58). Further studies are thus needed to establish suitable criteria for transplantation in patients with HCC. ALLOCATION POLICIES The allocation policy for organs from deceased donors was determined by waiting time and urgency (59). Patients with HCC were not considered to have a high priority for transplantation. Consequently, the waiting time frequently exceeded 1 year, resulting in a high dropout rate. The Model for End-Stage Liver Disease (MELD) score has proved to be an objective and reliable marker of early mortality in transplant candidates (60). In 2002, a MELD scorebased allocation policy was adopted in the USA. It has been rapidly recognized that the MELD score poorly correlates with disease severity in patients with compensated cirrhosis and HCC as the primary indication for transplantation. On the basis of the physiologic MELD score, these patients are unlikely to undergo transplantation in a timely manner. The MELD score therefore had to be adjusted to HCC. The aim was to equate the risk of tumor progression as assessed by the Milan criteria to that of death without transplantation. It was estimated that patients with Stage 1 (one lesion,2 cm)or 2 (one lesion,5 cm or two to three nodules each,3 cm) tumors had a dropout risk at 3 months of 15 and 30%, respectively. Experts convened and assigned corresponding MELD scoresof24and29topatientswithstage1and2tumors, respectively. Importantly, patients with Stage 3 or 4 tumors did not receive a corresponding MELD score, but could be listed according to their physiologic MELD score. LIVING-DONOR LIVER TRANSPLANTATION Living-donor liver transplantation will most likely enable patients to avoid the long waiting time and consequently reduce the dropout rate. Available data suggest that this option can provide long-term results comparable to those of cadaveric donor transplantation for HCC. In patients fulfilling the Milan criteria, the 5-year survival rate was 78% in the Japanese cohort of 653 patients (61). It also can be offered to those with HCC extending the Milan criteria to whom cadaveric donor is very unlikely allocated, and the 5-year survival rate was 60% (61). In the case of liver resection, the 5-year survival rate was around 30% for HCC extending the Milan criteria (62). A recent survey of global transplant surgeons revealed that 41% of respondents favored living-donor liver transplantation for use in patients with HCC that exceeds the Milan criteria (63). Patients who no longer fulfill the criteria because of the tumor size or the number of tumor may still be viable candidates for this transplantation. Because a potential 5-year survival rate of around 50% has been reported for patients in whom transplantation is justified by extended criteria (58), transplantation would offer a better chance of survival than would all other therapeutic options. RESECTION VS. ABLATION Whether surgical resection or ablation is the superior treatment for small HCC remains controversial. Many retrospective studies and a few prospective studies have compared resection with ablation (Table 3) (64 71). Because ablation therapy is a relatively new treatment for HCC, only preliminary results with short-term follow-up are available. Currently available results indicate that the therapeutic effectiveness and disease-free and overall survival rates are better after liver resection than after ablation, particularly when lesions exceed 3 cm in diameter. A Japanese nation-wide survey involving 7185 patients found that the recurrence rate was significantly lower for the resection group (70). The cohort was divided into patients who underwent hepatic resection (n ¼ 2857), radiofrequency ablation (RFA; n ¼ 3022) or ethanol injection (n ¼ 1306). All patients had Child s A or B cirrhosis with underlying liver disease, primarily caused by hepatitis C. Locoregional ablation was an independent predictor of poorer outcomes with respect to recurrence when compared with resection on multivariate analysis. Although tumor sizes were similar among the groups, the resection group had better liver function in terms of the Child Pugh score and indocyanine green clearance, implying that the groups were heterogeneous. Two recent RCTs have demonstrated the feasibility of ablation therapy for the management of HCC (64,65). Both trials concluded that the therapeutic effects of ablation therapy are similar to those of liver resection. However, these RCTs did not provide adequate evidence supporting the therapeutic equivalence of ablation therapy and resection. The RCT by Huang et al. (64) included 76 patients with less than two lesions,3 cm each. Similar recurrence and overall survival rates were reported for two options, but the study had major drawbacks, such as a small sample size not based on a power calculation. The other RCT by Chen et al. (65) had several problems, including imbalance among the baseline characteristics of the patients and a very high rate of conversion from surgery to ablation after randomization (21%, 19 of 90 patients). The conclusions of these RCTs thus remain a matter of debate, and a multicenter joint RCT (abbreviated to SURF trial after surgery vs. RFA) is being done in Japan to reach a strong conclusion (72). TREATMENT GUIDELINES Treatment guidelines for HCC in Europe were published in 2001 as the European Association for the Study of the Liver

5 Jpn J Clin Oncol 2011;41(4) 451 Table 3. Resection vs. ablation for hepatocellular carcinoma Author Year Comparison Tumor number Tumor size Liver function Outcome Huang et al. (64) 2005 Resection (n ¼ 38) vs. EI (n ¼ 38) by RCT 2 3 cm Child A/B Equivalent recurrence and survival Chen et al. (65) 2006 Resection (n ¼ 90) vs. RFA (n ¼ 71) by RCT 1,5 Child A Equivalent overall and disease-free survivals Lupo et al. (66) 2007 Resection (n ¼ 42) vs. RFA (n ¼ 60) cm Child A/B Equivalent overall and disease-free survivals Guglielmi et al. (67) 2008 Resection (n ¼ 91) vs. RFA (n ¼ 109) ND,6 Child A/B Better disease-free and overall survivals for resection Abu-Hilal et al. (68) 2008 Resection (n ¼ 34) vs. RFA (n ¼ 34) cm Child A/B Better disease-free survival for resection Schwarz and Smith et al. (69) 2008 Resection (n ¼ 426) vs. ablation a (n ¼ 328) Milan criteria Hasegawa et al. (70) 2008 Resection (n ¼ 2857) vs. RFA (n ¼ 3022) vs. EI (n ¼ 1306) Ueno et al. (71) 2009 Resection (n ¼ 123) vs. RFA (n ¼ 110) Milan criteria Milan criteria ND Better overall survival for resection,3,3 Child A/B Lower tumor recurrence for resection Milan criteria Child A/B Better disease-free and overall survivals for resection EI, ethanol injection; RCT, randomized controlled trial; ND, not defined; RFA, radiofrequency ablation. a Included RFA, EI, cryosurgery and other ablation techniques. Figure 1. Japanese treatment algorithm for hepatocellular carcinoma [reproduced from Makuuchi et al. (7)]. TAE, transarterial embolization; HAIC, hepatic arterial infusion chemotherapy. Selected when the severity of liver damage is Class B and tumor size is 2 cm or less. Tumor size is 5 cm or less if there is only one tumor. (EASL) Consensus (3) and in the USA in 2004 as the American Association for the Study of Liver Diseases (AASLD) Clinical Practice Guidelines (73). Both guidelines adopted the Barcelona Clinic Liver Cancer (BCLC) staging system, but the latter included a new entity of Stage 0 HCC (carcinoma in situ) (39). The BCLC staging system links the stage of HCC to treatment by means of an algorithm and attempts to incorporate prognosis estimation and potential treatment in a single unified proposal (2). Each stage considers tumor status and the liver functional status to be independently related to patients survival. JAPANESE GUIDELINES In 2005, a Japanese specialist committee generated Clinical Practice Guidelines for HCC, supported by Ministry of Health, Labour and Welfare of Japan. A full English version was uploaded onto the website of The Japanese Society of Hepatology ( in By an evidencebased methodology, the guideline has covered the six areas of prevention, diagnosis, surgery, chemotherapy, TAE and percutaneous ablation. A systematic review of the English medical literature was performed: a total of 7192 articles on HCC were extracted mainly from MEDLINE ( ), and 334 were

6 452 Surgical treatment for hepatocellular carcinoma Table 4. Treatment for hepatocellular carcinoma in Western and Eastern guidelines [reproduced from Takayama et al. (74)] Tumor number selected on the basis of the evidence level to form 58 pairs of clinical questions and recommendations (6,7). To facilitate clinical use, two types of algorithms for the surveillance and treatment of HCC were created. The treatment algorithm was based on three independent factors: degree of liver damage, tumor number and tumor size (Fig. 1). For the six patient subgroups, the first- or second-line treatment options were recommended as objectively as possible. COMPARISONS Tumor size (cm) Child Pugh class Treatment options BCLC guidelines Japanese guidelines Single 2 A, B Resection Resection Ablation A, B Resection Resection Transplantation or ablation A, B Resection Resection Transplantation 2 or 3 nodules 3 A, B Transplantation or ablation Resection Ablation C Palliative care Transplantation.3 A, B Chemoembolization Resection Chemoembolization 4 or more nodules A, B Chemoembolization Chemoembolization C Palliative care Palliative care BCLC, Barcelona Clinic Liver Cancer. Between the BCLC and Japanese treatment algorithms, there is agreement, in that liver resection is recommended as the best option for a single HCC (irrespective of size) in patients with well-preserved liver function (Child Pugh A or B) (Table 4) (74). However, the BCLC algorithm insists on a stricter policy than the Japanese with regard to the indications for resection. In the BCLC, resection is contraindicated in patients who have two or three tumors because of a poor 5-year survival rate (45%) and in those with portal hypertension because of a high incidence (73%) of postoperative liver decompensation (75). In a similar Japanese cohort, however, resection was associated with good 5-year survival rates in patients with multiple tumors (58%), as well as minimal morbidity rates (9%) (76). Moreover, a prospective Italian study has shown that resection provides a survival benefit for some patients with HCC of BCLC Stage B or Stage C (77). The BCLC algorithm recommends only liver transplantation for the surgical treatment of multiple tumors. Because graft shortages are a crucial problem, the indications for liver resection should be expanded to include multiple tumors, albeit as the second-best treatment. Both sets of algorithms agree that liver transplantation is the best option for HCC satisfying the Milan criteria in decompensated cirrhosis. These strict criteria have produced 5-year survival rates around 80%, with recurrence rates of,10% (11). The Japanese guidelines recommend transplantation for patients with Class C liver damage (i.e. HCC meeting the Milan criteria). This narrow indication range has resulted from the facts that most transplants are obtained from living donors in Japan and that the Japanese National Health Insurance system does not cover the costs for transplantation in patients with HCC not meeting the Milan criteria (7). CONCLUSIONS Liver resection is an established treatment for HCC owing to minimal surgical mortality and improved survival. Transplantation is one of the best treatments for HCC in patients who fulfill the selection criteria. Treatment guidelines for HCC will facilitate decision-making by both patients and physicians at every clinical step. By sharing the precise information in algorithm charts, physicians need to recommend treatment options and allow the patient to choose one. Funding This study was supported by a Grant-in-Aid for Scientific Research (No ) from the Ministry of Education, Science, and Culture of Japan. Conflict of interest statement None declared. References 1. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003;362: Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis 1999;19: Bruix J, Sherman M, Llovet JM, Beaugrand M, Lencioni R, Burroughs AK, et al. Clinical management of hepatocellular carcinoma: conclusions of the Barcelona 2000 EASL conference. J Hepatol 2001;35: Poon RT, Fan ST, Tsang FH, Wong J. Locoregional therapies for hepatocellular carcinoma: a critical review from the surgeon s perspective. Ann Surg 2002;235: Ryder SD. Guidelines for the diagnosis and treatment of hepatocellular carcinoma (HCC) in adults. Gut 2003;52(Suppl III):iii Makuuchi M, Kokudo N. Clinical practice guidelines for hepatocellular carcinoma: the first evidence based guidelines from Japan. World J Gastroenterol 2006;12:828 9.

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