6 Multidisciplinary Care of the Hepatocellular Carcinoma Patient 85 Transplant Surgeon The indications for resection versus transplantation of HCC remain controversial. Through technical improvements in both transplantation and resection, both fields continue to mature which contributes to the current lack of consensus. Adequate graft availability remains a practical constraint that also limits the availability of liver transplantation. Patients who have been treated for extrahepatic cancers are generally advised to successfully complete a disease-free surveillance period before undergoing liver transplantation for HCC, 5 years for solid malignancy or 2 years for a hematologic malignancy. Such waiting periods are not required prior to liver resection for HCC. The universally accepted candidate for liver transplantation is a patient with poorly compensated cirrhosis or portal hypertension whose HCC tumor burden meets the Milan or University of California San Francisco (UCSF) criteria. The Milan criteria specify the presence of 1 tumor ≤5cmor≤3 tumors each ≤3cm [28]. The UCSF criteria specify a single t umor ≤6.5 cm, a maximum of three total tumors ≤4.5 cm, and a cumulative tumor size ≤8cm[29]. Including the transplant Fig. 6.1 A 70-year-old male with elevated transaminases is found to have HCC of the right liver and undergoes hepatic artery embolization (panel a). Due to abutment of the middle hepatic vein and an insufficient FLR, he underwent right portal vein embolization with hypertrophy to 32% of the total liver volume (panel b). The patient then underwent extended right hepatectomy (panel c) 86 C.M. Contreras et al. surgeon in the multidisciplinary team can also help identify which patients will over the long term likely require liver transplantation. Select patients are then candidates for bridging procedures such as resection, TACE, or RFA which attempt to control the HCC until the point when the patient requires transplantation and a suitable graft is available. Fig. 6.2 A 54-year-old male presents with multiple bilateral liver nodules (panels a and b), initially deemed unresectable. Biopsy shows well-differentiated HCC. After five cycles of TACE, there was resolution of the nodules in the left liver (panel c), but persistent right-sided disease (panel d). Hepatic steatosis prompted right portal vein embolization with segment IV extension to induce hypertrophy of the FLR. The patient underwent extended right hepatectomy with common bile duct resection (panel e). He was alive without recurrence 3 years after the procedure 6 Multidisciplinary Care of the Hepatocellular Carcinoma Patient 87 Hepatobiliary Surgeon Together with the other members of the multidisciplinary team, an experienced hepatobiliary surgeon can help decide whether a patient’s HCC is resectable. Innovations in surgical technique and perioperative care have expanded the inclu- sion criteria for which patients are offered curative resection. Impediments to initial resectability include poorly controlled cirrhosis, multiple medical comorbidities, metastatic deposits, insufficient future liver remnant, or overwhelming involvement of critical vascular or biliary structures. The multidisciplinary conference is the ideal forum in which to discuss these concerns and to develop the most oncologically appropriate treatment strategy. The following case presentations (Figs. 6.1 and 6.2) illustrate how the multidisciplinary team maximizes efficient, high-quality care for patients with HCC. 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Hepatology 33: 1394–403 Chapter 7 Evidence-Based Guidelines for Treatment of Hepatocellular Carcinoma in Japan Kiyoshi Hasegawa and Norihiro Kokudo Keywords Evidence-based medicine · Clinical practice guidelines · Randomized controlled trial · Treatment algorithm Hepatocellular carcinoma (HCC) has five characteristics that are strikingly differ- ent from those of other malignant tumors of the digestive system: (1) a strong causal relationship with hepatitis viruses (especially type B and type C), (2) a major impact of the status of hepatic functional reserve and liver damage on the choice of treatment and the prognosis, (3) a high recurrence rate, with many of the recurrences developing within the liver, and the existence of two major routes of recurrence, i.e., multicentric carcinogenesis and intrahepatic metastasis, (4) the possibility of performing effective treatment, if confined to the liver and liver functional reserve permits, and (5) the existence of a clear outcome determi- nant as vascular invasion. Because of these characteristics, choosing the method of treatment for HCC is not easy, although several useful methods are available to treat HCC. Three methods of treatment are currently recognized as effective against HCC: surgery, including liver resection and liver transplantation, percutaneous ablation therapy as represented by radiofrequency ablation (RFA) and percu- taneous ethanol injection (PEI), and transcatheter arterial chemoembolization (TACE). Because almost all cases of HCC are associated with chronic liver damage in some degree, liver function conditions must be taken i nto consid- eration at the same time as tumor conditions when choosing treatment. Thus, treatment selection conditions are complicated. Especially, it is difficult to select surgery or percutaneous ablation therapy. Because studies that have evaluated the results of treatment scientifically have been inadequate, whenever it has been possible to select more than one method of treatment under certain tumor and liver function conditions, t he choice has often ultimately depended on N. Kokudo (B) Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, University of Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan 89 K.M. McMasters, J N. Vauthey (eds.), Hepatocellular Carcinoma, DOI 10.1007/978-1-60327-522-4_7, C Springer Science+Business Media, LLC 2011 90 K. Hasegawa and N. Kokudo the skill and convictions of the attending physician, customary practice at the institution, etc. The Clinical Practice Guidelines for Hepatocellular Carcinoma published in 2005 [1] were devised to allow the attending physician and the patient to select evidence-based care as much as possible. The methods to construct the guidelines are described in detail elsewhere [2], and their main body can be read in English on the web site of the Japanese Society of Hepatology (http://www.jsh.or.jp/). The essential features of the guidelines have been summarized in two figures, one for a hepatocellular carcinoma surveillance algorithm and the other for a hepatocel- lular carcinoma treatment algorithm. At present, 4 years after their release, both algorithms have come into widespread use in clinical settings of Japan. Here we will focus on the hepatocellular carcinoma t reatment algorithm and outline how treatment methods should be selected according to the algorithm. Explanation of the Treatment Algorithm As shown in Fig. 7.1 [1], the algorithm related to the treatment of HCC has been simplified based on three factors: degree of liver damage (Table 7.1)[3], number of tumors, and tumor diameter. The treatment methods that are recommended have been narrowed down to one or two, and the more highly recommended method Fig. 7.1 Treatment algorithm for HCC (Reproduced with permission from [1]). ∗ Presence of vas- cular invasion or extrahepatic metastasis to be indicated separately. † Selected when the severity of liver damage is class B and the tumor diameter is ≤2cm. †† Tumor diameter ≤5 cm, when there is only one tumor 7 Evidence-Based Guidelines for Treatment of Hepatocellular Carcinoma in Japan 91 Table 7.1 Liver damage Liver damage Items A B C Ascites None Responsive Unresponsive Serum bilirubin (mg/dL) <2.0 2.0–3.0 >3.0 Serum albumin (g/dL) >3.5 3.0–3.5 <3.0 ICG R15 (%) <15 15–40 >40 Prothrombin time (%) >80 50–80 <50 If more than one item is applicable to the patient, the clinical stage with the worst degree of all involved items should be recorded. ICG R15, indocyanine green retention rate at 15 min Reproduced with permission from [3] is printed above. Since including the treatment of advanced cases associated with extrahepatic lesions and portal vein tumor thrombus into the algorithm would have made it too complicated, it has been omitted and will be described in other part of the guidelines [1]. There have been very few evidences for effective treatments in those subgroups of patients. Selection of the Three Important Factors for the Algorithm Degree of liver damage is similar to Child–Pugh class except the inclusion of ICG test. Although several Japanese hepatologists have asserted that Child–Pugh class should be chosen as a determinant of the treatment algorithm, degree of liver damage is selected, because ICG test is indispensible to decide a surgical indication and an operative procedure for HCC in Japan [4]. ICG test enables a liver surgeon to more accurately evaluate liver function of a HCC carrying patient, i.e., in a case with Child–Pugh A class cirrhosis, liver resection is never selected, if a result of ICG test indicates poor liver function. On the other hand, in the BCLC and AASLD guidelines [5, 6], presence or absence of portal hypertension is a key factor for decision making in the treatment of HCC. However, a recent report from Japan showed that patients with portal hypertension or multiple tumors may have survival benefit by liver resection although their outcomes are inferior to that of patients without portal hypertension or with single tumors [7]. Thus, we regard degree of liver damage including ICG test as more important than presence or absence of portal hypertension. Number of tumors and tumor diameter are also chosen as determinants of the treatment algorithm. Vascular invasion would be the strongest prognostic factor as have been suggested in many previous reports; however, its presence or absence is difficult to be accurately assumed by the currently available diagnostic modalities before treatments. To the contrary, number of tumors and tumor diameter have much 92 K. Hasegawa and N. Kokudo advantage in that they can be easily known and have been included to other staging systems [5, 6, 8]. Thus, both are included in the treatment algorithm, but not vascular invasion. Degree of Liver Damage A and B When the degree of liver damage is A and B, liver function is good, and there is only a solitary liver tumor, as a rule liver resection is the treatment of first choice regardless of tumor diameter. The basis for this recommendation is that when the long-term results of liver resection and PEI were compared using data from a nation- wide follow-up study by the Liver Cancer Study Group of Japan, they showed that liver resection was significantly superior to PEI in several conditions [9]. However, because there were no differences in the results of liver resection and PEI when the degree of liver damage was B and the tumor was solitary and no more than 2 cm in diameter, percutaneous ablation therapy is also recommended. Although not stated in the algorithm, because realistically it is difficult to treat tumors greater than 3 cm in diameter curatively by percutaneous ablation treatment methods (including RFA), liver resection is the sole recommended method of treatment. When there are two or three tumors and their diameters do not exceed 3 cm, liver resection or percutaneous ablation treatment is recommended. When tumor diameter exceeds 3 cm, it is beyond percutaneous ablation treatment, and TACE is recommended instead. The results of a randomized controlled trial (RCT) by Llovet et al. that showed the efficacy of TACE are the basis for this recommendation [10]. When there are four or more tumors, TACE or hepatic arterial infusion ther- apy is recommended. There is no convincing evidence for hepatic arterial infusion therapy, and it has a recommendation degree of C1 (it is acceptable to consider performing it, but there is no scientific basis for it). Nevertheless, in view of the fact that it has been widely adopted in Japan and new treatment methods, such as combination with interferon, are anticipated, it has become the second recommendation. Degree of Liver Damage C Because liver function is poor in degree of liver damage C, treatment by any other means than liver transplantation, which can be expected to restore normal liver func- tion as well as treat the HCC, is dangerous. The Milan criteria, which are the most widely recognized criteria worldwide, have been adopted as indications for liver transplantation. More specifically, liver transplantation is recommended if the HCC is solitary and no larger than 5 cm or if there are no more than three tumors and each tumor is no larger than 3 cm. Because of the high risk of recurrence after liver transplantation and the high risk of liver failure when other methods of treatment are used, none of them are recommended when there are four or more tumors, and best supporting care should be considered. 7 Evidence-Based Guidelines for Treatment of Hepatocellular Carcinoma in Japan 93 Advanced Cancer Advanced HCC, in which there is extrahepatic metastasis or portal vein tumor thrombus, is not included in the algorithm. It has a poor prognosis, and no treat- ment that can be recommended has ever been established. Nevertheless, since there is a report that an improvement in outcome can be expected by combined use of TACE and liver resection [11], if liver function is good, “Liver resection is some- times selected in cases with degree A liver damage” has been stated separately. Chemotherapy is often considered when there is extrahepatic metastasis, but since no anticancer drugs had been demonstrated to be effective against HCC at the time the guidelines were drawn up, the guidelines only state, “Chemotherapy is sometimes selected in cases with degree of liver damage A.” How to Use the Algorithm The algorithm has been prepared by envisioning a scenario in which the attending physician selects the method of treatment while presenting it to the patient and dis- cussing it in a clinical setting. In the Hepato-Biliary-Pancreatic Surgery Division of the University of Tokyo Hospital, an explanation in which the algorithm is presented is routinely provided both at the time of the initial examination (outpatient clinic) and before surgery (after hospital admission). According to the results of a ques- tionnaire survey, the explanation has generally been favorably evaluated as easy to understand. Nevertheless, it must be borne in mind that treatment methods that do not con- form to the algorithm can be devised in individual cases. Since the evidence was compiled and generalized at the time the algorithm was drawn up, naturally it sometimes may not apply because of differences in a variety of conditions. These types of clinical practice guidelines are generally said to apply to 60–95% of all cases [12]. There is no problem per se with adding judgments based on physicians’ experience or trials of the most advanced treatment methods. However, when rec- ommending a method of treatment that differs from the guidelines to a patient, it would seem necessary to thoroughly explain at least two points to the patient, i.e., that the treatment differs from the recommendation in the guidelines and the rea- son for venturing to propose a different treatment, and then to obtain the patient’s consent. Evaluation of the Algorithm A questionnaire survey regarding the guidelines was conducted in March 2006, approximately 1 year after they were published [13]. Survey sheets were distributed to 2,279 members of the Liver Cancer Study Group of Japan, and replies were 94 K. Hasegawa and N. Kokudo obtained from 843 (37%) of them. Of those who replied, 55.4% were hepatolo- gists and 38% were liver surgeons, and more than 70% of those who replied were practicing at institutions that were also engaged in education, such as university hospitals. The same questionnaire was sent to 689 general internists responsible for primary care in Osaka Prefecture and Hyogo Prefecture, and replies were received from 332 (48.2%) of them. First, 71.9% of the hepatologists, 75.6% of the liver surgeons, and 61% of the general internists knew about the guidelines. Both the hepatologists and the liver surgeons often referred to medical journals, the litera- ture, guidelines, and the opinions of their colleagues in regard to clinical problems related to HCC, whereas the general internists tended to attach greater impor- tance to the opinions of specialists or their colleagues (Fig. 7.2a) [13]. Although 19–21% of the hepatologists and liver surgeons changed their clinical practice pat- terns as a result of the release of the guidelines, 50–52% had not changed them at all. It was learned that 43% of the general internists followed the recommenda- tions of the guidelines and had changed their clinical practice patterns (Fig. 7.2b) [13]. The results of the questionnaire survey showed that 1 year after the guide- lines were released, they had reached both specialists and general practitioners, and that they were being used to decide on clinical practice policy as originally intended. Fig. 7.2 From the results of questionnaire surveys about the treatment algorithm for HCC (Reproduced with permission from [1], cited from [13]). (a) What are your possible actions when you have clinical questions or problems in regard to the management of patients with hepatocel- lular carcinoma (HCC)? (a multiple-choice question). (b) Have you changed your practice pattern for HCC after reading the JHCC guidelines? (Responders who did not acknowledge the guidelines were excluded) . Treatment of Hepatocellular Carcinoma in Japan Kiyoshi Hasegawa and Norihiro Kokudo Keywords Evidence-based medicine · Clinical practice guidelines · Randomized controlled trial · Treatment algorithm Hepatocellular. including liver resection and liver transplantation, percutaneous ablation therapy as represented by radiofrequency ablation (RFA) and percu- taneous ethanol injection (PEI), and transcatheter arterial. the results of liver resection and PEI when the degree of liver damage was B and the tumor was solitary and no more than 2 cm in diameter, percutaneous ablation therapy is also recommended. Although