The main methods of treatment for hepatocellular carcinoma (HCC) in Japan are hepatic resection, radiofrequency ablation (RFA) and transcatheter arterial chemoembolization (TACE). Meticulous follow up is then undertaken to check for recurrence, which is treated using repeated RFA or TACE. Hepatic arterial infusion chemotherapy has been introduced as treatment for advanced HCC, and the molecular-targeted drug sorafenib is also now available. Rigorous medical care using these treatment methods and early diagnosis mean that the prognosis for HCC in Japan is the best in the world. This paper reviews the treatment strategies for HCC in Japan.
TREATMENT FOR HEPATOCELLULAR carcinoma (HCC) is peculiar in that, unlike other solid carcinomas, the treatment methods must be selected in consideration of the underlying clinical condition of the liver. A wide range of treatment methods is available, including hepatectomy, liver transplant, radiofrequency ablation (RFA), transcatheter arterial chemoembolization (TACE), sorafenib therapy, hepatic arterial infusion chemotherapy (HAIC) and radiotherapy. These treatment methods can also be used in combination. This paper reviews the treatment strategies for HCC in Japan.
CHOICE OF TREATMENT METHOD
MANY CASES OF HCC arise from liver cirrhosis, and are associated with deterioration in liver function. This means that in addition to cancer stage, hepatic reserve is also an important prognostic factor. This balance must be taken into account when choosing between different types of treatment. In Japan, the Japan Society of Hepatology issued consensus-based HCC treatment guidelines in 2010, which include a HCC treatment algorithm that offers the closest method of selecting treatment to current clinical practice (Fig. 1).1
In this algorithm, the treatment method is guided by five factors: extrahepatic lesions; hepatic reserve (Child–Pugh class); vascular invasion; number of tumors; and tumor diameter. This algorithm was prepared on the basis of another algorithm compiled in evidence-based clinical practice guidelines for HCC – the Japan Society of Hepatology 2009 update2– and reflects the consensus reached among HCC treatment specialists in Japan. This algorithm is somewhat complex, listing multiple methods of treatment with the addition of numerous comments, but reflects the current Japanese choices of treatment for HCC almost in their entirety.1
This treatment algorithm was basically prepared for the treatment of primary HCC, but also provides a reference for recurrent HCC, for which the treatment method is determined by taking into account the time to recurrence, type of recurrence, anticipated tumor malignancy according to tumor markers and pathology, age at recurrence, degree of deterioration in liver function between primary occurrence and recurrence, and the adverse effects of initial treatment.
ALONG WITH LIVER transplantation, this offers the most radical treatment, but the degree of surgical invasiveness, complications and the deterioration of hepatic reserve after resection must be taken into account.
Hepatic resection procedures include partial resection, subsegmental resection, segmental resection, two-segment resection, extended two-segment resection and three-segment resection. As HCC frequently metastasizes within the liver via the portal vein, anatomical resection of the entire portal segment where the cancer is located increases the curative nature of the procedure, and anatomical resection is therefore commonly performed provided hepatic reserve is sufficient. The standard procedure is to inject dye under guidance of ultrasonography (USG) into the portal vein in the segment containing the cancer, and to perform systematic subsegmental resection to remove all areas stained by the dye.3,4
It is important to evaluate hepatic reserve prior to hepatic resection, and the permissible extent of resection is considered on the basis of presence or absence of ascites, jaundice and the indocyanine green (ICG) retention rate at 15 min when determining the type of resection procedure.5 If necessary, technetium-99m diethylenetriamine pentaacetic acid galactosyl human serum albumin single photon emission computed tomography (CT) is used to evaluate patients who cannot be adequately evaluated by means of an ICG load test.6,7
According to the report of the 18th follow-up survey of primary liver cancer in Japan, hepatic resection was performed in 31.7% of all cases of HCC, with operative mortality of 1.4% (Fig. 2).9 Three-, 5- and 10-year survival rates after hepatic resection were 69.5%, 54.2% and 29.0%, respectively.9
As a recent trend in surgery, minimally invasive resection methods such as laparoscopic hepatectomy10–12 and robot surgery13 have been developed for some cases of HCC. Percutaneous isolated hepatic perfusion chemotherapy following debulking hepatectomy is reportedly useful in treating patients with severe advanced HCC with tumor thrombus of major vessels.14
LIVER TRANSPLANTATION IS the best treatment method for removing metastatic foci in the liver together with the cirrhotic liver from which the cancer develops. In Japan, living-donor liver transplantation has been covered by health insurance since January 2004.
According to reports published up to the end of 2009, almost all liver transplantations for HCC in Japan involved living donors, with 1131 transplantations from living donors and seven from deceased donors.15 As liver transplantations are taken from living donors, indications for liver transplantation in Japan only cover those patients who meet the Milan criteria (≤3 tumors with tumor diameter ≤3 cm or a single tumor ≤5 cm in diameter), but whose hepatic reserve has deteriorated severely (Child–Pugh class C),1,2 meaning that liver transplantations are regarded very differently in comparison with other countries where the majority of transplantations are from deceased donors.15
However, because most liver transplantations are from living donors, issues of the appropriate distribution of liver grafts and waiting times involved in transplantations from deceased donors are almost non-existent. Recently, tumor markers have also been included in the criteria, and attempts are being made to extend indications beyond those of the Milan criteria.16,17 In addition, donors are restricted to close relatives. As a result, blood groups are frequently mismatched, although in almost all cases this can be managed by the preoperative administration of anti-CD20 antibodies and plasmapheresis.18
According to a report by the Japanese Liver Transplantation Society, 1-, 3-, 5- and 10-year survival rates following liver transplantation from a living donor were 84.4%, 73.9%, 68.5% and 58.8%, respectively.15
The Act on Organ Transplantation was revised in July 2010 to enable organ donation with the family's permission even if the donor's own intentions had not been made clear, and since then the number of liver transplants from deceased donors has gradually been increasing.
LOCAL ABLATION THERAPY
LOCAL ABLATION THERAPY constitutes the main medical therapy for HCC in Japan. According to the report of the 18th follow-up survey, local ablation therapies were used in 30.6% of cases, administrated percutaneously in approximately 90% of those cases. RFA was used in 72.1% of cases (Fig. 2).9
Radiofrequency ablation has been covered by health insurance in Japan since April 2004, and its efficacy has been demonstrated in several subsequent randomized comparative trials,19–22 making this the first choice in percutaneous local therapy today.2 Percutaneous ethanol injection therapy, the therapy previously used, is still performed in rare cases for sites where insertion of an electrode for RFA is regarded as dangerous.
Indications for RFA are generally considered to be three or less tumors with a tumor diameter of 3 cm or less, with Child–Pugh class A or B liver function, no uncontrollable ascites and no hemorrhagic tendencies. In practice, commonly used criteria comprise platelet count of 50 000/µL or more, prothrombin time of 50% or more and serum bilirubin of 3 mg/dL or less. For tumors more than 3 cm in diameter, TACE is frequently performed first, followed by additional RFA.8
According to the report of the 18th follow-up survey, 1-, 3- and 5-year survival rates for RFA were 95.0%, 76.7% and 56.3%, respectively.9
Radiofrequency ablation is usually performed percutaneously; however, this method can be adapted by performing RFA laparoscopically for lesions on the liver surface or touching neighboring organs such as the intestines or diaphragm,23 and can also be carried out with artificial pleural effusion for lesions under the diaphragm or when the lungs intrude on the puncture route.24,25 Artificial ascites can also be used to prevent perforation of the digestive tract for lesions touching the intestines,24–28 and an endoscopic nasobiliary drainage tube can be used to cool the bile duct before treatment when the lesion is close to the bile duct and the latter is at risk of damage.24,29 For lesions in which the tumor boundaries are not clearly demarcated and that are difficult to visualize under b-mode USG, or when performing additional treatment to secure ablative margins around the target lesion, treatment can be assisted using contrast USG using Sonazoid24,30,31 or a real-time virtual sonography system that synchronizes image data from or multidetector-row computed tomography with the position of the USG probe, and simultaneously displays the USG images and virtual images from CT data.32
TRANSCATHETER ARTERIAL CHEMOEMBOLIZATION is widely used in Japan to treat HCC.9 Usually, an adequate amount of emulsion containing oil-based contrast agent Lipiodol and anticancer agents is injected through a catheter then the selected arteries are embolized by embolic agents. Formerly, the embolic agents used in Japan were the absorbent gelatin sponge materials Gelfoam or Spongel treated to create fine fragments, but Gelpart porous gelatin granules were approved for health insurance coverage in 2006 and are now in common use.
Superselective TACE is generally used in Japan to minimize damage to non-tumorous areas by using a microcatheter to embolize only the cancerous subsegment.33–35 Epirubicin and cisplatin are commonly used as anticancer agents, and miriplatin, a new platinum drug, came into use in 2010.36,37
Indications for TACE are wide-ranging, and the procedure is generally performed in patients with hypervascular HCC who are not indicated for surgery or local therapy for reasons such as multiple bilobar HCC, liver dysfunction, old age or comorbidity, and in whom the first branch from the main portal vein is not occluded. In practice, this technique is commonly indicated for patients who are Child–Pugh class A or B with multiple tumors with a diameter of 3 cm or more or with four or more HCC (Fig. 1).1,2
According to the report of the 18th follow-up survey, 3-, 5- and 10-year survival rates for TACE (including chemolipiodolization) used to treat HCC were all poor, at 43.2%, 24.1% and 6.6%, respectively.9 These outcomes are due to the inclusion of patients in poor condition with hepatic reserve or tumor stage that contraindicates hepatic resection or RFA. The same Japanese follow-up survey of outcomes for TACE as initial therapy for Child–Pugh class A patients with a single tumor found that 1-, 3- and 5-year survival rates were good, at 93%, 73% and 52%, respectively.35,38
Transcatheter arterial chemoembolization is performed as initial treatment in 31.7% of cases,9 but is the most frequently used treatment for recurrence, and it is no exaggeration to say that most HCC patients undergo this therapy at some point (Fig. 2). TACE is periodically repeated in Europe and the USA, but this situation rarely arises in Japan. When one to three intrahepatic lesions are present, TACE is followed by additional RFA with the aim of improving local control. With the advent of sorafenib, definitions of TACE failure/refractory HCC have now been proposed to prevent liver dysfunction from decreasing after excursively repeating TACE and to maintain opportunities to administrate sorafenib.1
SORAFENIB WAS APPROVED as a molecular-targeted drug for the treatment of HCC in Japan from May 2009. This agent was approved based on the results of two randomized control trials from outside of Japan39,40 and a phase I clinical trial carried out in Japan.41 However, studies continued after sorafenib entered the market due to a lack of experience with administration in Japan. A safety alert was initially issued due to early deaths resulting from liver failure and hepatic encephalopathy, but it has since been used correctly. The median survival period in Japan is 11.0 months and the response rate is 4%, almost the same outcomes as those of the SHARP trial, but reports to date have shown a tendency for a greater number of side-effects, including hand–foot skin reaction, diarrhea, hypertension, loss of appetite and fatigue.42
Sorafenib is used to treat Child–Pugh class A patients who have extrahepatic lesions or multiple intrahepatic lesions who are unable to undergo TACE or HAIC, and patients with vascular invasion.1
Measures taken in Japan to reduce side-effects include a low initial dose of 400 mg/day,42 but drug effectiveness at half dose has yet to be fully investigated. Sorafenib has also not been compared with HAIC, which was already being performed in Japan, and there is debate on its positioning in the treatment of advanced intrahepatic cancer. A study is currently underway to verify the effects of combining sorafenib therapy and HAIC.
HEPATIC ARTERIAL INFUSION chemotherapy has been used in Japan for some time to treat intrahepatic advanced HCC that is not expected to respond to other existing treatment methods. According to the report of the 18th follow-up survey, chemotherapy is used in approximately 5% of cases of primary HCC, and is administrated arterially in 87% of cases (Fig. 2).9 HAIC enables high-concentration anticancer agents to be administrated directly into the carcinoma, and is also used as a treatment method to keep systemic concentrations of anticancer agent low due to the first-pass effect, with the aim of reducing systemic side-effects. There is little evidence for the efficacy of this approach, with randomized control trials showing no effect in improving survival prognosis. In addition, the therapeutic regimen has not been standardized, and the treatment is associated with many side-effects including hematological toxicities (neutropenia and thrombopenia) and non-hematological toxicities (nausea, vomiting, peptic ulcers, reservoir infection, catheter dislocation and vasculitis along injection site).
In general, HAIC is indicated for patients with multiple intrahepatic lesions or vascular invasion who are excluded from the indications for TACE and other existing treatments or for whom these are not expected to be effective, other than Child–Pugh class C patients with severe liver dysfunction.1
In Japan, the main forms used are interferon-combined 5-fluorouracil (5-FU) HAIC,39,40,43–45 low-dose cisplatin-combined 5-FU HAIC43,46–48 and HAIC with cisplatin alone.43,49 All of these have a response rate of approximately 30–40%, and the addition of more curative therapy is known to dramatically improve prognosis in responders. Use of a subcutaneous implantable HAIC reservoir enables HAIC to be administrated in outpatient clinics.44,45 In terms of side-effects, attention must be paid not only to the side-effects of the anticancer agents used in treatment, but also to complications such as catheter displacement, reservoir infection and peptic ulcer that are specific to hepatic arterial infusion, and the management techniques affect treatment response.45
RADIOTHERAPY IS ANOTHER treatment option. According to the report of the 18th follow-up survey, this treatment is administrated to only 1.5% of cases,9 but reports in recent years have described the efficacy of stereotactic radiotherapy, which enables selective irradiation of the tumor alone while avoiding the background liver (which has a low tolerance for radiation), and of intensity-modulated radiotherapy,50 as well as of good outcomes from particle beam therapies such as proton-beam and carbon-beam therapy.51,52
PREVENTION OF RECURRENCE
HEPATOCELLULAR CARCINOMA HAS two mechanisms of recurrence – multicentric carcinogenesis and intrahepatic metastasis – and a high annual recurrence rate of 20–30% even after treatment.53 Aiming for long-term survival is thus impossible without suppressing this recurrence, even if curative treatment is performed. If the underlying condition is viral hepatitis, interferon therapy is administrated proactively with the aim of viral elimination in the case of hepatitis C, whereas the nucleoside analog entecavir is given for hepatitis B. Even if this cannot be administrated, alanine transferase levels are kept as low as possible and hepatitis proactively suppressed by means of glycyrrhizin, ursodeoxycholic acid, phlebotomy or low-dose long-term interferon therapy, and branched-chain amino acids are administrated and nutritional management implemented with the aim of preventing reduced hepatic reserve at the time of recurrence.
IN ADDITION TO the so-called three major cancer treatments of surgery, chemotherapy and radiotherapy, methods of treatment for HCC also include RFA, TACE and liver transplantation. These treatment methods are all major interventions that depend on therapeutic techniques, and it must be understood that treatment procedures vary greatly not only between Japan, Europe and the USA, but also between institutions within a single country. The good outcomes for HCC seen in Japan9 compared with those in Europe54 and the USA55 are the result of the meticulous medical care for HCC that has been practiced in Japan.