Masatoshi Kudo, MD, PhD.
Department of Gastroenterology and Hepatology
Kindai University Faculty of Medicine

Q. MANY DECADES AGO JAPAN PIONEERED THE POLICY OF SCREENING FOR LIVER CANCER. WHAT IS THE CURRENT STRATEGY?

In Japan, liver cancer screening using ultrasound and three tumor markers (AFP, PIVKA-II, and AFP-L3) is recommended every 3-4 months for extremely high-risk patients (cirrhosis caused by hepatitis B or hepatitis C virus) or every 6 months for high-risk patients (hepatitis B, hepatitis C, non-viral cirrhosis) for hepatocellular carcinoma (HCC)[1,2]. As a result, 62.5% of HCC cases are detected at their early-stage (BCLC stage 0 and A), who are candidates of curative therapy such as resection or ablation; 31.6% were intermediate stage HCC and were treated by using TACE. Only 6% of cases were advanced HCC with vascular invasion or extrahepatic spread (BCLC stage C) or Child-Pugh grade C HCC (BCLC stage D). This is different from the status in Western or other Asian countries where 50% of HCC cases were diagnosed at BCLC stage C or D. This indicates how well-established and developed the HCC surveillance system is in Japan.

Q. HOW JAPAN COULD IMPLEMENT STRATEGIES TO IMPROVE EARLY DIAGNOSIS OF HCC?

In the early 1980s, the Japan’s liver cancer screening system was not as effective as it currently is, due to inaccuracy of diagnostic imaging, and consequently, 5-year survival and median survival were unsatisfactory. In the period from 1978−1982, 5-year survival was as low as 5.1%, but gradually increased to 42.7% in the period from 2003−2005. This rise was buoyed by rapid advances in diagnostic imaging technologies, development of three tumor markers (AFP, PIVKA-II, and AFP-L3) with health insurance coverage, technological advances in surgery, locoregional therapy, and intra-arterial infusion chemotherapy. Similarly, median survival improved steadily from 4 months in the period from 1978−1982 to 50 months in the period from 2003−2005[3].

These improvements were attributed not only to the establishment of the screening system, advances in diagnostic imaging enabling early detection of small tumors, but also to improved therapeutic technologies. Indeed, assessment of outcomes of resection, ablation, TACE, and intra-arterial infusion chemotherapy in patients divided by 5-year intervals over 28 years shows steady improvement in all modalities. Moreover, therapy outcomes in patients with poor prognostic indicators (AFP level ≥ 400 ng/ml) are also improving steadily (median OS from 2 months to 20 months over 28 years)[3].

Q. WHAT IS THE STANDARD OF CARE FOR ADVANCED LIVER CANCER?

A global prospective non-interventional observational study GIDEON (global investigation of therapeutic decisions in HCC and of its treatment with sorafenib: NCT 00812175) examined HCC patients treated by sorafenib at 378 institutes across 39 countries (including 3,202 patients treated at 40 participating institute in Japan). Subgroup analysis of a vast amount of GIDEON data found regional variations in patients’ background at initial examination for HCC and therapy outcomes by BCLC stage in the Asia-Pacific region (n = 955), Europe (n = 1,115), Latin America (n = 90), the United States (n = 563), and Japan (n = 508)[4].

Notable regional variations were seen in the time from initial detection to death. Median survival in HCC patients in Japan was 79.6 months, which was much longer compared with other regions (20.9 months in the Asia-Pacific region, 25.0 months in Europe, 19.5 months in Latin America, and 14.8 months in the United States)[4].

Although each BCLC stage group is expected to consist of homogeneous patients in terms of tumor burden and liver function, median survival in patients with advanced BCLC stage was longest in Japan compared with other regions[4,5].

Q. HOW REAL LIFE PRACTICE HELPED IMPROVING HCC MANAGEMENT IN JAPAN?

Above results can be explained by Japan’s well-established nationwide screening system that enables early detection of small tumors in many cases. Another reason is the accurate and meticulous diagnostic imaging that is available in Japan, with which appropriate treatment in accordance with liver function and tumor burden/location can be offered. The better outcomes in patients with BCLC stage A liver cancer in Japan can be attributed to the sophisticated technical approach in resection and/or locoregional therapies.

In a standard RFA procedure in Japan, computed tomography (CT) or EOB-MRI is performed on the same day or day after RFA in order to assess the complete necrosis and the ablative margin. RFA is then repeated until an adequate ablative margin is achieved and complete response is confirmed during a single hospital stay. Thus, the rate of complete response, either in theory or in practice, is 100% in Japan. However, the procedures are completely different in other parts of world.

In patients with intermediate-stage (BCLC stage B) HCC, who would typically undergo TACE, the number and size of nodules tend to be smaller in Japan than in Western and other Asian countries, probably a beneficial effect of early detection of HCC in Japan. This means that patients can be treated by superselective cTACE with iodized oil (Lipiodol®). During this procedure, a catheter is inserted into a feeding vessel very close to the tumors. The lipiodol injection within the artery near the tumors causes reflux of lipiodol from the hepatic artery into the portal branches via the peribiliary plexus, and through physiologic arterioportal (A-P) communications, thereby temporarily blocking portal flow. The subsequent placement of a gelatin sponge from the arterial side blocks both arterial and portal blood flow, resulting in hepatic infarction, albeit on a small scale, can cause complete necrosis of subcapsular lesions, extracapsular spread, and even tiny satellite nodules, which would not be satisfactorily treated by arterial occlusion only. Furthermore, superselective embolization minimizes impairment of hepatic functional reserve, allowing repeated TACE, and thus improved prognosis is expected. Superselective cTACE, in addition to resection and ablation, is regarded as curative treatment for liver cancer within the up-to-seven criteria for HCC liver transplantation in Japan. This maneuver is not widely used in Europe and North America, but given that many intermediate-stage HCC patients in these regions present with numerous nodules (≥ 10) in both lobes or with a large tumor, the use of superselective cTACE might be unlikely.

The BCLC stage C population comprising patients with advanced HCC characterized by vascular invasion and/or extrahepatic spread is relatively homogeneous compared with other BCLC stage populations, and therefore, similar prognoses are expected among patients within the same stage. Indeed, median OS in Europe, Asia, Latin America, and the United States (8.5−11.2 months) is reasonable and similar to that in the sorafenib and placebo groups of the SHARP study. Why then does Japan have such an outstanding median OS (27.7 months)? In accordance with Japanese guidelines[2], HCC specialists in Japan opt for resection for treatment of liver cancer even in cases with vascular invasion, provided tumor conditions and liver function meet the requirements. Propensity score-matching analysis showed much better prognosis in vascular invasion-positive patients who had undergone resection than in those who had undergone other therapies [6]. Similarly, TACE is preferred to molecularly targeted therapy due to the curative effect in many cases of HCC with minor vascular invasion (Vp1, 2) when criteria for liver function are met; the benefits of TACE were also demonstrated by a systematic review.

Q. WHY INTRA-ARTERIAL INFUSION CHEMOTHERAPY IS POPULAR IN MOST FAR EAST REGIONS?

Another unique treatment for vascular invasion in Japan is intra-arterial infusion chemotherapy. This has not yet been proven in a prospective study, and thus is not globally recognized as a standard of care. Although performed in only Japan, South Korea, and Taiwan, it is clearly beneficial in treating HCC with major vascular invasion. Propensity score-matching analysis of data collected through a nationwide follow-up survey of primary liver cancer by the Liver Cancer Study Group of Japan showed distinctly better prognosis for HCC with vascular invasion treated with infusion chemotherapy compared with other therapies[7]. Also, as reported at the European Association for the Study of the Liver (EASL) International Liver Congress 2016, the SILIUS trial compared sorafenib alone with sorafenib plus infusion chemotherapy in treatment of patients with a tumor thrombus in the main trunk of the portal vein (Vp4, a stratification factor), and found that additional infusion chemotherapy extended median survival from 6.5 months to 11.4 months (HR = 0.493, 95% confidence interval 0.240-1.014, p = 0.050) [8]. Given the typical survival of 2−3 months in Vp4 HCC patients, these results suggest that intra-arterial infusion chemotherapy clearly provides additional benefits to the moderate extension of survival by sorafenib. Taken together, resection, TACE, and intra-arterial infusion chemotherapy, in addition to molecular targeted therapy, are more readily used in treatment of HCC with vascular invasion in Japan, albeit in selected cases only, than in other regions, which may prolong overall survival I advanced HCC as well. Moreover, because intrahepatic lesions are strong prognostic factor even with extrahepatic spread, locoregional therapy, such as TACE or intra-arterial infusion chemotherapy, is applied in these patients, and this may contribute to favorable outcomes of treatment of advanced HCC in Japan. Indeed, an only Japanese trial on second-line S-1 versus placebo in HCC patients refractory or intolerant to sorafenib showed survival of 11.3 months in the placebo group[9], longer than survival in similar placebo groups in other 2md line trials (BRISK-PS, 8.2 months; EVOLVE-1, 7.3 months; REACH, 7.6 months). It is likely that the unique practice pattern in Japan, with the more precise proactive use of resection, TACE, and intra-arterial infusion chemotherapy, may improve survival considerably.

Q. WHY LOCOREGIONAL THERAPY IS OFFERED ALSO TO CHILD-PUGH C PATIENTS?

Japan has the longest survival in patients with end-stage liver cancer (BCLC stage D and Child-Pugh class C). A follow-up survey by the Liver Cancer Study Group of Japan revealed that approximately half of Child-Pugh class C liver cancer patients in Japan received locoregional therapy (resection, ablation, and intra-arterial infusion chemotherapy). Propensity score matching analysis of data from this follow-up survey showed that ablation and superslective cTACE improved survival in patients with a Child-Pugh score of 10 or 11[10] and tumor burden within Milan criteria, consistent with other multicenter or single-center studies. Thus, in Japan, locoregional therapy is used in clinical practice for carefully selected patients with Child-Pugh C HCC under the Milan criteria, and superselective cTACE and ablation appear to be beneficial in such patients. Incidentally, the consensus-based clinical practice guidelines of the Japan Society of Hepatology include TACE and ablation as treatment options for Child-Pugh C HCC [2].

Q. WHAT ABOUT PATIENTS WITH TERMINAL HCC?

Analysis of data from the GIDEON study also showed that survival in even BCLC stage D HCC patients was better in Japan than in other regions, reflecting the unique clinical practice for HCC care and consequent favorable treatment outcomes in Japan. HCC patients in Japan seem to show best overall survival in the world irrespective of BCLC stage A, B, C or D because of the established nationwide surveillance and unique practice pattern in the management of HCC different from other parts of Japan.

References

[1] Kokudo N, Hasegawa K, Akahane M, Igaki H, Izumi N, Ichida T, Uemoto S, Kaneko S, Kawasaki S, Ku Y, Kudo M, Kubo S, Takayama T, Tateishi R, Fukuda T, Matsui O, Matsuyama Y, Murakami T, Arii S, Okazaki M, Makuuchi M: Evidence-based clinical practice guidelines for hepatocellular carcinoma: The japan society of hepatology 2013 update (3rd jsh-HCC guidelines). Hepatology research : the official journal of the Japan Society of Hepatology 2015;45:123-127.

[2] Kudo M, Matsui O, Izumi N, Iijima H, Kadoya M, Imai Y, Okusaka T, Miyayama S, Tsuchiya K, Ueshima K, Hiraoka A, Ikeda M, Ogasawara S, Yamashita T, Minami T, Yamakado K: Jsh consensus-based clinical practice guidelines for the management of hepatocellular carcinoma: 2014 update by the liver cancer study group of japan. Liver Cancer 2014;3:458-468.

[3] Kudo M, Izumi N, Sakamoto M, Matsuyama Y, Ichida T, Nakashima O, Matsui O, Ku Y, Kokudo N, Makuuchi M: Survival analysis over 28 years of 173,378 patients with hepatocellular carcinoma in japan. Liver Cancer 2016;5:190-197.

[4] Kudo M, Lencioni R, Marrero JA, Venook AP, Bronowicki JP, Chen XP, Dagher L, Furuse J, Geschwind JF, Ladron de Guevara L, Papandreou C, Sanyal AJ, Takayama T, Yoon SK, Nakajima K, Lehr R, Heldner S, Ye SL: Regional differences in sorafenib-treated patients with hepatocellular carcinoma: Gideon observational study. Liver international : official journal of the International Association for the Study of the Liver 2016;36:1196-1205.

[5] Kudo M, Ikeda M, Takayama T, Numata K, Izumi N, Furuse J, Okusaka T, Kadoya M, Yamashita S, Ito Y, Kokudo N: Safety and efficacy of sorafenib in japanese patients with hepatocellular carcinoma in clinical practice: A subgroup analysis of gideon. J Gastroenterol 2016;51:1150-1160.

[6] Kokudo T, Hasegawa K, Matsuyama Y, Takayama T, Izumi N, Kadoya M, Kudo M, Ku Y, Sakamoto M, Nakashima O, Kaneko S, Kokudo N: Survival benefit of liver resection for hepatocellular carcinoma associated with portal vein invasion. J Hepatol 2016;65:938-943.

[7] Nouso K, Miyahara K, Uchida D, Kuwaki K, Izumi N, Omata M, Ichida T, Kudo M, Ku Y, Kokudo N, Sakamoto M, Nakashima O, Takayama T, Matsui O, Matsuyama Y, Yamamoto K: Effect of hepatic arterial infusion chemotherapy of 5-fluorouracil and cisplatin for advanced hepatocellular carcinoma in the nationwide survey of primary liver cancer in japan. Br J Cancer 2013;109:1904-1907.

[8] Kudo M, Ueshima K, Yokosuka O, Obi S, Izumi N, Aikata H, Nagano H, Hatano E, Sasaki Y, Hino K, Kumada T, Yamamoto K, Imai Y, Iwadou S, Ogawa C, Okusaka T, Arai Y, Kanai F, Akazawa KaSSG: Prospective randomized controlled phase III trial comparing the efficacy of sorafenib versus sorafenib in combination with low-dose cisplatin/fluorouracil hepatic arterial infusion chemotherapy in patients with advanced hepatocellular carcinoma. EASL, Abstr LB04, 2016

[9] Kudo M, Moriguchi M, Numata K, Hidaka H, Tanaka H, Ikeda M, Kawazoe S, Ohkawa S, Sato Y, Kaneko S, Furuse J, Takeuchi M, Fang X, Date Y, Takeuchi M, Okusaka T: S-1 versus placebo in patients with sorafenib-refractory advanced hepatocellular carcinoma (S-CUBE): A randomised, double-blind, multicentre, phase 3 trial. The lancet Gastroenterology & hepatology 2017;2:407-417.

[10] Kitai S, Kudo M, Nishida N, Izumi N, Sakamoto M, Matsuyama Y, Ichida T, Nakashima O, Matsui O, Ku Y, Kokudo N, Makuuchi M, Japan ftLCSGo: Survival benefit of locoregional treatment for hepatocellular carcinoma with advanced liver cirrhosis. Liver Cancer 2016;5:175-189.