Abstract
Despite therapeutic advances, the overall survival of patients with hepatocellular carcinoma (HCC) has not been significantly improved in the last two decades. In the majority of the cases, there is underlying cirrhosis, therefore the prognosis of HCC depends not only on tumor stage but also on liver function. Patients at an early stage are those who present with an asymptomatic single HCC with a maximum diameter of 5cm or up to three nodules each less than 3cm. They will be benefitted by curative therapies, including resection, liver transplantation (LT), and percutaneous ablation, such as destroying tumor cells via the injection of chemical substances, radiation, or heating or cooling. Patients exceeding these limits, but who are free of cancer?related symptoms and vascular invasion or extrahepatic spread may be benefitted by palliation with chemoembolization and hepatic arterial infusion chemotherapy. Recently, other treatments were developed under investigation treatments arising from technical advances in ablation and radiation. New promising image?guided therapies are continuously emerging and minimize hepatic toxicity and ultimately improve quality of life and survival of patients with HCC. The 3? dimensional conformal RT, tomotherapy, stereotatic radiosurgery, high intensity focused ultrasound, and proton beam radiotherapy will provide the opportunity for curative treatment of HCC, while avoiding critical normal tissue. New drugs, such as tyrosine kinase inhibitors and anti-angiogenic agents, are currently being tested in the setting of clinical trials. These new approaches may help to address the enormous need for expanded treatment options for patients with HCC. In the future, patients with HCC will be best treated by a multidisciplinary team approach, utilizing a combination of techniques to improve the patient survival.
References
1. Bosch FX, Ribes J, Diaz M, Cleries R. Primary liver cancer: worldwide incidence and trends. Gastroenterology. 2004; 127(S):S5–S16.
2. Annual report cause of death 2004. National Stastical Office;2005.
3. Llovet JM, Schwartz M, Mazzaferro V. Resection and liver transplantation for hepatocellular carcinoma. Semin Liver Dis. 2005; 25:181–200.
4. Takayama T, Makuuchi M, Hirohashi S, Sakamoto M, Yamamoto J, Shimada K, Kosuge T, Okada S, Takayasu K, Yamasaki S. Early hepatocellular carcinoma as an entity with a high rate of surgical cure. Hepatology. 1998; 28:1241–1246.
5. Fong Y, Sun RL, Jarnagin W, Blumgart LH. An analysis of 412 cases of hepatocellular carcinoma at a Western center. Ann Surg. 1999; 229:790–799.
6. Llovet JM, Fuster J, Bruix J. Intention?to?treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology. 1999; 30:1434–1440.
7. Arii S, Yamaoka Y, Futagawa S, Inoue K, Kobayashi K, Kojiro M, Makuuchi M, Nakamura Y, Okita K, Yamada R. Results of surgical and nonsurgical treatment for small?sized hepatocellular carcinomas: a retrospective and nationwide survey in Japan. The Liver Cancer Study Group of Japan. Hepatology. 2000; 32:1224–1229.
8. Zhou XD, Tang ZY, Yang BH, Lin ZY, Ma ZC, Ye SL, Wu ZQ, Fan J, Qin LX, Zheng BH. Experience of 1000 patients who underwent hepatectomy for small hepatocellular carcinoma. Cancer. 2001. 91. : 1479–1486.
9. Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, Montalto F, Ammatuna M, Morabito A, Gennari L. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996; 334:693–699.
10. Bismuth H, Majno PE, Adam R. Liver transplantation for hepatocellular carcinoma. Semin Liver Dis. 1999; 19:311–322.
11. Jonas S, Bechstein WO, Steinmüller T, Herrmann M, Radke C, Berg T, Settmacher U, Neuhaus P. Vascular invasion and histopathologic grading determine outcome after liver trans plantation for hepatocellular carcinoma in cirrhosis. Hepatology. 2001; 33:1080–1086.
12. Gonzaález? Uriarte J, Valdivieso A, Gastaca M, Errasti G, Campo M, Hernandez MJ, Montejo M, Bustamante J, Suarez MJ, Testillano M, Fernandez JR, Ortiz de Urbina J. Liver transplantation for hepatocellular carcinoma in cirrhotic patients. Transplant Proc. 2003; 35:1827–1829.
13. Adam R, Azoulay D, Castaing D, Eshkenazy R, Pascal G, Hashizume K, Samuel D, Bismuth H. Liver resection as a bridge to transplantation for hepatocellular carcinoma on cirrhosis: a reasonable strategy? Ann Surg. 2003; 238:508–518.
14. Hayashi PH, Trotter JF, Forman L, Kugelmas M, Steinberg T, Russ P, Wachs M, Bak T, Kam I, Everson GT. Impact of pretransplant diagnosis of hepatocellular carcinoma on cadveric liver allocation in the era of MELD. Liver Transpl. 2004; 10:42–48.
15. Gondolesi GE, Roayaie S, Muñoz L, Kim ?Schluger L, Schiano T, Fishbein TM, Emre S, Miller CM, Schwartz ME. Adult living donor liver transplantation for patients with hepatocellular carcinoma: extending UNOS priority criteria. Ann Surg. 2004; 239:142–149.
16. Todo S, Furukawa H. Living donor liver transplantation for adult patients with hepatocellular carcinoma: experience in Japan. Ann Surg. 2004; 240:451–461.
17. Llovet JM, Real MI, Montaña X, Planas R, Coll S, Aponte J, Ayuso C, Sala M, Muchart J, Solá R, Rodés J, Bruix J. Barcelona Liver Cancer Group. Arterial embolisation or che-moembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet. 2002; 359:1734–1739.
18. Pelletier G, Ducreux M, Gay F, Luboinski M, Hagége H, Dao T, Van Steenbergen W, Buffet C, Rougier P, Adler M, Pignon JP, Roche A. Treatment of unresectable hepatocellular carcinoma with lipiodol chemoembolization: a multicenter randomized trial. Groupe CHC. J Hepatol. 1998; 29:129–134.
19. Bruix J, Llovet JM, Castells A, Montañá X, Brú , Ayuso MC, Vilana R, Rodés J. Transarterial embolization versus symptomatic treatment in patients with advanced hepatocellular carcinoma: results of a randomized, controlled trial in a single institution. Hepatology. 1998; 27:1578–1583.
20. Arii S, Yamaoka Y, Futagawa S, Inoue K, Kobayashi K, Kojiro M, Makuuchi M, Nakamura Y, Okita K, Yamada R. Results of surgical and nonsurgical treatment for small?sized hepatocellular carcinomas: a retrospective and nationwide survey in Japan. The Liver Cancer Study Group of Japan. Hepatology. 2000; 32:1224–1229.
21. Lin DY, Liaw YF, Lee TY, Lai CM. Hepatic arterial embolization in patients with unresectable hepatocellluar carcinoma?a randomized controlled trial. Gastroenterology. 1988; 94:453–456.
22. Bartolozzi C, Lencioni R, Caramella D, Vignali C, Cioni R, Mazzeo S, Carrai M, Maltinti G, Capria A, Conte PF. Treatment of large HCC: transcatheter arterial chemoem?bolization combined with percutaneous ethanol injection versus repeated transcatheter arerial chemoembolization. Radiology. 1995; 197:812–818.
23. Cheon JH, Park JW, Park KW, Kim YI, Kim SH, Lee WJ, Park HS, Park SJ, Hong EK, Hong EK, Kim CM. The clinical report of 1,078 cases of hepatocellular carcinomas: National Cancer Center experience. Korean J Hepatol. 2004; 10:288–297.
24. Beaugrand M, N'Kontchou G, Seror O, Ganne N, Trinchet JC. Local/regional and systemic treatments of hepatocellular carcinoma. Semin Liver Dis. 2005; 25:201–211.
25. Livraghi T, Giorgio A, Marin G, Salmi A, de Sio I, Bolondi L, Pompili M, Brunello F, Lazzaroni S, Torzilli G. Hepatocellular carcinoma and cirrhosis in 746 patients: long?term results of percutaneous ethanol injection. Radiology. 1995; 197:101–108.
26. Sakamoto M, Hirohashi S. Natural history and prognosis of adenomatous hyperplasia and early hepatocellular carcinoma: multi? institutional analysis of 53 nodules followed up for more than 6 months and 141 patients with single early hepatocellular carcinoma treated by surgical resection or percutaneous ethanol injection. Jpn J Clin Oncol. 1998; 28:604–608.
27. Omata M, Tateisho T, Yoshida H, Shiina S. Treatment of hepatocellular carcinoma by percutaneous tumor ablation methods: Ethanol injection theapy and radiofrequency ablation. Gastroenterology. 2004; 127:S159–S166.
28. Ebara M, Okabe S, Kita K, Sugiura N, Fukuda H, Yoshikawa M, Kondo F, Saisho H. Percutaneous ethanol injection for small hepatocellular carcinoma: therapeutic efficacy based on 20? year observation. J Hepatol. 2005; 43:458–464.
29. Lencioni R, Llovet JM. Percutaneous ethanol injection for hepatocellular carcinoma: alive or dead? J Hepatol. 2005; 43:377–380.
30. Rossi S, Di Stasi M, Buscarini E, Quaretti P, Garbagnati F, Squassante L, Paties CT, Silverman DE, Buscarini L. Percutaneous RF interstitial thermal ablation in the treatment of hepatic cancer. Am J Roentgenol. 1996; 167:759–768.
31. Buscarini L, Buscarini E, Di Stasi M, Vallisa D, Quaretti P, Rocca A. Percutaneous radiofrequency ablation of small hepatocellular carcinoma: long?term results. Eur Radiol. 2001; 11:914–921.
32. Tateishi R, Shiina S, Teratani T, Obi S, Sato S, Koike Y, Fujishima T, Yoshida H, Kawabe T, Omata M. Percutaneous radiofrequency ablation for hepatocellular cardinoma. An analysis of 1000 cases. Cancer. 2005; 103:1201–1209.
33. Lencioni R, Cioni D, Crocetti L, Franchini C, Pina CD, Lera J, Bartolozzi C. Early? stage hepatocellular carcinoma in cirrhosis: long?term results of percutaneous image?guided radiofrequency ablation. Radiology. 2005; 234:961–967.
34. Lencioni RA, Allgaier HP, Cioni D, Olschewski M, Deibert P, Crocetti L, Frings H, Laubenberger J, Zuber I, Blum HE, Bartolozzi C. Small hepatocellular carcinoma in cirrhosis: randomized comparison of radio?frequency thermal ablation versus percutaneous ethanol injection. Radiology. 2003; 228:235–240.
35. Lin SM, Lin CJ, Lin CC, Hsu CW, Chen YC. Radiofrequency ablation improves prognosis compared with ethanol injection for hepatocellular carcinoma < or = 4cm. Gastroenterology. 2004; 127:1714–1723.
36. Shiina S, Teratani T, Obi S, Sato S, Tateishi R, Fujishima T, Ishikawa T, Koike Y, Yoshida H, Kawabe T, Omata M. A randomized controlled trial of radiofrequency ablation with ethanol injection for small hepatocellular carcinoma. Gastroenterology. 2005; 129:122–130.
37. Huang GT, Lee PH, Tsang YM, Lai MY, Yang PM, Hu RH, Chen PJ, Kao JH, Sheu JC, Lee CZ, Chen DS. Percutaneous ethanol injection versus surgical resection for the treatment of small hepatocellular carcinoma. A prospective study. Ann Surg. 2005; 242:36–42.
38. Chlebowski RT, Brzechwa?Adjukiewicz A, Cowden A, Block JB, Tong M, Chan KK. Doxorubicin (75mg/m2) for hepatocellular carcinoma: clinical and pharmacokinetic results. Cancer Treat Rep. 1984; 68:487–491.
39. Falkson G, MacIntyre JM, Moertel CG, Johnson LA, Scherman RC. Primary liver cancer. An Eastern Cooperative Oncology Group Trial. Cancer. 1984; 54:970–977.
40. Melia WM, Johnson PJ, Williams R. Induction of remission in hepatocellular carcinoma. A comparison of VP 16 with adriamycin. Cancer. 1983; 51:206–210.
41. Falkson G, Ryan LM, Johnson LA, Simson IW, Coetzer BJ, Carbone PP, Creech RH, Schutt AJ. A random phase II study of mitoxantrone and cisplatin in patients with hepatocellular carcinoma. An ECOG study. Cancer. 1987; 60:2141–2145.
42. Patt YZ, Hassan MM, Lozano RD, Brown TD, Vauthey JN, Curley SA, Ellis LM. Phase II trial of systemic continuous fluorouracil and subcutaneous recombinant interferon Alfa?2b for treatment of hepatocellular carcinoma. J Clin Oncol. 2003; 21:421–427.
44. Colleoni M, Audisio RA, De Braud F, Fazio N, Martinelli G, Goldhirsch A. Practical considerations in the treatment of hepatocellular carcinoma. Drugs. 1998; 55:367–382.
45. Baur M, Walter R, Gebauer A, Tscholakoff D, Lochs H, Mühlbacher F, Turetschek K, Binder R, Hudec M, Gangl A, Ferenci P, Dittrich C. Chemoembolization with cisplatin, lipiodol and Gelfoam and subsequent systemic chemotherapy with cisplatin and interferon in patients with hepatocellular carcinoma: a non?randomized prospective study. Int J Oncol. 2003; 23:811–819.
46. Suzuki M, Suzuki H, Yamamoto T, Mamada Y, Mizuno H, Tominaga T, Suga M, Suemori S, Kato Y, Sato A, Yamanouchi E, Sakuyama K, Maeyama S, Shinagawa T, Okabe K. Indication of chemoembolization therapy without gelatin sponge for hepatocellular carcinoma. Semin Oncol. 1997; 24S:S110–S115.
47. Llovet JM, Real MI, Montan ?a X, Planas R, Coll S, Aponte J, Ayuso C, Sala M, Muchart J, Sola R, Rode's J, Bruix J. Barcelona Liver Cancer Group. Arterial embolisation or che-moembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet. 2002; 359:1734–1739.
48. Bruix J, Llovet JM, Castells A, Montan ?a' X, Bru' C, Ayuso MC, Vilana R, Rode's J. Transarterial embolization versus symptomatic treatment in patients with advanced hepatocellular carcinoma: results of a randomized, controlled trial in a single institution. Hepatology. 1998; 27:1578–1583.
49. Park JH, Chung JW, Lee SK. Chemoemboliazation of hepatocellular carcinoma: long?term survival and prognostic factors. J Korean Radiol Society. 1996; 35:315–323.
50. Lo CM, Ngan H, Tso WK, Liu CL, Lam CM, Poon RT, Fan ST, Wong J. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology. 2002; 35:1164–1171.
51. Haskell CM. Cancer treatment. 5th ed.Philadelphia: WB Saunders Company;2001. p. 2038–2039.
52. Iwamiya T, Sawada S, Ohta Y. Repeated arterial infusion chemotherapy for inoperable hepatocellular carcinoma using an implantable drug delivery system. Cancer Chemother Pharmacol. 1994; 33(S):S134–138.
53. Seno H, Ito K, Kojima K, Nakajima N, Chiba T. Efficacy of an implanted drug delivery system for advanced hepatocellular carcinoma using 5 ?fluorouracil, epirubicin and mitomycin C. J Gastroenterol Hepatol. 1999; 14:811–816.
54. Cheong JY, Lee KM, Cho SW, Won JH, Kim JK, Wang HJ, Hahm KB, Kim JH. Survival benefits of intra?arterial infusion chemotherapy in patients with advanced hepatocellular carcinoma with portal vein tumor thrombosis. Hepatol Res. 2005; 32:127–133.
55. Jang JW, Park YM, Bae SH, Choi JY, Yoon SK, Chang UI, Nam SW, Kim BS. Therapeutic efficacy of multimodal combination therapy using transcatheter arterial infusion of epirubicin and cisplatin, systemic infusion of 5 ?fluorouracil, and additional percutaneous ethanol injection for unresectable hepatocellular carcinoma. Cancer Chemother Pharmacol. 2004; 54:415–420.
56. Toyoda H, Nakano S, Kumada T, Takeda I, Sugiyama K, Osada T, Kiriyama S, Suga T, Takahashi M. The efficacy of continuous local arterial infusion of 5? fluorouracil and cisplatin through an implanted reservoir for severe advanced hepatocellular carcinoma. Oncology. 1995; 52:295–299.
57. Ando E, Tanaka M, Yamashita F, Kuromatsu R, Yutani S, Fukumori K, Sumie S, Yano Y, Okuda K, Sata M. Hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma with portal vein tumor thrombosis: analysis of 48 cases. Cancer. 2002; 95:588–595.
58. Ando E, Yamashita F, Tanaka M, Tanikawa K. A novel chemotherapy for advanced hepatocellular carcinoma with tumor thrombosis of the main trunk of the portal vein. Cancer. 1997; 79:1890–1896.
59. Sumie S, Yamashita F, Ando E, Tanaka M, Yano Y, Fukumori K, Sata M. Interventional radiology for advanced hepatocellular carcinoma: comparison of hepatic artery infusion chemotherapy and transcatheter arterial lipiodol chemoembolization. AJR Am J Roentgenol. 2003; 181:1327–1334.
60. Jang JW, Bae SH, Choi JY, Oh HJ, Kim MS, Lee SY, Kim CW, Chang UI, Nam SW, Cha SB, Lee YJ, Hoi BG, Byun JY, Yoon SK. Therapeutic value of combination therapy with transarterial chemo?lipiodolization and systemic chemo?infusion for large extensive hepatocellular carcinoma invading portal vein in comparison with conservative management. Cancer Chemother Pharmacol. 2007; 59:9–15.
61. Sim MK, Kim DY, Park JY, Kim JK, Kim SA, Ahn SH, Chon CY, Moon YM, Won JY, Lee DY, Han KH. Efficacy of repeated hepatic arterial infusion chemotherapy in advanced hepatocellular carcinoma with portal vein tumor thrombosis. Korean J Hepatol. 2005; 11:268–274.
62. Hwang JY, Jang BK, Kwon KM, Chung WJ, Park KS, Cho KB, Hwang JS, Ahn SH, Kim GC, Kim YH, Choi JS, Kwon JH. Efficacy of hepatic arterial infusion therapy for advanced hepatocellular carcinoma using 5?fluorouracil, epirubicin and mito-mycin?C. Korean J Gastroenterol. 2005; 45:118–124.
63. Kim JS, Han KH, Lee DY, Seong JS, Youn YH, Cheong JY, Ahn SH, Chon CY, Moon YM. Concurrent chemo?radiation therapy for advanced hepatocellular carcinoma with portal vein thrombosis. Taehan Kan Hakhoe Chi. 2002; 8:71–79.
64. Ishikura S, Ogino T, Furuse J, Satake M, Baba S, Kawashima M, Nihei K, Ito Y, Maru Y, Ikeda H. Radiotherapy after transcatheter arterial chemoembolization for patients with hepatocellular carcinoma and portal vein tumor thrombus. Am J Clin Oncol. 2002; 25:189–193.
65. Yamada K, Izaki K, Sugimoto K, Mayahara H, Morita Y, Yoden E, Matsumoto S, Soejima T, Sugimura K. Prospective trial of combined transcatheter arterial chemoembolization and three? dimensional conformal radiotherapy for portal vein tumor thrombus in patients with unresectable hepatocellular carcinoma. Int J Radiat Oncol Biol Phys. 2003; 57:113–119.
66. Seong J, Keum KC, Han KH, Lee DY, Lee JT, Chon CY, Moon YM, Suh CO, Kim GE. Combined transcatheter arterial chemoembolization and local radiotherapy of unresectable hepatocellular carcinoma. Int J Radiat Oncol Biol Phys. 1999; 43:393–397.
67. Shim SJ, Seong J, Han KH, Chon CY, Suh CO, Lee JT. Local radiotherapy as a complement to incomplete transcatheter arterial chemoembolization in locally advanced hepatocellular carcinoma. Liver Int. 2005; 25:1189–1196.
68. Choi IB, Choi BO, Kang YN, Han JY, Jung Kew, Bae SH, Choi JY, Yoon SK. Robotic Radiosurgery: CyberKnife Management of Primary HCC. Cyberknife Society. 2005. 279–286.
69. Lin SM, Lin CJ, Hsu CW, Tai DI, Sheen IS, Lin DY, Liaw YF. Prospectiverandomized controlled study of interferon?alpha in preventing hepatocellular carcinoma recurrence after medical ablation therapy for primary tumors. Cancer. 2004; 100:376–382.
70. Chung YH, Song IH, Song BC, Lee GC, Koh MS, Yoon HK, Lee YS, Sung KB, Suh DJ. Combined therapy consisting of intraarterial cisplatin infusion and systemic interferon?alpha for hepatocellular carcinoma patients with major portal vein thrombosis or distant metastasis. Cancer. 2000; 88:1986–1991.
71. Obi S, Yoshida H, Toune R, Unuma T, Kanda M, Sato S, Tateishi R, Teratani T, Shiina S, Omata M. Combination therapy of intraarterial 5?fluorouracil and systemic interferon?alpha for advanced hepatocellular carcinoma with portal venous invasion. Cancer. 2006; 106:1990–1997.
72. Takayama T, Sekine T, Makuuchi M, Yamasaki S, Kosuge T, Yamamoto J, Shimada K, Sakamoto M, Hirohashi S, Ohashi Y, Kakizoe T. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet. 2000; 356:802–807.
73. Kennedy JE. High?intensity focused ultrasound in the treatment of solid tumours. Nat Rev Cancer. 2005; 5:321–327.
74. Bush DA, Hillebrand DJ, Slater JM, Slater JD. High?dose proton beam radiotherapy of hepatocellular carcinoma: preliminary results of a phase II trial. Gastroenterology. 2004; 127(S):S189–193.
75. Liu L, Cao Y, Chen C, Zhang X, McNabola A, Wilkie D, Wilhelm S, Lynch M, Carter C. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res. 2006; 66:11851–11858.
76. Abou?Alfa GK, Schwartz L, Ricci S, Amadori D, Santoro A, Figer A, De Greve J, Douillard JY, Lathia C, Schwartz B, Taylor I, Moscovici M, Saltz LB. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2006; 24:4293–4300.
Table 1.
Table 2.
Reference | Actual survival (%) | |||
---|---|---|---|---|
N | 1 yr | 3 yr | 5 yr | |
1. Cadaveric liver transplantation | ||||
Mazzaferro (9) | 48 | 84 | 74* | |
Bismuth (10) | 45 | 82 | 72 | |
Llovet (6) | 79 | 86 | 75 | |
Jonas (11) | 120 | 90 | 71 | |
Gonzalez-Uriate (12) | 64 | 87 | 73 | |
Adam (13) | 195 | 80 | 61 | |
Hayashi (14) | 45 | – | 74 | |
2. Living donor liver transplantation | ||||
Gondolesi (15) | 15 | 86 | ||
Todo (16) | 137 | 79 |
Table 3.
Table 4.
Reference | Selection criteria | N |
Actual Survival (%) |
||
---|---|---|---|---|---|
1 yr | 3 yr | 5 yr | |||
Rossi (30) | single <3cm | 39 | 94 | 58 | 40 |
Buscarini (31) | single ≤3.5cm | 88 | 89 | 62 | 33 |
Omata (27) | single <5cm or | ||||
3 nodules <3cm | 434 | 95 | 78 | 68* | |
Tateishi (32) | 319 | 94 | 77 | 54 | |
≤2cm | 87 | 100 | 91 | 84 | |
2.1∼5cm | 215 | 93 | 74 | 45 |