Hepatocellular carcinoma medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] Associate Editor(s)-in-Chief: Dildar Hussain, MBBS [3]

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Overview

Patients with hepatocellular carcinoma are treated with sorafenib, ethanol injections, transcatheter arterial chemoembolization (TACE), sealed source radiotherapy, radiofrequency ablation (RFA), intra-arterial iodine-131-lipiodol administration, high intensity focused ultrasound (HIFU), hormonal therapy, and chemotherapy.

Medical Therapy

Medical therapy for hepatocellular carcinoma

Protein kinase inhibitors

Currently, Sorafenib has been approved as the sole management for systemic therapy of hepatocellular carcinoma in the advanced stages.[1][2] [3][4][5][6][7][8][9][10]

Molecular Targeted Agents for HCC

Percutaneous ethanol injection

  • Percutaneous ethanol injection (PEI) is best-known image-guided percutaneous ablation for hepatocellular carcinoma:[51][52][53][54][55][56][57]
    • It is well tolerated and is preferred in small (< 3 cm) solitary tumors.
    • It is an inexpensive procedure
    • It has few adverse effects
    • It can be repeated in patients with relapse
    • Survival is comparable with the patients who undergo surgical resection
    • Efficacy is comparable to radiofrequency ablation

Transcatheter arterial chemoembolization (TACE)

  • Transcatheter arterial chemoembolization is performed in the following conditions:[57][58][59][60][61][62][63][64]
  • Transcatheter arterial chemoembolization (TACE) is usually performed in the treatment of large tumors (larger than 3 cm and less than 4 cm in diameter), most frequently by intraarterially injecting an infusion of antineoplastic agents mixed with iodized oil (such as Lipiodol).
  • Combined PEI and TACE can be used for tumors larger than 4 cm in diameter.
  • TACE followed by sorafenib provides optimal results of progression-free survival and survival in patients with HCC who are non responsive to TACE.

Sealed source radiotherapy

  • Sealed source radiotherapy can be used to destroy the tumor from within (thus minimizing exposure to healthy tissue). TheraSphere is an FDA approved treatment which has been shown in clinical trials to increase survival rate of low-risk patients. This method uses a catheter (inserted by a radiologist) to deposit radioactive particles to the area of interest.[65]

Radiofrequency ablation (RFA)

Intra-arterial iodine-131–lipiodol administration

  • Intra-arterial iodine-131–lipiodol administration demonstrated some efficacy in unresectable tumors, especially in patients with portal vein thrombus. This treatment is also used as adjuvant therapy in resected patients. It is believed to raise the 3-year survival rate from 46 to 86%.

High intensity focused ultrasound (HIFU)

  • High intensity focused ultrasound (HIFU) is a new technique which uses much very powerful ultrasound to treat the tumour. Still at a very experimental stage. Most of the work has been done in China. Some early work is being done in Oxford and London in the UK.

Hormonal therapy

Chemotherapy

  • Oral synthetic retinoid for 12 months after resection/ablation maybe helpful in the treatment of hepatocellular carcinoma.[66]

Contraindicated medications

Hepatocellular carcinoma is considered an absolute contraindication to the use of the following medications:

Effectiveness of medical therapy

The effectiveness of medical therapy depends on the following:

  • Size
  • Involvement of liver vessels
  • Presence of a tumor capsule
  • Presence of extrahepatic metastases
  • Presence of daughter nodules
  • Vascularity of the tumor

References

  1. ↑ Howe CW (1968). "Experimental wound sepsis from transient bacteremia". Surg Gynecol Obstet. 126 (5): 1066–70. PMID 4870992.
  2. ↑ Zhang, Bingnan; Finn, Richard S. (2016). "Personalized Clinical Trials in Hepatocellular Carcinoma Based on Biomarker Selection". Liver Cancer. 5 (3): 221–232. doi:10.1159/000367763. ISSN 2235-1795.
  3. ↑ Wilhelm, Scott M.; Carter, Christopher; Tang, LiYa; Wilkie, Dean; McNabola, Angela; Rong, Hong; Chen, Charles; Zhang, Xiaomei; Vincent, Patrick; McHugh, Mark; Cao, Yichen; Shujath, Jaleel; Gawlak, Susan; Eveleigh, Deepa; Rowley, Bruce; Liu, Li; Adnane, Lila; Lynch, Mark; Auclair, Daniel; Taylor, Ian; Gedrich, Rich; Voznesensky, Andrei; Riedl, Bernd; Post, Leonard E.; Bollag, Gideon; Trail, Pamela A. (2004). "BAY 43-9006 Exhibits Broad Spectrum Oral Antitumor Activity and Targets the RAF/MEK/ERK Pathway and Receptor Tyrosine Kinases Involved in Tumor Progression and Angiogenesis". Cancer Research. 64 (19): 7099–7109. doi:10.1158/0008-5472.CAN-04-1443. ISSN 0008-5472.
  4. ↑ Chang, Yong S.; Adnane, Jalila; Trail, Pamela A.; Levy, Joan; Henderson, Arris; Xue, Dahai; Bortolon, Elizabeth; Ichetovkin, Marina; Chen, Charles; McNabola, Angela; Wilkie, Dean; Carter, Christopher A.; Taylor, Ian C. A.; Lynch, Mark; Wilhelm, Scott (2006). "Sorafenib (BAY 43-9006) inhibits tumor growth and vascularization and induces tumor apoptosis and hypoxia in RCC xenograft models". Cancer Chemotherapy and Pharmacology. 59 (5): 561–574. doi:10.1007/s00280-006-0393-4. ISSN 0344-5704.
  5. ↑ Llovet, Josep M.; Ricci, Sergio; Mazzaferro, Vincenzo; Hilgard, Philip; Gane, Edward; Blanc, Jean-Frédéric; de Oliveira, Andre Cosme; Santoro, Armando; Raoul, Jean-Luc; Forner, Alejandro; Schwartz, Myron; Porta, Camillo; Zeuzem, Stefan; Bolondi, Luigi; Greten, Tim F.; Galle, Peter R.; Seitz, Jean-François; Borbath, Ivan; Häussinger, Dieter; Giannaris, Tom; Shan, Minghua; Moscovici, Marius; Voliotis, Dimitris; Bruix, Jordi (2008). "Sorafenib in Advanced Hepatocellular Carcinoma". New England Journal of Medicine. 359 (4): 378–390. doi:10.1056/NEJMoa0708857. ISSN 0028-4793.
  6. ↑ Cheng, Ann-Lii; Kang, Yoon-Koo; Chen, Zhendong; Tsao, Chao-Jung; Qin, Shukui; Kim, Jun Suk; Luo, Rongcheng; Feng, Jifeng; Ye, Shenglong; Yang, Tsai-Sheng; Xu, Jianming; Sun, Yan; Liang, Houjie; Liu, Jiwei; Wang, Jiejun; Tak, Won Young; Pan, Hongming; Burock, Karin; Zou, Jessie; Voliotis, Dimitris; Guan, Zhongzhen (2009). "Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial". The Lancet Oncology. 10 (1): 25–34. doi:10.1016/S1470-2045(08)70285-7. ISSN 1470-2045.
  7. ↑ Kang, Tae Wook; Rhim, Hyunchul (2015). "Recent Advances in Tumor Ablation for Hepatocellular Carcinoma". Liver Cancer. 4 (3): 176–187. doi:10.1159/000367740. ISSN 2235-1795.
  8. ↑ Kudo, Masatoshi; Izumi, Namiki; Sakamoto, Michiie; Matsuyama, Yutaka; Ichida, Takafumi; Nakashima, Osamu; Matsui, Osamu; Ku, Yonson; Kokudo, Norihiro; Makuuchi, Masatoshi (2016). "Survival Analysis over 28 Years of 173,378 Patients with Hepatocellular Carcinoma in Japan". Liver Cancer. 5 (3): 190–197. doi:10.1159/000367775. ISSN 2235-1795.
  9. ↑ Okita, Kiwamu; Izumi, Namiki; Matsui, Osamu; Tanaka, Katsuaki; Kaneko, Shuichi; Moriwaki, Hisataka; Ikeda, Kenji; Osaki, Yukio; Numata, Kazushi; Nakachi, Kohei; Kokudo, Norihiro; Imanaka, Kazuho; Nishiguchi, Shuhei; Okusaka, Takuji; Nishigaki, Yoichi; Shiomi, Susumu; Kudo, Masatoshi; Ido, Kenichi; Karino, Yoshiyasu; Hayashi, Norio; Ohashi, Yasuo; Makuuchi, Masatoshi; Kumada, Hiromitsu (2014). "Peretinoin after curative therapy of hepatitis C-related hepatocellular carcinoma: a randomized double-blind placebo-controlled study". Journal of Gastroenterology. 50 (2): 191–202. doi:10.1007/s00535-014-0956-9. ISSN 0944-1174.
  10. ↑ 10.0 10.1 Hagiwara, Satoru; Nishida, Naoshi; Watanabe, Tomohiro; Sakurai, Toshiharu; Ida, Hiroshi; Minami, Yasunori; Takita, Masahiro; Minami, Tomohiro; Iwanishi, Mina; Chishina, Hirokazu; Ueshima, Kazuomi; Komeda, Yoriaki; Arizumi, Tadaaki; Kudo, Masatoshi (2016). "Outcome of Asunaprevir/Daclatasvir Combination Therapy for Chronic Liver Disease Type C". Digestive Diseases. 34 (6): 620–626. doi:10.1159/000448822. ISSN 0257-2753.
  11. ↑ Nakamura, N.; Shidoji, Y.; Yamada, Y.; Hatakeyama, H.; Moriwaki, H.; Muto, Y. (1995). "Induction of Apoptosis by Acyclic Retinoid in the Human Hepatoma-Derived Cell Line, HuH-7". Biochemical and Biophysical Research Communications. 207 (1): 382–388. doi:10.1006/bbrc.1995.1199. ISSN 0006-291X.
  12. ↑ 12.0 12.1 Yasuda I, Shiratori Y, Adachi S, Obora A, Takemura M, Okuno M, Shidoji Y, Seishima M, Muto Y, Moriwaki H (2002). "Acyclic retinoid induces partial differentiation, down-regulates telomerase reverse transcriptase mRNA expression and telomerase activity, and induces apoptosis in human hepatoma-derived cell lines". J. Hepatol. 36 (5): 660–71. PMID 11983450.
  13. ↑ Hoekman K (2001). "SU6668, a multitargeted angiogenesis inhibitor". Cancer J. 7 Suppl 3: S134–8. PMID 11779084.
  14. ↑ Park JW, Cheng AL, Kudo M, Park JH, Liang CP, Hidaka H, et al: A randomized, double-blind, placebo-controlled phase III trial of TSU-68 (orantinib) combined with transcatheter arterial chemoembolization in patients with unresectable hepatocellular carcinoma. J Hepatol 2015;62(suppl 1):abstract G06
  15. ↑ Kudo, Masatoshi; Han, Guohong; Finn, Richard S.; Poon, Ronnie T.P.; Blanc, Jean-Frederic; Yan, Lunan; Yang, Jijin; Lu, Ligong; Tak, Won-Young; Yu, Xiaoping; Lee, Joon-Hyeok; Lin, Shi-Ming; Wu, Changping; Tanwandee, Tawesak; Shao, Guoliang; Walters, Ian B.; Dela Cruz, Christine; Poulart, Valerie; Wang, Jian-Hua (2014). "Brivanib as adjuvant therapy to transarterial chemoembolization in patients with hepatocellular carcinoma: A randomized phase III trial". Hepatology. 60 (5): 1697–1707. doi:10.1002/hep.27290. ISSN 0270-9139.
  16. ↑ Mendel DB, Laird AD, Xin X, Louie SG, Christensen JG, Li G, Schreck RE, Abrams TJ, Ngai TJ, Lee LB, Murray LJ, Carver J, Chan E, Moss KG, Haznedar JO, Sukbuntherng J, Blake RA, Sun L, Tang C, Miller T, Shirazian S, McMahon G, Cherrington JM (2003). "In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship". Clin. Cancer Res. 9 (1): 327–37. PMID 12538485.
  17. ↑ Cheng, Ann-Lii; Kang, Yoon-Koo; Lin, Deng-Yn; Park, Joong-Won; Kudo, Masatoshi; Qin, Shukui; Chung, Hyun-Cheol; Song, Xiangqun; Xu, Jianming; Poggi, Guido; Omata, Masao; Pitman Lowenthal, Susan; Lanzalone, Silvana; Yang, Liqiang; Lechuga, Maria Jose; Raymond, Eric (2013). "Sunitinib Versus Sorafenib in Advanced Hepatocellular Cancer: Results of a Randomized Phase III Trial". Journal of Clinical Oncology. 31 (32): 4067–4075. doi:10.1200/JCO.2012.45.8372. ISSN 0732-183X.
  18. ↑ Johnson PJ, Qin S, Park JW, Poon RT, Raoul JL, Philip PA, Hsu CH, Hu TH, Heo J, Xu J, Lu L, Chao Y, Boucher E, Han KH, Paik SW, Robles-Aviña J, Kudo M, Yan L, Sobhonslidsuk A, Komov D, Decaens T, Tak WY, Jeng LB, Liu D, Ezzeddine R, Walters I, Cheng AL (2013). "Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study". J. Clin. Oncol. 31 (28): 3517–24. doi:10.1200/JCO.2012.48.4410. PMID 23980084.
  19. ↑ Cainap, Calin; Qin, Shukui; Huang, Wen-Tsung; Chung, Ik Joo; Pan, Hongming; Cheng, Ying; Kudo, Masatoshi; Kang, Yoon-Koo; Chen, Pei-Jer; Toh, Han-Chong; Gorbunova, Vera; Eskens, Ferry A.L.M.; Qian, Jiang; McKee, Mark D.; Ricker, Justin L.; Carlson, Dawn M.; El-Nowiem, Saied (2015). "Linifanib Versus Sorafenib in Patients With Advanced Hepatocellular Carcinoma: Results of a Randomized Phase III Trial". Journal of Clinical Oncology. 33 (2): 172–179. doi:10.1200/JCO.2013.54.3298. ISSN 0732-183X.
  20. ↑ Zhu, Andrew X.; Rosmorduc, Olivier; Evans, T.R. Jeffry; Ross, Paul J.; Santoro, Armando; Carrilho, Flair Jose; Bruix, Jordi; Qin, Shukui; Thuluvath, Paul J.; Llovet, Josep M.; Leberre, Marie-Aude; Jensen, Markus; Meinhardt, Gerold; Kang, Yoon-Koo (2015). "SEARCH: A Phase III, Randomized, Double-Blind, Placebo-Controlled Trial of Sorafenib Plus Erlotinib in Patients With Advanced Hepatocellular Carcinoma". Journal of Clinical Oncology. 33 (6): 559–566. doi:10.1200/JCO.2013.53.7746. ISSN 0732-183X.
  21. ↑ Yamamoto, Yuji; Matsui, Junji; Matsushima, Tomohiro; Obaishi, Hiroshi; Miyazaki, Kazuki; Nakamura, Katsuji; Tohyama, Osamu; Semba, Taro; Yamaguchi, Atsumi; Hoshi, Sachi; Mimura, Fusayo; Haneda, Toru; Fukuda, Yoshio; Kamata, Jun-ichi; Takahashi, Keiko; Matsukura, Masayuki; Wakabayashi, Toshiaki; Asada, Makoto; Nomoto, Ken-ichi; Watanabe, Tatsuo; Dezso, Zoltan; Yoshimatsu, Kentaro; Funahashi, Yasuhiro; Tsuruoka, Akihiko (2014). "Lenvatinib, an angiogenesis inhibitor targeting VEGFR/FGFR, shows broad antitumor activity in human tumor xenograft models associated with microvessel density and pericyte coverage". Vascular Cell. 6 (1): 18. doi:10.1186/2045-824X-6-18. ISSN 2045-824X.
  22. ↑ Ikeda, Kenji; Kudo, Masatoshi; Kawazoe, Seiji; Osaki, Yukio; Ikeda, Masafumi; Okusaka, Takuji; Tamai, Toshiyuki; Suzuki, Takuya; Hisai, Takashi; Hayato, Seiichi; Okita, Kiwamu; Kumada, Hiromitsu (2016). "Phase 2 study of lenvatinib in patients with advanced hepatocellular carcinoma". Journal of Gastroenterology. 52 (4): 512–519. doi:10.1007/s00535-016-1263-4. ISSN 0944-1174.
  23. ↑ Kudo M, Finn R, Qin S, Han K-H, Ikeda K, Piscaglia F, Baron A, Park J-W, Han G, Jassem J, Blanc JF, Vogel A, Komov D, Evans TRJ, Lopez C, Dutcus C, Guo M, Saito K, Kraljevic S, Tamai T, Ren M, Cheng A-L: A randomised phase 3 trial of lenvatinib vs. sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma
  24. ↑ Khajornjiraphan, Natthida; Thu, Nyein Aye; Chow, Pierce Kah Hoe (2015). "Yttrium-90 Microspheres: A Review of Its Emerging Clinical Indications". Liver Cancer. 4 (1): 6–15. doi:10.1159/000343876. ISSN 2235-1795.
  25. ↑ Edeline, Julien; Gilabert, Marine; Garin, Etienne; Boucher, Eveline; Raoul, Jean-Luc (2015). "Yttrium-90 Microsphere Radioembolization for Hepatocellular Carcinoma". Liver Cancer. 4 (1): 16–25. doi:10.1159/000343878. ISSN 2235-1795.
  26. ↑ Cucchetti, Alessandro; Cappelli, Alberta; Ercolani, Giorgio; Mosconi, Cristina; Cescon, Matteo; Golfieri, Rita; Pinna, Antonio Daniele (2016). "Selective Internal Radiation Therapy (SIRT) as Conversion Therapy for Unresectable Primary Liver Malignancies". Liver Cancer. 5 (4): 303–311. doi:10.1159/000449341. ISSN 2235-1795.
  27. ↑ Vilgrain V, et al: SARAH trial: Sorafenib vs Radioembolization in Advanced Hepatocellular Carcinoma.EASL 2017, GS012.
  28. ↑ Gandhi, Mihir; Choo, Su Pin; Thng, Choon Hua; Tan, Say Beng; Low, Albert Su Chong; Cheow, Peng Chung; Goh, Anthony Soon Whatt; Tay, Kiang Hiong; Lo, Richard Hoau Gong; Goh, Brian Kim Poh; Wong, Jen San; Ng, David Chee Eng; Soo, Khee Chee; Liew, Wei Ming; Chow, Pierce K. H. (2016). "Single administration of Selective Internal Radiation Therapy versus continuous treatment with sorafeNIB in locally advanced hepatocellular carcinoma (SIRveNIB): study protocol for a phase iii randomized controlled trial". BMC Cancer. 16 (1). doi:10.1186/s12885-016-2868-y. ISSN 1471-2407.
  29. ↑ Obi, Shuntaro; Sato, Shinpei; Kawai, Toshihiro (2015). "Current Status of Hepatic Arterial Infusion Chemotherapy". Liver Cancer. 4 (3): 188–199. doi:10.1159/000367746. ISSN 2235-1795.
  30. ↑ Lin, Chen-Chun; Hung, Chien-Fu; Chen, Wei-Ting; Lin, Shi-Ming (2015). "Hepatic Arterial Infusion Chemotherapy for Advanced Hepatocellular Carcinoma with Portal Vein Thrombosis: Impact of Early Response to 4 Weeks of Treatment". Liver Cancer. 4 (4): 228–240. doi:10.1159/000367737. ISSN 2235-1795.
  31. ↑ Ueshima, Kazuomi; Kudo, Masatoshi; Tanaka, Masatoshi; Kumada, Takashi; Chung, Hobyung; Hagiwara, Satoru; Inoue, Tatsuo; Yada, Norihisa; Kitai, Satoshi (2015). "Phase I/II Study of Sorafenib in Combination with Hepatic Arterial Infusion Chemotherapy Using Low-Dose Cisplatin and 5-Fluorouracil". Liver Cancer. 4 (4): 263–273. doi:10.1159/000367751. ISSN 2235-1795.
  32. ↑ Llovet, Josep M.; Decaens, Thomas; Raoul, Jean-Luc; Boucher, Eveline; Kudo, Masatoshi; Chang, Charissa; Kang, Yoon-Koo; Assenat, Eric; Lim, Ho-Yeong; Boige, Valerie; Mathurin, Philippe; Fartoux, Laetitia; Lin, Deng-Yn; Bruix, Jordi; Poon, Ronnie T.; Sherman, Morris; Blanc, Jean-Frédéric; Finn, Richard S.; Tak, Won-Young; Chao, Yee; Ezzeddine, Rana; Liu, David; Walters, Ian; Park, Joong-Won (2013). "Brivanib in Patients With Advanced Hepatocellular Carcinoma Who Were Intolerant to Sorafenib or for Whom Sorafenib Failed: Results From the Randomized Phase III BRISK-PS Study". Journal of Clinical Oncology. 31 (28): 3509–3516. doi:10.1200/JCO.2012.47.3009. ISSN 0732-183X.
  33. ↑ Zhu, Andrew X.; Kudo, Masatoshi; Assenat, Eric; Cattan, Stéphane; Kang, Yoon-Koo; Lim, Ho Yeong; Poon, Ronnie T. P.; Blanc, Jean-Frederic; Vogel, Arndt; Chen, Chao-Long; Dorval, Etienne; Peck-Radosavljevic, Markus; Santoro, Armando; Daniele, Bruno; Furuse, Junji; Jappe, Annette; Perraud, Kevin; Anak, Oezlem; Sellami, Dalila B.; Chen, Li-Tzong (2014). "Effect of Everolimus on Survival in Advanced Hepatocellular Carcinoma After Failure of Sorafenib". JAMA. 312 (1): 57. doi:10.1001/jama.2014.7189. ISSN 0098-7484.
  34. ↑ Santoro, Armando; Rimassa, Lorenza; Borbath, Ivan; Daniele, Bruno; Salvagni, Stefania; Van Laethem, Jean Luc; Van Vlierberghe, Hans; Trojan, Jörg; Kolligs, Frank T; Weiss, Alan; Miles, Steven; Gasbarrini, Antonio; Lencioni, Monica; Cicalese, Luca; Sherman, Morris; Gridelli, Cesare; Buggisch, Peter; Gerken, Guido; Schmid, Roland M; Boni, Corrado; Personeni, Nicola; Hassoun, Ziad; Abbadessa, Giovanni; Schwartz, Brian; Von Roemeling, Reinhard; Lamar, Maria E; Chen, Yinpu; Porta, Camillo (2013). "Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a randomised, placebo-controlled phase 2 study". The Lancet Oncology. 14 (1): 55–63. doi:10.1016/S1470-2045(12)70490-4. ISSN 1470-2045.
  35. ↑ Rimassa, Lorenza; Abbadessa, Giovanni; Personeni, Nicola; Porta, Camillo; Borbath, Ivan; Daniele, Bruno; Salvagni, Stefania; Van Laethem, Jean-Luc; Van Vlierberghe, Hans; Trojan, Jörg; De Toni, Enrico N.; Weiss, Alan; Miles, Steven; Gasbarrini, Antonio; Lencioni, Monica; Lamar, Maria E.; Wang, Yunxia; Shuster, Dale; Schwartz, Brian E.; Santoro, Armando (2016). "Tumor and circulating biomarkers in patients with second-line hepatocellular carcinoma from the randomized phase II study with tivantinib". Oncotarget. 7 (45). doi:10.18632/oncotarget.11621. ISSN 1949-2553.
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  40. ↑ 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 (2017). "S-1 versus placebo in patients with sorafenib-refractory advanced hepatocellular carcinoma (S-CUBE): a randomised, double-blind, multicentre, phase 3 trial". Lancet Gastroenterol Hepatol. 2 (6): 407–417. doi:10.1016/S2468-1253(17)30072-9. PMID 28497756.
  41. ↑ Wilhelm, Scott M.; Dumas, Jacques; Adnane, Lila; Lynch, Mark; Carter, Christopher A.; Schütz, Gunnar; Thierauch, Karl-Heinz; Zopf, Dieter (2011). "Regorafenib (BAY 73-4506): A new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity". International Journal of Cancer. 129 (1): 245–255. doi:10.1002/ijc.25864. ISSN 0020-7136.
  42. ↑ Bruix, Jordi; Qin, Shukui; Merle, Philippe; Granito, Alessandro; Huang, Yi-Hsiang; Bodoky, György; Pracht, Marc; Yokosuka, Osamu; Rosmorduc, Olivier; Breder, Valeriy; Gerolami, René; Masi, Gianluca; Ross, Paul J; Song, Tianqiang; Bronowicki, Jean-Pierre; Ollivier-Hourmand, Isabelle; Kudo, Masatoshi; Cheng, Ann-Lii; Llovet, Josep M; Finn, Richard S; LeBerre, Marie-Aude; Baumhauer, Annette; Meinhardt, Gerold; Han, Guohong (2017). "Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial". The Lancet. 389 (10064): 56–66. doi:10.1016/S0140-6736(16)32453-9. ISSN 0140-6736.
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  53. ↑ Livraghi T (2001). "Percutaneous ethanol injection in the treatment of hepatocellular carcinoma in cirrhosis". Hepatogastroenterology. 48 (37): 20–4. PMID 11268965.
  54. ↑ Yu SJ, Yoon JH, Lee JM, Lee JY, Kim SH, Cho YY, Yoo JJ, Lee M, Lee DH, Cho Y, Cho EJ, Lee JH, Kim YJ, Kim CY (2016). "Percutaneous ethanol injection therapy is comparable to radiofrequency ablation in hepatocellular carcinoma smaller than 1.5 cm: A matched case-control comparative analysis". Medicine (Baltimore). 95 (35): e4551. doi:10.1097/MD.0000000000004551. PMC 5008549. PMID 27583865. hair space character in |title= at position 125 (help)
  55. ↑ Basilico R, Filippone A, Muzi M, Sergiacomo L, Del Roio L, Bonomo L (1996). "[Assessment of the therapeutic effectiveness of alcohol administration in hepatocarcinoma: comparison of spiral computerized tomography and Doppler color ultrasonography]". Radiol Med (in Italian). 92 (1–2): 92–6. PMID 8966281.
  56. ↑ Beaugrand M, N'kontchou G, Seror O, Ganne N, Trinchet JC (2005). "Local/regional and systemic treatments of hepatocellular carcinoma". Semin. Liver Dis. 25 (2): 201–11. doi:10.1055/s-2005-871199. PMID 15918148.
  57. ↑ 57.0 57.1 57.2 CHEDID, Marcio F.; KRUEL, Cleber R. P.; PINTO, Marcelo A.; GREZZANA-FILHO, Tomaz J. M.; LEIPNITZ, Ian; KRUEL, Cleber D. P.; SCAFFARO, Leandro A.; CHEDID, Aljamir D. (2017). "HEPATOCELLULAR CARCINOMA: DIAGNOSIS AND OPERATIVE MANAGEMENT". ABCD. Arquivos Brasileiros de Cirurgia Digestiva (São Paulo). 30 (4): 272–278. doi:10.1590/0102-6720201700040011. ISSN 2317-6326.
  58. ↑ Ohki T, Sato K, Yamagami M, Ito D, Yamada T, Kawanishi K, Kojima K, Seki M, Toda N, Tagawa K (2015). "Efficacy of transcatheter arterial chemoembolization followed by sorafenib for intermediate/advanced hepatocellular carcinoma in patients in Japan: a retrospective analysis". Clin Drug Investig. 35 (11): 751–9. doi:10.1007/s40261-015-0333-3. PMC 4621710. PMID 26446004.
  59. ↑ Acunaş B, Rozanes I (1999). "Hepatocellular carcinoma: treatment with transcatheter arterial chemoembolization". Eur J Radiol. 32 (1): 86–9. PMID 10580325.
  60. ↑ Ahmad J, Rhee J, Carr BI (2005). "The effects of hepatic artery chemotherapy on viral hepatitis in patients with hepatocellular carcinoma". Dig. Dis. Sci. 50 (2): 331–5. PMID 15745096.
  61. ↑ Arai H, Kobayashi T, Izuka K, Ueno T, Mori K, Takizawa D, Toyoda M, Takayama H, Abe T (2012). "[Clinical evaluation of transcatheter arterial chemolipiodolization of miriplatin for multiple hepatocellular carcinoma]". Gan To Kagaku Ryoho (in Japanese). 39 (13): 2513–6. PMID 23235170.
  62. ↑ Lencioni, Riccardo; de Baere, Thierry; Martin, Robert C.; Nutting, Charles W.; Narayanan, Govindarajan (2015). "Image-Guided Ablation of Malignant Liver Tumors: Recommendations for Clinical Validation of Novel Thermal and Non-Thermal Technologies - A Western Perspective". Liver Cancer. 4 (4): 208–214. doi:10.1159/000367747. ISSN 2235-1795.
  63. ↑ Tsurusaki, Masakatsu; Murakami, Takamichi (2015). "Surgical and Locoregional Therapy of HCC: TACE". Liver Cancer. 4 (3): 165–175. doi:10.1159/000367739. ISSN 2235-1795.
  64. ↑ Arizumi, Tadaaki; Ueshima, Kazuomi; Minami, Tomohiro; Kono, Masashi; Chishina, Hirokazu; Takita, Masahiro; Kitai, Satoshi; Inoue, Tatsuo; Yada, Norihisa; Hagiwara, Satoru; Minami, Yasunori; Sakurai, Toshiharu; Nishida, Naoshi; Kudo, Masatoshi (2015). "Effectiveness of Sorafenib in Patients with Transcatheter Arterial Chemoembolization (TACE) Refractory and Intermediate-Stage Hepatocellular Carcinoma". Liver Cancer. 4 (4): 253–262. doi:10.1159/000367743. ISSN 2235-1795.
  65. ↑ Novell JR, Hilson A, Hobbs KE (1991). "Therapeutic aspects of radio-isotopes in hepatobiliary malignancy". Br J Surg. 78 (8): 901–6. PMID 1655152.
  66. ↑ [1] American Society of Clinical Oncology, 2005 Annual Meeting, Abstracts on Hepatobiliary Cancer


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