Multidisciplinary research and review journal | Online ISSN 3064-9870
REVIEWS   (Open Access)

Advancing Personalized Treatment for Hepatocellular Carcinoma: Integrating Targeted Therapies, Precision Medicine, and Bioengineering for Improved Outcomes

Md Mahedi Hasan Shabuj1, Bulbul Ahmed2, Md Moshiur Rahman3, Syeda Anjuman Ara Aunni4, Abdullah Al Numan1, Mst. Shahana Akter5, Tufael1*

+ Author Affiliations

Journal of Primeasia 1.2(1) 1-14 https://doi.org/10.25163/primeasia.1110015

Submitted: 02 January 2019  Revised: 27 December 2019  Published: 28 December 2019 

Abstract

Background: Hepatocellular carcinoma (HCC) remains a global health challenge, ranking as the fourth leading cause of cancer-related death. Despite advancements in diagnostic and therapeutic strategies, HCC is often diagnosed at advanced stages where curative treatments are limited. Systemic therapies, including targeted therapies and immunotherapy, have become essential in managing advanced HCC. Methods: This review explores the latest progress in HCC treatment, focusing on the development and integration of targeted therapies and immunotherapy into personalized treatment strategies. We analyze the molecular mechanisms of HCC, highlighting key genetic drivers and signaling pathways, and discuss the role of bioengineering models in improving drug resistance and personalized treatment approaches. Results: Targeted therapies, including tyrosine kinase inhibitors (TKIs) like sorafenib, lenvatinib, regorafenib, and cabozantinib, have shown varying degrees of success in prolonging survival. Recent studies emphasize combination therapies, including immunotherapy with anti-angiogenic agents, as promising approaches for enhancing treatment efficacy. Bioengineered patient-derived liver cancer models have emerged as valuable tools for improving the precision of these therapies by reflecting HCC's molecular and phenotypic diversity. Conclusion: The future of HCC treatment lies in the integration of targeted therapies with precision medicine, guided by molecular profiling and advanced bioengineering models. These strategies promise to improve patient outcomes by addressing tumor heterogeneity and overcoming drug resistance, with bioengineering platforms and next-generation sequencing offering critical insights into personalized treatment regimens.

Keywords: Hepatocellular carcinoma (HCC), Targeted therapy, Molecular profiling, Anti-angiogenic therapy, Bioengineering technology, Precision medicine

References

Abou-Alfa, G. K., Meyer, T., Cheng, A. L., El-Khoueiry, A. B., Rimassa, L., Ryoo, B. Y., ... & Madoff, D. (2018). Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. New England Journal of Medicine, 379(1), 54–63. https://doi.org/10.1056/NEJMoa1717002

Almela, T., Al-Sahaf, S., Brook, I. M., Khoshroo, K., Rasoulianboroujeni, M., Fahimipour, F., ... & Ejeian, F. (2018). 3D printed tissue-engineered model for bone invasion of oral cancer. Tissue and Cell, 52, 71–77. https://doi.org/10.1016/j.tice.2018.03.009

Al-Salama, Z. T., Syed, Y. Y., & Scott, L. J. (2019). Lenvatinib: A review in hepatocellular carcinoma. Drugs, 79(6), 665–674. https://doi.org/10.1007/s40265-019-01116-x

Bagrodia, S., Smeal, T., & Abraham, R. T. (2012). Mechanisms of intrinsic and acquired resistance to kinase-targeted therapies. Pigment Cell & Melanoma Research, 25(6), 819–831. https://doi.org/10.1111/pcmr.12007

Boyault, S., Rickman, D. S., de Reynies, A., Balabaud, C., Rebouissou, S., Jeannot, E., ... & Bioulac-Sage, P. (2007). Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology, 45(1), 42–52. https://doi.org/10.1002/hep.21467

Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A., & Jemal, A. (2018). Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 68(6), 394–424.

Broutier, L., Mastrogiovanni, G., Verstegen, M. M., Francies, H. E., Gavarro, L. M., Bradshaw, C. R., ... & Lemoine, N. R. (2017). Human primary liver cancer-derived organoid cultures for disease modeling and drug screening. Nature Medicine, 23(12), 1424–1435. https://doi.org/10.1038/nm.4438

Brown, Z. J., Heinrich, B., & Greten, T. F. (2018). Mouse models of hepatocellular carcinoma: An overview and highlights for immunotherapy research. Nature Reviews Gastroenterology & Hepatology, 15(9), 536–554. https://doi.org/10.1038/s41575-018-0033-6

Bruix, J., Qin, S., Merle, P., et al. (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. https://doi.org/10.1016/S0140-6736(16)32453-9

Bruix, J., Qin, S., Merle, P., Granito, A., Huang, Y. H., Bodoky, G., ... & Meyer, T. (2017). Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): A randomized, double-blind, placebo-controlled, phase 3 trial. The Lancet, 389(10064), 56–66. https://doi.org/10.1016/S0140-6736(16)32453-9

Bruix, J., Raoul, J. L., Sherman, M., Mazzaferro, V., Bolondi, L., Craxi, A., ... & Saltzman, D. (2012). Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: Subanalyses of a phase III trial. Journal of Hepatology, 57(4), 821–829. https://doi.org/10.1016/j.jhep.2012.06.014

Chau, I., Peck-Radosavljevic, M., Borg, C., Malfertheiner, P., Seitz, J. F., Park, J. O., ... & Hamdy, S. (2017). Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib: Patient-focused outcome results from the randomized phase III REACH study. European Journal of Cancer, 81, 17–25. https://doi.org/10.1016/j.ejca.2017.05.001

Cheng, A. L., Kang, Y. K., Chen, Z., Tsao, C. J., Qin, S., Kim, J. S., ... & Zhou, Y. (2009). Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: A phase III randomized, double-blind, placebo-controlled trial. The Lancet Oncology, 10(1), 25–34.

Cheng, A. L., Kang, Y. K., Chen, Z., Tsao, C. J., Qin, S., Kim, J. S., ... & Wang, L. (2009). Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: A phase III randomized, double-blind, placebo-controlled trial. The Lancet Oncology, 10(1), 25–34. https://doi.org/10.1016/S1470-2045(08)70285-7

Collins, F. S., & Varmus, H. (2015). A new initiative on precision medicine. New England Journal of Medicine, 372(9), 793–795. https://doi.org/10.1056/NEJMp1500523

Edge, S. B., & American Joint Committee on Cancer, A. C. S. (2010). AJCC cancer staging handbook: From the AJCC cancer staging manual (Vol. 19, p. 718). Springer.

El-Khoueiry, A. B., Sangro, B., Yau, T., Crocenzi, T. S., Kudo, M., Hsu, C., et al. (2017). Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): An open-label, non-comparative, phase 1/2 dose escalation and expansion trial. The Lancet, 389(10088), 2492–2502. https://doi.org/10.1016/S0140-6736(17)31046-2

European Association for the Study of the Liver. (2018). EASL clinical practice guidelines: Management of hepatocellular carcinoma. Journal of Hepatology, 69(1), 182–236. https://doi.org/10.1016/j.jhep.2018.03.019

Fan, H., Demirci, U., & Chen, P. (2019). Emerging organoid models: Leaping forward in cancer research. Journal of Hematology & Oncology, 12(1), 142. https://doi.org/10.1186/s13045-019-0832-4

Finn, R. S., Merle, P., Granito, A., Huang, Y. H., Bodoky, G., Pracht, M., et al. (2018). Outcomes of sequential treatment with sorafenib followed by regorafenib for HCC: Additional analyses from the phase III RESORCE trial. Journal of Hepatology, 69(2), 353–358. https://doi.org/10.1016/j.jhep.2018.04.010

Fisher, R., Pusztai, L., & Swanton, C. (2013). Cancer heterogeneity: Implications for targeted therapeutics. British Journal of Cancer, 108(3), 479–485. https://doi.org/10.1038/bjc.2012.581

Gilabert, M., & Raoul, J. L. (2018). Potential of ramucirumab in treating hepatocellular carcinoma patients with elevated baseline alpha-fetoprotein. Journal of Hepatocellular Carcinoma, 5, 91–98. https://doi.org/10.2147/JHC.S157413

Harding, J. J., Nandakumar, S., Armenia, J., Khalil, D. N., Albano, M., Ly, M., et al. (2019). Prospective genotyping of hepatocellular carcinoma: Clinical implications of next-generation sequencing for matching patients to targeted and immune therapies. Clinical Cancer Research, 25(7), 2116–2126. https://doi.org/10.1158/1078-0432.CCR-18-2293

He, S., Hu, B., Li, C., Lin, P., Tang, W. G., Sun, Y. F., et al. (2018). PDXliver: A database of liver cancer patient-derived xenograft mouse models. BMC Cancer, 18(1), 550. https://doi.org/10.1186/s12885-018-4459-6

Heinrich, M. A., Bansal, R., Lammers, T., Zhang, Y. S., Michel, S. R., & Prakash, J. (2019). 3D-bioprinted mini-brain: A glioblastoma model to study cellular interactions and therapeutics. Advanced Materials, 31(14), e1806590. https://doi.org/10.1002/adma.201806590

Hernandez-Gea, V., Toffanin, S., Friedman, S. L., & Llovet, J. M. (2013). Role of the microenvironment in the pathogenesis and treatment of hepatocellular carcinoma. Gastroenterology, 144(3), 512–527. https://doi.org/10.1053/j.gastro.2013.01.002

Hiraoka, A., Kumada, T., Kariyama, K., Takaguchi, K., Atsukawa, M., Itobayashi, E., et al. (2019). Clinical features of lenvatinib for unresectable hepatocellular carcinoma in real-world conditions: Multicenter analysis. Cancer Medicine, 8(1), 137–146. https://doi.org/10.1002/cam4.1909

Hoshida, Y., Nijman, S. M., Kobayashi, M., Chan, J. A., Brunet, J. P., Chiang, D. Y., et al. (2009). Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. Cancer Research, 69(18), 7385–7392. https://doi.org/10.1158/0008-5472.CAN-09-1089

Hospodiuk M., Dey M., Sosnoski D., Ozbolat I. T. (2017). The Bioink: A Comprehensive Review on Bioprintable Materials. Biotechnol. Adv. 35, 217–239. 10.1016/j.biotechadv.2016.12.006

Hu, B., Cheng, J. W., Hu, J. W., Li, H., Ma, X. L., & Tang, W. G., et al. (2019). KPNA3 confers sorafenib resistance to advanced hepatocellular carcinoma via TWIST-regulated epithelial-mesenchymal transition. Journal of Cancer, 10(17), 3914–3925. https://doi.org/10.7150/jca.31448

Huch, M., Gehart, H., van Boxtel, R., Hamer, K., Blokzijl, F., Verstegen, M. M., et al. (2015). Long-term culture of genome-stable bipotent stem cells from adult human liver. Cell, 160(1-2), 299–312. https://doi.org/10.1016/j.cell.2014.11.050

Iavarone, M., Invernizzi, F., Czauderna, C., Sanduzzi-Zamparelli, M., Bhoori, S., Amaddeo, G., et al. (2019). Preliminary experience on safety of regorafenib after sorafenib failure in recurrent hepatocellular carcinoma after liver transplantation. American Journal of Transplantation, 19(11), 3176–3184. https://doi.org/10.1111/ajt.15551

Ikeda, M., Sung, M. W., Kudo, M., Kobayashi, M., Baron, A. D., Finn, R. S., et al. (2019). A phase Ib trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) in unresectable hepatocellular carcinoma (uHCC): Updated results. Submitted Abstracts Gastrointestinal Tumours, Non-Colorectal, 30, V286–V287. https://doi.org/10.1093/annonc/mdz247.073

Karlovich, C. A., & Williams, P. M. (2019). Clinical applications of next-generation sequencing in precision oncology. Cancer Journal, 25(4), 264–271. https://doi.org/10.1097/PPO.0000000000000385

Knowlton, S., Onal, S., Yu, C. H., Zhao, J. J., & Tasoglu, S. (2015). Bioprinting for cancer research. Trends in Biotechnology, 33(9), 504–513. https://doi.org/10.1016/j.tibtech.2015.06.007

Kudo, M. (2018). Cabozantinib as a second-line agent in advanced hepatocellular carcinoma. Liver Cancer, 7(2), 123–133. https://doi.org/10.1159/000488542

Kudo, M., Finn, R. S., Qin, S., Han, K. H., Ikeda, K., Piscaglia, F., et al. (2018). Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: A randomised phase 3 non-inferiority trial. The Lancet, 391(10126), 1163–1173. https://doi.org/10.1016/S0140-6736(18)30207-1

Kudo, M., Finn, R. S., Qin, S., Han, K. H., Ikeda, K., Piscaglia, F., Baron, A., Park, J. W., Han, G., Jassem, J., et al. (2018). Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: A randomised phase 3 non-inferiority trial. The Lancet, 391, 1163–1173.

Kulkarni P., Marsan A., Dutta D. (2000). A Review of Process Planning Techniques in Layered Manufacturing. Rapid Prototyp. J. 6, 18–35. 10.1108/13552540010309859

Li, L., Knutsdottir, H., Hui, K., Weiss, M. J., He, J., Philosophe, B., et al. (2019). Human primary liver cancer organoids reveal intratumor and interpatient drug response heterogeneity. JCI Insight, 4(2), e121490. https://doi.org/10.1172/jci.insight.121490

Li, W. et al. LncRNA SNHG1 contributes to sorafenib resistance by activating the Akt pathway and is positively regulated by miR-21 in hepatocellular carcinoma cells. J. Exp. Clin. Cancer Res. 38, 183 (2019)

Llovet, J. M., Montal, R., Sia, D., & Finn, R. S. (2018). Molecular therapies and precision medicine for hepatocellular carcinoma. Nature Reviews Clinical Oncology, 15(10), 599–616. https://doi.org/10.1038/s41571-018-0073-4

Llovet, J. M., Ricci, S., Mazzaferro, V., Hilgard, P., Gane, E., Blanc, J. F., ... & Moscovici, M. (2008). Sorafenib in advanced hepatocellular carcinoma. New England Journal of Medicine, 359(4), 378–390.

Llovet, J. M., Ricci, S., Mazzaferro, V., Hilgard, P., Gane, E., Blanc, J. F., et al. (2008). Sorafenib in advanced hepatocellular carcinoma. New England Journal of Medicine, 359(4), 378–390. https://doi.org/10.1056/NEJMoa0708857

Mandrycky, C., Wang, Z., Kim, K., & Kim, D. H. (2016). 3D bioprinting for engineering complex tissues. Biotechnology Advances, 34(4), 422–434. https://doi.org/10.1016/j.biotechadv.2015.12.011

Mcgranahan, N., & Swanton, C. (2017). Clonal heterogeneity and tumor evolution: Past, present, and the future. Cell, 168(4), 613–628. https://doi.org/10.1016/j.cell.2017.01.018

Meyer, T., Fox, R., Ma, Y. T., Ross, P. J., James, M. W., Sturgess, R., et al. (2017). Sorafenib in combination with transarterial chemoembolisation in patients with unresectable hepatocellular carcinoma (TACE 2): A randomised placebo-controlled, double-blind, phase 3 trial. The Lancet Gastroenterology & Hepatology, 2(8), 565–575. https://doi.org/10.1016/S2468-1253(17)30156-5

Montal, R., Andreu-Oller, C., Bassaganyas, L., Esteban-Fabro, R., Moran, S., Montironi, C., et al. (2019). Molecular portrait of high alpha-fetoprotein in hepatocellular carcinoma: Implications for biomarker-driven clinical trials. British Journal of Cancer, 121(4), 340–343. https://doi.org/10.1038/s41416-019-0513-7

Munaz A., Vadivelu R. K., St. John J., Barton M., Kamble H., Nguyen N.-T. (2016). Three-dimensional Printing of Biological Matters. J. Sci. Adv. Mater. Devices 1, 1–17. 10.1016/j.jsamd.2016.04.001

Murphy, S. V., & Atala, A. (2014). 3D bioprinting of tissues and organs. Nature Biotechnology, 32(8), 773–785. https://doi.org/10.1038/nbt.2958

Nuciforo, S., Fofana, I., Matter, M. S., Blumer, T., Calabrese, D., Boldanova, T., et al. (2018). Organoid models of human liver cancers derived from tumor needle biopsies. Cell Reports, 24(5), 1363–1376. https://doi.org/10.1016/j.celrep.2018.07.001

Parikh, N. D., Singal, A. G., & Hutton, D. W. (2017). Cost effectiveness of regorafenib as second-line therapy for patients with advanced hepatocellular carcinoma. Cancer, 123(19), 3725–3731. https://doi.org/10.1002/cncr.30863

Park, J. W., Chen, M., Colombo, M., et al. (2015). Global patterns of hepatocellular carcinoma management from diagnosis to death: The BRIDGE study. Liver International, 35(9), 2155–2166.

Perche, F., & Torchilin, V. P. (2012). Cancer cell spheroids as a model to evaluate chemotherapy protocols. Cancer Biology & Therapy, 13(12), 1205–1213. https://doi.org/10.4161/cbt.21353

Pinyol, R., Montal, R., Bassaganyas, L., Sia, D., Takayama, T., Chau, G. Y., et al. (2019). Molecular predictors of prevention of recurrence in HCC with sorafenib as adjuvant treatment and prognostic factors in the phase 3 STORM trial. Gut, 68(6), 1065–1075. https://doi.org/10.1136/gutjnl-2018-316408

Qu, X. D., Chen, C. S., Wang, J. H., Yan, Z. P., Chen, J. M., Gong, G. Q., et al. (2012). The efficacy of TACE combined with sorafenib in advanced stages of hepatocellular carcinoma. BMC Cancer, 12, 263. https://doi.org/10.1186/1471-2407-12-263

Raoul, J. L., Bruix, J., Greten, T. F., Sherman, M., Mazzaferro, V., Hilgard, P., et al. (2012). Relationship between baseline hepatic status and outcome, and effect of sorafenib on liver function: SHARP trial subanalyses. Journal of Hepatology, 56(5), 1080–1088. https://doi.org/10.1016/j.jhep.2011.12.009

Ricard-Blum S. (2011). The Collagen Family. Cold Spring Harb. Perspect. Biol. 3, a004978. 10.1101/cshperspect.a004978

Ricard-Blum S. (2011). The Collagen Family. Cold Spring Harb. Perspect. Biol. 3, a004978. 10.1101/cshperspect.a004978

Rygaard, J., & Povlsen, C. O. (1969). Heterotransplantation of a human malignant tumour to "Nude" mice. Acta Pathologica et Microbiologica Scandinavica, 77(4), 758–760. https://doi.org/10.1111/j.1699-0463.1969.tb04520.x

Sato, T., Stange, D. E., Ferrante, M., Vries, R. G., Van Es, J. H., Van den Brink, S., et al. (2011). Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett’s epithelium. Gastroenterology, 141(5), 1762–1772. https://doi.org/10.1053/j.gastro.2011.07.050

Schulze, K., Imbeaud, S., Letouzé, E., Alexandrov, L. B., Calderaro, J., Rebouissou, S., et al. (2015). Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nature Genetics, 47(5), 505–511. https://doi.org/10.1038/ng.3252

Shoulders M. D., Raines R. T. (2009). Collagen Structure and Stability. Annu. Rev. Biochem. 78, 929–958. 10.1146/annurev.biochem.77.032207.120833

Soto-Perez-De-Celis, E., Aguiar, P. N., Cordon, M. L., Chavarri-Guerra, Y., & Lopes, G. L. (2019). Cost-effectiveness of cabozantinib in the second-line treatment of advanced hepatocellular carcinoma. Journal of the National Comprehensive Cancer Network, 17(6), 669–675. https://doi.org/10.6004/jnccn.2018.7275

Sun, F. X., Tang, Z. Y., Lui, K. D., Ye, S. L., Xue, Q., Gao, D. M., et al. (1996). Establishment of a metastatic model of human hepatocellular carcinoma in nude mice via orthotopic implantation of histologically intact tissues. International Journal of Cancer, 66(2), 239–243. https://doi.org/10.1002/(SICI)1097-0215(19960410)66:2<239::AID-IJC17>3.0.CO;2-7

Swaminathan, S., Hamid, Q., Sun, W., & Clyne, A. M. (2019). Bioprinting of 3D breast epithelial spheroids for human cancer models. Biofabrication, 11(2), 025003. https://doi.org/10.1088/1758-5090/aafc49

Takebe, T., Sekine, K., Enomura, M., Koike, H., Kimura, M., Ogaeri, T., et al. (2013). Vascularized and functional human liver from an iPSC-derived organ bud transplant. Nature, 499(7459), 481–484. https://doi.org/10.1038/nature12271

Teufel, M., Seidel, H., Kochert, K., Meinhardt, G., Finn, R. S., Llovet, J. M., et al. (2019). Biomarkers associated with response to regorafenib in patients with hepatocellular carcinoma. Gastroenterology, 156(6), 1731–1741. https://doi.org/10.1053/j.gastro.2019.01.261

Tharehalli, U., Svinarenko, M., & Lechel, A. (2019). Remodelling and improvements in organoid technology to study liver carcinogenesis in a dish. Stem Cells International, 2019, 3831213. https://doi.org/10.1155/2019/3831213

Topalian, S. L., Drake, C. G., & Pardoll, D. M. (2015). Immune checkpoint blockade: A common denominator approach to cancer therapy. Cancer Cell, 27(4), 450–461.

Tuveson, D., & Clevers, H. (2019). Cancer modeling meets human organoid technology. Science, 364(6444), 952–955. https://doi.org/10.1126/science.aaw6985

Villanueva, A. (2019). Hepatocellular carcinoma. The New England Journal of Medicine, 380(15), 1450–1462. https://doi.org/10.1056/NEJMra1713263

Wang, X., Zhang, X., Dai, X., Wang, X., Li, X., Diao, J., et al. (2018). Tumor-like lung cancer model based on 3D bioprinting. 3 Biotech, 8(12), 501. https://doi.org/10.1007/s13205-018-1519-1

Weis, S. M., & Cheresh, D. A. (2011). Tumor angiogenesis: Molecular pathways and therapeutic targets. Nature Medicine, 17(11), 1359–1370. https://doi.org/10.1038/nm.2537

Wong, R., & Corley, D. A. (2008). Racial and ethnic variations in hepatocellular carcinoma incidence within the United States. American Journal of Medicine, 121(6), 525–531.

Wree, A., Broderick, L., Canbay, A., Hoffman, H. M., & Feldstein, A. E. (2013). From NAFLD to NASH to cirrhosis—New insights into disease mechanisms. Nature Reviews Gastroenterology & Hepatology, 10(11), 627–636.

Yoo, C., Park, J. W., Kim, Y. J., Kim, D. Y., Yu, S. J., Lim, T. S., et al. (2019). Multicenter retrospective analysis of the safety and efficacy of regorafenib after progression on sorafenib in Korean patients with hepatocellular carcinoma. Investigational New Drugs, 37(3), 567–572. https://doi.org/10.1007/s10637-018-0707-5

Zhao, Y., Shuen, T., Toh, T. B., Chan, X. Y., Liu, M., Tan, S. Y., et al. (2018). Development of a new patient-derived xenograft humanised mouse model to study human-specific tumour microenvironment and immunotherapy. Gut, 67(10), 1845–1854. https://doi.org/10.1136/gutjnl-2017-315201

Zhao, Y., Zhu, X., Wang, H., Dong, D., Gao, S., Zhu, X., et al. (2019). Safety and efficacy of transcatheter arterial chemoembolization plus radiotherapy combined with sorafenib in hepatocellular carcinoma showing macrovascular invasion. Frontiers in Oncology, 9, 1065. https://doi.org/10.3389/fonc.2019.01065

Zhou, X., Zhu, W., Nowicki, M., Miao, S., Cui, H., Holmes, B., et al. (2016). 3D bioprinting a cell-laden bone matrix for breast cancer metastasis study. ACS Applied Materials & Interfaces, 8(44), 30017–30026. https://doi.org/10.1021/acsami.6b10673

Zhu, A. X., Baron, A. D., Malfertheiner, P., Kudo, M., Kawazoe, S., Pezet, D., et al. (2017). Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma: Analysis of REACH trial results by child-pugh score. JAMA Oncology, 3(2), 235–243. https://doi.org/10.1001/jamaoncol.2016.4115

Zhu, A. X., Kang, Y. K., Yen, C. J., Finn, R. S., Galle, P. R., Llovet, J. M., et al. (2019). Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): A randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet Oncology, 20(2), 282–296. https://doi.org/10.1016/S1470-2045(18)30937-9

Zhu, A. X., Kang, Y. K., Yen, C. J., Finn, R. S., Galle, P. R., Llovet, J. M., et al. (2019). Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): A randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet Oncology, 20(2), 282–296. https://doi.org/10.1016/S1470-2045(18)30937-9

Zhu, A. X., Park, J. O., Ryoo, B. Y., Yen, C. J., Poon, R., Pastorelli, D., et al. (2015). Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): A randomised, double-blind, multicentre, phase 3 trial. The Lancet Oncology, 16(7), 859–870. https://doi.org/10.1016/S1470-2045(15)00050-9

Zschäbitz, S., & Grüllich, C. (2018). Lenvatinib: A tyrosine kinase inhibitor of VEGFR 1-3, FGFR 1-4, PDGFRα, KIT and RET. Recent Results in Cancer Research, 211, 187–198. https://doi.org/10.1007/978-3-319-91442-8_13

Zucman-Rossi, J., Villanueva, A., Nault, J. C., & Llovet, J. M. (2015). Genetic landscape and biomarkers of hepatocellular carcinoma. Gastroenterology, 149(5), 1226–1239. https://doi.org/10.1053/j.gastro.2015.05.061

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