Share This Article:

Efficacy and Toxicity of Metronomic Capecitabine in Advanced Hepatocellular Carcinoma

Abstract Full-Text HTML XML Download Download as PDF (Size:233KB) PP. 71-77
DOI: 10.4236/jct.2012.31010    4,890 Downloads   7,980 Views   Citations
Author(s)    Leave a comment


Background: Hepatocellular carcinoma (HCC) is a hypervascular tumor. Metronomic chemotherapy; the continuous administration of low-dose chemotherapy; has both cytotoxic and antiangiogenic effects with low toxicity profile. We evaluated the efficacy and toxicity of metronomic capecitabine (MC) in patients with advanced HCC. Patients and Methods: From May 2010, we enrolled pts with either metastatic or locally advanced diseases not candidate for ablative or locoregional treatment and have acceptable liver function. Patients received oral MC in dose of 1000 mg/m2 daily in a 21 days cycle without interruption till disease progression or toxicity. Results: The study cohort consisted of 22 patients with a median age of 63 years. The median number of cycles received was 3 cycles (range 1 - 9). From 19 patients were evaluable for response we had 3 partial responders, 10 stable diseases and disease progression in 6 patients. Median time to progression (TTP) was 2.2 months (95% CI 1.4 - 6.24) and median survival time (OS) was 4.8 months (95% CI 1.8 - 7.9). For 20 patients evaluable for safety: no grade III/IV hematological toxic effects were observed. Non-hematological toxic effects included grade III vomiting and diarrhea in one patient and grade III hand-foot syndrome in one patient. There was no treatment-related mortality. Conclusions: Based on the observed response rate, TTP and OS; MC has a modest antitumor efficacy in pts with advanced HCC. However, due to its low toxicity profile it deserves further attention as a convenient, outpatient-based chemotherapy regimen.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

A. Farrag, "Efficacy and Toxicity of Metronomic Capecitabine in Advanced Hepatocellular Carcinoma," Journal of Cancer Therapy, Vol. 3 No. 1, 2012, pp. 71-77. doi: 10.4236/jct.2012.31010.


[1] D. M. Parkin, F. Bray, J. Ferlay et al., “Estimating the World Cancer Burden: Globocan 2000,” International Journal of Cancer, Vol. 94, No. 2, 2001, pp. 153-156. doi:10.1002/ijc.1440
[2] National Cancer Institute, “Egypt Cancer Registry 2002- 2003,” Cairo University, Accessed on 2 August 2011.
[3] A. El-Zayadi, H. Abaza, S. Shawky, et al., “Prevalence and Epidemiological Features of Hepatocellular Carcinoma in Egypt—A Single Center Experience,” Hepatology Research, Vol. 19, No. 2, 2001, pp. 170-179. doi:10.1016/S1386-6346(00)00105-4
[4] A. X. Zhu, “Systemic Therapy of Advanced Hepatocellular Carcinoma: How Hopeful Should We Be?” Oncologist, Vol. 11, No. 7, 2006, pp. 790-800. doi:10.1634/theoncologist.11-7-790
[5] J. M. Llovet, S. Ricci, V. Mazzaferro, et al., “Sorafenib in Advanced Hepatocellular Carcinoma,” The New England Journal of Medicine, Vol. 359, No. 4, 2008, pp. 378-390. doi:10.1056/NEJMoa0708857
[6] A. Cheng, Y. K. Kang, Z. Chen, et al., “Efficacy and Safety of Sorafenib in Patients in Asia-Pacific Region with Advanced Hepatocellular Carcinoma: A Phase III Randomised, Double-Blind, Placebo-Controlled Trial,” The Lancet Oncology, Vol. 10, No. 1, 2009, pp. 25-34. doi:10.1016/S1470-2045(08)70285-7
[7] G. K. Abou-Alfa, L. Schwartz, et al., “Phase II Study of Sorafenib in Patients with Advanced Hepatocellular Carcinoma,” Journal of Clinical Oncology, Vol. 24, No. 26, 2006, pp. 4293-4300. doi:10.1200/JCO.2005.01.3441
[8] M. Nakamura, H. Nagano, S. Marubashi, et al., “Pilot Study of Combination Chemotherapy of S-1, a Novel Oral DPD Inhibitor, and Interferon-α for Advanced Hepatocellular Carcinoma with Extrahepatic Metastasis,” Cancer, Vol. 112, No. 8, 2008, pp. 1765-1771. doi:10.1002/cncr.23356
[9] T. Urabe, S. Kaneko, E. Matsushita, et al., “Clinical Pilot Study of Intrahepatic Arterial Chemotherapy with Methotrexate, 5-Fluorouracil, Cisplatin and Subcutaneous Interferon-Alpha-2b for Patients with Locally Advanced Hepatocellular Carcinoma,” Oncology, Vol. 55, No. 1, 1998, pp. 39-47. doi:10.1159/000011833
[10] S. Obi, H. Yoshida, R. Toune, et al., “Combination Therapy of Intraarterial 5-Fluorouracil and Systemic Interferon-Alpha for Advanced Hepatocellular Carcinoma with Portal Venous Invasion,” Cancer, Vol. 106, No. 9, 2006, pp. 1990-1997. doi:10.1002/cncr.21832
[11] M. A. Friedman, “Primary Hepatocellular Cancer—Pre- sent Results and Future Prospects,” International Journal of Radiation Oncology Biology Physics, Vol. 9, No. 12, 1983, pp. 1841-1850.
[12] D. Y. Lin, S. M. Lin and Y. F. Liaw, “Non-Surgical Treatment of Hepatocellular Carcinoma,” Journal of Gastroenterology and Hepatology, Vol. 12, No. 9-10, 1997, pp. S319-S328. doi:10.1111/j.1440-1746.1997.tb00516.x
[13] M. Miwa, M. Ura, M. Nishida, et al., “Design of a Novel Oral Fluoropyrimidine Carbamate, Capecitabine, which Generates 5-Fluorouracil Selectively in Tumors by Enzymes Concentrated in Human Liver and Cancer Tissue,” European Journal of Cancer, Vol. 34, No. 8, 1998, pp. 1274-1281. doi:10.1016/S0959-8049(98)00058-6
[14] J. Schuller, J. Cassidy, E. Dumont, et al., “Preferential Activation of Capecitabine in Tumor Following Oral Administration to Colorectal Cancer Patients,” Cancer Chemotherapy and Pharmacology, Vol. 45, No. 4, 2000, pp. 291-297. doi:10.1007/s002800050043
[15] Y. Z. Patt, M. M. Hassan, A. Aguayo, et al., “Oral Capecitabine for the Treatment of Hepatocellular Carcinoma, Cholangiocarcinoma, and Gallbladder Carcinoma,” Cancer, Vol. 101, No. 3, 2004, pp. 578-586. doi:10.1002/cncr.20368
[16] C. Twelves, R. Gynne-Jones, J. Cassidy, et al., “Effect of Hepatic Dysfunction Due to Liver Metastases on the Pharmacokinetics of Capecitabine and Its Metabolites,” Clinical Cancer Research, Vol. 5, 1999, pp. 1696-1702.
[17] J. Folkman, “New Perspectives in Clinical Oncology from Angiogenesis Research,” European Journal of Cancer, Vol. 32, No. 14, 1996, pp. 2534-2539. doi:10.1016/S0959-8049(96)00423-6
[18] U. Emmenegger, S. Man, Y. Shaked, et al., “A Comparative Analysis of Low-Dose Metronomic Cyclophosphamide Reveals Absent or Low-Grade Toxicity on Tissues Highly Sensitive to the Toxic Effects of Maximum Tolerated Dose Regimens,” Cancer Research, Vol. 64, No. 11, 2004, pp. 3994-4000. doi:10.1158/0008-5472.CAN-04-0580
[19] R. S. Kerbel and B. A. Kamen, “The Antiangiogenicbasis of Metronomic Chemotherapy,” Nature Reviews Cancer, Vol. 4, No. 6, 2004, pp. 423-436. doi:10.1038/nrc1369
[20] Y. Shaked, F. Bertolini, S. Man, et al., “Genetic Heterogeneity of the Vasculogenic Phenotype Parallels Angiogenesis; Implications for Cellular Surrogate Marker Analysis of Antiangiogenesis,” Cancer Cell, Vol. 7, No. 1, 2005, pp. 101-111. doi:10.1016/S1535-6108(04)00369-1
[21] F. Bertolini, S. Paul, P. Mancuso, et al., “Maximum Tolerable Dose and Low-Dose Metronomic Chemotherapy Have Opposite Effects on the Mobilization and Viability of Circulating Endothelial Progenitor Cells,” Cancer Research, Vol. 63, No. 15, 2003, pp. 4342-4346.
[22] G. Brandi, S. Fanello, F. Piscaglia, et al., “Metronomic Capecitabine in Advanced Patients with Hepatocellular Carcinoma (HCC): Preliminary Results,” Journal of Clinical Oncology, Vol. 25, No. 18S, 2007, p. 15163.
[23] J. Bruix and M. Sherman, “Management of Hepatocellular Carcinoma,” Hepatology, Vol. 42, No. 5, 2005, pp. 1208-1236. doi:10.1002/hep.20933
[24] P. R. Galle, “Sorafenib in Advanced Hepatocellular Carcinoma—We Have Won a Battle Not the War,” Journal of Hepatology, Vol. 49, No. 5, 2008, pp. 871-873. doi:10.1016/j.jhep.2008.09.001
[25] M. R. Stockler, T. Sourjina, P. V. Grimison, et al., “A Randomized Trial of Capecitabine (C) Given Intermittently (IC) Rather Than Continuously (CC) Compared to Classical CMF as First-Line Chemotherapy for Advanced Breast Cancer (ABC),” Journal of Clinical Oncology, Vol. 25, No. 18S, 2007, p. 1031.
[26] S. Steinbild, J. Arends, M. Medinger, et al., “Metronomic Antiangiogenic Therapy with Capecitabine and Celecoxib in Advanced Tumor Patient—Results of a Phase II Study,” Onkologie, Vol. 30, No. 12, 2007, pp. 629-635.
[27] M. Nannini, E. Nobili, R. Di Cicilia, et al., “Widen the Setting of Cancer Patients Who Could Benefit from Metronomic Capecitabine,” Cancer Chemotherapy and Pharmacology, Vol. 64, No. 1, 2009, pp. 189-193. doi:10.1007/s00280-009-0930-z
[28] G. Brandi, V. Agostini, F. de Rosa, et al., “Metronomic Capecitabine in Child-Pugh a Patients with Unresectable Hepatocellular Carcinoma,” Gastrointestinal Cancer Symposium, Orlando, 22-24 January 2010.
[29] V. Boige, J. L. Raoul, J. P. Pignon, et al., “Multicentre Phase II Trial of Capecitabine plus Oxaliplatin (XELOX) in Patients with Advanced Hepatocellular Carcinoma: FFCD 03-03 Trial,” British Journal of Cancer, Vol. 97, 2007, pp. 862-867
[30] A. K. Nowak, P. K. Chow and M. Findlay, “Systemic Therapy for Advanced Hepatocellular Carcinoma: A Re- view,” European Journal of Cancer, Vol. 40, No. 10, 2004, pp. 1474-1484. doi:10.1016/j.ejca.2004.02.027
[31] I. O. Ng, C. L. Liu, S. T. Fan, et al., “Expression of P-Glycoprotein in Hepatocellular Carcinoma. A Determinant of Chemotherapy Response,” American Journal of Clinical Pathology, Vol. 113, No. 3, 2000, pp. 355-363.
[32] E. C. Lai, T. K. Choi, C. H. Cheng, et al., “Doxorubicin for Unresectable Hepatocellular Carcinoma. A Prospective Study on the Addition of Verapamil,” Cancer, Vol. 66, No. 8, 1990, pp. 1685-1687. doi:10.1002/1097-0142(19901015)66:8<1685::AID-CNCR2820660805>3.0.CO;2-W
[33] T. W. Leung, Y. Z. Patt, W. Y. Lau, et al., “Complete Pathological Remission Is Possible with Systemic Combination Chemotherapy for Inoperable Hepatocellular Carcinoma,” Clinical Cancer Research, Vol. 5, No. 7, 1999, pp. 1676-81.
[34] Y. Chao, W. K. Chan, M. J. Birkhofer, et al., “Phase II and Pharmacokinetic Study of Paclitaxel Therapy for Unresectable Hepatocellular Carcinoma Patients,” British Journal of Cancer, Vol. 78, No. , 1998, pp. 34-39. doi:10.1038/bjc.1998.438
[35] M. Hebbar, O. Ernst, S. Cattan, et al., “Phase II Trial of Docetaxel Therapy in Patients with Advanced Hepatocellular Carcinoma,” Oncology, Vol. 70, No. 2, 2006, pp. 154-158. doi:10.1159/000093007
[36] T. S. Yang, C. H. Wang, R. K. Hsieh, et al., “Gemcitabine and Doxorubicin for the Treatment of Patients with Advanced Hepatocellular Carcinoma: A phase I-II Trial,” Annals of Oncology, Vol. 13, No. 11, 2002, pp. 1771-1778. doi:10.1093/annonc/mdf303
[37] Z. Guan, Y. Wang, S. Maoleekoonpairoj, et al., “Prospective Randomised Phase II Study of Gemcitabine at Standard or Fixed Dose Rate Schedule in Unresectable Hepatocellular Carcinoma,” British Journal of Cancer, Vol. 89, No. 10, 2003, pp. 1865-1869. doi:10.1038/sj.bjc.6601369
[38] S. Louafi, V. Boige, M. Ducreux, et al., “Gemcitabine plus Oxaliplatin (GEMOX) in Patients with Advanced Hepatocellular Carcinoma (HCC): Results of a Phase II Study,” Cancer, Vol. 109, No. 7, 2007, pp. 1384-1390. doi:10.1002/cncr.22532
[39] T. C. Tang, S. Man, C. R. Lee, et al., “Impact of Metronomic UFT/Cyclophosphamide Chemotherapy and Anti-angiogenic Drug Assessed in a New Preclinical Model of Locally Advanced Orthotopic Hepatocellular Carcinoma,” Neoplasia, Vol. 12, No. 3, 2010, pp. 264-274.
[40] F. de Rosa, V. Agostini, S. Di Girolamo, et al., “Metronomic Capecitabine as Second-Line Treatment for Patients with Hepatocellular Carcinoma with Preserved Liver Function: A Phase II Study,” ASCO Annual Meeting, Chicago, 1-5 June 9, 2011, p. e14608.

comments powered by Disqus

Copyright © 2018 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.