Liver Cancer pp 277-286 | Cite as

Treatment of Hepatocellular Carcinoma with Thalidomide: Assessment with Power Doppler Ultrasound

  • Chiun Hsu
  • Chiung-Nien Chen
  • Ann-Lii Cheng
Part of the Methods of Cancer Diagnosis, Therapy and Prognosis book series (HAYAT, volume 5)

Hepatocellular carcinoma (HCC) is typically a hypervascular tumor and anti-angiogenesis therapy may be effective for the treatment of HCC. Thalidomide has been shown to inhibit angiogenesis induced by various proangiogenic factors and may produce objective tumor response in various cancers. In HCC, thalidomide may produce complete or partial remission in ~ 4–7% of patients and disease stabilization in 10–20% patients with advanced disease. We have performed a prospective study using power Doppler ultrasound to evaluate the vascular response to thalidomide treatment in patients with advanced HCC. Patients who achieved objective tumor response to thalidomide tended to have a higher pretreatment vascularity index, defined as the number of colored (vascular) pixels within a well-demarcated tumor area divided by the number of total pixels in that area, than patients who did not. The pretreatment vascularity index also correlated with levels of circulating angiogenic factors. The value of power Doppler ultrasound in future clinical trials of anti-angiogenesis therapy of HCC is discussed.


Vascular Endothelial Growth Factor Hepatocellular Carcinoma Proangiogenic Factor Power Doppler Ultrasound Objective Tumor Response 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Abou-Alfa, G.K., Schwartz, L., Ricci, S., Amadori, D., Santoro, A., Figer, A., De Greve, J., Douillard, J.Y., Lathia, C., Schwartz, B., Taylor, I., Moscovici, M., and Saltz, L.B. 2006. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J. Clin. Oncol. 24: 4293–4300.PubMedCrossRefGoogle Scholar
  2. Bertolotto, M., Pozzato, G., Croce, L.S., Nascimben, F., Gasparini, C., Cova, M.A., and Tiribelli, C. 2006. Blood flow changes in hepatocellular carcinoma after the administration of thalidomide assessed by reperfusion kinetics during microbubble infusion: preliminary results. Invest. Radiol. 41: 15–21.PubMedCrossRefGoogle Scholar
  3. Chen, C.N., Cheng, Y.M., Liang, J.T., Lee, P.H., Hsieh, F.J., Yuan, R.H., Wang, S.M., Chang, M.F., and Chang, K.J. 2000. Color Doppler vascular index can predict distant metastasis and survival in colon cancer patients. Cancer Res. 60: 2892–2897.PubMedGoogle Scholar
  4. Chen, C.N., Cheng, Y.M., Lin, M.T., Hsieh, F.J., Lee, P.H., and Chang, K.J. 2002. Association of color Doppler vascularity index and microvessel density with survival in patients with gastric cancer. Ann. Surg. 235: 512–518.PubMedCrossRefGoogle Scholar
  5. Chen, L.T., Liu, T.W., Chao, Y., Shiah, H.S., Chang, J.Y., Juang, S.H., Chen, S.C., Chuang, T.R., Chin, Y.H., and Whang-Peng, J. 2005. α-fetoprotein response predicts survival benefits of thalidomide in advanced hepatocellular carcinoma. Aliment. Pharmacol. Ther. 22: 217–226.PubMedCrossRefGoogle Scholar
  6. Cheng, W.F., Lee, C.N., Chu, J.S., Chen, C.A., Chen, T.M., Shau, W.Y., Hsieh, C.Y., and Hsieh, F.J. 1999. Vascular index as a novel parameter for the in vivo assessment of angiogenesis in patients with cervical carcinoma. Cancer 85: 651–657.PubMedCrossRefGoogle Scholar
  7. Choi, B.I., Kim, T.K., Han, J.K., Chung, J.W., Park, J.H., and Han, M.C. 1996. Power versus conventional color Doppler sonography: comparison in the depiction of vasculature in liver tumors. Radiology 200: 55–58.PubMedGoogle Scholar
  8. Choi, B.I., Kim, A.Y., Lee, J.Y., Kim, K.W., Lee, K.H., Kim, T.K., and Han, J.K. 2002. Hepatocellular carcinoma: contrast enhancement with Levovist. J. Ultrasound Med. 21: 77–84.PubMedGoogle Scholar
  9. Chow, N.H., Hsu, P.I., Lin, X.Z., Yang, H.B., Chan, S.H., Cheng, K.S., Huang, S.M., and Su, I.J. 1997. Expression of vascular endothelial growth factor in normal liver and hepatocellular carcinoma: an immunohistochemical study. Human Pathol. 28: 698–703.CrossRefGoogle Scholar
  10. Chow, N.H., Cheng, K.S., Lin, P.W., Chan, S.H., Su, W.C., Sun, Y.N., and Lin, X.Z. 1998. Expression of fibroblast growth factor-1 and fibroblast growth factor-2 in normal liver and hepatocellular carcinoma. Digest. Dis. Sci. 10: 2261–2266.CrossRefGoogle Scholar
  11. Choyke, P.L., Knopp, M.V., and Libutti, S.K. 2002. Special techniques for imaging blood flow to tumors. Cancer J. 8: 109–118.PubMedCrossRefGoogle Scholar
  12. D'Amato, R.J., Loughnan, M.S., Flynn, E., and Folkman, J. 1994. Thalidomide is an inhibitor of angiogenesis. Proc. Natl. Acad. Sci. U.S.A. 91: 4082–4085.PubMedCrossRefGoogle Scholar
  13. Evelhoch, J., Garwood, M., Vigneron, D., Knopp, M., Sullivan, D., Menkens, A., Clarke, L., and Liu, G. 2005. Expanding the use of magnetic resonance in the assessment of tumor response to therapy: workshop report. Cancer Res. 65: 7041–7044PubMedCrossRefGoogle Scholar
  14. Gee, M.S., Saunders, H.M., Lee, J.C., Sanzo, J.F., Jenkins, W.T., Evans, S.M., Trinchieri, G., Sehgal, C.M., Feldman, M.D., and Lee, W.M. 2001. Doppler ultrasound imaging detects changes in tumor perfusion during antivascular therapy associated with vascular anatomic alterations. Cancer Res. 61: 2974–2982.PubMedGoogle Scholar
  15. therapy on tumor blood flow. Cancer Res. 62: 6371–6375.PubMedGoogle Scholar
  16. Gschwind, A., Fischer, O.M., and Ullrich, A. 2004. The discovery of receptor tyrosine kinases: targets for cancer therapy. Nat. Rev. Cancer 4: 361–370.PubMedCrossRefGoogle Scholar
  17. Harada, T., Arii, S., Mise, M., Imamura, T., Higashitsuji, H., Furutani, M., Niwano, M., Ishigami, S., Fukumoto, M., Seiki, M., Sato, H., and Imamura, M. 1998. Membrane-type matrix metalloproteinase-1 (MT1-MMP) gene is overexpressed in highly invasive hepatocellular carcinomas. J. Hepatol. 28: 231–239.PubMedCrossRefGoogle Scholar
  18. Hsu, C., Chen, C.N., Chen, L.T., Wu, C.Y., Yang, P.M., Lai, M.Y., Lee, P.H., and Cheng, A.L. 2003. Low-dose thalidomide treatment for advanced hepatocellular carcinoma. Oncology 65: 242–249.PubMedCrossRefGoogle Scholar
  19. Hsu, C., Cheng, J.C., and Cheng, A.L. 2004. Recent advances in non-surgical treatment for advanced hepatocellular carcinoma. J. Formos. Med. Assoc. 103: 483–495.PubMedGoogle Scholar
  20. Hsu, C., Chen, C.N., Chen, L.T., Wu, C.Y., Hsieh, F.J., and Cheng, A.L. 2005. Effect of thalidomide in hepatocellular carcinoma: assessment with power Doppler US and analysis of circulating angiogenic factors. Radiology 235: 509–516.PubMedCrossRefGoogle Scholar
  21. Kenyon, B.M., Browne, F., and D'Amato, R. 1997. Effects of thalidomide and related metabolites in a mouse corneal model of neovascularization. Exp. Eye Res. 64: 971–978.PubMedCrossRefGoogle Scholar
  22. Kim, A.Y., Choi, B.I., Kim, T.K., Han, J.K., Yun, E.J., Lee, K.Y., and Han, M.C. 1998. Hepatocellular carcinoma: power Doppler US with a contrast agent: preliminary results. Radiology 209: 135–140.PubMedGoogle Scholar
  23. Korn, E.L., Arbuck, S.G., Pluda, J.M., Simon, R., Kaplan, R.S., and Christian, M.C. 2001. Clinical trial designs for cytostatic agents: are new approaches needed? J. Clin. Oncol. 19: 265–272.PubMedGoogle Scholar
  24. Krause, D.S., and Van Etten, R.A. 2005. Tyrosine kinases as targets for cancer therapy. N. Engl. J. Med. 353: 172–187.PubMedCrossRefGoogle Scholar
  25. Leach, M.O., Brindle, K.M., Evelhoch, J.L., Griffiths, J.R., Horsman, M.R., Jackson, A., Jayson G.C., Judson, I.R., Knopp, M.V., Maxwell, R.J., McIntyre, D., Padhani, A.R., Price, P., Rathbone, R., Rustin, G.J., Tofts, P.S., Tozer, G.M., Vennart, W., Waterton, J.C., Williams, S.R., Workman, P., and Pharmacodynamic/Pharma-cokinetic Technologies Advisory Committee, Drug Development Office, Cancer Research UK. 2005. The assessment of antiangiogenic and antivascular therapies in early-stage clinical trials using magnetic resonance imaging: issues and recommendations. Brit. J. Cancer 92: 1599–1610.PubMedCrossRefGoogle Scholar
  26. Lee, J.Y., Choi, B.I., Han, J.K., Lee, J.M., and Kim, S.H. 2006. State-of-the-art ultrasonography of hepatocellular carcinoma. Eur. J. Radiol. 58: 177–185PubMedCrossRefGoogle Scholar
  27. Lencioni, R., Pinto, F., Armillotta, N., and Bartolozzi, C. 1996. Assessment of tumor vascularity in hepatocellular carcinoma: comparison of power Doppler US and color Doppler US. Radiology 201: 353–358.PubMedGoogle Scholar
  28. Lin, A.Y., Brophy, N., Fisher, G.A., So, S., Biggs, C., Yock, T.I., and Levitt, L. 2005. Phase II study of thalidomide in patients with unresectable hepatocellular carcinoma. Cancer 103: 119–125.PubMedCrossRefGoogle Scholar
  29. Little, R.F., Wyvill, K.M., Pluda, J.M., Welles, L., Marshall, V., Figg, W.D., Newcomb, F.M., Tosato, G., Feigal, E., Steinberg, S.M., Whitby, D., Goedert, J.J., and Yachoan, R. 2000. Activity of thalidomide in AIDS-related Kaposi's sarcoma. J. Clin. Oncol. 18: 2593–2602.PubMedGoogle Scholar
  30. Liu, G., Rugo, H.S., Wilding, G., McShane, T.M., Evelhoch, J.L., Ng, C., Jackson, E., Kelcz, F., Yeh, B.M., Lee, F.T. Jr., Charnsangavej, C., Park, J.W., Ashton, E.A., Steinfeldt, H.M., Pithavala, Y.K., Reich, S.D., and Herbst, R.S. 2005. Dynamic contrast-enhanced magnetic resonance imaging as a pharmacodynamic measure of response after acute dosing of AG-013736, an oral angiogenesis inhibitor, in patients with advanced solid tumors: results from a phase I study. J. Clin. Oncol. 23: 5464–5473.PubMedCrossRefGoogle Scholar
  31. Miller, A.B., Hoogstraten, B., Staquet, M., and Winkler, A. 1981. Reporting results of cancer treatment. Cancer 47: 207–214.PubMedCrossRefGoogle Scholar
  32. Padhani, A.R., and Leach, M.O. 2005. Antivascular cancer treatments: functional assessments by dynamic contrast-enhanced magnetic resonance imaging. Abd. Imaging 30: 324–341Google Scholar
  33. Parkin, D.M. 2001. Global cancer statistics in the year 2000. Lancet Oncol. 2: 533–543.PubMedCrossRefGoogle Scholar
  34. Patt, Y.Z., Hassan, M.M., Lozano, R.D., Nooka, A.K., Schnirer, I.I., Zeldis, J.B., Abbruzzese, J.L., and Brown, T.D. 2005. Thalidomide in the treatment of patients with hepatocellular carcinoma: a phase II trial. Cancer 103: 749–755.PubMedCrossRefGoogle Scholar
  35. Philip, P.A., Mahoney, M.R., Allmer, C., Thomas, J., Pitot, H.C., Kim, G., Donehower, R.C., Fitch, T., Picus, J., and Erlichman, C. 2005. Phase II study of erlotinib (OSI-774) in patients with advanced hepatocellular cancer. J. Clin. Oncol. 23: 6657–6663.PubMedCrossRefGoogle Scholar
  36. Quaia, E., Calliada, F., Bertolotto, M., Rossi, S., Garioni, L., Rosa, L., and Pozzi-Mucelli, R. 2004. Characterization of focal liver lesions with contrast-specific US modes and a sulfur hexafluoride-filled microbubble contrast agent: diagnostic performance and confidence. Radiology 232: 420–430.PubMedCrossRefGoogle Scholar
  37. Rubin, J.M., Bude, R.O., Carson, P.L., Bree, R.L., and Adler, R.S. 1994. Power Doppler US: a potentially useful alternative to meanfrequency-based color Doppler US. Radiology 190: 853–856.PubMedGoogle Scholar
  38. Schwartz, J.D., Sung, M., Schwartz, M., Lehrer, D., Mandeli, J., Liebes, L., Goldenberg, A., and Volm, M. 2005. Thalidomide in advanced hepatocellular carcinoma with optional low-dose interferon-α2a upon progression. Oncologist 10: 718–727.PubMedCrossRefGoogle Scholar
  39. Schwartz, J.D., Schwartz, M., Lehrer, D., Cohen, E., Sung, M., Kinkhabwala, M., Siegel, A., Holloway, S., Ocean, A., and Wadler, S. 2006. Bevacizumab in unresectable hepatocellular carcinoma (HCC) for patients without metastasis and without invasion of the portal vein. Proc. Am. Soc. Clin. Oncol. 24: abstr 4144.Google Scholar
  40. Singhal, S., Mehta, J., Desikan, R., Ayers, D., Roberson, P., Eddlemon, P., Munshi, N., Anaissie, E., Wilson, C., Dhodapkar, M., Zeddis, J., and Barlogie, B. 1999. Antitumor activity of thalidomide in refractory multiple myeloma. N. Engl. J. Med. 341: 1565–1571PubMedCrossRefGoogle Scholar
  41. Stephens, T.D., Bunde, C.J., and Fillmore, B.J. 2000. Mechanism of action in thalidomide teratogenesis. Biochem. Pharmacol. 59: 1489–1499.PubMedCrossRefGoogle Scholar
  42. Torimura, T., Sata, M., Ueno, T., Kin, M., Tsuji, R., Suzaku, K., Hashimoto, O., Sugawara, H., and Tanikawa, K. 1998. Increased expression of vascular endothelial growth factor is associated with tumor progression in hepatocellular carcinoma. Human Pathol. 29: 986–991.CrossRefGoogle Scholar
  43. Vacca, A., Scavelli, C., Montefusco, V., Di Pietro, G., Neri, A., Mattioli, M., Bicciato, S., Nico, B., Ribatti, D., Dammacco, F., and Corradini, P. 2005. Thalidomide downregulates angiogenic genes in bone marrow endothelial cells of patients with active multiple myeloma. J. Clin. Oncol. 23: 5334–5346.PubMedCrossRefGoogle Scholar
  44. Vilana, R., Llovet, J.M., Bianchi, L., Sanchez, M., Pages, M., Sala. M., Gilabert, R., Nicolau, C., Garcia, A., Ayuso, C., Bruix, J., and Bru, C. 2003. Contrast-enhanced power Doppler sonography and helical computed tomography for assessment of vascularity of small hepatocellular carcinomas before and after percutaneous ablation. J. Clin. Ultrasound 31: 119–128.PubMedCrossRefGoogle Scholar
  45. Wang, J., Chen, L.T., Tsang, Y.M., Liu, T.W., and Shih, T.T. 2004a. Dynamic contrast-enhanced MRI analysis of perfusion changes in advanced hepatocellular carcinoma treated with an antiangiogenic agent: a preliminary study. Am. J. Roentgenol. 183: 713–719.Google Scholar
  46. Wang, T.E., Kao, C.R., Lin, S.C., Chang, W.H., Chu, C.H., Lin, J., and Hsieh, R.K. 2004b. Salvage therapy for hepatocellular carcinoma with thalidomide. World J. Gastroenterol. 10: 649–653.Google Scholar
  47. Wu, C.C., Lee, C.N., Chen, T.M., Shyu, M.K., Hsieh, C.Y., Chen, H.Y., and Hsieh, F.J. 1994. Incremental angiogenesis assessed by color Doppler ultrasound in the tumorigenesis of ovarian neoplasm. Cancer 73: 1251–1256.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science + Business Media B.V. 2009

Authors and Affiliations

  • Chiun Hsu
    • 1
  • Chiung-Nien Chen
    • 1
  • Ann-Lii Cheng
    • 1
  1. 1.Departments of Oncology and Internal MedicineNational Taiwan University HospitalTaipeiTaiwan

Personalised recommendations