Abstract
Chemotherapy is not effective for hepatocellular carcinoma (HCC). HMG-CoA redutase inhibitors have cytostatic activity for cancer cells, but their clinical usefulness is unknown. To investigate whether pravastatin, a potent HMG-CoA reductase inhibitor, prolongs survival in patients with advanced HCC, this randomized controlled trial was conducted between February 1990 and February 1998 at Osaka University Hospital. 91 consecutive patients <71 years old (mean age 62) with unresectable HCC were enroled in this study. 8 patients were withdrawn because of progressive liver dysfunction; 83 patients were randomized to standard treatment with or without pravastatin. All patients underwent transcatheter arterial embolization (TAE) followed by oral 5-FU 200 mg−1d for 2 months. Patients were then randomly assigned to control (n = 42) and pravastatin (n = 41) groups. Pravastatin was administered at a daily dose of 40 mg. The effect of pravastatin on tumour growth was assessed by ultrasonography. Primary endpoint was death due to progression of HCC. The duration of pravastatin administration was 16.5 ± 9.8 months (mean ± SD). No patients in either group were lost to follow-up. Median survival was 18 months in the pravastatin group versus 9 months in controls (P = 0.006). The Cox proportional hazards model showed that pravastatin was a significant factor contributing to survival. Pravastatin prolonged the survival of patients with advanced HCC, suggesting its value for adjuvant treatment. © 2001 Cancer Research Campaign http://www.bjcancer.com
Keywords: hepatocellular carcinoma, pravastatin, HMG-CoA reductase inhibitor, survival
Full Text
The Full Text of this article is available as a PDF (82.0 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Byington R. P., Jukema J. W., Salonen J. T., Pitt B., Bruschke A. V., Hoen H., Furberg C. D., Mancini G. B. Reduction in cardiovascular events during pravastatin therapy. Pooled analysis of clinical events of the Pravastatin Atherosclerosis Intervention Program. Circulation. 1995 Nov 1;92(9):2419–2425. doi: 10.1161/01.cir.92.9.2419. [DOI] [PubMed] [Google Scholar]
- Cavalli F., Rozencweig M., Renard J., Goldhirsch A., Hansen H. H. Phase II study of oral VP-16-213 in hepatocellular carcinoma. Eur J Cancer Clin Oncol. 1981 Oct;17(10):1079–1082. doi: 10.1016/0014-2964(81)90291-7. [DOI] [PubMed] [Google Scholar]
- Charnsangavej C., Chuang V. P., Wallace S., Soo C. S., Bowers T. Work in progress: transcatheter management of primary carcinoma of the liver. Radiology. 1983 Apr;147(1):51–55. doi: 10.1148/radiology.147.1.6298860. [DOI] [PubMed] [Google Scholar]
- Choi T. K., Lee N. W., Wong J. Chemotherapy for advanced hepatocellular carcinoma. Adriamycin versus quadruple chemotherapy. Cancer. 1984 Feb 1;53(3):401–405. doi: 10.1002/1097-0142(19840201)53:3<401::aid-cncr2820530306>3.0.co;2-l. [DOI] [PubMed] [Google Scholar]
- Di Bisceglie A. M. Hepatitis C and hepatocellular carcinoma. Semin Liver Dis. 1995 Feb;15(1):64–69. doi: 10.1055/s-2007-1007263. [DOI] [PubMed] [Google Scholar]
- El-Serag H. B., Mason A. C. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med. 1999 Mar 11;340(10):745–750. doi: 10.1056/NEJM199903113401001. [DOI] [PubMed] [Google Scholar]
- Falkson G., MacIntyre J. M., Moertel C. G., Johnson L. A., Scherman R. C. Primary liver cancer. An Eastern Cooperative Oncology Group Trial. Cancer. 1984 Sep 15;54(6):970–977. doi: 10.1002/1097-0142(19840915)54:6<970::aid-cncr2820540604>3.0.co;2-7. [DOI] [PubMed] [Google Scholar]
- Gibbs J. B., Pompliano D. L., Mosser S. D., Rands E., Lingham R. B., Singh S. B., Scolnick E. M., Kohl N. E., Oliff A. Selective inhibition of farnesyl-protein transferase blocks ras processing in vivo. J Biol Chem. 1993 Apr 15;268(11):7617–7620. [PubMed] [Google Scholar]
- Goldstein J. L., Brown M. S. Regulation of the mevalonate pathway. Nature. 1990 Feb 1;343(6257):425–430. doi: 10.1038/343425a0. [DOI] [PubMed] [Google Scholar]
- Goldstein J. L., Helgeson J. A., Brown M. S. Inhibition of cholesterol synthesis with compactin renders growth of cultured cells dependent on the low density lipoprotein receptor. J Biol Chem. 1979 Jun 25;254(12):5403–5409. [PubMed] [Google Scholar]
- Habenicht A. J., Glomset J. A., Ross R. Relation of cholesterol and mevalonic acid to the cell cycle in smooth muscle and swiss 3T3 cells stimulated to divide by platelet-derived growth factor. J Biol Chem. 1980 Jun 10;255(11):5134–5140. [PubMed] [Google Scholar]
- James G. L., Goldstein J. L., Brown M. S., Rawson T. E., Somers T. C., McDowell R. S., Crowley C. W., Lucas B. K., Levinson A. D., Marsters J. C., Jr Benzodiazepine peptidomimetics: potent inhibitors of Ras farnesylation in animal cells. Science. 1993 Jun 25;260(5116):1937–1942. doi: 10.1126/science.8316834. [DOI] [PubMed] [Google Scholar]
- Kandutsch A. A., Chen H. W. Consequences of blocked sterol synthesis in cultured cells. DNA synthesis and membrane composition. J Biol Chem. 1977 Jan 25;252(2):409–415. [PubMed] [Google Scholar]
- Kawata S., Takaishi K., Nagase T., Ito N., Matsuda Y., Tamura S., Matsuzawa Y., Tarui S. Increase in the active form of 3-hydroxy-3-methylglutaryl coenzyme A reductase in human hepatocellular carcinoma: possible mechanism for alteration of cholesterol biosynthesis. Cancer Res. 1990 Jun 1;50(11):3270–3273. [PubMed] [Google Scholar]
- Kohl N. E., Mosser S. D., deSolms S. J., Giuliani E. A., Pompliano D. L., Graham S. L., Smith R. L., Scolnick E. M., Oliff A., Gibbs J. B. Selective inhibition of ras-dependent transformation by a farnesyltransferase inhibitor. Science. 1993 Jun 25;260(5116):1934–1937. doi: 10.1126/science.8316833. [DOI] [PubMed] [Google Scholar]
- Maltese W. A., Defendini R., Green R. A., Sheridan K. M., Donley D. K. Suppression of murine neuroblastoma growth in vivo by mevinolin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. J Clin Invest. 1985 Nov;76(5):1748–1754. doi: 10.1172/JCI112165. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Matsuda Y., Kawata S., Nagase T., Maeda Y., Yamasaki E., Kiso S., Ishiguro H., Matsuzawa Y. Interleukin-6 in transcatheter arterial embolization for patients with hepatocellular carcinoma. Effects of serine protease inhibitor. Cancer. 1994 Jan 1;73(1):53–57. doi: 10.1002/1097-0142(19940101)73:1<53::aid-cncr2820730111>3.0.co;2-w. [DOI] [PubMed] [Google Scholar]
- Okuda K., Fujimoto I., Hanai A., Urano Y. Changing incidence of hepatocellular carcinoma in Japan. Cancer Res. 1987 Sep 15;47(18):4967–4972. [PubMed] [Google Scholar]
- Okuda K. Hepatocellular carcinoma: recent progress. Hepatology. 1992 May;15(5):948–963. doi: 10.1002/hep.1840150532. [DOI] [PubMed] [Google Scholar]
- Sebolt-Leopold J. S., Dudley D. T., Herrera R., Van Becelaere K., Wiland A., Gowan R. C., Tecle H., Barrett S. D., Bridges A., Przybranowski S. Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nat Med. 1999 Jul;5(7):810–816. doi: 10.1038/10533. [DOI] [PubMed] [Google Scholar]
- Shepherd J., Cobbe S. M., Ford I., Isles C. G., Lorimer A. R., MacFarlane P. W., McKillop J. H., Packard C. J. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995 Nov 16;333(20):1301–1307. doi: 10.1056/NEJM199511163332001. [DOI] [PubMed] [Google Scholar]
- Simonetti R. G., Cammà C., Fiorello F., Politi F., D'Amico G., Pagliaro L. Hepatocellular carcinoma. A worldwide problem and the major risk factors. Dig Dis Sci. 1991 Jul;36(7):962–972. doi: 10.1007/BF01297149. [DOI] [PubMed] [Google Scholar]
- Sinensky M., Beck L. A., Leonard S., Evans R. Differential inhibitory effects of lovastatin on protein isoprenylation and sterol synthesis. J Biol Chem. 1990 Nov 15;265(32):19937–19941. [PubMed] [Google Scholar]
- Stefanini G. F., Amorati P., Biselli M., Mucci F., Celi A., Arienti V., Roversi R., Rossi C., Re G., Gasbarrini G. Efficacy of transarterial targeted treatments on survival of patients with hepatocellular carcinoma. An Italian experience. Cancer. 1995 May 15;75(10):2427–2434. doi: 10.1002/1097-0142(19950515)75:10<2427::aid-cncr2820751007>3.0.co;2-j. [DOI] [PubMed] [Google Scholar]
- Tsujita Y., Kuroda M., Shimada Y., Tanzawa K., Arai M., Kaneko I., Tanaka M., Masuda H., Tarumi C., Watanabe Y. CS-514, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase: tissue-selective inhibition of sterol synthesis and hypolipidemic effect on various animal species. Biochim Biophys Acta. 1986 Jun 11;877(1):50–60. doi: 10.1016/0005-2760(86)90117-7. [DOI] [PubMed] [Google Scholar]
- Yamada R., Sato M., Kawabata M., Nakatsuka H., Nakamura K., Takashima S. Hepatic artery embolization in 120 patients with unresectable hepatoma. Radiology. 1983 Aug;148(2):397–401. doi: 10.1148/radiology.148.2.6306721. [DOI] [PubMed] [Google Scholar]