Advertisement

International Journal of Clinical Oncology

, Volume 13, Issue 1, pp 66–70 | Cite as

Effects of the mTOR inhibitor sirolimus in patients with hepatocellular and cholangiocellular cancer

  • Magnus RizellEmail author
  • Mats Andersson
  • Christian Cahlin
  • Larsolof Hafström
  • Michael Olausson
  • Per Lindnér
Original Article

Abstract

Background

Hepatocellular cancer (HCC), as well as cholangiocellular cancer (CCC), has an extremely poor prognosis due to the extent of tumor at diagnosis and the underlying liver disease. Sirolimus is used in the transplantation setting as an immunosuppressive agent, but it also possesses antiproliferative and antiangiogenic properties. The objective of the study was to evaluate the effect of sirolimus on HCC and CCC.

Methods

In a prospective single-arm protocol, the tumor response to sirolimus as the primary endpoint was studied in 21 patients with advanced HCC and nine with CCC. Sirolimus was administered once daily by mouth, with the dose adjusted to a serum trough level between 4 and 15 μg/ml. Tumor response was evaluated by computed tomography (CT) or magnetic resonance imaging (MRI), according to the Response Evaluation Criteria in Solid Tumors (RECIST), every third month. Secondary measures were overall survival, time to tumor progression, tumor markers, and side effects.

Results

Of the patients with HCC, one had partial remission (PR) and fi ve patients had stable disease (SD) at 3 months. Of the patients with CCC, three had SD. The median survival for patients with HCC was 6.5 months (range, 0.2–36 months) and that for patients with CCC was 7 months (range, 2.6–35 months).

Conclusion

Treatment of HCC and CCC with sirolimus can induce temporary PD or SD. This pilot study indicates that sirolimus might be a promising drug for this treatment, but further clinical studies elucidating the biological effects are advocated.

Key words

Primary liver cancer Hepatocellular cancer Cholangiocellular cancer Sirolimus mTOR inhibitor 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Llovet JM, Bruix J (2004) Unresectable hepatocellular carcinoma: meta-analysis of arterial embolization (letter). Radiology 230: 300–302PubMedCrossRefGoogle Scholar
  2. 2.
    Neuhaus P, Klupp J, Langrehr J (2001) mTOR inhibitors: an overview. Liver Transpl 7:473–484PubMedCrossRefGoogle Scholar
  3. 3.
    Ogawa T, Tokuda M, Tomizawa K, et al. (1998) Osteoblastic differentiation is enhanced by rapamycin in rat osteoblast-like osteo-sarcoma (ROS 17/2.8) cells. Biochem Biophys Res Commun 249:226–230PubMedCrossRefGoogle Scholar
  4. 4.
    Hosoi H, Dilling MB, Shikata T, et al. (1999) Rapamycin causes poorly reversible inhibition of mTOR and induces p53-independent apoptosis in human rhabdomyosarcoma cells. Cancer Res 59:886–894PubMedGoogle Scholar
  5. 5.
    Schumacher G, Oidtmann M, Rosewicz S, et al. (2002) Sirolimus inhibits growth of human hepatoma cells in contrast to tacrolimus, which promotes cell growth. Transplant Proc 34:1392–1393PubMedCrossRefGoogle Scholar
  6. 6.
    Schumacher G, Oidtmann M, Rueggeberg A. (2005) Sirolimus inhibits growth of human hepatoma cells alone or combined with tacrolimus, while tacrolimus promotes cell growth. World J Gastroenterol 11:1420–1425PubMedGoogle Scholar
  7. 7.
    Kim DH, Sarbassov DD, Ali SM, et al. (2002) mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110:163–175PubMedCrossRefGoogle Scholar
  8. 8.
    Guba M, von Breitenbuch P, Steinbauer M, et al. (2002) Rapamycin inhibits primary and metastatic tumour growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med 8:128–135PubMedCrossRefGoogle Scholar
  9. 9.
    Rizell M, Lindner P (2005) Inhibition of mTOR suppresses experimental liver tumours. Anticancer Res 25:789–793PubMedGoogle Scholar
  10. 10.
    Roskamps T (2006) Liver stem cells and their implication in hepatocellular and cholangiocarcinoma. Oncogene 25:3818–3822CrossRefGoogle Scholar
  11. 11.
    Guba M, Koehl GE, Neppl E, et al. (2005) Dosing of rapamycin is critical to achieve an optimal antiangiogenic effect against cancer. Transpl Int 18:89–94PubMedCrossRefGoogle Scholar
  12. 12.
    Franz DN, Leonard J, Tudor C, et al. (2006) Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Ann Neurol 59:490–498PubMedCrossRefGoogle Scholar
  13. 13.
    Therasse P, Arbuck SG, Eisenhauer EA, et al. (2000) New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205–216PubMedCrossRefGoogle Scholar
  14. 14.
    Therasse P, Eisenhauer EA, Verweij J. (2006) RECIST revisited: a review of validation studies on tumour assessment. Eur J Cancer 42:1031–1039PubMedCrossRefGoogle Scholar
  15. 15.
    Ratain MJ, Eckhardt G. (2004) Phase II studies of modern drugs directed against new targets: If you are fazed, too, then resist RECIST. J Clin Oncol 22:4442–4445PubMedCrossRefGoogle Scholar
  16. 16.
    National Cancer Institute. Common terminology criteria for adverse events (CTCAE). Version 3.0 Published date June 10, 2003, Ncl, RockvilleGoogle Scholar
  17. 17.
    Rizell M, Cahlin C, Friman S, et al.(2005) Impressive regression of primary liver cancer after treatment with sirolimus. Acta Oncol 44:496PubMedCrossRefGoogle Scholar
  18. 18.
    Xu X, Kobayashi S, Qiao W, et al.(2006) Induction of intrahepatic cholangiocellular carcinom by liver-specific disruption of Smad4 and Pten in mice. J Clin Invest 116:1843–1852PubMedCrossRefGoogle Scholar
  19. 19.
    Sahin F, Kannangai R, Adegbola O, et al. (2004) mTor and p70 s6 kinase expression in primary liver neoplasms. Clin Cancer Res 10:8421–8425PubMedCrossRefGoogle Scholar
  20. 20.
    Torimura T, Sata M, Ueno T, et al. (1998) Increased expression of vascular endothelial growth factor is associated with tumour progression in hepatocellular carcinoma. Hum Pathol 29:986–991PubMedCrossRefGoogle Scholar
  21. 21.
    Wang T E, Kao C R, Chen L T, et al. (2004) Salvage therapy for hepatocellular carcinoma with thalidomide. World J Gastroenterol 10:649–653PubMedGoogle Scholar
  22. 22.
    Schwartz J D, Schwartz M, Goldman D, et al. (2005) Bevacizumab in hepatocellular carcinoma (HCC) in patients without metastasis and without invasion of the portal vein. J Clin Oncol 2005 ASCO Annual Meeting Proceedings 23:412Google Scholar
  23. 23.
    Kneteman NM, Oberholzer J, Al Saghier M, et al. (2004) Sirolimusbased immunosuppression for liver transplantation in the presence of extended criteria for hepatocellular carcinoma. Liver Transpl 10:1301–1311PubMedCrossRefGoogle Scholar

Copyright information

© Japan Society of Clinical Oncology 2008

Authors and Affiliations

  • Magnus Rizell
    • 1
    Email author
  • Mats Andersson
    • 2
  • Christian Cahlin
    • 1
  • Larsolof Hafström
    • 1
  • Michael Olausson
    • 1
  • Per Lindnér
    • 1
  1. 1.Department of Surgery, Transplantation and Liver Surgery ServiceSahlgrenska University HospitalGoteborgSweden
  2. 2.Department of RadiologySahlgrenska University HospitalGöteborgSweden

Personalised recommendations