Effects of the mTOR inhibitor sirolimus in patients with hepatocellular and cholangiocellular cancer.
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 mug/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).


CONCLUSIONS
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.
Rizell
Magnus
M
Department of Surgery, Transplantation and Liver Surgery Service, Sahlgrenska University Hospital, S-413 45, Goteborg, Sweden. magnus.rizell@surgery.gu.se
Andersson
Mats
M
Cahlin
Christian
C
Hafström
Larsolof
L
Olausson
Michael
M
Lindnér
Per
P
D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D001650:Bile Duct Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D001653:Bile Ducts, Intrahepatic; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D018281:Cholangiocarcinoma / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism*; D020123:Sirolimus / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases
D000903:Antibiotics, Antineoplastic; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus