Int J Clin Oncol (2008) 13:66–70 DOI 10.1007/s10147-007-0733-3
© The Japan Society of Clinical Oncology 2008
ORIGINAL ARTICLE Magnus Rizell · Mats Andersson · Christian Cahlin Larsolof Hafström · Michael Olausson · Per Lindnér
Effects of the mTOR inhibitor sirolimus in patients with hepatocellular and cholangiocellular cancer
Received: May 8, 2007 / Accepted: September 29, 2007
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 five 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
M. Rizell (*) · C. Cahlin · L. Hafström · M. Olausson · P. Lindnér Department of Surgery, Transplantation and Liver Surgery Service, Sahlgrenska University Hospital, S-413 45 Goteborg, Sweden Tel. +46-31-3420-000; Fax +46-31-417-364 e-mail:
[email protected] M. Andersson Department of Radiology, Sahlgrenska University Hospital, Göteborg, Sweden All authors contributed to the conception of the study, analysis of data, and writing of the communication
further clinical studies elucidating the biological effects are advocated. Key words Primary liver cancer · Hepatocellular cancer · Cholangiocellular cancer · Sirolimus mTOR inhibitor
Introduction Patients with hepatocellular cancer (HCC), as well as those with cholangiocellular cancer (CCC), have an extremely poor prognosis due to the extent of the tumor at diagnosis and the underlying liver disease. HCC and CCC are the most common primary liver cancers and are known to be chemo-insensitive tumors. Chemoembolization, which targets the vascular bed of the tumor, can offer a limited survival benefit for selected patients with HCC.1 For most patients, only best supportive care is available. At present, liver resection and liver transplantation are the only options for cure. When transplantation is an option, sirolimus is one possible immunosuppressive agent. Sirolimus is an approved immunosuppressive agent used primarily for its anti-rejection properties after organ transplantation. Sirolimus is known to inhibit the cytosolic enzyme mammalian target of rapamycin (mTOR) and hamper T- and B-lymphocyte activation.2 Sirolimus is a macrocyclic lactone produced by Streptomyces hygroscopicus via bacterial fermentation.3–6 mTOR has an important role in controlling cell growth and is located downstream in the phosphatidylinositol 3-kinase (PI3K)/Akt pathway.7 mTOR-inhibition is known to reduce angiogenesis by diminishing vascular endothelial growth factor (VEGF).8 In vitro, sirolimus has induced a reduced growth rate of hepatoma.5 In experimental animals, promising retardation of liver tumor growth has been shown.9 A pilot study was undertaken to investigate whether sirolimus had a tumor effect in patients with hepatocellular (HCC) and those with cholangiocellular carcinoma (CCC) who were not candidates for surgical intervention. These cancers differ in terms of their pathogenesis, although mixed
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forms do occur, and common stem-cell etiology is probable,10 yet both were tested in the same setting. Consequently, the data were analyzed in two different cohorts, patients with HCC and patients with CCC, respectively. Sirolimus was given in adjusted doses to maintain a serum concentration level equivalent to levels sought after for anti-rejection purposes after liver transplantation; thereby the drug has an established, well-known profile of side effects. A continuous serum level, as compared to bolus injections, has been correlated, albeit experimentally, with tumor-growth inhibition, especially via the agent’s antiangiogenic effects.11 The serum level utilized in this study was based on experimental findings, but also corresponds with a sirolimus dose that is known to be tolerable (as anti-rejection therapy) in patients transplanted due to malignancy. There is also support that this dose has a growth-inhibiting effect on astrocytomas.12
Patients, materials, and methods Patients and tumors Thirty patients were included in the analysis, 21 in the HCC cohort, and 9 in the intrahepatic CCC cohort. Diagnosis was confirmed histopathologically, with the exception of 1 patient in whom diagnosis was established according to European Association for Study of the Liver (EASL) criteria, with radiologic confirmation of primary liver tumor and an α-fetoprotein (AFP) level of more than 25 000 µg/l. Child-Pugh scores and Karnofsky indices were estimated. Inclusion criteria allowed for the enrolment of patients with HCC or CCC who were not eligible for curative liver resection, liver transplantation, or radiofrequency ablation (RFA) and patients with a performance status Karnofsky score above 60%. Also taken into consideration were the possibilities of patients completing the treatment and follow up with good compliance. The demographics are depicted in Table 1. These inclusion criteria consequently excluded patients with poor performance and those unable to return to the Table 1. Demographics and clinical characteristics of the patients
n Male/Female Age (years), median (range) Child-Pugh score A/B/C Karnofsky score (%) 100/90/80/70/60 TNM classification T1N0M0 T1N1M0 T2N0M0 T2N1M0 T3N0M0 T3N0M1 T3N1M0 T3N1M1
HCC patients
CCC patients
21 18/3 64 (range, 42–74)
9 4/5 57 (range, 38–66)
15/4/2
8/1/0
14/0/3/2/2
5/3/0/1/0
1 0 1 1 12 1 3 2
0 2 0 0 4 1 2 0
hospital where follow up was to be performed. Of the patients with HCC, 14 had cirrhosis on the basis of excessive alcohol consumption, 1 had primary biliary cirrhosis, and 3 had hepatitis C and cirrhosis. Among the CCC patients, 1 had hemochromatosis and 1 had hepatitis B. Standard workup with computed tomography (CT) and/or magnetic resonance imaging (MRI) of the abdomen and thorax, and laboratory tests, including AFP and/or carbohydrate antigen 19-9 (CA 19-9), lipoproteins, and cholesterol were analyzed. Eight patients with HCC had an AFP level below 20 µg/l (Table 2). The TNM-staging of the cancer, as evaluated on CT or MRI, is shown in Table 1. Treatment The median daily dose of sirolimus was 1 mg (range, 0.5– 3 mg). Serum concentrations were measured initially once per week and thereafter at the discretion of the attending doctor. Doses were adjusted to a trough level between 4 and 15 µg/ml. The median number of sirolimus treatment days was 110 days for the HCC cohort and 114 days for the CCC cohort (Table 3). In accordance with standard care for transplantation patients, cancer patients received cytomegalovirus (CMV) prophylactic treatment with antiviral ganciclovir or valganciclovir, as well as prophylaxis against Pneumocystis Table 2. Pretreatment serum concentrations of alpha fetoprotein (AFP) and CA19-9 AFP (µg/l)
HCC patients (n)
CA 19-9 (ng/L)
CCC patients (n)
>5000 1000–5000 200–1000 20–200 10 000 5000–10 000 500–5000 100–500 100 ng/L), two with PD had a temporary decline in the marker.
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Safety Overall, 15 patients (50%) in the study reported no side effects. Eight patients had troublesome oral side effects (aphthous ulcers, stomatitis; Table 3). There were no specific safety events related to the sirolimus therapy, except for the aphthous ulcers. No significant pathologic changes in blood lipids, including cholesterol, were observed in the study population.
Discussion The absence of drug effects in patients with HCC or CCC is a strong incentive for prospective trials with new drugs and new strategies in patients who cannot be operated on with curative intent. The Akt pathway and mTOR may be important in the formation of HCC as well as CCC18,19 The inhibition of these pathways by sirolimus, as well as the inhibition of VEGF, provides additional support for a pilot trial in patients with primary liver cancer.20 There is also evidence in in vitro experiments and in experimental animals that sirolimus inhibits the growth of hepatoma cells.6,9 Based on these facts, the present prospective experimental study was initiated to explore whether the anti-rejection drug sirolimus had a tumor effect in patients with nonresectable primary liver cancer. In this study, a short-term effect on HCC tumor growth with sirolimus was identified, but there was no impact on survival. This statement is based on an impressive tumor regression in one patient who survived for 20 months; a median progression-free period of 6.5 months; and a median survival time of 10 months in five patients with stable disease (SD). One patient experienced a significant decrease in AFP. The dilemma of identifying tumor remission with antiangiogenic therapy is notorious, whereas SD for 6 months must be considered as an appreciable tumor effect. The temporary decline in AFP in three of our patients with radiological PD at 3 months is of interest when discussing a tumor effect. Median survival time from the start of sirolimus therapy was 6.5 months in the HCC cohort, which is within the natural course for untreated HCC patients with a high Karnofsky index and Child-Pugh liver function score A. The median survival time in Sweden after diagnosis for 176 patients with HCC (independent of treatment) was 6.0 months (range, 0.3–76 months; information from the Regional Cancer register of Vastra Gotaland, Sweden, 2000–2005). Previous studies with established drugs with an antiangiogenic profile have shown responses in the same range.21,22 The 21 HCC patients in our study were not eligible for chemoembolization, due to the preference of the patient (2 cases), manifestation of extrahepatic cancer (7 cases), recurrence after resection (1 case), tumor thrombosis in portal vein (8 cases), and unsuitability for chemoembolization as judged by the attending physician (3 cases). This selected cohort study is thus not comparable with the patients in randomized studies showing that chemoembolization prolongs survival.1
The limited side effects of sirolimus, predominantly aphthous ulcers, do not rule out further exploration of its use in patients with HCC. There was one reported early death in the present study; the patient was excluded immediately after inclusion, due to protocol violation, as there was a deterioration in homeostasis, shown in blood tests, but this had not been analyzed before the patient’s inclusion. It remains somewhat controversial to use an immunosuppressive agent in patients with latent hepatitis C. In the present pilot study, no exacerbation of the infection was observed during the treatment. The observation that no effect of sirolimus was registered in the three patients with HCC in a noncirrhotic liver requires the investigation of more patients with similar prerequisites to be confirmatory. For patients with CCC, the short-term effect of SD in three patients and the temporary decrease in CA 19-9 in two patients demonstrate that mTOR inhibition alone will not reduce the progress of the cancer. However, the limited number of patients does not rule out a minor effect. A sirolimus-based immunosuppressive regimen has been used to reduce tumor recurrence in patients who have undergone liver transplantation for HCC.23 Sirolimus posttransplantation could, theoretically, hamper the vascular bed and thus restrict the establishment of a recurring tumor. The results of that study23 do not support the idea that sirolimus alone would suffice as adjuvant treatment. A randomized study is ongoing. As HCC seems to be particularly sensitive to VEGFinduced angiogenesis, sirolimus–which has documented antiangiogenic properties–should be active in HCC treatment. The disease control (PR + SD) demonstrated in 6 patients out of 21 in our study makes sirolimus an attractive treatment approach, particularly in those patients with advanced, multifocal, HCC with portal vein involvement. As the effect of sirolimus, in and of itself, might not be sufficient, a combination with other drugs, aiming for increased antiangiogenic or metallomatrix protein-inhibiting properties might be beneficial. To elucidate the effects of sirolimus, we need to design more studies adovocating analysis of biological effects.
Conclusions A temporary disease-control rate (PR + SD) was identified in the treatment of HCC and CCC with sirolimus. Sirolimus has an acceptable toxicity profile and is associated with a transient, minor patient safety impact. We welcome further trials utilizing mTOR-inhibitors in patients with primary liver cancer.
Conflict of interest statement Per Lindnér reports being an employee of Genzyme Corp. No other conflicts of interest relevant to this article are reported.
70 Acknowledgements The study was supported by grants from the Swedish Cancer Research Foundation (Cancerfonden) no 5029 B06 02xBB. The authors thank nurses Liselotte Hilmersson and Lena Söderberg for their excellent care of the patients, and they thank Laura Fleming for correcting the language.
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