High levels of immunosuppressant may lead to tumor recurrence

A new study on the incidence of liver cancer after transplant found that high levels of the immunosuppressant cyclosporine favored tumor recurrence and identified blood levels of the drug that should not be exceeded. Lower levels of cyclosporine levels did not affect rejection rates.

The results of this study appear in the May 2005 issue of Liver Transplantation, the official journal of the American Association for the Study of Liver Diseases (AASLD) and the International Liver Transplantation Society (ILTS). The journal is published on behalf of the societies by John Wiley & Sons, Inc. and is available online via Wiley InterScience at www.interscience.wiley.com/journal/livertransplantation

Hepatocellular carcinoma (HCC, a type of liver cancer) occurs frequently in patients with chronic liver disease who are listed for liver transplants. However, the immunosuppressants necessary to prevent rejection can accelerate tumor growth, and the incidence of tumor recurrence is high.

Because of this, strict selection criteria of patients with HCC has limited their access to transplants, yet the role of immunosuprressants in tumor growth has not been well established. In a previous study, the authors demonstrated a close relationship between the amount of cyclosporine and tumor recurrence in liver transplant patients.

The current study further examines this association and identifies possible strategies to avoid it.

Led by Marco Vivarelli of the department of surgery and transplantation at the University of Bologna, Italy, the study examined 70 patients who took cyclosporine as the main immunosuppressant following liver transplants between 1991 and 2002. The cyclosporine dosage was determined by the clinician in charge based on clinical and biochemical indications, but without regard to blood levels achieved by the drug after it was administered. HCC recurred in 7 of the patients between 2 and 40 months after transplant. The researchers found that the absence of recurrence was significantly related to blood levels of cyclosporine, which were higher in patients whose tumors recurred. Other factors, such as recipient sex, underlying liver disease, or the use of cyclosporine with other immunosuppressants or steroids did not affect tumor recurrence.

“We provide here further evidence on the key role of immunosuppression in tumor recurrence after liver transplantation; in particular, we recommend that in those patients transplanted for hepatocellular carcinoma who receive CsA–based [cyclosporine] immunosuppression the exposure to the drug should not exceed the daily blood levels that we identified,” the authors state. Since higher and lower levels of cyclosporine did not affect rejection rates, they suggest that minimum dosage levels of the drug can be safely used. In addition, they suggest that immunosuppressive schedules might be tailored to individual patients based on the biology of their tumors, keeping in mind that high-risk patients would probably benefit from keeping cyclosporine levels as low as possible. They conclude that new immunosuppressant drugs shown to have anti-cancer effects are particularly promising for HCC patients.