Doctors claim use of a common immune-suppressing drug following liver transplantation may boost the risk of cancer recurrence in patients.¹

The medication is known as cyclosporine, which has emerged as a common immunosuppressant following liver transplant. Immunosuppressants have played a crucial role in the success of liver transplantation, significantly contributing to improved survival rates.²

Hi-Dose Immunosuppression and Cancer
However, in a new study from Italy, a group of physicians found that high doses of the drug after transplant increased the risk of liver cancer recurrence. The group established a dose threshold that should not be exceeded and noted that lower levels of the drug had no effect on liver rejection in the patients studied.

According to the investigators led by Marco Vivarelli, MD, of the department of Surgery and Transplantation at the University of Bologna, liver cancer—known medically as hepatocellular carcinoma—occurs frequently in people with chronic liver disease who are listed for liver transplant. But the immune-suppressing medications needed to prevent rejection of the new liver after the operation can boost the risk of tumor growth. Because of this, selection criteria for these patients are very strict, resulting in their limited access to these transplant procedures.

In a previous analysis,³ Vivarelli's group identified a close relationship between a specific dose of cyclosporine and hepatocellular carcinoma recurrence in liver transplant patients. The current analysis went one step further, more closely examining this association and identifying possible strategies to avoid it.

"We provide here further evidence on the key role of immunosuppression in tumor recurrence after liver transplantation," Vivarelli and his colleagues wrote. "In particular, we recommend that in those patients transplanted for hepatocellular carcinoma who receive [cyclosporine] immunosuppression, the exposure to the drug should not exceed the daily blood levels that we identified."

Establishing the Dose in Question
Vivarelli's team retrospectively examined a group of 70 people who had been given cyclosporine as the key immunosuppressant following liver transplants they'd received over a 10-year period. The dose of the medication given to each patient had been determined by the clinician in charge, based on several clinical and biochemical indications. However, levels of the medication in each person's bloodstream had not been measured after it was administered. "The cyclosporine administration schedule was not aimed at reaching an established blood level of the drug, but was determined by the clinician in charge on the basis of the clinical and biochemical picture of the patient," the research team wrote.

The researchers make a point that the increased risk of cancer recurrence can be avoided below a certain blood level of cyclosporine after it is given to a patient. Based on statistical analysis, they found that blood levels of the drug above 189.6 ng/mL (nanograms per milliliter) were significantly related to liver cancer recurrence in these patients.

Vivarelli and his associates learned that hepatocellular carcinoma returned in seven of the patients between 2 and 40 months after transplantation, and that they were significantly related to certain levels of cyclosporine in the blood. "Cyclosporine was higher in those patients who experienced tumor recurrence compared with patients who remained tumor free," the investigators wrote.

Other factors, such as the sex of the recipient, the recipient's age, underlying liver disease, the type of liver tumor noted or the use of cyclosporine in combination with other immunosuppressants or steroids had no effect on the tumor recurrence rate.

Recommendations
Since neither higher nor lower levels of cyclosporine affected the odds of liver rejection in these patients, Vivarelli and his colleagues suggest that minimum doses of the drug can be safely used to avoid the risk of cancer recurrence while still effectively staving off the possibility of rejection.

Further, the study team recommends that physicians design immunosuppressive schedules for individual patients based on the makeup of their tumors, keeping in mind that high-risk patients would likely benefit from keeping cyclosporine levels as low as possible. "[Cyclosporine] blood levels should be kept to the effective minimum in hepatocellular carcinoma patients," they wrote.

"In our study, the incidence of acute and chronic rejection did not differ between patients with higher and lower [cyclosporine] blood levels, which strengthens the importance of avoiding unnecessary overimmunosuppression," wrote the investigators.

In the meantime, they underscore the development of newer immune-suppressing medications in the pipeline that may provide significant anti-cancer effects. These, they say, are particularly promising for liver cancer patients who are candidates for transplantation.

1. Vivarelli M, Cucchetti A, Piscaglia F et al. Analysis of risk factors for tumor recurrence after liver transplantation for hepatocellular carcinoma: key role of immunosuppression. Liver Transpl 2005 May;11(5):497-503.
2. Furukawa H, Todo S. Evolution of immunosuppression in liver transplantation: contribution of cyclosporine. Transplant Proc 2004 Mar;36(2 Suppl):274S-284S.
3. Vivarelli M, Bellusci R, Cucchetti A et al. Low recurrence rate of hepatocellular carcinoma after liver transplantation: better patient selection or lower immunosuppression? Transplantation 2002 Dec 27;74(12):1746-51.

John Martin is a long-time health journalist and an editor for Priority Healthcare. His credits include coverage of health news for the website of Fox Television's The Health Network, and articles for the New York Post and other consumer and trade publications.