Although the 1-year survival rate after liver transplantation has risen dramatically, patients may be finding themselves at an increased risk for de novo cancer. The risk for de novo cancer in liver transplant recipients is estimated to be from 2.1 to 4.3 times higher than in the general population. Now, Dutch researchers report that treatment with cyclosporine is a significant risk factor for its development.

Reporting in the July issue of Liver Transplantation, the researchers found that cyclosporine, in comparison with tacrolimus, was the most important risk factor for de novo malignancy after the transplant procedure.

However, this higher cancer risk, note the authors, was not observed in all patients who received immunosuppressive treatment with cyclosporine. Rather, cyclosporine specifically enhanced the development of cancer in patients who were younger than 50 years and who underwent transplantation more recently (2005 – 2007).

In addition, the authors also point out that cyclosporine not only increased the risk for cancer but also was associated with the development of more aggressive malignancies, with 1-year survival rates of less than 30%.

No Change in Practice

Although early survival after liver transplantation has significantly improved, long-term survival (>10 years) is less well-defined and studied, comment the authors of an accompanying editorial. The increased risk for de novo malignancy after transplantation is a particular cause for concern, and they note that in part this may be the “result of an important trade-off to preserve early survival: trading reduction in acute rejection for relative oversuppression of immune surveillance.”

“An ideal immunosuppressive regimen would minimize the risk of acute rejection while maximizing long-term survival,” write James M. Abraham, MD, and Julie A. Thompson, MD, MPH, both from the University of Minnesota, Minneapolis. “Current immunosuppressive regimens are far less aggressive than they were in the early years of transplantation, but it is clear that current techniques still leave patients with risk of de novo malignancy.”

There has been some controversy as to the carcinogenicity of cyclosporine and tacrolimus, and as to which agent carries a higher risk for future cancer development, the editorialists point out. Some studies have shown cyclosporine to carry a higher risk, but it has not yet been definitively proven.

The current study is a small, single-center, unblended, retrospective one, and although the goal of “limiting immunosuppressant exposure to reduce future cancer risk via alternative drug level monitoring are important, conclusions necessitating a change in current practice cannot be drawn,” write Dr. Abraham and Dr. Thompson.

However, the current study does draw much-needed attention to concerns about overall immunosuppressant exposure and its relationship to long-term outcomes after liver transplantation, the editorialists note. These data serve as a call to reassess the aggressiveness of current immunosuppressive regimens.

“A question remains as we move forward: must cancer and rejection remain mutually exclusive?” the editorialists ask.

A question remains as we move forward: must cancer and rejection remain mutually exclusive?

Cyclosporine an Independent Risk Factor

In this study, Angela S. W. Tjon, MD, and colleagues from the Erasmus MC University Medical Centre, Rotterdam, the Netherlands, sought to determine the risk factors for de novo cancer after a liver transplantation and conducted a retrospective analysis that included 385 patients who underwent transplantation between 1986 and 2007.

Of this cohort, a total of 50 patients (13.0%) developed de novo malignancy. The cumulative incidence of de novo cancer at 1 year after transplantation was 2.9%, at 5 years it was 10.5%, at 10 years it was 19.4%, and at 15 years it was 33.6%. Overall, the standardized incidence ratio of transplant patients compared with that of the general population was 2.2.

Patients who developed de novo malignancy had a significantly shorter survival compared with those who remained cancer-free. Survival at 10 years after a cancer diagnosis was 50.8% vs 79.0% in the cancer-free group (P < .001).

After univariate analysis, the authors found that younger age (P = .025), immunosuppressive treatment with cyclosporine (P = .035), and the time of transplantation (P = .049) emerged as significant risk factors.

When a multivariate analysis was conducted, however, only cyclosporine treatment remained as a significant risk factor (P = .029) for de novo cancer. The effects of both age and treatment period were related to cyclosporine treatment and were not independent risk factors on their own.

Risk Possibly Related to Change in Monitoring

Another interesting finding was the increased cancer risk in patients who underwent transplantation after 2004, the authors note. Patients who underwent transplantation between 1989 and 1992 had a significantly higher risk for cancer (P = .004), but the rate declined considerably after that. However, among patients who underwent transplantation in the most recent period of 2005 to 2007, the incidence of de novo malignancy was increased.

Patients transplanted during this later period experienced a significantly higher rate of de novo malignancy during the first 4 years postprocedure compared with those transplanted during 2001 to 2004. The rise in cancer incidence was particularly high in the first year after transplantation — 7.2% in 2005 to 2007 compared with 1% during 2001 to 2004.

The authors also note that they could not find a difference in the cancer rate between cyclosporine- and tacrolimus-treated patients before 2005. “Most striking was that cyclosporine patients who underwent transplantation since 2005 showed a significantly higher de novo cancer risk in the early phase after liver transplantation, compared to the tacrolimus treated patients, which was 9.9-fold (95% CI=1.2-80.5, P= 0.032) higher,” they write.

The only explanation for the rise in de novo cancer appears to be a change in monitoring cyclosporine blood levels. Beginning in January 2005, monitoring blood concentration at 2 hours postdose (C2 monitoring) was introduced, whereas C0, or trough drug blood level, monitoring had been previously conducted for cyclosporine. As cyclosporine serum monitoring was the only major change made in the recent period, the data suggest that the C2 monitoring strategy was the reason for the increase in early de novo cancer risk, the authors note.

“Collectively, these observations indicate that dosing of cyclosporine based on cyclosporine-C2 monitoring results in more robust immunosuppression compared to treatment based on cyclosporine-C0, which consequently might impair immunosurveillance of developing malignancies,” they write.

The study has its limitations, including a retrospective design, a limited number of patients, and the lack of opportunity to compare C0 and C2 treatment within the same time period. Larger randomized trials with long-term follow-up are needed to confirm this hypothesis, they conclude, adding that a randomized trial that is going on right now comparing tacrolimus with cyclosporine-C2 in hepatitis C–related liver transplant patients might provide support for this finding.