UNOS DonateLife

October 26, 2005

OPTN/UNOS Data Shows Significant Difference in Cancer Incidence Rates in Transplant Recipients Based Upon Immunosuppression Regimen

Authors: H. Myron Kauffman, M.D., Wida S. Cherikh, Ph.D., Yulin Cheng, Douglas W. Hanto, M.D., Barry D. Kahan, M.D., Ph.D.

Richmond, VA -- In the Oct. 15 edition of the journal Transplantation, a retrospective analysis of data from more than 33,000 renal transplant patients in the OPTN/UNOS (Organ Procurement and Transplant Network/United Network for Organ Sharing) database showed that the relative risk of developing any post-transplant skin or non-skin malignancy is substantially reduced in patients receiving maintenance immunosuppression with mTOR inhibitors as compared to patients receiving treatment with traditional calcineurin inhibitors. This is the largest analysis of its kind, comparing different transplant drug regimens to see if newer drugs have had any impact on the disproportionate malignancy rates seen in transplant recipients.

"People who have a successful organ transplant are unfortunately facing an increased long-term risk of developing de-novo malignancies, and excessive immunosuppression, particularly with certain drugs, is a substantial contributing factor," said Dr. H. M. Kauffman, a Senior Research Scientist at UNOS. "Our study clearly shows that the mTOR inhibitors offer a significant benefit in reducing short-term malignancy rates in transplant recipients."

The retrospective study looked at more than 33,000 people who received a primary solitary kidney transplant between 1996 and 2001. The study authors examined the actual incidence of any de novo malignancies and de novo non-skin solid malignancies by drug regimens divided into three groups -- mTOR inhibitors (SRL/EVL), mTOR inhibitors plus a calcineurin inhibitor (SRL/EVL + CYA/TAC), or a calcineurin inhibitor alone (CYA/TAC). Only three patients taking mTOR inhibitors alone had a de novo malignancy, and there were no non-skin solid malignancies in this group. In contrast, there were 552 de novo malignancies in the calcinuerin inhibitor group, with 304 de novo non-skin solid malignancies.

Only 0.6% of those treated with the mTOR inhibitors (more than 97% receiving sirolimus) developed new cancers during the two years of follow up. This was significantly lower than patients treated with calcineurin inhibitors (cyclosporine or tacrolimus, 1.81%; p<0.001). In a risk adjusted multivariate analysis, patients treated with mTOR based immunosuppressant therapy had a 59% reduced relative risk of developing new cancers (relative risk 0.412, 95% CI 0.256, 0.663) than those given calcineurin-based therapy.  This was a highly significant reduction in relative risk (p=0.0003).

Animal evidence suggests that conventional calcineurin immunosuppression promotes rather than inhibits the development of cancer. Calcineurin inhibitors have been shown to induce cancer progression and increase transforming growth factor-B (TGF-B) expression that is associated with cellular changes that are characteristic of invasiveness. In contrast, mTOR inhibitors appear to have a negative growth effect on malignant cells. mTOR inhibitors, in animals, reduce TGF-B and vascular endothelial growth factor (VEGF) expression and inhibit tumor angiogenesis.

About Malignancies and Transplantation

Several recent studies have documented the risk of developing post-transplant malignancies. In a 1993 study of kidney patients surviving at least 10 years, malignancies caused 26 percent of deaths. A more recent University of Pittsburgh study of alcoholic liver recipients reported that 24 percent of deaths occurring after one year were caused by non-lymphoid de novo malignancy. A similar report on cardiac transplant recipients indicated that 21 percent of deaths occurring after two years were due to malignancies.

Transplant recipients have an increased risk of developing cancer in general (one to two percent per year) and a 15-20 fold higher incidence of certain types of cancer. The general incidence of all malignancies after kidney transplantation increases with advancing time and seems to be dependent on both duration and intensity of immunosuppression.

Skin cancer and post transplantation lymphoproliferative disorders such as non-Hodgkin's lymphoma are the most prevalent types of cancer seen post transplantation. The risk of cervical, breast cancer and colorectal cancer are also increased.

About UNOS

A private, nonprofit organization, UNOS manages the nation's organ transplant system and oversees the world's most comprehensive database of clinical transplant information under contract with the federal government. UNOS operates the 24-hour computerized organ sharing system, matching donated organs to patients registered on the national organ transplant waiting list. UNOS seeks to increase organ donation through education and improve transplant success rates through outcomes-based research and policymaking. The strength of the transplant database relies on the conscientious reporting of 470 UNOS member institutions.