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For Organ Transplant Recipients, Cancer Threatens Long-term Survival
Transplant recipients are three to four times more likely to develop cancer than the general population, and those that do get cancer face a much greater chance of dying from their disease.
Among kidney and heart recipients who have survived at least 3 years after a transplant, cancer is poised to become the leading cause of death over the next 20 years, said Joseph Buell, M.D., of the University of Louisville Jewish Hospital.
However, promising early studies indicate that a relatively new immunosuppressant medication called sirolimus may help keep cancer among transplant recipients in check.
"I truly believe [sirolimus] will have an effect on cancer," said Edward Geissler, Ph.D., of the University of Regensburg Medical Center in Germany.
Immunosuppressants make transplantation possible by warding off the body's rejection of the foreign organ, but they inevitably contribute to the development of cancer. Reining in the immune system protects the transplanted organ, but at the same time immunosuppressants cripple immune responses that can attack incipient tumors. Unfortunately, the most commonly used immunosuppressants, calcineurin inhibitors such as cyclosporine and tacrolimus, also have carcinogenic effects that go beyond immunosuppression. For example, a 2001 study by Michal Herman and colleagues from the Rabin Medical Center–Golda Campus and Tel Aviv University in Israel showed that white blood cells from kidney transplant patients taking cyclosporine were less able to repair DNA damage.
Furthermore, "once you have cancer, cyclosporine makes it more aggressive" by promoting blood vessel growth within the tumor and invasion of the tumor into surrounding tissues, Geissler said. Currently, nearly all transplant recipients take a calcineurin inhibitor; in 2004, 21% of transplant recipients in the United States received cyclosporine at the time of their transplant, and 72% received tacrolimus. Approximately 20% of transplant recipients will develop at least one cancer after 10 years of immunosuppressive therapy.
Sirolimus, in contrast, has anticancer as well as immunosuppressive properties. Both effects stem from its ability to inhibit an intracellular signaling molecule called mTOR. mTOR regulates a diverse array of processes, including immune cell proliferation and blood vessel growth in tumors. That means silencing mTOR both blocks the immune responses that lead to organ rejection and hampers tumor growth. The U.S. Food and Drug Administration approved sirolimus as an immunosuppressant in transplant recipients in 1999, and several clinical trials are currently under way testing sirolimus in cancer patients without transplants. Results of a phase III trial presented at the 2006 annual meeting of the American Society of Clinical Oncology demonstrated that temsirolimus, a sirolimus derivative, was better than the current first-line therapy for advanced kidney cancer.
An epidemiological study by H. Myron Kauffman, M.D., of the United Network for Organ Sharing in Richmond, Va., and colleagues hints at sirolimus’ potential to reduce cancer rates in the transplanted population. Analyzing data on more than 33,000 kidney transplant recipients, they found that patients whose immunosuppressive regimen included sirolimus or a closely related drug called everolimus were 60% less likely to get cancer within an average of 2.6 years after their transplant than those who used only calcineurin inhibitors. Kauffman points out that cancer was still more common in the sirolimus/everolimus group than in the general population and that the follow-up time was short—the cancer incidence increases dramatically with increasing time after the transplant. But the results indicate that sirolimus may be a valuable asset in the effort to reduce the use of carcinogenic calcineurin inhibitors.
So far, sirolimus is not a first-line immunosuppressive medication. Because the drug is relatively new, Kauffman said, "transplant surgeons are still feeling their way on how best to fit [it] into the overall drug armamentarium." Geissler estimates that only about 5%–10% of transplant patients take sirolimus or one of its relatives, almost always in combination with other immunosuppressants.
By contrast, calcineurin inhibitors have been in use since the early 1980s, and doctors trust them. "The fact is that calcineurin inhibitors work well in the short term. They are the standard of care, so it's very difficult to change a nephrologist's mind about that point," Geissler said. Plus, sirolimus has disadvantages of its own, including negative side effects: It can impair wound healing and, without proper precautions, may cause vascular complications after liver transplants.
Although not yet widely used, sirolimus has shown great promise for transplant patients who develop cancer or for those at especially high risk. In two small studies, kidney transplant recipients who got Kaposi sarcoma, a blood vessel cancer, switched from calcineurin inhibitors to sirolimus. All the patients—15 in one study and seven in the other—recovered completely from the cancer while their transplanted kidneys continued to function well. However, Geissler said, Kaposi sarcoma may be the "perfect tumor" to combat with sirolimus because of the drug's strong negative effect on blood vessel growth; other types of cancers that transplant recipients are likely to get, including skin cancer, lymphoma, and tumors of the genitals, may not respond as well.
When kidney transplant recipients develop cancer, doctors generally advise them to stop all immunosuppressive medications; most then reject their transplants and must return to dialysis. Anil Kumar, M.D., of Drexel College of Medicine in Philadelphia found that several of his patients balked at this recommendation. "These patients did not want to go back to dialysis at any cost," Kumar said. Some had accumulated several years’ supply of their medications and indicated that they planned to continue taking them, he said.
To help these patients, he and his colleagues started an experimental protocol that involved aggressive treatment for the cancer and a switch to sirolimus for immunosuppression. Thirty-two patients with a variety of cancers have participated so far; in all cases, the cancer went into remission and has not reoccurred during 2–8 years of follow-up. Kumar's group is also testing sirolimus in other transplant patients at high risk of cancer, including those who have had cancer in the past and those who received a kidney from a donor that has had cancer. Although the number of patients enrolled in these studies is still small, the preliminary results are positive.
More definitive data on the benefits of sirolimus for transplant recipients at high risk of cancer should come to light in the next few years when two large international studies are completed. One, led by Jeremy Chapman, M.D., of the University of Sydney in Australia, is testing sirolimus in transplant patients who develop squamous cell cancers, including skin, colorectal, and genital cancers. Researchers hope to enroll 600–800 patients. The second study, led by Geissler's group in Regensburg, will give sirolimus to patients with a history of liver cancer who receive liver transplants. In the meantime, Geissler said, "if I had a family member who had a transplant and had cancer, I definitely would switch to [sirolimus] because I think there is good evidence right now, although not proof, to suggest that it can inhibit tumors."
Overall, early experiences with sirolimus have led experts to be cautiously optimistic.
"The drug is good for a lot of reasons, but it's not without its complications," Buell said.
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