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Stem Cell Transplants for Patients with Kidney Cancer Patients with renal cell carcinoma, a form of kidney cancer, may have a new treatment option. Preliminary results of several small studies suggest that moderate dosages of chemotherapy, followed by a blood stem cell transplant, may shrink tumors in patients with metastatic (cancer that has spread to other parts of the body) renal cell carcinoma. Researchers at the National Heart, Lung and Blood Institute (NHLBI), who pioneered this treatment and have the largest experience to date, first reported their findings in September, 2000 in the New England Journal of Medicine. Nine of 19 patients who had an advanced form of renal cell carcinoma, and who had failed conventional therapies, were alive 287 to 831 days after treatment. The patients had received moderate dosages of cyclophosphamide and fludarabine, and were then transplanted with stem cells from a sibling. Since that report, a total of 54 patients have been treated with a similar therapy, says Richard Childs MD, who heads the research at the NHLBI. Twenty-two remain alive 6 months to four years after treatment. "Those who have responded to this therapy have all had clear cell histology, a subtype of kidney cancer," says Childs. "We have yet to see responses in patients with other sub-types of kidney cancer." Mini Transplant The type of transplant being offered to patients with renal cell carcinoma at the National Heart, Lung and Blood Institute and other research hospitals is called a "mini" or non-myeloablative transplant. Patients receive lower dosages of chemotherapy than those given patients who undergo a standard stem cell transplant. As a result, they experience fewer side effects from the drugs, and have a lower risk of infection than standard transplant patients. Patients enrolled in the NHLBI clinical trial receive moderate dosages of cyclophosphamide and fludarabine and then are infused with stem cells from a sibling. Although the moderate dosages of chemotherapy do not destroy the patient's cancer cells, the donor's white blood cells will attack the cancer cells after being infused into the patient. "The donor's white blood cells learn to recognize what cells belong in the patient's body," explains Childs. "They identify the cancer cells as foreign cells, and launch an immune system attack to destroy them. This is called the graft-versus-tumor effect." Unfortunately, the donor's white blood cells often perceive the patient's healthy organs and tissues as foreign cells that should be destroyed as well. When this situation occurs, the donor's white blood cells orchestrate an immune system attack on the patient's skin, stomach liver, intestines and/or lungs. This is called graft-versus-host disease (GVHD). Depending on the severity of the disease, GVHD can be a temporary irritation or life threatening. To reduce a patient's risk of developing severe GVHD, patients at the NHLBI are given cyclosporine and mycophenolate mofetil. Although this combination of drugs appears to be more effective in preventing severe GVHD than cyclosporine alone, using the drug combination can prolong the time it takes for the disease to regress, says Childs. "It's a difficult balancing act to give patients enough medication to prevent severe GVHD while, at the same time, allowing the donor's white blood cells to remain potent enough to kill the cancer cells," he notes. Most patients who have been treated with this novel therapy at the NHLBI have had only a partial response to the treatment. However, researchers view these early results as promising, and expect to open a new clinical trial in a year or so that will attempt to train the donor's immune cells to specifically target the patient's cancer cells, an outcome that would decrease toxicity while increasing efficacy, says Childs. The Houston Experience Researchers at MD Anderson Cancer Center in Houston TX have also been researching the usefulness of mini transplants to treat patients with metastatic renal cell carcinoma. In their program, patients receive higher dosages of chemotherapy than patients treated at the NHLBI. "Our hypothesis is that these stronger dosages of chemotherapy may better control the disease," says Nato Ueno MD, who heads the research. "It also enables us to use stem cells from unrelated donors and cord blood," he adds. Patients receive a combination of fludarabine and melphalan before being infused with donor stem cells. Tacroclimus and low dosages of methotrexate are given after transplant to control GVHD. To date, eleven patients with metastatic renal cell carcinoma have undergone this treatment. One had a nearly complete response to the treatment, four had no progression of their disease, three did not respond to the therapy, and three were treated too recently to evaluate the outcome. Eight remain alive 37 to 633 days after treatment. Other Research Researchers at a number of hospitals throughout the US are now exploring the possibility of treating patients who have advanced renal cell carcinoma with a mini-transplant. Researchers at the University of Chicago have treated 17 patients who have renal cell cancer with a mini-transplant. Patients received fludarabine and cyclophosphamide prior to transplant. Four achieved a partial response to treatment and are alive eight months to two years after treatment. Four died of transplant-related complications, and six developed extensive cases of GVHD. At the Fred Hutchinson Cancer Research Center in Seattle, researchers have treated six renal cell cancer patients with very low dosages of total body irradiation and fludarabine, followed by a stem cell transplant using cells from a related donor. One patient has survived with no progression of disease for 20 months, and another has had a very good partial response, says Brenda Sandmaier MD who heads the study. Thus far, one patient has died and the others have been treated too recently to evaluate the results, she says. A second study at the Fred Hutchinson Cancer Research Center, headed by Michael Maris MD, offers a similar therapy to patients using stem cells from an unrelated donor. Thus far, one patient with renal cell carcinoma has been treated with this therapy and is alive 40 days after transplant. Researchers at two other facilities-New York Medical College and UCLA -are investigating the use of pentostatin, rather than fludrabine and total body irradiation, prior to transplant in patients with advanced kidney cancer. In a new study at the Scripps Clinic in La Jolla, California patients will receive cladribine and total lymphoid irradiation, instead of total body irradiation, prior to transplant. Irradiating only the major lymphoid areas is less toxic in the short and long term, says James Mason MD, who directs the stem cell transplant program. Researchers at the Fox Chase Center and Temple University in Philadelphia are beginning to enroll patients in a clinical trial that uses fludarabine and total body irradiation prior to transplant. Patients who develop chronic graft-versus-host disease will be given thalidomide, a drug that has shown some activity against renal cell carcinoma in preliminary studies, says Kenneth Mangan MD who heads the trial. A Note of Caution More than two dozen hospitals now offer stem cell transplants to patients with renal cell cancer, according to data reported to BMT InfoNet in 2001. However, NHLBI's Richard Childs MD urges caution when considering this treatment option. "While early results have been promising, this technique needs perfecting before it can be considered for randomized trials that compare it to standard therapies for renal cell carcinoma," says Childs. "I liken this research to early attempts to fly at Kitty Hawk: we've gotten a few feet off the ground, but it will take a lot more time and research before we know whether this therapy can really fly." Useful Resources Information about ongoing clinical trials to treat renal cell cancer can be found at http://clinicaltrials.gov, on the website of the National Institutes of Health. The Kidney Cancer Association also maintains an online list of clinical trials for patients with renal cell carcinoma. This information, as well as publications about renal cell carcinoma can be obtained from their website www.kidneycancerassociation.org or by calling toll free at 800-850-9132.
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