Patience, especially in research, pays off.
Few groups know this better than the National Wilms Tumor Study Group, a pediatric oncology research consortium whose Data and Statistical Center is housed in the Public Health Sciences Division.
For 32 years, the group has tracked 10,379 survivors of Wilms tumor, a kidney cancer that is the most common solid tumor in children.
This almost unprecedented level of follow-up for a childhood disease has helped boost survival rates and yielded insight into potential long-term effects of radiation and chemotherapy on subsequent development and health of these children.
The group's staggering 10 gigabytes of follow-up data - the largest collection in the world of information on survivors of Wilms tumor - also has provided scientists with a unique resource to study the epidemiology and genetics of the disease, said Dr. Norman Breslow, Data and Statistical Center director and a University of Washington professor of biostatistics.
"The database allows us to determine long-term consequences of therapy, including rare, life-threatening outcomes such as second tumors, congestive heart failure and kidney failure," he said.
"It also enables us to determine the effects of treatment on adverse pregnancy outcomes, such as low birth weight or fetal malposition. We've also begun to look at genetic factors that may predispose some individuals to the disease."
The group even plans to take the study into the next generation, adding the offspring of Wilms tumor survivors to the follow-up program.
Wilms tumor accounts for about six percent of all childhood cancers in the United States and is distinct from adult forms of kidney cancer. With proper treatment - which has largely been determined by the study group - about 90 percent of patients survive and go on to lead relatively normal lives. Therapy typically involves surgical removal of the tumor followed by chemotherapy, with or without radiation therapy.
The National Wilms Tumor Study Group, whose members include oncologists, pathologists and surgeons, was established in 1969 to develop and evaluate effective treatments for the disease. A major focus of the Data and Statistical Center, established by Breslow, is to carry out follow-up research on the epidemiology and genetics of the disease as well as long-term effects of treatment.
The study group has led four clinical trials - and is in the midst of its fifth - to determine which drugs or drug combinations are most effective and to minimize the amount of radiation used in treatment. More than 400 children enter the study each year, representing about 70 percent of the total Wilms cases in the United States.
Anti-cancer drugs and radiation don't just target cancer cells. They also can damage healthy cells, particularly those that undergo continual cell division. Potential effects of such therapies, which can include development of secondary cancers later in life and decreased reproductive potential, may be more pronounced in younger patients.
A key achievement of the clinical trials has been to minimize the long-term toxicity of therapy, Breslow said.
"When we started the study in 1969, standard treatment for all Wilms Tumor patients included 40 gray (a unit to measure the absorbed dose) of radiation therapy following surgery," he said.
"Over the years, we have documented the adverse effects of such massive doses of radiation given to young children on skeletal and muscle development, second tumors including breast, colon and primary liver cancers at relatively young ages, and, in the case of female patients, adverse pregnancy outcomes.
"Today, fewer than 40 percent of patients receive radiation therapy and those who do typically receive only 10 gray. We have every reason to believe that this has drastically reduced the unfavorable long-term consequences, and part of the rationale for continued follow-up is to document this improvement."
The research has improved patient access to good health care, said Pat Norkool, project manager of the Data and Statistical Center.
"Many people don't live within easy commuting distance of a hospital that participates in our clinical studies," she said. "The treatment regimen used to consist of five days of chemotherapy repeated over the course of several months. But our research has shown that the treatment can be given in single doses. This makes it much easier for many children to get the best therapy by decreasing the length of admissions, which also saves hundreds of thousands of dollars."
Among Norkool's responsibilities as project manager of the data center is to field inquiries from patients and parents. Some 5,000 patients are under active surveillance.
"We continue to follow the patients even after age 18, at which time we must get their consent to continue participation directly rather than from their parents," she said. "Often when they are in high school and college, they aren't interested in the study. But when they are ready to have children of their own, they become interested."
The reason, Norkool said, is that radiation therapy, particularly the higher doses given before doctors understood its long-term consequences, can impact reproductive ability, particularly in women.
"Women who had early abdominal therapy can experience some reproductive problems," she said. "If we can let them know about this, it's information they can share with their doctors."
Breslow's research interest is to understand why and how children develop the disease. Only a small percentage of cases are thought to be inherited.
"We recently worked with a group of researchers at the Dana Farber Cancer Institute to study the rate of inherited mutations in the WT1 gene, the first - and, to date, only - Wilms tumor gene that has been cloned," he said.
"We found these mutations occurred in fewer than 10 percent of patients and that the mutations that did occur were concentrated largely in three rare subgroups of patients who have syndromes that predispose them to additional diseases."
With Dr. Vicki Huff at M.D. Anderson Cancer Center, Breslow and colleagues hope to pinpoint the chromosomal location of another Wilms tumor gene implicated in some hereditary cases of the disease.
In 2003, the next clinical trials for Wilms tumors will be conducted by the recently formed Children's Oncology Group, a consortium initiated last year by the merging of several smaller groups.
The National Wilms Tumor Study Group study on late effects will continue to be conducted by the Data and Statistical Center as an independent project funded by a National Institutes of Health renewal grant awarded last month.