© Oxford University Press 2006.
NEWS |
Late Effects of Pediatric Cancer Treatment Come Into Sharper Focus, Predictive Tests Are Emerging
Pediatric oncologists have known for some time that their patients, most of whom now survive into adulthood, can face serious, treatment-related health problems years after therapy. But the details of these so-called late effects—such as what doses of which treatments affect which patients—are still emerging.
Large databases of late effects are now making it possible to get a fix on these details and at the same time are spurring new research on interventions to prevent and manage late effects. Researchers are also beginning to look at ways to predict which survivors will be affected, envisioning a time when clinicians will be able to use biomarkers to tell childhood cancer survivors what effects to expect and how best to deal with them.
"Ultimately we will be able to have prognostic algorithms, taking into account the drug, age, doses, markers, and so on, as the number of cases grows," said Charles Sklar, M.D., a longtime researcher in this field and director of the Long-Term Follow-Up Program for childhood cancer survivors at Memorial Sloan-Kettering Cancer Center in New York.
|
Sklar is lead author of a study in this issue of the Journal (see p. 890) that helps illustrate where research on childhood cancer late effects is headed. The study provides new, detailed information on early menopause, a late effect besetting many women who were treated for childhood cancers that puts them at higher risk of osteoporosis and heart disease, as well as infertility and psychosexual problems.
Sklar and his colleagues were able to quantify the risk of early menopause associated with particular treatment regimens and doses. They report that the risk of nonsurgical early menopause was 13 times higher in a group of 2,819 survivors than in a control group made up of 1,065 survivors' sisters who did not have cancer. The risk increased with higher doses of radiation to the abdomen and pelvic area and alkylating chemotherapy agents. For survivors treated with both alkylating agents and abdominal–pelvic radiation, the risk of nonsurgical early menopause approached 30%.
"This is a study where we have very detailed information about therapy so we were able to ... demonstrate a clear dose–response relationship," said Sklar. "It helps us to understand the relationships in a more sophisticated way, with information that is more reliable and more precise."
The growing reliability and precision of data on late effects stems from major follow-up efforts that began in the 1990s. Sklar and his colleagues used data compiled by the Children's Cancer Survivorship Study, an ongoing project that is tracking 14,370 5-year survivors and 3,737 sibling control subjects at 26 clinical centers in North America. Launched in 1994, the CCSS so far includes survivors diagnosed from 1970 through 1986.
The CCSS database contains detailed information on long-term survivors and tracks dozens of late effects. Some of the most common are second cancers, cardiovascular disease, growth retardation, and neurocognitive problems, but there are many others. The Children's Oncology Group (COG) lists problems ranging from dental abnormalities, cataracts, and hearing loss to testicular dysfunction, seizures, pulmonary fibrosis, obesity, depression, and infertility in its late-effects management guidelines.
Moreover, late effects are not rare among survivors. An Institute of Medicine report in 2003 said that as many as two-thirds of childhood cancer survivors are likely to experience at least one late effect, with perhaps one-fourth experiencing an effect that is severe or life threatening.
Biomarkers for Risk
As details about late effects come into sharper focus, researchers are envisioning even more precise estimates of risk, based on biomarkers. For instance, one next step in managing the risk of early menopause, Sklar said, will be to look for possible biomarkers, such as, inhibin B and antimullerian hormone, to see if their levels can predict whether a woman will experience this late effect.
If a link is found, as suspected, the markers will give a woman a much better idea of whether she will have an early menopause and help her plan childbearing and health care accordingly. "We need to fine-tune our models so that we can give women better advice," Sklar said.
Zeroing in on individual risk for specific late effects is also the aim of a whole new generation of studies on genetic susceptibly, said Barry Anderson, M.D., Ph.D., scientific coordinator for the CCSS at the National Cancer Institute in Bethesda, Md., which funds the study. "If it were possible to predict who was at high risk for a late effect, that would then allow physicians and patients to tailor follow-up, perhaps even modify the initial treatment," he said.
In pursuit of this goal, the CCSS is now collecting specimens from participants—buccal cells from the inner cheek and lymphoblastic cells—to establish a repository for biomarker studies. Also, the Children's Oncology Group has begun to bank DNA and RNA from patients with key late effects (congestive heart failure, second malignancies, stroke, myocardial infarction, and avascular necrosis) and matched control subjects.
One recent CCSS study of genetic variations may explain why some childhood cancer survivors are susceptible to heart disease after treatment with chemotherapy drugs called anthracyclines. Richard Aplenc, M.D., of the University of Pennsylvania School of Medicine in Philadelphia, reported that variations in genes that control the metabolism of anthracyclines and others that control the elimination of oxygen free radicals were associated with increased risk of congestive heart failure in a CCSS cohort treated with anthracyclines.
Aplenc noted that the findings needed replication but also were just the beginning of exploration in this area. "We only looked at a few genes within these pathways," he said, speaking at the June meeting of the American Society for Clinical Oncology, where he presented the findings. "We'd like to expand that."
So far there has been only one other published study of genetic susceptibility, in the September 2004 issue of the Journal of Clinical Oncology, showing that a genetic change in the leptin receptor gene is associated with increased risk of obesity among survivors of childhood acute lymphoblastic leukemia, especially those who received cranial radiation. But many other studies are in the planning stage, said Sklar, who has been involved with the CCSS since its inception.
The authors of the leptin gene study, Julie Ross, Ph.D., and colleagues from the University of Minnesota in Minneapolis, suggest that identifying children at high risk for obesity could lead to early, targeted interventions. Developing interventions is another important research direction for childhood cancer survivors, said Smita Bhatia, M.D., a pediatric oncologist at the City of Hope in Duarte, Calif., and chair of the Children's Oncology Group Late Effects Committee.
"We need to be actively engaging in research on interventions now," she said.
Potential interventions include chemoprevention and lifestyle modifications to reduce the risk of second cancers and aggressive screening regimens for those at high risk of late effects, she said. One current CCSS study, for instance, is looking at mammography screening for survivors at increased risk of breast cancer and another is assessing smoking cessation education among survivors.
One overarching goal for CCSS researchers is to expand the patient base. The database now includes patients diagnosed between 1970 and 1986. Treatments have changed substantially since then, said Bhatia and Sklar, and the risk of developing late effects is expected to be different in patients diagnosed and treated more recently.
The CCSS has proposed enlarging its patient base to include more than 14,000 5-year survivors diagnosed between 1987 and 1999 along with about 4,000 more sibling control subjects. The new cohort would include extra patients whose treatment differed from that of the earlier group and ethnic/racial minorities. This expansion of the CCSS cohort is in the planning stage, NCI's Anderson said.
Increasing Awareness
Other ongoing research focuses on implementing guidelines for screening for and managing late effects once survivors enter the world of adult medicine. COG developed such guidelines in 2003, following a recommendation from the IOM, and the latest version was due out last month.
Now it's important to learn more about use of the guidelines, Bhatia said. "We don't know which health care providers are using the guidelines, the rate of adherence, or their impact on outcomes."
In a February 2006 article in Pediatric and Blood Cancers, Bhatia and Anna Meadows, M.D., at the Children's Hospital of Philadelphia, call for research into barriers to integrating the guidelines into clinical care and measuring changes in care once the guidelines are implemented.
In one effort to overcome such barriers, COG is developing an online tool that gives each patient's treatment history and suggested screening interventions. Known as Passport for Care, the program is under way at Baylor College of Medicine and Texas Children's Cancer Center in Houston.
Most pediatric oncologists know about the COG guidelines because they are members of COG, Bhatia said.
"Now it's important to make the guidelines user friendly for the community physicians," she said. "This is something we are actively working on."
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||