Childhood cancer survival rates are up, but so are long-term complications
SAN ANTONIO -- When Brittany Galan was diagnosed with leukemia at 6 weeks old, doctors warned her parents she had little chance of surviving -- she was so young and so sick. But after being treated with chemotherapy, "I lived and lived!" said the exuberant 24-year-old. "Everyone calls me the miracle baby."
The lifesaving chemo, however, took a heavy toll. It "messed me up neurologically," Galan said. In grade school, she had trouble with reading and math and eventually went on ADHD medication. In college, the once-avid runner developed a heart problem. Recently, Galan, who juggles two part-time jobs working with children with emotional problems, began taking medication for anxiety and depression.
"Sometimes I think, 'What's next?'" she said. "I take a lot of pills. I feel like an old lady."
One of medicine's greatest successes is the sharp rise in survival rates for children with cancer. But the flip side of that success is that many of those children are turning up years or even decades later with serious and sometimes life-threatening complications, including second cancers, heart disorders, cognitive problems and infertility.
"These treatments seem to accelerate the aging process," said Greg Aune, a researcher and pediatric oncologist who works at a clinic for childhood cancer survivors at University Hospital in San Antonio, where Galan gets her care.
Aune, like a growing number of scientists and clinicians, is focusing intently on "late effects" of cancer treatments. Many of these researchers work in clinics designed specifically to monitor the health of childhood cancer survivors and alert them to potential risks. With the ranks of survivors swelling, there is an urgent need to understand the treatments' effects on the entire body, not just the tumor, and to come up with less-toxic therapies.
Aune has a personal stake in the research. As a teenager growing up on a wheat farm in eastern Washington state, he was diagnosed with Hodgkin's lymphoma and treated with intensive radiation and chemo. Two decades later, he ended up in emergency surgery to replace a badly scarred heart valve and three blocked arteries, a direct result of the treatment. At 41, he had a mild stroke while at his daughter's gymnastics class and was diagnosed with diabetes. His childhood cancer treatment saved his life, and at 43, he appears robust, but he worries that his battered heart might fail.
"If I had been born a lot earlier, I wouldn't have to worry about late effects because I wouldn't be here," Aune said.
In the 1960s, fewer than half of children with cancer were alive five years after their diagnoses; now, more than 80 percent are. There are more than 420,000 childhood cancer survivors in the United States today, and the number is expected to increase to 500,000 by 2020.
Yet the improved survival rates "came at a high cost," said Gregory Armstrong, an oncologist at St. Jude's Children's Research Hospitalin Memphis. He runs the National Cancer Institute-sponsored Childhood Cancer Survival Study, which tracks more than 30,000 childhood cancer survivors. In the 1980s, survivors began worrying about new health problems, but the severity and connection to their treatments were not appreciated until years later. "This is a population that appears much older than its chronological age," Armstrong said.
As cancer doctors realized that patients might live not just for another five years but for another five decades or more, their just-keep-them-alive impulse evolved. Doctors carefully cut back on chemo and radiation for patients who seemed unlikely to relapse.
The less-punishing therapies bolstered long-term survival. Almost 11 percent of five-year survivors diagnosed with cancer in the 1970s were dead within 15 years of their diagnoses; that dropped to less than 6 percent for those treated in the 1990s, according to Armstrong's research.
Still, patients continue to suffer from severe late effects. By age 50, 1 in 3 women who received chest radiation for Hodgkin's lymphoma will develop breast cancer, compared with less than 1 in 20 in the general population, Armstrong said.
People who develop cancer as adults also can suffer from late effects. But children are more vulnerable to toxic therapies because their bodies are still developing, researchers say. And they have many more years of life in which complications can occur.
Immunotherapy, a new approach that uses the body's immune system to fight cancer, could cause less collateral damage -- but its use in children is a long way off. "For every patient I saw last week, I used the same medications we have had for the last 30 years," Aune said. "And they are very toxic."
The latest research
When Aune is not caring for patients at University Hospital, he spends much of his time in nearby Greehey Children's Cancer Research Institute, where he oversees experiments in mice on the effects of chemo, including drugs called anthracyclines that can be toxic to the heart. Much of the research on late effects involves the heart, which is especially vulnerable to aggressive childhood treatments.
On a recent day, his lab manager, Thomas Andrews, anesthetized an 8-week-old mouse before laying it on its back on a heated board. With a cotton swab smeared with Nair, he removed a bit of fur from the animal's chest, then used a very small probe to take a scan, shown on a monitor, of the mouse's left ventricle. The echocardiogram allowed Andrews to measure the animal's heart-pumping efficiency.
The mouse was destined for a study looking at whether vigorous exercise can limit heart problems caused by doxorubicin, which is also known as Adriamycin and is an anthracycline. After the mice receive several doses of the drug, some are put on treadmills for exercise, and others are not. Early data suggest that the ones on the treadmills do better, Aune said.
Another mouse experiment involves a medication called dexrazoxane, which is used to prevent heart damage caused by certain chemo drugs in breast-cancer patients. Its use in children has been controversial and spotty because some older studies have suggested that the medication, which is given at the same time as chemo, increases the risk of second cancers. There have also been concerns that it could blunt the cancer-fighting effectiveness of chemo.
But those worries have been largely disproved in recent years, and now a clinical trial in humans may be paving the way for widespread use of the drug, also called Zinecard.
Eric Chow, an oncologist at Fred Hutchinson Cancer Research Center in Seattle, is leading an effort to see whether the drug prevents long-term cardiac deterioration. He and other researchers are scrutinizing the cardiac function of people who were in trials in the late 1990s and early 2000s and treated with either doxorubicin alone or the chemo drug plus Zinecard, the heart-protectant.
"We didn't really know what happened to those patients and what happened in terms of heart disease," Chow said. "Did the medication have any protective effects that could be detected 20 years later?"
A preliminary analysis released earlier this month showed that the Zinecard group appeared to have "more preserved" heart function many years later. One theory is that the drug interferes with a protein that makes heart tissue more vulnerable to certain chemo agents.
Saro Armenian, a pediatric oncologist at City of Hope in Duarte, California, is taking another approach to counter the heart-damaging effects of anthracycline drugs. He is exploring whether giving childhood cancer survivors a common blood pressure drug will prevent heart failure as they get older.
"The question is," he said, "if you have been treated with chemo, can you take a drug to help the heart to heal?" He likened the approach to using low-dose baby aspirin to protect arteries among the general population.
Six-year-old Sammy Cuevas, decked out in black pants and a matching vest, watches videos on his mother's phone as he waits for his checkup at the University Hospital survivors' clinic. When he was 4 months old, he had surgery to remove a brain tumor called a medulloblastoma, followed by a year of chemo. "There were times," said his mother, Claudia Cuevas, "when I thought, 'The cancer won't kill him, but the chemo will.'"
He already has chemo-related problems, including mild deafness, severe constipation and what his doctors call an overall "failure to thrive." At 34 pounds and a little over 3 feet tall, the first-grader is in the third percentile for size for his age. As Sammy gets older, he will be monitored for late effects including leukemia and fertility problems.
Nevertheless, Sammy's doctor, Shafqat Shah, is optimistic about Sammy. "Our hopes for him are pretty dang good," she said. His mother also was upbeat. "He's very good with numbers," she told the doctor. "But he has a little trouble with pronunciations because of his hearing problem."
Patients are referred to the survivors' clinic -- officially called the South Texas Pediatric Cancer Survivorship Program -- three to five years after they are finished with treatment, when the threat of relapse has receded. Depending on their anticancer regimen, they may get comprehensive blood tests, echocardiograms, lung function tests and hearing examinations. Red flags prompt immediate referrals to specialists.
On a recent day in a clinic conference room, a few teenagers talked about life as childhood cancer survivors. High school senior Katelyn Garcia, who developed leukemia at 14 months and struggled with learning disabilities and seizures in middle school, is now headed to college and wants to become a "child-life specialist" -- someone who takes care of children undergoing cancer treatment. Her friend, Carmen Villarosa, who had a kidney tumor when she was younger, worries that her cancer treatment might make it difficult for her to have children when she is older.
Bryon Martinez, who was diagnosed with leukemia in the fifth grade and gets annual echocardiograms to check for heart problems, is an accomplished cross-country runner who hopes to go to Georgetown University and become a pediatric oncologist. When his mother, Ana Isabel Martinez, speaks in Spanish about his illness, she weeps quietly. "It was extremely difficult," she said.
Aune knows what the survivors are going through. When he was diagnosed with Hodgkin's lymphoma, he said, "people told me it was a good cancer, because it was fairly curable. Everyone said I should just get through the treatment, and then life would go back to normal."
At the time, his mother wisely urged him to bank his semen, an experience the 16-year-old found almost unbearably embarrassing. "My doctors didn't mention it," he said, "My mother read about it in Reader's Digest."
After he had surgery for the cancer, Aune had radiation to his chest and abdomen for nine weeks and received eight chemo drugs over nine months. He lost 70 pounds. It was years before he felt normal again.
Later, as a 35-year-old training to become a pediatric oncologist at the University of Texas Health Science Center, he became so exhausted that he could not walk more than 30 steps -- a fatigue he attributed to a demanding job and four small children but was actually due to the radiation and, probably, the chemo. (By then, he and his wife had managed to have two sets of twins via artificial insemination.)
After having heart surgery, he switched his career focus to late effects, vowing to fill research gaps and work with survivors. Having already dealt with a raft of medical problems, he is philosophical about his future. "You never know what's going to come your way," he said, "so you better do what you want to do now."