Long-term threat: young cancer survivors face risks later.

Childhood-cancer treatment is one of the success stories of the late 20th century. A child diagnosed with cancer in the 1970s had a 56 percent chance of surviving for 5 years. Today, that likelihood is nearly 80 percent. With that gain, however, doctors have noticed that cancer survivors seem prone to other life-threatening medical problems later. Recent studies confirm that survivors face a heightened danger of heart problems or another bout with cancer. In a cruel twist, the youngest cancer patients often face the greatest risk.

Up to 5 percent of childhood-cancer survivors get second cancers. That's several times the cancer risk that people in the general population face, National Cancer Institute data show.

While some subsequent tumors are recurrences of the primary cancer, many are new tumors biologically unrelated to the first one. Such a change suggests to scientists that either a child's original treatment contributed to the second cancer or that the person had a genetic predisposition that led to cancer twice.

The newly recognized dangers are the flip side of progress, says Elaine Ron, an epidemiologist at the National Cancer Institute in Bethesda, Md. "We wouldn't be worried about second cancers if we hadn't been so successful with the first ones," she says.

REAL RISKS A recent study revealed that survivors of the cancer called Hodgkin's disease, diagnosed between 1967 and 2000, subsequently had at least twice the incidence of deaths from heart attack as other people had. Children and teens treated for the cancer had 19 times the rate of deadly heart attack later in life that their contemporaries did, epidemiologist Anthony J. Swerdlow of the Institute of Cancer Research in Sutton, England, and his colleagues report in the Feb. 7 Journal of the National Cancer Institute (JNCI).

The incidence of heart attacks in survivors of the childhood cancer is still much lower than that of a general population of elderly people, but the findings raise concerns about the cancer treatments, says Swerdlow.

The chance of developing a cancer called a sarcoma within a decade of a childhood cancer is nine times as great among survivors as in other people, pediatric oncologist Tara O. Henderson of the University of Chicago School of Medicine and her colleagues report in the Feb. 21 JNCI. Sarcomas are cancers of muscle, bone, and tissues surrounding nerves. No screening test exists for these cancers. Doctors often find them when a patient reports having pain or an unusual mass, says Henderson.

"The only way to screen for sarcomas is for the clinician to have a high index of suspicion," she says. The new study may make doctors especially attentive to survivors of childhood cancers.

Unusually high numbers of brain tumors crop up in survivors of childhood cancers, particularly leukemia. A recent study showed that people who had had childhood cancers experience brain tumors called gliomas within the next decade at a rate nine times the population average. Pediatric oncologist Joseph P. Neglia and his team the University of Minnesota in Minneapolis described those findings in the Nov. 1, 2006 JNCI.

WHAT'S THE PROBLEM? Radiation therapy stands out as the leading culprit in heart problems and second cancers. Past work showed that radiation therapy of the chest may damage coronary arteries, which increases the risk of heart problems.

In the studies of sarcomas and brain tumors, survivors who got radiation were three and seven times, respectively, as likely to develop second cancers as were other survivors who didn't get radiation.

Although radiation "is still incredibly important for treating pediatric cancers, it can cause a whole host of problems," says Kevin Oeffinger, a physician at the Memorial Sloan-Kettering Cancer Center in New York. Second cancers often appear in the radiation field, that part of the body getting irradiated.

"Radiation is very good at breaking DNA strands," says radiobiologist David J. Brenner of the Columbia University Medical Center. That can stop cancer. Unfortunately, radiation "occasionally will mutate a gene that [normally] prevents a cell from overdividing," he says. "That's where radiation can be carcinogenic."

Over the past 2 decades, engineers and physicists have learned to focus therapeutic radiation into small beams, Brenner says. That enables doctors to boost the dosage while decreasing the size of the radiation field. While the higher doses cure more primary cancers, he says, only future studies will reveal whether the focused beams limit second-cancer risk.

Chemotherapy can also damage DNA. In the sarcoma study, chemotherapy that included high doses of anthracyclines or alkylating agents doubled the risk of having a second cancer, Henderson says. But research into the risks of chemotherapy in second cancers has lagged behind radiation studies, says Brenner.

Swerdlow's team attributed the increased heart attack risk in Hodgkin's disease survivors to both radiation and chemotherapy.

The role of genetics in second cancers remains murky. "We don't know [why] one child gets a secondary brain tumor and another, with almost identical treatment, doesn't," Neglia says. Genetic mutations reducing cells' production of enzymes needed to repair radiation damage might predispose a person to a second cancer, he says.

The good news is that the paradigm of childhood cancer has shifted, Henderson says. "A generation ago, pediatric cancer was almost a death sentence." Now, part of the challenge is to ensure that the cure carries as little risk as possible.