Pediatric Cancer Survivors at Risk for Stroke

Childhood survivors of brain tumors and leukemiaare at particular risk for stroke later inlife, according to research conducted throughthe University of Texas (UT) Southwestern MedicalCenter at Dallas.¹ The medical center is one of 26 facilitiesinvolved in the Childhood Cancer Survivor Study(CCSS), a large, ongoing research investigation on thelong-term effects of cancer and its treatment in the pediatricpopulation.

The study reviewed self-reports of stroke occurrence5 or more years after recovery from oncologicaldisease in 4828 survivors of pediatric leukemia and1871 survivors of pediatric brain tumors. Stroke occurrencealso was examined in a random sample of3846 siblings of pediatric cancer survivors.

The team, led by Daniel C. Bowers, MD, associateprofessor of pediatrics at the University of TexasSouthwestern Medical School, reported in their articlerecently published in the Journal of Clinical Oncology that stroke was 2 to 3 times more likely to occur downthe road in survivors of pediatric leukemia and 8 to 10times more likely to occur in survivors of pediatricbrain tumors than in siblings of cancer survivors.

"Our research started off as an observation," Bowersexplained. "We had a few kids from our institutionwho were survivors of brain tumors. We noted that 5,10, 15 years later, they had strokes. This was quiteshocking and frightening for the parents of these patients.A survey of the literature revealed that this wasan unknown area, so we took it on."

Bowers and his team began to examine stroke incidenceamong young persons who had been treated forbrain tumors at UT Southwestern Medical Center andconfirmed an increased prevalence of stroke. "Weused the findings of our single-institution experienceto propose that the CCSS examine the correlation betweenchildhood cancer and stroke risk," said Bowers.

Getting the go-ahead, Bowers and his team recapitulatedtheir original study using the CCSS database,which contains detailed information on the medicalhistory, diagnosis, therapy, and complications of therapyof thousands of cancer survivors who have beenfollowed for 5 to 30 years. "In looking through thedata, we realized that childhood survivors of Hodgkindisease, leukemia, and brain tumors were at high riskfor stroke later in life," said Bowers. Data on Hodgkindisease, which affects adolescents more than youngchildren, were separated from data on leukemia andbrain tumors.

"Although people think that brain tumors and leukemiaare different, they are similar, so we batchedthem together," Bowers explained. "Both leukemiaand brain tumors affect a similar age group-meanage, 5 years. These are young children who are goingthrough a lot of developmental changes. Also, thesediseases both require CNS-directed therapy."

Whereas increased risk of stroke was not exceptionallyhigh among survivors of childhood leukemia (1%at 25-year follow-up), the risk rate for survivors ofchildhood brain tumors at 25-year follow-up was 6%."These are kids diagnosed at age 5 years-and 6% areat risk for stroke at age 30. That's significant, consideringthat stroke in 30-year-olds is a rare event," Bowerscommented.

Treatment with cranial radiation therapy (meandose, 30 Gy or higher) appeared to be a major determinantof risk and was dose-dependent; highest riskwas associated with cranial radiation therapy at dosesof 50 Gy or higher. Patients with recurrent oncologicaldisease also were at particularly high risk for stroke,but this observation, Bowers noted, probably was relatedto increased radiation exposure.

Bowers and coinvestigators' data on survivors ofHodgkin disease, which were published earlier thanthe data on leukemia and brain tumors, also showedthat survivors were at increased risk for stroke later inlife (ie, after more than 5 years). In that study, it wasshown that mantle radiation therapy was a major determinantof stroke risk.²

COGNITIVE COMPLICATIONS ALSO
Another study conducted by Bowers' team showedthat radiation therapy also compromises cognitive development.³ In this study, 16 persons who had receivedradiation therapy for medulloblastoma at amean age of 7 years were evaluated at about 22 years."That study was quite sobering. In that study, the majorityof patients were very delayed or impaired," saidBowers. "Their processing speed was slow, their IQswere low, and from a functional standpoint, they werevery impaired. Most hadn't graduated from highschool, held a job, or dated or had a significant relationship,and most could not drive." Bowers addedthat cognitive effects were not evaluated in the morerecent studies on stroke and Hodgkin disease andleukemia and brain tumors. "The CCSS data are basedon self-reports and not designed to chart cognitive effects,"he explained.

MECHANISMS AND PREVENTIVE MEASURES
The mechanism through which radiation therapy putschildhood cancer survivors at risk for stroke and othercomplications such as cognitive deficits needs furtherelucidation, but it may be related to large cerebralvessel injury incited by radiation therapy, Bowers explained.Preventive measures have begun with a pushtoward reducing the dose of cranial radiation used inpediatric patients. Bowers noted that the Children'sOncology Group, a consortium that sets the pace fortreating children with brain tumors in the UnitedStates, is working on this.

Bowers said that his team's research "reminds usthat kids are not supposed to be radiated. More effortsare needed to identify therapies that do not include radiationto the brains of these youngsters. We knownew agents are coming out and current protocols useless radiation than they did 30 years ago. Maybe 30years from now, no radiation will be used. Our studyprovides very persuasive data in that direction."

He and colleagues will next embark on a study tofind a method to screen at-risk patients and then moveon to developing preventive interventions. "We aregoing to screen a substantial number of children tolook at the prevalence of silent cerebral vascular diseases.If it is high-which I anticipate it will be-wemight embark on some kind of intervention study,"confided Bowers. Whether screening initiatives areneeded for survivors of childhood cancer and whatkinds of interventions can be instituted in young personsare open questions that may take many years todefine, Bowers added.

REFERENCES1. Bowers DC, Liu Y, Leisenring W, et al. Late-occurring stroke among longtermsurvivors of childhood leukemia and brain tumors: a report from theChildhood Cancer Survivor Study. J Clin Oncol. 2006;24:5277-5288.
2. Bowers DC, McNeil DE, Liu Y, et al. Stroke as a late treatment effect ofHodgkin's disease: a report from the Childhood Cancer Survivor Study. J ClinOncol. 2005;23:6508-6515.
3. Maddrey AM, Bergeron JA, Lombardo ER, et al. Neuropsychological performanceand quality of life of 10 year survivors of childhood medulloblastoma.J Neurooncol. 2005;72:245-253.