BRAIN RADIOTHERAPY AND STROKE RISK

February 13, 2012 (New Orleans, Louisiana) — Survivors of childhood cancer who were treated with cranial radiation therapy (CRT) are at high risk for future stroke beginning as early as their 20s, the results of 2 new studies suggest.

The effect of CRT and modifiable risk factors on stroke risk in adulthood is not well understood, and the risk for recurrent stroke has not been assessed. Dr. Mueller and her research team, therefore, assessed rates, risk factors, and predictors of first and recurrent strokes in childhood cancer survivors treated with CRT.

"Treatment with CRT increases the late-occurring stroke risk in a dose-dependent manner, and this risk continues to increase with age," said Sabine Mueller, MD, from the University of California, San Francisco, Benioff Children's Hospital, who presented both studies here at the International Stroke Conference (ISC) 2012.

More Than 14,000 Survivors Assessed

The first study was based on data from the Childhood Cancer Survivor Study, a multi-institutional longitudinal cohort study of 14,358 childhood cancer survivors diagnosed between 1970 and 1986, and 4023 randomly selected sibling control patients. Forty percent of the survivors were diagnosed by age 4 years, with 42% diagnosed between 5 and 14 years of age and 17% diagnosed between age 15 and 20 years of age.

The age-adjusted incidence rates of self-reported late-occurring first stroke (≥ 5 years after cancer diagnosis) were calculated for survivors compared with siblings, and independent stroke predictors were determined after multivariable analysis.

During a mean follow-up of 23.3 years, 292 survivors reported a late-occurring stroke. Mean time from diagnosis to stroke was 18.6 years (range, 5 - 38 years), and median age at the time of stroke was 28.5 years (range, 6 - 53 years).

Of the 292 strokes, 125 (42.8%) occurred in survivors of central nervous system (CNS) tumors, who constituted only 13% of the survivor population, reported Dr. Mueller.

The age-adjusted stroke rate per 100,000 person-years at age 23 years was 77 for all pediatric cancer survivors and 292 for CNS tumor survivors; the rate for siblings was just 9.3.

CRT increased the stroke risk in a dose-dependent manner, and the cumulative incidence continued to rise decades after diagnosis. Treatment with 30 to 49 Gy CRT had a relative stroke risk of 5.9 compared with 11.0 for 50+ Gy CRT (P < .0001).

The cumulative incidence of stroke 20 years after diagnosis was 0.7% for no CRT, 2.9% for 30 to 69.9 Gy CRT, and 4.9% for 50 Gy or more CRT. For the 50+ Gy group, cumulative incidence was 1.1% 10 years after diagnosis, rising to 11.9% at 30 years, Dr. Mueller added.

"Hypertension increased the risk of late-occurring stroke in pediatric cancer survivors, an effect that was enhanced in black survivors," she reported.

Patients with hypertension, compared with normotensives, had a 4-fold increased risk; the hazard ratio was 3.8 in white hypertensives vs white normotensives, but rose to 15.9 for black hypertensives vs white normotensives, she noted.

If diabetes was present together with hypertension in CNS tumor survivors, the relative risk increased from 2.9 for hypertension alone to 14.4, she added.

"Modifiable risk factors further increase the stroke risk in CNS tumor survivors, and these patients should be monitored and treated aggressively to reduce the risk of late-occurring stroke," she said.

"Atherosclerotic risk factors such as hypertension increase the stroke risk, especially in black survivors, and they should be carefully monitored in these patients," Dr. Mueller suggested.

Stroke Recurrence Examined

In a separate presentation, Dr. Mueller reported the results of a retrospective cohort study that examined the risk and incidence of recurrent stroke in 384 childhood cancer survivors receiving CRT at a median age of 8 years at the University of California, San Francisco, between 1980 and 2009. Of these, 57.5% had been treated for brain tumors.

Data were obtained by chart abstraction and telephone interviews, and strokes were confirmed through a review of imaging.

The researchers identified 19 first strokes, of which 14 had correlative findings on imaging. The average annual stroke rate was 625 per 100,000 person-years, median age at first stroke was 23.6 years, and median time to develop a stroke after CRT was 12 years.

The study found a high rate of recurrent stroke, which rose over time and "persisted for decades after treatment," she said.

There were 6 recurrent strokes, with 5 confirmed by means of imaging (2 ischemic, 3 hemorrhagic, 1 unknown). Median age at the time of recurrent stroke was 27.3 years.

The cumulative incidence of recurrent stroke was 16% during the first year after the first stroke, 26% at 5 years after the first stroke, and 32% at 10 years after first stroke, Dr. Mueller reported.

"Stroke risk remains high decades after treatment, and the rate of stroke recurrence appears high in this population," she said.

She said larger studies are needed to identify predictors of recurrence, to design secondary stroke prevention strategies.

"Important New Information"

James Meschia, MD, chairman of neurology at the Mayo Clinic, Jacksonville, Florida, commented to Medscape Medical News, "This is very important new information, because it gives us insight into the late long-term complications in a quantitative way. In particular, as we get better treating pediatric cancers, the importance of minimizing the late complication of stroke grows exponentially."

"The investigators were able to demonstrate an increased and clinically significant rate of first and recurrent stroke. This is the 'good news, bad news' scenario: You have lived for 10 years after cancer diagnosis, but you have a clinically meaningful risk for a second problem," he said.

Dr. Meschia said future studies should explore the functional implications of these strokes, putting the findings in the context of neurological impairment that can stem from radiotherapy. "The functional implications of this over and above the effects of the cancer and the treatment were not addressed, and need clarification," he suggested.

From a therapeutic perspective, the effect of modifiable risk factors — especially hypertension and diabetes — should be appreciated, he added. The findings point to the need for therapeutic interventions to minimize the risk for stroke in this vulnerable population, he said.

"But what we are learning from the adult population is that the control of risk factors is suboptimal," he acknowledged, noting that many drugs are available, but therapeutic targets are often not achieved." In the pediatric population, it would be interesting to see the degree to which these risk factors could be modified, to know whether heightened awareness of this potential problem will change practice."

Dr. Mueller and Dr. Meschia have disclosed no relevant financial relationships.

International Stroke Conference (ISC) 2012: Abstracts 8 and 9. Presented February 1, 2012