Gene Reddick

Early Detection and Characterization of Late Effects

St. Jude investigators are evaluating various methods of long-term surveillance and screening of childhood cancer survivors to determine the best approaches for detecting and characterizing adverse late effects. Here we describe two such efforts in the areas of detecting cardiac dysfunction and neurocognitive late effects.

Improved Detection of Cardiomyopathy in Childhood Cancer Survivors

Two-dimensional (2D) and three-dimensional echocardiography are the current standard screening for cardiac late effects in childhood cancer survivors who received cardiotoxic therapy such as anthracycline chemotherapy or thoracic radiation therapy. Cancer treatments can impair cardiac function in children during treatment and are associated with long-term risk of cardiomyopathy.

In the cardiology field, cardiac magnetic resonance imaging (MRI) is considered the reference standard to which alternative cardiac imaging techniques are compared to assess structure and function. Therefore, Gregory T. Armstrong, MD, MSCE (Epidemiology & Cancer Control, Oncology), and colleagues recruited participants from the SJLIFE cohort to compare these screening methods for detecting cardiac late effects in childhood cancer survivors.

In the Journal of Clinical Oncology, Dr. Armstrong’s team reported their findings in 114 adult survivors whose mean age was 39 years; mean time from diagnosis of childhood cancer was 28 years; and whose cancer treatment included anthracycline chemotherapy, thoracic radiation therapy, or both. The investigators found that among childhood cancer survivors 2D echocardiography generally overestimated the mean ejection fraction (i.e., the volume of blood pumped out of the heart during each cardiac cycle).

As a result, the sensitivity of this approach in detecting a low ejection fraction (less than 50%) was only 25%, and the false-negative rate was 75% in asymptomatic survivors. Moreover, the use of 2D echocardiography resulted in misclassifying 11% of the survivors in this screened population in the direction of harm.

Dr. Armstrong and colleagues concluded that cardiac MRI is the more accurate approach to screening and monitoring cardiac function in survivors; cardiac MRI screening detected a high prevalence of cardiac dysfunction that was previously undiagnosed. These results have direct clinical implications for the future assessment of cardiac function among childhood cancer survivors at high risk for cardiac late effects.

Detecting Treatment-Related Cognitive Dysfunction in Adult Survivors of Childhood Medulloblastoma

Survivors of pediatric medulloblastoma are at risk for cognitive deficits, and treatment-related damage of the white matter of the brain has been linked to lower intelligence, poor academic performance, and executive functioning deficits. However, the long-term effects and potential associations between white matter integrity and cognitive function among adult survivors of medulloblastoma have not been examined.

In a paper published in the journal Neuro-Oncology, a team of St. Jude investigators led by Tara M. Brinkman, PhD (Epidemiology & Cancer Control, Psychology) and Wilburn E. Reddick, PhD (Radiological Sciences), reported their results from the first pilot study to examine this relation.

Drs. Brinkman and Reddick and coworkers performed comprehensive neurocognitive evaluations and MRI examinations on 20 adult medulloblastoma survivors from the SJLIFE cohort. The mean age of the group was 29 years, and the mean time from diagnosis was 18 years. All 20 survivors had received a total cumulative dose of cranial irradiation exceeding 50 Gy during their treatment for medulloblastoma.

Results from the MRI examinations revealed that 16 (80%) survivors had evidence of leukoencephalopathy. Diffusion tensor imaging demonstrated radial diffusivity (an indication of white matter abnormalities) in the frontal lobe of both brain hemispheres that was correlated with deficits in specific cognitive processes (i.e., shifting attention and cognitive flexibility).

In addition, reduced white matter integrity in multiple brain regions was correlated with poorer performance on tasks of executive function such as planning, attention, problem solving, verbal reasoning, working memory, and task switching. Eleven (55%) survivors showed deficits on two or more measures of executive function.

These results indicate that global neurocognitive impairment is prevalent among long-term adult survivors of childhood medulloblastoma and provide direction for future research that may lead to the clinical use of neuroimaging approaches, such as diffusion tensor imaging, to identify survivors at risk for abnormal neurocognitive processes.