Multiple studies have previously reported that survivors of childhood CNS malignancies treated with whole-brain or craniospinal radiation therapy experience significant neurocognitive deficits, particularly in the areas of memory and executive functioning.8,25–27
However, in this study, we have taken these findings 1 step further by identifying region-specific associations between cranial irradiation exposure and poor outcomes, including memory, task efficiency, and social functioning among adult survivors of childhood CNS malignancies. The identification of radiation dose–response relationships for these associations further increases the strength of the evidence for a causal relationship between poor outcome and region-specific radiation exposure.
Memory functions are largely localized in the temporal regions of the brain.16
Although a previous report had identified memory dysfunction in children with temporal lobe brain tumors,28
survivors in our study demonstrated an increased risk for memory difficulties with increasing dose above ≥30 Gy to the temporal lobe region, whereas no increase in risk was observed with increasing dose to other regions. By controlling for dose to other regions, we ostensibly identified the independent effect of radiation dose to the temporal lobes on memory. We did not identify, as we hypothesized, poor executive function outcomes (ie, Emotional Regulation, Task Efficiency, and Organization) associated with frontal lobe radiation. The relatively small number (n
= 63) of participants who received high dose (≥50 Gy) radiation may have limited our ability to identify such an association.
Recognizing that individuals treated for MB and PNET received whole-brain radiation and supplemental focal or regional irradiation of the tumor bed, we analyzed this population separately from survivors of other malignancies. Survivors of MB and PNET reported experiencing difficulties with Task Efficiency and Organization not seen in survivors of astrocytomas and other CNS tumors. Given the dependence of processing speed on white matter integrity,29
and the existence of rich white matter connectivity between the cerebellar region and the frontal brain regions,30
this pattern of deficits in MB survivors is not surprising. Disruption of these white matter tracts in the cerebellar region could result in executive functioning deficits via the loss of supratentorial connections between the cerebellar pathways and the frontal region.
Survivors who received temporal region irradiation also experienced significantly more difficulty in social functioning. It is established that patients with temporal lobe epilepsy demonstrate impairments in facial recognition.31
This is expected because temporal brain regions are involved in the interpretation of emotional expression and facial recognition.32
These potential perceptual limitations, combined with the impact of memory deficits on social communication skills, may account for the increased reliance of social functioning and temporal lobe integrity. Limitations in social functions can contribute to poor HRQOL and persist for several years after treatment for many survivors of CNS malignancies.33
Survivors with a history of radiation therapy to frontal and temporal regions also reported physical limitations and general health difficulties, which can also have an indirect impact on social functioning.
Limitations to the current study should be considered. The self-report medium may not be the most sensitive or specific method to determine neurocognitive deficits.34
However, recent studies have shown that self-reported neurocognitive data correlate with neuroimaging in older adults and children.35,36
As a next step in validating these measures, efforts are underway to compare these self-report measures with established neuropsychological batteries. An additional potential limitation is that we did not obtain complete participation from all survivors eligible for participation in the CCSS follow-up questionnaire. Also, although radiation exposure is certainly associated with poor outcomes, this study cannot control for the independent effects of both direct injury from the tumor itself and surgical procedures. However, the dose–response effect of radiation increases the strength of a causal relationship for radiation. Additionally, the inability to perform separate dosimetry estimates to the hypothalamic-pituitary axis and the temporal lobe may have resulted in deficits in social functioning due to hypothalamic injury being attributed to the temporal lobe. Finally, as noted by previous CCSS investigations,2
therapeutic regimens have changed over the years and some current regimens include increased use of chemotherapy with lower craniospinal doses and smaller boost volumes, which may make our results less generalizable to more recent survivors of childhood CNS malignancies.
Despite these limitations, our study provides valuable, region-specific information on the neurocognitive and HRQOL-related outcomes for adult survivors of pediatric brain malignancies after radiation therapy. Since the recent advent of conformal radiation therapy for the treatment of brain tumors in children, investigators have similarly sought to correlate cognitive outcomes with dose to functional subunits of the brain. In a study that included 86 children with ependymoma, Merchant et al.37
showed that the fractional volume of brain that received dose within specified intervals could be used to estimate IQ. The best models were developed using the dosimetry of supratentorial brain volumes, and the study demonstrated the importance of primary tumor location and correcting for factors, including age at the time of irradiation. Similar models have been developed for patients with craniopharyngioma,38
One poignant finding is that for most models, both high and low doses contribute to a decline in IQ; however, the volume that receives the highest dose always has the greatest effect.
In particular, these data highlight the importance of radiation dose to the temporal region by identifying associations with poor memory and social function outcomes. These findings accentuate the need for more targeted delivery modalities, such as conformal or intensity-modulated radiation therapy or proton therapy that can limit dose to normal brain volumes, and potentially lower rates of poor functional outcome. As these survivors are at-risk for experiencing difficulties with memory and social functioning, early intervention aimed at preventing the development of deficits and curbing the progression of deficits is warranted. Computerized and face-to-face interventions have been successful at effecting positive changes in memory with individuals with mild cognitive impairment.40,41
These interventions, however, have not yet been used with brain tumor survivors. Therefore, the validation of use of these strategies within the brain tumor survivor population is needed. Participation in social skills training opportunities at a young age and as young adults may facilitate development of social skills for CNS tumor survivors.42,43
Continued follow-up of the CCSS population will further identify the patterns of neurocognitive change as this population ages through middle adulthood.
Conflict of interest statement. None declared.