Proton Beam Radiation Therapy: The Future May Prove Brighter for Pediatric Patients With Brain Tumors

Multiple meta-analyses have demonstrated significant deficits in overall intellectual abilities, academic functioning, and specific cognitive skills, including attention, processing speed, and executive function, among pediatric brain tumor survivors treated with photon radiotherapy (XRT). The physical characteristics of heavy proton particles used in proton beam radiation therapy (PBRT), which permits delivery of maximal dose at the desired depth of tissue penetration while minimizing the exit dose of radiation to healthy surrounding tissue, have been well described. What has been missing from the literature is the extent to which proton radiation therapy (RT) differs from XRT in terms of cognitive, academic, visual, auditory, endocrine, vascular, and skin late effects. In the article that accompanies this editorial, Kahalley et al have evaluated a large retrospective sample of pediatric patients with brain tumors (n 5 150) previously treated with either XRT between the years 2002 and 2007 (n 5 60) or PBRT between the years 2007 and 2012 (n5 90) at the Texas Children’s Hospital/MD Anderson Proton Therapy Center. Overall, the survivors treated with PBRT did not demonstrate a significant decline on average in Full Scale Intelligence Quotient (FSIQ), whereas those treated with XRT evidenced, on average, a statistically significant decline of 1.1 FSIQ points per year. The FSIQ slopes between these two groups, however, did not differ significantly, as the trajectories of both groups declined over time. Upon further analysis by field of irradiation, the PBRT and XRT groups who received craniospinal irradiation evidenced stable FSIQ over time, and the slopes between the groups, once again, did not significantly differ. In contrast, a statistically significant difference between the two groups was displayed after receipt of focal RT. The FSIQ was stable for the PBRT group but significantly declined for the XRT group by an average of 1.57 points per year, whereas the trajectory of FSIQ slopes over time between the two groups did not significantly differ. Onemight be surprised that the focal XRT group significantly declined over time on FSIQ, given that narrower volume of RT has been demonstrated to be less neurotoxic to the CNS. From a different perspective, however, perhaps focal/local RT is the optimal scenario in which the physics of PBRT manifests maximal benefits by minimizing the scatter of radiation to the surrounding healthy brain tissue, as opposed to craniospinal irradiation, in which the entire brain and spine are treated. Kahalley et al cite the few published late-effects studies of pediatric brain tumor survivors treated with PBRT who received preand posttreatment IQ assessments for diagnoses that included low-grade gliomas, ependymoma, and high-risk medulloblastoma or supratentorial primitive neuroectodermal tumors. Although the sample sizes in these three studies were small (from five to 14 survivors), and the 2-year length of follow-up brief, the results indicate stable FSIQ, with the exception of patients with lowgrade gliomawhowere either younger than age 7 years at the time of PBRT or who received a dose of $15 Gy relative biological effectiveness to 20% of the volume of the left temporal lobe or hippocampus. Although prior research has documented that children treated for brain tumors with XRT display declines in FSIQ over time, further research has documented this decline in overall intelligence to primarily be the direct result of the diminution of two of the four IQ index scores that assess working memory (Working Memory Index) and processing speed (Processing Speed Index). Newer studies evaluating the neurocognitive late effects of the treatment of pediatric brain tumors with PBRT indicate that, on average, verbal comprehension, perceptual reasoning, and working memory remain stable, whereas processing speed can still be negatively impacted and declines over time after PBRT. As an illustration, a recently published follow-up study of 60 pediatric patients with brain tumors who were treated with PBRT at a mean age of 12 years and were retested after an average follow-up of 2.5 years reported no significant change in mean FSIQ, although the authors clearly portray the variable impact treatment can have upon individual survivors: FSIQ scores improved for 33 patients (55%) and declined for 24 patients (40%). Furthermore, this study analyzed the four constituent index scores that compose FSIQ and reported no significant change in verbal comprehension, perceptual reasoning, or working memory; however, processing speed significantly declined by a mean of 5.2 points, with subjects younger than 12 years at baseline displaying a decline of 8.8 points. This specific pattern of cognitive late effects arising from the treatment of pediatric brain tumors with PBRT is further supported by another recent follow-up study of 15 pediatric patients with brain tumors who were treated with PBRT at the mean age of 8 years old and re-evaluated approximately 3 years post-PBRT, and who also demonstrated stable FSIQ over time,