See the article by Brown et al. pp. 1337–1347.
Proton radiotherapy (PT) has an inherent advantage over photon radiotherapy in that the entrance dose is less than dose at depth and there is an almost complete absence of dose beyond the Bragg Peak, such that dose at depth can be delivered with less intermediate and low radiation doses in adjacent tissues. Initially, the aim of PT was to deliver higher doses than was formerly possible with conventional photon techniques with an expectation of better local control rates. The best example of this was the use of PT in the management of skull base chordomas and low-grade chondrosarcomas where the ability to safely deliver doses in the range of 70-78 Gy was indeed associated with better local control rates.1
In the last 15 years with the implementation of advanced new photon techniques, predominantly intensity-modulated radiation therapy (IMRT), volumetric modulated arc therapy (VMAT), and daily image guidance (predominantly cone-beam CT imaging), photon radiotherapy techniques have evolved to be able to deliver equivalent high-dose regions safely comparable to what is done with PT, such that there is no longer any expectation that PT will be associated with better local control rates.2
Accordingly, the main advantages of PT relate to the lower doses seen in the intermediate and low-dose regions in adjacent normal tissues outside of the high-dose volumes. With regard to the management of brain tumors, the potential advantages would be related to possible less acute and more importantly late long-term side effects: neurocognition, radiation-induced second tumors, loss of hormonal function, and decreased risk of late cerebrovascular events.
Accordingly, there has been a real shift in the management of pediatric brain tumors where increasingly a higher proportion of these cases are being managed with PT. This has been significantly seen in the following common pediatric brain tumors: low-grade gliomas, ependymoma, craniopharyngioma, and medulloblastoma. These cases are excellent choices as they all share critical characteristics where the benefits of PT can be realized: high likelihood of long-term control and survival and the significant sensitivity of the young brain to the late effects seen with the use of photon radiation therapy. Early published data seem to support the expectations of reduced late effects in this population of patients.3
In this issue, Brown and colleagues report on a randomized study of PT vs photons in 67 adult patients with glioblastoma.4 The primary outcome of the study was to determine if PT was associated with a delayed time to cognitive failure. The secondary endpoints of overall survival (OS) and progression-free survival (PFS) were not different, but there was a higher incidence of grade 2 or higher toxicities in the photon-treated cohort, and a higher incidence of patient-reported fatigue with photon therapy. PT was not associated with a delay in time to cognitive failure.
Possible reasons for the lack of benefit of PT at a cognitive level despite the fact that PT significantly reduced the radiation dose for nearly all structures may include the following: significant impact of tumor and surgery on baseline cognition prior to radiotherapy, lack of cognitive reserve in older adults, and inadequate time in PFS and OS in patients with glioblastoma for possible cognitive benefits seen with PT to be demonstrated.
Loss of cognitive capabilities at baseline diagnosis of a brain tumor has long been well recognized, as well as the possible impact of surgery on cognition.5
Cognitive studies in normal adults without a significant medical illness demonstrate a gradual decline in both cognitive abilities and cognitive reserves with increasing age.6 With the median age of 65 in patients with glioblastoma, this is a significant factor for these patients.7 In the study of PT by Brown and colleagues, the median ages were 53 and 55.5 for the photon and PT cohorts, respectively. Quite simply put, there are less cognitive abilities to preserve in this age group, particularly when one factors in the effects of presenting tumor and surgical effects on cognition prior to the initiation of radiotherapy.
Studies of cognition in low-grade gliomas have shown that it takes quite a length of time before the radiation-related cognitive decline is seen. In a study of cognitive effects of photon radiotherapy in patients with low-grade glioma, at a mean time of 6.1 years following conventionally fractionated radiotherapy, there were minimal cognitive effects seen over and above the baseline identified cognitive issues prior to radiotherapy.8 However, in the following update on the same population of patients, now with a mean follow up time of 12 years since photon radiotherapy, there was now a significant decline in cognitive abilities in patients who had received radiotherapy vs a cohort of low-grade gliomas who had not yet received radiotherapy.9 An additional point to make from these reports is the mean age at the time of radiotherapy in this study population was 42, so it is reasonable to state that these patients would have had less age-related cognitive decline and loss of cognitive reserve. These reports demonstrate that measurable radiation-related cognitive decline requires a relatively long time to become evident, apparently in the range of 6-12 years in middle-aged adults with low-grade gliomas. With this knowledge, it is likely that the major factor in time to cognitive failure in glioblastomas is related to tumor recurrence, in addition to other possible contributors such as anticonvulsant medication, physical deconditioning related to neurologic deficits and side effects of steroids, and possibly other factors.5
Currently, there is a randomized study of PT vs photon radiotherapy in adults with isocitrate dehydrogenase (IDH) mutant grade II or III gliomas, and in view of the relative youth of these patients and expected long-term survivals, I believe that this is an entirely appropriate group of patients in which to study the possible benefits of PT (NRG BN005). However, until such time that we are able to significantly prolong PFS and OS in adult patients with glioblastoma, I do not foresee a useful role for the use of PT in this patient population for the foreseeable future.
Acknowledgments
The text is the sole product of the authors and that no third party had input or gave support to its writing.
Funding
There was no funding related to the preparation of this manuscript.
Conflict of interest statement. N.J.L. has no conflict of interest.
Authorship statement. N.J.L. is solely responsible for all aspects of the preparation of this manuscript.
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