Adult central nervous system tumors

Low-grade gliomas

Gliomas have a broad spectrum of disease types with associated differences in outcomes. Our understanding of the molecular profiles of these tumors continues to evolve rapidly and is now informing us which patients may achieve long-term survival. Mutational profiling is now the standard of care for lower-grade gliomas, including the World Health Organization (WHO) grades II and III. Broadly speaking, patients may be grouped as those having or not having mutations in isocitrate dehydrogenase (IDH). Although a descriptor of grade II or III may be assigned by pathologists, evidence suggests little difference in outcomes based on grade, but the presence of an IDH mutation indicates favorable prognosis. ^, Conversely for patients with grade II or III tumors where no IDH mutation is identified, these tumors may be classified as a “molecular glioblastoma (GBM),” and patients may experience rapid disease progression similar to that seen with grade IV GBM.

RT has an integral role in the treatment of low-grade gliomas, and although mutational status is now influencing therapeutic decisions, historically, treatment decisions have been based on tumor grade. For WHO grade II gliomas, combined-modality therapy has contributed to improved survival rates, and early RT is associated with improved progression-free survival. ^, However, the timing of RT that is, whether it is delivered as adjuvant or salvage therapy, remains controversial. The existing controversy centers on the negative effects of radiation on cognitive function and quality of life, which are of special importance in patients with a long life expectancy. For patients with WHO grade III tumors, adjuvant RT is considered standard, although, as noted, mutational profiling allows the prediction of favorable outcomes for subsets of patients. In particular, grade III gliomas with an IDH mutation have favorable outcomes, and numerous patients will achieve long-term survival similar to that seen for patients with WHO grade II tumors. ^{, ,} As such, these patients are at substantial risk for cognitive decline after RT.

Cognitive decline after cranial irradiation is especially problematic for brain tumor survivors, as it is associated with reduced quality of life. ^, Historically, the overwhelming majority of radiation treatments have been delivered using photon-based techniques. Douw et al. retrospectively evaluated patients with low-grade gliomas treated with or without RT and found RT use to be associated with impaired attentional functioning and executive function. Gondi et al. prospectively evaluated the effects of radiation on cognitive function in adult patients with low-grade brain tumors treated with advanced photon radiation techniques, including IMRT. The trial included both baseline and postradiotherapy assessments including formal neurocognitive tests. Exposure of the bilateral hippocampi to doses as low as 7.3 Gy was associated with long-term memory impairment.

Such evidence has led practitioners to believe that proton therapy may be ideally suited for the treatment of these tumors. In addition to compelling dosimetric studies, initial clinical studies of proton therapy have suggested efficacy. Investigators from Massachusetts General Hospital (MGH) first used mixed photon/proton treatments for dose-escalation studies including patients with WHO grades II and III gliomas. Investigators from the University of Heidelberg, which uses scanning beam proton delivery technology, have also reported on 19 patients treated for low-grade gliomas. Similar to photon-based treatments, their initial results suggest high rates of tumor control and acceptable toxicity rates. The group at The University of Texas MD Anderson Cancer Center has also reported on outcomes after IMRT or proton therapy for these tumors. Although the latter was a retrospective study, disease control outcomes were similar. However, patients with oligodendroglioma treated with protons developed pseudoprogression sooner than those treated with photons. Formal cognitive testing outcomes were unfortunately not available. In a recent study, Shih et al. reported results of a prospective trial that enrolled patients with grade II gliomas. In addition to reporting excellent disease control rates, they assessed cognitive function and quality of life after proton therapy. Twenty patients, all with supra-tentorial tumors, were enrolled. With a median follow-up time of 5.1 years, measures of cognitive function were stable to improved relative to baseline, with no patients experiencing cognitive failure. Sherman et al. reported that compared with normative practice effects, these patients exhibited less improvement in the domains of processing speed, executive function, and verbal memory. However, because this was an uncontrolled, noncomparative trial, it is unclear if this relative stability reflects the absence of an expected practice effect in this treated population.

To provide the best evidence supporting the benefits of proton therapy in comparison with the best photon therapy (IMRT), randomized trials are needed. Historically, with a few exceptions, in the field of photon therapy, randomized trials have not been done to compare radiation techniques such as three-dimensional conformal versus IMRT. However, given that proton therapy is a fundamentally different form of radiation, it is not unreasonable that such trials be conducted. Currently, an ongoing randomized phase II trial is being conducted through the NRG Oncology Group, BN005 (clinicaltrials.gov identifier: NCT03180502). The schema for this trial is presented in Fig. 9.1 . Eligible patients include those with an IDH mutant grade II or III glioma and are randomized to receive protons versus photons. The central hypothesis is that the normal tissue-sparing offered by proton therapy will lead to superior preservation of cognitive function and reduced symptom burden relative to patients treated with photon-based therapy.