Long-Term Outcomes of a Prospective Trial on Proton Therapy for Low-Grade Glioma

Abstract

Low-grade gliomas occur in young adults, with many patients living for well over a decade. Choice of therapy must be weighed against late adverse effects, particularly in neurocognitive and neuroendocrine domains. Proton therapy offers advantages in reducing off-target dose, and may reduce the risk of late morbidity. We examined outcomes in several domains following proton therapy in this updated prospective cohort of patients with low-grade gliomas. Twenty patients with pathologically confirmed WHO grade 2 gliomas were enrolled in a prospective, single-arm trial of proton therapy. Patients received 54 Gy (RBE) in 30 fractions either upfront at time of diagnosis or at time of disease progression. Comprehensive baseline and longitudinal assessments of toxicity, neurocognitive and neuroendocrine function, and quality of life were performed up to 60 months following treatment. Patients were enrolled between 2007 and 2010, at a median age of 37.5 years. Median follow-up was 6.7 years from date of proton therapy start for all patients alive at the time of reporting. Six patients died (five of disease), six patients had progression of disease, and eight had no progression at the time of reporting. Median PFS from time of treatment initiation was 4.5 years. At 6 years follow-up, PFS was 39% and OS was 80%. At 10 years from time of first glioma diagnosis, PFS was 37% and OS was 69%. Seventeen tumors were tested for IDH mutations, of which 12 carried a mutation and 5 were wild-type. A different, overlapping subset of 17 tumors was tested for 1p/19q co-deletion, of which 5 carried the co-deletion. No association was found between IDH mutation or 1p/19q co-deletion status and survival outcomes, although this was limited by analysis in a small cohort. Baseline cognitive function was within normal limits in most domains and on average there was no overall decline in cognitive function. However, a small subset of patients (n = 4) showed mild decline in processing speed, executive function, and intellectual domains. These patients also consistently reported symptoms of grade > 1 affecting cognition or mood during the follow-up period. Six patients developed neuroendocrine deficits within 40 months of starting treatment, with corticosteroid deficits being the most common. No patients developed new deficits after 40 months. There were no unexpected early or late toxicities. The majority of patients with low-grade glioma who receive proton therapy retain good overall cognitive and neuroendocrine function long-term. Despite high prevalence of IDH mutations and 1p/19q loss, no association was observed between mutational status and outcome.