Reducing Radiation-Induced Cognitive Toxicity: Sparing the Hippocampus and Beyond

Abstract

The hippocampi, bilateral subcortical structures that play a fundamental role in learning and memory and are implicated in posttreatment cognitive toxicity after brain radiation therapy (RT), have gained tremendous attention in recent years. Early data from rodent models identified a relationship between increased apoptosis and reduced production of neural progenitor cells in the dentate gyrus of the hippocampus and progressive cognitive decline after brain radiation. 1 Peissner W. Kocher M. Treuer H. et al. Ionizing radiation-induced apoptosis of proliferating stem cells in the dentate gyrus of the adult rat hippocampus. Brain Res Mol Brain Res. 1999; 71: 61-68 Crossref PubMed Scopus (172) Google Scholar These effects begin within hours of radiation, are dose-dependent, occur at doses as low as 2 Gy, and persist for months. 2 Tada E. Parent J.M. Lowenstein D.H. et al. X-irradiation causes a prolonged reduction in cell proliferation in the dentate gyrus of adult rats. Neuroscience. 2000; 99: 33-41 Crossref PubMed Scopus (251) Google Scholar In the late 2000s, the hippocampus as an organ at risk emerged as a hot topic 3 Barani I.J. Benedict S.H. Lin P.-S. Neural stem cells: Implications for the conventional radiotherapy of central nervous system malignancies. Int J Radiat Oncol Biol Phys. 2007; 68: 324-333 Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar ; studies in humans reported a relationship between hippocampal radiation dose and cognitive toxicity in both adults 4 Hsiao K.-Y. Yeh S.-A. Chang C.-C. et al. Cognitive function before and after intensity-modulated radiation therapy in patients with nasopharyngeal carcinoma: A prospective study. Int J Radiat Oncol Biol Phys. 2010; 77: 722-726 Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar , 5 Jalali R. Mallick I. Dutta D. et al. Factors influencing neurocognitive outcomes in young patients with benign and low-grade brain tumors treated with stereotactic conformal radiotherapy. Int J Radiat Oncol Biol Phys. 2010; 77: 974-979 Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar , 6 Gondi V. Hermann B.P. Mehta M.P. et al. Hippocampal dosimetry predicts neurocognitive function impairment after fractionated stereotactic radiotherapy for benign or low-grade adult brain tumors. Int J Radiat Oncol Biol Phys. 2012; 83: e487-e493 Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar and children. 7 Armstrong G.T. Jain N. Liu W. et al. Region-specific radiotherapy and neuropsychological outcomes in adult survivors of childhood CNS malignancies. Neuro Oncol. 2010; 12: 1173-1186 Crossref PubMed Scopus (100) Google Scholar ,8 Redmond K.J. Mahone E.M. Terezakis S. et al. Association between radiation dose to neuronal progenitor cell niches and temporal lobes and performance on neuropsychological testing in children: A prospective study. Neuro Oncol. 2013; 15: 360-369 Crossref PubMed Scopus (69) Google Scholar Subsequently, data from single-arm prospective clinical trials in patients with brain metastases, 9 Gondi V. Pugh S.L. Tome W.A. et al. Preservation of memory with conformal avoidance of the hippocampal neural stem-cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): A phase II multi-institutional trial. J Clin Oncol. 2014; 32: 3810-3816 Crossref PubMed Scopus (662) Google Scholar small cell lung cancer prophylactic cranial irradiation, 10 Redmond K.J. Hales R.K. Anderson-Keightly H. et al. Prospective study of hippocampal-sparing prophylactic cranial irradiation in limited-stage small cell lung cancer. Int J Radiat Oncol Biol Phys. 2017; 98: 603-611 Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar and glioblastoma 11 Gui C. Vannorsdall T.D. Kleinberg L.R. et al. A prospective cohort study of neural progenitor cell-sparing radiation therapy plus temozolomide for newly diagnosed patients with glioblastoma. Neurosurgery. 2020; 87: E31-E40 Crossref PubMed Scopus (6) Google Scholar were published, supporting this hypothesis. Here, we highlight recent prospective studies focusing on cognitive outcomes correlated with RT dose and injury to specific brain substructures, including the hippocampi. We also discuss the effect of our growing understanding of complex structural-functional-neurocognitive relationships that may inform future cognitive-sparing clinical trials in patients with brain tumors.