In this review article, we provide a detailed and comprehensive discussion of the rationale for using modern IMRT techniques to spare the subgranular zone of the hippocampus during cranial irradiation. We review the literature on neurocognitive effects of cranial irradiation; discuss clinical and preclinical data associating damage to neural progrenitor cells located in subgranular zone of the hippocampus with radiation-induced neurocognitive decline, specifically in terms of short-term memory formation and recall; and present a review of our pilot investigations into the feasibility and risks of sparing the subgranular zone of the hippocampus during whole-brain radiotherapy for brain metastases. We also introduce our phase II cooperative group clinical trial (RTOG 0933) designed to prospectively evaluate the postulated neurocognitive benefit of hippocampal subgranular zone sparing and scheduled to open in 2010. Neurocognitive Toxicity after Cranial IrradiationCranial irradiation is an effective therapeutic modality in multiple different settings of oncologic management: whole-brain radiotherapy (WBRT) for brain metastases, prophylactic cranial irradiation (PCI) for small cell lung cancer (and controversially for nonsmall-cell lung cancer), and cranial or craniospinal irradiation for pediatric central nervous system malignancies. The benefit of cranial irradiation in these settings largely arises from 1) the inadequate penetration of systemic therapies across the blood-brain barrier and 2) the ability of cranial irradiation to effectively target microscopic and/or gross intracranial disease.Several prospective randomized trials have shown that withholding WBRT in patients with brain metastases leads to a 70-300% increase in the relative risk of developing brain metastases, compared to delivering up-front WBRT at the time of diagnosis of brain metastases, and this observation was reinforced in the recently completed (but as yet unpublished) EORTC trial (1-4). For example, in the landmark Patchell et al. study (2), the absolute risk of any intracranial failure with and without up-front WBRT was 18% vs 70%, implying an absolute increase of 52% in any brain failure without WBRT over a baseline Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. (3,7,8). This early component primarily reflects verbal and short-term memory recall (9-11). However, whether this early decline in memory is associated with long-term and/or permanent decline has not been adequately studied, and some preliminary data suggest a possible late rebound, implying the presence of an earlyresponding cel...

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