Why avoid the hippocampus? A comprehensive review

Abstract

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.

Conflict of interest statement

Conflicts of Interest Statement: Wolfgang Tome serves as a consultant to and receives research funding from Philips Radiation Oncology Systems. Minesh Mehta serves or has served as a consultant for Adnexus, Bayer, Genentech, Merck, Tomotherapy, and YM BioSciences; has stock ownership in Pharmacyclics and Tomotherapy; and, serves on the Board of Directors of Pharmacyclics.

Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Figures

Figure 1. Decline in memory-related neurocognitive domains at 4 months after WBRT

Change of mean normalized neurocognitive function (NCF) test scores in patients who were surviving at the fourth month. The scores were normalized to individual patient’s own baseline. Figure represents NCF tests where higher scores reflect better function. (A) Recall, (B) delayed recall, (C) recognition, and (D) controlled oral word association (COWA). Each data point represents the mean NCF score ± SE. r represents Spearman’s correction coefficient between mean test scores and time. (*) P value < 0.05 is considered statistically significant.

Figure 2. No change in executive function and fine motor coordination neurocognitive domains at 4 months after WBRT

Change of mean normalized neurocognitive function (NCF) test scores in patients who were surviving at the fourth month. The scores were normalized to individual patient’s own baseline. Figure represents NCF tests where higher scores reflect better function. (A) Pegboard Dominant Hand, (B) Pegboard Nondominant Hand, (C) Trailmaking A, and (D) Trailmaking B. Each data point represents the mean NCF score ± SE. r represents Spearman’s correction coefficient between mean test scores and time. (*) P value < 0.05 is considered statistically significant.

Figure 3. Targeted approach to avoiding the hippocampus

(A) The hippocampus (orange) was contoured by focusing on the dentate gyrus and cornus ammonus, rather than the entire limbic circuit, using T1-weighted magnetic resonance imaging (MRI) sagittal and coronal sequences. The hippocampal avoidance region (green) was generated by expanding the hippocampal contour by 5 mm volumetrically to account for setup error. (B) Spatial isodose distribution for 1 sample patient at the level of the hippocampi for hippocampal-avoidance during whole-brain radiotherapy (prescription of 30 Gy in 10 fractions) using helical tomotherapy. Orange contour represents the hippocampal avoidance region. Green isodose represents 12 Gy; light blue, 27 Gy; pink, 29 Gy; yellow, 30 Gy; red, 38 Gy, in 10 fractions.