ReviewWhy avoid the hippocampus? A comprehensive review
Section snippets
Neurocognitive toxicity after cranial irradiation
Cranial 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 non-small-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
Clinical and preclinical rationale for avoiding the hippocampus
The central role of the hippocampus in supporting memory function was first understood more than fifty years ago, in the case study of H.M., a gentleman who underwent a bilateral medial temporal lobectomy for the relief of medically intractable epilepsy. Immediately following the procedure, H.M. showed a severe anterograde amnesia characterized by impairment in declarative memory (the conscious recollection of facts and events). H.M.’s amnesia, however, did not include the remaining components
Feasibility of avoiding the hippocampus
Avoiding the hippocampus during cranial irradiation, while allowing for uniform dose delivery to the remainder of the brain, poses important challenges given the central location and unique anatomic shape of the hippocampus. Recently, we demonstrated the ability of modern intensity-modulated radiotherapy (IMRT) techniques, including helical tomotherapy and LINAC-based IMRT, to allow for the delivery of highly conformal dose distributions (Fig. 3) [46]. For a prescription dose of 30 Gy in 10
Risk of perihippocampal disease progression
Sparing the hippocampus and perihippocampal region (hippocampus + 5 mm margin) of therapeutic doses of radiation poses the theoretical risk of intra-cranial disease progression in these regions. The degree of this risk is largely dependent on the volume of brain tissue that is spared. The hippocampus consists of two U-shaped interlocking laminae: the cornu ammonus and the dentate gyrus. It is a component of the entire limbic circuit, which includes white matter tracts, such as the fimbriae and
RTOG 0933: A phase II trial of hippocampal sparing
To prospectively evaluate the neurocognitive benefit of hippocampal sparing, the RTOG has developed a phase II clinical trial (RTOG 0933) to test hippocampal sparing during WBRT in patients with brain metastases (Table 2). The primary endpoint will be delayed recall assessed using HVLT at 4 months after treatment, and a planned statistical comparison will be made to an historical control of patients who received WBRT without hippocampal avoidance on a recent phase III trial (PCI-P120–9801) [55],
Summary and future directions
In summary, preclinical and clinical evidence suggest that radiation dose received by the neural stem cells of the subgranular zone in the hippocampus may play a role in radiation-induced neurocognitive decline, specifically memory recall. Although neurocognitive assessment in patients receiving WBRT can be confounded by intra-cranial metastatic disease, analyses from our group and others suggest a differential sensitivity to WBRT of various memory-related neurocognitive domains, such as
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.
References (56)
- et al.
Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial
Lancet Oncol
(2009) - et al.
Neuropsychological effects of cranial radiation: current knowledge and future directions
Int J Radiat Oncol Biol Phys
(1995) - et al.
Memory function before and after whole brain radiotherapy in patients with and without brain metastases
Int J Radiat Oncol Biol Phys
(2008) - et al.
Feasibility of neurocognitive outcome evaluations in patients with brain metastases in a multi-institutional cooperative group setting: results of Radiation Therapy Oncology Group trial BR-0018
Int J Radiat Oncol Biol Phys
(2004) - et al.
Relationship between neurocognitive function and quality of life after whole-brain radiotherapy in patients with brain metastasis
Int J Radiat Oncol Biol Phys
(2008) - et al.
Neurocognitive effects of therapeutic irradiation for base of skull tumors
Int J Radiat Oncol Biol Phys
(2000) - 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) - et al.
Separable roles of hippocampal granule cells in forgetting and pyramidal cells in remembering spatial information
Brain Res
(1987) - et al.
Differentiation of newly born neurons and glia in the dentate gyrus of the adult rat
Neuroscience
(1993) - et al.
Arrested neuronal proliferation and impaired hippocampal function following fractionated brain irradiation in the adult rat
Neuroscience
(2003)