Elsevier

Radiotherapy and Oncology

Volume 97, Issue 3, December 2010, Pages 370-376
Radiotherapy and Oncology

Review
Why avoid the hippocampus? A comprehensive review

https://doi.org/10.1016/j.radonc.2010.09.013Get rights and content

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.

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)

  • V. Gondi et al.

    Hippocampal-sparing whole-brain radiotherapy: a “how-to” technique using helical tomotherapy and linear accelerator-based intensity-modulated radiotherapy

    Int J Radiat Oncol Biol Phys

    (2010)
  • A.N. Gutierrez et al.

    Whole brain radiotherapy with hippocampal avoidance and simultaneously integrated brain metastases boost: a planning study

    Int J Radiat Oncol Biol Phys

    (2007)
  • H.A. Cameron et al.

    Adult neurogenesis is regulated by adrenal steroids in the dentate gyrus

    Neuroscience

    (1994)
  • E. Tada et al.

    X-irradiation causes a prolonged reduction in cell proliferation in the dentate gyrus of adult rats

    Neuroscience

    (2000)
  • V. Gondi et al.

    Estimated risk of perihippocampal disease progression after hippocampal avoidance during whole-brain radiotherapy: safety profile for RTOG 0933

    Radiother Oncol

    (2010)
  • A. Ghia et al.

    Distribution of brain metastases in relation to the hippocampus: implications for neurocognitive functional preservation

    Int J Radiat Oncol Biol Phys

    (2007)
  • H. Aoyama et al.

    Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial

    JAMA

    (2006)
  • R.A. Patchell et al.

    Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial

    JAMA

    (1998)
  • R.P. Mueller et al.

    Adjuvant whole-brain radiotherapy versus observation after radiosurgery for surgical resection of 1–3 cerebral metastases: results of the EORTC 22952-26001 study

    J Clin Oncol

    (2009)
  • L.M. DeAngelis et al.

    Radiation-induced dementia in patients cured of brain metastases

    Neurology

    (1989)
  • J. Li et al.

    Regression after whole-brain radiation therapy for brain metastases correlates with survival and improved neurocognitive function

    J Clin Oncol

    (2007)
  • C.A. Meyers et al.

    Role and relevance of neurocognitive assessment in clinical trials of patients with CNS tumors

    J Clin Oncol

    (2006)
  • C.A. Meyers et al.

    Neurocognitive function and progression in patients with brain metastases treated with whole-brain radiation and motexafin gadolinium: results of a randomized phase III trial

    J Clin Oncol

    (2004)
  • Movsas B, Kae K, Meyers C, et al. Phase III study of prophylactic cranial irradiation vs. observation in patients with...
  • W.B. Scoville et al.

    Loss of recent memory after bilateral hippocampal lesions

    J Neurol Neurosurg Psychiatry

    (1957)
  • S. Corkin

    What’s new with the amnesic patient H.M.?

    Nat Rev Neurosci

    (2002)
  • B. Milner

    Disorders of learning and memory after temporal lobe lesions in man

    Clin Neurosurg

    (1972)
  • D.A. Levy et al.

    Impaired visual and odor recognition memory span in patients with hippocampal lesions

    Learn Mem

    (2003)
  • Cited by (0)

    View full text