The goal of this review is to summarize the rationale for and feasibility of hippocampal sparing techniques during brain irradiation. Radiotherapy is the most effective non-surgical treatment of brain tumors and with the improvement in overall survival for these patients over the last few decades, there is an effort to minimize potential adverse effects leading to possible worsening in quality of life, especially worsening of neurocognitive function. The hippocampus and associated limbic system have long been known to be important in memory formation and pre-clinical models show loss of hippocampal stem cells with radiation as well as changes in architecture and function of mature neurons. Cognitive outcomes in clinical studies are beginning to provide evidence of cognitive effects associated with hippocampal dose and the cognitive benefits of hippocampal sparing. Numerous feasibility planning studies support the feasibility of using modern radiotherapy systems for hippocampal sparing during brain irradiation. Although results of the ongoing phase II and phase III studies are needed to confirm the benefit of hippocampal sparing brain radiotherapy on neurocognitive function, it is now technically and dosimetrically feasible to create hippocampal sparing treatment plans with appropriate irradiation of target volumes. The purpose of this review is to provide a brief overview of studies that provide a rationale for hippocampal avoidance and provide summary of published feasibility studies in order to help clinicians prepare for clinical usage of these complex and challenging techniques.

Department of Radiation Oncology Faculty of Medicine Masaryk University and Masaryk Memorial Cancer Institute Zluty kopec 7 656 53 Brno Czech Republic

See more in PubMed

Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64(1):9–29. PubMed

Larson DA, Rubenstein JL, McDermott MW. In: Devita, Hellman & Rosenberg’s Cancer: Principles & Practice of Oncology. 8. DeVita VT, Lawrence TS, Rosenberg SA, editor. Philadelphia: Lippincott Williams & Wilkins; 2001. Metastatic Cancer to the Brain; pp. 2461–2475.

Laack NN, Brown PD. Cognitive sequelae of brain radiation in adults. Semin Oncol. 2004;31(5):702–713. PubMed

Caine C, Mehta MP, Laack NN, Gondi V. Cognitive function testing in adult brain tumor trials: lessons from a comprehensive review. Expert Rev Anticancer Ther. 2012;12(5):655–667. PubMed

Abe E, Aoyama H. The role of whole brain radiation therapy for the management of brain metastases in the era of stereotactic radiosurgery. Curr Oncol Rep. 2012;14(1):79–84. PubMed

Gondi V, Tomé WA, Mehta MP. Why avoid the hippocampus? A comprehensive review. Radiother Oncol. 2010;97(3):370–376. PubMed PMC

Chen XJ, Xiao JP, Li XP, Jiang XS, Zhang Y, Xu YJ, Dai JR, Li YX. Risk factors of distant brain failure for patients with newly diagnosed brain metastases treated with stereotactic radiotherapy alone. Radiat Oncol. 2011;6:175. PubMed PMC

Aoyama H, Shirato H, Tago M, Nakagawa K, Toyoda T, Hatano K, Kenjyo M, Oya N, Hirota S, Shioura H, Kunieda E, Inomata T, Hayakawa K, Katoh N, Kobashi G. Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA. 2006;295(21):2483–2491. PubMed

Meyers CA, Brown PD. Role and relevance of neurocognitive assessment in clinical trials of patients with CNS tumors. J Clin Oncol. 2006;24(8):1305–1309. PubMed

Brown PD, Pugh S, Laack NN, Wefel JS, Khuntia D, Meyers C, Choucair A, Fox S, Suh JH, Roberge D, Kavadi V, Bentzen SM, Mehta MP, Watkins-Bruner D. Radiation Therapy Oncology Group (RTOG) Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial. Neuro Oncol. 2013;15(10):1429–1437. PubMed PMC

Gondi V, Mehta MP, Pugh S, Tome WA, Kanner A, Caine C, Rowley H, Kundapur V, Greenspoon JN, Kachnic L. Memory preservation with conformal avoidance of the hippocampus during whole-brain radiation therapy for patients with brain metastases: primary endpoint results of RTOG 0933. Int J Radiat Oncol Biol Phys. 2013;87(5):1186.

Meyers CA, Rock EP, Fine HA. Refining endpoints in brain tumor clinical trials. J Neurooncol. 2012;108(2):227–230. PubMed

Tallet AV, Azria D, Barlesi F, Spano JP, Carpentier AF, Gonçalves A, Metellus P. Neurocognitive function impairment after whole brain radiotherapy for brain metastases: actual assessment. Radiat Oncol. 2012;7:77. PubMed PMC

Raber J, Rola R, LeFevour A, Morhardt D, Curley J, Mizumatsu S, VandenBerg SR, Fike JR. Radiation-induced cognitive impairments are associated with changes in indicators of hippocampal neurogenesis. Radiat Res. 2004;162(1):39–47. PubMed

Lautin A. Limbic Brain. New York: Kluwer Academic/Plenum; 2001.

Tofilon PJ, Fike JR. The radioresponse of the central nervous system: a dynamic process. Radiat Res. 2000;153(4):357–370. PubMed

Wong CS, Van der Kogel AJ. Mechanisms of radiation injury to the central nervous system: implications for neuroprotection. Mol Interv. 2004;4(5):273–284. PubMed

Cameron HA, Woolley CS, McEwen BS, Gould E. Differentiation of newly born neurons and glia in the dentate gyrus of the adult rat. Neuroscience. 1993;56(2):337–344. PubMed

Barani IJ, Benedict SH, Lin PS. Neural stem cells: implications for the conventional radiotherapy of central nervous system malignancies. Int J Radiat Oncol Biol Phys. 2007;68(2):324–333. PubMed

Gage FH, Kempermann G, Palmer TD, Peterson DA, Ray J. Multipotent progenitor cells in the adult dentate gyrus. J Neurobiol. 1998;36(2):249–266. PubMed

Song H, Stevens CF, Gage FH. Astroglia induce neurogenesis from adult neural stem cells. Nature. 2002;417(6884):39–44. PubMed

Palmer TD, Willhoite AR, Gage FH. Vascular niche for adult hippocampal neurogenesis. J Comp Neurol. 2000;425(4):479–494. PubMed

Bellinzona M, Gobbel GT, Shinohara C, Fike JR. Apoptosis is induced in the subependyma of young adult rats by ionizing irradiation. Neurosci Lett. 1996;208(3):163–166. PubMed

Peissner W, Kocher M, Treuer H, Gillardon F. Ionizing radiation-induced apoptosis of proliferating stem cells in the dentate gyrus of the adult rat hippocampus. Brain Res Mol Brain Res. 1999;71(1):61–68. PubMed

Yoneoka Y, Satoh M, Akiyama K, Sano K, Fujii Y, Tanaka R. An experimental study of radiation-induced cognitive dysfunction in an adult rat model. Br J Radiol. 1999;72(864):1196–1201. PubMed

Abayomi OK. Pathogenesis of irradiation-induced cognitive dysfunction. Acta Oncol. 1996;35(6):659–663. PubMed

Mizumatsu S, Monje ML, Morhardt DR, Rola R, Palmer TD, Fike JR. Extreme sensitivity of adult neurogenesis to low doses of X-irradiation. Cancer Res. 2003;63(14):4021–4027. PubMed

Bálentová S, Hajtmanová E, Kinclová I, Lehotský J, Dobrota D, Adamkov M. Radiation-induced long-term alterations in hippocampus under experimental conditions. Klin Onkol. 2012;25(2):110–116. PubMed

Monje ML, Mizumatsu S, Fike JR, Palmer TD. Irradiation induces neural precursor-cell dysfunction. Nat Med. 2002;8(9):955–962. PubMed

Lee WH, Warrington JP, Sonntag WE, Lee YW. Irradiation alters MMP-2/TIMP-2 system and collagen type IV degradation in brain. Int J Radiat Oncol Biol Phys. 2012;82(5):1559–1566. PubMed PMC

Greene-Schloesser D, Robbins ME, Peiffer AM, Shaw EG, Wheeler KT, Chan MD. Radiation-induced brain injury: a review. Front Oncol. 2012;2:73. PubMed PMC

Fike JR, Rosi S, Limoli CL. Neural precursor cells and central nervous system radiation sensitivity. Semin Radiat Oncol. 2009;19(2):122–132. PubMed PMC

Acharya MM, Lan ML, Kan VH, Patel NH, Giedzinski E, Tseng BP, Limoli CL. Consequences of ionizing radiation-induced damage in human neural stem cells. Free Radic Biol Med. 2010;49(12):1846–1855. PubMed

Limoli CL, Giedzinski E, Rola R, Otsuka S, Palmer TD, Fike JR. Radiation response of neural precursor cells: linking cellular sensitivity to cell cycle checkpoints, apoptosis and oxidative stress. Radiat Res. 2004;161(1):17–27. PubMed

Parihar VK, Limoli CL. Cranial irradiation compromises neuronal architecture in the hippocampus. Proc Natl Acad Sci U S A. 2013;110(31):12822–12827. PubMed PMC

Lawrence YR, Li XA, el Naqa I, Hahn CA, Marks LB, Merchant TE, Dicker AP. Radiation dose-volume effects in the brain. Int J Radiat Oncol Biol Phys. 2010;76(Suppl 3):S20–S27. PubMed PMC

Gondi V, Tolakanahalli R, Mehta MP, Tewatia D, Rowley H, Kuo JS, Khuntia D, Tomé WA. 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;78(4):1244–1252. PubMed PMC

Marsh JC, Godbole R, Diaz AZ, Gielda BT, Turian JV. Sparing of the hippocampus, limbic circuit and neural stem cell compartment during partial brain radiotherapy for glioma: a dosimetric feasibility study. J Med Imaging Radiat Oncol. 2011;55(4):442–449. PubMed

van Kesteren Z, Belderbos J, van Herk M, Olszewska A, Lamers E, De Ruysscher D, Damen E, van Vliet-Vroegindeweij C. A practical technique to avoid the hippocampus in prophylactic cranial irradiation for lung cancer. Radiother Oncol. 2012;102(2):225–227. PubMed

Hall EJ, Giacci AJ. In: Radiobiology for the Radiologist. 6. Hall EJ, Giacci AJ, editor. Philadelphia: Lippincott Williams & Wilkins; 2006. Dose–Response Relationships for Model Normal Tissues; pp. 303–326.

Merchant TE, Kiehna EN, Kun LE, Mulhern RK, Li C, Xiong X, Boop FA, Sanford RA. Phase II trial of conformal radiation therapy for pediatric patients with craniopharyngioma and correlation of surgical factors and radiation dosimetry with change in cognitive function. J Neurosurg. 2006;104(2 Suppl):94–102. PubMed

Merchant TE, Conklin HM, Wu S, Lustig RH, Xiong X. Late effects of conformal radiation therapy for pediatric patients with low-grade glioma: prospective evaluation of cognitive, endocrine, and hearing deficits. J Clin Oncol. 2009;27(22):3691–3697. PubMed PMC

Gondi V, Hermann BP, Mehta MP, Tomé WA. 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(4):e487–e493. PubMed PMC

Taylor BF, Picone J, Kimmett J, Chen Z, Knisely JPS. Improved Hippocampal-sparing using an asymmetric conformal Arc technique for treatment of pituitary lesions. Int J Radiat Oncol Biol Phys. 2011;81(2):S291–S292.

Marsh JC, Godbole R, Diaz A, Herskovic A, Turian J. Feasibility of cognitive sparing approaches in children with intracranial tumors requiring partial brain radiotherapy: a dosimetric study using tomotherapy. J Cancer Ther Res. 2012;1:1.

Nevelsky A, Ieumwananonthachai N, Kaidar-Person O, Bar-Deroma R, Nasrallah H, Ben-Yosef R, Kuten A. Hippocampal-sparing whole-brain radiotherapy using Elekta equipment. J Appl Clin Med Phys. 2013;14(3):4205. PubMed PMC

Gutiérrez AN, Westerly DC, Tomé WA, Jaradat HA, Mackie TR, Bentzen SM, Khuntia D, Mehta MP. Whole brain radiotherapy with hippocampal avoidance and simultaneously integrated brain metastases boost: a planning study. Int J Radiat Oncol Biol Phys. 2007;69(2):589–597. PubMed PMC

Prokic V, Wiedenmann N, Fels F, Schmucker M, Nieder C, Grosu AL. Whole brain irradiation with hippocampal sparing and dose escalation on multiple brain metastases: a planning study on treatment concepts. Int J Radiat Oncol Biol Phys. 2013;85(1):264–270. PubMed

Awad R, Fogarty G, Hong A, Kelly P, Ng D, Santos D, Haydu L. Hippocampal avoidance with volumetric modulated arc therapy in melanoma brain metastases - the first Australian experience. Radiat Oncol. 2013;8:62–67. PubMed PMC

Hsu F, Carolan H, Nichol A, Cao F, Nuraney N, Lee R, Gete E, Wong F, Schmuland M, Heran M, Otto K. Whole brain radiotherapy with hippocampal avoidance and simultaneous integrated boost for 1–3 brain metastases: a feasibility study using volumetric modulated arc therapy. Int J Radiat Oncol Biol Phys. 2010;76(5):1480–1485. PubMed

Marsh JC, Gielda BT, Herskovic AM, Wendt JA, Turian JV. Sparing of the hippocampus and limbic circuit during whole brain radiation therapy: a dosimetric study using helical tomotherapy. J Med Imaging Radiat Oncol. 2010;54(4):375–382. PubMed

Marsh JC, Godbole RH, Herskovic AM, Gielda BT, Turian JV. Sparing of the neural stem cell compartment during whole-brain radiation therapy: a dosimetric study using helical tomotherapy. Int J Radiat Oncol Biol Phys. 2010;78(3):946–954. PubMed

Konrad C, Ukas T, Nebel C, Arolt V, Toga AW, Narr KL. Defining the human hippocampus in cerebral magnetic resonance images-an overview of current segmentation protocols. Neuroimage. 2009;47(4):1185–1195. PubMed PMC

Stěpán-Buksakowska I, Szabó N, Hořínek D, Tóth E, Hort J, Warner J, Charvát F, Vécsei L, Roček M, Kincses ZT. Cortical and subcortical atrophy in Alzheimer disease: parallel atrophy of thalamus and hippocampus. Alzheimer Dis Assoc Disord. 2014;28(1):65–72. PubMed

Hippocampal contouring: a contouring Atlas for RTOG 0933. [ http://www.rtog.org/LinkClick.aspx?fileticket=59vaU8vfgQc%3d&tabid=338]

Chera BS, Amdur RJ, Patel P, Mendenhall WM. A radiation oncologist’s guide to contouring the hippocampus. Am J Clin Oncol. 2009;32(1):20–22. PubMed

Marsh JC, Ziel GE, Diaz AZ, Wendt JA, Gobole R, Turian JV. Integral dose delivered to normal brain with conventional intensity-modulated radiotherapy (IMRT) and helical tomotherapy IMRT during partial brain radiotherapy for high-grade gliomas with and without selective sparing of the hippocampus, limbic circuit and neural stem cell compartment. J Med Imaging Radiat Oncol. 2013;57(3):378–383. PubMed

Boehling NS, Grosshans DR, Bluett JB, Palmer MT, Song X, Amos RA, Sahoo N, Meyer JJ, Mahajan A, Woo SY. Dosimetric comparison of three-dimensional conformal proton radiotherapy, intensity-modulated proton therapy, and intensity-modulated radiotherapy for treatment of pediatric craniopharyngiomas. Int J Radiat Oncol Biol Phys. 2012;82(2):643–652. PubMed

Marsh JC, Herskovic AM, Gielda BT, Hughes FF, Hoeppner T, Turian J, Abrams RA. Intracranial metastatic disease spares the limbic circuit: a review of 697 metastatic lesions in 107 patients. Int J Radiat Oncol Biol Phys. 2010;76(2):504–512. PubMed

Gondi V, Tome WA, Marsh J, Struck A, Ghia A, Turian JV, Bentzen SM, Kuo JS, Khuntia D, Mehta MP. Estimated risk of perihippocampal disease progression after hippocampal avoidance during whole-brain radiotherapy: safety profile for RTOG 0933. Radiother Oncol. 2010;95(3):327–331. PubMed PMC

Ghia A, Tomé WA, Thomas S, Cannon G, Khuntia D, Kuo JS, Mehta MP. Distribution of brain metastases in relation to the hippocampus: implications for neurocognitive functional preservation. Int J Radiat Oncol Biol Phys. 2007;68(4):971–977. PubMed

Hong AM, Suo C, Valenzuela M, Haydu LE, Jacobsen KD, Reisse CH, Fogarty G. Low incidence of melanoma brain metastasis in the hippocampus. Radiother Oncol. 2014;111(1):59–62. PubMed

Evers P, Lee PP, DeMarco J, Agazaryan N, Sayre JW, Selch M, Pajonk F. Irradiation of the potential cancer stem cell niches in the adult brain improves progression-free survival of patients with malignant glioma. BMC Cancer. 2010;10:384. PubMed PMC

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