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 Table of Contents  
Year : 2020  |  Volume : 11  |  Issue : 4  |  Page : 178-182

Dosimetric evaluation of hippocampus incidental radiation dose in nasopharyngeal cancer patients treated with intensity-modulated radiotherapy

Department of Radiation Oncology, Father Muller Medical College, Mangalore, Karnataka, India

Date of Submission28-Oct-2020
Date of Acceptance21-Jan-2020
Date of Web Publication30-Dec-2020

Correspondence Address:
Dr. M S Athiyamaan
Department of Radiation Oncology, Father Muller Medical College, Mangalore, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jrcr.jrcr_56_20

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Background: The incidental radiation exposure to hippocampus during radiation therapy for nasopharyngeal cancers may contribute to short-term toxicity like disequilibrium and lack of inhibition and also to long-term memory loss. Objective: To diametrically evaluate the dose received by hippocampus in patients with nasopharyngeal cancer undergoing intensity-modulated radiotherapy (IMRT). Materials and Methods: Eleven patients with histologically proven locally advanced nasopharyngeal squamous cell carcinoma were retrospectively analyzed in this study. The total prescribed dose to the planning target volume was 70 Gy (D95%) delivered in 2 Gy daily fractions using IMRT technique. Employing the anatomical guidelines and magnetic resonance imaging coregistration, the hippocampi were delineated on axial imaging from the simulation computed tomography scan for each patient. IMRT treatment plans were generated without applying dose–volume constraints to the hippocampus. Maximum hippocampus dose, mean hippocampus dose, minimum hippocampus dose, and hippocampus volume receiving 3 Gray dose (V3Gy) were analyzed. Results: The mean hippocampus volume was 4.7 cm3. The average minimum dose to the entire hippocampus was 5.276 Gy (range, 0.072–18.609 Gy); the average maximum point dose to the hippocampus was 21.405 Gy (range, 0.595–59.832 Gy); and the average mean dose to the entire hippocampus volume was 10.922 Gy (range, 0.194–34.706 Gy) and V3Gy was 79.15 Gy (range, 0%–100%). Conclusion: The dosimetric analysis suggests that patients who underwent IMRT for nasopharyngeal cancer received significantly high incidental dose to the hippocampus. The study creates awareness regarding the need to routinely delineate hippocampus as an organ at risk in the radiotherapy for nasopharyngeal cancers.

Keywords: Dosimetry, hippocampus, intensity-modulated radiotherapy, nasopharyngeal cancers

How to cite this article:
Jacob T, Fernandes D, Athiyamaan M S, Rao B S, Shankar S, Vidyasagar M S, Mohsina V. Dosimetric evaluation of hippocampus incidental radiation dose in nasopharyngeal cancer patients treated with intensity-modulated radiotherapy. J Radiat Cancer Res 2020;11:178-82

How to cite this URL:
Jacob T, Fernandes D, Athiyamaan M S, Rao B S, Shankar S, Vidyasagar M S, Mohsina V. Dosimetric evaluation of hippocampus incidental radiation dose in nasopharyngeal cancer patients treated with intensity-modulated radiotherapy. J Radiat Cancer Res [serial online] 2020 [cited 2021 Jun 25];11:178-82. Available from: https://www.journalrcr.org/text.asp?2020/11/4/178/305728

  Introduction Top

Intensity-modulated radiotherapy (IMRT) is the current standard treatment for patients with head-and-neck cancer. The use of highly conformal plans with steep fall-off gradients comes at the expense of significant doses to those organs that are not delineated.[1] Due to the anatomical relationship of many head-and-neck cancers to the central nervous system, studies are being investigated to see the effects on neurocognitive function due to radiation exposure on specific structures in the brain. The hippocampus is a paired horseshoe-shaped structure of the limbic system, located within the temporal lobes. Its main function is to relate the formation of new memories, spatial navigation, and connecting the emotions and senses of sound and smell, to memories.

It has been hypothesized that incidental exposure to hippocampus may contribute not only to short-term toxicity, such as lack of inhibition and disequilibrium, but also to long-term memory loss.[2] Therefore, the purpose of this study was to assess the dosimetric parameters in nasopharyngeal cancer patients treated by IMRT to assess incidental exposure to the hippocampus.

  Materials and Methods Top


Eleven patients with histopathologically confirmed locally advanced nasopharyngeal carcinoma treated by IMRT constituted the study population after obtaining institutional ethics committee approval. [Table 1] shows the patient and treatment characteristics. During simulation, the head, neck, and shoulders were immobilized in a hyperextended position with the help of thermoplastic head mask with the neck supported on a carbon fiber board. The isocenter was placed within the primary gross tumor. Axial slices with 2.5-mm spacing were obtained on a computed tomography (CT)-based simulator and transferred into the? ECLIPSE Aria version 13 Treatment Planning System, Varian Medical Systems Inc. Ltd, Hansen Way, California, USA treatment planning system.
Table 1: Patient characteristics and tumor staging

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Intensity-modulated radiotherapy treatment planning

The gross tumor volume (GTV) was defined as the extent of tumor defined by imaging studies and clinical examination. Magnetic resonance imaging (MRI) was coregistered with the planning CT data to assist in defining the extent of tumor. Target volumes were defined: clinical target volume (CTV), which included the GTV with a 0.5–1 cm margin to account for microscopic spread and the nodal areas both at high risk and low risk for recurrence. An additional margin of 0.5 cm was added to the CTV to compensate for the treatment setup errors and internal organ motion to create separate planning target volumes (PTVs). The aim of IMRT was to deliver a prescribed dose of 70 Gy to 95% of the PTV, over 35 treatments with once-daily conventional fractionation. The field size reduction was applied during the course of radiation therapy. Plans were optimized using an inverse planning module that used anisotropic analytical algorithm. Dose was prescribed based on a dose distribution corrected for heterogeneities. The plans were evaluated qualitatively by visually inspecting various isodose curves on axial slices and quantitatively with dose–volume histogram. Hippocampus was not assigned as a critical structure delineated for avoidance.

Hippocampus contouring

For all patients, bilateral hippocampi were retrospectively delineated on axial images obtained from simulation CT. Using the anatomical contouring guidelines by Chera et al.[3] and the MRI coregistration, the right and left hippocampi were contoured starting from the anterior most portion of the lateral ventricle, where the medial, lateral, and anterior portions of the hippocampus were identified.[3] Superiorly, the boundary of hippocampus consisted of the medial most region of the temporal lobe. Inferiorly, the boundary of hippocampus was defined at the level of the pituitary gland and the pons.


Ranges of dose–volume statistics for every patient's hippocampus were then calculated. The mean hippocampus volume (cm3), maximum hippocampus dose (Dmax), mean hippocampus dose, minimum hippocampus dose, and hippocampus volume receiving 3 Gray dose (V3Gy) were analyzed. [Figure 1] demonstrates the hippocampus, with dose color wash of 50% of treatment isodose.
Figure 1: Dose wash for a typical nasopharyngeal intensity-modulated radiotherapy

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  Results Top

The mean hippocampus volume was 4.7 cm3. [Table 2] summarizes the dosimetric characteristics for all the patients. The average minimum dose to the entire hippocampus was 5.276 Gy (range, 0.072–18.609 Gy); the average maximum point dose to the hippocampus was 21.405 Gy (range, 0.595–59.832 Gy); and the average mean dose to the entire hippocampus volume was 10.922 Gy (range, 0.194–34.706 Gy) and V3Gy was 79.15 Gy (range, 0%–100%).
Table 2: Hippocampus dosimetric characteristics

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  Discussion Top

Our study shows with evidence that patients with nasopharyngeal carcinoma undergoing IMRT receive significant incidental radiation dose to the hippocampus. Of the 11 patients studied, 10 show a significantly high dose to bilateral hippocampi. Study by Scoccianti et al.[4] provided dose constraints to various structures in brain and showed a Dmax of =6 Gy and V3Gy =20% to bilateral hippocampi, but the average Dmax and V3Gy observed in the current study was 21.405 Gy and V3Gy 79.15%, which far exceeded the constraints described.

The cognitive dysfunction seems to be proportional to the volume and amount of irradiated tissue in this location; the delineation of this portion of hippocampus has recently become a crucial point during the treatment planning process. Chera et al.[3] have recently published the contouring guidelines for the hippocampus. The constraints used for the hippocampus vary a lot in the literature,[2],[5],[6],[7],[8],[9],[10] but they have seldom been associated with clinical outcome.

Previous studies have demonstrated that hippocampus-dependent deficits of memory and learning occur in nasopharyngeal cancer patients after high dose of definitive radiation therapy. Lee et al.[11] in their observation of 16 patients with nasopharyngeal cancer after a mean follow-up of 6 years after treatment showed that the inferior temporal lobe, which includes only a portion of the hippocampus, received an average dose of 53 Gy. Further, on comparison with control subjects who had yet to be treated with radiation therapy, these patients had lower overall intelligence quotient and deficits in nonverbal memory recall with a significant number of memory-related complaints. Hsiao et al.[12] conducted a prospective study comparing the neurocognitive function of patients with nasopharyngeal cancer before and after IMRT. Patients who received a mean dose 36 Gy to the temporal lobe had significantly lower score on the neurocognitive examination at a mean follow-up of 18 months after treatment. The study also found that patients who received more than 60 Gy to 10% of their temporal lobe scored much lower on the neurocognitive examination.

The hippocampus-dependent complications relate to temporal lobe necrosis, which is due to radiation-induced reactive white matter inflammation, and show a hypodense or cystic findings on imaging. The incidence of temporal lobe necrosis has been observed to range from 5% in 10 years with conventional fractionation to as high as 35% in 5 years with accelerated fractionation.[13],[14],[15]

Cheung et al.[16] observed significantly greater neurocognitive deficits after nasopharyngeal cancer radiation therapy who developed temporal lobe necrosis than in those who did not. These deficits included deterioration in verbal and visual memory, motor ability, language, planning, and abstract thinking.

It is proven that the hippocampus is one of the regions of the brain where multipotent stem cells reside. These neuronal stem cells within the dentate gyrus subgranular zone of the hippocampus undergo active cell division and differentiation.[17] The neuronal stem cells are highly sensitive to radiation. In vivo animal studies targeting the subgranular zone have reported that 10 Gy of radiation exposure will lead to both declines in neurogenesis and deficits in cognitive function. The threshold for cognitive injury is as little as 5 Gy of the exposure.[18],[19],[20],[21],[22] Many of these progenitor stem cells may undergo apoptosis, while majority of the surviving cells adopt a glial change. The lack of neurogenesis leads to failure to replenish the population of cells essential for the functions of hippocampus--dependent learning and memory.

The small sample size of the study and the lack of prospective clinical correlation to assess the neurocognitive status of patient after a long-term follow-up were a few limitations of the study.

  Conclusion Top

This study is to create awareness regarding the need to delineate the hippocampus as an organ at risk (OAR) for patients undergoing IMRT treatment for nasopharyngeal cancer. This hypothesis-generating study shows that nasopharyngeal cancer patients undergoing definitive radiation receive significant doses to the hippocampus. With the advent of newer radiation delivery techniques, there is a significant increase in the overall survival benefit. The clinical implications will become increasingly significant as patients survive longer with improvements in treatment. Further prospective studies assessing the relationship between clinical neurocognitive functioning and the hippocampus dosimetry will help in defining optimal constraints for this OAR in the future.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Rosenthal DI, Chambers MS, Fuller CD, Rebueno NC, Garcia J, Kies MS, et al. Beam path toxicities to non-target structures during intensity-modulated radiation therapy for head and neck cancer. Int J Radiat Oncol Biol Phys 2008;72:747-55.  Back to cited text no. 1
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:e487-93.  Back to cited text no. 2
Chera BS, Amdur RJ, Patel P, Mendenhall WM. A radiation oncologist's guide to contouring the hippocampus. Am J Clin Oncol 2009;32:20-2.  Back to cited text no. 3
Scoccianti S, Detti B, Gadda D, Greto D, Furfaro I, Meacci F, et al. Organs at risk in the brain and their dose-constraints in adults and in children: A radiation oncologist's guide for delineation in everyday practice. Radiother Oncol 2015;114:230-8.  Back to cited text no. 4
Gondi V, Tolakanahalli R, Mehta MP, Tewatia D, Rowley H, Kuo JS, 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;78:1244-52.  Back to cited text no. 5
Kazda T, Jancalek R, Pospisil P, Sevela O, Prochazka T, Vrzal M, et al. Why and how to spare the hippocampus during brain radiotherapy: The developing role of hippocampal avoidance in cranial radiotherapy. Radiat Oncol 2014;9:139.  Back to cited text no. 6
Franco P, Numico G, Migliaccio F, Catuzzo P, Cante D, Ceroni P, et al. Head and neck region consolidation radiotherapy and prophylactic cranial irradiation with hippocampal avoidance delivered with helical tomotherapy after induction chemotherapy for non-sinonasal neuroendocrine carcinoma of the upper airways. Radiat Oncol 2012;7:21.  Back to cited text no. 7
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;78:946-54.  Back to cited text no. 8
Pinkham MB, Bertrand KC, Olson S, Zarate D, Oram J, Pullar A, et al. Hippocampal-sparing radiotherapy: The new standard of care for World Health Organization grade II and III gliomas? J Clin Neurosci 2014;21:86-90.  Back to cited text no. 9
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.  Back to cited text no. 10
Lee PW, Hung BK, Woo EK, Tai PT, Choi DT. Effects of radiation therapy on neuropsychological functioning in patients with nasopharyngeal carcinoma. J Neurol Neurosurg Psychiatry 1989;52:488-92.  Back to cited text no. 11
Hsiao KY, Yeh SA, Chang CC, Tsai PC, Wu JM, Gau JS. Cognitive function before and after intensity-modulated radiation therapy in patients with nasopharyngeal carcinoma: A prospective study. Int J Radiat Oncol Biol Phys 2010;77:722-6.  Back to cited text no. 12
Lee AW, Foo W, Chappell R, Fowler JF, Sze WM, Poon YF, et al. Effect of time, dose, and fractionation on temporal lobe necrosis following radiotherapy for nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 1998;40:35-42.  Back to cited text no. 13
Leung SF, Kreel L, Tsao SY. Asymptomatic temporal lobe injury after radiotherapy for nasopharyngeal carcinoma: Incidence and determinants. Br J Radiol 1992;65:710-4.  Back to cited text no. 14
Su SF, Huang SM, Han F, Huang Y, Chen CY, Xiao WW, et al. Analysis of dosimetric factors associated with temporal lobe necrosis (TLN) in patients with nasopharyngeal carcinoma (NPC) after intensity modulated radiotherapy. Radiat Oncol 2013;8:17.  Back to cited text no. 15
Cheung M, Chan AS, Law SC, Chan JH, Tse VK. Cognitive function of patients with nasopharyngeal carcinoma with and without temporal lobe radionecrosis. Arch Neurol 2000;57:1347-52.  Back to cited text no. 16
Eriksson PS, Perfilieva E, Björk-Eriksson T, Alborn AM, Nordborg C, Peterson DA, et al. Neurogenesis in the adult human hippocampus. Nat Med 1998;4:1313-7.  Back to cited text no. 17
Tada E, Parent JM, Lowenstein DH, Fike JR. X-irradiation causes a prolonged reduction in cell proliferation in the dentate gyrus of adult rats. Neuroscience 2000;99:33-41.  Back to cited text no. 18
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;71:61-8.  Back to cited text no. 19
Nagai R, Tsunoda S, Hori Y, Asada H. Selective vulnerability to radiation in the hippocampal dentate granule cells. Surg Neurol 2000;53:503-6.  Back to cited text no. 20
Monje ML, Mizumatsu S, Fike JR, Palmer TD. Irradiation induces neural precursor-cell dysfunction. Nat Med 2002;8:955-62.  Back to cited text no. 21
Raber J, Rola R, LeFevour A, Morhardt D, Curley J, Mizumatsu S, et al. Radiation-induced cognitive impairments are associated with changes in indicators of hippocampal neurogenesis. Radiat Res 2004;162:39-47.  Back to cited text no. 22


  [Figure 1]

  [Table 1], [Table 2]


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