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Table of Contents
REVIEW ARTICLE
Year : 2021  |  Volume : 4  |  Issue : 1  |  Page : 8-11

Hippocampus sparing: A new perspective in neurocognitive sparing radiotherapy of brain metastasis


Department of Radiation Oncology and Radiodiagnosis, Cancer Research Institute, Swami Rama Himalayan University, Swami Rama Nagar, Dehradun, Uttarakhand, India

Date of Submission29-Oct-2020
Date of Acceptance20-May-2021
Date of Web Publication12-Apr-2022

Correspondence Address:
Dr. Meenu Gupta
Department of Radiation Oncology and Radiodiagnosis, Cancer Research Institute, Swami Rama Himalayan University, Swami Rama Nagar, 248140, Dehradun, Uttarakhand.
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJNO.IJNO_24_20

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  Abstract 

Patients with brain metastasis survival has been improved due to better diagnostic and treatment approaches. Quality of life is a major concern for these subset of patients. Seahorse of brain “Hippocampus” is the structure which plays a major role in cognitive functions which can be further alter the quality of life of these patients. Hippocampus sparing whole brain external beam radiotherapy in brain secondaries with simultaneously respecting the doses to the target volumes can be considered a novel approach for acceptable quality of life in these patients.

Keywords: Hippocampus, radiotherapy, quality of life


How to cite this article:
Gupta M, Nautiyal V, Bansal S, Saini M, Kumar V, Badola A, Ahmad M. Hippocampus sparing: A new perspective in neurocognitive sparing radiotherapy of brain metastasis. Int J Neurooncol 2021;4:8-11

How to cite this URL:
Gupta M, Nautiyal V, Bansal S, Saini M, Kumar V, Badola A, Ahmad M. Hippocampus sparing: A new perspective in neurocognitive sparing radiotherapy of brain metastasis. Int J Neurooncol [serial online] 2021 [cited 2022 Jun 27];4:8-11. Available from: https://www.Internationaljneurooncology.com/text.asp?2021/4/1/8/342820




  Introduction Top


Brain metastasis, a poor prognostic indicator, is the most common type of intracranial malignancy.[1] Brain metastases affect 30% of patients with diagnosis of primary cancer with incidence of 10 per 100,000 population across the world.[2] It is estimated to be responsible for 7.7 million deaths with an annual rate of more than 12 million diagnoses.[3] According to the GLOBOCAN 2018, the estimated incidence of the brain metastasis is 28,142 in all ages and both sexes. The overall estimated mortality in India in 2018 was 24,003 cases. The median survival rate is less than 1 year.[4]

The most common primaries to result in brain metastases are bronchogenic cancer (40–50%), breast malignancies (15–25%), melanoma (15–20%), renal cell carcinoma (5–10%), and colonic (2–5%) malignancies.[5] Extracranial primaries are mostly associated with multiple brain metastases in two-thirds to three-fourths of the patients.[6] The commonest site involved in brain metastasis is cerebral hemispheres in approximately 80% of the patients, followed by cerebellum in 15% and brainstem in 5% of cases. Frontal and parietal lobes are most commonly involved. Supratentorial involvement (80%) is more common when compared with the involvement of the infratentorial region. Symptoms at presentation are due to raised intracranial pressure such as headache (70%), frequent seizures (30%), impairment of cognitive function (30%), papilledema (8%), and various other focal neurologic deficits.[7] Whole brain radiotherapy has historically represented the standard care for individuals with brain metastases. Benefits are rapid palliation of neurological symptoms due to local control of disease, once it is delivered as an adjuvant to surgical resection or as radiosurgery modality.[8] Whole brain prophylactic irradiation is indicated for small cell carcinoma of lung, ALL, and for non-small cell lung cancers (controversial). Penetration of systemic therapies across the blood–brain barrier is limited, so cranial irradiation has an advantage of its ability to target the microscopic and/or gross intracerebral disease more accurately and precisely.[9] Various prospective randomized trials have shown that withholding “whole brain radiation therapy” in patients with metastatic brain disease resulted in “70–300% increase in the relative risk” of developing brain metastases, as cranial irradiation at the initial diagnosis of brain secondaries.[5]

Although there is dramatic reduction in neurological symptoms after radiation therapy, neurocognitive toxicity is a matter of utmost concern. In a clinical research of brain metastases survivors (>12 months) who were delivered whole brain radiation therapy, 11% of these patients develop severe dementia in which high dose per fraction schedule was given.[10]


  Radiation and hippocampus Top


Hippocampus is a small organ located in the medial temporal lobe of brain which has a compartment containing radiosensitive neural stem cells located in the “subgranular zone” responsible for processing and storage of short-term memory and converting to long-term memory. Spatial and navigation memories along with supporting life-long neurogenesis are also important and crucial functions of hippocampus. Damage to hippocampus neural stem cells during whole brain radiotherapy is associated with inability to remember new memory function suppression and impaired recall or memory retrieval including cognitive deterioration and cerebellar dysfunction with decreasing patient’s subjective quality of life.[11]

Evidence suggested that apoptosis in the subgranular zone of young rats and mice was caused by relatively small doses of radiation which was confirmed by morphology of their cells, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining, and laddering pattern of DNA. Simultaneously, minimal or “no apoptosis” was observed in other cerebral areas. Chronic decline in the subgranular zone neurogenesis by radiation resulted in cognitive deficits such as deficits in “learning, memory, and spatial processing.”[12]

Hippocampus-sparing radiation is a new option in patients of brain metastasis. This new approach preserved cognitive function, but patient prognosis is to be considered simultaneously. Hippocampus injury during radiation therapy might be prevented by the hippocampus-sparing whole brain radiotherapy. According to RTOG 0933, hippocampal avoidance whole brain radiotherapy vs. whole brain radiotherapy showed 7% vs. 30% memory score decline measured by the Hopkins verbal learning test. Avoidance of neural stem cells in the hippocampus helps to reduce neurotoxicity of whole brain radiotherapy. The principal of hippocampal avoidance whole brain radiotherapy centered around preservation of radiosensitive memory-specific neural stem compartment, the ability to reduce mean dose to this neural stem cell compartment by at least 80%, while providing acceptable coverage and dose homogeneity to the remaining whole brain parenchyma.[8] Although hippocampus-sparing radiotherapy is a new approach in brain metastasis, this option is not recommended for all cases of patients with brain metastasis.

It was announced in American Society for Radiation Oncology (ASTRO) meeting 2018 that hippocampal avoidance using intensity-modulated radiotherapy should be considered standard of care for patients with brain metastasis whose expected survival is more than 4 months.[13]

Fernandez Gonçalo et al. performed a study to assess the quality of life for patients with brain secondaries after radiotherapy treatments. Thirty-nine patients with brain metastases were enrolled in this study. All patients completed the “EORTC QLQ-C30/BN-20 questionnaire” independently. Results of this study showed differences between the baseline and 3 months post-radiotherapy follow-up in worsening of the global health status (P = 0.034), cognitive function (P = 0.004), as well as drowsiness (P = 0.001), loss of appetite (P = 0.031), and hair loss (P = 0.005). Tendency for deterioration of physical function (P = 0.004), deficit in communication (P = 0.012), and weakness of legs (P = 0.024) between baseline and at 1 month were evaluated. Global cognitive status between different evaluations showed no difference. Global quality of life status showed little deterioration, and large deterioration was noticed for cognitive function post-radiotherapy. Also there was worsening of symptom items related with brain metastasis.[14] The QLQ-BN20 and the FACT-Br tools used extensively in the brain cancer patients are both valid and reliable tools.[15] Gondi et al.[13] reported results of their patients who were delivered whole brain radiation therapy with drug memantine. They concluded that cognitive function failure at 6 months was seen in 59.5% of patients who were in the hippocampus-sparing group when compared with 68.2% of those in the control group (hazard ratio 0.76, P=0.03). Data of several previous retrospective studies indicate that none or very rare metastasis lays inside the hippocampus, and hippocampus can be safely spared during whole brain radiation therapy in patients with brain metastasis. Wu et al.[16] conducted a study on 632 patients with 6034 metastases, in which they have analyzed that hippocampal metastases located inside the hippocampus were 0.5% and 0.6% found in the perihippocampal region. Ghia et al.[17] investigated 100 patients with 272 metastases and their data showed that 3.3% of metastasis found within 5 mm of the hippocampi, 4.4% were within 5–10 mm of the hippocampi, 6.3% within 10–15 mm of the hippocampi and 86.4% were located within more than 15 mm of the hippocampi. None of these lesions was located inside the hippocampus in this study.


  Hippocampus delineation Top


Optimal imaging technique can be achieved by using three-dimensional “spoiled gradient (3D-SPGR) axial MRI scan” of the head with standard axial and coronal FLAIR, axial T2-weighted, and gadolinium contrast-enhanced T1-weighted sequence acquisitions. For contouring the hippocampus, 1.25 mm thickness is preferred. For CT simulation, non-contrast enhanced CT scan with 1.25–1.5 mm slice thickness is preferred. MRI–CT fusion is preceded by contouring the hippocampus on T1-weighted MRI axial sequences. Contouring should be initiated at the “caudal/inferior extent of the crescentic-shaped floor of the temporal horn of the lateral ventricle” and hypointense gray matter located medial to the CSF hypointensity to be contoured as shown in [Figure 1]. White or the bright white matter not to be contoured. Contouring to be continued in a cephalad/superior direction along the medial aspect of the temporal horn of the lateral ventricle, and hypointense gray matter is to be contoured. Contouring has to be kept in line with the “curved banana-shaped structure of the hippocampus” in superior posterior direction. The fimbriae and amygdala and uncus (gray matter) have to be avoided. The anterior boundary of the hippocampus is defined by the anterior edge of the temporal horn, and the “boomerang-shaped” uncus defines the medial boundary of the hippocampus. Uncal recess of the temporal horn emergence defines the anterior boundary of the hippocampus. Posterocranially, the medial boundary of the hippocampus is defined by the lateral edge of the quadrageminal cistern. The hippocampal tail remained posterior to the thalamus as it curves medially toward the splenium of the corpus callosum. Hippocampal contours are to be terminated at that point where the T1-hypointense structure no longer borders the atrium of the lateral ventricle. Here the crux of the fornix emerges anteriorly and the corpus callosum splenium can be visualized posteriorly. Contouring should be stopped where the “gray signal from the hippocampus” is no longer visible. The hippocampal avoidance zone is generated using a 5 mm volumetric expansion on the hippocampus. In the plane of the lateral ventricle, banana shape is emerged on the sagittal images.[18]
Figure 1: Delineation of the hippocampus separated from neighboring structures

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  Conclusion Top


Earlier decades, it was thought that the human brain was radioresistant and with progress of clinical and technological sectors of health, there are advancements in radiation treatment and techniques. Hippocampal sparing is one of the examples of advancement in technology. Patients can be benefited more from this palliative treatment, especially if they are being given treatment such as prophylactic cranial radiation.



 
  References Top

1.
Ranjan T, Abrey LE Current management of metastatic brain disease. Neurotherapeutics 2009;6:598-603.  Back to cited text no. 1
    
2.
Stelzer KJ Epidemiology and prognosis of brain metastases. Surg Neurol Int 2013;4(Suppl. 4):S192-202.  Back to cited text no. 2
    
3.
Patel AP, Fisher JL, Nichols E, Abd-Allah F, Abdela J, Abdelalim A Global, regional, and national burden of brain and other CNS cancer, 1990–2016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2019;18:376-93. doi: 10.1016/S1474-4422(18)30468-X.  Back to cited text no. 3
    
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Dhillon PK, Mathur P, Nandakumar A, Fitzmaurice C, Kumar GA, Mehrotra R, et al. The burden of cancers and their variations across the states of India: The Global Burden of Disease Study 1990–2016. Lancet Oncol 2018;19:1289-6. doi: 10.1016/S1470-2045(18)30447–9.  Back to cited text no. 4
    
5.
Gondi V, Tomé WA, Mehta MP Why avoid the hippocampus? A comprehensive review. Radiother Oncol 2010;97:370-6.  Back to cited text no. 5
    
6.
Tsao MN, Lloyd N, Wong RK, Chow E, Rakovitch E, Laperriere N, et al. Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases. Cochrane Database Syst Rev2012;2012:CD003869. Update in: Cochrane Database Syst Rev.2018;1:CD003869.  Back to cited text no. 6
    
7.
Saha A, Ghosh SK, Roy C, Kaya P Treatment outcomes in patients with multiple brain metastases: A prospective randomized study. Clin Cancer Investig J 2014;3:269-75.  Back to cited text no. 7
    
8.
Kim KH, Cho BC, Lee CG, Kim HR, Suh YG, Kim JW, et al. Hippocampus-sparing whole-brain radiotherapy and simultaneous integrated boost for multiple brain metastases from lung adenocarcinoma: Early response and dosimetric evaluation. Technol Cancer Res Treat2016;15:122-9.  Back to cited text no. 8
    
9.
Lim M, Puttick S, Houston ZH, Thurecht KJ, Kalita-de Croft P, Mahler S, et al. Innovative therapeutic strategies in the treatment of brain metastases. Int J Mol Sci 2019;20:1280.  Back to cited text no. 9
    
10.
DeAngelis LM, Delattre JY, Posner JB Radiation-induced dementia in patients cured of brain metastases. Neurology 1989;39:789-96.  Back to cited text no. 10
    
11.
Gondi V, Pugh SL, Tome WA, Caine C, Corn B, Kanner A, et al. Preservation of memory with conformal avoidance of the hippocampal neural stem-cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): A phase II multi-institutional trial. J Clin Oncol 2014;32:3810-6.  Back to cited text no. 11
    
12.
Yazlovitskaya EM, Edwards E, Thotala D, Fu A, Osusky KL, Whetsell WO, et al. Lithium treatment prevents neurocognitive deficit resulting from cranial irradiation. Cancer Res2006;66:11179-86.  Back to cited text no. 12
    
13.
Gondi V, Deshmukh S, Brown PD, Wefel JS, Tome WA, Bruner DW, et al. Preservation of neurocognitive function (NCF) with conformal avoidance of the hippocampus during whole-brain radiotherapy (HA-WBRT) for brain metastases: Preliminary results of Phase III Trial NRG Oncology CC001. Int J Radiat Oncol Biol Phys2018;102:1607.  Back to cited text no. 13
    
14.
Caissie A, Nguyen J, Chen E, Zhang L, Sahgal A, Clemons M, et al. Quality of life in patients with brain metastases using the EORTC QLQ-BN20+2 and QLQ-C15-PAL. Int J Radiat Oncol Biol Phys 2012;83:1238-45.  Back to cited text no. 14
    
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Chow R, Lao N, Popovic M, Chow E, Cella D, Beaumont J, et al. Comparison of the EORTC QLQ-BN20 and the FACT-Br quality of life questionnaires for patients with primary brain cancers: A literature review. Support Care Cancer 2014;22:2593-8.  Back to cited text no. 15
    
16.
Wu S-G, Rao M-Y, Zhou J, Lin Q, Wang Z-J, Chen Y-X, et al. Distribution of metastatic disease in the brain in relation to the hippocampus: A retrospective single-center analysis of 6064 metastases in 632 patients. Oncotarget 2015;6:44030-6.  Back to cited text no. 16
    
17.
Ghia A, Tomé WA, Thomas S, Cannon G, Khuntia D, Kuo JS, et al. Distribution of brain metastases in relation to the hippocampus: Implications for neurocognitive functional preservation. Int J Radiat Oncol Biol Phys 2007;68:971-7.  Back to cited text no. 17
    
18.
Holmes CJ, Hoge R, Collins L, Woods R, Toga AW, Evans AC, et al. Enhancement of MR images using registration for signal averaging. J Comput Assist Tomogr 1998;22:324-33.  Back to cited text no. 18
    


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