TYPE Review
PUBLISHED 24 January 2024
DOI 10.3389/fonc.2024.1342669
Hippocampal sparing in whole-
OPEN ACCESS brain radiotherapy for brain
EDITED BY
Rahul Krishnatry,
Tata Memorial Hospital, India
metastases: controversy,
REVIEWED BY
Raees Tonse,
technology and the future
Baptist Hospital of Miami, United States
Hong Qi Tan, Rui Liu 1,2, GuanZhong Gong 2, KangNing Meng 1,2,
National Cancer Centre Singapore, Singapore
ShanShan Du 2 and Yong Yin 2*
*CORRESPONDENCE
Yong Yin 1
Department of Graduate, Shandong First Medical University, Shandong Academy of Medical
Sciences, Jinan, China, 2 Department of Radiation Oncology Physics and Technology, Shandong
Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical
RECEIVED 22 November 2023
Sciences, Jinan, China
ACCEPTED 15 January 2024
PUBLISHED 24 January 2024
CITATION
Liu R, Gong G, Meng K, Du S and Yin Y (2024) Whole-brain radiotherapy (WBRT) plays an irreplaceable role in the treatment of brain
Hippocampal sparing in whole-brain metastases (BMs), but cognitive decline after WBRT seriously affects patients’ quality of life.
radiotherapy for brain metastases:
The development of cognitive dysfunction is closely related to hippocampal injury, but
controversy, technology and the future.
Front. Oncol. 14:1342669. standardized criteria for predicting hippocampal injury and dose limits for hippocampal
doi: 10.3389/fonc.2024.1342669 protection have not yet been developed. This review systematically reviews the clinical
COPYRIGHT efficacy of hippocampal avoidance - WBRT (HA-WBRT), the controversy over dose limits,
© 2024 Liu, Gong, Meng, Du and Yin. This is an
common methods and characteristics of hippocampal imaging and segmentation,
open-access article distributed under the terms
of the Creative Commons Attribution License differences in hippocampal protection by common radiotherapy (RT) techniques, and
(CC BY). The use, distribution or reproduction the application of artificial intelligence (AI) and radiomic techniques for hippocampal
in other forums is permitted, provided the
original author(s) and the copyright owner(s) protection. In the future, the application of new techniques and methods can improve the
are credited and that the original publication consistency of hippocampal dose limit determination and the prediction of the occurrence
in this journal is cited, in accordance with
of cognitive dysfunction in WBRT patients, avoiding the occurrence of cognitive
accepted academic practice. No use,
distribution or reproduction is permitted dysfunction in patients and thus benefiting more patients with BMs.
which does not comply with these terms.
KEYWORDS
hippocampus avoidance, brain metastases, whole brain radiotherapy, new radiotherapy
techniques, contour, dose limits
Introduction
Brain metastases (BMs) are the most common central nervous system (CNS) malignancies
and may occur at a rate more than 10 times greater than that of primary malignant tumors of
the brain (1). Commonly used treatments for BMs include surgery, radiotherapy (RT), and
systemic therapies (immunotherapy, targeted drugs). Since 60% of patients have multiple
lesions, 5% of them have concurrent meningeal metastases and significant neurological
symptoms (2). Therefore, whole-brain RT (WBRT) plays an irreplaceable role in the
treatment of BMs. WBRT increases the median survival time to 3-6 months and completely
relieves headache and intracranial hypertension in more than 50% of patients, making it the
This study source
Frontiers was downloaded by 100000899194722 from CourseHero.com on
in Oncology 0105-30-2025 13:05:23 GMT -05:00 frontiersin.org
https://www.coursehero.com/file/249350324/fonc-14-1342669pdf/
, Liu et al. 10.3389/fonc.2024.1342669
treatment of choice for patients with multiple lesions and significant Progress in the study of hippocampal
symptoms (3). However, even though modern local RT techniques are
improving tumor control, cognitive dysfunction caused by WBRT has
dose limits in WBRT
become a non-negligible problem in the current clinical application of
There are more studies on the dose limits for hippocampal injury,
WBRT. It is especially important for patients who can survive for a long
but no uniform conclusion has been reached. Table 2 lists the studies
time. A significant dose−effect relationship exists between cognitive
of several scholars on hippocampal protective dose limits (13–17).
decline after RT and the dose received in the hippocampus (4).
One of the primary reasons for the contradictory findings
Hippocampal avoidance-WBRT (HA-WBRT) has become the
among scholars may be the lack of a precise definition of the
routine technique of choice for treating BMs during WBRT. Several
hippocampal region and varying criteria for contouring, leading to
scholars have reviewed the HA-WBRT protocol and summarized the
different actual hippocampal exposure doses and consequently
clinical efficacy, technical feasibility, potential neurotoxicity,
different outcomes. The latest guidelines for assessing
hippocampal dose limits, and characteristics of different RT
hippocampal contours, as defined in the RTOG0933 study, do not
techniques implemented in HA-WBRT (5–8).
include the entire hippocampus but focus on a subregion of granule
This review addresses the current problems faced by HA-WBRT
cells in the dentate gyrus, which is crucial for memory formation
in terms of differences in clinical efficacy and varying standards of
and challenging to contour clearly and reliably by imaging (18). The
hippocampal dose limits and summarizes the imaging characteristics
criteria for dose limits based on hippocampal boundaries continue
of the hippocampus on computed tomography (CT) and images and
to require discussion. The initial step in RT involves contouring the
magnetic resonance imaging (MRI). The differences in hippocampal
tumor target area and identifying critical organs such as the
protection induced by commonly used RT techniques include
hippocampus. This step is pivotal and dictates the success of the
volumetric modulated arc therapy (VMAT), helical Tomotherapy
entire RT regimen.
(Tomo), and intensity-modulated proton therapy (IMPT), as well as
the application of hippocampal automatic and semi-automatic
segmentation methods, these findings provide insight into the
direction of the future development of HA-WBRT. Progress of hippocampal contours
The hippocampus is an elongated structure located deep in the
Controversies regarding HA-WBRT medial temporal lobe that anatomically resembles the hippocampus
(19). Its structure is mainly C-shaped at the base of the temporal
Although preserving the hippocampus has become the standard horn of the lateral ventricle, with a rostral projection approximately
protocol for WBRT, some scholars have questioned the efficacy of 5 cm long (20). Unlike other vulnerable brain structures, such as the
HA-WBRT, as originally proposed by Gondi et al. (9) Gondi et al. brainstem or optic chiasm, the hippocampus is situated within the
and Westover KD et al. (10) achieved good clinical outcomes in temporal lobe. It has unique anatomical features characterized by a
their studies of HA-WBRT, in which 23% and 49.4%, improved small size and complex shape. These attributes make accessing
cognitive function preservation, respectively. Conversely, the HA- hippocampal contours time-consuming and challenging.
WBRT studies by Beblerbos et al. (11) and Vees et al. (12) did not Furthermore, the hippocampus appears different in CT images
yield significant clinical results. Table 1 lists the controversies and MRI, each playing a distinct role in determining the
studied by scholars. hippocampal contour.
TABLE 1 The controversies of HA-WBRT clinical outcome.
Study Neuropsychological test Primary Result
time point end points
Support Gondi et al. (2014) (9) When baseline, 2, 4, and 6 months HVLT- 4 month‘s HVLT- Cognitive score with HA-WBRT VS WBRT decline:7.0%
R DR R DR Vs 30%
Westover et al. When baseline, 3, 6, 9, 12 months 3 month’s HVLT-R Cognitive score with HSIB-WBRT VS WBRT decline:
(2020) (10) HVLT-R 10.6% Vs : 60%
Oppose Beblerbos et al. When baseline, 4, 8, 12, 18, 24 months 4 month’s HVLT-R HA-PCI NCF VS PCI dropped to five points: 28%Vs 29%
(2020) (11) HVLT-R
Vees et al. (2020) (12) When baseline 6 weeks, 6and 12months NCF decline at No NCF decline at 6VS 12 months: 34.2% VS 48.5%
HVLT-R 6 months
HVLT-R, Hopkins Verbal Learning Test -Revised; HVLT-DR, Hopkins Verbal Learning Test -Delay Revised; PCI, Prophylactic Cranial Irradiation.
This study source
Frontiers was downloaded by 100000899194722 from CourseHero.com on
in Oncology 0205-30-2025 13:05:23 GMT -05:00 frontiersin.org
https://www.coursehero.com/file/249350324/fonc-14-1342669pdf/
PUBLISHED 24 January 2024
DOI 10.3389/fonc.2024.1342669
Hippocampal sparing in whole-
OPEN ACCESS brain radiotherapy for brain
EDITED BY
Rahul Krishnatry,
Tata Memorial Hospital, India
metastases: controversy,
REVIEWED BY
Raees Tonse,
technology and the future
Baptist Hospital of Miami, United States
Hong Qi Tan, Rui Liu 1,2, GuanZhong Gong 2, KangNing Meng 1,2,
National Cancer Centre Singapore, Singapore
ShanShan Du 2 and Yong Yin 2*
*CORRESPONDENCE
Yong Yin 1
Department of Graduate, Shandong First Medical University, Shandong Academy of Medical
Sciences, Jinan, China, 2 Department of Radiation Oncology Physics and Technology, Shandong
Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical
RECEIVED 22 November 2023
Sciences, Jinan, China
ACCEPTED 15 January 2024
PUBLISHED 24 January 2024
CITATION
Liu R, Gong G, Meng K, Du S and Yin Y (2024) Whole-brain radiotherapy (WBRT) plays an irreplaceable role in the treatment of brain
Hippocampal sparing in whole-brain metastases (BMs), but cognitive decline after WBRT seriously affects patients’ quality of life.
radiotherapy for brain metastases:
The development of cognitive dysfunction is closely related to hippocampal injury, but
controversy, technology and the future.
Front. Oncol. 14:1342669. standardized criteria for predicting hippocampal injury and dose limits for hippocampal
doi: 10.3389/fonc.2024.1342669 protection have not yet been developed. This review systematically reviews the clinical
COPYRIGHT efficacy of hippocampal avoidance - WBRT (HA-WBRT), the controversy over dose limits,
© 2024 Liu, Gong, Meng, Du and Yin. This is an
common methods and characteristics of hippocampal imaging and segmentation,
open-access article distributed under the terms
of the Creative Commons Attribution License differences in hippocampal protection by common radiotherapy (RT) techniques, and
(CC BY). The use, distribution or reproduction the application of artificial intelligence (AI) and radiomic techniques for hippocampal
in other forums is permitted, provided the
original author(s) and the copyright owner(s) protection. In the future, the application of new techniques and methods can improve the
are credited and that the original publication consistency of hippocampal dose limit determination and the prediction of the occurrence
in this journal is cited, in accordance with
of cognitive dysfunction in WBRT patients, avoiding the occurrence of cognitive
accepted academic practice. No use,
distribution or reproduction is permitted dysfunction in patients and thus benefiting more patients with BMs.
which does not comply with these terms.
KEYWORDS
hippocampus avoidance, brain metastases, whole brain radiotherapy, new radiotherapy
techniques, contour, dose limits
Introduction
Brain metastases (BMs) are the most common central nervous system (CNS) malignancies
and may occur at a rate more than 10 times greater than that of primary malignant tumors of
the brain (1). Commonly used treatments for BMs include surgery, radiotherapy (RT), and
systemic therapies (immunotherapy, targeted drugs). Since 60% of patients have multiple
lesions, 5% of them have concurrent meningeal metastases and significant neurological
symptoms (2). Therefore, whole-brain RT (WBRT) plays an irreplaceable role in the
treatment of BMs. WBRT increases the median survival time to 3-6 months and completely
relieves headache and intracranial hypertension in more than 50% of patients, making it the
This study source
Frontiers was downloaded by 100000899194722 from CourseHero.com on
in Oncology 0105-30-2025 13:05:23 GMT -05:00 frontiersin.org
https://www.coursehero.com/file/249350324/fonc-14-1342669pdf/
, Liu et al. 10.3389/fonc.2024.1342669
treatment of choice for patients with multiple lesions and significant Progress in the study of hippocampal
symptoms (3). However, even though modern local RT techniques are
improving tumor control, cognitive dysfunction caused by WBRT has
dose limits in WBRT
become a non-negligible problem in the current clinical application of
There are more studies on the dose limits for hippocampal injury,
WBRT. It is especially important for patients who can survive for a long
but no uniform conclusion has been reached. Table 2 lists the studies
time. A significant dose−effect relationship exists between cognitive
of several scholars on hippocampal protective dose limits (13–17).
decline after RT and the dose received in the hippocampus (4).
One of the primary reasons for the contradictory findings
Hippocampal avoidance-WBRT (HA-WBRT) has become the
among scholars may be the lack of a precise definition of the
routine technique of choice for treating BMs during WBRT. Several
hippocampal region and varying criteria for contouring, leading to
scholars have reviewed the HA-WBRT protocol and summarized the
different actual hippocampal exposure doses and consequently
clinical efficacy, technical feasibility, potential neurotoxicity,
different outcomes. The latest guidelines for assessing
hippocampal dose limits, and characteristics of different RT
hippocampal contours, as defined in the RTOG0933 study, do not
techniques implemented in HA-WBRT (5–8).
include the entire hippocampus but focus on a subregion of granule
This review addresses the current problems faced by HA-WBRT
cells in the dentate gyrus, which is crucial for memory formation
in terms of differences in clinical efficacy and varying standards of
and challenging to contour clearly and reliably by imaging (18). The
hippocampal dose limits and summarizes the imaging characteristics
criteria for dose limits based on hippocampal boundaries continue
of the hippocampus on computed tomography (CT) and images and
to require discussion. The initial step in RT involves contouring the
magnetic resonance imaging (MRI). The differences in hippocampal
tumor target area and identifying critical organs such as the
protection induced by commonly used RT techniques include
hippocampus. This step is pivotal and dictates the success of the
volumetric modulated arc therapy (VMAT), helical Tomotherapy
entire RT regimen.
(Tomo), and intensity-modulated proton therapy (IMPT), as well as
the application of hippocampal automatic and semi-automatic
segmentation methods, these findings provide insight into the
direction of the future development of HA-WBRT. Progress of hippocampal contours
The hippocampus is an elongated structure located deep in the
Controversies regarding HA-WBRT medial temporal lobe that anatomically resembles the hippocampus
(19). Its structure is mainly C-shaped at the base of the temporal
Although preserving the hippocampus has become the standard horn of the lateral ventricle, with a rostral projection approximately
protocol for WBRT, some scholars have questioned the efficacy of 5 cm long (20). Unlike other vulnerable brain structures, such as the
HA-WBRT, as originally proposed by Gondi et al. (9) Gondi et al. brainstem or optic chiasm, the hippocampus is situated within the
and Westover KD et al. (10) achieved good clinical outcomes in temporal lobe. It has unique anatomical features characterized by a
their studies of HA-WBRT, in which 23% and 49.4%, improved small size and complex shape. These attributes make accessing
cognitive function preservation, respectively. Conversely, the HA- hippocampal contours time-consuming and challenging.
WBRT studies by Beblerbos et al. (11) and Vees et al. (12) did not Furthermore, the hippocampus appears different in CT images
yield significant clinical results. Table 1 lists the controversies and MRI, each playing a distinct role in determining the
studied by scholars. hippocampal contour.
TABLE 1 The controversies of HA-WBRT clinical outcome.
Study Neuropsychological test Primary Result
time point end points
Support Gondi et al. (2014) (9) When baseline, 2, 4, and 6 months HVLT- 4 month‘s HVLT- Cognitive score with HA-WBRT VS WBRT decline:7.0%
R DR R DR Vs 30%
Westover et al. When baseline, 3, 6, 9, 12 months 3 month’s HVLT-R Cognitive score with HSIB-WBRT VS WBRT decline:
(2020) (10) HVLT-R 10.6% Vs : 60%
Oppose Beblerbos et al. When baseline, 4, 8, 12, 18, 24 months 4 month’s HVLT-R HA-PCI NCF VS PCI dropped to five points: 28%Vs 29%
(2020) (11) HVLT-R
Vees et al. (2020) (12) When baseline 6 weeks, 6and 12months NCF decline at No NCF decline at 6VS 12 months: 34.2% VS 48.5%
HVLT-R 6 months
HVLT-R, Hopkins Verbal Learning Test -Revised; HVLT-DR, Hopkins Verbal Learning Test -Delay Revised; PCI, Prophylactic Cranial Irradiation.
This study source
Frontiers was downloaded by 100000899194722 from CourseHero.com on
in Oncology 0205-30-2025 13:05:23 GMT -05:00 frontiersin.org
https://www.coursehero.com/file/249350324/fonc-14-1342669pdf/
