Radiotherapy and Oncology xxx (2018) xxx–xxx

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Radiotherapy and Oncology

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Cognitive impairment and morphological changes after radiation

therapy in brain tumors: A review
Julian Jacob a,b,⇑, Thomas Durand b,c, Loïc Feuvret a, Jean-Jacques Mazeron a, Jean-Yves Delattre c,d,
Khê Hoang-Xuan c,d, Dimitri Psimaras c,d, Hassen Douzane c, Monica Ribeiro b,c, Laurent Capelle e,
Alexandre Carpentier d,e, Damien Ricard b,f,g, Philippe Maingon a
a
Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière-Charles Foix, Department of Radiation Oncology; b Sorbonne Université, CNRS,
Service de Santé des Armées, Cognition and Action Group, Paris; c Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière-Charles Foix,
Department of Neurology; d Sorbonne Université, INSERM, CNRS, Assistance Publique-Hôpitaux de Paris, Institut du Cerveau et de la Moelle épinière; e Sorbonne Université, Assistance
Publique-Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière-Charles Foix, Department of Neurosurgery; f Service de Santé des Armées, Hôpital d’Instruction des Armées Percy,
Department of Neurology, Clamart; and g Service de Santé des Armées, Ecole du Val-de-Grâce, Paris, France

a r t i c l e i n f o a b s t r a c t

Article history: Life expectancy of patients treated for brain tumors has lengthened due to the therapeutic improvements.
Received 15 February 2018 Cognitive impairment has been described following brain radiotherapy, but the mechanisms leading to
Received in revised form 25 May 2018 this adverse event remain mostly unknown.
Accepted 28 May 2018
Technical evolutions aim at enhancing the therapeutic ratio. Sparing of the healthy tissues has been
Available online xxxx
improved using various approaches; however, few dose constraints have been established regarding
brain structures associated with cognitive functions.
Keywords:
The aims of this literature review are to report the main brain areas involved in cognitive adverse
Brain
Radiotherapy
effects induced by radiotherapy as described in literature, to better understand brain radiosensitivity
Cognition and to describe potential future improvements.
Toxicity Ó 2018 Elsevier B.V. All rights reserved. Radiotherapy and Oncology xxx (2018) xxx–xxx
Radiosensitivity

Introduction ionizing radiation and occurring for instance in cerebral white

matter (WM) have been reported [9]. Multimodal mechanisms,
Cognitive impairment has been observed following brain implying namely neurons and blood vessels, have been suggested
radiotherapy and can significantly alter the quality of long-term to explain the brain injuries induced by radiotherapy [10]. How-
survivors’ life [1–3]. Cognitive dysfunction, which can be assessed ever, the knowledge of the cerebral areas’ radiosensitivity and
using various specific tests, seems related to many factors like the brain radiation toxicities such as leukoencephalopathy has to
disease progression but also to radiotherapy itself [4,5]. Several be improved [11].
radiation parameters, such as total dose, dose per fraction, treated The main purposes of this literature review are to report the
volume, could lead to these adverse events [6]. pathophysiological processes leading to the cognitive adverse
Neuronal networks appear to play a very important role in var- effects induced by radiotherapy, to describe the tolerances of the
ious cognitive functions [7,8]. Different tissue changes induced by healthy cerebral tissues exposed to radiation and to propose poten-
tial technical improvements.
Abbreviations: AD, axial diffusivity; ADC, apparent diffusion coefficient; BED,
biologically equivalent doses; CT, computed tomography; DTI, diffuse tensor Methods
imaging; FA, fractional anisotropy; FDG, 18F-fluorodeoxyglucose; gEUD, general-
ized uniform equivalent dose; HGG, high-grade gliomas; HVLT-R, Hopkins Verbal
Learning Test-Revised; IMRT, intensity modulated radiotherapy; LGG, low-grade This literature review was performed using MEDLINE via
gliomas; MD, mean diffusivity; MRI, magnetic resonance imaging; NSC, neural stem PubMed to identify articles published before May 2018. The key-
cells; PRV, planning-at-risk volume; PTV, planning target volume; RD, radial words ‘‘brain”, ‘‘radiotherapy”, ‘‘cognition” were used to select the
diffusivity; SVZ, subventricular zones; WBRT, whole-brain radiation therapy; WM,
studies dealing with the pathophysiology of the cognitive impair-
white matter.
⇑ Corresponding author at: Department of Radiation Oncology, Groupe Hospital- ment following radiotherapy for brain tumors. Furthermore, we
ier Pitié-Salpêtrière-Charles Foix, 47-83, boulevard de l’Hôpital, 75013 Paris, France. searched works reporting data about the radiosensitivity of the
E-mail address: [email protected] (J. Jacob). specific brain areas involved in cognitive functions considering the

https://doi.org/10.1016/j.radonc.2018.05.027
0167-8140/Ó 2018 Elsevier B.V. All rights reserved.

Please cite this article in press as: Jacob J et al. Cognitive impairment and morphological changes after radiation therapy in brain tumors: A review. Radio-
ther Oncol (2018), https://doi.org/10.1016/j.radonc.2018.05.027
2 Cognitive effects of brain radiotherapy

following keywords: ‘‘hippocampus”, ‘‘cerebral cortex”, ‘‘cerebral Clinical implications

white matter”, ‘‘subventricular zones”. We also aimed at developing According to clinical works, cognitive impairment following
the clinical and technical approaches proposed in order to improve brain radiotherapy could be partly explained by the doses admin-
patients’ quality of life. In addition, bibliographic references of the istered to the hippocampi [32,33]. A prospective observational
included studies were reviewed for relevant works that would have study assessed the cognitive effects of the hippocampal dose deliv-
been missed by this electronic search. Ongoing clinical trials were ery in 29 patients treated with fractionated stereotactic radiother-
searched using the ClinicalTrials.gov database. apy for benign brain tumors or low-grade gliomas (LGG) [32]. A
comparator group of 12 healthy patients was also recruited in
order to determine differences in cognitive test results (e.g., Wech-
Pathophysiology sler Memory Scale-III Word Lists Immediate and Delayed Recall,
Hooper Visual Organization Test). In univariate analysis, a signifi-
Several mechanisms have been suggested to explain the cogni- cant risk of verbal memory impairment at 18 months was reported
tive impairment observed following brain radiotherapy [12]. in patients with biologically equivalent doses (BED) to 40% of the
Deoxyribonucleic acid damage induced by X-rays can lead to the total hippocampal volume exceeding 7.3 Gy (2 Gy per fraction,
death of normal cells and, hence, to the dysfunction of healthy tis- a/b ratio: 2 Gy). These results were confirmed in multivariate anal-
sues [13]. Dynamic processes related to inflammation and oxida- ysis. Univariate analysis also revealed altered visual integration
tive stress also seem to be implicated in the occurrence of late when the maximum dose to the left hippocampus was greater than
toxicities [14,15]. Furthermore, animal studies in rodents have 15 Gy and the dose delivered to 30% of the left hippocampus upper
reported the depletion of endothelial cells and alteration of to 6.2 Gy; however, no statistically significant differences were
microvascularization following brain radiotherapy [16,17]. observed in multivariate analysis [32].
The hippocampus is an important region in terms of cognition Mahajan et al. followed up 18 patients, 16 of whom had high-
[18]. The pathophysiology of radiotherapy-related hippocampal grade gliomas (HGG) and 2 presented LGG [33]. Deformable image
injury has been widely studied [19,20]. In preclinical studies, inhi- registration was used to delineate the hippocampi on CT and MRI
bition of neurogenesis in the hippocampus secondary to X-ray irra- scans. Cognitive tests were performed before and after irradiation,
diation has been suggested as a possible reason for alterations in with a mean time of 14 months following completion of treatment.
memory tests [21,22]. Rola et al. showed that decreases in neuro- The median prescribed dose was 57 Gy delivered in 30 fractions.
genesis following brain radiotherapy resulted in a significant risk Tumors were left sided in 10 patients and right sided in 8. The
of cognitive impairment in young mice [23]. It is possible that median mean doses to the left and right hippocampus were 45.5
the process of neurogenesis could be altered by the effect of and 25.8 Gy, respectively. The median maximum doses to the left
radiation-induced inflammation on neural stem cells (NSC) [24]. and right hippocampus were 53.3 Gy and 30.4 Gy, respectively. A
According to Monje et al., ionizing radiation could disrupt the statistically significant relationship was reported between the
interactions between the NSC and blood vessels [25,26]. A strong maximum dose to the left hippocampus and cognitive decline
microglial inflammatory response and microvasculature damages (learning, delayed recall) [33].
have also been reported, suggesting the important role of the
cerebral microenvironment in the occurrence of radiation-
induced brain injuries [26]. Radiotherapy could significantly alter Hippocampal-sparing approaches
this special cerebral micromilieu. Considering the radiosensitivity of the hippocampi and its clin-
Brain irradiation also triggers neuronal dysfunction, especially ical implications, hippocampal-sparing approaches have been
regarding the synaptic response [27]. Demyelination is another developed [34,35]. These techniques have been evaluated in
process induced by ionizing radiation and contributes to neurolog- patients managed by focal brain radiotherapy [36–40]. Intensity
ical impairment [25]. The loss of oligodendrocytes, implied in Modulated Radiotherapy (IMRT) was used in 12 patients with glio-
remyelination, has been described [28,29]. mas [36]. Planned doses were 54 Gy in 30 fractions in seven
So, the pathophysiology of cognitive impairment following patients with LGG and 60 Gy in 30 fractions in five patients with
brain radiotherapy is a complex multimodal process implying HGG. A planning-at-risk volume (PRV) was created after delin-
marked modifications of the cerebral microenvironment. Further eation of the hippocampi, the subventricular zones and the limbic
well-designed studies are required to improve knowledge and to circuit by application of isotropic three-dimensional margins of 3
confirm suggested hypotheses. mm. The maximal dose delivered to the hippocampal PRV did not
exceed 4 and 12 Gy in patients with LGG and HGG, respectively.
Irrespective of the doses prescribed, dosimetric results showed
Radiosensitivity of healthy cerebral tissues
an important decrease in mean BED planned to the hippocampal
PRV (2 Gy per fraction, a/b ratio: 2 Gy): 20 Gy versus 58.9 Gy
Hippocampus
(HGG), 15.1 Gy versus 42.1 Gy (LGG), 21.3 Gy versus 36.9 Gy
Dosimetric data (brainstem LGG) [36]. The dosimetric benefits of IMRT in terms
The radiation doses delivered to the hippocampus were esti- of hippocampal dose reduction have been highlighted in patients
mated in 52 patients treated for primary brain tumors, mainly glio- treated for glioblastoma [37–39]. In 20 patients managed for pitu-
mas [30]. Co-registration of computed tomography (CT) and itary lesions (macroadenoma, meningioma; prescribed dose: 50.4
magnetic resonance imaging (MRI) scans was performed using a Gy in 28 fractions), a decrease in hippocampal exposure was
methodology previously reported [31]. In univariate analysis a sig- demonstrated using an asymmetric conformal arc technique [40].
nificant correlation was observed between the mean dose to each Many studies proposed a hippocampal-sparing approach in
hippocampus and the hippocampal volume loss one year after the patients receiving whole-brain radiation therapy (WBRT) with
radiotherapy started. A mean dose of greater than 40 Gy adminis- curative or prophylactic intent [41–52]. The Table 1 reports the
tered to the hippocampus was associated with a significant risk of published dosimetric data. IMRT, delivered using Helical
atrophy one year after the initiation of radiotherapy. In multivariate Tomotherapy or Volumetric Modulated Arc Therapy, was the most
analysis, mean dose to one hippocampus and patient age were both frequently studied technique. The mean BED or equivalent uniform
statistically significant predictors of the hippocampal volume doses delivered to the hippocampi ranged from 4.9 to 20.4 Gy
decrease. (Table 1).

Please cite this article in press as: Jacob J et al. Cognitive impairment and morphological changes after radiation therapy in brain tumors: A review. Radio-
ther Oncol (2018), https://doi.org/10.1016/j.radonc.2018.05.027
 J. Jacob et al. / Radiotherapy and Oncology xxx (2018) xxx–xxx 3

Table 1
Hippocampi dosimetric data in patients treated with whole brain radiotherapy using hippocampal avoidance approaches.

Authors Number of Radiotherapy Prescribed total dose to Hippocampi dose constraints Delivered dose to the Hippocampus
patients techniques the whole brain hippocampi a/b
Gutiérrez 10 HT 32.25 Gy in 15 fractions Dmax < 6 Gy Dmean: 5.78–5.94 Gy1,2 2 Gy
et al. [41] Dmedian: 5.29–5.40 Gy1,2
Gondi et al. 5 HT 30 Gy in 10 fractions Dmax < 6 Gy, 3 Gy < 20% (HT), Dmax < 11 Gy, Dmean: 4.9 Gy (HT), 7.3 Gy2 2 Gy
[42] LINAC-based 9 Gy < 40% (LINAC-Based IMRT) (LINAC-Based IMRT)
IMRT Dmedian: 5.5 Gy (HT), 7.8 Gy
(LINAC-Based IMRT)
2
Hsu et al. [43] 10 VMAT 32.25 Gy in 15 fractions Dmean < 6 Gy Dmean: 5.23 Gy 2 2 Gy
SIB
3
Marsh et al. 11 HT PCI: 30 Gy in 15 Dmean < 11 Gy PCI: Dmean: 14.23 Gy 2 Gy
[44] fractions Dmax < 15 Gy
3
WBRT: 35 Gy in 14 WBRT: Dmean: 16.07 Gy
fractions
Marsh et al. 10 HT PCI: 30 Gy in 15 / PCI: Dmean: 15.7 Gy2 2 Gy
[45] fractions
WBRT: 35 Gy in 14 WBRT: Dmean: 16.8 Gy2
fractions
van Kesteren 10 LINAC 30 Gy in 12 fractions / Dmean: 5.4 Gy2 10 Gy
et al. [46] 3D-CRT
Nevelsky 10 LINAC-based 30 Gy in 10 fractions Dmax < 16 Gy Dmax: 14.35 Gy /
et al. [47] IMRT D100% < 9 Gy D100%: 8.37 Gy
Prokic et al. 10 VMAT 30 Gy in 12 fractions / Dmean: 7,55 Gy2 (SIB) 2 Gy
[48] SIB Dmean: 9.8 Gy2 (SFRT)
SFRT
Giaj Levra 10 VMAT 20 Gy in 5 fractions D100%: 6 Gy Dmean: 7.7 Gy /
et al. [49] SIB Dmax: 10.7 Gy D100%: 6.7 Gy
Dmean: 8 Gy
Pokhrel et al. 10 VMAT 30 Gy in 10 fractions Dmax < 16 Gy Dmean: 11.2 Gy /
[50] D100% < 9 Gy D100%: 8.4 Gy
Awad et al. 30 VMAT 28.6–37.5 Gy, 5 to 15 / Dmean: 20.4 Gy /
[51] HA: 20 SIB fractions Dmedian: 21.9 Gy
patients 3D-CRT
Kim et al. [52] 11 HT 25–28 Gy in 10 to 14 Dmean < 15 Gy Dmean: 13,65 Gy2 3 Gy
SIB fractions

D100%: Dose delivered to 100% of the hippocampus, Dmax: Maximal dose, Dmean: Mean dose, Dmedian: Median dose, 3D-CRT: Three-dimensional Conformal Radiotherapy, HA:
Hippocampal avoidance, HT: Helical Tomotherapy, IMRT: Intensity Modulated Radiotherapy, LINAC: Linear Accelerator, PCI: Prophylactic Cranial Irradiation, SIB: Simulta-
neous Integrated Boost, SFRT: Stereotactic Fractionated Radiotherapy, VMAT: Volumetric Modulated Arc Therapy, WBRT: Whole Brain Radiotherapy, 1according to Field
Width and Pitch, 2Biologically equivalent dose 2 Gy, 3Equivalent uniform dose.

The Table 2 reports the main cognitive test results in patients also described similar dose–response relationships considering
treated using hippocampal-sparing techniques [53–55]. Cognitive each single hippocampus. In patients with glioblastoma, the max-
benefits have been suggested in a multicentric phase II trial led imum doses to both hippocampi were significantly associated with
on 113 patients treated with WBRT for brain metastases [53]. modifications in HVLT-R Delayed Recall in multivariate analysis.
Gondi et al. defined hippocampal avoidance regions by applying
isotropic three-dimensional margins of 5 mm to the hippocampi. Biomarkers
The prescribed dose was 30 Gy in 10 fractions using IMRT. The dose The role of potential biomarkers has been investigated [56–58].
delivered to 100% of the hippocampi and the maximal hippocam- Using dynamic contrast enhanced-MRI, Farjam et al. studied varia-
pal dose should not exceed 9 Gy and 16 Gy, respectively. Cognitive tions in microvascularization of the hippocampal area in 27
assessments were performed at baseline, 2, 4 and 6 months of patients treated for primary brain tumors [56]. The gadolinium
follow-up. At 4 months, mean relative decline in verbal learning transfer constant of the hippocampi increased significantly with
and memory assessed by the Hopkins Verbal Learning Test- the mean radiotherapy dose, especially in elderly female patients.
Revised (HVLT-R) Delayed Recall was significantly reduced using Furthermore, in treated women, variations in the mean transfer
the hippocampal-sparing technique. In univariate analysis, the constant at one month following completion of radiotherapy
dose delivered to 100% of the hippocampi was predictive of a appeared to predict cognitive decline as measured by the HVLT-R
greater decline in HVLT-R Delayed Recall. six and 18 months after irradiation. Thus, the authors suggested
Ma et al. considered the data of three prospective trials imply- that hippocampal vascularization could constitute a relevant bio-
ing 60 patients treated with WBRT (prophylactic treatment of non- marker of the adverse cognitive effects induced by brain radiother-
metastatic small cell lung cancer) or focal brain irradiation for apy. These data confirm trends previously reported in 10 patients,
glioblastoma [54,55]. Hippocampal avoidance structures were whereby a statistically significant relationship was observed
defined using a 5-mm radial margin to the hippocampi and dosi- between modifications of vascular volumes and blood–brain bar-
metric data generated using IMRT plans. BED were calculated using rier permeability in the left frontal and temporal lobes, and cogni-
a specific a/b ratio of 2 Gy. If the trial led by Redmond et al. in tive test results (verbal learning, recall) 6 months after completion
patients treated with prophylactic cranial irradiation didn’t show of radiotherapy [57].
significant cognitive decline at 6 and 12-months’ assessments, A study performed in 35 patients treated with WBRT for brain
the pooled analysis showed dose–response relationships [54,55]. metastases using magnetic resonance spectroscopy imaging
BED of 10.9 Gy and 59.3 Gy delivered to 100% of both hippocampi reported a statistically significant correlation between decreases
exposed to 20% and 50% probabilities of decline in HVLT-R Delayed in hippocampal N-acetylaspartate concentrations (reflective of
Recall at 6 months of the end of radiotherapy, respectively. Authors neuronal density) and cognitive impairment as measured by the

Please cite this article in press as: Jacob J et al. Cognitive impairment and morphological changes after radiation therapy in brain tumors: A review. Radio-
ther Oncol (2018), https://doi.org/10.1016/j.radonc.2018.05.027
4 Cognitive effects of brain radiotherapy

Table 2
Main cognitive test results in patients treated with in Intensity Modulated Radiotherapy using hippocampal avoidance approaches.

Authors Number of Prescribed Hippocampi Delivered dose to Hippocampus Median Main cognitive test results
patients total dose dose constraints the hippocampi a/b follow-up
(months)
Gondi et al. [53] 113 WBRT for BM: 30 Dmax < 16 Gy / / / Significant reduction in HVLT-R
Gy in 10 fractions D100% < 9 Gy Delayed Recall (verbal learning
and memory) decline at 4
months compared to historical
control
Over time: significant decline in
HVLT-R Delayed Recall; No
significant decline in HVLT-R
Total Recall and Immediate
Recognition; D100% predictive of
decline in HVLT-R Delayed Recall
(univariate analysis)
Redmond et al. [54] 20 PCI: 25 Gy in 10 Dmean < 8 Gy Hippocampi: Dmean: / 16.7 At 6 and 12 months following
fractions 7.4 Gy the completion of IMRT: No
Avoidance structure: significant decline in HVLT-R
Dmean: 10.25 Gy Delayed Recall, Trail Making Test
(information processing speed,
executive function), Controlled
Oral Word Association Test
(verbal fluency) compared to
baseline
Ma et al. [55] 60 PCI: 25 Gy in 10 PCI: Dmean < 8 Gy PCI: Mean D50%: 5.1 2 Gy / D50% of 22.1 Gy and 62.9 Gy
fractions (n = 21) GBM: Dose Gy (EUD) exposed to 20% and 50%
GBM: 60 Gy in 30 reduced as much Mean D100%: 4.2 Gy probabilities of HVLT-R Delayed
fractions (n = 39; as possible to the Mean Dmax: 7.6 Gy Recall decline, respectively
30 treated using NPC GBM HAA: Mean D50%: D100% of 10.9 Gy and 59.3 Gy
HAA) (patients treated 23.6 Gy (EUD) exposed to 20% and 50%
using HAA) Mean D100%: 12.0 Gy probabilities of HVLT-R Delayed
Mean Dmax: 42.8 Gy Recall decline, respectively
GBM without HAA: GBM: Dmax associated to HVLT-
Mean D50%: 54.5 Gy R Delayed Recall results’ change
Mean D100%: 44.7 Gy (univariate and multivariate
Mean Dmax: 61.7 Gy analyses)

BM: Brain metastases, D50%: Dose delivered to 50% of the hippocampi, D100%: Dose delivered to 100% of the hippocampi, Dmax: Maximal dose, Dmean: Mean dose, EUD:
Equivalent Uniform Dose, GBM: Glioblastoma Multiforme, HAA: Hippocampal avoidance approach, HVLT-R: Hopkins Verbal Learning Test-Revised, NPC: Neural Progenitor
Cells, PCI: Prophylactic Cranial Irradiation, WBRT: Whole Brain Radiotherapy.

Auditory Verbal Learning Test and the revised Brief Visuospatial significant increases and decreases dependent on radiotherapy
Memory Test following radiotherapy [58]. This prompted the dose and time after treatment. Results were not significantly mod-
authors to suggest N-acetylaspartate as a relevant biomarker of ified when edema was excluded. Kassubek et al. reported FA reduc-
cognitive toxicity induced by radiotherapy. tions in the hemisphere invaded by the tumor [61]. Significant
To sum up, the reported results have to be interpreted with cau- correlations were described between the interhemispheric FA dif-
tion due to the heterogeneity of the patients’ clinical features, pre- ferences and the time elapsed since the end of radiotherapy [61].
scribed doses, radiation techniques and suggested hippocampus In patients treated for primary brain tumors, DTI assessments
a/b ratios. Many cognitive functions were assessed using different also highlighted axial diffusivity (AD) decreases, related to axonal
neuropsychological tests. Dosimetric analyses have considered dif- damage, and radial diffusivity (RD) increases, highlighting
ferent parameters (mean dose, maximal dose) on various volumes demyelination, in the months following focal brain radiotherapy
(one hippocampus, both hippocampi, hippocampal PRV). Despite [62,63]. Apparent diffusion coefficient values significantly
these limitations, available data suggest that hippocampal- increased in regions exposed to dose levels between 15 and 35
sparing approaches could reduce the risk of delayed cognitive Gy several years after completion of irradiation, suggesting WM
and memory dysfunction. injury [64].
While many articles dealt with hippocampal exposure to ioniz- WM radiosensitivity seems to change over time but also accord-
ing radiation, the cognitive effects could be explained by dosimet- ing to the anatomical location. Using similar methodology to the
ric parameters regarding other healthy cerebral tissues. previously described work, Connor et al. observed FA differences
in various brain regions [65]. Reduced FA values were reported
for the corpus callosum, the cingulum bundle and the fornix nine
Cerebral white matter
to twelve months after radiotherapy. The MD also increased signif-
Leukoencephalopathy induced by ionizing radiation could icantly in these structures, suggesting a specific dose-dependent
explain cognitive impairment following brain radiotherapy, sug- radiosensitivity. In 25 patients, whose majority was managed for
gesting a potential clinical effect of the doses delivered to WM [59]. HGG, linear MD increase and FA decrease were observed in the
genu and splenium of the corpus callosum following focal brain
Dosimetric data radiotherapy [66]. In these tissues, a dose-dependent alteration
Connor et al. studied cerebral WM dosimetry using diffuse ten- of the RD was described 3 and 19 weeks after the start of
sor imaging (DTI) in 15 patients treated for glioblastoma [60]. The radiotherapy.
mean diffusivity (MD) and fractional anisotropy (FA), parameters The effects induced by WBRT on WM have also been studied in
reflecting the mobility of water molecules, presented respective 14 patients treated with different dose levels: 30 Gy in 10 fractions

Please cite this article in press as: Jacob J et al. Cognitive impairment and morphological changes after radiation therapy in brain tumors: A review. Radio-
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 J. Jacob et al. / Radiotherapy and Oncology xxx (2018) xxx–xxx 5

or 37.5 Gy in 15 fractions [67]. The inferior cingula, fornix and cor- variate analysis [82]. A similar trend was reported for overall sur-
pus callosum presented statistically significant mean FA decreases vival. These relationships were established in patients treated with
and RD increases one month after completion of radiotherapy. initial gross total resection. Although no cognitive test was per-
These modifications were observed as early as one week following formed, a higher dose to the ipsilateral SVZ did not expose patients
the last session of irradiation. No statistically significant relation- to a higher risk of general status alteration; no statistically signif-
ship was observed between age, sex or radiation dose and the icant differences were observed in terms of Karnofsky Performance
alterations estimated using DTI. These data confirm previously Status score variations.
published trends regarding WM modifications in the limbic circuit
following WBRT [68]. FA decrease has also been reported in other Perspectives
areas like the cerebellum, the frontal lobes and the corona radiata A dosimetric study assessed the feasibility of sparing the NSC,
in patients treated with WBRT at different dose levels [69,70]. including the SVZ, using single-patient CT [83]. In both evaluated
settings (HGG managed with focal brain irradiation and metastatic
Clinical considerations disease treated with WBRT), total doses to these areas were
After brain radiotherapy, WM physiology is modified whatever reduced using IMRT. For example, the dose to all the regions con-
the target volumes considered. Do these radiological modifications taining NSC could be decreased by 25% in the treatment planning
lead to clinical consequences? In a prospective study performed in for HGG (prescribed dose to the PTV: 60 Gy in 30 fractions). A dose
patients with primary brain tumors, AD decreases were observed reduction of 87% to the contralateral SVZ was reported in IMRT
in the parahippocampal cingulum three weeks after the initiation compared with conventional radiotherapy.
of radiotherapy [71]. Chapman et al. also highlighted that early The techniques aiming at sparing the NSC are under evaluation.
modifications could predict later changes, reported until 78 weeks In 30 patients treated for glioblastoma using IMRT with avoidance
following the first radiotherapy session. AD decreases in the cingu- of the NSC (prescribed dose: 60 Gy in 30 fractions, no SVZ dose
lum were significantly predictive of the late decline in HVLT Total constraint), decline in verbal learning/memory, processing speed
Recall. AD in the cingulum was the only dosimetric or functional and executive function at 6 months was significantly associated
parameter for which a statistically significant relationship with with poorer oncological outcomes regarding progression-free and
the cognitive test results was observed. overall survival [84]. No statistically significant association was
Another prospective work performed on 27 patients with LGG observed between the total dose to the NSC and survival. An ongo-
or other benign brain tumors highlighted similar trends [72]. AD ing randomized phase II trial evaluates, in terms of oncological effi-
decreases and RD increases were observed in the parahippocampal cacy and cognitive impairment, the technical sparing of the NSC
cingulum during radiotherapy. In univariate analysis, AD decreases compared to SVZ radiation in patients with glioblastoma treated
and RD increases were significantly associated with late impair- using IMRT [85].
ment of the delayed verbal memory assessed using the HVLT-R
Percent Retained and of the verbal fluency evaluated by the Con-
trolled Oral Word Association Test, respectively. The multivariate Cerebral cortex
analysis showed RD increases exposed to a significant risk of verbal
Dosimetric studies
fluency late decline.
A retrospective study assessed the radiosensitivity of cerebral
Although the published clinical data are heterogeneous due to
cortex regions [86]. The cohort was composed of 54 patients trea-
the various cognitive tests used, this evidence tends to highlight
ted with focal brain radiotherapy for primary tumors, including
cerebral WM sensitivity to ionizing radiation. The neurophysiology
mixed HGG and LGG. The association cortex, mainly involved in
of some areas, mainly the cingulum, corpus callosum, fornix, but
cognitive functions, was exposed to a significant risk of atrophy
also cerebellar WM, could be significantly altered by radiotherapy
one year after the start of radiotherapy when these regions were
in a dose-dependent manner [60,63,67]. The modifications reported
exposed to a mean radiotherapy dose greater than 40 Gy. Consid-
with DTI can occur in the year following completion of radiother-
ering the whole cortex, the thinning described in several regions
apy, but the reversibility of these events remains uncertain. Statis-
increased with the mean dose.
tically significant relationships have been described between
Similarly, a study in 15 patients with HGG suggested a statisti-
diffusivity changes in the cingulum and the cognitive test results
cally significant dose effect on cortical thickness one year after
performed months after completion of radiotherapy [71,72].
radiotherapy [87]. The majority of treated patients (approximately
two thirds) presented a tumor developed in one temporal lobe.
Subventricular zones: controversies Cortical thinning increased with the total dose, but varied depend-
ing on the location; i.e., 0.0024 mm per Gy in the frontal lobe and
Clinical data
0.0046 mm per Gy in the temporal lobe. Moreover, patient age and
The subventricular zones (SVZ) play an essential role in neuro-
chemotherapy were not associated with a significant risk of corti-
genesis and, consequently, in cognitive neurophysiology, even in
cal atrophy.
adults [73]. However, these areas present a risk of involvement
Based on these studies, a cortex-sparing approach has been
by HGG [74,75]. A meta-analysis concluded that glioblastomas pre-
described [88]. In patients treated with radiotherapy for HGG, a
senting anatomic contact with the lateral ventricles appear to be
normal tissue complication probability was estimated for the cere-
more aggressive and can be associated with shorter survival [76].
bral cortex. A total dose of 28.6 Gy was associated with a 20% prob-
In a retrospective study of 207 patients treated for glioblastoma,
ability of cortical thinning of 5% or more. However, these
those with tumors in contact with the SVZ presented a higher risk
preliminary dosimetric results regarding the cerebral cortex need
of recurrence, and shorter progression-free and overall survival
to be confirmed, for instance by assessing their clinical relevance
[77].
using cognitive tests in a high number of patients.
Regarding radiotherapy, several authors suggested a favorable
effect of high total doses delivered to the SVZ in terms of oncolog-
ical prognosis [78–81]. In a retrospective study of 116 patients, Potential improvements
Chen et al. highlighted a statistically significant correlation
between mean doses to the ipsilateral SVZ of greater than 40 Gy In order to reduce the exposure of healthy organs to ionizing
delivered in 30 fractions and progression-free survival in multi- radiation, various approaches have been developed.

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ther Oncol (2018), https://doi.org/10.1016/j.radonc.2018.05.027
6 Cognitive effects of brain radiotherapy

Other studies evaluated DTI as a tool in order to improve the ropsychological tests. Nevertheless, technical perspectives appear
accuracy of target volume delineation in patients treated with to improve radiotherapy accuracy. To optimize the use of these
radiotherapy for HGG [89,90]. Preliminary data showed a trend tools, data on radiosensitive cerebral areas are already available
to PTV reduction [89]. Wang et al. described IMRT considering pre- but require deeper investigation. Multidisciplinary management
motor complexes and corticospinal tracts, delineated using DTI of patients requires consideration of clinical, radiological and bio-
[90]. IMRT treatment plans highlighted a significant dose reduction logical information. Prospective studies are warranted in order to
to these healthy areas without altering PTV coverage. propose dose constraints to the healthy cerebral structures impli-
In addition, brain metabolism alteration could be implied in cated in cognitive physiology.
cognitive impairment following radiotherapy and require further
investigation. Indeed, in ten patients managed with radiotherapy Acknowledgements
for primary brain tumors, using 18F-fluorodeoxyglucose (FDG)
positron emission tomography, Hahn et al. showed decreased tra- The authors acknowledge Doctor Mostefa Bourkaib and collab-
cer uptake in areas exposed to doses exceeding 40 Gy delivered in orators for their writing assistance.
1.8 to 2.0 Gy daily fractions [91]. A statistically significant correla-
tion was established between FDG decrease and executive func- Conflicts of interest statement
tioning decline six months after the completion of radiotherapy.
The Biologically Guided Radiotherapy concept aims at tailoring The authors have no conflict of interest to disclose.
treatment by considering the tumor and healthy tissue responses
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Please cite this article in press as: Jacob J et al. Cognitive impairment and morphological changes after radiation therapy in brain tumors: A review. Radio-
ther Oncol (2018), https://doi.org/10.1016/j.radonc.2018.05.027