Structural brain alterations following adult non-CNS cancers: a systematic review of the neuroimaging literature

Figures & data

Figure 1. Several pathways are hypothesized to underlie the detrimental impact of cancer and cancer treatments on the brain and cognitive functions. First, cancer and cancer treatments (e.g., chemotherapy) may either directly, or indirectly through various pathophysiological mechanisms including epigenetic changes, DNA damage and oxidative stress, mitochondrial dysfunction, pro-inflammatory cytokine release, and endocrine and circadian disruptions, result in brain alterations and cognitive impairment (A). These mechanisms should be regarded as co-occurring and dependent processes as indicated by the white arrow. Second, cancer and cancer treatments may lead to increased psychological distress (e.g., symptoms of depression and anxiety) and behavioral changes (e.g., sleep disturbances), which may again, either directly or indirectly, impact the brain and cognitive functions (B+C). Third, activated mechanisms and associated brain alterations, as well as cognitive changes, may on their own have a negative impact on psychological and behavioral factors resulting in a negative feedback loop (C). Finally, known genetic and demographic risk factors may moderate these pathways.

Figure 2. Flowchart of included studies according to PRISMA.

Table 1. Main study characteristics.

Study	Cancer	Design	Time since treatment (mean)	Groups	Group nos.	Brain structure	Imaging modality	Main analysis
Abraham et al. (2008) [31]	Breast	Cross-sectional	1.8 years post-CT	HC CT+	9 10	WM	DTI	ROI
Amidi, Agerbaek et al. (2017) [44]	Testicular	Longitudinal	Post-surgery 3 months post-CT	CT− CT+	43 22	GM	T1	VBM ROI
Amidi, Hosseini et al. (2017) [42]	Testicular	Longitudinal	Post-surgery 3 months post-CT	CT− CT+	42 22	WM	DTI	WBNA
Apple et al. (2017) [36]	Breast	Cross-sectional	14.4 months post-CT/on hormone therapy	HC CT+	18 16	HPC	T1	DMA
Bergouignan et al. (2011) [27]	Breast	Cross-sectional	1.5–3 years post-RT	HC CT+	21 16	HPC	T1	ROI
Billiet et al. (2018) [15]	Breast	Longitudinal	Post-surgery/pre-CT 4.2 months post-CT 3.5 years post-CT	HC CT− CT+	15 14 25	WM	DTI DKI MWI	VBA ROI
Chao et al. (2013) [48]	Prostate	Longitudinal	Pre-ADT 6 months after	ADT- ADT+	12 12	GM	T1	VBM
Chen et al. (2018) [26]	Breast	Longitudinal	Post-surgery/pre-CT 22 d post-CT	HC CT+	14 16	GM WM	T1	ROI
Conroy et al. (2013) [19]	Breast	Cross-sectional	6.4 years post-CT	HC CT+	23 24	GM	T1	VBM
Correa et al. (2013) [46]	Hematol.	Longitudinal	Pre-HSCT 1 year post-HSCT	HC HSCT (CT+) HSCT (CT + fTBI)	10 19 9	GM Ventricles	T1	VBM BVQ
Correa et al. (2016) [45]	Hematol.	Longitudinal	Pre-HSCT 1 year post-HCST	HC Allogeneic Autologous	10 10 12	WM	DTI	TBSS ROI
Correa et al. (2017) [49]	Ovarian	Cross-sectional	2.7 months post-CT	HC CT+	18 18	GM	T1	VBM
de Ruiter et al. (2012) [22]	Breast	Cross-sectional	9.6 years post-CT	CT− CT+	17 15	GM WM	T1 DTI 1H-MRS	VBM TBSS PRESS
Deprez et al. (2011) [28]	Breast	Cross-sectional	4.2 months post-CT	HC CT− CT+	15 10 14	WM	DTI	VBA
Deprez et al. (2012) [21]	Breast	Longitudinal	Post-surgery/pre-CT 4.7 months post-CT	HC CT− CT+	19 16 34	WM	DTI	VBA
Eberling et al. (2004) [33]	Breast	Cross-sectional	On tamoxifen	TAM+ ERT+ ERT-/TAM-	10 15 15	HPC	T1 T2	ROI
Hosseini et al. (2012) [23]	Breast	Cross-sectional	4.5 years post-CT	HC CT+	38 37	GM	T1	WBNA
Inagaki et al. (2007) [30]	Breast	Cross-sectional	3.9 months post-CT 3.3 years post-CT	HC CT− CT+	(1 y: 3 y) 55 : 37 55 : 59 51 : 73	GM WM CSF	T1	VBM
Kesler et al. (2013) [34]	Breast	Cross-sectional	4.8 years post-CT	HC CT+	35 42	HPC	T1	ROI
Kesler et al. (2015) [39]	Breast	Cross-sectional	5.8 years post-treatment	HC CT+	36 34	WM	T1 DTI	TBSS WBNA
Kesler et al. (2017) [37]	Breast	Cross-sectional	Pre-surgery	HC Pre-surgery	50 74	GM	T1	WBNA
Koppelmans et al. (2012) [24]	Breast	Cross-sectional	21.1 years post-CT	HC CT+	368 184	GM WM HPC	T1	VBM
Koppelmans et al. (2014) [17]	Breast	Cross-sectional	21.2 years post-CT	HC CT+	374 187	WM	DTI	TBSS
Koppelmans et al. (2015) [40]	Breast	Cross-sectional	21.1 years post-CT	HC CT+	374 187	GM WM	T1 3D-PDW T2 FLAIR	CMB LCIR
Lepage et al. (2014) [18]	Breast	Longitudinal	Post-surgery/pre-CT 1 months post-CT 1.2 years post-CT	HC CT+	19 19	GM	T1	VBM ROI
McDonald et al. (2010) [29]	Breast	Longitudinal	Post-surgery/pre-CT 1 month post-CT 1 year later	HC CT− CT+	18 12 17	GM	T1	VBM
McDonald et al. (2013) [20]	Breast	Longitudinal	Post-surgery/pre-CT 1 month post-CT	HC CT− CT+	24 28 27	GM	T1	VBM
Menning et al. (2015) [41]	Breast	Cross-sectional	Pre-CT	HC pre-CT− pre-CT+	38 32 33	GM WM	T1 DTI 1H-MRS	VBM TBSS Fazekas ratings PRESS
Menning et al. (2018) [35]	Breast	Longitudinal	Post-surgery/pre-CT 6.6 months post-CT	HC CT− CT+	30 23 26	WM	DTI	TBSS ROI
Mo et al. (2017) [38]	Breast	Longitudinal	Pre-CT 2–3 weeks post-CT or surgery for neoadjuvants	HC CT+	19 11	WM	DTI	ROI
Sato et al. (2015) [16]	Breast	Longitudinal	1.5 d pre-surgery 5.6 d post-surgery	HC Post-surgery	20 32	GM	T1	VBM
Scherling et al. (2012) [25]	Breast	Cross-sectional	Post-surgery/pre-CT	HC Pre-CT	23 23	GM WM	T1	VBM
Simó et al. (2015) [47]	Lung	Cross-sectional	NSCLC – pre-CT SCLC – 1 months post-CT	HC CT− (NSCLC) CT+ (SCLC)	20 20 28	GM WM	T1 DTI	VBM VBA
Stouten-Kemperman, de Ruiter, Caan et al. (2015) [43]	Testicular	Cross-sectional	14.7 years post-CT	CT− CT+	18 27	GM WM	T1 DTI DKI	VBM TBSS
Stouten-Kemperman, de Ruiter, Koppelmans et al. (2015) [14]	Breast	Cross-sectional	11.5 years post-CT	HC RT CT+ High dose CT++	20 15 20 17	GM WM	T1 DTI 1H-MRS	VBM TBSS Fazekas ratings PRESS
Yoshikawa et al. (2005) [32]	Breast	Cross-sectional	3.5 years post-CT	CT− CT+	31 44	HPC	T1	ROI

Groups – ADT: androgen deprivation therapy; CT: chemotherapy; ERT: estrogen replacement therapy; fTBI: full-dose total body irradiation; Hematol: hematological; HC: healthy controls; HSCT: hematopoietic stem cell transplant; NSCLC: non-small-cell lung cancer; RT: radiotherapy; SCLC: small-cell lung cancer; TAM: tamoxifen. Brain structure – CSF: cerebrospinal fluid; Gray matter; HPC: hippocampus; WM: white matter. Imaging modality – 1H-MRS: single voxel proton spectroscopy; DTI: diffusion tensor imaging; DKI: diffusion kurtosis imaging; FLAIR: fluid attenuated inversion recovery; MWI: myelin water imaging; PDW: proton density-weighted imaging; T1: T1-weighted imaging; T2: T2-weighted imaging. Analysis – BVQ: brain ventricular quantification; CMB: cerebral microbleeds; DMA: deformation mapping analysis; LCIR: lacunar and cortical infarct rating; PRESS: point-resolved spectroscopy; ROI: region of interest; TBSS: tract-based spatial statistics; VBA: voxel-based analysis; VBM: voxel-based morphometry; WBNA: whole-brain network analysis.

Table 2. Results by the comparison group.

Study	Design	Cancer	Cancer group versus HC	Treatment (e.g., CT+) versus HC	Treatment (e.g., CT+) versus cancer control	Other results
Abraham et al. (2008) [31]	Cross-sectional	Breast		1. CT+ < HC: FA genu 2. CT = HC: FA splenum
Amidi, Agerbaek et al. (2017) [44]	Longitudinal	Testicular			1. CT+↓ > CT−: GM prefrontal regions including R paracingulate gyrus	1. CT+↓: GM prefrontal & parieto-frontal areas 2. CT− ↓: GM parieto-frontal, parieto-occipital, occipital, and subcortical areas 3. CT+ ↑: GM only in R Crus I and II in cerebellum
Amidi, Hosseini et al. (2017) [42]	Longitudinal	Testicular			1. CT+↓ > CT−: Global and local brain network properties: small-worldness, network clustering, and local efficiency
Apple et al. (2017) [36]	Cross-sectional	Breast		1. CT+ > HC: HPC deformation, HPC volume 2. CT+ < HC: HPC volume
Bergouignan et al. (2011) [27]	Cross-sectional	Breast		1. CT+ < HC: HPC volume, posterior HPC volume 2. CT+ = HC: anterior HPC volume
Billiet et al. (2018) [15]	Longitudinal	Breast				1. T1-T2 CT+↓, HC→ : FA in 4 ROIs 2. T2-T3: CT+↑, HC→: FA in 4 ROIs 3. T3: CT+ = CT− = HC: advanced diffusion magnetic resonance imaging, myelin-water imaging metrics in all ROIs & whole-brain voxel-wise analyses
Chao et al. (2013) [48]	Longitudinal	Prostate			1. ADT+↓ > ADT− : GM primary motor cortex, frontopolar cortex, and dorsolateral prefrontal cortex
Chen et al. (2018) [26]	Longitudinal	Breast		1. CT+ = HC: T1, T2 and over time, total GM, total WM, segmented lobar brain structures		1. TC regimen↓ > non-TC/HC: temporal lobe volume
Conroy et al. (2013) [19]	Cross-sectional	Breast		1. CT+↓ > HC: GM in L temporal lobe, R midbrain, L thalamus, R cerebellum, R insula.
Correa et al. (2013) [46]	Longitudinal	Hematol.	1. HSCT↑ > HC and 2. HSCT(CT)↑ > HC: L lateral ventricular volume	1. HSCT = HC: T1 regional brain volume or lateral ventricle volume 2. HSCT(CT)↓ > HC: L middle frontal gyrus volume over time.		1. HSCT↓: GM middle frontal gyrus bilaterally and L caudate nucleaus 2. HSCT(CT)↓: GM L middle frontal gyrus 3. HSCT↑: total lateral ventricle volume, total ventricle volume
Correa et al. (2016) [45]	Longitudinal	Hematol.		1. HSCT↓ > HC: MD/AD in diffuse WM regions	1. Allo↓ > Auto/HC: MD genu, middle cerebellar peduncle 2. Allo↑ > Auto/HC: MD fornix 3. Auto↓ > Allo/HC: MD R external capsule, uncinate fasciculus, fornix	1. HSCT↓: MD several WM tracts
Correa et al. (2017) [49]	Cross-sectional	Ovarian		1. CT+ < HC: GM frontal (R middle & superior frontal gyrus; L inferior frontal operculum) & parietal (L supramarginal gyrus into L angular gyrus).
de Ruiter et al. (2012) [22]	Cross-sectional	Breast			1. CT+ > CT−: MD, AD across WM skeleton 2. CT+ < CT−: FA L anterior corona radiata, L external capsule, L sagittal stratum 3. CT+ > CT−: Widespread MD and RD 4. CT+ = CT−: NAA, Cho, Cr 5. CT+ < CT−: NAA/Cr 4. CT+ < CT−: GM L lateral posterior parietal cortex, bilateral precuneus, L occipital cortex and bilateral cerebellum.
Deprez et al. (2011) [28]	Cross-sectional	Breast		1. CT+ < HC: FA frontal (superior fronto-occipital fasciculus, anterior limb of internal capsula, superior corona radiata) & temporal (inferior longitudinal, fronto-occipital fasciculus) WM tracts 2. CT+ > HC: MD and RD in frontal WM tracts (superior longitudinal fasciculus, superior corona radiata, corpus callosum, cingulum)	1. CT+ < CT−: FA (same regions as compared with HC) 2. CT+ > CT−: MD, RD (same regions as compared with HC)
Deprez et al. (2012) [21]	Longitudinal	Breast				1. CT+↓: FA corona radiata and corpus callosum; frontal and parietal (superior longitudinal fasciculus), occipital (forceps major) WM tracts 2. HC →: FA 3. CT− →: FA
Eberling et al. (2004) [33]	Cross-sectional	Breast				1. TAM+ = ERT-/TAM-: HPC volume
Hosseini et al. (2012) [23]	Cross-sectional	Breast		1. CT+ < HC: Clustering coefficient, small-world index 2. CT+ < HC: highly interactive nodes, degree/centrality in frontotemporal regions 3. CT+ = HC: network path lengths
Inagaki et al. (2007) [30]	Cross-sectional	Breast	1. CT+/CT− = HC: GM & WM (1-year and 3-year studies)		1. CT+ < CT − GM and WM in prefrontal, parahippocampal, and cingulate gyrus, and precuneus in (1-year study) 2. CT+ = CT−: GM & WM (3-year study)
Kesler et al. (2013) [34]	Cross-sectional	Breast		1. CT+ < HC: L HPC volume
Kesler et al. (2015) [39]	Cross-sectional	Breast		1. CT+ < HC: FA in multiple regions 2. CT+ > HC: number of streamlines 3. CT+ < HC: streamline lengths and FA NETWORK ANALYSIS 3. CT+ > HC: clustering coefficient, path length, small-worldness index 4. CT+ < HC: tolerance to targeted attacks on both nodes and edges 5. CT+ = HC: Tolerance to random attacks
Kesler et al. (2017) [37]	Cross-sectional	Breast	1. BC = HC: global network clustering
Koppelmans et al. (2012) [24]	Cross-sectional	Breast		1. CT+ < HC: total brain and GM volumes 2. CT+ = HC: total intracranial, WM, CSF volume, R and L HPC volumes, regional GM
Koppelmans et al. (2014) [17]	Cross-sectional	Breast		1. CT+ = HC: WM integrity.		1. CT+: time since treatment↑ ⇒ global and focal WM integrity↓
Koppelmans et al. (2015) [40]	Cross-sectional	Breast		1. CT+ > HC: Total CMBs and CMBs in deep/infratentorial region 2. CT+ = HC: infarctions, WM lesion volume.
Lepage et al. (2014) [18]	Longitudinal	Breast				1. T1-T2: CT+↓: GM volume (frontal, temporal, parietal, and occipital regions) 2. T1-T3: CT+: partial GM recovery, persistent reduction frontal, temporal 3. T1-T2: HC↑: GM R amygdala 4. T1-T3: HC: GM increase no longer significant.
McDonald et al. (2010) [29]	Longitudinal	Breast	1. T1–T2: CT−↓ > HC: GM R cerebellum 2. T2–T3: CT− = HC: GM	1. T1–T2: CT+↓ > HC: GM: bilateral middle frontal gyri and L cerebellum 2. T2–T3: CT+ = HC: GM	1. T2–T3: CT+ = CT−: GM 2. T1–T3: CT+↓ > CT−: GM in bilateral cerebellar regions	1. CT+ = CT− = HC: GM at baseline. 2. T1–T2: CT+↓: GM in bilateral frontal, temporal, cerebellar regions, R thalamus 3. T3: CT+: GM recovery in bil. superior frontal, L middle frontal, R superior temporal and cerebellar regions 4. T3: CT+: GM persistent decreases in bil. cerebellum, R thalamus and medial temporal lobe, L middle frontal gyrus, R precentral, medial frontal, and superior frontal gyri 5. CT− →, HC →: GM
McDonald et al. (2013) [20]	Longitudinal	Breast	1. CT−↓ = HC: GM	1. CT+↓ > HC: GM density in L middle frontal gyrus at T2.	1. CT+↓ = HC: GM	1. CT+↓: GM L middle and superior frontal gyri 2. CT−→, HC→: GM
Menning et al. (2015) [41]	Cross-sectional	Breast	1. BC < HC: FA 2. BC > HC: MD			1. Pre-CT+ = Pre-CT− = HC: regional GM and WM, brain metabolites, Fazekas rating for WM lesions
Menning et al. (2018) [35]	Longitudinal	Breast	1. T2: CT− < HC: FA 2. T2: CT− > HC: MD	1. T2: CT+ > HC: MD	1. CT+↓ > CT−: FA in R superior longitudinal fasciculus	1. CT+ = CT− = HC: voxel-wise WM integrity over time 2. CT−↓, HC↑: MD in genu.
Mo et al. (2017) [38]	Longitudinal	Breast				1. CT+↓: FA in 3/50 ROIs in fornix, L and R superior fronto-occipital fasciculus. No differences after FDR corrections.
Sato et al. (2015) [16]	Longitudinal	Breast		1. BC↓ HC↑: regional GM volume in R thalamus.		1. BC: Anesthesia ⇏ regional GM volume in thalamus over time.
Scherling et al. (2012) [25]	Cross-sectional	Breast	1. BC = HC: GM whole brain and ROIs, whole brain WM values 2. BC < HC: WM volumes in bil. inferior frontal, L pre & postcentralgyri, L insula, L striatum, R supramarginal-gyrus, L inferior parietal, R middle temporal gyrus, L precuneus and L corpus callosum
Simó et. al. (2015) [47]	Cross-sectional	Lung	1. CT+/CT− < HC: GM density in L insula, bilateral parahippocampal gyrus, L anterior cingulate cortex. 2. CT+/CT− < HC: FA & CT+/CT− > HC: AD in L inferior longitudinal fasciculus. 3. CT− < HC: FA & CT− > HC: AD in widespread regions in L cingulum & superior corona radiata, R superior longitudinal fasciculus	1. CT+ < HC: GM density in R insula, bilateral parahippocampal gyrus, L anterior cingulate cortex 2. CT+ > HC: AD in L cingulum.
Stouten-Kemperman, de Ruiter, Caan et al. (2015) [43]	Cross-sectional	Testicular			1. CT+ = CT−: Global and focal GM and WM volumes. 2. CT+ = CT−: MD, FA, MK, and AK values across WM skeleton 3. CT+ > CT−: RK across skeleton 4. CT+ > CT−: RK in widespread areas: corpus callosum, bilateral internal capsula, bilateral superior longitudinal fasciculus, and bilateral corona radiata.
Stouten-Kemperman, de Ruiter, Koppelmans et al. (2015) [14]	Cross-sectional	Breast		1. RT > HC: GM volume in cerebellum, occipital cortex, cingulum, calcarine sulcus and precuneus; MD in superior longitudinal fasciculus.	1. CT++ < RT: GM volume in posterior brain areas incl. cerebellum, occipital cortex, posterior parietal cortex, precuneus 2. CT+ < RT: GM volume in occipital cortex and cerebellum 2. CT++ > RT: MD in body and genu of corpus callosum, cingulum, posterior & superior fronto-occipital/longitudinal fasciculus.	1. CT++ > CT+/RT: MD, (NAA + NAAG)/CR ratio showing WM injury 2. CT++ = CT+ = RT: Fazekas ratings of WM hyperintensities, FA values 3. CT++ > CT+: MD values in body and genu of corpus callosum, anterior & superior corona radiata, external & internal capsule, sagittal striatum & superior longitudinal fasciculus.
Yoshikawa et al. (2005) [32]	Cross-sectional	Breast			1. CT+ = CT−: HPC volumes

Groups – ADT: androgen deprivation therapy; Allo: allogeneic hematopoietic stem cell transplant; Auto: autologous hematopoietic stem cell transplant; BC: breast cancer patients; CT: chemotherapy; HC: healthy controls; HSCT: hematopoietic stem cell transplant; RT: radiotherapy; TAM: tamoxifen; TC: docetaxel and cyclophosphamide. Brain structure – CSF: cerebrospinal fluid; Gray matter; HPC: hippocampus; WM: white matter. Neurochemical indices – Cho: choline-containing metabolites; Cr: creatine; NAA: N-acetylaspartate. Analysis: ROI: region of interest; CMB: cerebral microbleeds. Results – AD: axial diffusivity; AK: axial kurtosis; bil.: bilateral; FA: fractional anisotropy; FDR: false discovery rate; L: left; MD: mean diffusivity; MK: mean kurtosis; R: right; RD: radial diffusivity; RK: radial kurtosis. Symbols: ↑: increase over time; ↓: decrease over time; →: stable over time; =: not significantly different; >: significantly greater than; <: significantly less than; ⇒: associated with; ⇏: not associated with.

Figure 3. Number of publications by patient sample size.

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