Neurological Complications of Breast Cancer

and Its Treatment 23

Emilie Le Rhun, Sophie Taillibert, and Marc C. Chamberlain

List of Abbreviations
AED Antiepileptic drugs
AMPAR Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor
APOE Apolipoprotein E
ASIA American Spinal Injury Association
BC Breast cancer
BM Brain metastases
BCRA BReast CAncer
CIPN Chemotherapy-induced peripheral neuropathy
CMF Cyclophosphamide, methotrexate, and 5-fluorouracil
CNS Central nervous system
COMT Catechol-O-methyltransferase
COWA Controlled Oral Word Association
CVD Cerebrovascular disease
CSF Cerebrospinal fluid
CT Computed tomography
DTI Diffusion tensor imaging
DNA Desoxyribose nucleic acid
ECOG Eastern Cooperative Oncology Group
EIAED Enzyme-inducing antiepileptic drugs
EORTC European Organization for Research and Treatment of Cancer
EpCAM Epithelial cell adhesion molecule
ER Estrogen receptors
ESCC Epidural spinal cord compression

E. Le Rhun (&) S. Taillibert

Department of Neurosurgery and Neuro-oncology, Department of Radiation Oncology, Pitié-Salpétrière Hospital,
University Hospital, 59037 Lille Cedex, France UPMC-Paris VI University, 47 Boulevard de l’Hôpital,
e-mail: emilie.lerhun@chru-lille.fr 75013 Paris, France
E. Le Rhun M.C. Chamberlain
Breast unit, Department of Medical Oncology, Department of Neurology and Neurological Surgery,
Oscar Lambert Center, 59020 Lille Cedex, France Seattle Cancer Care Alliance, University of Washington,
835 Eastlake Ave East, Seattle, WA 98109, USA
E. Le Rhun
e-mail: chambemc@uw.edu
PRISM Inserm U1192, Villeneuve d’Ascq, France
S. Taillibert
Department of Neurology, Pitié-Salpétrière Hospital,
UPMC-Paris VI University, 47 Boulevard de l’Hôpital,
75013 Paris, France
e-mail: sophie.taillibert@pal.aphp.frsophie.taillibert@gmail.com

© Springer International Publishing AG 2018 435

D. Schiff et al. (eds.), Cancer Neurology in Clinical Practice,
DOI 10.1007/978-3-319-57901-6_23
436 E. Le Rhun et al.

FLAIR Fluid-attenuated inversion recovery

18FDG-PET [(18)F] 2-fluoro-2-deoxyglucose–positron emission tomography
fMRI Functional MRI
5-FU 5 fluorouracil
GPA Graded prognostic assessment
Gy Gray
HA-WBRT Hippocampal avoidance whole-brain radiotherapy
HER2 Human epidermal growth factor receptor 2
HRQOL Health-related quality of life
HLVT-R DR Hopkins Verbal Learning Test-Revised Delayed Recall
HVLT-R Hopkins Verbal Learning Test-Revised
ICCTF International Cognition and Cancer Task Force
ICH Intracranial hemorrhage
ISCM Intramedullary spinal cord metastasis
KPS Karnofsky performance status
LM Leptomeningeal metastases
LMWH Low molecular weight heparin
MBP Myelin basic protein
MMSE Mini-mental status examination
MRI Magnetic resonance imaging
mTOR Mammalian target of rapamycin
NCCN National Comprehensive Cancer Network
NF2 Neurofibromatosis 2
NGF Nerve growth factor
NMDA N-methyl-D-aspartate
OS Overall survival
PARP Poly (ADP-ribose) polymerase
PET Positron emission tomography
PI3K Phosphoinositide 3-kinase
PNS Paraneoplastic neurological syndromes
PR Progesterone receptors
PFS Progression-free survival
PRES Posterior reversible encephalopathy
PS Performance status
QoL Quality of life
RECIST Response Evaluation Criteria In Solid Tumors
RIBP Radiation-induced brachial plexopathy
RT Radiotherapy
RTOG Radiation Treatment Oncology group
SEER Surveillance epidemiology and end results
SMART Stroke-like migraine attacks after radiation therapy
SRS Stereotactic surgery
SRT Stereotactic radiotherapy (stereotactic hypofractionated radiotherapy)
STIR Short TI inversion recovery
tPA Tissue-type plasminogen activator
TMT Trail Making Test
uPA Urokinase plasminogen activator
US USA
VEGF Vascular endothelial growth factor
VTE Venous thromboembolism
WBRT Whole-brain radiotherapy
WHO World Health Organization
23 Neurological Complications of Breast Cancer and Its Treatment 437

Introduction BM in BC most often are metachronous in presentation

Breast cancer (BC) is one of the most common cancers in
women with approximately 1 in 8 developing BC. Neuro-
logical complications of BC can result from metastases,
treatment, and other causes. Neurological signs and symp-
toms may involve both the central (CNS) nervous system
and the peripheral (PNS) nervous system. CNS metastases
portend a poor outcome in patients with BC, and in all cases,
the neurological complications of BC have a significant
impact on the functional status and quality of life (QoL) of
the patient. An outline of the chapter is illustrated in
Table 23.1.
Metastatic Complications
Central Nervous System Metastases
Parenchymal Brain Metastases (Fig. 23.1)
Breast cancer (BC) is one the most frequent systemic cancers
resulting in brain metastases (BM). Between 10 and 30% of
BC patients will develop BM [1]. BM often have a signifi-
cant clinical impact by reducing the QoL and compromising
survival [2].
Table 23.1 Neurological complications of breast cancer: outline
Metastatic complications Central nervous system
of breast cancer Cranial
Parenchymal brain metastases
Skull base metastases
Dural metastases
Spinal
Intramedullary spinal cord
metastases
Spinal epidural metastases
Leptomeningeal metastases
Peripheral nervous system
Peripheral nervous system
metastases
Neoplastic plexopathy
Non-metastatic, Paraneoplastic syndromes
non-treatment-related Meningiomas
complications
Treatment related Central nervous system
complications Encephalopathy
Cognitive injury
Radionecrosis
Cardiovascular complications
Meningitic syndromes
Myelopathy
Peripheral nervous system
Plexopathy
Radiculopathy
Neuropathy
Peripheral neuropathy
Myopathy
and seen in patients with known cancer (80%), but can also
be the first manifestation of cancer (5–10%) [3] or discov-
ered concomitantly with systemic disease. BM are solitary in
20 to 30% of patients and are oligometastatic (2 or 3 lesions)
in the same proportion [2, 3]. Signs and symptoms of BM
are related to the anatomic localization of the metastases.
Approximately 50% of patients present with headache, and
30% present with focal neurological signs, mostly seizures
[4]. Cranial computed tomography (CT) scan is able to
detect BM; however, the sensitivity and specificity of mag-
netic resonance imaging (MRI) are considerably higher [5].
Contrast MRI permits a more precise evaluation of the
number and location of BM. BM are located in the cerebral
hemispheres (80% overall) and less frequently in the cere-
bellum (15%) or brainstem (5%). Once developed, the
neurological symptoms/signs do not always resolve, even in
patients responding to treatment. Early diagnosis and serial
follow-up after BM are diagnosed as important to minimize
emergence of CNS disease that may compromise QoL and
survival. In the CEREBEL study of human epidermal
growth factor receptor 2 (HER2)-positive metastatic BC,
nearly 20% of the patients had asymptomatic BM. Consid-
ering the high proportion of BM in BC and the increasing
treatment options in the HER2-positive population, serial
brain MRI appears clinically appropriate [3].
The incidence of and the time to presentation of BM vary
according to the subtype of BC (categorized as luminal A:
ER/PR positive, HER2 negative; luminal B: triple positive;
HER2: HER2 positive, ER/PR negative; and basal: triple
negative). In a cohort of 383 BC patients treated for BM,
both the median time between BC and BM diagnoses and
the median overall survival (OS) following discovery of BM
were significantly different among the different BC subtypes
[6]. The shortest interval between BC diagnosis and BM
diagnosis was observed in the basal/triple negative and the
HER2 subtypes (Table 23.2) [7, 8]. The overexpression of
HER2 is associated with a higher risk of BM; between 30
and 50% of HER2-positive patients will develop BM [9–12].
Several risk factors for BM have been identified in BC
patients, including overexpression of HER2, estrogen
receptor negativity, triple negative status, young age, nodal
involvement, high-grade tumors, and larger tumor size [7, 8,
13–15].
In a Japanese retrospective cohort of 1256 BC patients
with BM, the median OS was 8.7 months [16]. Shortest OS
was observed in the non-HER2-positive subtypes in the
cohort of Sperduto et al. [7, 8, 15]. No significant difference
in OS was observed among HER2-positive tumors in a large
cohort of 423 HER2-positive BC patients with BM [17]. In
this cohort, BM patients treated with trastuzumab and lap-
atinib had a significantly longer survival as compared to
patients treated with trastuzumab alone, lapatinib alone, or
438
Fig. 23.1 Brain metastases.
Brain MRI, T1 W
gadolinium-enhanced axial
images
no HER2-targeting agent. The subtype of BC appears to not
only influence prognosis but cause death as well. Half of all
patients with HER2-positive BM die of CNS disease pro-
gression, whereas patients with triple negative BC die most
commonly of systemic disease [9, 18].
The Breast Graded Prognostic Assessment (Breast-GPA)
instrument developed by the RTOG (Radiation Treatment
Oncology Group) can assist in determining the prognosis of
BC patients with BM and guide treatment. For BC, the GPA
instrument used a single prognostic factor, the Karnofsky
Performance Status (KPS) [19]. In another RTOG cohort of
newly diagnosed BC patients, significant prognostic factors
included the KPS, the HER2, ER/PR status, and the inter-
action between ER/PR and HER2 [6]. The initial
Breast-GPA was revised based on a larger cohort of BC
patients with BM and now includes, KPS, BC subtype, and
age (Table 23.3). The median OS was estimated at
3.4 months for patients with a Breast-GPA score >1 and at
25.3 months for patients with a BC-GPA score between 3.5
and 4.0 [6]. Notably, the number of BM was not integrated
in the revised Breast-GPA; however, a recent analysis of
another large cohort of patients with BC and BM suggested
that the number of BM (>3 vs.  3) has a significant impact
on survival [20]. In the aforementioned Japanese cohort,
multivariate analyses found increased survival in patients
diagnosed with BM within 6 months of metastatic BC
diagnoses, with asymptomatic BM, or with HER2-positive/
estrogen receptor-positive tumors [16]. In another retro-
spective cohort of 215 BC patients, non-luminal subtype,
presence of extracranial disease, time to CNS metas-
tases <15 months, the presence of >3 BM, and a low
Breast-GPA were associated with a shorter survival [21].
Relatively few trials have been prospectively studied in
BC patients with BM. Indeed, in the majority of BM trials,
lung cancer patients represent the largest population. As BC
E. Le Rhun et al.
and lung cancer share a better radiosensitivity relative to
melanoma [22], the management of BC BM can be in part
extrapolated from the results of these trials. Initial treatment
for newly diagnosed BC-related BM includes surgery,
whole-brain radiotherapy (WBRT), stereotactic radiotherapy
(stereotactic radiosurgery [SRS] and stereotactic radiother-
apy [SRT]), systemic therapy, clinical trials, and palliative
care. The choice of treatment depends on the number,
localization, and volume of BM, the neurological and overall
status of the patient, and the control of the systemic disease
[23, 24]. The intent of BM-directed treatment in BC can be
curative or palliative. Additionally, supportive care is
important following BM diagnosis. The lowest effective
dose of steroids is recommended for the management of
vasogenic edema to avoid steroid-related toxicity that may
further compromise QoL. According to the American
Academy of Neurology and European guidelines, prophy-
lactic antiseizure treatment is not recommended in patients
with BM [25, 26]. In a patient with seizures and BM in
whom an antiepileptic drug is indicated, the use of non
enzyme-inducing agents is recommended to minimize
interactions with systemic anticancer treatments.
Surgical resection is considered for patients with acces-
sible and limited BM. In a cohort of 42 BC patients with
BM, the median OS after surgery was 16 months [27]. In
this case series, age was the only factor significantly corre-
lated in multivariate analyses with OS. In another cohort of
116 BC patients with BM, the median OS was 11.5 months
[28]. Surgical resection is performed in patients with a
solitary BM in non-eloquent brain regions and in patients
with well-controlled systemic disease. Surgical resections of
all lesions in patients with up to 3 BM may improve survival
as well [29, 30]. Indications are less clear in patients with
multiple BM or uncontrolled extracranial disease, but in
some cases, surgery can provide rapid relief of symptoms
23 Neurological Complications of Breast Cancer and Its Treatment 439

Table 23.2 Incidence, median delay between breast cancer (BC) diagnosis and brain metastases (BM) diagnosis, and median overall survival
after BM diagnosis
Incidence of the different Median delay between BC Median survival after References
BC subtypes in BM (%) diagnosis and BM diagnosis (months) BM diagnosis (months)
Luminal A 20 54.4 10.0 Sperduto [6]
14 30 9.3 Niikuara [16]
7.4 Aversa [15]
5 Bachmann [8]
Luminal B 25.5 47.4 22.9 Sperduto [6]
35 96 16.5 Niikuara [16]
33.5 19.2 Aversa [15]
16.5 Hayashi [17]
HER2 31 35.8 17.9 Sperduto [6]
49 36 11.5 Niikuara [16]
33.5 7 Aversa [15]
11.5 Hayashi [17]
Basal /triple negative 23.5 27.5 7.2 Dawood [399]
22 35 7.3 Sperduto [6]
4.9 Niikuara [16]
4.9 Aversa [15]
5 Bachmann [8]
Abbreviations: BC breast cancer, BM brain metastases

Table 23.3 Revised breast cancer graded prognostic assessment

Factor 0.0 0.5 1.0 1.5 2.0
KPS  50 60 70–80 90–100 –
Genetic subtype Basal – Luminal A HER2 Luminal B
Age  60 <60 – – –
Group Breast-GPA MST (months) (95% CI) 1 year OS (95% CI) 2 year OS (95% CI) 3 year OS (95% CI)
Group 1 0.0–1.0 3.4 (2.4–4.9) 15 (4–33) 0 0
Group 2 1.5–2.0 7.7 (4.8–9.7) 32 (23–41) 13 (6–20) 6 (2–13)
Group 3 2.5–3.0 15.1 (10.8–17.9) 55 (46–63) 29 (21–37) 19 (11–27)
Group 4 3.5–4.0 25.3 (20.4–30.4) 77 (69–84) 53 (43–61) 31 (22–40)
Abbreviations: KPS Karnofsky performance score, MST Median survival time, OS Overall survival
Used with permission of Springer Science from Sperduto et al. [6]

due to intracranial hypertension and obstructive hydro-
cephalus, particularly in patients with a large symptomatic
lesion [31]. In summary, resective surgery is indicated for
(1) therapeutic indications including a large symptomatic or
asymptomatic lesion; (2) diagnostic indications including the
absence of known primary tumor, doubt regarding the
metastatic origin of the lesion, uncertainty between
radionecrosis, and progression after brain irradiation; and
(3) histological and molecular biological documentation.
Advances in surgery include functional MRI (fMRI) with
fiber tract mapping, transcranial stimulation, and
intra-operative MRI. Piecemeal resection should be avoided
as the recurrence rate is 1.7 times higher than tumors
removed en bloc, particularly for lesions in the posterior
fossa and in contact with CSF pathways [32, 33]. When
feasible, a microscopic total resection with a 5-mm margin
of normal-appearing tissue may lead to a reduced incidence
of local recurrence [34]. When surgery is performed, histo-
logical and molecular biomarkers should be re-examined to
verify the concordance between the primary BC and the BM
and to identify potential druggable targets.
The indications for stereotactic radiosurgery (SRS) or
stereotactic RT (SRT) include BM in patients with surgically
inaccessible metastases, post-surgical treatment of the
operative cavity, and progressive BM in patients previously
treated with WBRT (re-irradiation). SRT is used in patients
with a limited number of BM, limited lesional volume, and
controlled systemic disease. SRS is often used for patients
with less than 5 BM. However, large retrospective cohorts
with up to 15 lesions have reported similar outcomes to
those with 1–4 BM [35–38]. The total volume of tumor has
been suggested to be more important than total number of
440
lesions [39]. Local control rates observed after SRS range
from 64 to 94% [31]. SRS alone may be as effective as
surgery and SRS of the resection cavity [40–42]. In a cohort
of 136 BC patients presenting with 1–3 BM and treated with
SRS, local failure rate was 10% at 12 months and the
median OS was 17.6 months. On multivariate analyses,
patients with >1 lesion, triple negative BC, and poorly
controlled extracranial disease had a shorter OS [43]. In
another cohort of 131 BC patients with BM treated by SRS,
the median OS varied significantly according to the type of
BC, ranging from 7 months in triple negative patients, to
16 months in ER-positive HER2-negative patients,
23 months in ER-negative HER2-positive patients, and
26 months in ER-positive HER2-positive patients [44]. The
dose of SRS varies according to the volume of the lesion and
the potential risk of radionecrosis. In a small study, the dose
of SRS in BC patients with 1–3 BM was evaluated by
comparing 20 patients treated with 20 Gy versus 10 patients
treated with 16–18.5 Gy [45]. The local control rates were
94% after 20 Gy and 48% after 16–18.5 Gy.
WBRT has long been the standard treatment for BM,
though its role has changed with the advent of SRS/SRT,
new methods of WBRT, such as hippocampal avoidance,
and improved knowledge of outcome based upon BC sub-
type. Notably, however, WBRT decreases local and distant
failures after either surgery or SRS/SRT [46]. Addition of
WBRT results in a clinically significant benefit in 64–83%
of patients with BM and is associated with an increase of 2–
6 months in overall survival [47]. BC, as well as non-small
cell lung cancer (NSCLC), are more likely to respond to
WBRT compared to other histologies [48]. Response rates to
WBRT in BC patients with BM vary from 65 to 82% [48–
50]. The combination of WBRT and systemic agents con-
stitutes another potential treatment for BC BM. The addition
of temozolomide to WBRT in BC patients did not improve
local control or survival in a phase II randomized trial (NCT
00875355) [51]. The addition of veliparib, an oral PARP
inhibitor, to WBRT was well tolerated and showed
encouraging preliminary efficacy data in a cohort with 31%
of BC patients [52].
A phase III European Organization for Research and
Treatment of Cancer trial (EORTC 22952-26001) assessed
the impact of WBRT after surgery or SRS on the preser-
vation of functional independence in patients with 1–3 BM
(>90% with a solitary BM) from solid tumors (excluding
small cell lung cancer) with stable extracranial disease and a
0–2 WHO performance status (PS) [53]. In this study, 199
patients underwent SRS and 160 underwent surgery. The
median time to a deterioration of WHO PS by more than 2
points was 10.0 months after observation and 9.5 months
after WBRT. OS was not significantly different between the
2 arms (10.9 months after WBRT and 10.7 after observa-
tion). The 2-year relapse rate at both the initial treated site
E. Le Rhun et al.
and at new sites of disease was significantly reduced after
WBRT, although BC represented only 12% of all tumors in
this trial. The role of WBRT added to SRS in BC patients
with 1–3 BM has been reported in a retrospective cohort of
30 patients treated by SRS alone and 28 treated by SRS plus
WBRT [54]. The addition of WBRT to SRS resulted in
significantly longer survival without new BM but no dif-
ference was observed in survival between the 2 groups. In
the EORTC trial, a significantly better health-related quality
of life (HRQOL) was observed in the observation arm
compared to the WBRT arm during the first year after
treatment [55]. The authors conclude that WBRT was
detrimental to several elements of the HRQOL. This study
also reported that frequent monitoring for BM recurrence did
not have a negative impact on HRQOL. The impact of
WBRT on cognition was assessed in a small randomized
controlled study (NCT 00548756). In this trial, patients with
1–3 newly diagnosed BM were randomly assigned to SRS
plus WBRT or SRS alone. The primary endpoint was cog-
nition measured by Hopkins Verbal Learning Test-Revised
(HVLT-R) total recall at 4 months. The study was stopped in
accordance with trial stoppage guideline, after determination
of a 96% probability that patients in the SRS + WBRT
group were significantly more likely to have cognitive
decline as compared to patients treated by SRS alone [56]. In
the Alliance trial (NCT00377156), 213 patients with 1–3
BM, each <3 cm were randomized between SRS alone or
SRS plus WBRT [57]. The primary objective was to eval-
uate cognitive decline. After SRS alone, intracranial tumor
control with SRS was 66.1% at 6 months and 50.5% at
12 months. After SRS plus WBRT, intracranial tumor con-
trol was 88.3% at 6 months and 84.9% at 12 months.
Median OS was 10.7 months after SRS alone and
7.5 months after SRS plus WBRT. Moreover, despite better
local control after WBRT without improvement of OS, the
cognitive decline was higher after SRS plus WBRT.
The incidence of radiation-induced white matter injury
has been assessed in a retrospective cohort of 35 BC patients
treated by SRS plus WBRT and 30 patients treated by SRS
alone. A higher incidence of white matter hyperintensities by
brain MRI was observed after combined treatment. At one
year, 71.5% of the patients treated with both SRS and
WBRT demonstrated white matter lesions (limited periven-
tricular hyperintensity in 42.9%, diffuse white matter
hyperintensity in 28.6%), whereas only one patient treated
with SRS developed white matter lesions [58].
The use of WBRT is increasingly deferred, given evi-
dence that WBRT negatively impacts QoL and cognition,
and because BC patients, especially those with HER2 pos-
itive tumors, are living longer. Initial treatment with SRS
and close radiographic monitoring is thus preferred in
patients with a limited number of BM. The indications for
WBRT include multiple and disseminated BM, and failure
23 Neurological Complications of Breast Cancer and Its Treatment
of stereotactic radiotherapy [31]. The incidence of cognitive
decline as assessed by a decline in the Mini-Mental Status
Examination (MMSE) was determined in a prospective
randomized trial comparing WBRT plus SRS versus SRS
alone in 110 patients with 1–4 BM [59]. Deterioration in the
MMSE was seen in 39% of patients in the WBRT plus SRS
group and 26% of patients in the SRS only group. On
average deterioration occurred at 13.6 months in the WBRT
plus SRS group and at 6.8 months in the SRS group. Rec-
ognizing the limitations of the MMSE as an instrument to
assess cognition, these data suggested that cognitive
impairment in patients with treated BM may result from
radiation-related toxicity as well as recurrence of BM. Thus
the control of brain disease is of particular importance for
preservation of cognition.
Several approaches have been evaluated to minimize
RT-associated cognitive decline. Memantine, a N-methyl-D-
aspartate (NMDA) receptor agonist, was assessed in a ran-
domized double-blind placebo controlled trial in patients
treated with WBRT [60]. Memantine was well tolerated but
the difference in delayed recall, the primary endpoint, was
not significant between treatment arms. Nonetheless signif-
icantly longer time to cognitive deterioration, reduction in
the rate of decline in delayed recognition, executive function
and processing speed was observed with memantine. Peri-
hippocampal stem cells injury as a consequence of WBRT
may contribute to RT associated cognitive decline, and thus
shielding the hippocampal neural stem cell compartment was
evaluated in a phase II study utilizing hippocampal avoid-
ance WBRT (HA-WBRT) in patients with BM (RTOG
0933) [61]. In this study, the median OS was 6.8 months.
The mean relative decline in Hopkins Verbal Learning
Test-Revised Delayed Recall (HLVT-R DR) at 4 months
(primary endpoint) was 7.0%, significantly lower than his-
torical controls.
The efficacy of liposomal doxorubicin in combination
with cyclophosphamide was evaluated in a retrospective
study of 29 BC patients. The objective response rate in brain
was 41.4% after 3 cycles (50% in the absence of prior brain
RT). The median OS from brain diagnosis was 23 months
[62]. BM responses have also been reported with
anthracycline-based regimens, CMF (cyclophosphamide,
methotrexate and 5-fluorouracil), and high-dose methotrex-
ate [23]. Temozolomide as single agent in metastatic BC and
BM has little activity based upon two small phase II studies
in which the objective response rate was <6% and transient
[63, 64]. Similarly gefitinib has no activity, based on a single
phase II trial [65]. Interim analyses of the phase II did not
meet the efficacy point [23]. TPI-287, a microtubule-
stabilizing agent, designed to bypass the MDR-1 drug
efflux resistance mechanism is undergoing study [23]. Other
new agents under development include cabazitaxel
(NCT01913067), ANG1005 (NCT01480583), TPI-287
441
(NCT01332630) and 2B3-101 a glutathione-pegylated dox-
orubicin (NCT01386580).
Targeted therapies are highly efficacious in BC. Genomic
and epigenomic profiling of metastases may provide a basis
for future therapeutic strategies [66, 67]. Endocrine therapies
represent the oldest targeted therapies in BC, and responses
of BM to tamoxifen, aromatase inhibitors and megestrol
acetate have been reported in small case reports [3]. How-
ever, loss of hormonal receptor positivity is frequent in BM
(when compared to the matched primary tumor) often
obviating the use of hormonal agents [68]. In a cohort of 36
paired samples of the primary BC and BM, the discordance
rates were 28% for ER and 20% for PR [69]. Additionally
the majority ER-positive BC is endocrine-refractory when
BM is diagnosed [23].
Anti-HER2 targeted agents play an important role in the
management of BM in HER2 positive breast cancer. In the
cohort of 36 paired tumors mentioned above, the discordant
rate was only 3% only for HER2 status [69]. Improved OS
has been reported in several retrospective studies in HER2
positive BC patients with BM when treated with trastuzu-
mab [12, 70, 71]. Approximately one third of metastatic BC
patients receiving trastuzumab develop BM [12, 72]. In
50%, BM are diagnosed when systemic disease is controlled.
BM has been shown to develop later in patients treated with
trastuzumab [70]. Furthermore, a survival benefit has been
reported with continuation of trastuzumab-based therapies
after development of BM [70, 73–77]. However, the impact
on OS may relate more to control of extracranial disease.
The efficacy and the safety of lapatinib alone was first
evaluated in 39 patients with HER2 positive progressive BM
all previously treated by trastuzumab and by WBRT in 37
cases [78]. The objective response rate was low (2.6%). The
median time to progression was 3.0 months suggesting very
limited activity as a single agent. In a phase II study, 242
HER2 positive BC patients with progressive BM previously
treated with trastuzumab and cranial RT were treated with
lapatinib alone [79]. The objective response rate was 6%;
21% had a volumetric response of 20% or more. Of the 50
patients enrolled in the extension phase of the study that
added capecitabine to lapatinib, a CNS objective response
was observed in 20% (according to RECIST criteria) and
40% (based on volumetric response of 20% or more).
Importantly, the effect of capecitabine alone cannot be
excluded in the extension phase, although lapatinib may
have had an additive effect. The modest activity of lapatinib
in the CNS replicates that seen in systemic disease as well
[80]. The efficacy of the combination of lapatinib and
capecitabine was confirmed in a cohort of 22 evaluable
HER2 positive BC patients with previously treated BM [81].
Partial responses were observed in 7 patients and stabiliza-
tion was observed in 6 patients. The median brain PFS was
5.6 months and the median OS was 27.9 months,
442
significantly longer than in patients treated with
trastuzumab-based therapies after CNS progression
(16.7 months). The response rates observed with lapatinib
and capecitabine were replicated in several expanded access
programs [18% response reported by Boccardo and 21%
reported by Sutherland] [82, 83]. In combination with
capecitabine, CNS response rates vary from 18 to 38% [78,
79, 81–84].
Excess toxicity and lack of efficacy was observed in a
study comparing the combination of lapatinib plus topotecan
versus lapatinib plus capecitabine [84]. The efficacy of the
combination of lapatinib and capecitabine was studied in the
LANDSCAPE phase II trial (NCT00967031) in untreated
asymptomatic BM with HER2 positive BC [85]. A high
partial response rate of 66% was seen. The median time to
progression was 5.5 months. This approach constitutes an
option for patients with HER2 positive tumors that are low
volume and paucisymptomatic. The CEREBEL trial,
designed to demonstrate that the combination of lapatinib
plus capecitabine could reduce the incidence of BM com-
pared to trastuzumab plus capecitabine, was closed early due
to a low incidence of BM (3% in the lapatinib plus capeci-
tabine group and 4% in the trastuzumab plus capecitabine
group) [86].
In a retrospective study, Bartsch evaluated the impact of
trastuzumab and lapatinib on 80 HER2 positive BC patients
with BM [71]. Median OS was 13 months in patients treated
with trastuzumab after diagnosis of BM, 9 months in
patients treated with chemotherapy and 3 months in patients
treated with RT only. Addition of lapatinib to trastuzumab,
either sequentially or concomitantly, prolonged OS com-
pared to trastuzumab alone. Thus, the combination of lapa-
tinib and trastuzumab may be an option for BC BM.
The combination of trastuzumab and WBRT resulted in a
response rate of 74% suggesting possible radiosensitization
[87]. The potential radiosensitizing impact of lapatinib in
combination with WBRT was evaluated in a phase I trial in
which a response rate of 79% was observed [88]. Further
studies are ongoing. New anti-HER2 therapies (pertuzumab,
TDM-1) have been approved recently; however, their impact
on BM is not yet well defined. Regimens containing afatinib,
an irreversible HER2 and EGFR inhibitor, failed to improve
PFS in a phase III trial, compared to either trastuzumab or
lapatinib [89]. Only a few responses were observed with
neratinib in a phase II study enrolling 40 BC patients with
progressive BM previously treated (NCT01494662) [90].
The association of neratinib and capecitabine is also under
investigation [91]. Other new anti-HER2s, including
ARRY-380, a HER2-selective tyrosine kinase inhibitor, are
in development [24, 91].
A CNS response of 63% was observed on prespecified
volumetric criteria in a phase II trial evaluating the combi-
nation of carboplatin and bevacizumab in BC BM patients
E. Le Rhun et al.
[92]. By RECIST criteria, the response rate was 45%. In
another phase II trial, the objective CNS response rate
according to RECIST criteria was 77% for the combination
of bevacizumab, etoposide and cisplatin [93]. The median
CNS PFS and OS were 7.3 and 10.5 months, respectively.
mTOR, PI3 K and dual mTOR/PI3 K inhibitors are
currently being explored in breast cancer. Everolimus, a
rapamycin analogue that inhibits mTOR signalling, is being
evaluated in a phase II trial in combination with trastuzumab
and vinorelbine in HER2 positive BC with BM. BKM20, an
oral pan-PI3 K inhibitor, is also being studied in HER2
positive BC patients with BM (NCT01132664). PARP
inhibitors, which disrupt DNA repair, such as ABT-888, are
also being investigated in BM patients (NCT00649207).
Iniparib, initially developed as a PARP inhibitor but sub-
sequently shown not to have any PARP inhibitor activity,
showed a modest activity in BM [24]. Immune-based
approaches including ipilimumab and anti-PD-1 therapies
may also be new promising approaches if activity is con-
firmed in BC.
Skull Base Metastases
Skull base metastases occur in approximately 4% of cancer
patients [94], and are found in 22% of autopsy cases [95].
BC is one of the most common causes of skull base
metastases, accounting for 20.5–40% of all cases [94–96].
Skull base metastases are most often diagnosed in patients
with disseminated disease, particularly to other skeletal
elements [96]. Direct hematogenous spread is the primary
route of dissemination to the skull base. Rarely, retrograde
seeding through the valveless venous plexus of Batson has
been proposed [97, 98]. Progressive ipsilateral involvement
of cranial nerves is the main presentation of skull base
metastases. The clinical manifestations depend on the size,
location and growth rate of the metastases. The etiology of
signs and symptoms is multifactorial and includes stretching
of the dura, compression of cranial nerves, irritation of
adjacent brain and occlusion of dural venous sinuses [99].
Five main clinical syndromes have been defined based on
anatomic site of disease (Table 23.4) [96].
Contrast MRI is the technique of choice for the diagnosis
of skull base metastases. Fat suppression techniques are
particularly useful. Bone metastases are characterized by a
hypointense lesion on non-enhanced T1-weighted MRI
sequence [100]. Contrast enhancement is variable on T1
weighted sequences with fat suppression. MRI further per-
mits determination of invasion of the cavernous sinus, the
dura or cranial nerves. Orbital CT may help by demon-
strating bone anatomy and associated erosion. Importantly, a
normal imaging study does not exclude the diagnosis [94].
Radionuclide bone scan can reveal skull base metastases, but
sensitivity is poor particularly for osteolytic lesions [101].
FDG-PET has a similar accuracy to that of bone scintigraphy
23 Neurological Complications of Breast Cancer and Its Treatment
Table 23.4 Main clinical Clinical syndrome
syndromes associated with skull
base metastases Sellar and parasellar syndrome (29%)
Occipital condyle syndrome (16%)
Orbital syndrome (12.5–15%)
Middle fossa syndrome, or Gasserian
ganglion syndrome (6%)
Jugular foramen syndrome (3.5%)
Numb chin syndrome
Hemibasis syndrome
Data from: Laigle-Donadey [94], Boldt and Nerad [400], Johnston [401]
[102]. Rarely, biopsies are needed to establish the diagnosis.
The role of a cerebrospinal fluid (CSF) analysis is to exclude
co-associated leptomeningeal metastases (LM).
Skull base metastases are most often a late event in the
course of cancer [94].The overall prognosis depends of the
type of cancer, remaining therapeutic options, and the site
and extent of the skull base metastases. In the cohort of
Laigle Donadey, BC had the longest survival, with a median
survival of 60 months [94]. Cranial nerve palsies are asso-
ciated with a poorer OS [94].
Asymptomatic skull base metastases can be followed
[100] and symptomatic patients treated with supportive
therapy including steroids, analgesics, and bisphosphonates,
as needed. Radiotherapy, alone or in combination with
chemotherapy or surgery, is the most frequently used
443
Clinical description
Sellar
Characterized by co-occurring pituitary metastases
Most often silent as near complete destruction of the
adenohypophysis is necessary to produce clinical manifestations
Posterior metastases: diabetes insipidus
Anterior metastases: hypopituitarism and visual loss
Lateral extension: cranial neuropathies affecting oculomotor and
trigeminal nerves
Parasellar
Oculomotor and trigeminal nerve palsies
Frontal headache, facial paresthesia or pain, and periorbital
swelling are also reported
Unilateral severe and constant pain in the occipital region
followed by ipsilateral 12th cranial nerve palsy leading to
dysarthria and dysphagia, atrophy of the ipsilateral tongue with
associated fasciculations
Meningismus is frequent
Radiation of pain to the forehead
Isolated hypoglossal nerve palsy
Progressive frontal headaches particularly over the ipsilateral
affected eye with associated blurred vision and diplopia
Sensory loss of the forehead due to trigeminal sensory
involvement
Proptosis and ophthalmoplegia of the involved eye
Local signs such as periorbital swelling
Facial paresthesias, numbness, and pain of the face sparing the
forehead
Headache uncommon
Sensory loss of the second and third divisions of the trigeminal
nerve and more rarely the first division
Motor deficits of the trigeminal nerve or of the abducens nerve
common
Hoarseness, dysphagia, and unilateral dull pain in the occipital
and pharyngeal areas
Paralysis with involvement of cranial nerves 9th–11th observed
Glossopharyngeal neuralgia-associated syndrome with syncope
or papilledema
Numbness of the chin usually unilateral
Progressive ipsilateral paralysis of at least seven cranial nerves
therapy (in >70%) [94]. Excellent pain relief and regression
of cranial nerve dysfunction may occur and improved neu-
rological function is seen if treatment commences early [93,
103]. SRS may be an alternative therapy, in particular for
previously irradiated areas and for small metastases [94, 100,
104]. Lastly, surgery may be used in selected patients [94,
105]. Chemotherapy and endocrine therapies may be an
option for patients with chemoresponsive disease [94].
Dural Metastases
Dural metastases are localized to dural and surrounding
space (epidural and subdural) [106] and are most frequently
associated with breast, prostate, lung, head and neck, and
hematologic malignancies. Overall, BC is the primary cancer
most often associated with dural metastases, occurring in
444
16.5–34% of cases [106–108]. Intracranial dural metastases
occur in up to 10% of BC patients in autopsy series [106,
107]. Four mechanisms of dural seeding have been pro-
posed: direct extension from skull metastases, hematogenous
dissemination, seeding through Batson’s plexus, and spread
from the lymphatic circulation [107]. Those derived from
direct extension of skull metastases account for 60% and
dural metastases from hematogenous spread for 36% [106,
108]. In most patients with BC and dural metastases,
recurrent/progressive systemic disease (>80%) is found
[106].
In a retrospective cohort of 122 patients with intracranial
dural metastases, the most frequent symptoms include
headache (due to increased intracranial pressure) and cranial
nerve palsy (due skull base location), followed by visual
disorders, alterations in mental status, and seizures [106].
Signs and symptoms are related to the location and the
extent of the dural metastases. Between 11 and 20% of
patients are asymptomatic and diagnosed incidentally by
brain imaging [106, 107]. Non-traumatic subdural hema-
toma, also called “pachymeningitis interna hemorrhagica,”
can be observed in 15–40% of cases and generally are
asymptomatic [106–108]. Cerebral venous thromboses have
been described secondary to infiltration of the cerebral
venous sinuses [106]. In one study, 56% of the patients had a
single dural metastasis and 25% demonstrated diffuse dural
enhancement. The most common sites of dural metastases
were parietal (36%) or frontal (32%). Infratentorial lesions
were observed in 11%. Dural metastases can appear as a
localized thickening of the dura or as nodules, usually
biconvex or lenticular in shape [106, 108]. A combination of
diffuse dural enhancement and dural nodules can be
observed as well. Homogeneous intense post-contrast
enhancement is most often seen. MRI findings include a
dural tail (44%), vasogenic edema (53%), and brain invasion
(34%), most commonly by direct extension from skull [106].
Skull metastases are observed in 70% of cases [106]. Other
findings may include venous sinuses involvement and sub-
dural hematoma or effusions. Meningioma is the main dif-
ferential diagnosis [106, 108]. Infections or inflammatory
lesions may be considered as well in appropriate context.
Treatment is not standardized. Surgery should be con-
sidered as the first option in patients with a resectable soli-
tary lesion, controlled extracerebral disease, and acceptable
surgical risk [106–108]. In the cohort of Nayak, 25% of the
patients underwent surgical resection, consisting of complete
resection in 63% of the cases. Focal radiotherapy, SRS/SRT,
and WBRT are also options, alone or in combination with
surgery. In the cohort of Nayak, 52% of patients received RT
of whom 47% received WBRT and 53% focal RT or SRS.
Systemic treatment may be an option in some cases as these
lesions are outside the blood–brain barrier [106]. Best
E. Le Rhun et al.
supportive care, including corticosteroids, may be indicated
in some patients.
In a literature review, the median OS was 6 months
varying whether surgery was performed, to control
extracranial disease and the primary tumor type [108]. In this
review, dural metastases from BC were associated with a
more favorable outcome compared to other tumor types,
with a median OS of 9 months. In the cohort of Nayak, the
median PFS was 3.7 months and the median OS was
9.5 months. The initial site of progression was intracranial in
30% of the patients and both intracranial and systemic in
21%. The intracranial progression was local in the dura in
86% of patients, distant in the dura in 37%, intraparenchy-
mal in 41%, and leptomeningeal in 6% [106]. In this study,
surgical resection was shown to improve PFS and OS.
Chemotherapy prolonged PFS, but not OS. An impaired PS
was associated with a worse outcome.
Intramedullary Spinal Cord Metastases
BC is the second most common solid tumor responsible for
intramedullary spinal cord metastasis (ISCM), after lung
cancer. In a meta-analysis of 96 autopsy-proven cases with
ISCM, lung cancer (49%) and BC (14%) were the most
common primary cancers [109]. Treatment options include
best supportive care, surgery, RT, and systemic therapy.
Treatment depends on the number, volume, and location of
the metastases, the extent of systemic disease, the general
and neurological status of the patient, and life expectancy
[110]. In all cases, the treatment is urgent so as to forestall
paraplegia. Symptomatic treatment with corticosteroids can
be a useful adjunct. After supportive care only, clinical
deterioration is observed in 89% of the cases [111].
In highly selected patients with solitary metastases, with a
reasonable life expectancy, and without leptomeningeal,
brain, or widespread metastases, the prognosis may be
improved by surgery [111–114]. A gross total resection can
sometimes be achieved in these otherwise well-
circumscribed metastases [114]. After surgery, improve-
ment in clinical symptoms can be observed in 58% of the
cases, no change in 31%, and clinical deterioration in 11%.
Adjuvant RT following surgery should be administered
[112].
As BC is radiosensitive, RT may be effective and is the
most commonly used treatment for the majority of patients.
After RT, transient stabilization of neurological disease
progression and a reduction in pain is often achieved [109,
111]. The schedule of RT should be shortened so as to
account for the poor OS [115]. Stereotactic radiotherapy is
also an option. After SRT treatment, clinical improvement is
noted in 21% of the cases, no change in 63%, and clinical
deterioration in 11% [110]. BC is chemosensitive as well,
and systemic agents may be effective depending on the
23 Neurological Complications of Breast Cancer and Its Treatment
neurological status, the volume of the metastases, available
systemic treatment options, and the extent of the systemic
disease. Nevertheless, no clear impact on survival has been
shown [110].
For a more complete review of ISCM please refer to
Chap. 6 of this text.
Spinal Epidural Metastases (Fig. 23.2)
Metastatic epidural spinal cord compression (ESCC) is seen
in 5–10% of all patients with BC [114, 116–120], usually in
the context of known metastatic disease [114] and often
(25%) with concurrent CNS metastases [121]. Median sur-
vival of patients with ESCC may be longer for patients with
Fig. 23.2 Epidural spinal cord compression. Spinal MRI, T1 W
gadolinium-enhanced sagittal image
445
breast cancer in comparison to other tumor types. While the
median overall survival for all patients with ESCC has been
reported to range between 4 and 14 months [121], survival
in BC patients with ESCC was the longest (21.5 months) in
a study of 81 patients that included 23.6% BC patients [119].
For a complete review of spinal epidural metastases and
ESCC, including presenting symptoms, treatment, and
prognostic factors, please refer to Chap. 6.
Leptomeningeal Metastases (Fig. 23.3 a, b)
Leptomeningeal metastasis (LM) or
neoplastic/carcinomatous meningitis is diagnosed in 1–8%
of patients with solid tumors during the course of the cancer;
however, it is diagnosed at autopsy in 19% of patients with
premorbid neurological signs and symptoms [122–126]. BC,
in addition to lung cancer and melanoma, is one of the most
common primary cancers responsible for LM. Risk factors
of LM in BC include an infiltrating lobular carcinoma and
cancers negative for estrogen and progesterone receptors
[18, 127–130]. Triple negative status in BC has been
reported as being a risk factor of LM [129, 131, 132]. In
contrast, LM is observed in only 3–5% of HER2-positive
BC; thus, HER2-positive status is not considered a risk
factor for LM [18]. Other risk factors have been identified
and include piecemeal resection instead of en bloc resection
[33], surgical resection of parenchymal cerebellar metastases
[133–135], surgical resection of supraventricular BM that
violates the ventricular system [136–138], deferring WBRT
after BM resection [139], and improved survival due to more
effective systemic therapy often associated with poor CNS
penetration [124].
The median OS of untreated patients with LM is limited
to 4–6 weeks [123–125]. Despite aggressive treatment,
survival is limited to a few months. Compared to patients
with LM disease from other solid tumors, BC patients have a
better prognosis [123–125, 140, 141]. The median OS in BC
patients is estimated at 3.3–5 months [123, 124, 130, 140–
153]. One-year survival varies from 7–24% [154]. Prog-
nostic factors enumerated by the NCCN CNS guidelines
include a poor risk group defined by a KPS below 60,
multiple neurologic deficits, extensive systemic disease with
few treatment options, bulky CNS disease, and the presence
of a LM-related encephalopathy [155]. On multivariate
analyses, an association has been observed between OS and
the PS, age at LM diagnosis and treatment (number of prior
chemotherapy regimens, receipt of combined treatment
modality, coadministration of systemic chemotherapy, and
intra-CSF chemotherapy) [140, 141, 156]. Other prognostic
factors in BC patients include histological characteristics
(histological grade and hormone receptor status), number of
prior chemotherapy regimens, status of systemic disease,
initial response to treatment, cytologic response to treatment,
and in one study, the concentration of cyfra 21-1 (a fragment
446
Fig. 23.3 a, b Leptomeningeal
metastases. a Brain MRI, T1 W
gadolinium-enhanced axial
images. b Spinal MRI, T1 W
gadolinium-enhanced sagittal
image
of cytokeratin 19 thought to represent a tumor marker) in the
CSF [130, 143–146].
Treatment of LM should ideally be initiated as early as
possible before the appearance of disabling neurologic def-
icits [124]. In the majority of patients, progressive
extracranial disease coexists and must be taken into account
in the management of LM. Only one randomized trial, pre-
maturely closed for low accrual (n = 35), was performed in
LM BC patients comparing systemic therapy and RT with or
without intra-CSF methotrexate [157]. No significant dif-
ference between groups was observed in clinical response
(neurologic improvement: 41 vs. 39%; disease stabilization:
18 vs. 28%) or median survival (18.3 vs. 30.3 week).
However, treatment-related complications were higher in
patients treated with intra-CSF chemotherapy compared to
the no intra-CSF chemotherapy arm (47 vs. 6%). Further
studies are needed to define the role of intra-CSF therapy in
the treatment of BC LM. Combined treatment (both systemic
chemotherapy and intra-CSF chemotherapy) is preferred
when possible in patients considered for LM treatment due
to an improvement in survival.
Chemotherapy allows simultaneous treatment of the
entire neuraxis and can be administered systematically or
intra-CSF. The choice of agent is based on the chemosen-
sitivity profile of the primary tumor and the ability of drug to
penetrate into the CSF compartment [124, 125]. Paclitaxel
and docetaxel are effective in metastatic BC, but have poor
penetration into the CNS [158].
Capecitabine in case reports has produced responses and
disease stabilization in BC LM [159–163]. As in BC BM,
E. Le Rhun et al.
temozolomide for the treatment of LM was disappointing
[164]. The efficacy of new agents such as eribulin has not
been yet demonstrated. High-dose methotrexate or cytara-
bine is not often administered due to significant systemic
toxicity and the requirement for hospitalization. Efficacy of
endocrine therapies has been demonstrated in case reports,
but acquired resistance is often present at this stage of the
disease. Bevacizumab, a monoclonal antibody targeting the
vascular endothelial growth factor (VEGF) ligand, has
shown prolonged responses in case reports with LM [165–
168]. Prospective trials are ongoing to confirm the role of
bevacizumab in LM (NCT NCT00924820). A response to
trastuzumab emtansine has been reported [169]. The efficacy
of other anti-HER2 therapies such as lapatinib and per-
tuzumab has not been demonstrated. A glutathione-
pegylated liposomal formulation of doxorubicin and
anthracycline is under investigation in BC LM
(NCT01818713).
Intra-CSF treatment, in combination with systemic ther-
apy, is often used for the treatment of LM notwithstanding
its superiority relative to systemic therapy only has never
been established in a randomized trial [123, 124]. The goal
of intra-CSF treatment is to bypass the blood–CSF barrier
which is only partially disrupted in LM and increase drug
exposure in the CSF compartment while mitigating systemic
toxicity [124, 125]. Three main intra-CSF chemotherapy
agents are used: cytarabine (free or liposomal), methotrexate
(standard and high-dose regimens), and thiotepa with dif-
fering doses and schedules (Table 23.5). The optimal dose
and schedule, particularly concerning maintenance therapy,
23 Neurological Complications of Breast Cancer and Its Treatment
Table 23.5 Intra-CSF chemotherapy dose and schedule
Drug Description of the drug
Liposomal cytarabine Pyrimidine nucleoside analogue,
cell cycle specific
Methotrexate Folate antimetabolite,
cell cycle-specific drug
Thiotepa Alkylating ethyleneimine compound,
cell cycle non-specific drug
Abbreviations: CSF cerebrospinal fluid, mg milligrams, d day, wk week
are not well defined [125, 154, 170]. Many studies have
reported no differences in efficacy among these agents,
including in patients with BC-related LM [130, 143–150].
Liposomal cytarabine, which resulted in a significant longer
survival as compared to methotrexate in one randomized
trial, requires less frequent clinic visits and may have less
impact on QoL [171]. Combination (multi-agent) intra-CSF
chemotherapy has not demonstrated improved results and is
not recommended for the treatment of BC-related LM.
Intra-CSF etoposide has shown modest efficacy [172]. Pro-
longed responses have been reported after intra-CSF trastu-
zumab in case studies [173–176]. Two studies are currently
ongoing to define the safety and efficacy profile of intra-CSF
trastuzumab in HER2-positive BC patients (NCT01325207
and NCT01373710).
For a complete review of LM, please refer to Chap. 5.
Peripheral Nervous System Metastases
Neoplastic Plexopathy
Neoplastic plexopathy typically occurs at the time of local or
regional progression of cancer. BC is the second (32%) most
common cause of neoplastic brachial plexopathy after lung
cancer, and the third (11%) leading cause of lumbosacral
neoplastic plexopathy after lung cancer and soft tissue sar-
coma [177, 178]. Neoplastic plexopathy manifests as severe
pain, followed by motor weakness and sensory disturbances
in the distribution of plexus involvement [177, 178]. When
the brachial plexus is involved, the lower trunk is most
frequently affected. Pain is observed in 75–83% of the
patients and is usually located in the shoulder and axilla
[177, 179]. Radicular pain is common and radiates into the
arm with extension into the fourth and fifth digits. Motor
weakness and loss of reflexes are seen in 75% of cases,
mostly in the lower plexus distribution. More widespread
447
CSF half-life Description of the regimen
14–21 days 50 mg every 2 weeks (total, 8 wks) then 50 mg
once every 4 weeks
4, 5–8 h Standard regimen
10–15 mg twice weekly (total, 4 wks),
then 10–15 mg once weekly (total, 4 wks)
then 10–15 mg once monthly
Low-dose regimen
2 mg/d (d1–d5) every other week
High-dose regimen
15 mg/d (d1–d5) every other wk
3–4 min 10 mg twice weekly (total, 4 wks) then 10 mg
once weekly (total, 4 wks) then 10 mg once a month
signs of whole plexus involvement are occasionally noted.
A Horner’s syndrome occurs in 23% of the patients with a
neoplastic brachial plexopathy [177]. In lymphedema-
associated plexopathy, patients present with neuropathic
extremity pain (90%), followed by weakness (86%), sensory
loss (73%), reflex loss (64%), and limb edema (47%) [177].
Tumor spread to the plexus most commonly occurs by direct
invasion of the plexus or hematogenous spread from distant
metastases. Adjacent structures, such as infiltrated lymph
nodes or soft tissues, can also result in direct compression of
the plexus [177, 179, 180].
Contrast MRI is more sensitive than CT in the identifi-
cation of neoplastic plexopathy [177, 179]. Increased
T2/FLAIR MRI intensity in nerve trunks with or without
contrast enhancement is commonly observed. If no lesion is
observed, a repeat MRI examination within a 4- to 6-week
interval commonly reveals tumor not previously appreciated
on initial examination [177]. The presence of tumor recur-
rence, especially in the area of plexus, in combination with a
supportive examination, is presumptive for a diagnosis of
metastatic plexopathy. The sensitivity and specificity of PET
are not clear, but PET can be helpful in instances of negative
MRI. Electromyography demonstrates a unilateral lesion
often with more extensive denervation than clinically pre-
dicted [177]. Lower medial trunk/cord lesions or whole
plexus lesions are more frequent than upper trunk lateral
cord lesions [179].
The main differential diagnosis is radiation-induced
plexopathy (Table 23.6). The pattern of distribution of
weakness and the results of nerve conduction studies may
help to distinguish between neoplastic and radiation-induced
brachial plexopathy [181]. A more complete discussion on
this topic is featured later in this chapter. Other differential
diagnosis include LM, ESCC, paraneoplastic plexopathy,
complications of regional intra-arterial chemotherapy,
post-infectious plexopathy, and primary plexus tumors
448 E. Le Rhun et al.

Table 23.6 Differential Presentation Neoplastic plexopathy Radiation associated plexopathy

diagnosis: Neoplastic brachial
plexopathy and radiation-induced
brachial plexopathy
Clinical Severe and early pain, occasional Paresthesia and weakness, pain late
presentation edema, involvement of the lower during the course of the disease, edema
brachial plexus, Horner’s syndrome common, impairment of the whole
common, plexus, Horner’s syndrome unusual,
No tissue necrosis local tissue necrosis common
Electromyography Myokymia unusual Myokymia usually present
MRI Nerve contrast enhancement Usually no nerve contrast enhancement
PET scan High SUV max Low SUV max
Abbreviations: MRI magnetic resonance imaging, PET positron emission tomography, SUV standardized
uptake value
Used with permission of Thieme from Jaeckle [177]

Table 23.7 Autoantibodies and Autoantibodies Common paraneoplastic syndrome

common paraneoplastic
syndromes (PNS) associated with Amphiphysin Stiff person syndrome, myelopathy and myoclonus, encephalomyelitis, sensory
breast cancer neuronopathy
Ri (ANNA2) Brainstem encephalitis, opsoclonus myoclonus
Yo (PCA1) Paraneoplastic cerebellar degeneration
AMPAR Limbic encephalitis
CAR Retinopathy

[177]. Radiotherapy of the involved area is the most com-
monly used treatment and often results in durable responses.
Chemotherapy and endocrine therapy may be used with
some utility in chemosensitive cancer [180]. Pain should be
treated according to the WHO guidelines. Physical therapy
may help to augment and preserve neurologic function.
Non-metastatic, Non-treatment-related
Complications
Paraneoplastic Syndromes
Paraneoplastic neurological syndromes (PNS) affect less
than 1% of patients with BC [182]. BC is most often asso-
ciated with the following PNS: cerebellar degeneration,
sensory neuropathy, encephalomyelitis, opsoclonus myo-
clonus, stiff person syndrome, myelopathy, and brainstem
encephalitis (Table 23.7) [183, 184]. Subacute cerebellar
degeneration is the most common PNS seen with BC [185].
Other paraneoplastic syndromes, such as retinopathy, have
been reported in BC (Table 23.8). Associated systemic
symptoms including weight loss, anorexia, fever, and fatigue
may be observed [186].
The best characterized onconeural antibodies associated
with BC and PNS are amphiphysin associated with the stiff
person syndrome, myelopathy, myoclonus, encephalomyeli-
tis, and sensory neuronopathy; Ri (ANNA2) associated with
brainstem encephalitis and opsoclonus myoclonus; and
Yo (PCA1) associated with paraneoplastic cerebellar
degeneration [184]; AMPAR (amino-3-hydroxy-5-methyl-4-
isoxazolepropionic acid receptor) associated with limbic
encephalitis; and anti-Ma2 (anti-Ta) associated with limbic
encephalitis, brainstem encephalitis, and cerebellar degener-
ation [184, 187, 188].
PNS precedes the diagnosis of cancer in more than 80%
of the cases by several months to years [183, 189]. In most
cases, an underlying cancer is identified within 5 months
after the diagnosis of PNS. The risk of a coexistent cancer
decreases after 2 years and is considered as highly unlikely
after 4 years [183]. When BC is considered in a patient with
a PNS, a cancer screen should include a clinical examination
and mammography followed by breast MRI and body
FDG-PET in cases with negative initial screening [184, 188].
When the initial screen is negative, repeat assessments
should be performed every 6 months for at least 2 years
[188].
For a complete review of PNS, please refer to Chap. 13.
Meningiomas (Fig. 23.4)
Meningioma is one of the most common primary tumors of
the CNS in adults and accounts for 13–26% of all intracra-
nial tumors [190–192]. The only well-established risk fac-
tors are prior ionizing brain RT and some rare hereditary
diseases such as neurofibromatosis [190–195]. Mutation in
the NF2 gene and genetic variants in genes involved in DNA
repair pathway are often identified in meningioma [196].
Several observations suggest a link between a patient’s
hormonal status and meningioma. In intracranial menin-
gioma, the female: male ratio is 2–3.5, which is even higher
23 Neurological Complications of Breast Cancer and Its Treatment
Table 23.8 Most frequent Name of the PNS
paraneoplastic syndromes
(PNS) in breast cancer Subacute cerebellar
degeneration
Sensory neuronopathy
Encephalomyelitis
Opsoclonus myoclonus
syndrome
Stiff person syndrome
Subacute progressive
myelopathy
Brainstem encephalitis
Data from: Gatti et al. [182], Honnorat and Antoine [183], Graus and Dalmau [184], Graus and Delattre [185]
in spinal meningioma (4:1 ratio) [194, 197, 198]. Proges-
terone receptors are detected in 70–98% of meningiomas;
estrogen and androgen receptors are seen in 20–40% of
meningiomas [193, 195, 199, 200]. Increased meningioma
growth rate is reported during pregnancy [193, 194]. An
association between BC and meningioma has been demon-
strated [193, 195, 201]. In addition, a link between use of
exogenous hormones and meningioma has been reported
[194], as well as a positive association with endometriosis or
uterine fibrosis [196]. A non-significant association has been
shown between age at menarche, age at menopause, meno-
pausal status, parity, age at first birth, and meningioma [193,
194, 202–204]. A protective role of breastfeeding has also
been observed [204–207]. The evidence that use of oral
contraceptives and hormone replacement therapy increase
449
Description of the paraneoplastic syndrome
Development in <12 weeks of a severe pancerebellar syndrome without
cerebellar atrophy on MRI other than age expected
Initial gait ataxia followed by appendicular ataxia
Initial symptoms may also include dizziness, visual problems (diplopia,
blurry vision, oscillopsia), nausea/vomiting, or dysarthria
These rapidly progressive symptoms stabilize after culminating in a severe
pancerebellar syndrome
Other neurological symptoms and signs that may be seen include cognitive
impairment, lethargy, bulbar palsy, or limb weakness
Other PNS (paraneoplastic peripheral neuropathy or Lambert–Eaton
myasthenic syndrome) sometimes associated
Cerebellar atrophy on MRI in the late stages of the disease
often associated with anti-Yo antibodies
Subacute and asymmetric numbness, paresthesia, pain, cramps,
proprioceptive loss of upper and lower extremities and abolition of
deep-tendon reflexes
Radicular symptoms and signs sometimes associated
Involvement of the sensory fibers on electroneurography
Involvement of multiple parts of the CNS such as the hippocampus,
brainstem, spinal cord, or dorsal root ganglia
Manifests as limbic encephalopathy, brainstem encephalitis, dysautonomia,
myelitis, and sensory neuronopathy
Spontaneous large amplitude saccades occurring in all directions of gaze
Myoclonus of the trunk and limbs
Encephalopathy sometimes associated
Often associated with Ri antibodies
Slowly progressive stiffness and rigidity of axial musculature
Followed by proximal muscle rigidity
Leads to difficulties in walking and fixed deformities. Associated with
superimposed muscle spasms that are increased by sensory stimuli
Variant form with an onset of stiffness in upper limbs
Antibodies against amphiphysin
Continuous motor activity at rest on electroneurography
Progressive symptoms and signs of myelopathy
Symmetric MRI T2 abnormalities and gadolinium enhancement that involves
the spinal gray matter in usually >3 segments
Antibodies against amphiphysin
Rapidly progressive symptoms and signs of brainstem dysfunction.
Antibodies against Ri (ANNA2)
the risk of meningioma remains controversial; however, in
most studies [194, 204], no association was found [193–195,
203–206, 208–213].
An association between BC and meningioma has been
postulated. In a large Swedish cohort, an increased risk of
meningioma was observed after BC with a relative risk of
meningioma estimated at 1.6 [214]. In another US
population-based retrospective cohort analysis, the risk of
BC in patients previously diagnosed with a meningioma was
1.54, and the risk of meningioma in BC patients was 1.40
[211]. In a five-state US cancer registry, the incidence of
meningioma was 2.6 cases per 100,000 women and the
incidence of BC was 61 cases per 100,000 women. The
association between the two cancers was higher than
expected [201]. The pathophysiology of this association is
450
Fig. 23.4 Meningioma. Brain MRI, T1 W gadolinium-enhanced
sagittal image
not well understood. BRCA1 and BRCA2 mutations do not
seem to contribute to the development of meningioma [215].
In a large US SEER registry, associations between BC and
meningioma were reported [216]. BC preceded meningioma
by >2 months in 48% of the women, and tumors were
synchronous (within 2 months) in 20%. Hormone receptor
status of BC was not different between BC only and BC plus
meningioma groups. BC disease stage was more advanced in
the BC plus meningioma group than in the BC only
group. Contrary to this study, in a large retrospective study
of BC patients, the 10-year cumulative incidence of
meningioma was only 0.37%, suggesting no increased risk
[217]. Use of aromatase inhibitors confers a non-significant
increased risk of meningioma in patients with BC [217],
whereas tamoxifen use may be protective. The risk of
meningioma has been shown to be lower in patients treated
with tamoxifen compared to those not treated with this agent
[192].
Complications of Breast Cancer Treatment
Central Nervous System Complications
Encephalopathy
Any anticancer drug given at conventional dose can be
responsible for causing a toxic encephalopathy [218]. Toxic
chemotherapy-related encephalopathy may manifest as a
confusional state, posterior reversible leukoencephalopathy,
seizures, a cerebellar syndrome, myelopathy, or cere-
brovascular complications [219, 220]. The signs and
symptoms can vary from mild and transient to severe and
chronic [219, 221]. 5-FU (5-fluorouracil) and capecitabine
represent the most frequent chemotherapy agents responsible
E. Le Rhun et al.
for CNS toxicity in BC. The symptoms can originate within
days to months after the initial administration of the drug.
Most toxic encephalopathies are transient, last only days,
and are associated with complete neurologic recovery [222–
225]. MRI changes seen with toxic encephalopathies resolve
more slowly than clinical manifestations. The pathophysi-
ology of toxic encephalopathy is not clearly understood.
Direct endothelial cell injury has been proposed with asso-
ciated vasogenic edema [222, 226]. Most occurrences of
encephalopathy are believed to be idiosyncratic and with a
low risk of recurrence [219, 220, 227].
Several antineoplastic agents used in BC may induce an
encephalopathy (Table 23.9). Methotrexate results in
encephalopathy in less than 2% of patients [219, 228].
Administration of methotrexate and brain RT further
increases the risk of CNS neurotoxicity [221]. Acute ence-
phalopathies have been described after the administration of
paclitaxel or very rarely docetaxel, vinorelbine, and pegy-
lated liposomal doxorubicin in BC patients, notwithstanding
limited penetration of the CNS with these agents [229–233].
Anti-VEGF agents such as bevacizumab are rarely the cause
of posterior reversible encephalopathy or PRES [234, 235].
Leukoencephalopathy and encephalopathy were observed in
2.5 and 5% of patients with LM following lumbar injection
and 7.5 and 5% after ventricular injection of liposomal
cytarabine in a large cohort of patients treated for LM [236].
In a smaller cohort of patients treated with intraventricular
methotrexate, leukoencephalopathy was observed in 64% of
patients [237]. Leukoencephalopathy can be delayed,
developing 3–15 months after intra-CSF methotrexate [237].
Patients may manifest with personality changes, cognitive
deficits, and apathy followed by hemiparesia or quadri-
paresia and coma. Lesions predominate in the periventricular
white matter, and histological examination demonstrates
demyelination, axonal degeneration, astrocytosis, and
necrosis [238]. An elevation in MBP (myelin basic protein)
can be observed in the CSF. Risk factors include high
cumulative doses of intra-CSF methotrexate and concomi-
tant systemic methotrexate plus WBRT [237]. An accidental
overdose of intra-CSF methotrexate can lead to death. An
acute transient mild encephalopathy with fever may be
observed after intra-CSF methotrexate and which likely
represents expansion of a treatment-related chemical
meningitis discussed below [237].
Other potential causes of encephalopathy must be
excluded including CNS metastases (e.g., BM or LM), other
toxic agents (e.g., antiepileptics, opioids, benzodiazepines),
metabolic encephalopathies (such as hyper or hypoglycemia,
azotemia, hepatic failure, electrolyte disorders), stroke, and
infectious etiologies [222]. Cessation of the offending drug
is indicated until resolution of symptoms. Neurological
manifestations usually clear within a few days after dis-
continuing the chemotherapy [218, 222–224]. Nonetheless,
23 Neurological Complications of Breast Cancer and Its Treatment
in some patients, persistent neurological deficits are reported
after discontinuation of the offending agent [223]. Steroids
are of questionable benefit [223–225]. Dihydropyrimidine
dehydrogenase deficiency, a genetic risk factor for MTX
neurotoxicity, should be excluded [224]. In the absence of
alternative chemotherapy, careful re-introduction of the drug
at reduced dose and under close supervision is usually safe
and associated with a low risk of recurrence [224].
Cognitive Impact of Endocrine Therapy
and Chemotherapy
Cognitive impairment associated with chemotherapy is
referred to as chemobrain or chemofog [239]. There are no
established criteria that define the syndrome, related in part
to methodological inconsistencies observed between studies
discussed below. In BC, post-chemotherapy cognitive defi-
cits have been observed in 17–75% of patients, as compared
with 4–11% in healthy controls in retrospective
cross-sectional studies [240–251]. Most longitudinal studies
have confirmed a negative cognitive effect of chemotherapy
in 15–25% of patients [244, 252–254]. In several prospec-
tive cohorts of BC patients, objective cognitive impairments
have been observed in 20–35% at baseline before any sys-
temic therapy without clear explanation as to cause [239,
241, 244, 255, 256]. Cognitive impairment due to
chemotherapy emerges months to years after completion of
treatment [257]. In prospective cohorts, cognitive decline
was observed within the first 6 months after initiation of
chemotherapy [246]. The duration of cognitive impairment
is poorly defined. In longitudinal studies, cognitive impact
appears to resolve over time, and stable or improved cog-
nition has been observed 12–18 months following comple-
tion of chemotherapy [245, 252, 258]. Improvements in
cognition may be delayed, and there exist a small subset of
patients with refractory and intractable cognitive complaints
after completion of chemotherapy [258–260].
Cognitive changes observed during chemobrain are often
mild to moderate in severity and differ clinically from
encephalopathy observed after chemotherapy [261]. The
most common cognitive deficits include difficulties in
attention and concentration, working memory, and executive
and psychomotor functions [251, 258]. Deficits in verbal
learning, nonverbal and visuospatial memory, psychomotor
processing speed, mental flexibility, memory retrieval, con-
frontational naming, complex visuoconstruction, and fine
motor dexterity have been reported as well [246, 250, 258,
262]. Patients report an inability to concentrate, organize
their daily activities, or multitask. They also endorse mem-
ory loss, confusion, slow thinking, and fatigue [258]. The
impact of these cognitive deficits in day-to-day activities
varies and may be related to the patient’s pre-illness level of
function, type of work or lifestyle, ability to manage, coping
style, premorbid cognitive reserve, age, and other
451
comorbidities such as mood or personality disorders, fatigue,
and psychosocial issues [234, 239, 258, 261, 263–265].
Different studies have demonstrated that cognitive com-
plaints are better correlated with emotional distress, coping
skills, and cancer-related fatigue than with objective neu-
ropsychological testing [239, 243, 261, 262, 266, 267].
The role of chemotherapy dose is not clear. One study
demonstrated a greater deficit among women treated with
high-dose chemotherapy compared to women treated with
standard doses of chemotherapy [268]. In another longitu-
dinal study, progressive cognitive decline was observed at
each subsequent time point. This suggests a dose–response
relationship with linear worsening following each cycle of
chemotherapy [269]. Patients treated with combined
chemotherapy and endocrine therapy have the most exten-
sive pattern of cognitive deficits [245, 252, 260, 262]. Pre-
treatment cognitive impairment has been shown to be
independent of fatigue or emotional distress, surgical factors,
or medical comorbidities [261]. The exact mechanisms
underlying the effects of chemotherapy on cognition are not
clearly understood [244, 261]. Chemotherapy may have a
direct neurotoxic effect and may induce oxidative stress,
DNA damage, telomere shortening, damage to neural stem
cells, hormonal changes, immune dysregulation, activation
of pro-inflammatory cytokines, thrombosis in brain
microvasculature, white matter abnormalities, metabolic
abnormalities including anemia, and reduced brain func-
tional connectivity [241, 261, 262, 270]. The role of genetic
factors such as apolipoprotein E (APOE) and catechol-O-
methyltransferase (COMT) has also been suggested [241,
244, 262, 271].
An evaluation of treatment-related cognitive disorders
requires a neuropsychological assessment. In order to
improve between-study comparisons, the International
Cognition and Cancer Task Force (ICCTF) has developed
recommendations for neuropsychological testing [242]. The
Hopkins Verbal Learning Test-Revised (HVLT-R), Trail
Making Test (TMT), and the Controlled Oral Word Asso-
ciation (COWA) of the Multilingual Aphasia Examination
measuring learning and memory, processing speed, and
executive function are recommended [242]. Baseline eval-
uation and an appropriate control group are suggested as is
an evaluation of emotional functioning [261].
Volumetric brain MRI and diffusion tensor MRI
(DTI) have shown widespread reduction in white matter tract
integrity and gray matter volume over time in patients
treated with chemotherapy and with cognitive deficits [251,
261]. A correlation has been observed between reduction in
brain activation by fMRI and cognitive performance after
chemotherapy in a longitudinal study [272]. Studies using
fMRI have demonstrated alteration in brain activation and
connectivity in BC patients after chemotherapy treatment
[251, 258, 261]. Decreased activation by fMRI appears to
452 E. Le Rhun et al.

Table 23.9 Breast cancer Agent Clinical description Brain MRI

chemotherapy associated with
toxic encephalopathy 5-FU (5 Cerebellar syndrome or multifocal Normal or showing diffuse white
fluorouracil) leukoencephalopathy with altered mental matter alterations, with T2 and FLAIR
and status ranging from confusion to coma, periventricular hyperintensities of both
capecitabine memory deficits, ataxia, dysarthria, hemispheres
nystagmus, headache, seizures, trismus,
slurred speech, diplopia, and paresthesias
Methotrexate Acute encephalopathy to severe delayed Diffuse T2/FLAIR abnormalities
chronic encephalopathies with cognitive
deficits, aphasia, and hemiparesis
Bevacizumab Headache, visual disturbances, seizures, Parieto-occipital white matter
confusion, and relative hypertension abnormalities on T2/FLAIR sequences
Less frequently involvement of
anterior brain regions
Data from
5-FU (5 fluorouracil) and capecitabine: Videnovic et al. [223], Tipples et al. [224], Formica et al. [225],
Niemann et al. [402], Couch et al. [403], Fantini et al. [404], Lyros et al. [222]
Methotrexate: Erbetta et al. [226]
Bevacizumab: Schiff et al. [234], Tlemsani et al. [235]

relate to impaired cognition, whereas increased activation,
typically seen in the context of absent or mild cognitive
deficits, is thought to represent compensatory neural acti-
vation required to be maintained. PET shows similar acti-
vation patterns as seen with fMRI [241, 258, 261, 273].
Electrophysiological studies have shown a reduction in the
amplitude of the P-300 event-related brain potential and a
reduction in the P-300 latency, corresponding to the timing
and duration of chemotherapy. This pattern was consistent
with changes in information processing capacity [241, 258].
Chemobrain is a diagnosis of exclusion wherein PNS,
CNS metastases, medication toxicity (corticosteroids,
antiepileptics), fatigue, sleep disorders, pain, and preexistent
neurological disease need to be excluded [261, 263]. The
effectiveness of donepezil, an acetylcholinesterase inhibitor,
for the treatment of chemotherapy cognitive deficits is
uncertain [261]. No significant positive impact of psychos-
timulants such as methylphenidate, dexmethylphenidate, and
modafinil, has been shown for the treatment of cognitive
impairment in non-CNS cancer patients [239, 261]. Gingko
biloba administered concomitantly with chemotherapy had
no effect on cognitive function [274]. New approaches are
needed, and promising results in animal studies suggest
agents that prevent oxidative stress (2-mercaptoethane sul-
fonate, N-acetylcysteine, or melatonin), stimulate neuroge-
nesis (insulin-like growth factor-1, fluoxetine, or glucose), or
improve chemotherapy-induced cognitive effects (dex-
tromethorphan or memantine) may be useful [261]. Learning
compensatory strategies can help to minimize the impact of
chemotherapy-related cognitive deficits [265]. Cognitive
rehabilitation aims to improve cognitive abilities, functional
capacity, and real-world skills [261]. Several studies show a
significant improvement in both subjective and objective
cognitive deficits with these interventions [244, 261]. Sleep
disturbances, psychological distress, and fatigue, if present,
should be addressed as treating these elements secondarily
improves cognition [261]. Other medications that may affect
cognition should be reduced or discontinued when possible.
Physical activity has been associated with improved cogni-
tion, mostly executive function, in human and animal studies
[275]. Neurofeedback and transcranial magnetic stimulation
have been suggested as possibly useful interventions [261,
276].
Several studies have suggested a negative impact on
cognition in BC patients treated with endocrine therapies,
affecting mostly verbal memory and executive functions
[277–286]. Deficits in processing speed and verbal memory
were observed in postmenopausal patients compared to
controls [279–281, 287]. A negative impact of tamoxifen or
anastrozole on speed measures of letter fluency, complex
visuomotor attention, and manual dexterity has also been
reported [288]. In a separate trial, postmenopausal women
with early-stage BC were treated with anastrozole or
tamoxifen and the cognitive impact of each treatment was
compared. A more severe impact on verbal and visual
learning as well as on memory tests was observed after
anastrozole [288]. Notably, no cognitive decline was
reported at 6 and 24 months in the randomized IBIS II trial
conducted in high-risk postmenopausal women without BC
receiving anastrozole or placebo [282]. In the TEAM (ta-
moxifen and exemestane adjuvant multinational) study, no
cognitive impact was found after exemestane treatment, but
poorer performances on verbal memory and executive
function were observed after tamoxifen compared to healthy
controls [277]. In a phase III randomized trial, aromatase
inhibitors did not appear to negatively affect verbal episodic
memory during a 1-year follow-up [289]. The discordant
findings in the above-mentioned studies could be explained
by methodological inconsistencies such as differences in the
characteristics of population studied (prior chemotherapy or
23 Neurological Complications of Breast Cancer and Its Treatment
not, inclusion of pre- or postmenopausal women), differ-
ences in the neurocognitive testing batteries, trial design
(prospective vs. cross-sectional), timing and the duration of
follow-up, and whether the evaluation of cognitive function
was a primary study objective [277–281, 286, 287, 289].
Importantly, the impact of mood or fatigue on cognition is
often not reported [268, 279, 290–294].
Cardiovascular Complications (Ischemic, Central
Venous Thrombosis, Sinus Thrombosis)
In an autopsy cohort of cancer patients, cerebrovascular dis-
ease (CVD) was seen in 14.6%, of whom half had clinical
symptoms during life [295]. In a database of the Eastern
Cooperative Oncology Group (ECOG) trials for BC, the fre-
quency of both venous thrombosis and arterial thrombosis was
5.4% among patients treated with adjuvant therapy and 1.6%
in patients on observation only [296]. A higher risk of stroke in
cancer patients as compared to controls without cancer was
reported in a Swedish cohort [297]. In a study of hospitalized
stroke patients, cancer patients represented 9.1% of all cases
and BC was the second most common type of malignancy
[298]. In the Norwegian Stroke Research Registry (NOR-
STROKE), the prevalence of cancer was higher among
patients presenting with a stroke and BC was the third most
frequent cancer associated with stroke [299]. The cumulative
incidence of stroke in BC is 1.5% compared to 1.1% in con-
trols [300]. The highest risk of stroke is observed soon after
diagnosis of cancer [297, 300] and is estimated at 12% [301].
Cancer is a prothrombotic state with acquired protein S or
C deficiency, activated protein C resistance, antiphospho-
lipid antibodies and the antiphospholipid syndrome, hyper-
fibrinogenemia, thrombocytosis, and D-dimer elevation
[302, 303]. Thrombotic angiopathy has been observed in BC
and was reported to be linked to cancer therapy, but was also
observed after treatment when the cancer was in remission.
In the ECOG cohort mentioned above, the association of
chemotherapy and tamoxifen increased the risk of both
venous and arterial strokes compared to chemotherapy alone
in premenopausal patients [296]. In another cohort of
women with BC, tamoxifen was associated with an
increased risk of stroke [304]. In BC, supraclavicular and
internal mammary nodal RT may accelerate atherosclerosis
of the carotid artery and increase the risk of stroke [304–
306]. The EORTC study NCT00002851 (Lymph Node
Radiation Therapy in Patients With Stage I, Stage II, or
Stage III Breast Cancer That Has Been Surgically Removed)
will provide more data on the risk of stroke and RT. The
management of stroke in cancer patients depends on the
etiology. Patients with cancer have been for the most part
excluded from trials of thrombolysis. Treatment with
thrombolysis may result in a higher in-hospital mortality in
patients with cancer due to medical comorbidities, but there
453
does not appear to be a higher risk of intracranial hemor-
rhage (ICH) [307].
Cancer patients also have an increased risk of venous
thromboembolism (VTE), and VTE is associated with a
significant risk of morbidity and mortality in cancer patients
[308, 309]. In the Iowa SEER, the standardized morbidity
ratio, estimated by dividing the observed number of cancers
in the VTE incident cohort by expected number, was 8.4 for
BC [310]. The risk of VTE has been associated with several
factors including the type of cancer, the stage of the cancer,
performance of surgery, administration of chemotherapy or
endocrine therapy, the presence of a central venous catheter,
patient age, whether non-ambulatory, and prior episode of
VTE [311]. The Khorana predictive score of VTE risk in
ambulatory patients includes 5 variables: the site of cancer,
the prechemotherapy platelet count, the hemoglobin level,
the use of erythropoietic agents, the leukocyte count, and the
body mass index [312]. In this score, BC is considered at
low risk of VTE.
Thromboembolic events are more frequent in women
treated by chemotherapy for BC [313]. Tamoxifen, a
selective estrogen receptor modulator with estrogen antag-
onistic effects, may also increase the risk of thromboembolic
complications [314, 315]. The combination of chemotherapy
and tamoxifen further increases the risk of VTE compared to
tamoxifen alone in postmenopausal patients [296]. Systemic
treatment may increase the risk of VTE by several mecha-
nisms including acute and non-acute damages to vessel walls
and decrease in protein C, protein S, factor VII or fibrinogen,
and platelet activation [303, 308, 311].
Cerebral venous occlusion can be observed in cancer
patients, either in superficial cortical veins, internal cerebral
veins, or dural sinuses [302]. Systemic cancer accounts for
3.2% of all causes of cerebral venous occlusion [316].
Cerebral sinus or veins can also be affected by compression
or local invasion by brain, dural, or skull metastases [317,
318]. A BC patient with VTE receiving tamoxifen in the
adjuvant setting should be transitioned to an aromatase
inhibitor [308]. Thrombolytic agents are contraindicated in
patients with intracranial tumors [319].
For a complete review of cerebrovascular dysfunction in
cancer, please refer to Chap. 10.
Meningitic Syndromes
Chemical Meningitis
Chemical meningitis is the most common side effect of
intra-CSF chemotherapy and is characterized by headache,
photophobia, fever, nausea and vomiting, meningismus, and
confusion [320]. It occurs in 15–33.3% of patients following
liposomal cytarabine administration regardless of the route of
administration (lumbar vs. ventricular) [320]. The incidence of
aseptic meningitis may be reduced by prophylactic oral
454
dexamethasone initiated on the day of intra-CSF drug adminis-
tration. Most symptoms of chemical meningitis occur within the
first days after drug administration. Mild symptoms resolve
within days; however, symptomatic treatment with intravenous
corticosteroids and fluids may be required in severe cases. Sub-
sequent intra-CSF drug administration is dose reduced and used
in combination with more liberal prophylactic oral steroids [320].
Acute aseptic meningitis may also be observed after adminis-
tration of any intra-CSF drug including methotrexate, cytarabine,
and thiotepa [237]. The main differential diagnosis of chemical
meningitis is infectious meningitis or LM disease progression
and is primarily differentiated by the time course of chemical
meningitis and the failure to culture bacteria from CSF [123].
Infections
Intra-CSF agents can be administered either by the
intralumbar or by the ventricular route. Intraventricular
injections offer several advantages compared to lumbar
administration, such as the certainty of drug delivery into the
CSF compartment (10% of all intrathecal injections are epi- or
subdural) and a relatively pain-free procedure [321, 322].
A survival benefit has also been suggested for intraventricular
administration compared to lumbar injection [321]. However,
intraventricular drug administration requires placement of
ventricular access device resulting in a risk of infection not
unlike that seen with a vascular access device. In a prospective
cohort of patients (mostly BC) with the 10% of complications
seen with the use of a ventricular access device, the majority
(70%) were bacterial infections [323]. The infection rate was
estimated at 3.6% per patient and 0.38% per injection. This
rate was similar to other series [320, 324, 325]. Bacterial
meningitis is less frequent after lumbar injection (3.75% vs.
0%) [320]. In the cohort of Zairi, the ventricular access device
was removed in all cases and antibiotics were administered for
2 weeks. Nevertheless, no clear recommendations exist for the
management of infected ventricular access devices. Some
authors propose preservation of the device and administration
of combined systemic and intra-CSF organism-specific
antibiotic therapy [326, 327].
Other CNS Adverse Effects
Other CNS toxicities seen after intra-CSF liposomal
cytarabine administration include a communicating hydro-
cephalus, decreased visual acuity, and seizures [320].
Stroke-like events that rapidly resolve have been reported
after intra-CSF methotrexate injection [328].
Peripheral Nervous System Complications
Plexopathy
Axillary lymph node dissection for BC is a fundamental part
of treatment, but can be responsible for post-surgical injury
complications including chronic pain syndromes, numbness,
E. Le Rhun et al.
shoulder restriction, lymphoedema, and rarely plexopathy.
Damage to the nerves traversing the axillary fat and in
particular the intercostobrachial nerve prone to injury during
axillary dissection can result in chronic pain.
One week after surgery, up to 78% of patients report
moderate to severe pain [329]. Neuropathic pain after BC
surgery is seen in 14.7–52% of patients during the first year
after surgery [329–331]. Other neurological symptoms
include paresthesia, dyesthesias, swelling sensation, and
hypoesthesia. Number of axillary nodes dissected (more than
15 lymph nodes excised), age <40 years, African American
race, diabetes, fibromyalgia, and taxane-based chemotherapy
have been identified as risk factors for neuropathic pain after
BC surgery [330, 331]. Sentinel lymph node biopsy has been
developed for axillary staging and minimizes the morbidity
of axillary lymph node dissection in patients with BC.
Sentinel node dissection alone has been shown to signifi-
cantly reduce the rate of paresthesia, dyesthesias, swelling
sensation, or pain compared to axillary node dissection
[332–334]. Pharmacological treatment of pain consists of
tricyclic antidepressants, duloxetine, AEDs (carbamazepine,
gabapentin, pregabalin), transdermal lidocaine, and
capsaicin.
The risk of loco-regional recurrence is reduced after chest
wall and axillary node RT among women with a
node-positive BC [335]. Radiation-induced brachial plex-
opathy (RIBP) is the most frequent peripheral nervous sys-
tem complication after BC irradiation [336]. The incidence
is <1% with 50 in 2 Gy fractions [337]. The interval
between RT and symptom onset varies from 3 months to
26 years with a median of 1.25–4.25 years [179, 337–339].
Rarely, early acute transient RIPB have been reported within
2–14 months after supraclavicular–axillary RT at 50 Gy
[337].The delay between RT and clinical deficits is partly
related to the dose per fraction, total dose, and volume
irradiated [340]. Signs and symptoms of RIBP include
paresthesias, pain, hyporeflexia, and motor impairment with
potentially flaccid paralysis of the ipsilateral arm [335, 337,
338]. RIBP usually begins with paresthesias or dyesthesias
followed by hypoesthesia and anesthesia. Tinel’s sign has
been reported with paresthesia evoked after axillary or
supraclavicular stimulation. Pain is the most common
symptom and is seen in >75% of patients. Progressive motor
weakness appears later and can be associated with fascicu-
lations and amyotrophy [337]. The first motor signs are
usually observed in the thenar muscles [337].The topogra-
phy varies with the level of plexus damage though typically
appears distally and progressively spread to forearm and
upper arm [337]. The onset is insidious, but signs and
symptoms gradually increase and often lead to paralysis of
the upper limb with severe impairment of useful hand
function [337–339]. Rapid neurological worsening has been
described after trauma related to surgery, upper limb
23 Neurological Complications of Breast Cancer and Its Treatment
lymphedema, or traction of the affected arm [341]. Direct
neuronal and endothelial injury with associated demyelina-
tion and ischemia and compression by radiation-induced
fibrosis have been suggested as potential mechanisms of
RIBP [327, 338].
Pain and paresthesia can be treated with AEDs,
non-opioid and opioid analgesics, tricyclic antidepressants,
and benzodiazepines. Quinine may be used for cramps and
carbamazepine for myokymia. The role of B vitamins, cor-
ticosteroids, or anticoagulants is controversial. A random-
ized phase III trial evaluating the association of
pentoxifylline, tocopherol, and clodronate (PENTOCLO,
NCT01291433) in radiation-induced neuropathies is cur-
rently ongoing. Physiotherapy can aid in the development of
strategies to maintain and improve function. Reducing
comorbid factors that may aggravate the plexopathy such as
diabetes, high blood pressure, alcohol abuse, and statins is
recommended. Hyperbaric oxygen has been evaluated in
small case series, but currently, there is no evidence to
support its use in the treatment of RIBP [342]. Surgery with
nerve or muscle transfer [343–345] and neurolysis [346]
have been reported to be useful in highly select patients with
RIBP [342].
For a complete discussion on radiation-induced plex-
opathies, please refer to Chap. 14.
Radiculopathy
Isolated radiculopathy is rare in BC and may be a mani-
festation of ESCC, LM, or Herpes zoster. Herpes zoster
infection, an opportunistic infection, may be enabled by
adjuvant chemotherapy with secondary treatment-induced
immunosuppression. In a large study of early-stage BC
patients, 1.9% developed zoster [347]. In this cohort, the
incidence of Herpes zoster infection was estimated at
55/1000 cases/year, whereas the incidence in the general
population varies between 2.2 and 4.1 per 1000
patients/year. Thus, in early BC patients, the risk of infection
is 13- to 25-fold higher compared to the incidence in the
general population [347]. Treatment utilizes analgesics and
antiviral medications such as acyclovir. Delayed late
post-herpetic neuralgia, a neuropathic syndrome, may
appear in a small subset and may require chronic opioid
treatment.
Radiation Neuropathy
The peripheral nervous system is often characterized as
radioresistant; nevertheless, radiation-induced neuropathies
are reported. The signs and symptoms are heterogeneous and
differ according to the affected part of the peripheral nervous
system (nerve root, nerve plexus, nerve trunk). Radiation
neuropathies are often progressive and irreversible and may
have a considerable impact on QoL. Generally, radiation
neuropathies appear years after RT [336, 337].
455
Peripheral Neuropathy
Chemotherapy-induced peripheral neuropathy (CIPN) is a
frequent adverse consequence of BC treatment. CIPN is
observed in 30–40% of patients receiving chemotherapy and
varies according to the cytotoxic drug regimen, duration of
treatment, cumulative dose, and neuropathy-related risk
factors [348]. CIPN can be severe and have a significant
impact on activities of daily living and overall QoL [349,
350]. In severe cases, chemotherapy dose delays, reductions,
or discontinuation of treatment is required [348, 349, 351].
The potential impact of dose reductions or treatment delays
due to CIPN on PFS CIPN is unknown [351]. The overall
clinical presentation of CIPN is similar, although some dif-
ferences are observed among the chemotherapy agents.
Several risk factors have been associated with CIPN. The
role of older age as a risk factor for CIPN is controversial
[352]. Diabetes has been shown to increase the risk and
severity of CIPN related to weekly paclitaxel treatment
[353]. Moreover, more frequent chemotherapy dose delays
and dose reductions are observed in patients with diabetes.
Treatment-related risk factors include chemotherapy dose
per cycle, treatment schedule, cumulative dose, and duration
of infusion [351, 354, 355]. The class of chemotherapy and
the class of biochemical characteristics influence the risk of
CIPN. For example, docetaxel induces less CIPN than
paclitaxel (1–9% vs. 30%) [348]. Inter-individual variability
in toxicity is observed, and genetic factors likely are of
importance, but are difficult to determine a priori [355].
Pharmacogenomic approaches using single nucleotide
polymorphisms (SNPs) have been used to correlate the risk
of toxicity to specific agents. For paclitaxel, studies have
focused on several candidate genes such as CYP2C8,
CYP3A4, CYP3A5, and ABCB1 [350, 355, 356]. Associ-
ations have also been reported between the risk of neu-
ropathy and FGD4, EPHA5, and FZD3 genes [350]. Higher
TUBB2A gene expression may lead to a lower sensitivity to
paclitaxel [357]. For docetaxel, candidates include glu-
tathione S-transferase detoxification enzyme GSTP1 poly-
morphism [350, 358]. GSTP1 polymorphism has also been
suggested to increase the risk of oxaliplatin and cisplatin
neurotoxicity [349]. The results are not always consistent
between studies, and further research is needed to confirm
the relevant associations between genotype and risk of
CIPN.
Taxanes, microtubule-stabilizing agents, are among the
most active drugs used in BC. The most important
dose-limiting toxicity is CIPN, and the incidence of all
grades of CIPN after taxanes varies from 11 to 87% [354,
359]. Microtubules are critical for peripheral nerve axonal
transport processes and are affected by taxanes [349]. Tax-
anes induce microtubule polymerization and inhibit
depolymerization leading to an impairment of axonal
transport [349, 351], which has been speculated to play a
456
role in CIPN. Severe CIPN is reported in 1–18% of patients
following taxane treatment. The incidence of all grades of
docetaxel-induced CIPN varies from 11–64% [358, 359].
The incidence of serious (grade 3/4) sensory and motor
neuropathy in patients treated with docetaxel was 1.6 and
0%, respectively [360]. Patients presenting with CIPN after
initial docetaxel infusion often receive fewer cycles without
dose modification as compared to patients without CIPN
[361]. The incidence of all grades of CIPN with paclitaxel is
higher and varies from 59 to 87% [351, 359]. Grade 3–4
CIPN is observed in 7–33% of patients treated with pacli-
taxel [351]. The incidence of serious (grade 3/4) sensory and
motor neuropathy in patients treated with paclitaxel was 7
and 5%, respectively [362]. A dose reduction in taxanes due
to a CIPN is required in 2–26% of patients [351, 354, 363–
365]. One study observed a 17% dose reduction due to CIPN
resulted in a decreased relative dose intensity of 73.4%
[351]. The clinical manifestations of taxane CIPN are mainly
sensory. Sensory symptoms include numbness, paresthesia,
burning, and hyperalgesia. Loss of deep-tendon reflexes is
rare in taxane-induced CIPN. Motor neuropathy occurs less
frequent than sensory CIPN and may result in weakness of
distal limb muscles. Myalgias and arthralgias have been
associated with CIPN from paclitaxel [349]. A toxic optic
neuropathy has been reported after docetaxel treatment
[366].
Symptoms of acute CIPN occur within 24–72 h follow-
ing taxane infusion [348, 351, 367, 368]. Symptoms may be
observed after the first infusion, but are more frequent after 2
or more infusions [354]. Clinical manifestations usually
disappear spontaneously after discontinuation of the drug
[348]. However, axonal degeneration can sometimes be
observed, especially after prolonged administration, and be
responsible for permanent CIPN. Approximately 50% of the
symptoms resolve within 9 months [369]. In a cohort of 69
patients treated with docetaxel, paclitaxel, or both,
taxane-induced CIPN completely resolved in only 14% of
the patients after cessation of treatment, and long-term
neurotoxicity was observed in 60% in the docetaxel group
and 70% in the paclitaxel group [353]. Long-term symptoms
were, however, minor in most patients [359]. In a cohort of
1031 patients treated with adjuvant docetaxel, 23% reported
grades 2–4 neuropathy, CIPN persisted for 1–3 years in 34%
of patients though generally subsiding to grades 0–1. In this
cohort, 15% of survivors reported a significant impact on
QoL due to docetaxel CIPN at 1–3 years after cessation of
treatment [370]. After paclitaxel, CIPN of all grades was
observed in 41% of the 219 patients 3 years after treatment
[364], while in another cohort of 50 patients, 81% of the
patients still reported CIPN symptoms 6 months to 2 years
after paclitaxel treatment, with up to 27% reporting severe
symptoms [365].
E. Le Rhun et al.
The symptoms of neuropathy induced by taxanes appear
at cumulative doses  300 mg/m2. An increased single dose
of paclitaxel is also associated with a higher risk of neuro-
toxicity. Shorter infusions appear to increase the risk of
neurotoxicity (comparing 1–3 h(s) vs. 24 h infusions) [349].
Paclitaxel is more toxic than docetaxel and results in more
frequent CIPN [348, 359]. In a phase III trial, paclitaxel
versus docetaxel in patients with metastatic BC, more grade
3/4 sensory (7% vs. 4%) and motor CIPN (5% vs. 2%) was
observed. In this study, more discontinuation of treatment
due to CIPN was observed after docetaxel [371]. Weekly
administration of paclitaxel results in more frequent CIPN
than the every 3-week schedule (24% vs. 12% for grade 3
sensory CIPN and 9% vs. 5% for grade 3 CIPN) [362]. In
contrast, more grade 3 CIPN has been observed after every
3-week docetaxel schedule (10% vs. 5%) [372]. New for-
mulations of paclitaxel, such as nanoparticle albumin-bound
(Nab) paclitaxel and liposomal-encapsulated paclitaxel,
appear to reduce neurotoxicity [350, 362, 373].
Eribulin mesylate is a non-taxane microtubule dynamic
inhibitor. Eribulin binds to microtubules and suppresses
microtubule growth [374].In trials, CIPN of any grade
occurred in 14–35% after eribulin. Grade 3 CIPN was
observed in 3–27% and grade 4 CIPN in less than 1% [375–
377]. Drug interruption was required in 4–5% due to CIPN
[375, 376, 378]. Signs and symptoms were observed after a
median of 9 months of treatment and resolved after
12 months [378] of CIPN. Treatment with carboplatin may
result in CIPN, but causes less CIPN as compared to cis-
platin [379, 380]. Oxaliplatin and cisplatin and vinca alka-
loids (vinorelbine) can cause CIPN, but are only
occasionally used in BC. Vinorelbine, the most commonly
used vinca alkaloids in metastatic BC, interferes with
microtubule assembly [381]. Unlike with other vinca alka-
loids, neuropathy is relatively infrequent with this agent.
Cisplatin and carboplatin are used for the treatment of
metastatic BC, in particular for triple negative BC. Cis-
platin CIPN can result in a worsening of the neuropathy
following discontinuation of chemotherapy, a phenomenon
termed coasting [348, 370]. Additionally, cisplatin can cause
progressive and irreversible hearing loss in many patients
[380, 382, 383]. Bilateral sensorineural hearing loss may be
observed in 19–77% of the patients treated with cisplatin,
and permanent tinnitus may be seen in 19–42%. Raynaud
phenomena, a localized autonomic neuropathy, may be
observed with cisplatin as well [384].
A neuropathy scale exists for the cisplatin-induced neu-
rotoxicity with elements that include CIPN, ototoxicity, and
Raynaud phenomena [349, 385]. Although carboplatin is
generally thought to be less frequently responsible for CIPN,
a meta-analysis of platinoid chemotherapy toxicity (carbo-
platin vs. cisplatin) used in association with third-generation
23 Neurological Complications of Breast Cancer and Its Treatment
agents for advanced-stage non-small cell lung cancer
demonstrated a twofold higher rate of neurotoxicity in the
carboplatin group [379].
Other sensory neuropathies, such as Charcot-
Marie-Tooth, diabetic neuropathy, alcoholic neuropathy,
paraneoplastic neuropathy, and discogenic nerve root com-
pression, should be excluded [221, 350, 351, 354, 355, 364,
386]. Taxanes may cause lymphedema, which can lead to a
bilateral carpal tunnel syndrome mimicking or worsening
signs and symptoms of CIPN [359, 387]. The onset of
symptoms and their relationships with chemotherapy
administration help to identify the casualty of the cytotoxic
agent. Early detection and recognition of CIPN are critical so
as to allow chemotherapy dose delays or dose reduction
prior to the appearance of severe neurologic symptoms [349,
350]. Drug discontinuance is recommended for all
high-grade neuropathies [350]. Antiepileptics (gabapentin or
pregabalin) and antidepressants (tricyclics, duloxetine, or
venlafaxine) are often proposed for the treatment of neuro-
pathic pain despite relatively limited effectiveness in CIPN
[348, 350, 351, 380, 388–391]. Numerous other treatments
have been evaluated in preventive studies including nerve
growth factor (NGF) stimulants (all-trans-retinoic acid);
antioxidants or antioxidant-related agents (a-Lipoic acid,
vitamin E, glutathione, glutamine, N-acetylcysteine, D-
methionine, omega-3 fatty acids, amifostine); electrolytes,
chelators, ion channel modulators (calcium/magnesium
infusion, carbamazepine and oxcarbazepine, nimodipine),
and other compounds (acetyl-L-carnitine, xaliproden [a
5-hydroxytryptamine(HT)1A agonist], venlafaxine, gosha-
jinkigan [Kampo medicine composed of 10 natural ingre-
dients], topical gel with baclofen + amitriptyline +
ketamine, erythropoietin, recombinant human leukemia
inhibitory factor), and none have proved effective. Dex-
tromethorphan, a N-methyl-D-aspartate receptor antagonist,
has not been evaluated in CIPN, but shows efficacy in
painful diabetic neuropathy and in postoperative pain [388].
A randomized double-blind trial using dextromethorphan in
CIPN is currently under recruitment (NCT02271893).
Non-pharmaceutical approaches such as acupuncture have
also been studied [351]. A phase II randomized trial is
currently evaluating the efficacy of acupuncture in prevent-
ing dose reductions due to CIPN in patients with BC which
is currently ongoing (NCT01881932). Other approaches
include the non-invasive electro-analgesia device referred to
as “Scrambler” therapy and manual therapy such as mas-
sage. Physiotherapy may help to improve gait impairment
and assist patients by providing life-relevant adaptive
strategies [349].
457
Myopathy
Although skeletal muscles comprise more than 50% of total
body mass, skeletal muscle metastases are rare. In a cohort
of 73 patients with skeletal muscle metastases, BC was
identified as the primary in only 14% of the cases, preceded
by lung cancer (34%) and gastrointestinal cancer (18%)
[392]. Paraneoplastic necrotizing myopathy is rarely repor-
ted in BC [393, 394]. Patients present with a proximal,
symmetric, and rapidly progressive myopathy. Myalgia can
be absent, and deep-tendon reflexes are hypoactive. An
increase in serum creatinine kinase and myoglobin is com-
monly observed. Electromyogram may show an incomplete
interference pattern during voluntary contraction. Treatment
of BC and corticosteroids may lead to an improvement in
neurological deficits.
Myopathy can also be a result of treatment. Corticosteroids
are frequently used in cancer patients and are a frequent cause
of myopathy with clinical symptoms in up to 60% of patients
[395]. Steroid myopathy is characterized by proximal muscle
weakness predominantly in the lower extremities that may
interfere with the activities of daily living. Symptoms may
appear insidiously and can be observed within days after
steroid initiation and are related in part to cumulative dose.
Respiratory muscle weakness may lead to symptomatic dys-
pnea, sometimes in the absence of proximal muscles symp-
toms. Acute severe myopathy has been described after
high-dose steroids [396]. Serum muscle enzymes can be nor-
mal as is electromyography [396, 397]. Muscle biopsy shows
atrophy of type IIb fibers without necrosis or inflammation
[397]. Steroid myopathy is reversible after reduction or dis-
continuation of steroids, though recovery may require weeks.
Fluorinated steroids (dexamethasone, triamcinolone) are more
often responsible for myopathy than non-fluorinated steroids
(prednisone, hydrocortisone) [395].Radiotherapy-induced
myopathy is very rare in BC. Muscles weakness is observed,
serum creatinine kinase values are normal, and electromyog-
raphy shows myopathic changes [398]. Musculoskeletal
symptoms and myopathy can be induced by other agents such
as cytarabine, cyclophosphamide, methotrexate, and aro-
matase inhibitors. Other conditions such as hypercalcemia
may also lead to myopathy.
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