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Original Article · Originalarbeit
Breast Care 2008;3:118–123 Published online: April 15, 2008
DOI: 10.1159/000121688
Schlüsselwörter
Mammakarzinom · Leptomeningeale Metastasen ·
Meningeosis carcinomatosa · Neoplastische Meningitis ·
Intrathekale Chemotherapie
Zusammenfassung
Hintergrund: Meningeosis carcinomatosa ist eine sehr ernst
zu nehmende Verlaufsform fortgeschrittener Krebserkran-
kungen. Trotz aggressiver multimodaler Therapie ist das
mediane Überleben sehr kurz. Methoden: Die Daten aller
Mammakarzinompatientinnen mit Meningeosis carcinoma-
tosa wurden retrospektiv analysiert (n = 27). Ergebnisse:
Das mediane Überleben betrug 9 Wochen. Patienten
mit kontrastmittelaufnehmenden meningealen Läsionen
(n = 11), die durch MRT entdeckt wurden, hatten ein media-
nes Überleben von 33 Wochen versus 8 Wochen bei Patien-
ten, die diese Läsionen nicht aufwiesen (n = 9; p = 0,0407).
Patienten, die eine systemische Therapie erhielten (n = 18),
hatten ein medianes Überleben von 15 Wochen versus 7
Wochen (n = 9; p = 0,0106). Patienten, die bestrahlt wurden
(n = 8), hatten ein medianes Überleben von 17 Wochen ver-
sus 5 Wochen (n = 18; p = 0,0188). In einer multiplen Cox-Re-
gressionsanalyse stellten sich die Abwesenheit einer syste-
mischen Therapie (Hazard Ratio, HR 89,5; p = 0,002) und ein
negativer Hormonrezeptorstatus (HR 4,2; p = 0,027) als Risi-
kofaktoren heraus. Zudem wurde im Interaktionsmodell
kontrastmittelspeichernde Läsion als Effektmodifizierer für
die systemische Therapie identifiziert (p = 0,03). Schlussfol-
gerung: Kontrastmittelaufnehmende meningeale Läsionen,
systemische Therapie und Strahlentherapie waren signifi-
kant mit einem längeren Überleben assoziiert. Patienten mit
kontrastmittelaufnehmenden Läsionen, die systemisch be-
handelt wurden, hatten das längste Überleben. Wir können
weitere Hinweise dafür liefern, dass systemische Therapie
bei Brustkrebs-induzierter Meningeosis carcinomatosa wirk-
sam ist und daher Bestandteil des multimodalen Behand-
lungskonzepts sein sollte.
Key Words
Breast cancer · Leptomeningeal metastases ·
Carcinomatous meningitis · Neoplastic meningitis ·
Intrathecal chemotherapy
Summary
Background: Leptomeningeal metastasis (LM) is a devastat-
ing complication of advanced cancer. Despite aggressive
therapy survival is very poor. Methods: Data of all breast
cancer patients with LM were retrospectively analyzed
(n = 27). Results: Median survival was 9 weeks. Patients with
contrast-enhancing meningeal lesions (n = 11) detected
by MRI had a median survival of 33 weeks versus 8 weeks
for patients without contrast-enhancing lesions (n = 9;
p = 0.0407). Patients who received systemic chemotherapy
(n = 18) had a median survival of 15 weeks versus 7 weeks
(n = 9; p = 0.0106). Patients undergoing radiotherapy (n = 8)
had a median survival of 17 weeks as compared to 5 weeks
for patients without radiotherapy (n = 18; p = 0.0188). In a
multiple Cox regression analysis, lack of systemic therapy
(hazard ratio, HR 89.5; p = 0.002) and negative hormone re-
ceptor status (HR 4.2; p = 0.027) emerged as significant main
risk factors, together with contrast-enhancing lesion as ef-
fect modifier for systemic therapy (p = 0.03). Conclusion:
Contrast-enhancing meningeal lesions, systemic therapy,
and radiotherapy were significantly associated with longer
survival. Patients with contrast-enhancing lesions who were
treated systemically had the longest survival. Evidence is in-
creasing that systemic therapy plays an important role and
should be applied in breast cancer patients with LM.
Dr. med. Anne C. Regierer
Medizinische Klinik mit Schwerpunkt Onkologie und Hämatologie
Charité Universitätsmedizin Berlin, Campus Mitte
Charitéplatz 1, 10117 Berlin, Germany
Tel. +49 30 450 513-403, Fax -952
E-mail anne.regierer@charite.de
Contrast-Enhancing Meningeal Lesions Are
Associated with Longer Survival in Breast Cancer-Related
Leptomeningeal Metastasis
Anne Constanze RegiereraAndrea StrouxbDagmar KühnhardtaAnnette Dieinga
Silvia Lehenbauer-DehmaBernd FlathcKurt PossingeraJan Euckera
aAbteilung für Onkologie und Hämatologie,
bAbteilung für Biometrie und Klinische Epidemiologie, Charité Universitätsmedizin Berlin,
cHämatologisch-onkologische Praxis Altona, Hamburg, Germany
© 2008 S. Karger GmbH, Freiburg
Accessible online at:
www.karger.com/brc
Fax +49 761 4 52 07 14
E-mail Information@Karger.de
www.karger.com
Breast Care
Introduction
Leptomeningeal metastasis (LM) is a devastating complica-
tion of advanced cancer. Despite aggressive therapy prognosis
of patients is very limited with a median survival of several
weeks or months only. The incidence in breast cancer is 3–5%
and appears to be increasing [1] partly due to longer survival
because of more effective therapies and to earlier diagnosis
because of higher awareness and widespread use of MRI. In
addition cerebrospinal fluid (CSF) is a sanctuary for many
chemotherapeutical agents which cannot cross the intact
blood-CSF barrier, hence allowing CNS relapse.
Standard therapy comprises radiation of symptomatic lesions,
intrathecal or intraventricular chemotherapy (hence referred
to as intra-CSF therapy), and sometimes systemic treatment.
While the role of intra-CSF therapy is not clear, there is
increasing evidence of the efficacy of systemic therapy.
Many publications collected data from different tumor entities
ignoring the vastly different biological properties of these car-
cinomas. To exclude these differences, our study focussed on
LM in breast cancer only. As previously described [2–4],
15–30% of patients survive 6 months or longer. This subgroup
of patients has not been well described yet. Therefore, we
compared these patients with those who survived less than 6
months. Survival data was analyzed in order to define possible
prognostic factors and to evaluate the impact of systemic ther-
apy on LM of breast cancer patients.
Patients and Methods
Study Population
We retrospectively analyzed all breast cancer patients diagnosed with LM
between 1998 and 2005 at the Department of Oncology of University
Hospital Charité Berlin, Germany. Collected data included age, time of di-
agnosis of primary tumor, time of first metastasis, primary TNM stage, his-
tology of primary tumor, grading, localization of metastasis, number of
previous systemic therapies, status of systemic disease, Karnofsky perfor-
mance status (KPS), CSF findings, available neuroimaging findings
(MRI), neurological signs and symptoms, and treatment for LM (intra-
CSF chemotherapy, radiation, systemic therapy).
The diagnosis of LM was based on malignant cells in CSF or typical MRI
findings with neurological signs or symptoms or both. CSF was collected
by lumbar puncture. Cytology, protein level, lactate, and glucose were ana-
lyzed routinely. Neurological examinations were done on the same day as
initial lumbar puncture and thereafter repeated approximately every 2
weeks. Neuroimaging findings were divided into diffuse leptomeningeal
contrast enhancement and nodular contrast-enhancing deposits in the
subarachnoid space.
Neurological signs and symptoms were categorized as related to the cere-
brum, cranial nerves, or spinal cord. Cerebral symptoms comprised
headaches, nausea, vomiting, confusion, seizures, and mental status
changes. Most frequently cranial nerves III, IV, and VI were impaired with
ptosis and diplopia, but other cranial nerve symptoms such as visual im-
pairment and facial paresthesia were also observed. Spinal symptoms con-
sisted of pain, sensory deficits, and cauda equina syndrome.
Therapy
All available data on therapy was collected. Methotrexate (MTX),
thiotepa, and liposomal cytarabine were used as intra-CSF therapy. MTX
was used in a dosage of 10–15 mg twice weekly, thiotepa 10 mg twice
weekly, and liposomal cytarabine 50 mg every 2 weeks. Thiotepa and lipo-
somal cytarabine were used as second-line therapy after progression
under MTX. For systemic therapy anthracyclines, taxanes, vinorelbine,
capecitabine, and an aromatase inhibitor were used.
Statistical Analysis
Statistical analysis was performed using commercially available software
(SPSS 12). Descriptives include absolute and relative frequencies for cate-
gorial data, and median and range for numerical measurements.
Analyses with regard to time to death used Kaplan-Meier presentation
and the logrank test in the univariate setting. For confirmatory analysis,
potential predictors for survival time, i.e. factors having univariate p-val-
ues equal or less than 0.05, were included into a multiple Cox regression
analysis with forward and backward selection. Additionally, an interaction
term between systemic therapy and enhancing lesion condition was mod-
elled into the selection process, in order to investigate if the presence of
enhancing lesions represented a risk-modifying effect on systemic therapy.
Only those 19 patients with information regarding all variables under con-
sideration were included into this multivariate analysis.
Comparisons with respect to the group of long-time survivors were per-
formed with Fisher’s exact test to take account for the small number of
patients. P-values for these explorative analyses are presented without
Bonferroni correction.
Breast Care 2008;3:118–123
Breast Cancer-Related Leptomeningeal
Metastasis
119
Table 1.
Pretreatment data of 27 breast cancer patients with lep-
tomeningeal metastasis (LM)
Median Patients,
(range) n (%)
Age at diagnosis of LM, years 50 (31–76)
Time from diagnosis of breast cancer to
1st metastasis, months 27 (0–149)
Time from 1st metastasis to LM, months 14 (0–89)
Histology
Invasive ductal 17 (74)
Invasive lobular 4 (17)
Others 2 (9)
Unknown 4
Hormone receptors
Positive 15 (60)
Negative 10 (40)
Unknown 2
Her2/neu
Positive 6 (32)
Negative 13(68)
Unknown 8
Number of metastatic sites at diagnosis of LM 3 (1–8)
Visceral metastasis 17 (63)
Soft tissue metastasis 17 (63)
Bone metastasis 19 (70)
Brain metastasis 14 (52)
Number of palliative chemotherapy lines
prior to LM 2 (0–5)
Activity of systemic disease at diagnosis of LM
No evidence of systemic disease 0
Remission or stable disease 4 (15)
Progressive disease 22 (81)
Unknown 1
Karnofsky performance score
<70% 13 (48)
*70% 14 (52)
Results
Twenty-seven female breast cancer patients with LM were
identified between 1998 and 2005 at the Department of On-
cology, University Hospital Charité Berlin, Germany. Patient
characteristics are listed in table 1.
Presenting signs and symptoms were categorized as cerebral,
cranial nerve dysfunction, and spinal. 63% of the patients had
cerebral signs and symptoms, 44% cranial nerve involvement,
and 41% spinal signs and symptoms. 13 patients had symp-
toms in only 1 region, 9 patients in 2, and 3 in 3 regions. In
81% (21/26) of the patients malignant cells in the CSF were
detected in the first lumbar puncture. Except for one, cytol-
ogy-negative patients showed other CSF abnormalities such
as elevated protein or lactate in the first lumbar puncture. Of
the 5 cytology-negative patients, CSF drawing was repeated in
4. In one patient cytology became positive in the second punc-
ture, in the other 3 patients CSF remained cytology-negative.
MRI was performed in 20 patients. Meningeal enhancement
was seen in 15 patients, and contrast-enhancing lesions were
seen in 11.
Systemic chemotherapy was concomitantly administered in 18
patients. The palliative systemic regimen was changed after di-
agnosis of LM in 14 patients. In all of these patients, disease
was also progressive. Chemotherapy comprised of monothera-
py with vinorelbine, taxanes, doxorubicin or capecitabine. One
patient was systemically treated with an aromatase inhibitor
only, she subsequently survived for more than 16 months.
Survival Analysis
Median survival after diagnosis of LM was 9 weeks. Patients
with contrast-enhancing lesions detected by MRI (n = 11) had
a median survival of 33 weeks, whereas patients without such
lesions (n = 9) had a median survival of only 8 weeks (fig. 1;
p = 0.0407). Patients who received systemic therapy (n = 18)
had a median survival of 15 weeks versus 7 weeks for those
who did not receive systemic therapy (n = 9; p = 0.0106).
Patients with radiotherapy (n = 8) had a median survival of
17 weeks as compared to 5 weeks for patients without radio-
therapy (n = 18; p = 0.0188). Patients with hormone receptor-
positive tumors (n = 15) survived 22 weeks versus 7 weeks
in patients with hormone receptor-negative tumors (n = 10;
p = 0.053).
All other potential predictors for survival time (age, histology,
grading, HER2-neu, CSF parameters, site of symptoms, KPS,
status of systemic disease) produced p-values greater than 0.05
in the analysis.
For confirmatory analysis, contrast-enhancing lesion, hormone
receptor status, systemic therapy, and radiotherapy were
selected as variables, and a multiple Cox regression analysis
was performed, including the four main effects and, in order
to identify potential effect modification on therapy through
enhancing lesion, the interaction term ‘enhancing lesion* sys-
temic therapy’ into the model.
After both backward and forward selection, lack of systemic
therapy (hazard ratio, HR 89.5; p = 0.002) and negative hor-
mone receptor status (HR 4.2; p = 0.027) emerged as signifi-
cant main risk factors, together with enhancing lesion as risk
modifier for systemic therapy (fig. 2; multivariate p = 0.030).
This means that patients with enhancing lesions profited most
120 Breast Care 2008;3:118–123 Regierer/Stroux/Kühnhardt/Dieing/
Lehenbauer-Dehm/Flath/Possinger/Eucker
0
,
00 200
,
00 400
,
00 600
,
00 800
,
00 1000
,
00
0,0
0,2
0,4
0,6
0,8
1,0
Survival time, days
Cumulative survival
Survival time, days
Cumulative survival
0,00 200,00 400,00 600,00 800,00 1000,00
0,0
0,2
0,4
0,6
0,8
1,0
Fig. 1.
Overall survival in groups of patients with (n = 11) and without (n
= 9) contrast-enhancing lesions detected in MRI (p = 0.0407). Solid line:
enhancing lesion; dotted line: no enhancing lesion.
Fig. 2.
Overall survival in the four groups of patients in the interaction
model: meningeal lesion and systemic therapy. Patients with contrast-en-
hancing lesions profited most from systemic therapy, whereas contrast-en-
hancing lesion had no benefit in the group of patients who were not treat-
ed systemically. Bold solid line: systemic therapy, enhancing lesion; bold
dotted line: systemic therapy, no enhancing lesion; thin solid line: no sys-
temic therapy, enhancing lesion; thin dotted line: no systemic therapy, no
enhancing lesion.
from systemic therapy, whereas systemic therapy had no bene-
fit in the group of patients with no enhancing lesions. Systemi-
cally treated patients with no enhancing lesions tended to fare
even worse than those patients without systemic therapy at all
(fig. 2; multivariate p = 0.030). In figure 2, the Kaplan-Meier
presentation for the four groups, with/without systemic thera-
py and with/without contrast-enhancing lesion, is displayed.
Long-Time Survivors
In our analysis, 8 patients (29%) survived for more than
6 months and 5 (22%) for more than 12 months. In order to
characterize these patients more accurately we compared
long-time survivors (>6 months) with those who survived less
than 6 months. Contrast-enhancing meningeal lesions as de-
tected by MRI were seen in 6 of 7 long-time survivors versus
5 of 13 short survivors (p = 0.043). All long-time survivors
were treated with systemic chemotherapy (8/8) versus only 10
of 19 short survivors (p = 0.017). Lactate in initial CSF was
within normal limits in 3 of 6 long-time survivors versus 1 of
15 short survivors (p = 0.022). Only 1 of 8 long-time survivors
was hormone receptor negative versus 9 of 17 short survivors
(p = 0.054).
Toxicity
Toxicity data was available in 20 patients only. Arachnoiditis
was present in 3 patients, with symptoms completely resolving
under dexamethasone therapy. Three of 4 patients in whom
an intraventricular device (Rickham reservoir) was implanted
developed reservoir-related adverse events. In one patient
leakage of CSF occurred, in one patient the tip of the catheter
was misplaced into the brain parenchyma, and 2 patients de-
veloped bacterial meningitis, which was efficiently treated
with systemic antibiotics. Leukoencephalopathy was seen in 2
of the 8 (25%) long-time survivors and was accompanied with
severe dementia. In another long-time survivor mild dementia
was present, but no imaging study was undertaken. Two pa-
tients developed systemic toxicity after intraventricular MTX
(thrombopenia, mucositis); both patients were heavily pre-
treated with chemotherapy. One patient had a singular
episode of a grand mal seizure followed by a transient aphasia
and agraphia after the fifth intra-CSF MTX application. How-
ever, this was completely reversible, and after 3 days the pa-
tient had normal neurological functions. MTX therapy was
discontinued.
Discussion
Leptomeningeal metastasis is a rare manifestation of breast
cancer, and available data has mainly been collected in retro-
spective studies such as ours. Only few randomized and
prospective data have been published. Many publications col-
lected data from different tumor entities ignoring the different
biological properties of these tumors.
Despite unsatisfying evidence most patients are treated in a
multimodality approach with radiation, intra-CSF chemother-
apy, and systemic therapy. The rationale to deliver chemother-
apy directly into the subarachnoid space is derived from the
insufficient ability of most chemotherapeutical drugs to pene-
trate the intact blood-CSF barrier [5, 6]. However, an altered
blood-CSF barrier with improved penetration of drugs has
been described in animal models of LM [7, 8]. As an increased
protein level in the CSF and meningeal contrast enhancement
in MRI [9] – both commonly seen in LM – are signs for a dis-
rupted blood-CSF barrier, it can be hypothesized that there is
a sufficient drug concentration in the subarachnoid space after
systemically administered therapy in LM patients with dis-
rupted blood-CSF barrier.
Different pathological types of LM have been described. Thin
coating of the meninges (sometimes only as single layer) is
often seen in leukemic and lymphomatous meningitis, whereas
metastatic nodules predominate in solid tumors [10]. These
nodular lesions are contrast enhancing, which is a sign for
blood-CSF barrier disruption. There is also increasing evi-
dence of neovascularization of such lesions, as vascular en-
dothelial growth factor (VEGF) was detected in CSF of LM
patients [11–14]. VEGF is a potent inducer of neovasculariza-
tion but also of vascular permeability [15], therefore poten-
tially contributing to the disruption of the blood-CSF barrier.
The above-mentioned different pathological tumor subtypes
might contribute to the different therapeutic efficacy of intra-
CSF therapy in leukemic and lymphomatous meningitis as
compared to solid tumor meningitis. Intra-CSF therapy pene-
trates only the superficial layers of the tumor [16], therefore
contrast-enhancing lesions might not be treated efficiently
with this local therapy. On the other hand, systemic therapy
reaches the whole nodule because of the tumor’s own blood
supply as well as the impaired blood-CSF barrier. This might
explain why in our series as well as in the series of Herrlinger
et al. [17] the presence of contrast-enhancing lesions is a good
prognostic factor in systemically treated patients.
To our knowledge there is only one published prospective ran-
domized trial comparing intra-CSF treatment with non-intra-
CSF treatment [18]. However, there is increasing evidence
that systemic therapy might be efficacious in LM. In the ran-
domized trial, LM patients with breast cancer were treated
with appropriate systemic chemotherapy and radiation, with
or without intra-CSF chemotherapy. Boogerd et al. [18] found
a median survival of 18 weeks in the intra-CSF-treated pa-
tients (n = 17) and of 30 weeks for the non-intra-CSF group
(n = 18). This did not reach significance due to the small num-
ber of patients. Treatment toxicity occurred in 47% of the
intra-CSF group and only in 6% of the non-intra-CSF group
(p = 0.0072). Previously similar results of nonrandomized
studies have been published [4, 19, 20].
Bokstein et al. [2] retrospectively compared two groups of LM
patients that differed only in the application of intra-CSF ther-
apy. Both groups were treated with radiation if necessary and
Breast Care 2008;3:118–123
Breast Cancer-Related Leptomeningeal
Metastasis
121
systemic chemotherapy, with one group additionally being
treated with MTX intraventricularly and the other not receiv-
ing any intra-CSF therapy. Both groups did not significantly
differ in median survival or in the proportion of long-time sur-
vivors. However, early neurological toxicity was described in
31% and late toxicity (leukoencephalopathy) in 20% of intra-
CSF-treated patients, with no neurological toxicity in the sec-
ond group.
In many studies, including ours, patients who received sys-
temic therapy had better outcomes. Grant et al. [21] described
a median overall survival of 20 weeks for intravenously treat-
ed breast cancer patients compared to 3 weeks for patients
without intravenous treatment. Herrlinger et al. [17] reported
that systemic chemotherapy was highly significantly associated
with longer survival in patients with contrast-enhancing
meningeal lesions and in patients with systemic tumor. Fizazi
et al. [3] also identified concomitant systemic chemotherapy as
a positive prognostic factor for breast cancer patients. There is
also a wealth of case reports of patients who have been suc-
cessfully treated with systemic therapy [22–25]. Many other
studies did not analyze the influence of systemic chemothera-
py although some patients received systemic therapy and oth-
ers did not [26–28].
In summary, there remain many questions about the best ther-
apeutic approach. Intra-CSF therapy is an invasive procedure
and, with the exception of liposomal cytarabine, the need for
twice-weekly injections poses a disadvantage in this palliative
setting. In addition, repeated intra-CSF therapy has consider-
able toxicity [29, 30]. Arachnoiditis, the most frequent adverse
event, comprises headaches sometimes accompanied by dizzi-
ness and nausea and is generally easily manageable with corti-
costeroids. However, late toxicity such as leukoencephalopa-
thy is very often irreversible and occurs in up to 50% of the
long-time survivors [2, 4, 19]. This risk is augmented by radia-
122 Breast Care 2008;3:118–123 Regierer/Stroux/Kühnhardt/Dieing/
Lehenbauer-Dehm/Flath/Possinger/Eucker
tion and MTX. We found cognitive dysfunctions in 38% of our
long-time survivors. Many patients develop severe and irre-
versible cognitive dysfunctions such as dementia, confusion,
and memory loss.
In accordance with our series, 10–30% of the patients survive
for longer than 6 months [3, 4, 17, 31]. Only scarce information
is available on the characteristics of these long-time survivors.
In our series long-time survivors had a significantly higher in-
cidence of contrast-enhancing meningeal lesions as seen in
MRI, and all of them were treated systemically. In addition,
most of them were hormone receptor positive. Boogerd et al.
[4] reported that 10/12 patients who survived 6 months and
longer had been treated with systemic therapy as compared to
only 8/19 patients who survived 6 weeks to 6 months. Again,
this is in accordance with our findings.
Due to the retrospective nature of this and other analyses
there are restrictions interpreting the results. It is possible that
patients surviving only a few days did not get the chance to re-
ceive systemic treatment, therefore introducing a survival bias
and ultimately influencing the results.
LM shows a wide range of natural courses with most patients
dying within a few weeks, regardless of aggressive therapy, and
only a minority of patients surviving for more than 6 months.
The current standard of treating every patient diagnosed with
LM aggressively in a multimodality approach might still need
to be corrected. In our opinion, systemic therapy is one of the
mainstays of treatment strategy in breast cancer-related LM.
On the other hand, the indication for intra-CSF therapy needs
to be defined more precisely. A prospective clinical trial is ur-
gently needed to help define the best therapeutic approach to
LM including the role of intra-CSF and systemic chemothera-
py. Because of the rarity of the disease this needs to be done in
a multi-institutional, multinational design. Only with com-
bined effort this can be successfully undertaken.
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Breast Cancer-Related Leptomeningeal
Metastasis
