# Have Changes in Systemic Treatment Improved Survival in Patients with Breast Cancer Metastatic to the Brain?

Authors: Carsten Nieder; Kirsten Marienhagen; Astrid Dalhaug; Jan Norum
Journal: Journal of Oncology
 (2008)

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## Abstract

Newly developed systemic treatment regimens might lead to improved survival also in the subgroup of breast cancer patients that harbour brain metastases. In order to examine this hypothesis, a matched pairs analysis was performed that involved one group of patients, which were treated after these new drugs were introduced, and one group of patients, which were treated approximately 10 years earlier. The two groups were well balanced for the known prognostic factors age, KPS, extracranial disease status, and recursive partitioning analysis class, as well as for the extent of brain treatment. The results show that the use of systemic chemotherapy has increased over time, both before and after the diagnosis of brain metastases. However, such treatment was performed nearly exclusively in those patients with brain metastases that belonged to the prognostically more favourable groups. Survival after whole-brain radiotherapy has remained unchanged in patients without further active treatment. It has improved in prognostically better patients and especially patients that received active treatment, where the 1-year survival rates have almost doubled. As these patient groups were small, confirmation of the results in other series should be attempted. Nevertheless, the present results are compatible with the hypothesis that improved systemic therapy might contribute to prolonged survival in patients with brain metastases from breast cancer.


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## Body

## 1. Introduction

Whole brain  radiotherapy (WBRT) continues to represent
an important palliative treatment option for patients with brain metastases
from breast cancer. Median overall survival typically is limited to 4–6 months [1]. However,
many patients have active extracranial disease and eventually die from
extracranial cancer progression. Within the last decade, several important new
treatment options for metastatic breast cancer became available, for example,
trastuzumab, taxane-based chemotherapy, capecitabine, and more effective
aromatase inhibitors. Therefore, the possibility exists that more effective
systemic treatment might lead to improved survival also in the subgroup of
patients harbouring brain metastases. In order to examine this hypothesis, a
matched pairs analysis was performed that involved one group of patients, which
were treated after these new drugs were introduced, and one group of patients,
which were treated approximately 10 years earlier.


## 2. Patients and Methods

The contemporary group
included all patients with brain metastases from breast cancer, which received
WBRT with 10 fractions of 3 Gy between 2000 and 2007 at the University Hospital
of North-Norway. The patients (n=32) were identified from the database of the
Radiation Oncology facility. No patients with carcinomatous meningitis were
included. Positron emission tomography for staging was not available. A
historical control group treated with the same WBRT regimen between 1987 and 1997
was generated. From this larger group (n=47), patients were selected for a
matched pairs analysis without survival information available at the time of
matching. To obtain two groups with comparable baseline characteristics, two
matching criteria were used: prognostic class according to the published
recursive partitioning analysis (RPA class) [3, 4] and the use of additional
local treatment for relapses after WBRT, for example, radiosurgery (RS) or
surgical resection. Information on primary tumour features, such as hormone
receptor status and HER2 receptor status, was not available in the historical
group. Information on lymphopenia [5, 6] was not available at all. We used the Kaplan-Meier
method to generate actuarial survival curves. These were compared with the log
rank test. Wilcoxon- and Kruskal-Wallis tests were used to compare the baseline
characteristics between the two groups. A P-value <.05 was
considered statistically significant.


## 3. Results

Table1 shows the patient
characteristics for the contemporary group and the matched group of 32
historical patients. As can be seen, the groups were balanced for the
established prognostic factors. More patients in the contemporary group had
received chemotherapy before diagnosis of brain metastases. Time to development
of brain metastases was significantly longer. The fact that more patients in
the historical group were recorded to have had single brain metastases apparently
was not related to increased use of magnetic resonance imaging in recent years.Table 1
Patient characteristics.
Contemporary group,n=32Historical group,n=32P-valueMedian age, range55 yrs., 34–8153 yrs., 29–72>.1Median KPS, range70%, 50–9070%, 30–90>.1Median timeinterval*52 mo., 3–21634 mo., 7–118<.05% single brain metastasis1634<.05% with MRI scan of the brain4441>.1% uncontrolled primary30>.1% without extracranial metastases99>.1% RPA class I versus II versus III6 : 59 : 346 : 56 : 38>.1% GPA group I versus II versus III versus IV0 : 0 : 62 : 380 : 6 : 56 : 38>.1Median GPA score1.51.5>.1% chemotherapy before brain metastases diagnosis8169< .1% T1/2 N0 versus T3/4 N0 versus N+25 : 6 : 6919 : 6 : 75>.1% with HR positive tumour42not available% with HER-2 positive tumour69not availableKPS:
Karnofsky performance status,*from breast cancer diagnosis to brain
metastases, MRI: magnetic resonance imaging, RPA: recursive partitioning
analysis, GPA: graded prognostic assessment (Sperduto et al. [2]: 0-1 point
(most unfavourable) defined as group IV, 1.5–2.5 points defined as group III, 3
points defined as group II, 3.5–4 points defined as group I), HR: hormone
receptor.The majority of patients in
the contemporary group were lymph node positive, hormone receptor negative, and
HER-2 positive. Neither hormone receptor status nor HER-2 status was statistically
significant prognostic factor in this group (P>.3). Only 4 patients
had not received systemic treatment, 2 had received endocrine treatment only,
and 26 had received chemotherapy before development of brain metastases (5
patients had 3 different lines of chemotherapy). Twelve patients remained
without systemic treatment after WBRT, 5 received endocrine treatment only, 11
one line of chemotherapy, and 4 at least 2 lines of chemotherapy. Three
patients received trastuzumab-containing treatment after WBRT. As this was a
matching criterion, 3 patients in each group received RS or surgical resection
for progressive brain metastases. As a striking difference, only 8 patients in
the historical group received additional chemotherapy after WBRT (endocrine
treatment unfortunately was not recorded).In the contemporary group, 60%
of the patients achieved at least a partial remission of their brain metastases
based on imaging after WBRT (reduction in largest diameter of each lesion by at
least 50% without development of new lesions). At 6 months after WBRT, 59% of
the patients were progression-free in the central nervous system. These data
are not available for the historical group. Median survival from first
diagnosis of breast cancer was 102 months in contemporary patients with initial
T1/2 N0 disease and 47.5 months in patients with more advanced disease (P<.05). These figures are higher than in historical patients (60.9 versus 34.7 months). Table 2 demonstrates that the recent survival improvement from the
start of WBRT is entirely derived from RPA class II patients, while no obvious progress
was achieved in RPA class III. Analysis of class I was not meaningful, as this
group included only 2 patients. Only 2 of the contemporary patients in RPA
class III received chemotherapy after WBRT (versus one patient in the
historical group). Patients without active treatment after WBRT had a median
survival of 3.5 versus 3.2 months, that is, no improvement over time. For
patients with active treatment, median survival also remained stable (9.0 versus
7.9 months), while the 1-year survival rate improved from 25 to 43%. The small
group (n=6) of patients that received the most aggressive treatment, defined as
trastuzumab-containing regimens and/or brain salvage treatment, had a median
survival of 15.4 months (4 patients survived >1 year).Table 2
Survival results for the two groups.
Contemporary group,n=32Historical group,n=32P-value (log-rank test)Median survival5.0 mo.3.6 mo.1-year survival31%19%<.1Median survival RPA class II9.0 mo.3.4 mo.1-year survival RPA class II42%22%<.05Median survival RPA class III2.4 mo.3.1 mo.1-year survival RPA class III18%8%>.1


## 4. Discussion

This matched pairs analysis
was performed with two groups of patients, which received identical local treatment
for their brain metastases and were well balanced for the known prognostic
factors age, KPS, extracranial disease status, graded prognostic assessment
(GPA) group, and RPA class. Unlike the newly developed GPA, RPA class has been confirmed
as prognostic factor in patients with primary breast cancer in several studies
(Table3). In order to obtain enough historical patients for the matching
procedure, the treatment period was extended back to the year 1987. The
recently suggested prognostic factor lymphopenia [5, 6] has not been routinely
assessed in our department and could, therefore, not be included. A further
point that needs to be mentioned is the lack of information on hormone receptor
status, HER-2 status, and endocrine treatment in the historical patient group,
which was treated before 1998. Thus, imbalances regarding these parameters,
which might have influenced the survival results to some degree, cannot be
ruled out. As demonstrated in Table 4, the prognostic impact of hormone
receptor and HER-2 status is difficult to interpret at this time, as the
published studies reported inconsistent results and are all limited in size. None
of the patients in the historical group received trastuzumab, taxanes,
capecitabine, or new-generation aromatase inhibitors.Table 3
Comparison with the literature, median WBRT dose 30 Gy in all studies.
Own contemporary patientsMahmoud-Ahmed et al. [7]Claude et al. [5]Bartsch et al. [8]Le Scodan et al. [6]Treated2000–20071984–20001991–20011994–20041998–2003n32116120174117Upfront surgery/RSnonoyesyesnoMedian age55 y.50 y.54 y.55 y.53 y.Median interval52 m.22.5 m.38 m.35 m.39 m.Extracranial met.91%68%80%unknown94%Previous Ctx81%unknown84%unknown79%HR positive42%unknown66%unknown48%Median survival5.0 m.4.2 m.5.0 m.7.0 m.5.0 m.1-year survival31%17%25%30%28%Median survival class II9.0 m.6.1 m.9.0 m.unknown8.0 m.Median survival class III2.4 m.1.7 m.3.0 m.unknown3.0 m.RS: radiosurgery, Ctx: chemotherapy, HR: hormone receptor.Table 4
Prognostic impact of hormone receptor and HER-2 status.
nPrognostic impact of hormone receptor statusPrognostic impact of HER-2 statusClaude et al. [5]120nonenot examinedBartsch et al. [8]174nonenoneLe Scodan et al. [6]117receptor negative significantly worsenoneNam et al. [9]126receptor negative significantly worseHER-2 negative significantly worseKirsch et al. [10]95not examinedHER-2 negative significantlyworse*Eichler et al. [11]83noneHER-2 negative significantlyworse⋀Melisko et al. [12]112receptor negative significantly worsenoneHarputluoglu et al. [13]144nonenonePark et al. [14]125noneHER-2 positive significantly worseChurch et al. [15]86not examinedHER-2 negative significantlyworse*Own contemporary group32nonenone⋀80% of HER-2 overexpressing cases received trastuzumab after diagnosis of brain metastases.
*The difference in survival was limited to patients with HER-2 overexpressing cancer treated with trastuzumab after diagnosis of brain metastases.The first interesting finding
was that the interval from initial breast cancer treatment to brain metastases
has increased by 18 months, that is, 53%. Median interval was longer than
previously reported in the literature (Table3). Accordingly, increased overall
survival from first diagnosis of breast cancer was evident, in particular in
patients with initial T1/2 N0 disease. Such results might be explained by a
change in the biology of the disease. However, the numbers of patients with
node-positive disease, receptor-negative disease, and HER-2 positive disease
between 2001 and 2007 argues against this explanation. Especially HER-2
overexpression and hormone receptor negativity appear to influence the risk of
brain metastases development [16]. In fact, the data favour changes in
treatment regimens as a more likely explanation. The use of systemic
chemotherapy has increased over time, both before and after the diagnosis of
brain metastases. However, such treatment was performed nearly exclusively in
those patients with brain metastases that belonged to the prognostically more
favourable groups (better RPA class). Whether changes in systemic treatment are
the only explanation for the marked survival improvement in RPA class II in the
present study is difficult to assess. Other factors might potentially influence
the results. It is, for example, possible that more patients that previously
would have been assigned to RPA class I would now be assigned to class II,
based on better methods for detection of extracranial metastatic disease. In
addition, RPA class II is a quite inhomogeneous group of patients with large
potential differences, for example, in extent of CNS involvement and KPS.In the present analysis, survival
after WBRT has remained unchanged in patients without further active treatment.
It has improved in prognostically better patients and especially patients that
received active treatment, where the 1-year survival rates have almost doubled.
As these patient groups were small, confirmation of the results in other series
should be attempted. When looking at the literature, the series that is best
comparable to our own contemporary patients is the one reported by Le Scodan et
al. [6], which provides almost identical survival data (Table 3). The series
that included the oldest data (back to 1984) [7], is very close to our own
historical group. Bartsch et al. confirmed that patients without systemic
treatment have significantly poorer median survival (5 months versus 10 months
in patients with systemic treatment) [8]. These authors also found that
intensified local therapy of brain metastases improved the outcome. Lee et al.
confirmed the value of both intensified local and systemic treatment in a
series of 198 patients [17]. Other nonrandomized series suggest that RS might
lead to better local control and survival than that reported from WBRT series [18].
The impact of chemotherapy on brain control is less clear [19], although recent
data suggest that capecitabine might be able to induce remission of central
nervous system metastases from breast cancer [20]. Taken together, the present
results and the literature overview are compatible with the hypothesis that
improved systemic therapy might contribute to longer survival in patients with
brain metastases from breast cancer, which qualify for active systemic therapy
in addition to upfront WBRT.



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