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APPROACHES IN BRAIN METASTASES
Targeted and Immunotherapeutic Approaches in
Brain Metastases
Manmeet S. Ahluwalia, MD, and Frank Winkler, MD
OVERVIEW
Brain metastases are a common and devastating complication of cancer. The approach to the management of brain metastases is often
multidisciplinary and includes surgery, whole-brain radiation therapy (WBRT), stereotactic radiosurgery (SRS), and systemic therapeutic
agents. Until recently, systemic therapy has had a limited role in the management of brain metastases because of a lack of activity,
challenges of blood-brain barrier penetration, the heterogeneous patient population, and a heavily pretreated patient population.
Advances in the understanding of the biology of brain metastases and molecularly defined disease subsets have facilitated an emerging
role of novel therapeutic agents, including targeted therapies and immunotherapy, in the management of brain metastases.
Brain metastases are serious complications of systemic
cancer that occur in 10% to 30% of adults with cancer. 1
The most common malignancies that metastasize to the
brain are lung, breast, and melanoma. 2-5 Eighty percent of
patients present with brain metastases within the cerebral
hemispheres; 15% are within the cerebellar hemispheres and
5% are within the brainstem. 6 Key determinants in the management
of brain metastases include the tumor histology,
number, size, and site of lesions; the status of extracranial
metastases; and the performance status of the patient. One of
the challenges in the development of effective therapies for
brain metastases is the presence of the blood-brain barrier, a
highly selective permeability barrier made of capillary endothelial
cells connected by tight junctions and astrocyte foot
processes that limit entry of systemic therapies into the
brain. 7,8 In addition, active transport mechanisms of drug
efflux and high plasma protein binding of agents further
lower the volume of distribution of agents in the brain parenchyma.
8 An additional challenge is that patients who
develop brain metastases often are heavily pretreated with
tumors that are more likely to be resistant to therapy at
diagnosis of the brain metastases. The role of systemic
therapy (chemotherapy, targeted agents, or immunotherapy)
in brain metastases is not well defıned, because there
is no level-1 evidence favoring the use of systemic therapy
compared with local approaches. However, in recent
years, the development of novel cytotoxic agents and targeted
therapies with better blood-brain barrier penetration
have increased the interest in use of systemic
therapies in brain metastases.
TARGETING BRAIN HOST CELLS
Another potential mechanism of resistance in metastatic tumor
cells in the brain is their interaction with brain resident
cells. The brain metastatic process depends on the perpetuation
of a perivascular niche, at least during the early steps, 9
and this niche has been associated with promotion and/or
maintenance of a stem-like and resistant cellular phenotype,
per se, in brain tumors. The components of the blood-brain
barrier (endothelial cells, pericytes, astrocytic foot processes,
and/or the vascular basement membrane) 10 are likely candidates
to provide this supportive niche for cancer cells. Conversely,
the high ineffıciency of the brain metastatic process
(with 95% to 99% of brain-arrested cancer cells failing to successfully
grow to a macrometastasis 9 ) raises the question of
whether some of these components are more foe than friend
for extravasating cancer cells in the brain. A recent report
suggested that the astrocyte-produced plasminogen activator
forces brain metastatic cancer cells into apoptosis and that
cancer cells need to inhibit this process to survive this brain
protective mechanism. 11 In contrast, astrocytes might protect
brain metastatic cancer cells from the adverse effects of
chemotherapy by buffering intracellular calcium increases
via gap junction coupling and other mechanisms. 12 Thus, the
role of many brain resident cells appears to be complex, and
further research is required to understand the potential to
target them for brain metastasis prevention or treatment.
The brain endothelial cell (the main cell type reacting to angiogenic
growth factors produced by tumor cells) appears to
be among the most promising cellular target that is emerging,
as detailed in this review.
From the Burkhardt Brain Tumor Neuro-Oncology Center, Neurological Institute, Cleveland Clinic, Cleveland, OH; Neurology Clinic, University of Heidelberg and German Cancer Research Center,
Heidelberg, Germany.
Disclosures of potential conflicts of interest are found at the end of this article.
Corresponding author: Manmeet S. Ahluwalia, MD, Burkhardt Brain Tumor and Neuro-Oncology Center, Neurological Institute, Cleveland Clinic, 9500 Euclid Ave., S70, Cleveland, OH 44195;
email: ahluwam@ccf.org.
© 2015 by American Society of Clinical Oncology.
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK 67