NcXHF

AHLUWALIA AND WINKLER
TARGETING ANGIOGENESIS
Preclinical data from multiple animal models support the
potential role of antiangiogenic agents for the prevention
and treatment of brain metastases. Elevated vascular endothelial
growth factor (VEGF) expression has been
linked to the development of brain metastasis in a murine
model. 13 Kimetal 14 showed that treatment with a VEGF
receptor tyrosine kinase inhibitor reduced angiogenesis
and restricted the growth of brain metastasis in a murine
breast cancer model. 14 In another mouse model, inhibition
of VEGF signaling using bevacizumab effıciently
inhibited angiogenesis-dependent macrometastases formation
of brain-metastasizing lung adenocarcinoma cells,
arresting micrometastases in a chronic dormant state. 9
However, the growth pattern of different tumor (sub-
)types in the brain is highly different; for example, lung
carcinoma is highly angiogenesis dependent, and melanoma
is less dependent on angiogenesis (because of the
ability to grow co-optively along pre-existing brain microvessels
9 ). These preclinical observations support the clinical
evaluation of antiangiogenic agents in brain metastases
therapy and prevention. Antiangiogenic agents (e.g., those
targeting the VEGF pathway) have to reach only the endothelial
cell to inhibit ligand-receptor interactions and may
not need to fully cross the blood-brain barrier. Initial experience
with bevacizumab in six patients who had non–small
cell lung cancer (NSCLC) with brain metastases was shown
to be safe and resulted in a partial response in two patients,
KEY POINTS
A multidisciplinary approach involving the neurosurgeon,
medical oncologist, neuro-oncologist, and radiation
oncologist is recommended in the management of brain
metastases.
A number of agents that target epidermal growth factor
receptor and anaplastic lymphoma kinase mutations have
been effective in the treatment of brain metastases that
harbor these mutations.
The greatest advances in the systemic treatment of breast
cancer brain metastases have been made in patients who
have HER2-positive disease.
Small-molecule tyrosine kinase BRAF inhibitors that target
BRAF V600 -mutant melanoma have demonstrated activity in
active melanoma brain metastases. Ipilimumab is an
immunotherapeutic agent that has demonstrated activity in
a prospective, phase II trial conducted in patients who
have melanoma with asymptomatic brain metastases.
(Patients who did not require corticosteroid therapy had a
better response than those who needed corticosteroids
because of brain edema.)
There is a need for prospective clinical trials to test new
combinations of targeted and immunotherapeutic agents
with local therapies to address the optimal sequencing of
local and systemic therapies in the management of brain
metastases.
stable disease in three patients, and disease progression in
one patient. 15 Initial safety concerns about the risk of bleeding
in the brain with such agents have not been supported by
reported experience. 16 A phase II trial of bevacizumab in
combination of carboplatin showed an overall response rate
in the central nervous system (CNS) of 45% by RECIST. 17 An
initial report of a phase II study of cisplatin, etoposide, and
bevacizumab demonstrated a response rate of 60% in patients
who have breast cancer with brain metastases. 18 These
high response rates with bevacizumab may be a result of
pseudoresponse (decrease in contrast enhancement on MRI
because of the antipermeability effect of bevacizumab on the
vasculature) and not necessarily an antitumor effect. 19
TARGETING EPIDERMAL GROWTH FACTOR
RECEPTOR AND ANAPLASTIC LYMPHOMA KINASE
IN LUNG CANCER WITH BRAIN METASTASES
Approximately 40% to 50% of patients who have locally
advanced NSCLC will develop brain metastases. 20 Activating
mutations in the epidermal growth factor receptor
(EGFR) occur in approximately 10% to 15% of NSCLC.
Multiple small-molecule tyrosine kinase inhibitors, such
as erlotinib, gefıtinib, and afatinib, are U.S. Food and Drug
Administration (FDA) approved for the treatment of lung
cancer with EGFR mutations. An EGFR inhibitor, such as
erlotinib, can serve as a potential radiation sensitizer to
increase the effıcacy of the radiation. In a phase II study of
40 patients who had NSCLC with brain metastases, the
combination of whole-brain radiation therapy and erlotinib
was reported to be safe (no reported increase in neurotoxicity).
21 The median survival time was 11.8 months
for the whole cohort. The overall survival (OS) time was
19.1 months in the patients with mutant EGFR compared
with an OS time of 9.3 months in the patients with wildtype
EGFR (Table 1). 21 However, a phase III trial (RTOG
0320) failed to show any additional benefıt of erlotinib in
combination with WBRT and stereotactic radiosurgery
(SRS) in patients who had brain metastases from
NSCLC. 22 However, one limitation of the study was that
patients were not stratifıed according to EGFR mutational
status. In a large cohort of 110 patients who had EGFRmutant
lung cancer with newly diagnosed brain metastases,
patients treated with WBRT (32 patients) had a longer
median time to intracranial progression than the 63 patients
who received erlotinib as up-front therapy (24 vs. 16
months). 23 Patients treated with erlotinib or SRS experienced
intracranial failure as a component of fırst failure
more often, whereas patients who received WBRT experienced
failure outside the brain more often. The OS was
similar between the WBRT and erlotinib groups; patients
treated with SRS initially had a longer OS than those who
received erlotinib. In a phase II study of 41 patients who
had NSCLC (unselected for EGFR mutation), treatment
with gefıtinib resulted in an objective response rate of 10%
in the brain. 24 Higher response rates with EGFR inhibitors
have been reported in studies that are enriched with pa-
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