1. health and fitness
2. disease
3. cancer

Immune-based and targeted therapy
may be active in melanoma metastatic
to the brain.
Tenzin Norbu Lama. By Moonlight.
Novel Treatments for Melanoma Brain Metastases
Rajappa S. Kenchappa, PhD, Nam Tran, MD, PhD, Nikhil G. Rao, MD,
Keiran S. Smalley, PhD, Geoffrey T. Gibney, MD,Vernon K. Sondak, MD, and Peter A. Forsyth, MD
Background: The development of brain metastases is common in patients with melanoma and is associated with
a poor prognosis. Treating patients with melanoma brain metastases (MBMs) is a major therapeutic challenge.
Standard approaches with conventional chemotherapy are disappointing, while surgery and radiotherapy have
improved outcomes.
Methods: In this article, we discuss the biology of MBMs, briefly outline current treatment approaches, and
emphasize novel and emerging therapies for MBMs.
Results: The mechanisms that underlie the metastases of melanoma to the brain are unknown; therefore, it is
necessary to identify pathways to target MBMs. Most patients with MBMs have short survival times. Recent use
of immune-based and targeted therapies has changed the natural history of metastatic melanoma and may be
effective for the treatment of patients with MBMs.
Conclusions: Developing a better understanding of the factors responsible for MBMs will lead to improved
management of this disease. In addition, determining the optimal treatments for MBMs and how they can be
optimized or combined with other therapies, along with appropriate patient selection, are challenges for the
management of this disease.
From the Departments of Neuro-Oncology (RSK, NT, PAF), Cutaneous Oncology (GTG, VKS), Radiation Oncology (NGR), and
Molecular Oncology (KSS) at the H. Lee Moffitt Cancer Center &
Research Institute, Tampa, Florida, and the Departments of Oncologic Sciences (NT, NGR, KSS, GTG, VKS, PAF) and Surgery (NT,
VKS) at the University of South Florida College of Medicine, Tampa, Florida.
Submitted February 11, 2013; accepted May 21, 2013.
Address correspondence to Peter A. Forsyth, MD, Department of
Neuro-Oncology, Moffitt Cancer Center, 12902 Magnolia Drive,
Tampa, FL 33612. E-mail: Peter.Forsyth@Moffitt.org
No significant relationship exists between the authors and the
companies/organizations whose products or services may be referenced in this article.
298 Cancer Control
Introduction
Twenty years ago, treatment options for patients with
melanoma brain metastases (MBMs) were limited, and
these patients would generally die of the disease within
2 months.1 Because of today’s rapid progress of effective surgical, radiation, and systemic therapies for
metastatic melanoma, hope exists for these patients:
MBMs respond to treatment, and patients are living longer. New treatment paradigms are emerging, possibly
translating into longer survival rates and better quality
of life. Clinical trials may now include patients with
MBMs, including those with active MBMs on systemic
therapy trials. Furthermore, trials are being specifically
designed for patients with MBMs rather than “lumping”
them together with all types of brain metastases. We
believe this approach will accelerate the discovery of
October 2013, Vol. 20, No. 4
effective and personalized therapy for MBMs. In this
review of MBMs, we discuss the underlying biology,
patient outcomes, and existing treatment strategies,
with a focus on emerging therapeutic approaches.
Epidemiology
The incidence of metastatic brain tumors is 200,000
cases per year in the United States, which is 10 times
higher than the incidence of primary brain tumors.2
Melanoma is the third most common cancer that metastasizes to the brain (5% to 10%, compared with
20% to 30% of breast cancer and 40% to 50% of lung
cancer), with a reported average survival of less than
9 months.1,3-6 A total of 50% to 75% of the patients
diagnosed with melanoma revealed brain metastases
at autopsy, and approximately 60% of these patients
were diagnosed with brain metastases before death.7
However, studies on the molecular mechanisms underlying MBMs are limited and current treatments
are palliative. An understanding of the biological
mechanisms of MBMs is critical to devising effective
treatment strategies.
Biology and Treatment Opportunities
The metastatic process, particularly as it applies to the
brain, is complex and poorly understood. It involves
an orchestrated series of events that require cancer
cells to escape from the primary tumor site, invade,
intravasate into the circulation, extravasate into the
brain parenchyma, survive, induce angiogenesis, and
proliferate by responding to the brain microenvironment (Fig 1). Each step is regulated by various genes
Primary Metastatic Melanoma
(A) Intravasation [STAT3 + Neurotrophin Signaling]
Melanoma Cells
(B) Arrest in Capillary Bed
(C) Extravasation
[STAT3 + Neurotrophin Signaling]
(D) Blood Vessel Co-Option
[Beta 1-Integrin + VEGF-A]
Activated Microglia
Tumor Cell Survival,
Colonization + Proliferation
(E) Angiogenesis [VEGF-A]
Brain Parenchyma
Activated Astrocytes
Fig 1A-E. — Schematic illustration of melanoma brain metastases. (A) Once metastatic tumor cells escape from the primary melanoma site, they will
intravasate into circulation, (B) they arrest in the capillary bed, and (C) then extravasate into the brain parenchyma. STAT3 and neurotrophin signaling
mediate melanoma cell intravasation and extravasation. Following the extravasation into the brain parenchyma, (D) melanoma cells either grow along blood
vessels (co-option) and/or (E) establish angiogenesis; beta 1-integrin and VEGF-A are associated in this process. STAT3 = signal transducer and activator
of transcription 3, VEGF = vascular endothelial growth factor.
October 2013, Vol. 20, No. 4
Cancer Control 299
and signaling pathways. Metastases are inefficient
and uncommon from a cellular perspective; only a
small number of cells (0.01% to 0.03%) in a primary
tumor metastasize to target organs.7-11
Tumors are also biologically heterogeneous, and
certain tumor types show a remarkable predilection for some organs but not others. For example,
melanoma metastasizes to the brain in about 40% of
patients, while brain metastases are rare in patients
with prostate cancer. Paget’s “seed” (ie, tumor cell)
and “soil” (ie, target organ) model remains useful.12
Ewing13 proposed that circulatory patterns between
the primary tumor and its target organ also determine the tissue specificity. A modern refinement of
Paget’s theory suggests that tumor cell “seeds” carry
their own “soil” (secreting extracellular matrix [ECM]
components) to the target site.14 Although the metastatic cascade of MBMs is poorly understood, several
pathways are available as therapeutic targets (Fig 1).
Successful metastasis depends on the survival
of tumor cells in the circulation and the successful
communication of cancer cells with the brain microenvironment. Once primary malignant melanomas
advance to the aggressive stage, tumor cells invade or
migrate and intravasate. These processes are dependent on their capacity to degrade ECM components
and invade endothelial cells or tight junctions that
underlie the tumor–blood barrier through proteolysis.
Melanoma cells achieve this via two or more different
pathways: via neurotrophin signaling15 and through
activation of plasmin and matrix metalloproteinases
(MMPs).16,17 MMPs break down the ECM, particularly
type 1 collagen, fibronectin, and laminin in the ECM.16
Malignant melanoma cells derived embryologically
from the neuroectoderm also express neurotrophins
and their receptors; in turn, the activation of these receptors (via ligand binding or cleavage and regulated
intramembrane proteolysis in a manner analogous to
Notch expression) increases heparinase production,
an ECM proteolytic enzyme, which cleaves the heparin
sulfate chain of the ECM. Heparinase degrades not
only ECM but also the basement membrane of the
blood–brain barrier (BBB),15-18 facilitating the extravasation of MBMs. A specific melanoma cell antigen
called melanotransferrin is present that activates plasminogen that, when targeted using a monoclonal antibody (L235) in animal models, reduces MBMs. This
is an important example of targeting a mechanistic
pathway to prevent experimental brain metastases.
The mechanism behind the tropism of melanomas for the brain is unknown. Although the process
is unproven, it is likely that the brain secretes neurotrophins or other factors that act as chemokines
and interact with receptors on melanoma cells that
modulate survival in the blood stream and tropism
to the brain. Once the metastatic melanoma cells
300 Cancer Control
reach the brain circulation, they arrest in the capillary bed on the basis of tumor/vessel size. Some of
these will cross the vascular endothelial cells of the
brain, a process that may support metastatic tumor
proliferation and invasion.19,20 After the tumor cells
have crossed the endothelial cells, they encounter several host stromal cell types in the brain parenchyma,
such as astrocytes and microglia, and begin establishing vascular connections necessary for sustained
tumor growth and invasion. The response of the host
stromal cells within the brain microenvironment is a
critical component for tumor growth. For example,
activated microglias make the brain microenvironment
favorable for tumor growth and invasion.21 In addition, astrocytes may protect metastatic melanoma cells
from cytotoxic agents.22 Neurotropic factors and their
receptors are also implicated in melanoma growth in
the brain parenchyma.14,23 These observations suggest
that astrocytes and microglia stimulate metastatic tumor growth through direct contact and release of trophic factors. Two tumor suppressor genes are known
to act on proliferation of melanoma cells when they
metastasize: NM23 and BrMS1. NM23 controls cell
growth by encoding for a nucleotide diphosphate
protein kinase, whose reduced levels in melanoma are
associated with enhanced brain metastases.24 BrMS1
prevents tumor cell growth, and its functional reduction is associated with the increased metastatic capacity of melanomas.25 Studies have indicated that the
altered microenvironment and compromised tumor
suppressor genes help facilitate MBMs.24,25
Another important factor in metastatic tumor
growth is the establishment of a sufficient blood supply. Experimental models of MBMs have shown that
the recruitment of blood vessels occurs through different mechanisms: (a) utilizing the existing blood
vessels by cancer cells for growth (co-opting), (b) extending vascular budding from existing blood vessels
(angiogenesis), and (c) establishing a new vascular
system (vasculogenesis).26 Studies using real-time
imaging through the cranial windows of MBM in mice
reveal that a metastatic tumor can grow up to 3 mm
through co-opting pre-existing blood vessels.10,27 Following extravasation, metastatic melanoma cells have
a close association with pre-existing blood vessels10
and may remain dormant for long periods of time unless they establish a blood supply. Several molecules
exist that mediate the establishment of blood supply
to metastatic tumors cells. Beta 1-integrin expressed
by tumor cells is an important molecule and facilitates the co-opting of tumor cells to blood vessels.28
Vascular endothelial growth factor (VEGF)-A is also
vital for co-opting of pre-existing brain blood vessels
in MBMs.29 When tumors grow beyond a microscopic
size (~ 3 mm), they develop vasculature via angiogenesis, which also involves the VEGF pathway.30 AberOctober 2013, Vol. 20, No. 4
rant VEGF activity can occur as a hypoxic response in
the tumor31 or through dysregulated tumor suppressors and oncogene activation.32,33 Therefore, blocking
angiogenesis may be a promising approach to MBMs
but will not affect their initial extravasation or affect
them in their dormant or quiescent state.
Others have studied the roles of suppressor of
cytokine signaling 1 (SOCS-1) and signal transducer
and activator of transcription 3 (STAT3) in the promotion of MBMs. In this paradigm, loss of SOCS-1 (the
negative regulator of STAT3) leads to STAT3 activation and favors MBM development.34,35 The loss of
SOCS-1 and the activation of STAT3 were confirmed
in MBM tissue from patients. STAT3 may have several
prometastatic roles by promoting tumor cell migration, evading anoikis, and promoting angiogenesis,
the latter via the expression of basic fibroblast growth
factor, MMP2 and VEGF.35 Hence, targeting STAT3
may be a useful target to prevent MBMs.
Some melanomas metastasize to the brain parenchyma while others still metastasize to the leptomeninges or dura. To address this experimentally in
syngeneic mouse models of melanoma, Fidler et al36
used two different melanoma cell lines in two different
mouse strains (K-175 melanoma line in C3H/HeN mice
and B-16 melanoma line in C57BL/6 mice). Mice were
injected with these cells either intra-arterially via the
carotid artery or directly inoculated into the cerebrum.
Independent of the route of administration, K-175
preferentially produced parenchymal tumors and B16
preferentially produced tumor in the leptomeninges
and ventricles. They implicated gelatinase-A as predisposing to parenchymal metastases and responsible
for extravasation. Transforming growth factor-beta 2
(TGFβ2) is highly expressed in the brain and inhibits
MBM growth in the brain parenchyma,37-39 thus highlighting the targeted approach of chemokines and
immunomodulatory proteins (eg, TGFβ2) to prevent
or inhibit the growth of MBMs. Identifying subsets
of patients with melanoma at high risk for MBMs may
justify a therapeutically preventive approach.
Standard Treatment
Important contributions to optimizing care for patients
with MBMs include multidisciplinary care through
specialized MBM clinics, comprehensive tumor board
meetings, and the availability of clinical trials specifically for this subset of patients. Multidisciplinary
care should include medical and surgical oncologists
who specialize in melanoma, as well as clinical pharmacists, radiation oncologists, neurosurgeons, and
neuro-oncologists.
Surgical Treatment
The decision to resect brain metastasis is a complex
process that depends on the need to establish a hisOctober 2013, Vol. 20, No. 4
tologic diagnosis, lesion size and accessibility, the
presence of neurological symptoms, the performance
status of the patient, and the overall status of the
systemic disease.40 Per guidelines from the National
Comprehensive Cancer Network (NCCN), when possible, surgery is the first step for the management of
MBM in patients with a reasonable prognosis, particularly in those with one to three brain metastasis,41 a recommendation that predates the evidence
of efficacy of v-raf murine sarcoma viral oncogene
homolog B1 (BRAF) inhibitors in MBM. This rule
should be heavily qualified. For example, in patients
with extensive extracranial metastases, initial treatment with BRAF or other targeted treatments may take
priority, with surgery for MBM reserved for salvage.42
Resection eliminates tumor-associated edema and obviates the need for sustained corticosteroid therapy
and associated adverse events, which represents an
important consideration in melanoma metastases because corticosteroids may impair the effectiveness of
immunotherapeutic treatment regimens. For small,
asymptomatic MBM lesions (< 2 cm) in deep locations,
stereotactic radiosurgery (SRS) may be considered
as first-line treatment over surgery. However, SRS is
associated with vasogenic edema, radiation necrosis,
and hemorrhage.43
Radiotherapy
Surgical treatment alone is not sufficient for prolonging survival.41 Historically, whole-brain radiotherapy
(WBRT) has been used to augment surgical resection,44-46 and it is the only form of radiotherapy (RT)
for brain metastases that has category 1 evidence.
However, SRS is the treatment of choice for patients
who are not surgical candidates (eg, > 3 brain metastases, 1 lesion > 3 cm in diameter, or other reasons)
in an effort to “save the brain.” Melanomas are less
sensitive to RT than, for example, lymphomas are, so
the efficacy of WBRT is lower. Moreover, the longterm cognitive “costs” are high. Focused RT minimizes
neurocognitive deficits. Hence, whenever possible,
WBRT should be delayed or avoided if other treatment options are available. The advent of effective
systemic treatments (eg, ipilimumab, vemurafenib) to
treat MBMs may further change the cost–benefit ratio
in favor of SRS. A new paradigm might include SRS
to provide local control followed by systemic therapy
to treat and prevent “micro”-brain metastases.
Chemotherapy
The results of standard chemotherapy for the treatment of MBMs are disappointing. This may be due
to poorly understood factors such as inadequate BBB
penetration, drug efflux pumps, intrinsic resistance,
or astrocyte protection against chemotherapy-induced
apoptosis via paracrine signaling, among others.36,47
Cancer Control 301
Because the BBB is disrupted when tumors grow
beyond 1 to 2 mm,48 it is unknown whether the BBB
is clinically important for the treatment of established
metastases. Temozolomide and fotemustine, both
of which do penetrate the BBB, have the best response rates among conventional chemotherapies;
however, even they are associated with low response
rates and short durations of response (Table).49-57 A
phase II trial of temozolomide revealed an objective
response rate in MBMs of 7%.49 Other phase II temozolomide studies were performed in combination
with thalidomide, WBRT, or both and had similar
response rates to temozolomide alone.3,50,51 Clinical
activity with fotemustine in MBMs was initially suggested in a phase III study of fotemustine compared
with dacarbazine.58 A subsequent phase III study of
fotemustine produced a response rate of 7.4% when
used as monotherapy vs 10% when combined with
WBRT,59 but no improvement was seen in overall
survival. A retrospective study found that combining WBRT with temozolomide was safe and possibly
prolonged survival in some patients.60
some patients with MBMs, raising the possibility of
changing future treatment approaches for patients
with MBMs.
Antiangiogenics
Although antiangiogenics are commonly studied in
systemic cancer, few clinical trials study them in MBMs
because of their tendency to produce hemorrhage
(up 20% in some series). Although melanoma is a
highly vascular tumor that secretes VEGF and preclinical models show that angiogenesis is required
for “dormant” MBMs to grow,28 a small phase II trial
using bevacizumab did not show benefit in systemic
melanoma (MBMs were excluded).61 No trial of antiangiogenics has been conducted for isolated MBMs.
The approach of targeting angiogenesis may be important because its efficacy could be independent of
the mutational status of the tumor (eg, BRAF or NRAS
mutations) or the patient’s ability to mount an antitumor immune response. A theoretical disadvantage of
antiangiogenic therapies is the potential development
of a proinvasive phenotype as observed in patients
with glioblastoma multiforme. Other drugs that are
also antiangiogenic but not antibody-based and have
acceptable BBB penetration include the receptor tyrosine inhibitors sunitinib and cediranib, which, although interesting and potentially important, have not
been evaluated in clinical trials for MBMs.
Novel Treatments
The use of selective BRAF inhibitors (eg, vemurafenib,
dabrafenib) or immunotherapies (eg, ipilimumab)
has indicated that these agents are safe, have significant activity in systemic melanoma, and are active in
Table. — Selected Prospective Clinical Trials of Systemic Therapies for MBMs
Study
Regimen
Phase
No. of Patients
Response Rate (%)
Long52
Dabrafenib
II
Cohort Aa: 24
Cohort Bb: 17
33 OIRR (81 V600E, 7 V600K)
50 OIRR (89 V600E, 22 V600K)
Mornex56
Fotemustine
III
39
7.4
Mornex56
Fotemustine + WBRT
III
37
10.0
Margolin53
Ipilimumab
II
Cohort Ac: 51
Cohort Bd: 21
10 (0 CR, 5 PR)
5 (0 CR, 1 PR)
Ipilimumab + fotemustine
II
86
50 (6 iCR, 19 iPR)
Lomustine + temozolomide
I/II
26
0
Temozolomide
II
117
7 (1 CR, 7 PR)
Thalidomide
II
35
0
Temozolomide + thalidomide
II
15
12 (2 CR, 1 PR)
Temozolomide + thalidomide + WBRT
I/II
39
7.6 (1 CR, 2 PR)
Temozolomide + WBRT
I/II
31
9.7 (1 CR, 2 PR)
Di Giacomo54
Larkin57
Agarwala49
55
Vestermark
Hwu51
Atkins50
Margolin53
a
No corticosteroids.
Corticosteroids required.
c No prior brain therapy.
d Prior brain therapy.
CR = complete response, iCR-iPR = immune-related complete response or partial response, OIRR = overall intracranial response rate, PR = partial
response, WBRT = whole-brain radiation therapy.
b
302 Cancer Control
October 2013, Vol. 20, No. 4
BRAF Pathway Inhibitors
With the remarkable responses of BRAF V600-mutant
melanomas to selective inhibitors of the mutant BRAF
protein,62,63 these BRAF inhibitors are now being investigated in patients with BRAF V600-mutant MBMs.
One of these agents, dabrafenib, was studied in a
small cohort of patients with untreated MBMs.64 Nine
of 10 patients with MBM responded to therapy in this
trial. Following that trial, BREAK-MB, a phase II study
of dabrafenib, was conducted and reported promising
results.52 A total of 172 patients with between 1 to 4
active MBMs (0.5 to 4 cm in diameter) were stratified
into two cohorts: no prior brain therapy (cohort A)
or prior brain therapy (cohort B). The overall intracranial response rates in patients with BRAF V600Emutant melanoma were 39% and 31% in cohorts A and
B, respectively. The median progression-free survival
was 16.1 for cohort A and 16.6 months for cohort
B, while the median overall survival rates were 33.1
and 31.4 months, respectively. A lower response rate
was seen in patients with BRAF V600K-mutant melanoma. The drug was well tolerated, and common
Pretreatment
3 Months on Vemurafenib
adverse events were limited to fatigue, nausea, and
pyrexia. Data have also been presented for the BRAF
inhibitor vemurafenib in previously treated patients
with MBM,65 and a phase II trial of vemurafenib in
patients with BRAF V600E-mutant MBMs is underway (NCT01378975). An example of a patient with a
V600E-mutant MBM who responded to vemurafenib
is shown in Fig 2. Overall, the response rates seen
in MBMs with BRAF inhibitors mirror extracranial
response rates. Combination therapy strategies with
targets downstream of BRAF, such as combination
BRAF/mitogen-activated protein kinase inhibitors,
have shown promise in patients with extracranial
BRAF V600E-mutant melanoma.66 However, it remains
to be seen whether combination BRAF-targeted strategies will be more effective for MBMs.
Patients with BRAF V600E-mutant melanoma may
develop brain metastases while taking BRAF inhibitor
therapy, with the central nervous system (CNS) as the
only site of disease progression in 19% of patients.67
It will be important to investigate the underlying
mechanisms involved in this paradoxical phenomenon
and the potential strategies to prevent it. Multiple
mechanisms may be responsible, including involvement of the tumor microenvironment and evolving
melanoma phenotype/resistance during drug treatment. Currently, patients who develop MBMs while
experiencing control of their extracranial disease on
BRAF inhibitor therapy can be managed with RT or
surgery while temporarily withholding the drug. An
intact BBB may also protect small micrometastases
from the effects of systemic BRAF inhibitors until
these micrometastases grow large enough to damage
or destroy that barrier, in which case some MBMs that
develop while patients are on BRAF inhibitor therapy
may retain a degree of sensitivity to the drugs.
Immunotherapies
High-Dose Interleukin
Reports exist of complete response (CR) in patients
with MBMs who were treated with high-dose interleukin 2 (HD IL-2). A retrospective analysis of 1,069
patients with either metastatic melanoma or renal cell
carcinoma found that 7 patients had untreated brain
metastases and 2 had a brain response.68 Another
retrospective review of 15 patients with MBMs treated
with HD IL-2 reported that 2 patients had a CR.69
Given the nature of this treatment, it is unlikely to be
used routinely for this indication, and a theoretical
risk of excessive inflammation and vasogenic edema
could occur in MBMs responding to IL-2.
Fig 2. — Example of a patient with melanoma brain metastases (MBMs)
who responded to systemic vemurafenib therapy. Previous treatment for
the MBMs included surgery and radiotherapy. In these active MBMs within the brainstem/posterior fossa (upper figures) and right temporal lobe
(lower figures), modest regression was seen over the course of 3 months
on vemurafenib.
October 2013, Vol. 20, No. 4
Adoptive Cell Therapy
A retrospective analysis was performed in 26 patients
with untreated MBMs discovered incidentally in a cohort undergoing immunodepletion (with chemotherCancer Control 303
apy or total body irradiation) followed by autologous
tumor-infiltrating lymphocytes (TILs) or autologous
peripheral lymphocytes transduced with a T-cell receptor (TCR) to recognize MART-1 or gp100.70 Of the 17
patients who received adoptive cell therapy with TILs,
7 (41%) had a CR in the brain and 6 (35%) achieved
an overall partial response (PR). Similarly, 2 (22%) of
9 patients who received TCR-transduced lymphocytes
had a CR in the brain. Therefore, aggressive immunotherapy used in patients with small asymptomatic
MBMs may produce CRs. These results also suggest
that activated T cells traffic into MBMs in the CNS.
Ipilimumab
Another strategy that has changed the treatment of
melanoma is the use of drugs to upregulate T-cell
function using antibodies to block the cytotoxic T-lymphocyte antigen (CTLA) 4, which potentiates antitumor immune responses. Ipilimumab, the anti–CTLA-4
monoclonal antibody, prolonged overall survival rates
in patients with metastatic melanoma in two phase
III studies.71,72 Although traditional radiographic responses were seen in a small percentage of patients
(~ 10% to 15%), many of these responses lasted months
to years. These first pivotal studies excluded patients
with MBMs. Retrospective analyses of phase II studies with ipilimumab that did not exclude patients
with small asymptomatic brain metastases showed
evidence of clinical activity in patients with MBM.73,74
These reports led to a prospective phase II study of
ipilimumab specifically to treat MBMs (CA184-042).53
Patients were stratified into two cohorts based on
symptoms and current corticosteroid use. Patients in
cohort A were neurologically asymptomatic and not
receiving corticosteroids, whereas those in cohort B
were symptomatic and taking a stable dose of corticosteroids. Overall, there was CNS disease control
(broadly defined as a CR, PR, or stable disease) in
approximately 25% of patients in cohort A and approximately 10% of patients in cohort B. One patient
(5%) in cohort B had a CR and 8 patients (16%) in cohort A had a PR. The only grade 3 CNS adverse events
were headaches in 4% of patients and confusion in
1%, although these events may have been attributed
to the disease. One patient had a grade 4 intratumoral hemorrhage attributed to the disease, not the
treatment. The results from this study revealed that
ipilimumab has activity in MBMs, particularly when
patients are asymptomatic and not receiving corticosteroids. Moreover, the treatment appeared safe in
the small number of patients treated. However, it is
unknown whether the treatment was more effective in
larger MBMs in which the highly permeable BBB may
allow a greater ingress of activated cytotoxic T cells.
A degree of patience and optimism to monitor
clinical benefit is required when using immunothera304 Cancer Control
pies. Early in the course of treatment, lesions may
grow and become symptomatic, which is a pattern
seen in systemic melanoma lesions treated with ipilimumab, even though a significant clinical response
will ultimately occur. In general, we attempt to wait
until the end of the induction phase of ipilimumab
(4 doses given every 3 weeks) before concluding the
presence of progressive disease.
One retrospective review sought to answer whether combination therapy with CTLA-4 antibodies was
effective.75 Control rates using SRS combined with
ipilimumab were reported and favorable survivals and
response rates were seen. In this context, SRS may
synergistically work with ipilimumab by lysing tumor
cells and presenting a broader antigen repertoire to
primed T cells. A prospective phase II combination
trial of ipilimumab with fotemustine, an alkylating
agent with BBB penetration, was conducted in Europe.54 The trial included 20 patients with asymptomatic MBMs and found that one-half of participants had
stable disease or a response following treatment. A
phase III study is planned.
Data suggest that ipilimumab produces antitumor
T-cell responses in the brain without significantly
different response rates or toxicities from extracranial melanoma. It is not clear whether activity
seen in small or asymptomatic brain lesions (such
as those detected in routine magnetic resonance
imaging) will apply to larger symptomatic lesions.
Whether response rates are lower in patients who
require corticosteroids for symptom control remains
undetermined. It is possible that surgery, SRS, or a
BRAF inhibitor may be used first, followed by an immunological therapy to provide sustained and longterm responses. Similarly, strategies to promote BBB
breakdown (eg, mannitol, small molecule inhibitors)
may improve the efficacy of ipilimumab by enhancing
T-cell migration to MBMs.
Programmed Death 1 Inhibitors
Programmed death (PD) 1 is an inhibitory co-receptor
on antigen-activated T-cells. Activated T cells may be
suppressed by ligands PD-L1 (B7-H1) and PD-L2 (B7DC), which are expressed by tumor or stromal cells.
Activated PD-1 inhibits T-cell activation and effector
function by suppressing phosphatidylinositide 3-kinase/Akt activation in T cells as well as by many other
unknown mechanisms. Inhibiting the PD-1 receptor
with a blocking antibody enhances T-cell responses and
antitumor activity. Response rates have been reported
in melanoma and in non–small-cell lung cancer.76,77
Patients with radiographically stable (≥ 8 weeks) brain
metastases were enrolled in these trials, but results in
MBMs were not separately reported. Clinical trials are
in progress for systemic melanoma that may include
patients with small asymptomatic MBMs.
October 2013, Vol. 20, No. 4
Special Challenges in Novel Therapies in
Patients With MBM
The use of immune modulators (eg, CTLA-4, PD-1
antibodies) poses several challenges in the setting of
brain metastases. Thus far, no direct evidence exists
of the enhancement of T-cell function by ipilimumab
within the MBM tumor tissue. Although T cells pass
through an intact BBB, which is disrupted in MBMs,
the brain remains “immunoprivileged” and is deficient
in adoptive immune responses.78 This suggests that
strategies to increase BBB penetration may increase
the efficacy of immune-based approaches. Curiously,
no clear report has addressed CNS inflammation in or
around the brain metastases associated with CTLA-4
antibody treatment, nor has there been a clear association with the immune-related hypophysitis, which
occurs in 1% to 6% of patients treated with ipilimumab with activity against MBMs (assuming that the
occurrence of hypophysitis is a surrogate for T-cell
trafficking into the CNS and possibly a predictor of
response).79 However, some CNS inflammation may
be necessary for efficacy.
Response criteria for CNS lesions are challenging because no criteria have been developed specifically for brain metastases. The concept of delayed
response — for example, with anti-CTLA-4 antibody
treatment — is important to avoid discontinuing a
drug too early because of changes in volume enhancement unrelated to tumor growth. Uniform criteria for
measuring MBM responses to immunotherapy and
corticosteroid management are needed to compare
therapies across different studies.
Clinical trial design, particularly tissue interrogation of MBMs following an experimental treatment, is
an important issue. For example, small phase 0 clinical
trials that study the surgical resection of MBMs following treatment with an experimental agent may help
determine drug penetration, target modulation (eg,
BRAF, mitogen-activated protein kinase, extracellular
signal-regulated kinase inhibition), immunological response, and phenotypic changes (eg, necrosis, relative
T-cell populations, cytokine activation). Doing so may
help clarify the biology, develop new therapies, and
prioritize agents to take to phase II studies. However, many of these trials were performed on atypical
patients with MBMs. Most of the patients treated
had small asymptomatic lesions that did not require
corticosteroids. Therefore, future clinical trials should
investigate the usefulness of these therapies in patients
with large symptomatic lesions, which represent those
more typically encountered in real practice.
Conclusions
New treatment approaches show real activity in melanoma brain metastases that will likely change current
treatment. Whole-brain radiotherapy and its cognitive
October 2013, Vol. 20, No. 4
adverse events may be avoided by using cytoreductive-targeted therapies followed by immunological
therapy for long-term control or cure. How to improve these treatments and how or when to combine
them are important questions. Patients at high risk
for melanoma brain metastases should be identified
and strategies should be developed to prevent these
metastases. Finally, clinical trials that incorporate tissue interrogation following exposure to a novel treatment in melanoma brain metastases may accelerate
drug discovery and improve patient care.
References
1. Fife KM, Colman MH, Stevens GH, et al. Determinants of outcome
in melanoma patients with cerebral metastases. J Clin Oncol. 2004;22(7):
1293-1300.
2. Patchell RA. The management of brain metastases. Cancer Treat
Rev. 2003;29(6):533-540.
3. Hofmann M, Kiecker F, Wurm R, et al. Temozolomide with or without
radiotherapy in melanoma with unresectable brain metastases. J Neurooncol. 2006;76(1):59-64.
4. Sampson JH, Carter JH Jr, Friedman AH, et al. Demographics, prognosis, and therapy in 702 patients with brain metastases from malignant
melanoma. J Neurosurg. 1998;88(1):11-20.
5. Davies MA, Liu P, Mclntyre S, et al. Prognostic factors for survival in
melanoma patients with brain metastases. Cancer. 2011;117(8):1687-1696.
6. Wen PY, Loeffler JS. Brain metastases. Curr Treat Options Oncol.
2000;1(5):447-458.
7. McWilliams RR, Rao RD, Buckner JC, et al. Melanoma-induced brain
metastases. Expert Rev Anticancer Ther. 2008:8(5):743-755.
8. Yano S, Shinohara H, Herbst RS, et al. Expression of vascular endothelial growth factor is necessary but not sufficient for production and growth
of brain metastasis. Cancer Res. 2000;60(17):4959-4967.
9. Shaffrey ME, Mut M, Asher AL, et al. Brain metastases. Curr Probl
Surg. 2004;41(8):665-741.
10. Kienast Y, Von Baumgarten L, Fuhrmann M, et al. Real-time imaging
reveals the single steps of brain metastasis formation. Nat Med. 2010;16(1):
116-122.
11. Kang M, Fujimaki T, Yano S, et al. Biology of brain metastases. In:
Ali-Osman F, ed. Brain Tumors. Totowa, NJ: Humana Press Inc; 2005:91-106.
12. Paget S. The distribution of secondary growths in cancer of the
breast. Cancer Metastasis Rev. 1989:8(2):98-101.
13. Ewing J. Neoplastic diseases: a treatise on tumors. Br J Surg.
1928;16(61):174-175.
14. Duda DG, Duyverman AM, Kohno M, et al. Malignant cells facilitate lung metastasis by bringing their own soil. Proc Natl Acad Sci U S A.
2010;107(50):21677-21682.
15. Denkins Y, Reiland J, Roy M, et al. Brain metastases in melanoma:
roles of neurotrophins. Neuro Oncol. 2004;6(2):154-165.
16. Perides G, Zhuge Y, Lin T, et al. The fibrinolytic system facilitates tumor cell migration across the blood-brain barrier in experimental melanoma
brain metastasis. BMC Cancer. 2006;6:56.
17. Hotary K, Li XY, Allen E, et al. A cancer cell metalloprotease triad regulates the basement membrane transmigration program [published correction
appears in Genes Dev. 2007;21(9):1139]. Genes Dev. 2006;20(19):26732686.
18. Nathoo N, Chahlavi A, Barnett GH, et al. Pathobiology of brain metastases. J Clin Pathol. 2005;58(3):237-242.
19. Marchetti D, Denkins Y, Reiland J, et al. Brain metastatic melanoma:
a neurotrophic perspective. Pathol Oncol Res. 2003;9(3):147-158.
20. Lorger M, Felding-Habermann B. Capturing changes in the brain microenvironment during initial steps of breast cancer brain metastasis. Am J
Pathol. 2010;176(6):2958-2971.
21. Carbonell WS, Ansorge O, Sibson N, et al. The vascular basement
membrane as “soil” in brain metastasis. PLoS One. 2009;4(6):e5857.
22. Fitzgerald DP, Palmieri D, Hua E, et al. Reactive glia are recruited by
highly proliferative brain metastases of breast cancer and promote tumor cell
colonization. Clin Exp Metastasis. 2008;25(7):799-810.
23. Lin Q, Balasubramanian K, Fan D, et al. Reactive astrocytes protect melanoma cells from chemotherapy by sequestering intracellular calcium through gap junction communication channels. Neoplasia. 2011;12(9):
748-754.
24. Menter DG, Herrmann JL, Nicolson GL. The role of trophic factors
and autocrine/paracrine growth factors in brain metastasis. Clin Exp Metastasis. 1995;13(2):67-88.
25. Sarris M, Scolyer RA, Konopka M, et al. Cytoplasmic expression of
nm23 predicts the potential for cerebral metastasis in patients with primaCancer Control 305
ry cutaneous melanoma [published correction appears in Melanoma Res.
2004;14(3):239]. Melanoma Res. 2004;14(1):23-27.
26. Seraj MJ, Samant RS, Verderame MF, et al. Functional evidence for
a novel human breast carcinoma metastasis suppressor, BRMS1, encoded
at chromosome 11q13. Cancer Res. 2000;60(11):2764-2769.
27. Jain RK, di Tomaso E, Duda DG, et al. Angiogenesis in brain tumours. Nat Rev Neurosci. 2007;8(8):610-622.
28. Küsters B, Westphal JR, Smits D, et al. The pattern of metastasis of
human melanoma to the central nervous system is not influenced by integrin
alpha(v)beta(3) expression. Int J Cancer. 2001;92(2):176-180.
29. Küsters B, Leenders WP, Wesseling P, et al. Vascular endothelial
growth factor-A(165) induces progression of melanoma brain metastases without induction of sprouting angiogenesis. Cancer Res. 2002;62(2):341-345.
30. Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other
disease. Nat Med. 1995;1(1):27-31.
31. Neufield G, Cohen T, Gengrinovitch S. Vascular endothelial growth
factor (VEGF) and its receptors. FASEB J. 1999;13(1):9-22.
32. Blancher C, Moore JW, Robertson N, et al. Effects of ras and von
Hippel-Lindau (VHL) gene mutations on hypoxia-inducible factor (HIF)-1alpha, HIF-2alpha, and vascular endothelial growth factor expression and their
regulation by the phosphatidylinositol 3’-kinase/Akt signaling pathway. Cancer Res. 2001;61(19):7349-7355.
33. Zundel W, Schindler C, Haas-Kogan D, et al. Loss of PTEN facilitates
HIF-1-mediated gene expression. Genes Dev. 2000;14(4):391-396.
34. Huang FJ, Steeg PS, Price JE, et al. Molecular basis for the critical role of suppressor of cytokine signaling-1 in melanoma brain metastasis.
Cancer Res. 2008;68(23):9634-9642.
35. Xie TX, Huang FJ, Aldape KD, et al. Activation of stat3 in human
melanoma promotes brain metastasis. Cancer Res. 2006;66(6):3188-3196.
36. Fidler IJ. The role of the organ microenvironment in brain metastasis.
Semin Cancer Biol. 2011;21(2):107-112.
37. Schackert G, Fidler IJ. Site-specific metastasis of mouse melanomas
and a fibrosarcoma in the brain or meninges of syngeneic animals. Cancer
Res. 1988;48(12):3478-3484.
38. Schackert G, Price JE, Zhang RD, et al. Regional growth of different
human melanomas as metastases in the brain of nude mice. Am J Pathol.
1990;136(1):95-102.
39. Fujimaki T, Fan D, Staroselsky A, et al. Critical factors regulating
site-specific brain metastasis of murine melanomas. Int J Oncol. 1993;3(5):
789-799.
40. Ewend MG, Morris DE, Carey LA, et al. Guidelines for the initial management of metastatic brain tumors: role of surgery, radiosurgery, and radiation therapy. J Natl Compr Canc Netw. 2008;6(5):505-514.
41. National Comprehensive Cancer Network. NCCN Clinical Practice
Guidelines in Oncology: Central Nervous System Cancers. V.2.2013. http://www.
nccn.org/professionals/physician_gls/pdf/cns.pdf. Accessed June 17, 2013.
42. Carlino MS, Fogarty GB, Long GV. Treatment of melanoma brain
metastases: a new paradigm. Cancer J. 2012;18(2):208-212.
43. Mathieu D, Kondziolka D, Cooper PG, et al. Gamma knife radiosurgery in the management of malignant melanoma brain metastases. Neurosurgery. 2007;60(3):471-482.
44. Patchell RA, Tibbs PA, Regine WF, et al. Postoperative radiotherapy
in the treatment of single metastases to the brain: a randomized trial. JAMA.
1998;280(17):1485-1489.
45. Patchell RA, Tibbs PA, Walsh JW, et al. A randomized trial of surgery
in the treatment of single metastases to the brain. N Engl J Med. 1990;
322(8):494-500.
46. Kocher M, Soffietti R, Abacioglu U, et al. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to
three cerebral metastases: results of the EORTC 22952-26001 study. J Clin
Oncol. 2011;29(2):134-141.
47. Rades D, Panzner A, Dziggel L, et al. Dose-escalation of whole-brain
radiotherapy for brain metastasis in patients with a favorable survival prognosis. Cancer. 2012;118(15):3852-3859.
48. Eichler AF, Chung E, Kodack DP, et al. The biology of brain metastases-translation to new therapies. Nat Rev Clin Oncol. 2011;8(6):344-356.
49. Agarwala SS, Kirkwood JM, Gore M, et al. Temozolomide for the
treatment of brain metastases associated with metastatic melanoma: a
phase II study. J Clin Oncol. 2004;22(11):2101-2107.
50. Atkins MB, Sosman JA, Agarwala S, et al. Temozolomide, thalidomide,
and whole brain radiation therapy for patients with brain metastasis from
metastatic melanoma: a phase II Cytokine Working Group study. Cancer.
2008;113(8):2139-2145.
51. Hwu WJ, Lis E, Menell JH, et al. Temozolomide plus thalidomide in
patients with brain metastases from melanoma: a phase II study. Cancer.
2005;103(12):2590-2597.
52. Long GV, Trefzer U, Davies MA, et al. Dabrafenib in patients with
Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain
(BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol.
2012;13(11):1087-1095.
53. Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab in patients with
melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012;13(5):459-465.
306 Cancer Control
54. Di Giacomo AM, Fonsatti PA, Pittiglio E, et al. A phase II study combining ipilimumab and fotemustine in patients with metastatic melanoma: the
NIBIT-M1 trial. J Clin Oncol. 2011;29:TPS230.
55. Vestermark LW, Larsen S, Lindeløv B, et al. A phase II study of thalidomide in patients with brain metastases from malignant melanoma. Acta
Oncol. 2008;47(8):1526-1530.
56. Mornex F, Thomas L, Mohr P, et al. A prospective randomized multicentre phase III trial of fotemustine plus whole brain irradiation versus fotemustine alone in cerebral metastases of malignant melanoma. Melanoma
Res. 2003;13(1):97-103.
57. Larkin JM, Hughes SA, Beirne DA, et al. A phase I/II study of lomustine and temozolomide in patients with cerebral metastases from malignant
melanoma. Br J Cancer. 2007;96(1):44-48.
58. Margolin K, Atkins B, Thompson A, et al. Temozolomide and whole
brain irradiation in melanoma metastatic to the brain: a phase II trial of the
Cytokine Working Group. J Cancer Res Clin Oncol. 2002;128(4):214-218.
59. Avril MF, Aamdal S, Grob JJ, et al. Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study.
J Clin Oncol. 2004;22(6):1118-1125.
60. Devito N, Yu M, Chen R, et al. Retrospective study of patients with
brain metastases from melanoma receiving concurrent whole-brain radiation
and temozolomide. Anticancer Res. 2011;31(12):4537-4543.
61. Kim KB, Sosman JA, Fruehauf JP, et al. BEAM: a randomized phase
II study evaluation the activity of bevacizumab in combination with carboplatin plus paclitaxel in patients with previously untreated advanced melanoma.
J Clin Oncol. 2012;30(1):34-41.
62. Chapman PB, Hauschild A, Robert C, et al. Improved survival with
vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med.
2011;364(26):2507-2516.
63. Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open label, phase 3 randomised
controlled trial. Lancet. 2012;380(9839):358-365.
64. Falchook GS, Long GV, Kurzrock R, et al. Dabrafenib in patients with
melanoma, untreated brain metastases, and other solid tumours: a phase 1
dose-escalation trial. Lancet. 2012;379(9829):1893-1901.
65. Dummer R, Hauschild A, Guggenheim M, et al. Cutaneous melanoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
Ann Oncol. 2012(23 suppl 7):86-91.
66. Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK
inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367(2):107-114.
67. Kim KB, Flaherty KT, Chapman PB, et al. Pattern and outcome of disease progression in phase 1 study of vemurafenib in patients with metastatic
melanoma (mm). J Clin Oncol. 2011(29 suppl):8519.
68. Guirguis LM, Yang JC, White DE, et al. Safety and efficacy of highdose interleukin-2 therapy in patients with brain metastases. J Immunother.
2002;25(1):82-87.
69. Powell S, Dudek AZ. Single-institution outcome of high-dose interleukin-2 (HD IL-2) therapy for metastatic melanoma and analysis of favorable
response in brain metastases. Anticancer Res. 2009;29(10):4189-4193.
70. Hong JJ, Rosenberg SA, Dudley ME, et al. Successful treatment of
melanoma brain metastases with adoptive cell therapy. Clin Cancer Res.
2010;16(19):4892-4898.
71. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):
711-723.
72. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;
364(26):2517-2526.
73. Weber JS, Amin A, Minor D, et al. Safety and clinical activity of ipilimumab in melanoma patients with brain metastases: retrospective analysis of
data from a phase 2 trial. Melanoma Res. 2011;21(6):530-534.
74. Schartz NE, Farges C, Madelaine I, et al. Complete regression of
a previously untreated melanoma brain metastasis with ipilimumab. Melanoma Res. 2010;20(3):247-250.
75. Knisely JP, Yu JB, Flanigan J, et al. Radiosurgery for melanoma brain
metastases in the ipilimumab era and the possibility of longer survival. J
Neurosurg. 2012;117(2):227-233.
76. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune
correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):24432454.
77. Brahmer JR, Tykodi SS, Chow L, et al. Safety and activity of antiPD-L1- antibody in patients with advanced cancer. N Engl J Med. 2012;
366(26):2455-2465.
78. Ransohoff RM, Brown MA. Innate immunity in the central nervous
system. J Clin Invest. 2012;122(4):1164-1169.
79. Weber JS, Kahler KC, Hauschild A, et al. Management of immunerelated adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30(21):2691-2697.
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