Approach to the patients with brain metastases

APPROACH TO THE PATIENTS WITH
BRAIN METASTASES
Dr.K.V.Pradeep Babu,MD
DNB Resident
Rajiv Gandhi Cancer Instiute &
Research centre

Brain metastasis
• Among the many undesirable effects of systemic cancer is metastatic
spread to the brain.
• Metastatic tumours involving the brain overshadow primary brain
neoplasms in frequency.
• This is an important complication in the overall management of many
cancers.
• Currently, no effective measures are available to reliably prevent this
event
• Intense vigilance for relevant symptoms is necessary to detect early
involvement of the brain due to cancer metastases
• Surgery and radiation remain the cornerstones of the therapy for
symptomatic lesions

Epidemiology of brain metastasis
• The estimated prevalence of new brain metastases
in the USA is between 7–14 persons per 100,000
based on population studies.
• The expected incidence of newly diagnosed
patients with brain metastases is estimated to be
between 21,651 to 43,301 per year.
• The prevalence of metastases to the brain is
expected to continue to increase in the future.

• Interestingly, the primary cancer sites associated with brain
metastases have varied over the past decades, reflecting
underlying cancer incidence and mortality patterns.
• For example, in a comparison of patients with brain
metastases treated in the years 1983–1989 versus 2005–
2009 (n = 103 per cohort), Nieder et al. found ::
• a reduced incidence of primary lung cancers (52% versus
40%)
• an increased frequency of melanomas (5% versus 9%)
• substantial increases in the number of patients with primary
colorectal and kidney cancers (8% versus 24%)
• breast cancer cases remained stable (17%).

• The global prevalence of brain metastases in patients with cancer is
probably around 8.5–9.6%.
• The most common primary tumours responsible for brain metastases
are lung cancer (19.9%), melanoma (6.9%), renal cancer (6.5%),
breast cancer (5.1%) and colorectal cancer (1.8%).
• The true prevalence of brain metastases, however, might be far
higher than reported in these surveys
• Asymptomatic brain metastases can go undetected, and symptomatic
brain metastases might not be reported in patients with widespread
metastatic disease.
• Brain metastases were identified in 40% of patients with melanoma
and in 16–30% of patients with breast cancer in whom autopsies
were performed.
• These numbers far exceed those published in the aforementioned
population-based studies.

Factors causing increased brain mets recently
• Improvements in imaging technologies (MRI)and increased usage (64% of
patients with cancer versus 2% 20 years ago).
• Global increase in cancer prevalence , and in particular those that have a
predilection to metastasize to the brain, such as lung cancer.
• Improvements in the survival of patients with cancer due to earlier detection
and improved treatment
• The wipespread introduction of targeted therapies that have limited
bioavailability in the brain might also have resulted in an iatrogenic increase in
brain metastasis.
• For example, the monoclonal antibody trastuzumab is effective in the
treatment of HER2-positive breast cancer; has a limited capacity to enter the
central nervous system (CNS) has led to the suggestion that this agent might
make the CNS a potential ‘sanctuary’ site for meta-static disease

PATHOPHYSIOLOGY
• For metastatic cells to reach the brain, the primary
tumor usually gets access to the circulation either by
invading the venules or lymph channels.
• Before reaching the brain such circulating tumor cells
necessarily pass through the right side of the heart and
the first capillary bed they encounter, is the lung.
• Accordingly, patients with symptomatic brain metastasis
usually have involvement of the lung (primary tumors or
metastases).

Factors influencing intracranial metastases
• In the resting state, the brain receives 15%-20% of the
body’s blood flow.
• This high volume making it likely that circulating tumor
cells will have greater chance of reaching the brain.
• Tumor cells from certain primaries find the brain an
appropriate place for metastatic colony formation and
growth.
• This is one of the reasons that the probability of brain
metastases varies among tumor types.
• Renal, colon and breast carcinomas generally produce
single metastases whereas malignant melanoma and
lung generally produce multiple secondary lesions

• The site and distribution of brain metastases is also
determined by the size of the region and its vasculature.
• Hence, about 85% of brain metastases are found in the
cerebral hemispheres- in the watershed area between
middle and posterior cerebral arteries.
• Approximately 10%-15% of metastases are found in the
cerebellum and only about 3% of metastases are found
in the brainstem.
• Renal-cell, gastrointestinal and pelvic cancers tend to
metastasize to the infratentorial area, whereas breast
carcinoma is commonly found in the posterior pituitary.

The biology of brain metastases

SEED AND SOIL HYPOTHESIS
“The seeds of a plant are carried in all directions;
but they can only live and grow if they fall on
congenial soil”
– Paget 1889
The successful growth of metastatic cells depends
on the interactions and properties of cancer cells
(seeds) and their potential target organs (soil)

• In 2011, Eichler et al.published a Review on
the biology of brain metastases in clinical
oncology journal ,Nature.
• In this Review, the process of escape of cancer
cells from a primary tumour site and
colonization of the CNS was described

The relevance of astrocytes
• The brain microenvironment, including brain vascular endothelial
cells and stromal cells (microglia and astrocytes), provides
growth and invasion advantages to the disseminated tumour
cells.
• Astrocytes are intimately involved in maintaining normal
homeostasis of the brain microenvironment.
• It is accomplished through transport of nutrients to the neurons
and protection of injured neurons from apoptosis.

• The normal neuro protective role of activated
astrocytes was shown to extend to metastatic brain
tumour cells in vitro after exposure to
chemotherapeutic agents
• Moreover, activated astrocytes also induced
upregulation of survival genes, such as GSTA5,
BCL2L1 and TWIST1, in tumour cells, which was
associated with increased resistance to
chemotherapy in vitro.

The importance of angiogenesis
• The growth of metastatic brain tumours is critically
dependent on angiogenesis
• Disordered angiogenesis results in structural and
functional abnormality of tumour-associated blood
vessels, characterized by defective endothelial cells,
pericyte covering and basement membranes
• These abnormalities can directly restrict the delivery of
oxygen, leading to intratumoural hypoxia.
• Impaired efficacy of chemo and radiation therapy due to
limited perfusion of the cancer tumour bed  lead to
the establishment of functional sanctuary sites for cancer
cells.

• Theorotically , the use of antiangiogenic
therapies might be expected to decrease the
efficacy of cytotoxic therapies
• However, the opposite effect has in fact been
reported, probably through ‘normalization’ of
the disordered blood flow and reduced
interstitial pressure within the tumour bed.

Inhibitors of angiogenesis in brain tumors
• In a phase II clinical trial in primary glioblastoma, the pan-VEGFR
small-molecule inhibitor, cediranib, combined with chemoradiation,
improved tumour perfusion in a subset of patients.
• The increased perfusion of cancer tissue correlated with changes in
relevant angiogenic biomarkers, such as plasma levels of placenta
growth factor (PGF) and soluble VEGFR2.
• Importantly, overall survival improved in this patient subset
compared with the population with no improvement in tumour
perfusion.
• Although these data are from patients with primary brain tumours,
the biological mechanism elucidated might be pertinent to cerebral
metastatic disease.

Cancer cell phenotypes in brain metastasis
• The specific mechanisms and characteristics of cancer cells that drive and/or
facilitate colonization of the CNS and genetic underpinnings of CNS
metastases are being investigated.
• Zhang et al. characterized circulating tumour cells (CTCs) from patients with
breast cancer and identified a predictive signature for cancer cells with
increased capacity for brain involvement.
• This includes lack of expression of epithelial cell adhesion molecule (EpCAM)
and positivity for HER2, EGFR, heparanase (HPSE) and Notch1 expression.
• Bos et al.characterized the gene-expression profiles of brain infiltrating
cancer cells from patients with metastatic breast cancer .
• They identified prostaglandin G/H synthase 2 (also known as c
yclooxygenase-2 [COX2]), the EGFR ligand heparin-binding EGF-like growth
factor (HBEGF), and ST6GalNAc5, as mediators of cancer cell breach of the
BBB.

A: Expression of EMT markers zinc finger
protein SNAI1 (SNAIL) and twist-related protein 1 (TWIST), mesenchymal
marker vimentin and stem cell marker CD44 in metastatic tumor samples.
Images are shown at ×10 and ×20 magnifications.

Venn diagram displaying the percentage of SNAIL, TWIST, vimentin and
CD44 expression in metastatic brain tumor samples (n=26), with
varying degree of overlap amongst the markers within samples

Fluorescent immunohistochemical analysis of antibody-tagged E-cadherin (red)
and vimentin (green) revealing areas of expression and colocalization in
metastatic brain tumor samples

Cartoon diagram depicting the signaling pathway of platelet-derived growth factor (PDGF), tumor
growth factor beta (TGFβ), receptor tyrosine kinase (RTK) and other growth factors (GF) promoting
EMT and MET. Stem cells may lie at the interface of this transition.

Clinical features
• The clinical presentation can vary widely and may include ::
• Headache
• Motor weakness
• Sensory disturbance
• Nausea and/or vomiting
• Cranial nerve abnormalities
• Change in mental status
• Seizures
• Ataxia
• Speech difficulties
• Coordination abnormalities

Neurocognitive decline
• A great deal of attention has been focused on the
potential neurocognitive effects of WBRT.
• The majority of patients have neurocognitive
deficits prior to the initiation of WBRT with a
comprehensive phase 3 trial reporting that >90%
of patients have some decline in neurocognitive
function (NCF) prior to WBRT.
• So it is suggested to test NCF prior to starting
WBRT for baseline assessment with a battery of
tests.

• The imaging modality of choice is an MRI as it
is more sensitive than CT for determining the
number, distribution, and size of lesions.
• The detection of brain metastases may
increase after the use of triple dose contrast.
• Typically, brain metastases are solid or ring
enhancing lesion(s), pseudospherical in shape,
multiple in number, occur in the grey-white
junction

• Mets Occur most frequently in the cerebral
hemispheres (80%) followed by the cerebellum
(15%) and brain stem (<5%).
• Hemorrhagic lesions are seen more commonly
with germ cell tumors, melanomas, thyroid
carcinoma, choriocarcinoma, and renal cell
carcinoma.
• Rarely, the leptomeninges can also be involved.

DIFFERENTIAL DIAGNOSIS
• Nonmalignant causes such as abscess, infection,
demyelination and hemorrhage, and primary brain
tumors.
• If uncertainty exists regarding diagnosis, biopsy or
surgery should be performed to confirm diagnosis.
• For patients with known cancer, restaging scans, which
typically include CT scan with and without contrast of
the chest, abdomen, and pelvis, should be performed to
assess primary and extracranial disease status.

MRI IN THE DIAGNOSIS OF BRAIN METS
• Advances in MRI have improved the identification of the brain metastases.
• Multiple brain metastases are often visualized on contrast-enhanced T1-
weighted images.
• A solitary metastasis often have some similarities in appearance to high-
grade gliomas, such as evidence of central necrosis.
• Two major advances in MRI technique have been shown to produce data
that enables differentiation between metastatic and primary tumours:
• Magnetic resonance spectroscopy (MRS)
• Perfusion-weighted imaging (PWI).

• MRS characterizes regions of brain based on the
abundance of specific metabolites.
• Spectra from MRS analyses of tumours differ from
those characteristic of normal brain tissues.
• Cancer tissues have increased levels of choline—a
marker of cell proliferation—and decreased levels of
the neuronal biomarker N-acetylaspartate (NAA).
• In addition, PWI-derived relative cerebral blood
volume (rCBV) measurements can be used to identify
and quantify areas of neovascularization within the
brain.

Differentiation between primary and mets on MRI
• Although choline to NAA ratios and rCBV values are
similar in high-grade gliomas and brain metastases
themselves, these characteristics are markedly different
in the peritumoural region .
• This lies outside the contrast-enhancing margins of
these tumours.
• High-grade gliomas have a highly infiltrative nature,
and thus have peritumoural regions containing
infiltrating tumour cells, the tissues surrounding brain
metastases usually contain no infiltrating cancer cells

• As a result, the choline to NAA ratio in the peritumoural
region of high-grade gliomas is typically substantially
higher than normal brain.
• In brain metastases, the peritumoural regions of have
almost the same choline and NAA levels as normal brain.
• Similarly, the rCBV of peritumoural regions in high-
grade glioma is higher than that of normal brain tissue
due to neovascularisation .
• whereas rCBVs of peritumoural tissues associated with
brain metastases and normal brain tissue are
comparable

• Infusions of recombinant human tumour necrosis factor (TNF) has
been reported to induce selective permeabilization of the BBB to
imaging tracers at sites of brain metastases.
• This method enabled the detection of smaller tumours than are
currently visualized using standard imaging techniques.
• This is based on the fact that metastatic tumor cells in brain have
predominant expression of TNF .
• MRI using antibodies targeting vascular cell adhesion molecule-1
(VCAM-1) conjugated to microparticles of iron oxide has also been
shown to enable early detection of metastatic brain tumours.
• This conjugate could be detected in tumours as early as the 1,000-
cell stage.
• VCAM-1 was chosen as the targeted delivery vehicle due to its
presence on endothelial cell membranes in developing tumour-
associated blood vessels

steroids
• As brain metastases can cause peritumoral vasogenic edema, corticosteroids
are frequently used to help temporarily control brain edema.
• Dexamethasone, which has low mineralocorticoid effect, is typically used
given its long half-life.
• For initial symptom control, dexamethasone is administered at loading dose
of 10-20mg followed by doses of 4mg four times a day.
• This usually results in rapid reduction of the edema and symptom control.
• Side effects associated with corticosteroids include myopathy,
hyperglycemia, edema, weight gain, vascular necrosis and psychosis.
• All cancer patients on prolonged corticosteroids should receive prophylactic
therapy for pneumocystis carini pneumonia .
• Steroids should be tapered as early as possible (decreasing the dose every
three days, as tolerated) to minimize side effects.

• For patients with more severe symptoms from
increased intracranial pressure, doses of 16
mg/day or higher should be considered.
• If possible, steroids should be tapered within 1
week of initiation and discontinued within 2
weeks.
• When tapering dexamethasone, it is important to
recognize withdrawal symptoms such as
headaches, lethargy, weakness, dizziness,
anorexia, diffuse arthralgias, and myalgias.

Anticonvulsants
• Anticonvulsants are indicated for all patients who develop a seizure.
• Prophylactic anticonvulsants have not been shown to be beneficial
except in metastasis to motor cortex, synchronous brain metastases
and leptomeningeal metastasis.
• Patients who present with seizures or who develop seizures during
therapy should receive AEDs, preferably with agents that do not
interact with hepatic cytochrome P450 (e.g., levetiracetam).
• For patients on dexamethasone, phenytoin levels can be affected by
its use.
• In addition, phenytoin can affect clearance of chemotherapy agents
and also can cause Stevens Johnson syndrome, which may be
precipitated if radiation is used.

Venous Thromboembolism
• Because patients with brain tumors and thromboembolism are at
higher risk for intracranial hemorrhage with anticoagulation,
guidelines were established by the American Society of Clinical
Oncology for prophylaxis and treatment of venous thromboembolism
in patients with cancer.
• Low-molecular weight heparin is recommended for prophylaxis of
hospitalized and higher-risk ambulatory patients given the minimal
monitoring of coagulation and rare chance for major bleeding
episode.
• Protamine can be used to reverse low-molecular weight heparin in
an emergency.
• For patients with brain tumors and venous thromboembolism,
anticoagulation is indicated unless the patient has had an
intracerebral bleed or other contraindication for anticoagulation.
• The insertion of an inferior vena cava filter is an alternative but is
associated with a higher risk of thrombosis distal to the filter

SURGICAL MANAGEMENT: HISTORIC AND CURRENT
CONCEPTS
• In 2010, the first evidence-based compendium for the
treatment of patients with brain metastases published.
• It states a level 1 recommendation for surgical
resection combined with radiation therapy to prolong
life in relatively young patients with good functional
status and a newly diagnosed solitary brain metastasis.

• In 1990, Patchell et al. published a definitive study
reporting that surgery followed by radiation
therapy yielded a median survival of 40 weeks
compared with 15 weeks in patients who received
radiation alone.
• The currently available data indicate that resection
of all lesions confers a similar survival advantage to
resection of a single solitary metastasis.
• In cases of recurrent disease a considerable survival
advantage, as well as improved quality of life, has
been observed with repeat surgical resection.

STEREOTACTIC RADIOSURGERY
• The use of stereotactic radiosurgery (SRS),
involving noninvasive ablation of cells using high-
dose radiation, is an option when conventional
surgery is not considered for metastatic brain
tumours.
• RTOG 9508 study, published in 2004, showed a
survival benefit in patients undergoing SRS and
whole-brain radiation therapy (WBRT) compared
with individuals treated with WBRT alone (6.5
months versus 4.9 months)

• Local failure rate at 1-year after treatment with SRS and
WBRT is (8%) compared with WBRT alone (100%).
• Notably, no class I evidence from adequately powered,
randomized controlled studies comparing SRS to
standard surgical resection exists.
• NO class I data available on the role of resection
followed by SRS .

SURGICAL DECISION MAKING
• Currently, class I evidence is available in support
of surgical resection followed by WBRT in patients
with a newly diagnosed solitary brain metastasis,
without advanced systemic disease, with PS 2 -3 .
• Additional surgical considerations include the
accessibility and size of the lesion, as well as its
relative proximity to eloquent brain and the
degree of mass effects and presence of
hydrocephalus

The ideal surgical patient of brain mets
• A relatively young (aged <65 years)
• Medically fit individual in need of a diagnosis
• Excellent performance status
• Limited extracranial disease
• Lesion is located in the right frontal pole.

Post op complications
• In the past 5 years, a better understanding of the effect
of postoperative complications has also emerged,
further underscoring the need to perform surgery as
safely as possible.
• For example, evidence from studies in high-grade
glioma indicates that a new postoperative neurological
deficit decreases survival up to 3–4 months
• Any substantial postoperative complication negatively
affects functional status and the patient’s ability to
undergo subsequent radiation treatments
• Both of which are highly important factors in
determining survival.

NEW SURGICAL TECHNIQUES
• At advanced centres for the management of brain tumours, patients
now commonly undergo extensive preoperative imaging.
• It provide detailed information that facilitates intra operative
navigation, including functional MRI, MRS and diffusion tractography
, in addition to intra operative MRI (iMRI).
• iMRI provides valuable information regarding the extent of
resection, as well as real-time intra operative feedback that enables
compensation for brain shift during longer surgeries for complicated
or extensive cases of brain metastasis .
• The literature suggests at least level 2 evidence supports the utility of
iMRI in improving the extent of resection, survival and quality of life
in patients with brain tumor .

• Additional intraoperative techniques within the
neuro-surgical armamentarium include awake
craniotomy and neurophysiological monitoring for
functional assessment during resection.
• Other optical and molecular visualization
technologies includes 5-aminolevulinic acid (5-
ALA) fluorescence or fluorescein staining of
malignant tissues within the operative bed.
• Intraoperative confocal microscopy for
histological markers and detection of tumour cells
using fluorescein is a practical and useful tool.

Future directions of surgical methods
• Molecular imaging technologies hold a great deal of
promise, including Raman spectroscopy.
• It is a technology that can enable identification of brain
tumour cells in vivo according to their molecular
polarization potential.
• When used as an intraoperative probe device, this
technology is sensitive enough to distinguish between
areas of normal brain, brain tissues undergoing invasion
by tumour cells and brain tumour tissue.
• Thus, one can envision this technology augmenting
tumour surgery, subsequently leading to maximally safe,
efficacious resection.

Whole brain radio therapy
• WBRT has historically been used as the primary non-
surgical therapeutic modality for the treatment of
brain metastasis (present also).
• Data revealed based on previous RTOG protocols,
even patients with brain metastasis who had the best
prognosis had a median survival of only 7 months after
WBRT alone.

Problems with WBRT
• WBRT alone is increasingly found to be inadequate in the long-term control
of brain metastasis.
• In addition, with these improved outcomes, many patients in whom control
of brain disease is achieved with WBRT are surviving to experience the
considerable neurocognitive sequelae and declines in quality of life .
• The classic neuro cognitive toxicity associated with WBRT in adults is a
moderate-to-severe dementia that occurs several months to years after
treatment.
• DeAngelis et al. observed a 2–5% incidence of severe dementia in
populations of patients who had undergone .
• An early neurocognitive decline, predominantly in verbal memory,
occurring 1–4 months after WBRT has also been described.

Combination with systemic therapies
• These are mainly aimed at exploring either
adjuncts that can improve the control of brain
disease with radiation, or strategies to limit the
neurocognitive sequelae of WBRT.
• With regard to the latter approach, multiple
RTOG studies evaluating dose escalation with
altered WBRT fractionation schemes have not
proven to be beneficial.

• Although different chemotherapies can penetrate
the BBB to varying extents and have been
evaluated in combination with WBRT for
treatment of brain metastases, the therapeutic
benefits of these agents in this context have been
largely disappointing.
• The lipid soluble alkylating agent temozolomide,
which can cross the BBB freely, has been combined
with WBRT in phase II trials,but provided limited
or no benefit compared with WBRT alone.

WBRT and targeted treatments
• Advantages of combining WBRT with targeted drugs,
rather than traditional chemotherapies, could include
potentially decreased toxicities and the opportunity for
a biomarker-driven approach to disease management.

Overall and CNS failure-free survival after treatment of brain metastases with whole-brain
radiation therapy and erlotinib.
James W. Welsh et al. JCO 2013;31:895-902©2013 by American Society of Clinical Oncology
• Overall survival for (A) all
patients (n = 40) and (B) by
epidermal growth factor
receptor (EGFR) mutation
status (n = 17).
• Survival without CNS
progression for (C) all
patients and (D) by EGFR
mutation status.
• Cumulative incidence of
CNS progression for (E) all
patients and (F) by EGFR
mutation status.

WBRT and/or SRS
• SRS alone has been advocated in patients with better prognosis and a
limited number of metastases.
• Two randomized studies have demonstrated that such patients
(populations with either one to three or four lesions) receiving SRS
alone had a similar survival to patients who received WBRT and SRS.
• A series of meta-analyses of randomized controlled studies that
investigated WBRT and SRS confirmed that WBRT did not enhance
overall survival in patient with a limited number of brain metastases
(up to four)
• However, reduced local and distant control of brain metastasis was
observed after treatment with SRS alone compared with WBRT and
SRS.
• Patients treated with SRS alone do experience increased recurrences
of metastasis elsewhere in the brain.

• EORTC further supports the validity of using local
therapy only (SRS or surgery) versus local therapy
combined with WBRT in patients with one to three brain
metastases, demonstrating no improvement in overall
survival with the addition of WBRT.
• Pooled results from three randomized trials(comprising
a total of 364 patients) have now been reported in
abstract form
• This in fact, revealed an apparent survival advantage in
younger patients (<50 years) treated with SRS alone
compared with WBRT and SRS
• At present, the use of SRS alone in patients with more
than three metastatic lesions in the brain can be
considered

Radiation necrosis in SRS
• Unlike WBRT, SRS increases the risk for radiation necrosis, which
can lead to significant side effects such as steroid dependency.
• As radiation necrosis can closely mimic tumor recurrence, the
diagnosis and treatment of radiation necrosis can be very difficult.
• . Figure 123.3 shows an algorithm that we use to diagnose and
treat radiation necrosis. In terms of imaging, cerebral blood volume
can have high sensitivity and specificity.[111] Based on a double-
blind, placebo-controlled phase 3 trial, the use of bevacizumab is
the therapy with the best supported evidence for patients who are
refractory to steroids.[112] One novel approach for treatment of
steroid refractory radiation necrosis that is being explored is
focused laser interstitial thermal therapy.

Figure showing a sequence of images from diagnosis, after SRS, images
confirming radiation necrosis, and resolution of radiation necrosis
after treatment

Stereotactic Radiosurgery to Resection Cavity
• Because patients undergoing surgical resection alone are at
high risk for local recurrence, the use of radiosurgery rather
than WBRT has been explored given the potential side effects
of WBRT and the convenience of SRS.
• Choi et al. reported that the 12-month cumulative incidence
rates of LF with and without a 2-mm margin around the
defined tumor bed were 3% and 16%, respectively (p = 0.042).
• For most patients, the greatest resection cavity volume change
occurred immediately after surgery (postoperative days 0 to 3)
with no significant volume change occurring up to 33 days
after surgery.
• Although the risk for leptomeningeal spread after SRS is low,
patients with breast cancer histology has been found to have a
higher rate of leptomeningeal spread.

• The North Central Cancer Treatment Group, in
collaboration with RTOG, has an ongoing phase 3 trial
(RTOG 1270/N107C) of postsurgical SRS compared with
WBRT for resected brain metastases for patients with
four or fewer brain metastases.
• The resection cavity must measure <5 cm in maximal
extent on the postoperative MRI (or CT) brain scan
obtained ≤35 days prior to preregistration.
• The primary objective is whether there is improved
overall survival in patients who receive SRS to the
surgical bed compared to patients who receive WBRT.
In addition, neurocognitive progression at 6 months
postrandomization is being assessed.

Intraoperative Radiation Therapy and Brachytherapy
to the Resection Cavity
• Intraoperative radiation therapy has been investigated
to decrease local recurrence after resection of brain
metastases.
• Brachytherapy has also been investigated using high-
activity iodine injected into double lumen balloon that
is placed in the surgical cavity.
• As both intraoperative radiation therapy and
brachytherapy increases operating room time and may
also increase complications such as radiation necrosis,
neither technique has been widely adopted.

Salvage Therapy
• A number of therapeutic options may be considered for
salvage therapy.
• If WBRT is given upfront and the patient later develops
recurrence of brain metastases, the patient can be safely
salvaged with SRS.
• A retrospective study from Chao et al. reviewed 111 patients
treated from 1996 to 2004 who received SRS following failure
from WBRT.
• Local control was 73% at a median time of 15.4 months.
• Median overall survival time was influenced by time from
WBRT to recurrence.

• Repeat WBRT is not usually done as salvage for patients with
better prognosis given concerns about the long-term effects
of radiation.
• For patients with limited prognosis, lower doses and smaller
fraction sizes, such as 20 to 25 Gy in 10 fractions or 30 Gy in
30 fractions (1 Gy twice a day), may be considered with
outcomes are similar to that obtained following initial WBRT
for RPA class II or III patientswith symptomatic improvement
in most patients.
• Surgery is not often repeated, although reoperation can be
considered for selected patients.
• Bindal et al. reported median survival following reoperation
of 11.5 months, no operative mortality or morbidity, and
neurologic improvement in most patients (75%).

Prophylactic cranial irradiation
• Slotman et al. reported improved overall
survival, but no change in global health status,
in patients with small-cell lung cancer (SCLC)
randomly assigned to receive prophylactic
cranial irradiation (PCI) versus no PCI

• However, the use of PCI is not supported in the
treatment of locally advanced stage III NSCLC.
• It is based on the results of the RTOG 0214
trial,which found no difference in overall survival
in patients randomized between the PCI with
standard therapy (surgery and/or radiation
therapy with or without chemotherapy) cohort
• The observation cohort who received standard
therapy only, despite a marked decrease in the
rate of brain metastasis at 1-year follow up in the
patients who underwent PCI.

Preventing neuro cognitive decline
• Pharmacologic intervention has been explored as a
means of preserving neuro cognitive function after
WBRT.
• RTOG 0614, a randomized phase III study, evaluated the
neurocognitive outcomes in patients with brain
metastasis treated with WBRT with or without
memantine.
• It is a drug that blocks N-methyl-d-aspartate (NDMA)-
type glutamate receptors and is used to treat moderate-
to-severe Alzheimer disease.

• In this study, >500 patients were randomized
into two well-balanced cohorts, with
substantially reduced decline in a number of
neuro-cognitive parameters observed in the
WBRT plus memantine arm in comparison with
the WBRT plus placebo control arm.

HA -WBRT
• Investigators at the University of Wisconsinhave pioneered a
technique :: to treat the whole brain while selectively
‘under-dosing’ the bilateral hippocampi, a small volume of
brain that harbours active neural stem cells and is believed to
be critical for the retention of short-term memories.
• These advanced radiotherapy approaches can potentially be
used not only to selectively spare portions of the brain (that
is, hippocampi)
• It might also be adapted to selectively expose known
metastatic lesions to higher doses of radiation, possibly
improving disease control

• The use of hippocampal-avoidance WBRT (HA-
WBRT) has already been tested in a multi-
institutional setting .
• Preliminary results of this phase II RTOG 0933 trial
suggested that patients who underwent HA-WBRT
had improved neurocognitive functioning
compared with the results expected in comparable
patients receiving conventional WBRT

SYSTEMIC THERAPY FOR BRAIN METASTASES

Chemotherapy in Brain metastasis
• One of the major challenges to success of chemotherapy has been that of drug
delivery due to the presence of the blood–brain barrier (BBB).
• This barrier is comprised of the tight junctions between endothelial cells that
line cerebral capillaries.
• In general, two broad classes of drugs have the potential to cross the BBB.
• Lipid soluble molecules are able to traverse the endothelial cell membranes
and cytosol to reach the brain tumor cell by passive diffusion. Examples of such
agents include carmustine or lomustine.
• Small molecules can pass through the tight junctions. In general, these
molecules must be less than approximately 500 kDa.
• Examples of such molecules are temozolomide and many “small molecule”
targeted agents such as lapatinib and erlotinib.

• In addition, several drugs, such as bevacizumab, act on the abluminal
side of the capillaries, obviating the need to cross the BBB in order to
have activity.
• Several other factors can limit access of drug to the brain tumor.
• Protein binding of molecules within the vascular space (e.g., imatinib)
leaves only a small percentage of a compound as free drug to reach
the tumor.
• The BBB contains several drug efflux pumps, which reverse the
movement of molecules across the barrier.
• The PgP drug transporter is probably the most prevalent of these
pumps.
• Finally, interstitial pressure within the tumor can create a mechanical
barrier to convection of molecules toward the tumor.

Goals of chemotherapy in brain mets
• Toimprovesurvival,delayprogression,andpreserveorimprove
apatient’sfunctionandqualityoflife
• Theenhancementofefficacyofradiationtherapy
(radiosensitization)
• Thedelayfortheneedofradiationtherapy
• Thesimultaneouscontrolofsystemicdisease
• Theabilitytoaddresstheentirebrainparenchymainpatients
whomayalreadyhavereceivedWBRT.

• Onefinalgoalistotreattheleptomeningesinthesettingwhere
intrathecalchemotherapyislikelytobeineffective.
• Bulkyleptomeningealdiseasegiventhelimitedpenetrationof
intrathecalchemotherapyintoleptomeningealdeposits)or
unsafeduetounpredictablecerebrospinalfluid(CSF)
distribution(e.g.,impairedCSFflowrelatedtoobstructive
hydrocephalus).
• Forexample,high-doseintravenousmethotrexateforthe
treatmentofbreastcancerbrainand/orleptomeningeal
diseasecanreachtheCSFincytotoxicconcentrations.

The selection of patients
• The patient’s performance status has a major impact on
the likelihood that a patient might benefit from
chemotherapy.
• The status of the patient’s systemic disease matters—a
patient whose systemic disease is uncontrolled is unlikely to
benefit from a chemotherapy regimen intended for the
CNS.
• As an increasing number of agents becomes available for
the treatment of a patient’s systemic disease, the patient
may have been heavily pretreated by the time CNS
metastatic disease occurs.

• Thus end organ functional reserve, such as that of the bone marrow,
must be evaluated carefully to ensure the safe administration of
chemotherapy to such patients.
• The molecular phenotype of the patient’s tumor must be considered
as it can have a significant impact on prognosis and selection of
treatment.
• Importantly, the phenotype of the metastasis may differ from that of
the primary tumor, an example of which is the loss/lack of HER2
receptor in a patient whose original tumor was HER2 positive.
• In such a patient, the use of lapatinib would be inappropriate.
• Therefore, in the occasional patient who has undergone a resection
or biopsy of a brain metastasis, one should obtain molecular marker
tests in the resected lesion if the results would alter the selection of
chemotherapeutic agents.

• Despite multiple trials that have evaluated the
concurrent use of chemotherapy with WBRT, none have
documented a meaningful clinical benefit.
• Currently, however, chemotherapy does not have a
standard role as a radiosensitizer.
• Because CNS imaging of asymptomatic patients with
cancer has become more prevalent, the paradigm of
preirradiation chemotherapy has become a more active
area of investigation.
• The efficacy of chemotherapy against CNS metastases
approximates that against systemic cancer when given
in the preirradiation setting.

The potential advantages of preirradiation
chemotherapy
• The possibility of delaying the need for radiation therapy.
• The theoretical possibility of improved drug delivery to
unirradiated tumor
• The delay of neurocognitive toxicity of radiation therapy in the
high-risk patient
• The possibility of simultaneous treatment of systemic disease.
• Several recent trials have documented the efficacy of
preirradiation chemotherapy.
• This paradigm remains a promising area of research.

• For patients with progressive brain metastases after
radiation therapy, chemotherapy can be used based on
nonrandomized trials.
• Prevention strategies are beginning to emerge in clinical
trials.
• Primary prevention refers to the use of chemotherapy with
the goal of preventing the emergence of brain metastases in
patients at high risk for CNS metastases (e.g., triple negative
[ER negative/PR negative/HER2 negative] breast cancer
• Secondary prevention refers to the use of chemotherapy to
delay or prevent the outgrowth of new metastases following
the primary treatment of brain metastases with surgical
resection or SRS.

• At present, no standard cytotoxic chemotherapy exists
for the treatment of secondary brain tumours.
• Instead, the patients in whom the disease is not
amenable to local control with surgery or radiation are
typically treated using the same cytotoxic
chemotherapy employed for the treatment of
extracranial disease.
• Alternatively, cytotoxic agents with good CNS
penetration, such as topotecan, irinotecan,
procarbazine, and carboplatin, are also employed for
empiric therapy, even in cases in which these agents are
not the standard therapy for the primary tumour site.

Targeted theapies
• Deregulated EGFR and HER2 signalling in co
operation with activated HGFR (also known as c-
Met) pathway induce an epithelial-to-
mesenchymal phenotype transition, which can
promote increased metastatic potential and
higher likelihood of brain involvement.
• Increased longevity of patients with cancer
treated with targeted biological agents might also
increase the likelihood of brain meta-stasis over
the course of the disease.

Possible effects of targeted therapy on brain mets
• The eventuality from failure of the targeted agents to eradicate
micrometastatic deposits in the brain is due to limited penetration through
the BBB.
• There wil be selective pressure leading to the emergence of treatment-
resistant clones with increased capacity for invasion and meta stasis to distant
sites.
• Paradoxically, the limited penetration of some targeted therapies into the
brain could result in intracranial metastatic deposits that remain sensitive to
these agents, even in the context of the development of drug resistance
within the extracranial tumour compartments.
• Conversely, exposure of intracranial tumour deposits to subtherapeutic drug
concentrations might promote the early development of drug resistance and
isolated disease progression in the brain, while the extra-cranial disease
remains sensitive to treatment.

• Leptomeningeal metastases (LM) or neoplastic meningitis represents
a devastating, serious complication of the CNS in patients with
advanced solid or hematologic malignancies.
• Because LM is often underdiagnosed, treatment is mostly palliative
• Early detection and treatment can result in stabilization and
prevention of neurologic deterioration, which may improve quality of
life.
• As LM from solid tumors is often associated with an advanced stage
of systemic disease, the prognosis is poor with median survival of 2 to
3 months and 1-year survival of 15%.
• For patients with leukemic and lymphomatous meningitis, the
outcomes are better.

Epidemiology
• Approximately 5% to 15% of patients with cancer are
diagnosed with this complication.
• The incidence 0.8% to 8 % of LM varies depending on the
type of primary cancer and stage of disease.
• For patients with solid tumors, LM is estimated to occur in
5% to 18% of patients.
• For patients with hematologic cancers such as leukemia and
lymphoma, the incidence is 5% to 15% compared to 1% to
2% for patients with primary brain tumors, who appear to
have the lowest incidence.
• In autopsy series, the estimated rate of LM has been
reported as high as 19%.

Clinical Presentation
• LM can easily be overlooked given the subtle signs and symptoms.
• Cranial nerves, spine, nerve roots, and brain may be affected
• Symptoms and signs may occur such as headache, altered mental status,
nausea/vomiting, seizures, difficulty swallowing, visual loss, facial
numbness, focal weakness, and abnormalities of bowel and bladder
function.
• Greater than 50% of patients have spinal cord dysfunction as the primary
presenting symptom followed by cranial neuropathies, hemispheric
defects and nonfocal presentations.
• For patients with hydrocephalus due to obstruction of the cerebral
aqueduct or the arachnoid granulations, placement of an external
ventricular drain and/or ventriculoperitoneal shunt may be used.

Diagnosis of leptomeningeal mets
• Because the diagnosis of LM is difficult, a thorough neurologic
history and physical examination, contrast-enhanced MRI of the
brain, and examination of the CSF are important in establishing the
diagnosis of LM.
• In addition to history and physical examination, a sign and
symptom–directed contrast-enhanced MRI of the spine should be
completed.
• Radiographic presentations may include hydrocephalus without an
identifiable intracranial lesion, partial or full obstruction of CSF flow,
and leptomeningeal enhancement.
• Approximately 50% of patients with LM and spinal symptoms have
abnormal imaging studies using gadolinium-enhanced MRI.
• In addition, imaging may be the only positive diagnostic modality in
40% of cases.

• Examination of the CSF, which is usually performed via high-
volume lumbar puncture, represents the sole diagnostic
criteria for LM in approximately one-half of cases.
The CSF is examined for ::
• opening pressure
• Appearance
• Glucose
• Protein
• White and red blood cell counts with differential
• Cytology or flow cytometry.
• Unfortunately, cytologic evaluation of the CSF is an
insensitive test with 40% to 50% of patients having negative
CSF cytology.

• Given the rapid degradation of malignant cells, CSF samples
should be processed quickly.
• In addition, adequate amounts of CSF (at least 10 mL, 1 to 2 mL,
and 1 to 3 mL) should be sent for cytologic examination, flow
cytometry, and routine studies, respectively.
• For patients with leukemia or lymphoma, flow cytometry allows the
earlier detection of LM before the onset of clinical symptoms and
CSF pleocytosis and has superior sensitivity compared to standard
cytology.
• If the initial examination of the CSF is negative, up to two repeat
CSF examinations should be performed to increase diagnostic
sensitivity.
• Some biochemical markers such as CA 27.29 for breast cancer and
CA-125 for ovarian cancer can be useful to help make diagnosis of
LMD.

Radiation Therapy
• Radiation therapy provides effective palliation in many cases of LM,
particularly in areas of bulk disease, obstruction of CSF flow, and
symptomatic sites and regions.
• It is also useful for patients with cranial neuropathies and cauda equina
syndrome.
• Craniospinal irradiation (CSI) is generally not recommended given the
potential toxicities of CSI and previous radiation treatment that may
have encompassed the brain or spine.
• In addition, the volume of bone marrow irradiated with CSI may
preclude the use of future bone marrow suppressing chemotherapy.
• As a result, the use of involved field radiation therapy possibly followed
by intrathecal chemotherapy is generally recommended given the
complementary nature of both treatments.

Intra–Cerebrospinal Fluid Chemotherapy
• Given the BBB, the best approach to administer chemotherapy
within the leptomeningeal space without bulky disease is
through an intraventricular access device .
• Device such as an implanted subcutaneous reservoir and
ventricular catheter (Ommaya reservoir)
• Intrathecal delivery via lumbar puncture is an alternative.
• Intra-CSF chemotherapy with agents such as cytarabine and
methotrexate has limited systemic toxicity and allows for more
uniform distribution and therapeutic levels of drug in the
subarachnoid space
• It is used for the treatment and prevention of LM from both
solid and hematologic tumors.

• A limitation of this approach is impaired or obstructed
CSF flow from bulky meningeal disease.
• Bulky meningeal disease, which impairs or obstructs CSF
flow, may be reversed with local irradiation.
• Generally, radiation therapy is delivered prior to intra-
CSF therapy.
• Based on limited and older data, radiation therapy and
intra-CSF therapies are not delivered concurrently
secondary to concerns of increased neurotoxicity.
• Commonly used intrathecal chemotherapy agents
include methotrexate, cytarabine, liposomal form of
cytarabine, and thiotepa.

Complications associated with intra-csf chemotherapy
• Treatment-related meningitis that most frequently presents as a
chemical arachnoiditis.
• Fewer than 10% of patients experience bacterial meningitis, usually
with Gram-positive organisms.
• Myelosuppression can occur with high-dose methotrexate and
thiotepa.
• Migration or malposition of the catheter and catheter obstruction
can also occur including a 1% risk of postoperative hemorrhage.
• A small percentage of patients may experience chemotherapy-
related leukoencephalopathy, which appears to occur most
commonly in patients who receive intrathecal methotrexate
following cranial irradiation.

Systemic Chemotherapy and Other Agents
• Unlike most water-soluble drugs, high-dose systemic administration
of methotrexate results in therapeutic drug levels in the CSF.
• As a result, high-dose methotrexate is active in neoplastic meningitis
in lymphoma and in some solid tumors.
• High-dose intravenous methotrexate administration is active even
when there is obstruction of CSF flow, which can sometimes
compromise the subarachnoid administration of drugs.
• High-dose methotrexate administration requires detailed inpatient
monitoring of fluid status and renal function, urine alkalinization, and
leucovorin rescue, which makes this approach not appropriate or
practical for all patients.
• Other agents that have been investigated include rituximab for
lymphomatous meningitis, topotecan for lung cancer, trastuzumub for
breast cancer, and etoposide for SCLC in germ cell tumors.

Recommendations
Diagnosis
• When neurological symptoms and/or signs develop in a
patient with known systemic cancer, brain metastases
must always be suspected.
• Careful medical history and physical examination with
emphasis on the presence/activity of the systemic
disease and the general physical condition (estimation
of the performance status) are recommended (GPP).
• CT is inferior to MRI (Level B), but it is sufficient when it
shows multiple brain metastases.

• Contrast-enhanced MRI is indicated when:
(a) surgery or radiosurgery are considered for one
or two metastases on contrast-enhanced CT and a
KPS ≥ 70
(b) contrast-enhanced CT is negative but the history
is strongly suggestive for the presence of brain
metastases in a patient with established malignant
disease
(c) CT is not conclusive to eliminate non-neoplastic
lesions (abscesses, infections, demyelinating
diseases, vascular lesions)

• Diffusion MRI is useful for the differential diagnosis of
ring-enhancing lesions (Level C).
• EEG is indicated where there is suspicion of epilepsy,
but there remains clinical uncertainity (GPP).
•
• Tissue diagnosis (by stereotactic or open surgery)
should be obtained when:
(a) the primary tumour is unknown
(b) the systemic cancer is well controlled and the
patient is a long-term survivor
(c) lesions on MRI do not show the typical aspect of
brain metastases
(d) there is clinical suspicion of an abscess (fever,
meningism) (Level B).

In patients with unknown primary tumour, CT of the
chest/ abdomen and mammography are recommended
But a further extensive evaluation is not appropriate in the absence
of specific symptoms or indications from the brain biopsy (GPP).
FDG PET can be useful for detecting the primary tumour (GPP)
• The histopathologic studies on the brain metastasis may provide
valuable information in indicating a likely organ of origin and
guiding further specialized diagnostic work-up: in this regard
immunohistochemical staining to detect tissue-, organ-, or tumour-
specific antigens is useful (GPP).
• CSF cytology and contrast enhanced MRI of the spine are needed
when the coexistence of a carcinomatous meningitis is suspected
(GPP).

Supportive care
• Dexamethasone is the corticosteroid of choice and twice-daily
dosing is sufficient (GPP).
• Starting doses should not exceed 4–8 mg per day, but patients with
severe symptoms, including impaired consciousness or other signs
of increased intracranial pressure, may benefit from higher doses
(≥16 mg/day) (Level B).
• An attempt to reduce the dose should be undertaken within 1 week
of initiation of treatment; if possible, patients should be weaned off
steroids within 2 weeks.
• If complete weaning off is not possible, the lowest possible dose
should be looked for.
• Asymptomatic patients do not require steroids. Steroids may
reduce the acute side effects of radiation therapy. All
recommendations are Good Practice Points.

• AEDs should not be prescribed prophylactically (Level A).
• In patients who suffer from epileptic seizures and need a concomitant
treatment with chemotherapeutics, enzyme-inducing antiepileptic drugs
(EIAEDs) should be avoided (Level B).
• In patients with venous thromboembolism low molecular weight heparin
is effective and well tolerated for both initial therapy and secondary
prophylaxis (Level A).
• A duration of the anticoagulant treatment ranging from 3 to 6 months is
recommended (GPP).
• Prophylaxis in patients undergoing surgery is recommended (Level B).

Treatment of single brain metastasis
• when the size is large, the mass effect is considerable, and an
obstructive hydrocephalus is present (GPP).
• Surgery is recommended when the systemic disease is absent/
controlled and the Karnofsky Performance score is 70 or more (Level
A).
• When the combined resection of a solitary brain metastasis and a
non-small-cell lung carcinoma (stage I and II) is feasible, surgery for
the brain lesion should come first, with a maximum delay between
the two surgeries not exceeding 3 weeks (GPP).
• Patients with disseminated but controllable systemic disease (i.e.
bone metastases from breast cancer) or with a radioresistant primary
tumour (melanoma, renal cell carcinoma) may benefit from surgery
(GPP).
• Surgery at recurrence is useful in selected patients (Level C).

• Stereotactic radiosurgery should be considered in patients with
metastases of a diameter of ≤3–3.5 cm and/or located in eloquent
cortical areas, basal ganglia, brainstem, or with comorbidities
precluding surgery (Level B).
• Stereotactic radiosurgery may be effective at recurrence after prior
radiation (Level B).
• WBRT alone is the therapy of choice for patients with active systemic
disease and/or poor performance status and should employ
hypofractionated regimens such as 30 Gy in 10 fractions or 20 Gy in
five fractions (Level B).
• For patients with poor performance status supportive care only can
be employed (GPP).
• Following surgery or radiosurgery, in case of absent/ controlled
systemic disease and Karnofsky Performance score of 70 or more, one
can either withhold adjuvant WBRT if close follow-up with MRI
(every 3–4 months) is performed or deliver early WBRT with fractions
of 1.8–2 Gy to a total dose of 40–55 Gy to avoid late neurotoxicity
(GPP).

Treatment of multiple brain metastases
• In patients with up to three brain metastases, good
performance status (KPS of 70 or more) and controlled
systemic disease, stereotactic radiosurgery is an alternative
to WBRT (Level B)
• surgical resection is an option in selected patients (Level C).
• In patients with more than three brain metastases WBRT
with hypofractionated regimens is the treatment of choice
(Level B)
• For patients with poor performance status supportive care
only can be employed (GPP).
• Targeted therapies can be employed in patients with brain
metastases recurrent after radiation therapy (GPP).

Chemotherapy
• Chemotherapy may be the initial treatment
for patients with brain metastases from
chemosensitive tumours, like small-cell lung
cancers, lymphomas, germ cell tumours, and
breast cancers, especially if asymptomatic,
chemo-naïve, or an effective chemotherapy
schedule for the primary is still available
(GPP).

Finally…
Why treatment of cancer is so difficult ?
Answer is simple, the deception.
The language of cancer is grammatical, methodical and
to say frankly, is beautiful.
Genes talk to genes and pathways to pathways in a perfect
pitch, producing a familiar yet foreign music that rolls
faster and faster into a lethal rhythm.
Underneath what might seem like overwhelming diversity
is a deep genetic unity.
Cancer is really a pathway disease

But as the old proverb runs, there are
mountains beyond mountains………
…….Equally we humans have HOPE
beyond what at present we think is possible !!

Approach to the patients with brain metastases

Approach to the patients with brain metastases

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