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

INDIAN EPIDEMIOLOGICAL DATA

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 fingerprotein 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

Clinical features

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.

Investigations 

• 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

TREATMENT

Medical Management

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.

SURGERY +RADIATION

 RADIATION

SURGERY +RADIATION

 RADIATION

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.

Radiation therapy

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 Wisconsin have 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• To improve survival, delay progression, and

preserve or improve a patient’s function and quality of life

• The enhancement of efficacy of radiation therapy (radiosensitization)

• The delay for the need of radiation therapy

• The simultaneous control of systemic disease

• The ability to address the entire brain parenchyma in patients who may already have received WBRT.

• One final goal is to treat the leptomeninges in the setting where intrathecal chemotherapy is likely to be ineffective .

• Bulky leptomeningeal disease given the limited penetration of intrathecal chemotherapy into leptomeningeal deposits)or unsafe due to unpredictable cerebrospinal fluid (CSF) distribution (e.g., impaired CSF flow related to obstructive hydrocephalus). 

• For example, high-dose intravenous methotrexate for the treatment of breast cancer brain and/or leptomeningeal disease can reach the CSF in cytotoxic concentrations. 

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.

Prognosis

Leptomeningeal metastasis

• 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 !!