Management of Metastatic
Brain Tumours
Bruno Arekhandia
Outline
• Introduction
• Epidemiology
• Aetiology/sources
• Pathophysiology
• Pathology
• Clinical features
• Investigation
• Differential diagnosis
• Treatment
• Follow-up
• Prognosis
• Local challenges
• Conclusion
Introduction
• Metastases of neurosurgical importance:
• brain, spinal cord, peripheral nerves, meninges, skull and vertebrae
• intracranial metastases → skull, meningeal spaces and brain parenchyma
• cerebral metastasis ≈ brain metastasis
• Most common brain tumour seen clinically (in adults)
• Definition1
• solid metastases to the brain from systemic cancer
• excludes leptomeningeal metastatic disease (LMD)
• excludes direct invasion from adjacent tissues
1: CONGRESS OF NEUROLOGICAL SURGEONS SYSTEMATIC REVIEW AND EVIDENCE-BASED GUIDELINES FOR THE TREATMENT OF ADULTS WITH METASTATIC BRAIN TUMOURS
Epidemiology
Incidence
True incidence is unknown
Increasing in incidence
25% at autopsy
Age/source
Children: (6% of paediatric cancers) leukemia > lymphoma > sarcoma > GCTs
Adults (5th – 7th decade) → lung, breast, unknown, kidney, GI, melanoma
Gender
M≈F
Racial predilection
Same incidence for all races
Site
Cerebrum (80%) > cerebellum (16%) > brainstem (3%)
Aetiology/sources
• Adults
• Lung (44%) > breast (10%) ≈ unknown (10%) > kidney+ (7%) > GI (6%) >
melanoma (3%)
• Risk of developing cerebral metastasis:
• malignant melanoma > lung ca. (SCLC and adenocarcinoma > squamous cell carcinoma) >
breast ca. > leukaemia > lymphoma
• Children
• Sources: leukemia, lymphomas, osteogenic sarcomas, rhabdomyosarcoma,
Ewing sarcoma, neuroblastoma, Wilm’s tumour
• ≤15yr → leukemia > lymphoma > sarcomas
• >15yr → GCTs
• Specific metastases
•
•
•
•
small-cell carcinomas (20% lung cancers) account for 50% BM from lung ca.
in patients with newly diagnosed NSCLC, 30 – 50% will develop BM
66 – 75% melanomas give BM
melanoma: most prone to spread to brain, most often multifocal and has a
unique tendency to haemorrhage
• prostate ca. rarely metastasizes to brain; frequently to spine
• unknown: most often adenocarcinomas or squamous cell carcinomas
• 11% mass lesions in patients with cancer are not metastases
Pathophysiology
• The process by which a tumor cell leaves its primary tumour, travels
through the vasculature, and ends up in the brain to proliferate and
cause neurologic injury → death
Pathophysiology
Escape/intravasation
A complex set of interactions that allow the tumour clones break free from the
primary tumour and enter the vasculature.
1Reduced
intercellular adhesion and disordered cytoarchitecture; 2ECM
degradation to clear a pathway for invasion
Vascular dissemination
Most spread haematogenously (arterial and venous)
Arrest/extravasation
A complex set of interactions that allow the tumour clones that have invaded the
blood stream to arrest at a secondary site and extravasate from the vasculature to
establish a metastasis in a new organ.
Neurotropism: yet undiscovered brain-specific homing capacity within the tumour
cells that result in brain metastasis.
BBB breakdown: unknown; related genes
Metastatic clone proliferation
Deposit
At the GWMJ/watershed zones; within the end vessels
Reflects its tissue volume and rate of blood flow; frontal and parietal
Size of emboli
Intratumoural changes
Angiogenesis: VEGF-B → leading to leaky vascular networks
Necrosis: growth in size outstrip their available blood supply
Rare: seeding of a pre-existing metastatic deposit by circulating organisms
Peri-tumoural changes
Vasogenic oedema
Compressive: vascular, cranial nerves, parenchyma
Irritative
Changes in intracranial dynamics
RICP (compensated → decompensated)
Pathology
Number of lesions
1 tumour: single tumour
2 – 3 tumours: oligometastases
4 – 8 tumours: diffuse multifocal disease
≥ 9 tumours: miliary disease
Single brain tumour: one brain lesion with at least one other site of extracranial disease
Solitary brain tumour: one brain lesion without evidence of extracranial metastasis
Location
As discussed earlier
Macroscopy
Well-demarcated from the surrounding parenchyma, and usually, there is a zone of
peri-tumoural edema out of proportion with the tumour size
Adenocarcinomas (± collections of mucoid material), haemorrhage (relatively frequent
in metastases of choriocarcinoma, melanoma, RCC, thyroid), melanoma (brown to black
colour)
Histopathology
Diverse as in primary tumours from which they arise
IHC
Similar to tumours from which they arise
Lung cancer
Melanoma
Clinical features
• Asymptomatic versus symptomatic
• Symptomatic
• acute (acute HCP, tumour TIA) versus chronic
• Focal versus global (↑ICP)
• Timing of clinical presentation
• Brain metastasis versus primary tumour
• Brain metastasis versus patient’s functional status (ability to physically
perform activities such as self-care, being mobile, and independence
at home or in the community) (KIV status of primary malignancy)
Clinical features
• The clinical presentation of a metastasis reflects the location and
size of the tumour, status of the primary malignancy
Symptoms and signs
Due to raised ICP
Mass effect, HCP (49%)
Focal deficits
Parenchyma, cranial nerves, vascular involvement
Focal weakness (30%), speech difficulty (18%), gait ataxia (21%), visual
disturbance (6%), sensory disturbance (6%)
Seizures (10 – 18%)
Mental status changes
Impaired cognition (58%)
Symptoms suggestive of a TIA
(“tumor TIA”)
Vascular occlusion, haemorrhage, infarction (tumour embolus)
Asymptomatic
60 – 75% at the time of imaging
Precocious
BM discovered before the evidence of primary disease (e.g., lung ca.)
Synchronous
BM discovered at the same time as primary tumour diagnosis
Metachronous
BM discovered during/after treating the 1o cancer
NB
Metachronous > synchronous or precocious
KARNOFSKY PERFORMANCE STATUS SCALE DEFINITIONS RATING (%) CRITERIA
Able to carry on normal activity and to
work; no special care needed.
Unable to work; able to live at home and
care for most personal needs; varying
amount of assistance needed.
100
Normal no complaints; no evidence of disease.
90
Able to carry on normal activity; minor signs or symptoms of disease
80
Normal activity with effort; some signs or symptoms of disease
70
Cares for self; unable to carry on normal activity or to do active work.
60
Requires occasional assistance, but is able to care for most of his personal needs.
50
Requires considerable assistance and frequent medical care
Unable to care for self; requires
40
equivalent of institutional or hospital care;
30
disease may be progressing rapidly.
20
Disabled; requires special care and assistance.
10
Moribund; fatal processes progressing rapidly
0
Dead
Severely disabled; hospital admission is indicated although death not imminent.
Very sick; hospital admission necessary; active supportive treatment necessary.
WHO/EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) [THE ECOGACRIN CANCER RESEARCH GROUP] PERFORMANCE STATUS
Grade
ECOG performance status
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a
light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities; up and
about more than 50% of waking hours
3
Capable of only limited self-care; confined to bed or chair more than 50% of waking hours
4
Completely disabled; cannot carry on any self-care; totally confined to bed or chair
5
Dead
Investigations
• Patient
• Imaging/cytological examination of neuraxis
• Adjunct investigations
• Search for systemic cancer
• Biopsied specimen
• Histopathological/molecular tests
Imaging/cytological examination of the neuraxis
Investigation
Findings
Contrast brain CT
Screening in acute presentation
Many are invisible (isodense) → underestimation
Brain MRI +
gadolinium
Most are isointense on T1WI and hyperintense on T2WI; altered by haemorrhage,
calcification
T1 + C: different enhancement patterns
If MRI is normal → repeat with triple-dose gadolinium in 1 month.
MRI spectroscopy
Chamber’s rule applies: “Whoever counts the most metastases is right.”
FDG-PET
Value is highly questionable
CSF
Cytological examination in leptomeningeal metastases reveals malignant cells
Biopsy
Timing
Solitary: need for biopsy → histologic verification
Cf. 11% of single brain lesions thought to be metastases on CT → different pathology.
Multiple BM: no need for pre-op biopsy
Histology stain
S-100: Melanoma, sarcoma
HMB-45: Melanoma
Melanoma: S-100, HMB-45, and microphthalmia transcription factor (MITF)
Keratin: carcinomas
CEA: adenocarcinoma, thyroid medullary carcinoma, squamous carcinoma
Oestrogen and progesterone receptors: breast and uterus
Adjunct investigations
Complete blood count
Electrolyte panel
Coagulation screen
Liver function panel
Specific markers: CEA, PSA, CA125 (ovarian), CA15-3 (breast), AFP, HCG, LDH
Search for systemic cancer (CUP)
Stool guaiac
Gynaecologic/pelvic examination (incl. testicles). TVUSS.
Skin and thyroid examination
Chest radiography if negative → chest CT; if negative → CT of abdomen-pelvis
Mammogram
Whole-body FDG-PET/CT
Radionuclide bone scan
Differential diagnosis
Primary brain neoplasm especially glioblastoma
Cerebral abscess
Subacute stroke
Meningioma
Post-treatment effects (post-surgical or post-radiation)
Brain metastasis
Tuberculomas
Radionecrosis
Demyelination
Resolving contusion
GBM
Stroke
Cerebral toxoplasmosis
PCNSL
Treatment
• Preamble
• Evolution* from past to modern treatment
• Complex → multidisciplinary*
• Symptomatic* versus definitive* versus palliative*
• Symptomatic: ASMs/AEDs,
• Definitive: WBRT, surgical resection, SRS, chemotherapy, emerging therapy
• Evidence-based medicine*
• Algorithms*
Evolution of Modern Treatment
Evolution of Modern Treatment – surgery
• Late 19th century: clear recognition of BM (Hare A.W.)
• Mid-1920s – early 1930s:
• BM established as a separate entity from other brain tumours
• surgery not of any permanent value (Grant); beneficial in the condition of urgent ↑ICP
• long-term survivors of BMs after surgical resection (Oldberg)
• 1930s – 1980s:
• surgery for BM uncommon (prior to the emergence of modern imaging techniques)
• limited role of surgical resection with trivial survival gains (median survival < 6 months)
• unacceptable postoperative mortality (10–30%)
• 1990s:
• the benefit of surgical resection of single brain metastasis in combination
with adjuvant WBRT was validated for the first time in a randomized tria
Evolution of Modern Treatment – XRT
• Late 1920s
• XRT for BM might have been tried
• 1931
• palliative effect of XRT in breast ca. patients with ↑ ICP due to BM (Lenz and Freid)
• 1954
• first systematic analysis of WBRT for brain metastases management was performed.
WBRT recommended as a primary treatment for BM based on its good palliative
effect shown in > 60% of the cases
• 1980s
• Radiation Therapy Oncology Group (RTOG) undertook a series of controlled trials to
determine the best dosage and schedule of WBRT for the treatment of BM → 30 Gy
in 10 fractions
Evolution of Modern Treatment – chemotherapy
• Historically,
• chemotherapy for BM has been reserved as salvage therapy with little expectations
for survival benefit
• 1945
• availability of chemotherapeutic agents to treat systemic cancer
• 1952
• ineffectiveness and toxicity of intracarotid administration of nitrogen mustard
• Since 1990s
• application of BBB permeable drugs such as TMZ
• combination with XRT either (concomitant or adjuvant)
• development of targeted agents
Evolution of Modern Treatment – steroids
• 1957
• the first report of a steroid effect on BM – in the improvement of neurological
symptoms
• 1961
• demonstration of steroids being effective for reducing brain oedema from
brain tumours by (Galicich and French)
• There are several early studies showing that steroid treatment can
improve QoL and achieve a slight survival gain (1 or 2 months) in BM
patients
Evolution of Modern Treatment – Radiosurgery
• The application of SRS for BM is a relatively recent event cf. to other treatment
strategies for BM
• 1949
• introduction of Leksell frame (Lars Leksell)
• 1951
• development of the concept of radiosurgery (Lars Leksell and Borje Larsson) → prototype
Gamma Knife prototype Gamma Knife in 1968
in 1968
• 1987
• the first series of 12 patients with BM successfully treated by radiosurgery using a linear
accelerator (Sturm et al.)
• 1990s
• retrospective studies have shown that radiosurgery is effective at controlling BM and
prolonging survival (median survival from 8 to 13.5 months)
• Late 1990s
• aside from the limitation of target size, lesion numbers and certain critical
locations, radiosurgery has rapidly taken over the primary management of BM
in selected patients
• non-invasive, outpatient procedure and excellent local control rate
• Late 2000s
• comparison between radiosurgery alone and WBRT alone, published
• overall, single-dose radiosurgery alone appears to be superior to WBRT alone for
patients with small metastatic BM of ˂ 3 lesions in terms of patient survival advantage
Evolution of Modern Treatment – Multimodal Rx
• 1990s
• effectiveness of diverse combinations of multimodal treatment for brain metastases was
documented in several randomized controlled studies and multiple retrospective studies
• Combinations
•
•
•
•
Surgery + WBRT ˃ surgery alone in patients with good PS
Surgery + WBRT ˃ WBRT alone in patients with good PS
Radiosurgery + WBRT ˃ WBRT alone
Surgery + Radiosurgery
• Key role: radiosurgery → easily combined/ does not interrupt other treatment schedules
• selection of the management strategies should be personalized taking size, number and
location of the lesions, and performance status of the patients
• Present day
• Flexible personalized application of multimodal treatment is the widely accepted current
and future management strategy
Treatment of BM – Evidence Based Medicine
Treatment of BM – Evidence Based Medicine
Treatment of BM – Evidence Based Medicine
• There continues to be unanswered clinical questions in the area of
radiosurgery, postoperative radiation for single BM, and molecular targeted
agents for BM.
• For example, should there be a limit on the number of BM treated with
radiosurgery?
• Will molecular targeted agents help in terms of survival, brain control and QoL in the
management of BM?
• Will there be better pharmacologic agents used to improve symptoms in patients
with BM, such as drugs which reduce the symptoms of brain oedema without the
side effects of steroids or drugs which help with neuro-cognition?
• It is anticipated that further gains in the management of BM will come in
this decade and beyond as several of these questions become addressed in
future research trials
Symptomatic – Oedema
• Steroids
• Asymptomatic brain metastases without mass effect - insufficient evidence
exists to make a recommendation.
• Brain metastases with symptoms related to mass effect
• Level 3 recommendation: corticosteroids are recommended to provide
temporary relief of symptoms related to ↑ICP and oedema:
• mild symptoms - starting dose of 4 - 8 mg/d of dexamethasone
• moderate to severe symptoms - 16 mg/d of dexamethasone
• Level 3 recommendation: dexamethasone is the best DOC
• Generalized symptoms respond > focal symptoms and signs
Symptomatic – Seizures
• AEDs/ASMs
• Level 3 recommendation: prophylactic AEDs are not recommended for
patients with BMs who did not undergo surgical resection and are otherwise
seizure-free
• Level 3 recommendation: post-craniotomy AED use for seizure-free patients is
not recommended
• seizure prophylaxis (not necessary if no history of seizure; i.e. anticonvulsants
must be administered only to patients at risk for seizure)
• anticonvulsants should be started (routinely) before XRT/surgery
• most commonly used drugs: levetiracetam, phenytoin, carbamazepine,
valproic acid
Symptomatic – Others
• Anticoagulation
• Intracranial hemorrhage is frequently observed in patients with brain
metastases but therapeutic anticoagulation does not increase the risk of
intracranial hemorrhage
• Cognition
• There is increasing data to suggest that medications, such as methylphenidate
and donepezil, can improve cognition, mood and QoL in patients with brain
tumours
Definitive – WBRT
• Recognized as the mainstay of treatment for the most patients with
intraparenchymal metastases and widely available.
• XRT is recommended for both radiosensitive and moderately
radiosensitive metastases following surgery
• Commonly delivered to patients with:
• 1multiple BM, 2poor functional status, or 3active or disseminated systemic
disease with effective palliation of neurological symptoms and 4following
surgery
• WBRT can prolong median survival 3 – 6 months from 1 – 2 months
• The most common regimen employed is 30 Gy delivered in 3.0 Gy
fractions over 2 weeks
WBRT
SRS
• Radio-sensitizers have failed to show benefit in either local brain
tumour control or overall survival in RCTs
• commonly: lonidamine, metronidazole, misonidazole, motexafin, gadolinium
and bromodeoxyuridine
• WBRT and low-dose TMZ (75mg/m2) daily has shown promising
response rates
• Significant risk of acute and long-term complications.
• Acutely, fatigue, headache, nausea and vomiting may occur during and shortly
after treatment and neurologic deficits may be exacerbated
• Chronically, STM impairment (cf. hippocampal sparing modification), alopecia,
dementia, ataxia and urinary incontinence
Definitive – Surgery
• Metastasectomy
• Indications for surgical resection (in patient with good performance
status):
• solitary metastasis > 3 cm (lesions ≤ 3 cm: better SRS unless tissue diagnosis is
needed)
• life-threatening strategically located metastasis (e.g. cerebellar lesion with
ventricular obstruction) (steroid-resistant neurological symptoms) despite
other multiple cerebral metastases (symptomatic lesion is resected, for
remaining lesions → XRT)
• need for tissue diagnosis
• Pre-requisites
• lesion in non-eloquent area
• limited number of lesions
• limited and/or controlled systemic disease
N.B. extracranial metastases is important independent predictor of mortality
i.e. most patients succumb to systemic cancer rather than intracranial lesion –
may mask benefit of surgery!
• Karnofsky score > 70 (able to function independently)
• life expectancy > 6 months
• Contraindications
• radiosensitive tumour (e.g. small-cell lung tumor, GCT, lymphoma / leukemia /
multiple myeloma, choriocarcinoma)
N.B. non-small cell lung metastases are mostly radio-resistant – may benefit
from surgery!
• life expectancy < 3 months (WBRT indicated)
• multiple lesions
• leptomeningeal disease
Definitive – SRS
• Gamma Knife, linear accelerator and proton beam achieve their effects by
treating a discrete tumour with a high volume of radiation
• Indicated for surgically inaccessible lesions
• A reasonable treatment option in patients with:
• up to 3 metastatic lesions in selected patients regardless of extracranial disease
status
• ≥ 4 metastases, with no extracranial disease
• Limited to tissue volumes no greater than 3 cm in diameter
• Major drawback → its biological effect of “radionecrosis” (in 4–6% of
patients within 1–2 weeks of treatment)
• Median survival is extended to about 10 months
Definitive – Chemotherapy
• Limited at present
• Reserved for patients who have failed other treatment modalities or
for “chemosensitive” diseases
• Methods to reduce systemic toxicity
• intra-arterial infusions, intrathecal administration, direct placement of drug
into tumour
• NB: ?reason for ineffectiveness → local BBB breakdown present in
BM/lipid soluble agents not effective
• TMZ for recurrent BM, esp. NSCLC ; synergism with WBRT has shown
promise
Palliative
• Caregiver and patient perspectives
• Specialty palliative care (PC) clinicians assist oncologists, neurologists, and
surgeons in addressing complex QoL issues for patients with BM
• Assessment of intervention and symptom management options, planning
end-of-life care, and prioritizing goals
• PC improves patients’ understanding of their disease and prognosis,
facilitating advance care planning, and coping
• Corticosteroids, anticonvulsants, radiotherapy, surgery, radiosurgery
and chemotherapy
Brain lesion on MRI suggestive of metastasis
Metastatic work-up
Known cancer
Not sure of brain metastasis
No primary
Stereotactic biopsy/resection
Metastatic tumour confirmed
Primary found
Single brain metastasis on MRI
Mass effect
No mass effect
Non-lobar, non-resectable
Lobar, resectable
Resection
Complete Resection
SRS ± WBRT
Residual tumour
Tumour bed SRS/XRT
Tumour recurrence
Local
Resection/repeat SRS
New lesions
SRS/WBRT
Limited brain metastasis on MRI
Confirm limited number of BM with high-resolution, thin-slice, double dose
contrast enhanced MRI. Assess systemic disease and functional status.
v
Good
Radio-sensitive
Poor
Radio-resistant
SRS alone
SRS ± WBRT
WBRT ± SRS boost
Tumour progression
Local
New lesions
Repeat SRS
SRS/WBRT
Multiple brain metastasis on MRI
Conventional management
Emerging strategies
WBRT
SRS ± WBRT
Tumour progression
Tumour progression
SRS
Limited WBRT boost
Repeat SRS
Limited WBRT boost
Treatment of brain metastasis – summary
• The optimal treatment of BMs must consider several factors,
including the:
•
•
•
•
•
patient’s neurologic and general medical condition,
number, location and size of the lesions,
histology,
extent,
prior treatment and the response to treatment of the systemic disease
• Two current trends in the approach to BM are evident:
• a shift from mere palliation of symptoms to tumour eradication, in an effort
to improve survival, and
• an increased emphasis on the patient’s quality of life
Follow-up
• MRI every 2–3 months for one year, then every 3-4 months (less
frequent beyond 2 years if both are present – no relapse before 2
years and tumor total volume < 5 mL)
• Univ of Pittsburgh protocol: MRI every 3 mo for the first year of
follow-up, every 4 mo for year 2, then every 6 mo thereafter, with
limited consensus beyond 4 to 5 yr.
Prognosis
• Factors associated with improved prognosis:
• High Karnofsky score (> 70)
• Age < 60 yrs
• Number and location of CNS metastases (one BM - improved QoL, survival
benefit from surgical resection or radiosurgery).
• Sensitivity of tumour to therapy
• No systemic disease or systemic disease controlled
• No systemic metastases within 1 year of diagnosis of primary lesion
• Female patients
• Most important factor for decision making – status of extracranial
disease
• Role of treatment modality
• [Surgical resection and WBRT - 36 months, surgical resection - 22 months, SRS
and WBRT - 16 months, SRS - 11 months, WBRT - 6 months, Untreated - 1
month (can be doubled by corticosteroids)]
• Role of tumour site
• Role of number of metastases
Median survival: tumour site
• Median survival: tumour site
•
•
•
•
•
•
Breast: 13 months [3 – 25]
NSCLC: 7 months [3 – 14]
SCLC: 5 months [2 – 17]
Melanoma: 6 months [3 – 13]
Renal cell: 9 months [3 – 14]
GI: 5 months [3 – 13]
Local Challenges
• Patient-based
• Healthcare system based
Conclusion
• BMs are a common and unfortunate complication of cancer, with
significant impact on patients’ QoL and function
• Decision-making
• Poor functional status, significantly advanced disease burden, and
multiple metastases/LMD → symptomatic/palliative treatment
• Good functional status and a single metastatic lesion → surgical resection or
SRS depending on the location of the lesion
• Multiple lesions → WBRT
• Flexible personalized application of multimodal treatment is the
widely accepted current and future management strategy
THAnK YǑU
WBRT
SRS
• Radio-sensitizers have failed to show benefit in either local brain
tumour control or overall survival in RCTs
• commonly: lonidamine, metronidazole, misonidazole, motexafin, gadolinium
and bromodeoxyuridine
• WBRT and low-dose TMZ (75mg/m2) daily has shown promising
response rates
• Significant risk of acute and long-term complications.
• Acutely, fatigue, headache, nausea and vomiting may occur during and shortly
after treatment and neurologic deficits may be exacerbated
• Chronically, STM impairment (cf. hippocampal sparing modification), alopecia,
dementia, ataxia and urinary incontinence
Definitive – Surgery
• AKA metastasectomy
• Indications for surgical resection (in patient with good KPS):
• solitary metastasis > 3 cm (lesions ≤ 3 cm: better SRS unless tissue diagnosis is
needed)
• life-threatening strategically located metastasis (e.g. cerebellar lesion with
ventricular obstruction) (steroid-resistant neurological symptoms) despite
other multiple cerebral metastases (symptomatic lesion is resected, for
remaining lesions → XRT)
• need for tissue diagnosis
• Pre-requisites
• lesion in non-eloquent area
• limited number of lesions
• limited and/or controlled systemic disease
N.B. extracranial metastases is important independent predictor of mortality
i.e. most patients succumb to systemic cancer rather than intracranial lesion –
may mask benefit of surgery!
• Karnofsky score > 70 (able to function independently)
• life expectancy > 6 months
• Contraindications
• radiosensitive tumour (e.g. small-cell lung tumor, GCT, lymphoma/leukemia
/multiple myeloma, choriocarcinoma)
N.B. non-small cell lung metastases are mostly radio-resistant – may benefit
from surgery
• life expectancy < 3 months (WBRT indicated)
• multiple lesions
• leptomeningeal disease
Definitive – SRS
• Gamma Knife, linear accelerator and proton beam achieve their effects by
treating a discrete tumour with a high volume of radiation
• Indicated for surgically inaccessible lesions
• A reasonable treatment option in patients with:
• up to 3 metastatic lesions in selected patients regardless of extracranial disease
status
• ≥ 4 metastases, with no extracranial disease
• Limited to tissue volumes no greater than 3 cm in diameter
• Major drawback → its biological effect of “radionecrosis” (in 4–6% of
patients within 1–2 weeks of treatment)
• Median survival is extended to about 10 months
Definitive – Chemotherapy
• Limited at present
• Reserved for patients who have failed other treatment modalities or
for “chemosensitive” diseases
• Methods to reduce systemic toxicity
• intra-arterial infusions, intrathecal administration, direct placement of drug
into tumour
• NB: ?reason for ineffectiveness → local BBB breakdown present in
BM/lipid soluble agents not effective
• TMZ for recurrent BM, esp. NSCLC; synergism with WBRT has shown
promise
Palliative
• Caregiver and patient perspectives
• Specialty palliative care (PC) clinicians assist oncologists, neurologists, and
surgeons in addressing complex QoL issues for patients with BM
• Assessment of intervention and symptom management options, planning
end-of-life care, and prioritizing goals
• PC improves patients’ understanding of their disease and prognosis,
facilitating advance care planning, and coping
• Corticosteroids, anticonvulsants, radiotherapy, surgery, radiosurgery
and chemotherapy
Brain lesion on MRI suggestive of metastasis
Metastatic work-up
Known cancer
Not sure of brain metastasis
No primary
Stereotactic biopsy/resection
Metastatic tumour confirmed
Primary found
Single brain metastasis on MRI
Mass effect
No mass effect
Non-lobar, non-resectable
Lobar, resectable
Resection
Complete Resection
SRS ± WBRT
Residual tumour
Tumour bed SRS/XRT
Tumour recurrence
Local
Resection/repeat SRS
New lesions
SRS/WBRT
Limited (2 – 4) brain metastasis on MRI
Confirm limited number of BM with high-resolution, thin-slice, double-dose
contrast enhanced MRI. Assess systemic disease and functional status.
v
Good
Radio-sensitive tumour
Poor
Radio-insensitive tumour
SRS alone
SRS ± WBRT
WBRT ± SRS boost
Tumour progression
Local
New lesions
Repeat SRS
SRS/WBRT
Multiple brain metastasis on MRI
Conventional management
Emerging strategies
WBRT
SRS ± WBRT
Tumour progression
Tumour progression
SRS
Limited WBRT boost
Repeat SRS
Limited WBRT boost
Treatment of brain metastasis – summary
• The optimal treatment of BMs must consider several factors,
including the:
•
•
•
•
•
patient’s neurologic and general medical condition,
number, location and size of the lesions,
histology,
extent,
prior treatment and the response to treatment of the systemic disease
• Two current trends in the approach to BM are evident:
• a shift from mere palliation of symptoms to tumour eradication, in an effort
to improve survival, and
• an increased emphasis on the patient’s quality of life
Follow-up
• MRI every 2–3 months for one year, then every 3-4 months (less
frequent beyond 2 years if both are present – no relapse before 2
years and tumor total volume < 5 mL)
• University of Pittsburgh protocol:
• MRI every 3 months for the first year of follow-up, every 4 months for year 2,
then every 6 months thereafter, with limited consensus beyond 4 to 5 yr.
Prognosis
• Factors associated with improved prognosis:
• High Karnofsky score (> 70)
• Age < 60 yrs
• Number and location of CNS metastases (one BM - improved QoL, survival
benefit from surgical resection or radiosurgery).
• Sensitivity of tumour to therapy
• No systemic disease or systemic disease controlled
• No systemic metastases within 1 year of diagnosis of primary lesion
• Female patients
• Most important factor for decision making – status of extracranial
disease
• Role of treatment modality
• [Surgical resection and WBRT - 36 months, surgical resection - 22 months, SRS
and WBRT - 16 months, SRS - 11 months, WBRT - 6 months, Untreated - 1
month (can be doubled by corticosteroids)]
• Role of primary tumour
• Role of number of metastases
Median survival: primary tumour
• Median survival: tumour site
•
•
•
•
•
•
Breast: 13 months [3 – 25]
NSCLC: 7 months [3 – 14]
SCLC: 5 months [2 – 17]
Melanoma: 6 months [3 – 13]
Renal cell: 9 months [3 – 14]
GI: 5 months [3 – 13]
Local Challenges
• Patient-based
• Healthcare system based
Conclusion
• BMs are a common and unfortunate complication of cancer, with
significant impact on patients’ QoL and function
• Decision-making
• Poor functional status, significantly advanced disease burden, and
multiple metastases/LMD → symptomatic/palliative treatment
• Good functional status and a single metastatic lesion → surgical resection or
SRS depending on the location of the lesion
• Multiple lesions → WBRT
• Flexible personalized application of multimodal treatment is the
widely accepted current and future management strategy
THAnK YǑU