MANAGEMENT OF BRAIN

METASTASIS

Presented by : Dr Jyotishna
Dania
Moderator: Dr Kushal Narang
Scheme of Presentation
• Introduction
• Epidemiology
• Pathophysiology
• Clinical Presentation
• Neurological Examination
• Investigations
• Treatment Modalities and Guidelines
INTRODUCTION
• Most common intracranial tumors in adults with an incidence of 35%
• Median time from primary diagnosis: 8.5 to 12 months

• Rising incidence due to

Increasing survival from recent advances in therapy
Greater availability and use of Magnetic Imaging Resonance
EPIDEMIOLOGY (Ref: Perez and Brady’s 7 th
edition)
PATHOPHYSIOLOGY
BIOLOGY OF BRAIN METASTASES
• In 2011 Eichler et al. published a Review on biology of brain
metastases in Clinical Oncology Journal, Nature – where he described
process of escape from a primary tumor site and colonization of the
CNS -
1. Arrest in primary capillary bed (due to size restriction)
2. Extravasation across BBB ( genes- HBEGF, COX2 and ST6GALNAC5)
3. Metastasizing tumor cells (seeds) may bring their own host
cells(soil)
4. Perivascular growth (growth along pre-existing blood vessels)
5. Neoangiogenesis
Markers found in metastatic brain lesions
SITE AND DISTRIBUTION OF BRAIN
METASTASES
• The site and distribution of brain metastasis is determined by various
tumor types and vasculature of the brain.
• Renal, colon and breast carcinoma generally produce single metastasis
whereas malignant melanoma and lung produce multiple metastases.
• 85% of brain mets- found in cerebral hemisphere- watershed area
between middle and posterior cerebral arteries
• 10-15% mets in cerebellum and 3% in brainstem
• Renal cell, gastrointestinal and pelvic cancers tend to metastasize to
infratentorial area, whereas breast ca is commonly found in posterior
pituitary
Classifications for Brain Metastases
CLINICAL PRESENTATION
Deviation of face- 7th Nerve palsy Left Lateral Rectus Palsy-6th

Gait ataxia, vertigo – Cerebellar Mets Right LPS palsy-3rd nerve#

Detecting location of brain lesions from
clinical presentation
Function/Dysfunction Likely site of metastases in brain
Decreased motor power Precentral gyrus of Frontal Lobe
Altered sensations Thalamus or Post central area of Parietal lobe
Speech abnormalities Broca’s and Wernicke’s Area
Visual Disturbance Occipital Lobe
Personality/ Behaviour change Frontal Lobe
Difficulty in smooth body movements Basal Ganglia
Disturbed homeostasis – Changes in body Hypothalamus
temperature, autonomic system, aggression, hormonal
changes
Change in emotional behaviour and memory Limbic system- Amygdala, Hippocampus
Imbalance, Nystagmus, Vertigo Cerebellum
Cranial Nerve Compression symptoms Brainstem
NEUROLOGICAL EXAMINATION
Higher Mental Examination
Cranial Nerve Examination
Motor System
Deep Tendon Reflexes
Sensation
Cerebellar function
HIGHER MENTAL FUNCTION
• Level of consciousness- Arousal and Awareness (Orientation)
• Glasgow Coma Scale (E,V,M)
• Concentration
• Memory (Immediate Recall, Short term and Long term memory)
• Language (Aphasia/Dysarthria, command following, fluency,
Repetition)
• Repetition screens for Receptive, Expressive and Conductive Aphasia
Glasgow Coma Scale
Detecting location of lesion from Cranial
nerve Examination
Presentation Cranial Nerve likely involved Site of brain likely involved
Change in smell Olfactory Nerve Cerebrum near cribrifom plate
Visual disturbance Optic Nerve Optic chiasma, near sella turcica,
occipital lobe
Nystagmus, Diplopia, Drooping of Occulomotor Nerve Midbrain
eyelid
Restriction in eye movements Occulomotor, Trochlear Nerve Midbrain
Abducent Nerve Pons-medullary Junction
Aletered sensations from face Trigeminal Nerve involvement Midbrain, Pons and medulla
Difficulty in chewing food
Deviation of face, Lagophthalmos Facial Nerve Pons-medullary Junction
Nystagmus, decreased hearing, Vestibulocochlear nerve Pons-medullary Junction
imbalance
Altered taste, difficulty swallowing, Glossopharyngeal Nerve Pons-medullary Junction
absent gag reflex
Palatal, pharyngeal and laryngeal Vagus Nerve Medulla
paralysis
Unable to shrug shoulders Spinal accessory nerve Medulla

Difficulty in speaking, swallowing Hypoglossal Nerve Medulla

(motor movement of tongue)
MOTOR EXAMINATION
CEREBELLAR FUNCTION ASSESSMENT
• Broad based gait
• Nystagmus
• Absence of rebound phenomenon ( when patient’s wrist pushed
down briskly)
• Hypotonia on side of cerebellar region
• Coordination test- Finger to nose test, Dysdiadochokinesia, Heal shin
test
Heel Shin Test Finger Nose test

Rebound Phenomenon
WORKUP
• Basic Investigations – Blood workup, Chest X Ray, USG Abdomen
• CNS Imaging:
 Modern Era of CNS Imaging began with introduction of CT in 1973 and with MRI in
1979
MRI is the investigation of choice
CT Scan:
contrast enhancement in CT scan helps to identify isodense tumor from
surrounding parenchyma and hypodense lesions in edematous areas,
offers lower cost,
shorter scanning time
more sensitive method to detect calcification and bony involvement
- Calcification (rare) seen in mets from Mucinous adenocarcinoma, Sarcomas
 Haemorrhagic
Mets
Finger in Glove
appearance

-RCC,
Chorioca,
CECT Melanoma
MRI
• Typically brain mets are seen as solid or ring enhancing lesions,
spherical in shape.
• Haemorrhage can be seen in mets from melanoma, RCC,
choriocarcinoma, thyroid cancer, lung and breast cancer.

• T1
Typically iso to hypointense
If haemorrhagic, may have intrinsic high signal
Non haemorrhagic melanoma metastases can also have high intrinsic
signal due to paramagnetic properties of melanin
• T1C+
Usually intense, - enhancement pattern can be uniform, punctate or
ring enhancing
Delayed sequences may show additional lesions – so CE MRI is the
current standard for small metastases detection

• T2 FLAIR
 Typically hyperintense
Hyperintense peri tumoral edema of variable amounts
Helps to identify periventricular lesions via suppressing the CSF signal
T1 Contrast T2 Contrast T2 FLAIR T2 FLAIR with C+
• DW MRI
Measures apparent diffusion coefficient(ADC)
Lower ADC favours diagnosis of tumor

• Perfusion MRI
Measures Relative cerebral blood volume(rCBV)
Higher rCBV for a lesion- higher is the probability of lesion to be
malignant

• MR Spectroscopy
Higher Choline/ NAA peak favours the lesion to be tumoral
MANAGEMENT
MEDICAL MANAGEMENT

• STEROIDS
ANTICONVULSANTS
• Klein et al in a study showed the correlation between the use of
anticonvulsants(even without seizures) and decrease in quality of life
and neurocognitive function
• So based on four negative randomized trials, the American Academy
of Neurology in 2000 recommended that prophylactic anticonvulsants
should not be started in newly diagnosed patients with brain tumors
who have never experienced a seizure.
SURGICAL MANAGEMENT
• Helps in obtaining a pathological diagnosis of intracranial lesion
• Immediate relief of tumor mass effect
• Mostly preferred in less number of metastatic lesions

Terminology-
• Single Lesion: Presence of only one intracranial lesion irrespective of
extracranial disease
• Solitary lesion: Intracranial lesion being the only site of metastatic
disease (no extracranial mets)
• The studies by Patchell et al, Noordijk et al and Mintz et al compared
OS between treatment of brain mets by surgery followed by RT and
Radiation alone .
Study Surgery+RT RT alone

Patchell et al 40 weeks 15 weeks

Noordijk et al 10 months 6 months

Mintz et al 5.6 months 6.3 months

• Reason for difference in outcomes of the studies is believed to be:

Better performance status of patients in first two studies
More incidence of extracranial metastases in Mitntz’s study
ASCO-SNO-ASTRO Gudelines
in paper by Michael A Vogelbaum et al in 2021
 RADIATION THERAPY
• Whole Brain RT
• WBRT followed by Stereotactic Radiosurgery Boost
• Stereotactic Radiosurgery – single or multiple fractions
POSTSURGERY OR
POSTRADIOSURGERY RADIOTHERAPY
• CONCLUSION->
• Phase III trials have shown meaningful benefit of WBRT in terms of preventing
brain failure
• Adjuvant WBRT should therefore be considered after local therapy with surgical
resection or SRS. However this is very controversial, as WBRT comes with some
adverse effects too.
• RADIOSURGERY BOOST TRIALS

(WBRT+SRS)
(WBRT Alone)
ASTRO GUIDELINES FOR RADIATION
THERAPY IN BRAIN METASTASES
- Paper by Vinai Gondi et al. in May 2022
Indications of SRS alone in patients with intact
brain metastases

 ECOG 0-2, < or = 4 intact brain mets

 ECOG 0-2, 5-10 intact brain mets
 < 2cm in diameter:- Single # SRS 20 or 24 Gy
or 27Gy/3# or 30Gy/5#
 > or = 2cm to 3 cm:- 18Gy/1# or 27Gy/3# or 30Gy/5#
 > or = 3 to 4 cm:- 27Gy/3# or 30Gy/5#
 >4cm:- Surgery> Multifraction SRS> Single fraction SRS
• Brain mets ineligible for surgery and/or SRS-> WBRT to 30Gy/10#
• For brain mets receiving WBRT-> hippocampal avoidance
• For brain mets receiving WBRT or HA- WBRT-> Use of memantine
• Favourable prognosis and limited brain mets-> Addition of routine
WBRT to SRS is NOT recommended.

• Unfavourable prognosis-> Palliative care with symptomatic

management (omission of WBRT)
 Figure 1

Practical Radiation Oncology 2022 12265-282DOI: (10.1016/[Link].2022.02.003)

Copyright © 2022 Terms and Conditions
 Figure 2

Practical Radiation Oncology 2022 12265-282DOI: (10.1016/[Link].2022.02.003)

Copyright © 2022 Terms and Conditions
NCCN guidelines for management of brain
mets
HIPPOCAMPUS AVOIDANCE- WBRT
• Mean relative decline in Hopkin Verbal
learning test from baseline to 4 months
was 7.0% - >significantly lower in
comparison with the historical control

• Concluded that Conformal avoidance of

the hippocampus during WBRT is
associated with preservation of
memory and QOL as compared with
historical series
ROLE OF MEMANTINE IN WBRT
• RTOG 0614 compared patients receiving
concurrent and adjuvant Memantine
(20mg/day within 3 days of RT for 24
weeks) with patients who received
placebo instead along with WBRT
• Probability of cognitive function failure at
24 weeks was 53.8% in the memantine
arm and 64.9% in the placebo arm
• Concluded that memantine delayed time
to cognitive decline and reduced the rate
of decline in memory, executive function,
and processing speed in patients
receiving WBRT
RADIONECROSIS
• SRS leads to necrosis in 10% of patients, particularly when combined
with WBRT
• The necrosis area has decreased vascularity
• Radionecrosis can be confused with progression on CE-MRI
• DW MRI, Perfusion and MR Spectroscopy sequences can help
distinguishing between progression and pseudoprogression due to
radionecrosis
• T/t: Corticosteroids help reduce edema and improve neurological
function
• Surgical removal of the radiation necrosis is the other treatment.
ASTRO GUIDELINES
ASTRO guidelines for systemic therapy
WHERE TO DRAW THE LINE
BEST SUPPORTIVE CARE if:
• Poor performance status Score 3-4
• Disseminated disease
• Extracranial metastases- Multisystem involvement
• Clinically unstable
• Very poor prognosis

• Prognostication and counselling of the family is equally important

TAKE HOME MESSAGE
• Approach to brains mets is increasingly individualized with the
evolution of surgical, radiation and systematic modalities
• Surgery for large and not so deep tumors to decrease mass effect and
confirmation of diagnosis
• Radiation therapy upfront or post surgery to the surgical bed
• WBRT for diffuse mets and SRS for less number of brain mets
• Try to preserve neurocognitive function
• Management of radionecrosis is important
• Treatment of the primary
• Moral and emotional support of patient and family