Brain metastasis

Brain metastasis

1. Brain metastasis
Evidence based management
DR KIRAN

2. Introduction
•Brain metastasis is the most common intracranial tumor in adults.
•It is estimated that 20% to 40% of cancer patients will develop brain metastases
during the course of their illness.
•The main route of delivery of metastatic disease to the brain is by hematogenous
spread.
•Parenchymal metastatic lesions characteristically occur at the grey-white matter
junction, most frequently in the cerebral hemispheres (80%),followed by the
cerebellum (15%) and brainstem (<5%).
Diameter of arterioles decreases while the penetrating artery extends from the cortex
into the subcortical white matter where the typical size tumor emboli gets lodged.

3. 1.Barnholtz-Sloan JS, Sloan AE, Lai P: J Clin Oncol 2004;22(14):2865–2872.
2.Schouten LJ, Rutten J, Huveneers HAM: Cancer 2002;94(10):2698–2705.
Surveillance, Epidemiology,and End Results (SEER) Program, patients with small-cell lung cancer
(SCLC) or non-small-cell lung cancer (NSCLC) have the highest rates of brain metastases at diagnosis, while
those with melanoma have the highest risk of presenting with brain-metastatic disease

4. Hemorrhagic Brain metastases
•Melanomas,
•Choriocarcinomas,
•Germ cell tumors,
•Thyroid cancers
•Renal cell carcinomas (RCCs).
Sources of cerebral metastasis inChildren
•Neuroblastoma
•Rhabdomyosarcoma
•Wilm’stumor

5. •The higher flow anterior circulation accounts for approximately 80% of
parenchymal metastases compared to 20% for the lower flow posterior circulation
(15% cerebellum, 5% brainstem).
•ThehighestincidenceofparenchymalmetastasisisposteriortotheSylvainfissure
nearthejunctionoftemporal,parietal,andoccipitallobes(presumablydueto
embolicspreadtoterminalMCAbranches).
•It is the most common p-fossa tumor in adults, thus “a solitary lesion in the posterior
fossa of an adult is considered a metastasis until proven otherwise.”
PREDILECTION

6. Primarily caused by local mass effect, brain inflammation and increasedintracranial
pressure.
•Headache
•FND
•Mentalchange
•Seizures
: 50%; Mass effect orHydrocephalus.
:40%;
:30%;
:15%
SYMPTOMS
Symptoms may have a gradual presentation or rapidprogression
•Impairedcognition
•Hemiparesis
•Ataxia
•Papilledema

7. •MRI Imaging modality of choice
•Typical metastatic lesions are spheroid, surrounded by a zone ofedema.
•The peri-tumoralregion in metastases is assumed to show greater diffusion
restriction in DW-MRI as well as lower perfusion values in perfusion MRI
compared to the peri-tumoralregion in primary braintumors.
IMAGINGSTUDY-WORK UP FOR BRAIN
METS

8. A.Shows heterogeneous signal in the mass including subtle T1 shortening that represents blood
products.
B.The mass is moderately hypointense suggestive of blood. Highlights the vasogenic edema.
C.Demonstrates hypo-intensity in the mass indicative of blood products.

9. •CECT failed to identify multiplicity in 31% of the patients studied
whencompared to contrast-enhanced MRI.
•When MRI is contraindicated it is reasonable to perform CECT to
detect metastasis but the protocol should be optimized to include
double-dose and delayed imaging.
Schellinger PD, Meinck HM, Thron A. Diagnostic accuracy of MRI compared to CECT in patients with brain metastases. Journal ofNeuro-
Oncolgy. 1999;44:275–281.

10. RPA-Classes
Class I
< 65 years, KPS ≥ 70,
controlled primary
no extracranial mets
Class II-Rest
Class III-KPS <70
4.2
2.3
6
5
4
3
2
1
0
7
7.1
8
I IIIII
Gaspar, et al JNCI1997

12. •Overall patients with brain metastases typically have a mean survival of
onemonth without treatment.
•With treatment, survival improves, but it is still dismal.
•The mean age of survival is still less than one year, although in some
patients with solitary metastases longer survival is encountered.
PROGNOSIS

13. •Individualised approach, taking into account:
1.Karnofsky performance scale (KPS) score,
2.Medical comorbid conditions,
3.Systemic disease status,
4.Number of metastases,
5.Size and location of metastases, and
6.Symptoms.
7.Furthermore, it is important to remember that choice of treatment(s) of
the brain metastases may have little impact on overall survival.
CHOICE OFTHERAPY

14. Treatment
•SymptomManagement
•Surgery
•RadiationTherapy

15. Symptomatic Management
Seizures:
There is no standard antiepileptic drug regimen for seizure
control in patients with tumors; however, levetiracetam(1000-
4000mg/day) is preferentially used because of its favorable
pharmacologic properties and relatively benign side-effect
profile.(1)
1.(Yuan Y, YunheM, Xiang W, et al. P450 enzyme-inducing and non enzymeinducing
antiepileptic drugs for seizure prophylaxis after glioma resection surgery: A meta-analysis.
Seizure. 2014;23:616–621.)

16. Cerebral oedema:
•Glucocorticoids used :Dexamethasone preferred because of minimal
mineral-corticoid effects.
•Lower doses :shown to be as effective as higher doses-2 to 4 mg bd preferred
•should be discontinued or tapered to the lowest dose necessary, as soon as
possible.
•Taper is necessary to prevent rebound in cerebral edema and also to allow
the pituitary–adrenal axis to recover.

20. •In case of solitary metastases surgical treatment is indicated if the latter
are >3 cm.
•Removal of intracerebral metastases is indicated with a limited (≤3)
number of focal lesions and the presence of a resectable lesion greater
than 3 cm in diameter.
•<3 cm and located in functionally important areas, and symptomatic
(neurological symptoms) and there is no response to the steroid test
(administration of 8–24 mg of dexamethasone per day for 5 days), a
surgical removal can be considered.
•For patients with multiple cerebral metastases, the classic surgical
treatment strategy is for resection of only large lesions with symptomatic
mass effect.
•However, when choosing between surgical and radiosurgical methods, one
should consider a higher probability of persistent residual neurological
deficit after the surgery.
Recommendation ofexcision
Dolgushin M: editors: Brain Metastasis: 2018; PP18

21. •In case of multiple brain metastases, the role of surgery is limited to
obtainingabiopsy or eliminating mass effect symptoms caused by large
lesions.
(Loshakov 2005; Paek et al. 2005; Stark et al.2005).
•Therearesomeretrospectivefindingsshowingthebenefitsofa
surgicaltumorresection(bestoverallsurvival)forcertainpatients
withagoodprognosisandlimited(2–3lesions)brainmetastases
(Mintzetal.1996;Schackertetal.2000).

22. •Indications:
1.Clinical manifestations of mass effect, accompanied by signs of intracranial
hypertension
2.Midline shift
3.An extensive peri-focal swelling spreading to the nearby lobes and the opposite
hemisphere
4.A threat of blocking the cerebrospinal fluid pathways
SURGERY FOR BRAINMETS

23. Treatment Algorithms for Patients with
Single Brain Metastases

24. 1-3LESIONS

26. MORE THAN 3LESIONS

28. •The presence of a limited number of metastases (≤3foci)
•Lesions with the maximum diameter ≤3cm).
•Can also be indicated in patients with multiple (3–10lesions)
(Golan et al.2015).
Indication ofSRS

29. •Evidence

30. S+RT vs RT
•For single brain metastases, 2 out of 3 trials have
shown surgical resection+ RT has OS & LC advantage
over RT alone.
Trial N Endpoint Surgery
+RT
RT p value Ref
Patchell et al
(University of
Kentucky)
48 OS*
Local failure
40 weeks
20%
15 weeks
52%
<0.01
<0.02
N Engl J Med
1990;322:
494-500.
Noordjik et
al (Dutch)
63 OS*
FIS*
10 months
7.5 months
6 months
3.5 months
0.04
0.06
Int J Radiat
Oncol Biol Phys
1994;
29:711-17.
Mintz et al
(Canadian)
84 OS*
FIS %
5.6 months
32%
6.3 months
32%
NS
NS
Cancer 1996;78:
1470-76.

31. S+SRS vs S
•Phase III RCT
•N=132
•1-3 metastases; resection cavity
=<4cm
•Post-op SRS (N=64)vs
observation (N=68)
•SRS done within 30 days of
resection; dose=12-16Gy
•Median FU =11.1 months
•Median 12-month freedom
from local recurrence was
significantly better for SRS
(72%) vs observation (43%)

32. S + SRS vs
S+WBRT
•Phase III RCT
•N=194
•One resected brain metastases
•Resection cavity =<5cm
•diameter
•SRS (12-20Gy) [N=98]
•vs WBRT[N=96](30Gy/10#/2weeks
OR 37.5Gy/15#/3 weeks)
•Significantly longer cognitive
•–deterioration free survival
with SRS (median 3.7 vs 3
months)
•Significantly poorer surgical
bed control at 6 months with
SRS (80.4%) vs WBRT (87.1%)
•Median OS similar :12.2
months (SRS) vs 11.6 months
(WBRT)

33. S vsSRS
•No randomized trials
•Similar LC rates 80-90% (when either one is combined
with WBRT)

34. SRS +WBRT
vsWBRT
•3 randomised trials (2small/non-standard).
•RTOG 9508N=333: OS benefit for single unresectable brain met
(no breast cancer patients analysed in this subgroup), LC benefit
for 2-3 brain mets, steroid-usage lowered with SRS.
•Subset analysis shows OS benefit for single brain met, NSCLC, RPA
class I,tumor <2cm.
•For breast cancer patients with 1-3 brain metastases, presence of
extracranial disease, TNBC &having >1 brain metastasis
predicts for worse OS.
Int J Radiation Oncol BiolPhys,
2014;90:526-31

35. SRS +WBRT
vsSRS
•Meta-analysis of 3
randomised trials
•N=364
•SRS alone 51%;
SRS+WBRT 49%
•Forpatients<50yearsagewith1-4
brainmetastases,SRShasOS
advantageoverSRS+WBRT.
•Patients with single metastases had
significantly better OS than with 2-4
metastases.
•Local control significantly better with
WBRT in all age groups.

36. Immediate vs delayedRT
for asymptomatic oligo brainmetastases
•Korean trial
•Metastatic NSCLC; 1-4 asymptomatic brain metastases
•N=105
• SRS (N=49) followed by chemotherapy vs upfront chemotherapy (N=49)
•No difference in OS / time to CNS progression

37. Neurocognitivedecline
•Patients with brain metastases tend to have reduced neurocognition at the time of
presentation, which is frequently not evaluated;
•Disease-progression, both intra-and extra-cranially, will negatively skew
population distributions of neurocognitive scores;
•The effects of therapeutic interventions, such as chemotherapy, anticonvulsants,
steroids, opiates, etc., remain inadequately documented.

39. RTOG0933
•Single-arm phase II trial of HA-WBRT (30 Gy in 10 fractions)
•Credentialing and central review of hippocampal contouring and IMRT planning
0
5
10
15
20
25
30
0
HVLT
Score
Recall Recognition DelayedRecall
2 4 6
Months from Start ofTreatment
•Mean decline in HVLT-Delayed
Recall from baseline to 4
months:7.0% (95% CI: -4.7-18.7%)
•Significant compared to
historical control: 30%
(p=0.0003)
Need phase III data for level Ievidence
Gondi et al. JCO2014

40. NRG-CC001: Phase III Trial Memantine and WBRT with or without Hippocampal
Avoidance in Patients with Brain Metastases
Basic Eligibility: Brain metastases 5mm outside hippocampus; KPS>70; 3D MRI scan; hydrocephalus/ventricular
distortion excluded; baseline NCF testing
Brain
Metastasis
S
t
r
a
t
i
f
y
RPA
Prior Therapy
R
a
n
d
o
m
i z
e
WBRT 30Gy+
Memantine
HA-WBRT 30Gy+
Memantine

41. PrimaryEndpoint
Hippocampal avoidance prolongs time to
cognitive function failure
6 months:
HA-WBRT+memantine 59.5%
WBRT+memantine: 68.2% Hazard ratio =
0.76p=0.03
Separation of the curves starting at 3
months and maintained through the
follow-up period
Median follow-up for alive patients:
7.90 months

42. Dose prescription-Brain Metastases
•<2cm:24Gy
•2.1-3cm:18Gy
•3.1-4cm: 15Gy
•SRS:(RTOG 90-05) •FSRT:
•30Gy/5#
•40Gy/10#
•Target=tumour+smallmargin(1-2mm)
•UnlikeconventionalRT,dosedistributionisdeliberatelymadeinhomogeneous,
bycoveringperipheryoftumorby50-80%,ratherthan95%.Thisensureshigh
doseatthecentreofthetumouraswellasrapidfalloffofdosebeyondthe
peripheryofthetumour.

43. LateComplication
•Nerve Damage
•Vertebral Compression Fracture-
•1-and 2-year cumulative incidences 12.35% and 13.49%, respectively (24Gy/SF)
and 8.5% and 13.8%. (24Gy/2#), (Tseng et al)
•dose per fraction increases beyond 19 Gy, risk increases
• significantly higher risk of VCF for the 24 Gy/fraction group and 20 to 23
Gy/fraction group.
•baseline VCF, lytic tumor, and spinal misalignment
(kyphosis/ scoliosis and subluxation/translation)werepredictive.
Sahgalet al, JCO, Sept2013

44. Stereotactic radiosurgery (SRS)
•Considered for≤4 lesions all≤3cm diameter that are surgically inaccessible, with limited or quiescent
systemic involvement.
•Relative contraindications: hemorrhagic lesions, lesions with significant mass effect surrounding edema.
Surgery
•Patients with 1-4 CNS metastases that can be completely resected when systemic disease is absent or slowly
progressive: long-term survival is possible.
Patients with intracranial mets that cannot be completely removed or with uncontrolled systemic disease may
be surgical candidates for the following:
a)for symptomatic relief: e.g. lesion causing painful pressure
b)life-threatening lesion: e.g. large p-fossa lesion with 4th ventricle compression
c)for hemorrhagic lesion causing symptoms by mass effect from the clot
Whole-brain radiation therapy (WBRT)
WBXRT provides 2–3 month survival benefit and may be considered for palliation in patients with
multiple mets that preclude complete excision or SRS.
Summary

45. •Thank You
Reference:
1.Perez and Brady principles of Radiation Oncology 7
th
edition.
2.NCCN 2020