management of cerebral metastasis

1. Dr. Shahnawaz Alam
Resident; MCh-Neurosurgery
Moderated by:
Dr. V. C. Jha
HOD, Dept. of Neurosurgery
MANAGEMENT OF
CEREBRAL METASTASES

2. INTRODUCTION
 Brain metastases are an increasingly common consequence of systemic
malignant disease and represent a challenge for clinicians to manage.
 First described by Buchholz in 1898; Originate outside of the CNS and spread
to the brain primarily via a hematogenous mechanism.
 Most common intracranial tumor in adults and represent a significant source
of morbidity in patients with systemic malignancy.
 Melanomas and lung, breast, colorectal, and renal cancers show the most
predisposition for the brain mets.
 Lung cancer is the primary tumor in about 40%-50% of patients
diagnosed with brain mets; Breast cancer is unique in its longer latency to
forming BMs.

3.  The microenvironment is a prominent player in metastatic outgrowth; It is
becoming increasingly clear that cancer cells are able to exploit the expression
of CNS-specific genes to ease their way through the BBB into the brain
metastatic microenvironment.
 There is now evidence to suggest that reciprocating communication between
cancer cells and the tumor microenvironment orchestrates homing,
dormancy, proliferation, formation of micrometastases, and tumor growth.
 Neurotransmitters, growth factors and cytokines facilitate reciprocating
communication between tumor cell and host stroma.
 The treatment of brain metastases has changed drastically over the past two
decades with novel surgical, radiotherapeutic, chemotherapeutic, and
immunotherapeutic approaches.

4. Barriers to brain metastasis
Primary stage: Enters the bloodstream in the beginning phases of mets;
Circulating tumor cells in the bloodstream arrive at three different locations in
the CNS: BBB, BCSFB and BSCB. Each of these barriers is composed of
different molecules designed to shield the CNS from external influence.
BBB: Tight junctions (zonulae occludens) between endothelial cells,
which create a mostly impenetrable barrier; Tight junctions include
transmembrane and cytoplasmic proteins consisting of occludin,
claudins, and junctional adhesion molecules (JAMs); These are further
associated with regulatory proteins including ZO-1, ZO-2, ZO-3, and
cingulin.
BCSFB, although similar to the BBB in its framework, lacks tight
junctions on its endothelial cells and therefore has a more permeable
barrier relative to the BBB.
PATHOPHYSIOLOGY OF BRAIN METASTASES

5. Metastatic stage: Once inside the brain, metastases can utilize
neurotransmitters and neurotrophic factors such as BDNF, NGF,
norepinephrine, and dopamine to facilitate metastatic colonization.
 Additionally, the expression of complement protein (C3) has been shown to
disrupt the barrier, allowing entrance into the CSF in cases of leptomeningeal
mets.
 Following the formation of a metastatic lesion in the brain, the remnants of the
BBB (referred to as the “brain-tumor barrier”) has increased permeability to
drugs and contrast agents, resulting in significant enhancement on
gadolinium-enhanced MRI.

7.  The spread of primary tumor cells to the brain via hematogenous seeding is a multistep process. Once in the circulation, these cells begin
extravasating from the microvasculature of the brain.
 Occur most commonly at the GM-WM junction as a result of longer relative mean transit times of blood flow, allowing for circulatory
arrest and more time for cells to overcome the BBB.
 Extravasated tumor cells can then migrate along leptomeningeal and parenchymal vasculature or disseminate via the CSF to spread
intracranially. Although most individual cells will not go on to form metastases, it is thought that tumor cell clusters can act
synergistically to promote metastatic growth within the brain microvasculature.

8. EPIDEMIOLOGY
 The annual incidence of brain metastases 11.1/100,000; the highest incidence
occurred in persons 65-74 yrs; Unlike adults, the incidence of brain mets in
children is much lower than primary brain tumors (MC solid tumor). It is
estimated to occur in 1.4%-13% of children with solid tumors, most
commonly from germ cell tumors and sarcomas.

9. Metastasis Anatomy
 Typically well circumscribed and only marginally infiltrate surrounding
tissue; Macroscopically; “pseudocapsule” composed of a wall of gliosis
demarcating the lesion from adjacent parenchyma.
 The surrounding tissue contains neovascularization and gliosis that results in
the peritumoral, vasogenic edema viewed on imaging.
 The tumor mass can consist of solid and/or cystic components, particularly
for breast or lung carcinoma and central necrosis.
 Furthermore, cystic components are known to be radioresistant, and
surgical resection is preferable to stereotactic aspiration or radiotherapy.

10.  Hemorrhage of the lesion is another feature of brain metastases that can
contribute to morbidity and is most often observed in RCC, choriocarcinoma,
and melanoma.
 Spread to the brain by a hematogenous route, via the pulmonary arterial
circulation; gray/white matter junction within the distribution of the
middle cerebral artery; Outside of the parenchyma, it can be seen in the
leptomeninges, dura, subarachnoid space, and skull.
 Leptomeningeal spread is another common route for metastases to the brain
and is typical of melanoma and SCLC; however, breast carcinoma composes
the majority of leptomeningeal metastases because of a higher incidence
overall.

11.  Supratentorial metastases are often categorized by their vicinity to gyri, sulci,
and the cortex, for example, subsulcal, subgyral, and subcortical. Deep, white
matter lesions not adjacent to these structures are often termed lobar.
 Furthermore, metastases adjacent to the insula or corpus callosum may be
accordingly viewed in relation to these structures, for example, subinsular and
midline, respectively.
 Cerebellar metastases are categorized as deep or hemispheric with hemispheric
lesions subdivided into lateral and medial (medial lesions lie within the
cerebellar vermis).
 Metastases of the posterior fossa are often seen with primary gastrointestinal
tumors as well as prostate and endometrial carcinoma and are particularly
difficult to treat because of the proximity of the brainstem, venous sinuses, and
fourth ventricle.

12. Lung Cancer
• Continues to be the most common underlying cause of brain mets, followed by
breast cancer, melanoma, RCC, and colorectal cancer, which account for most
intraaxial metastases.
• Specifically, patients with small cell lung cancer (SCLC) have an 80% chance
of brain metastases 2 years from diagnosis.
• Non-small cell lung cancer (NSCLC) is the most common lung carcinoma
subtype. Although patients with NSCLC have a 9% chance of developing brain
mets during the course of their disease.
• Brain mets from both SCLC and NSCLC have a higher incidence in females
compared with males despite the higher overall cases of brain metastases from
lung cancer in males.

13. • Studies have identified a number of genetic mutations that alter the metastatic
properties of NSCLC, specifically. Mutations in the epidermal growth factor
receptor (EGFR) oncogene have been identified as a prognostic risk factor for
brain metastases, both for squamous and non-squamous histologies.
• Consequently, treatment with tyrosine kinase inhibitors (TKIs) (e.g., getfitinib
or erlotinib) for patients with somatic EGFR may reduce the incidence of CNS
metastases.
• Translocation of the anaplastic lymphoma kinase (ALK) gene is observed in
5% to 6% of patients with NSCLC and also confers a significantly higher risk for
metastasis to the CNS.
• Conversely, translocation of the ROS protooncogene 1, receptor tyrosine
kinase (ROS1) gene has been shown to reduce the incidence of brain metastases
in patients with ALK-rearranged NSCLC.

14. Breast Cancer
• 2nd MC histology of brain mets; 18%-30% for breast cancer patients.
Similar to the various NSLC oncogenomic drivers, mutation in the human
epidermal growth factor receptor 2 (HER2) gene has been shown to
significantly increase the incidence of brain mets.
Melanoma
• It ranks 3rd in incidence of brain mets; 6%-11% of all metastatic
intraaxial tumors. However, it is considered to have the strongest
propensity to metastasize to the brain, with 10%-40% of patients with
advanced melanoma estimated to develop intracranial mets.
• Historically patients with melanoma brain mets demonstrated particularly
poor survival, ranging from 17-22 weeks after diagnosis. Further, a higher
incidence of brain metastases is seen in head and neck melanoma when
compared with other locations.

15. Other Histologies
• Although colorectal carcinoma and RCC are the 4th and 5th MC primary
brain mets histology, respectively; Patients with esophageal adenoCa are
significantly more likely to develop brain mets than those with esophageal
SqCCa.
• Choriocarcinoma, although very rare, is the MC gynecologic tumor to
metastasize to the CNS. Incidence rates in the literature vary between 3%-
27%, although autopsy reports estimate a significantly higher incidence
(66.7%) for this patient population.

16. HA-WBRT=hippocampal avoidance WBRT; mAbs=monoclonal antibodies; NaSRS=neoadjuvant SRS; TKIs=tyrosine
kinase inhibitors; LITT= Laser Interstitial Thermocoagulation Therapy
Treatment options

17. TREATMENT MODALITIES
 In symptomatic patients with brain mets, corticosteroids are often the initial
therapy to decrease peritumoral edema and improve neurological function.
 Although systemic cytotoxic chemotherapy is useful for control of the
primary disease and extracranial metastases, its effect is limited for
intracranial lesions because of the selective permeability of the BBB.
 Currently, whole-brain radiotherapy (WBRT), forms of stereotactic
radiotherapy including stereotactic radiosurgery (SRS) and fractionated
stereotactic radiotherapy (FSRT), as well as cytoreductive operative
techniques compose the armamentarium against brain mets.

18. WHOLE-BRAIN RADIATION THERAPY
• Since the first description in 1954, it has been increasingly utilized as an
adjuvant and standalone treatment to establish local control for brain
metastases because of its simple, noninvasive implementation, particularly
when multiple lesions are present.
• For the treatment of multiple metastases, either alone or in combination with
other therapies, a 2018 Cochrane review of 54 published trials found improved
local and distant intracranial disease control for WBRT in addition to SRS,
although no benefit for overall survival was appreciated, and poorer cognitive
outcomes were observed.
• Despite these findings, WBRT remains a treatment option to acutely improve
neurological function and control peritumoral edema for patients who are
poor candidates for surgery or SRS with good performance status.

19. • Current evidence suggests that >60% of patients with brain metastases will
have a complete or partial response with amelioration of presenting
symptoms further preserving WBRT as a viable palliative therapy.
• The Congress of Neurological Surgeons (CNS) Evidence-Based Guidelines
recommend WBRT combined with surgery as first-line therapy for patients
with single brain metastases and in combination with SRS as first-line
therapy to improve local and distant intracranial control in patients with
multiple brain metastases.

20. • Age, performance status, primary tumor
status, and presence of extracranial
metastatic disease have been known be the
primary contributors to patient outcomes.
 Diener-West et al. performed recursive
partitioning analysis (RPA) on three
consecutive trials of brain mets from the
Radiation Therapy Oncology Group (RTOG)
to identify favorable patient characteristics for
treatment candidacy.
 The scoring index for radiosurgery (SIR) was described utilizing a multivariate
Cox model, the authors identified five prognostic factors to compose the SIR: age,
KPS, extracranial disease control, number of intracranial metastases, and volume of
the largest metastatic lesion.
 Each category is scored from 0-2 for a possible combination of 10 (best prognosis).
The SIR scores are further grouped into low (0-3), intermediate (4-7), and high (8-
10) categories with associated median survival of 2.9 months, 7.0 months, and
31.4 months, respectively.
PATIENT PARAMETERS AND PROGNOSTIC FACTORS

21. • In an effort to reduce the subjectivity of previously developed prognostic scoring
indices, particularly in defining the control of extracranial disease, the graded
prognostic assessment (GPA) was developed from five RTOG trials and has
become the most widely used prognostic index for patients with brain
metastases.
• The GPA incorporates age, KPS, primary tumor histology, number of
intracranial metastases, and the presence of brain and bone metastases.
• More recently, the GPA has been updated for breast cancer, melanoma, and
NSCLC metastases to incorporate molecular markers (Breast-GPA,
Melanoma-molGPA, and Lung-molGPA, respectively). which have further
facilitated more accurate prognostication of the most common brain metastasis
histologies.

23. WHOLE-BRAIN RADIOTHERAPY
 Dose-fractionation schemes : For brain mets, WBRT is MC delivered in 10
daily fractions of 3 Gy for a total dose of 30 Gy.
 Altered fractionation schemes: for patients with favorable survival prognoses
who are otherwise poor candidates for surgery or SRS. Dose escalation beyond
30 Gy in 10 fractions to 40 Gy in 20 fractions.
 Accelerated WBRT fractionation: 54 Gy in 10 fractions; RTOG phase 3 trial
found no improvement in survival over conventional fractionation schedules.
 Adjuvant radiosensitizer therapy: Current evidence based on meta-analysis of
prior RCTs is weak and remains in an experimental stage; The CNS guidelines
do not recommend the use of temozolomide and chloroquine as radiation
sensitizers in patients with brain metastases receiving WBRT.
 However, there is evidence of marginal survival benefits for particular
histology; provides direction for future research.

24. PROPHYLACTIC CRANIAL IRRADIATION (PCI)
FOR SMALL CELL LUNG CANCER
 SCLC in particular is characterized by aggressive tumor growth and early
distant metastases compared with other primary tumors. An estimated 10% of
SCLC patients will present with brain metastases at the time of diagnosis with
another 40%-50% observed to develop brain metastases during the subsequent
disease course.
 Despite the concerns of cognitive decline, PCI has been established as an
effective method for reducing the incidence of brain mets, preserving quality of
life, and prolonging survival; The efficacy of PCI is less defined in patients
with extensive stage SCLC.
 The current recommendations are for PCI in asymptomatic patients with
limited-stage SCLC at a regimen of 25 Gy in 10 fractions as a benefit on overall
survival.

25. COMPLICATIONS OF WBRT
 Dose-dependent presence of cognitive decline in the domains of executive
function, episodic memory, processing speed, and fine-motor control.
 A few neuroprotective pharmacologic compounds have been explored to
mitigate risk and improve patient outcomes; Memantine, an N-methyl-d-
aspartate receptor blocker and Donepezil, an acetylcholinesterase inhibitor
(used in the treatment of Alzheimer disease).
HA-WBRT treatment volumes
Hippocampal-Avoidance WBRT/HA-WBRT
 Episodic memory loss is often the most
significant component of cognitive
decline; Memory formation has been
thought to result from lifelong
neurogenesis in a radiosensitive
compartment of neural stem cells within
the hippocampus.

26. SURGICAL RESECTION
 Indications include need for tissue diagnosis to guide subsequent
management, cerebral decompression particularly to reduce symptomatic
mass effect, and vasogenic edema.
 Surgical resection provides a direct reduction of tumor burden immediately
resolving the source of increased ICP and edema.
 The benefits of surgical resection for metastatic lesions may be greater than
for primary tumors as metastases expand and compress surrounding structures
instead of infiltrating adjacent parenchyma like many primary tumors.
 Historically, the standard of care combined surgical resection and WBRT as
first-line treatment to extend survival in patients with good performance
status and controlled extracranial disease.

27. PATIENT SELECTION AND PROGNOSTIC FACTORS
Evaluation of a number of clinical and tumor characteristics are required for
selection of surgical candidates. These can be summarized in three general
categories; primary tumor histology, radiologic features from brain tumor imaging
(including size, location, and number of lesions), and clinical status.

28. Radiographically Determined Features
Tumor Number
• The benefit of surgical resection of single metastases has been well
established by multiple studies. However, the role of surgery in patients with
multiple brain metastases is less established as no RCT has been conducted to
investigate its potential benefit.
• Historically, multiple lesions were a contraindication to surgical intervention,
however, a retrospective study by Bindal et al. suggested that resection of two or
three intracranial metastases may prolong survival. In the subsequent years,
multiple retrospective studies reported similar findings.
• Current CNS guidelines recommend resection in patients with symptoms from
mass effect that have surgically accessible lesions that can be approached
feasibly without introducing new deficits and otherwise have good systemic
disease control.

29. Tumor Size
 There is currently no evidence to suggest that tumor size alone affects survival
in surgical resection of brain metastases.
 A 2003 study by Chang et al. suggested that SRS should be used for lesions up to
1 cm. Subsequent studies have shown that for smaller lesions (<3 cm), SRS
provides acceptable regional control, however, lesions 3 cm and greater are
associated with higher rates of local failure and radiation necrosis.
 Thus, for intracranial metastases ≥3 cm, resection should be the primary
approach to reduction of tumor burden.

30. Tumor Location
 The location of the metastatic lesion is an important factor in determining suitability
for surgery as the proximity of the mass to critical neurovascular structures can
impede resectability.
 The advent of stereotactic imaging guidance, which provides real-time feedback of the
3-D coordinates of registered instruments within the patient’s regional anatomy, has
improved the precision of neurosurgical procedures.
 For tumors encroaching on eloquent cortical regions, navigated transcranial magnetic
stimulation (nTMS) is one effective technique for precisely and noninvasively mapping
the motor cortex to maximize extent of resection while minimizing postoperative
morbidity.
 Similarly, DTI is an advanced MRI sequence that provides accurate delineation of
white matter tracts pre- operatively for precise resection of lesions proximal to these
structures.
 Despite these advances, tumors within or adjacent to the brainstem, basal ganglia, or
thalamus are approached with caution and are generally managed nonoperatively as
the risk for morbidity from operating in this region outweighs the benefits, particularly
given the overall poor prognosis of patients with brain metastases.

31. Histology
• Histology of the primary tumor is an indicator of survival in patients with
brain metastases, thus more aggressive cancer types that confer a poorer
prognosis generally benefit less from surgical intervention.
• Additionally, sensitivity to chemotherapy or radiotherapy should also
contribute to whether or not surgery is indicated.
 For example, it may be appropriate to
pursue more aggressive surgical
management of histologies known to be
somewhat more resistant to radiation.
 Conversely, surgical management is less crucial for those metastases that are
known to be particularly chemosensitive and/or radiosensitive.

32. Clinical Assessment
• It is the most significant determinant of outcome; however, within the
context of systemic malignancy, this includes the extent of the primary
disease as well as the presence of extracranial metastases; The current
evidence mentioned suggests that patients with extensive extracranial
malignancy stand the least to benefit surgery.
• The interval from original cancer diagnosis to brain metastasis diagnosis
is also a predictor of outcome after surgery.
• Finally, a general preoperative risk assessment is critical to assessing a
patient’s candidacy for resection.
• Hyperglycemia has also been shown to contribute to higher rates of
perioperative morbidity.

33. SURGICAL TECHNIQUES
 Gross total resection of CNS metastases requires not only utilization of
advanced surgical techniques but incorporation of technology for preoperative
surgery planning and intraoperative imaging guidance as well.
 Utilization of frameless stereotactic navigation probes and registered
instrumentation whenever possible has become the standard of care for most
surgical resections.
 Cortical mapping techniques using the nTMS as well as functional MRI
(fMRI) and intraoperative direct cortical stimulation (DCS) are recommended
to prevent morbid motor and speech deficits postoperatively, particularly for
lesions in eloquent regions.

34. Surgical Approaches
• The anatomic location determines
the surgical approach.
• For supratentorial lesions, a
transcortical approach is often
used involving an incision over the
adjacent sulcus and removal of the
overlying cortex.
• For subgyral or subsulcal lesions,
an incision is often made by
“splitting” the sulcus to the lesion
(transsulcal approach).
• Deep-seated metastases within or adjacent to white matter tracts can be accessed with a
transcortical or transsulcal approach. Interventricular metastases can be approached
transcortically or transcallosally, if possible.
• Splitting of the Sylvian fissure is often required for tumors in the subinsular cortex.
Furthermore, deep seated lesions within the midline can be accessed by splitting the
longitudinal fissure.

35.  The surgical approach to the posterior fossa depends on the subregional loci of
the metastasis within the cerebellum.
 Midline metastases may require splitting of the cerebellar vermis for total
resection. Access via the supracerebellar cistern is often utilized for superior
hemispheric lesions with conscious avoidance of the transverse venous sinus
during craniotomy.
 Resection of lateral cerebellar lesions may require entering the
paracerebellar cisterns, depending on the posterior trajectory. Finally,
opening the foramen magnum is required for inferior cerebellar lesions,
depending on the location.

36.  There are two categories of resection technique commonly utilized for the
resection of brain metastases; en bloc and piecemeal resection.
 En bloc resection of the tumor mass is the preferred technique as it
facilitates gross total resection with less likelihood for residual tumor.
 Piecemeal resection, on the other hand, does not allow for the same
level of control over the tumor mass as en bloc. However, this method is
often used for friable lesions in deep loci, which does not allow for an en
bloc technique.
 Further, a piecemeal approach is often performed for larger metastases as
part of an “inside-out” piecemeal resection. A piecemeal approach is
thought to increase the risk for local recurrence as there is a higher
risk for residual tumor, and it is therefore avoided whenever possible.
 CNS guidelines recommend (level III evidence) an en bloc resection
technique whenever possible to decrease the risk for leptomeningeal
carcinomatosis postoperatively.

37. Intraoperative photographs depicting removal of a metastasis from the motor area of the brain.
(A) The brain prior to resection demonstrating slightly clouded leptomeninges along with an enlarged gyrus. (B) A
bipolar cortical stimulator was used to electrically stimulate the cerebral cortex, and a motor response was elicited.
(C) The cortical stimulation resulted in hand movement in the area marked by the white label (Hst). The white
arrowhead marks a sulcus overlying the tumor. (D) The tumor has been completely resected and all vascular
and all vascular structures preserved using a transsulcal approach through the sulcus identified in C.

38. (A) Axial and (B) coronal postcontrast MRI scans of the brain showing an anterior left temporal lobe brain metastasis from
sarcoma. (C) Photograph of the planned temporal craniotomy. (D) Intraoperative photograph showing the circumscribed
and encapsulated metastasis that has been dissected from the brain. (E) Brain metastasis after resection demonstrating an
en bloc resection with the tumor capsule largely intact. (F) Axial and (G) coronal images showing gross total resection of
the brain metastasis.

39. OUTCOME AND PROGNOSIS WITH SURGERY
Most series to date reporting surgical outcomes for brain metastases are
retrospective and included patients who had well-controlled systemic disease,
good neurological function, and single brain metastases, although some included
patients with multiple metastases.
Perioperative Mortality
• Surgical or perioperative morality, most often defined as death within 30 days
or death during hospital stay, has improved substantially from the 38%
mortality rate described by Harvey Cushing in 1932, which was higher for
brain metastases than for primary tumor resections.
• Subsequent studies have estimated surgical mortality to be as low as 2% based
on a 2005 study of 208 patients and 3% based on a 2015 study of 1033 patients
treated at the University of Texas MD Anderson Cancer Center between 1993
and 2012.

40. Postoperative Morbidity
• Refers to worsening neurological status and other general surgical
complications, such as wound infection, pulmonary embolism, deep vein
thrombosis, pneumonia, and hemorrhage.
• Current evidence estimates worsening neurological status to occur in ≤5%
of patients receiving surgical resection for brain metastases; although this
is dependent on the location and preoperative functional status of the patient.
 Patchell and colleagues reported a perioperative morbidity rate of 8%
considering both neurological and nonneurological morbidities. Patel et
al. separated the two aspects of morbidity in their 2005 study and reported a
general perioperative morbidity rate of 8% and a neurological morbidity
rate of 5%.

41. Survival
• Estimated survival following resection of brain metastases has increased
drastically over the past decades due to improvements in neurosurgical
techniques as well as novel chemo-, immuno-, and radiotherapies for better
local and systemic disease control.
• Larger studies reported 1-year survival rates of 50% and median survival
times of 14 months for patients with single brain metastases. These rates
are similar for patients with multiple metastases for whom gross total
resection was achieved for all lesions.

42. REOPERATION FOR RECURRENT METASTASES
 Local recurrences are common, particularly if residual tumor is left within
the resection bed; Moreover, new intracranial metastases can develop, termed
distant recurrences, complicating subsequent management.
 Estimated rates of local recurrence after surgical resection of brain
metastases with postoperative radiotherapy are between 21-51%.
 Despite the limited data, current guidelines recommend repeat craniotomy for
intracranial recurrence after original resection.
 Laser interstitial thermal therapy (LITT) is an alternative, minimally invasive
operative technique for the management of recurrent brain metastases. A 2019
study by Hong et al. concluded LITT to be as efficacious as craniotomy for
treating recurrent brain metastases failing SRS.

43. STEREOTACTIC RADIOTHERAPY
 It is an alternative radiotherapy technique that has been developed to precisely
irradiate a target with minimal radiotoxicity to surrounding tissue.
 It functions by precisely intersecting multiple low-dose, non-coplanar
radiation beams over an intracranial target using stereotactic guidance.
 The result is high-dose radiation delivery to a small target volume with
rapid dose fall-off at the edges of the target and minimal irradiation of
adjacent tissue. SRT can be fractionated in the case of FSRT or delivered in a
single dose in the case of SRS.

44. STEREOTACTIC RADIOSURGERY
Vs
CONVENTIONAL SURGERY
 A 1996 study of 75 patients by Bindal et al. found that surgery was twice as
effective at prolonging overall survival as SRS alone (16.4 months and 7.5
months, respectively) in patients with brain metastases. The authors concluded
that SRS should be limited to poor surgical candidates or patients with
surgically inaccessible lesions.
 Garell et al. reported on the results of a 1999 study of 162 patients comparing
SRS to microsurgical resection as initial treatment for intracranial metastases.
The authors found longer rates of overall survival in patients receiving SRS
(12.5 months) when compared with surgical resection (8 months), although
this was not found to be statistically significant.

45.  Schöggl and colleagues described the outcomes of SRS compared with
microsurgery, both with adjuvant WBRT, in the management of solitary brain
metastases. The authors found a higher median survival for patients treated
with SRS (12 months) when compared with microsurgical resection (9
months). Like the previous study, this finding was not statistically significant,
and the authors concluded both modalities to be equally efficacious in
prolonging survival. However, in managing local tumor control and minimizing
morbidity, Schöggl et al. stated that SRS was superior.
 Similarly, a 2003 retrospective study of 97 patients at the Mayo Clinic found no
significant difference in patient survival between surgical resection and SRS,
though it was noted that SRS was significantly more effective at establishing
local control.

46.  Ultimately, SRS is a valid option for patients with newly diagnosed single
metastases, and clinicians should evaluate on a case-by-case basis whether
surgical resection or SRS will better resolve current symptoms and
prolong overall survival and quality of life.
 CNS guidelines currently recommend SRS over surgical resection for single
brain metastases when surgical intervention is likely to introduce new deficits
and the location is likely to result in significant radiotoxicity to surrounding
structures (level III evidence).

47.  Radiation necrosis is the most common complication of SRS, occurring in up
to 15% of treated intracranial tumors. Although fractionated and hypo-
fractionated SRS regimens have been shown to reduce rates of radiation necrosis
in newly diagnosed brain metastases >2 cm.
 Prior radiation to the lesion and tumor size are known to be the two most
important risk factors for developing radiation necrosis after SRS because of the
increased radiation doses required to be biologically effective. In fact, some
retrospective evidence indicates that metastases >1 cm treated with SRS are at a
higher risk for developing radiation necrosis than smaller tumors.
 Radiation necrosis can be managed with glucocorticoids, bevacizumab,
surgical resection, or LITT.

48. SRS + WBRT
 3 RCTs from 2006 to 2011 investigating adjuvant WBRT and SRS therapy
consistently showed improved intracranial control over SRS alone, without a
clear survival benefit.
 The “Alliance” RCT, a multi-institutional phase 3 study from the North
Central Cancer Treatment Group, reported that patients receiving
combination SRS and WBRT had a significant decline in quality of life and
cognitive function at 3 months, though had better rates of local control when
compared with patients receiving SRS alone. Furthermore, like previous trials,
the study demonstrated no survival benefit for patients receiving adjuvant
WBRT over SRS alone.

49.  Current CNS guidelines recommend SRS alone instead of WBRT to prolong
survival for patients with any number of metastases when cumulative tumor
volume is <7 mL (level III evidence).
 Additionally, the addition of WBRT is recommended only in patients with
greater than 4 brain metastases if the cumulative volume exceeds 7 mL, there
are greater than 15 metastases, or the location is not amenable to resection or
SRS (level III evidence).

50. POSTOPERATIVE RADIOTHERAPY
 A 2010 retrospective study of 358 patients receiving adjuvant WBRT found
that adjuvant WBRT significantly reduces local and distant intracranial
failure, particularly for larger tumors (>3 cm) or with aggressive extracranial
disease. Despite these findings, WBRT was often withheld following resection
because of concerns of cognitive decline, particularly for patients with few
metastatic lesions. Consequently, SRS was explored as an alternative
adjunctive therapy for providing local control.
 Finally, in 2017 a phase 3 RCT compared postoperative SRS to the resection
cavity to resection alone in 128 patients with 1 to 3 metastases. The authors
reported significantly lower rates of local recurrence for patients receiving
SRS to the resection cavity and concluded that SRS could be a safe alternative
to WBRT in this setting.
 Current CNS guidelines recommend SRS after surgical resection for single
metastases to establish local control (level III evidence).

51. NOVEL THERAPIES
 Alternating Electric Field Therapy/Tumor Treating Fields/TTFields:
• A noninvasive treatment; also studied in primary intracranial tumors; Work by
delivering electric fields at varying intensity and frequency throughout the
brain parenchyma, which causes apoptosis in rapidly dividing cells by
disrupting the mitotic spindle; There is currently no evidence to support
TTFields for the treatment of brain metastases other than some early in vitro
studies.
 Laser Interstitial Thermocoagulation Therapy:
• Magnetic resonance guided LITT using a neodymium-doped yttrium
aluminum garnet (Nd:YAG) laser is a minimally invasive operative technique
that can be used to precisely ablate intracranial targets.
• The development of magnetic resonance thermography for real-time
temperature feedback during ablation has made LITT a feasible option in the
management of brain tumors. Evidence to support the use of LITT for brain
metastases is still nascent and consists primarily of small retrospective and pilot
studies.

52.  A 2018 multicenter prospective study reporting the results of the Laser
Ablation After Stereotactic Radiosurgery (LAASR) trial has provided the
strongest evidence to support LITT for biopsy confirmed recurrent metastases.
The authors concluded that as a salvage treatment for patients with few
cytoreductive alternatives, LITT preserved cognition and quality of life in the
majority of cases. LITT is often used for surgical candidates who would benefit
from direct reduction of tumor burden in whom gross total resection would be too
difficult to achieve.
• However, current CNS guidelines state that there is insufficient evidence to
make a recommendation for the routine use of LITT in patients with brain
metastases, and additional studies are needed.

53. METASTASES FROM RCC, MELANOMA, AND SARCOMA
• Brain metastases from RCC, melanoma, and sarcoma have been known
to be “radioresistant” to conventional WBRT. With the advent of
stereotactic radiotherapy, it was thought that these radioresistant metastases
would also exhibit similar resistance patterns to SRS. However, early studies
of SRS reported similar rates of local control regardless of histology.
• Additionally, there is some retrospective evidence to suggest that neither
surgical resection nor WBRT added to SRS contributes to overall survival.
Clear management guidelines for these radioresistant metastases are still not
established because of a lack of concrete evidence, and more studies are
needed.

54. (A) Left posterior thalamic brain metastasis from lung cancer treated with stereotactic radiosurgery. (B) Three-month post-
radiosurgery scan demonstrates reduction in size. (C) One-year post-radiosurgery scan demonstrates enlargement of the lesion.
(D) Coronal and (E) sagittal intraoperative MRI scans demonstrating placement of a probe to treat the enlarging lesion with laser
interstitial thermal therapy (LITT). (F) Axial postcontrast MRI 1 year after LITT demonstrating further regression of the lesion.

55. LEPTOMENINGEAL DISEASE
• Leptomeningeal carcinomatosis, carcinomatous meningitis, or LMD is a rare, late
stage complication of intracranial disease and refers to multifocal seeding of the
leptomeninges (piamater, arachnoid mater, subarachnoid space) with tumor.
• LMD is estimated to occur in 5%-8% of patients with systemic malignancy and is
most commonly associated with breast cancer, melanoma, acute lymphoblastic
leukemia, non-Hodgkin lymphoma, and lung cancers.
• LMD can occur in one of two ways, either by direct extension of a mass adjacent to
the meninges or by intraoperative seeding of the tumor mass along the resection
cavity (piecemeal resection technique contributes a higher risk for LMD than en bloc
resection).
• LMD in the context of systemic malignancy is a devastating diagnosis with median
survival estimated at 4-8 weeks in untreated patients.
• Aggressive multimodality therapy is indicated for palliation of symptoms and
preservation of neurological function, although this does not significantly extend
survival.

56. • WBRT is given in standard dosing (30 Gy in 10 fractions), although this has no
survival benefit for LMD patients.
• Intrathecal administration of chemotherapeutics, typically with a ventricular
reservoir, is considered the standard of care for most cases of LMD, although the
benefit of direct CSF administration is poorly understood, and concerns exist
regarding the associated drug specific toxicity profiles.
• Methotrexate, cytarabine, and thiotepa are common chemotherapeutics
administered to LMD patients; however, there are few data comparing their
efficacy.
• Furthermore, various experimental cancer therapies including antimetabolites
(e.g., pemetrexed), systemic small-molecule TKIs (e.g., gefitinib), and
monoclonal antibodies (e.g., bevacizumab, trastuzumab, rituximab) are
increasingly being explored for the management of LMD with some success.

57. Re-irradiation
• Current guidelines for the management of brain metastases recommend
craniotomy for locally recurrent tumors after initial resection or SRS.
• Evidence to support reirradiation for recurrent brain metastases is emerging,
both for establishing local control and for palliation of symptoms.
• However, these studies are small and retrospective in nature, and none directly
compare the efficacy and safety of reirradiation with WBRT to SRS.
• Thus, clinicians should use caution when treating these patients and carefully
evaluate the cumulative dose, time from the last radiation dose, and status of
extracranial disease.

58. CHEMOTHERAPY
 Novel chemotherapeutics are increasingly emerging with the ability to
cross the BBB as a result of high lipid solubility and small molecular
structure.
 Further, there is evidence to suggest that intracerebral tumors compromise
the integrity of the BBB to allow passage of molecules that would otherwise
be unable to enter into the CSF.
 Additionally, the advent of numerous immunotherapy drugs for the
management of several brain metastasis histologies has transformed the
current standard of care, particularly for NSCLC, breast cancer, and
melanoma.

59. Lung Cancer
• SCLC brain metastases have been known to be sensitive to a variety of chemotherapeutics
despite the presence of the BBB, with reported response rates of 53%-85%.
• Teniposide, topotecan, and irinotecan are topoisomerase inhibitors that have been
extensively studied in the treatment of SCLC metastases, both intracranial and
extracranial.
• Combined therapy with WBRT and teniposide had higher complete response rates than
teniposide alone, although this did not confer an overall survival benefit.
• It is known that NSCLC has limited chemosensitivity by the time it metastasizes to
the brain, thus it is less responsive than SCLC to systemic chemotherapy.
• Additionally, patients with known oncogenic drivers, including EGFR mutation or
ALK rearrangement not only have a particularly high incidence of brain metastases, but
can be treated with therapies directly targeted to their specific disease.

60. • For patients with EGFR-mediated NSCLC, first- and second-generation EGFR
TKIs are active within the CNS, including getfitinib, afatinib, and erlotinib;
associated with a 35%-55% response rate and prolonged survival when compared
with non-EGFR-mutated NSCLC brain metastases.
• Osimertinib is a novel anti-EGFR agent that has been shown to have better BBB
penetration than previous TKIs. After a phase 3 trial found significantly longer median
progression-free survival in NSCLC patients treated with osimertinib compared with
other TKIs.
• For ALK-rearranged NSCLC brain metastases, the administration of specific TKIs
including crizotinib, alectinib, brigatinib, and ceritinib has been established by phase
3 studies. The results of the J-ALEX study in 2017 found alectinib to be superior to
crizotinib in prolonging progression-free survival, thus shifting the standard of care.
• Immunotherapies directed against lymphocytic programmed cell death protein 1
(PD-1) (e.g., pembrolizumab, nivolumab) have also been shown to promote survival
in patients with NSCLC expressing PD-L1. Although this therapy has become the
standard of care for select patients and is increasingly utilized in the multimodality
management of NSCLC.

61. Breast Cancer
• Multiple chemotherapeutic agents have been used to treat metastatic breast carcinoma
including fluorouracil, methotrexate, doxorubicin, cyclophosphamide, capecitabine,
temozolomide, and etoposide.
• Despite the poor BBB penetration of many of these compounds, many have shown to
affect a response in brain metastases because of increased vascular permeability in and
around the tumor and malignant disruption of the BBB.
• For patients with HER2-mutated breast cancer CNS metastases, a 2009 multicenter
phase 2 study reported “modest” intracranial antitumor activity of lapatinib, a small-
molecule inhibitor of EGFR and HER2, with 40% of the cohort observed to have a ≥
20% volumetric reduction of their brain metastases.
• Trastuzumab is an anti-HER2 monoclonal antibody that has been shown to have some
CNS activity based on retrospective evidence.
• Neratinib is a more recently developed TKI that has been shown to be effective against
refractory HER2- mutated breast cancer intracranial metastases when combined with
capecitabine.

62. Melanoma
• Currently, no chemotherapeutics have been shown to be effective in the
treatment of melanoma brain metastases. However, numerous targeted and
immunotherapies have been described.
• For patients with V600 BRAF-mutated melanoma, combined
dabrafenib/trametinib and vemurafenib, all BRAF inhibitors, have been
studied.
• A 2017 phase 2 trial of combined dabrafenib and trametinib for brain
metastases reported an intracranial response rate of 58%.
• It is important to note that many BRAF inhibitors have been associated with
increased radiotoxicity following WBRT, thus current guidelines recommend
holding these drugs for at least 3 days before and after WBRT.

63. • Nivolumab and ipilimumab are two monoclonal antibodies that have been
separately studied for the treatment of melanoma brain metastases.
• Ipilimumab is an inhibitor of cytotoxic T-lymphocyte–associated protein
type 4 (CTLA-4) that is shown to confer an intracranial response.
• Similarly, nivolumab is a PD-1 inhibitor that is shown to be active against
melanoma brain metastases.
• A 2018 phase 2 RCT by Tawbi et al. found a significant benefit with combined
nivolumab and ipilimumab that has since defined this regimen as the standard
of care in multimodality treatment of melanoma brain metastases.

64. Current Recommendations
• In the approach to management of patients with brain metastases, current CNS
guidelines state that cytotoxic chemotherapy alone is insufficient and does not
provide a survival benefit (level I evidence).
• Within the context of multimodality therapy, however, the order of therapy has
been shown to be significant. Guidelines recommend that although combined
chemotherapy with SRS is recommended (level II evidence) and provides a
survival benefit, it should not be administered post-SRS (level I evidence).
• Similarly, combined temozolomide with WBRT is recommended for
discovered metastases from triple-negative breast cancer (level III evidence)
but should not be administered following cranial irradiation (level I
evidence).

65. *Current data support use of SRS for up to three BMs. However, there is a
trend toward using SRS in treatment of up to 10 BMs; OM,
oligometastases; POD, progression of disease; PS, performance status; PT,
primary tumor.

66. Radiotherapy (RT) recommendations

67. CONCLUSION
 The approach to and management of brain metastases has changed drastically
over the past few decades. Namely, the dominance of WBRT as an adjunctive
radiation therapy has shifted to SRS because of less radiotoxicity and
associated cognitive decline.
 Despite this, novel radiation delivery techniques including HA-WBRT show
promise as a safer cranial irradiation technique for palliative therapy
because of increased understanding of the toxicity profile of WBRT and
advances in radiation delivery technology.
 This becomes especially relevant with emerging data suggesting that the smaller
radiation treatment field of SRS contributes to higher rates of
leptomeningeal and/or pachymeningeal metastatic disease in the absence of
WBRT.

68.  New technologies and techniques for cortical mapping have allowed for
safer, more precise, and more aggressive resections with less risk for
neurological morbidity in the postoperative period.
 Furthermore, there has been a multitude of targeted therapies and
immunotherapies with demonstrated activity in the CNS that is continually
shaping the full multimodality brain metastases therapy regimen.
 Moving forward, clinicians and surgeons will have to keep an understanding
of the ever-changing therapeutic arena to provide the highest quality care for
these patients.

69. References:
• Youmans and Winn neurological surgery 8th edition
• Schmidek and Sweet: Operative Neurosurgical Techniques 6th edition
• Ramamurthi & Tandon's textbook of neurosurgery 3rd edition
• Internet
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