Imaging in Glioblastoma Multiforme: Diagnosis, Treatment ...eradiology.bidmc.harvard.edu/LearningLab/central/Mak.pdf · Imaging in Glioblastoma Multiforme: Diagnosis, Treatment, and

Imaging in Imaging in

GlioblastomaGlioblastoma

MultiformeMultiforme: :

Diagnosis, Treatment, Diagnosis, Treatment,

and Followand Follow--UpUp

Kimberley Kimberley MakMak, HMS III, HMS III

Gillian Lieberman, MDGillian Lieberman, MD

Harvard Medical SchoolHarvard Medical School

Radiology Clerkship, BIDMCRadiology Clerkship, BIDMC

May 19th, 2008May 19th, 2008K Mak

Overview of Management:Overview of Management:

Clinical and Radiologic PresentationClinical and Radiologic Presentation

Adapted from LJ Adapted from LJ CeruloCerulo, , http://www.cinn.org/crarticles/CRhttp://www.cinn.org/crarticles/CR--gliomas.htmlgliomas.html

Patient 1Patient 1

�� 52 M presents with 2 month 52 M presents with 2 month h/oh/o bifrontalbifrontalheadaches worsened by cough or headaches worsened by cough or ValsavaValsava

�� Head CT performed in EDHead CT performed in ED

Clinical Presentation

Patient 1: Mass on Head CTPatient 1: Mass on Head CT

�� Large mass in R frontal Large mass in R frontal

lobe with extensive lobe with extensive

surrounding surrounding edema edema

crossing corpus crossing corpus

callosumcallosum** into into

contralateral frontal lobecontralateral frontal lobe

�� 7.3 mm leftward midline 7.3 mm leftward midline

shift and compression of shift and compression of

R lateral and 3R lateral and 3rdrd

ventriclesventricles

Radiologic Presentation

3.6 x 5.2 cm

PACS, BIDMC

Axial Head CT: Contrast -

Patient 1: Mass on Head CTPatient 1: Mass on Head CT�� GamutsGamuts DDxDDx for common low attenuation for common low attenuation

supratentorialsupratentorial lesions on CT:lesions on CT:

�� InfarctInfarct

�� Edema (Edema (vasogenicvasogenic vs. vs. cytotoxiccytotoxic))

�� AstrocytomaAstrocytoma (including GBM)(including GBM)

�� MetastasisMetastasis

�� Hematoma (3Hematoma (3--6 wk)6 wk)

�� Cyst Cyst

�� Cystic neoplasmCystic neoplasm

�� AbscessAbscess

�� GranulomaGranuloma

�� Multiple sclerosis (Multiple sclerosis (periventricularperiventricular))

�� Narrowed Narrowed DDxDDx for corpus for corpus callosumcallosum edema edema (Courtesy Dr. Lee)(Courtesy Dr. Lee)

�� GBMGBM

�� Primary CNS lymphomaPrimary CNS lymphoma

�� MetastasisMetastasis

�� DemyelinationDemyelination

� Hypodensity extending through cortex to surface of brain

� Corpus callosum edema

Highly suspicious for Glioblastoma multiforme]

Radiologic Presentation

3.6 x 5.2 cm

PACS, BIDMC

Axial Head CT, Contrast -

GlioblastomaGlioblastoma MultiformeMultiforme: : WhatWhat’’s in a name?s in a name?

�� Harvey Cushing and Percival Bailey coined the term Harvey Cushing and Percival Bailey coined the term in 1926in 1926

�� Malignant cells thought to be derived from Malignant cells thought to be derived from ““GlioblastsGlioblasts””, the most primitive precursors of , the most primitive precursors of glialglialcells: cells:

�� Now thought to be misnomer: malignant cells Now thought to be misnomer: malignant cells arise from dedifferentiated mature cellsarise from dedifferentiated mature cells

�� ““MultiformeMultiforme”” as complex and highly variable as complex and highly variable morphologymorphology

GlioblastomaGlioblastoma MultiformeMultiforme: : WhatWhat’’s in a name?s in a name?

�� Classified as Grade IV Classified as Grade IV astrocytomaastrocytoma by 1993 WHO criteria:by 1993 WHO criteria:

PoorlyPoorly--differentiated, differentiated, increased increased cellularitycellularity; variable mitotic ; variable mitotic

activity; activity; prominent vascular proliferation or necrosisprominent vascular proliferation or necrosisGlioblastomaGlioblastoma

MultiformeMultiformeIVIV

PleomorphismPleomorphism and nuclear and nuclear atypiaatypia;; increased increased cellularitycellularity and and

mitotic activity; no vascular proliferation or necrosismitotic activity; no vascular proliferation or necrosisAnaplasticAnaplastic

astrocytomaastrocytomaIIIIII

Diffusely infiltrating, Diffusely infiltrating, wellwell--differentiated; minimal differentiated; minimal pleomorphismpleomorphism

or nuclear or nuclear atypiaatypia; no vascular proliferation or necrosis; no vascular proliferation or necrosisAstrocytomaAstrocytomaIIII

Generally benign, wellGenerally benign, well--circumscribed; most common example is circumscribed; most common example is

juvenile juvenile pilocyticpilocytic astrocytomaastrocytomaCircumscribed Circumscribed

astrocytomaastrocytomaII

CharacteristicsCharacteristicsNameNameWHOWHO

GradeGrade

�� Regardless of initial grade at diagnosis, all diffuse Regardless of initial grade at diagnosis, all diffuse astrocytomasastrocytomas tend to progress tend to progress

to GBMto GBM

Peripheral location, resembling dural process

Large intra-axial hemorrhage‘Cyst with a nodule’Multifocal

Posterior fossa Leptomeningeal

All images from Rees et al.

Diagnosis: Examples of “Multiforme” Appearances of GBM on Head CT and MRI

EpidemiologyEpidemiology

�� MOST COMMON primary brain MOST COMMON primary brain malignancy in adults malignancy in adults

�� 20% of all primary brain tumors20% of all primary brain tumors

�� 1212--15% of all intracranial 15% of all intracranial neoplasmsneoplasms

�� Annual incidence 15,000Annual incidence 15,000--20,00020,000

�� Male:femaleMale:female = 1.6:1 = 1.6:1

�� Caucasian > African, Asian, Latin Caucasian > African, Asian, Latin AmericanAmerican

�� Most frequently in cerebral hemisphere Most frequently in cerebral hemisphere at 45at 45--70 yr70 yr

�� Primary GBM if no evidence of precursor Primary GBM if no evidence of precursor lesion, mean age 55 yrlesion, mean age 55 yr

�� Secondary GBM if progression of Secondary GBM if progression of existing existing astrocytomaastrocytoma, mean age 40 yr, mean age 40 yr

�� Rarely in cerebellum, spinal cord and Rarely in cerebellum, spinal cord and childrenchildren

�� 2nd most common cause of death due 2nd most common cause of death due to intracranial disease after stroketo intracranial disease after stroke

�� Very poor prognosis: despite surgical Very poor prognosis: despite surgical resection with adjuvant resection with adjuvant chemoradiationchemoradiation, , median survival 12median survival 12--14 14 monthsmonths

�� 90% die within 18 months from 90% die within 18 months from diagnosisdiagnosis

�� 55--yr survival 3.3% yr survival 3.3%

�� Without therapy, survival is <6 monthsWithout therapy, survival is <6 months

�� No substantial improvement in survival No substantial improvement in survival since 1970ssince 1970s

SymptomsSymptoms

�� LocalizingLocalizing signs such as focal neurologic deficits, signs such as focal neurologic deficits, seizures, behavioral changes, or seizures, behavioral changes, or strokelikestrokelike symptomssymptoms

�� NonNon--localizinglocalizing symptoms such as severe headaches, symptoms such as severe headaches, tonictonic--clonicclonic seizures, seizures, JacksonianJacksonian seizuresseizures

�� Uncommonly Uncommonly asymptomaticasymptomatic and diagnosed as incidental and diagnosed as incidental finding for e.g. head traumafinding for e.g. head trauma

�� Most common symptoms:Most common symptoms:�� Headache (30Headache (30--50%) 50%)

�� Seizures (30Seizures (30--60%)60%)

�� Focal neurologic deficits (40Focal neurologic deficits (40--60%)60%)

Diagnosis of GBMDiagnosis of GBM

�� Made by imagingMade by imaging prior to tissue diagnosis prior to tissue diagnosis

�� CT +/CT +/-- contrast contrast offers information on calcification (rare in GBM)offers information on calcification (rare in GBM)

�� MRI +/MRI +/-- contrast contrast modality of choicemodality of choice

�� Improved capacity for tumor detection vs. CT because of Improved capacity for tumor detection vs. CT because of superior softsuperior soft--tissue resolutiontissue resolution

�� High sensitivity with standard T1High sensitivity with standard T1-- and T2and T2--weighted MRIweighted MRI

�� Typically see a large, heterogeneous mass in Typically see a large, heterogeneous mass in supratentorialsupratentorialwhite matter white matter

�� Defining features: hemorrhage and necrosisDefining features: hemorrhage and necrosis

�� Surrounding Surrounding ““fingers of edemafingers of edema”” (extensive) (extensive)

�� Usually considerable mass effectUsually considerable mass effect

Patient 2: Mass on Head CTPatient 2: Mass on Head CT

�� 64 M with left64 M with left--sided weakness sided weakness for 3 months, for 3 months, s/ps/p 2 falls2 falls

�� 7x7x8 cm area of low 7x7x8 cm area of low attenuationattenuation consistent with consistent with vasogenicvasogenic edemaedema in R frontal in R frontal lobe surrounding large masslobe surrounding large mass

�� Edema in corpus Edema in corpus callosumcallosum

�� Significant Significant mass effectmass effect with with compression of R lateral and compression of R lateral and 33rdrd ventricles, ventricles, subfalcialsubfalcialherniationherniation and 2.5 cm L and 2.5 cm L displacement of septum displacement of septum pellucidumpellucidum

�� No calcificationsNo calcifications

Diagnosis

PACS, BIDMC

Axial Head CT, Contrast -

Classic Buzzword Appearance: Classic Buzzword Appearance: ““ButterflyButterfly””

�� RimRim--enhancing mass enhancing mass crosses midline via the crosses midline via the corpus corpus callosumcallosum

�� DdxDdx is is narrow: narrow: �� High grade High grade astrocytomaastrocytoma

(usually GBM)(usually GBM)

�� Primary CNS lymphomaPrimary CNS lymphoma

�� Edema or infection unlikely Edema or infection unlikely to cross midlineto cross midline

�� Most frequently in frontal Most frequently in frontal lobes, but can be lobes, but can be posterior posterior

Diagnosis

Gaillard, http://www.radpod.org/2007/04/21/butterfly-glioma/

Coronal Head MRI (T1), Contrast +

Patient 1: T1Patient 1: T1--Weighted MRIWeighted MRI

�� Area of Area of low signal low signal intensityintensity in R frontal lobein R frontal lobe

Axial Head MRI (T1), Contrast -

�� 4.7 X 3.6 x 4.2 cm 4.7 X 3.6 x 4.2 cm heterogeneously rimheterogeneously rim--enhancing, necroticenhancing, necrotic lesionlesion

Diagnosis

PACS, BIDMCPACS, BIDMC

Axial Head MRI (T1), Contrast +

DDxDDx RimRim--enhancing lesionenhancing lesion

�� MM etastasisetastasis

�� AA bscessbscess

�� GG liomalioma (GBM)(GBM) or or

11o o CNS lymphomaCNS lymphoma

�� II nfarctionnfarction

�� CC ontusionontusion

�� DD emyelinationemyelination

�� RR esolvingesolving hematomahematoma

Diagnosis

PACS, BIDMC

PACS, BIDMC

Coronal Head MRI (T1), Contrast +

Sagittal Head MRI (T1), Contrast +

�� Heterogeneous enhancement due to hemorrhage Heterogeneous enhancement due to hemorrhage with blood products in various stages of liquidity or with blood products in various stages of liquidity or oxidation, necrosis, and edemaoxidation, necrosis, and edema

Patient 1: T2Patient 1: T2--Weighted MRIWeighted MRI

�� Heterogeneously enhancing lesionHeterogeneously enhancing lesion

�� Extensive surrounding edema in Extensive surrounding edema in vasogenicvasogenic patternpattern

�� SulciSulci effacedeffaced in brain surrounding lesionin brain surrounding lesion

�� ““Fluid attenuated inversion recoveryFluid attenuated inversion recovery””sequencesequence

�� CSF suppressed CSF suppressed while edema while edema enhancedenhanced

Diagnosis

PACS, BIDMCPACS, BIDMC

Patient 1: MRI (FLAIR)Patient 1: MRI (FLAIR)Axial Head MRI (T2) Axial Head MRI (FLAIR)

Patient 1: MRI Patient 1: MRI -- Susceptibility Weighted Imaging (SWI)Susceptibility Weighted Imaging (SWI)

�� Exploits magnetic Exploits magnetic susceptibility susceptibility differences of various differences of various tissues such as blood, tissues such as blood, Fe, calcificationFe, calcification

�� Demonstrates Demonstrates hemorrhage and hemorrhage and calcificationcalcification

�� Levels of Levels of ferritinferritin and and transferrintransferrin receptors receptors correlated with human correlated with human grade in human grade in human gliomasgliomas

Diagnosis

PACS, BIDMC

No evidence of hemorrhageNo evidence of hemorrhage

Axial Head MRI (SWI)

Perfusion MRIPerfusion MRI

�� Relative tumor blood Relative tumor blood volume (volume (rTBVrTBV): ratio of ): ratio of maximal tumor blood maximal tumor blood volume to region of interest volume to region of interest in normal white matter. in normal white matter.

�� Increases with Increases with neoplasm grade neoplasm grade

�� Exception: lowException: low--grade grade oligodendrogliomasoligodendrogliomas(high (high rTBVrTBV))

�� NeoplasmsNeoplasms have increased have increased permeability parameters on permeability parameters on imaging due to abnormal imaging due to abnormal angiogenesisangiogenesis

T1W

WHO Grade III

rTBV

WHO Grade IV (GBM)

WHO Grade II

Cha et al.

Diagnosis

Axial Head Perfusion MRIs

Magnetic Resonance Spectroscopy (MRS)Magnetic Resonance Spectroscopy (MRS)

Al-Okaili et al.

�� Analyzes chemical Analyzes chemical composition of a brain composition of a brain region to assist in region to assist in differentiating tumor from differentiating tumor from other lesionsother lesions

�� Helpful in determining Helpful in determining extent of tumor within extent of tumor within volume of T2 signal volume of T2 signal change (edema)change (edema)

Diagnosis

Magnetic Resonance Magnetic Resonance

Spectroscopy (MRS)Spectroscopy (MRS) ELEVATED IN GBM:ELEVATED IN GBM:

�� CHOLINECHOLINE:: in all cell membranes, in all cell membranes, thus increased with cell thus increased with cell membrane turnover membrane turnover

�� LACTATELACTATE:: product of anaerobic product of anaerobic respiration, thus respiration, thus increased in increased in necrotic tumors, necrotic tumors, infection or infection or strokestroke

�� LIPIDLIPID: : indicates necrosis, thus indicates necrosis, thus increased inincreased in highhigh--grade grade neoplasmsneoplasms

�� Elevated Elevated Choline:CreatineCholine:Creatine ratio ratio >1 distinguishes tumor from >1 distinguishes tumor from abscess (Se 79%, Sp 77%; abscess (Se 79%, Sp 77%; accuracy increased using accuracy increased using additional MRS variables)additional MRS variables)

Al-Okaili et al.

Diagnosis

Magnetic Resonance Magnetic Resonance

Spectroscopy (MRS)Spectroscopy (MRS)

Al-Okaili et al.

Diagnosis

DECREASED IN GBM:DECREASED IN GBM:

�� CREATINE:CREATINE: marker of cellular marker of cellular bioenergetics, bioenergetics, decreased to decreased to varying degrees in GBMvarying degrees in GBM

�� NN--ACETYLASPARTATE ACETYLASPARTATE (NAA)(NAA): : byproduct of byproduct of neurotransmitter glutamate, neurotransmitter glutamate, thus found in synaptic thus found in synaptic terminals of neurons and terminals of neurons and decreased in decreased in gliomasgliomas

Overview of Management: Surgery and PathologyOverview of Management: Surgery and Pathology


Tissue DiagnosisTissue Diagnosis

�� Done at time of surgical resectionDone at time of surgical resection

�� In cases where lesion not amenable to resection In cases where lesion not amenable to resection

(deeply situated, or diffuse and non(deeply situated, or diffuse and non--focal), or focal), or

the patientthe patient’’s clinical condition will not permit s clinical condition will not permit

surgery, stereotactic biopsy is performedsurgery, stereotactic biopsy is performed

Pathology

Stereotactic Brain BiopsyStereotactic Brain Biopsy

�� CT or MRI performed with rigid frame CT or MRI performed with rigid frame including including fiducialfiducial bars fixed to the bars fixed to the skull to eliminate movementskull to eliminate movement

�� Or Or ““framelessframeless”” stereotactic device with stereotactic device with fiducialfiducial markers placed on scalp markers placed on scalp before imagingbefore imaging

�� Coordinates created to pass needle Coordinates created to pass needle within 1 mm accuracy to biopsy within 1 mm accuracy to biopsy target, guided by known location of target, guided by known location of the the fiducialsfiducials relative to target relative to target

�� Use of PET, perfusion imaging, or MRS Use of PET, perfusion imaging, or MRS may assist selection of biopsy site may assist selection of biopsy site most likely to contain most aggressive most likely to contain most aggressive portion of tumorportion of tumor

�� U/S guidance also usedU/S guidance also used

Both images from http://www.sd-neurosurgeon.com/practice/stereotactic.html

Pathology

Patient 1: Patient 1:

Surgical planning with Surgical planning with

Axial MRI (MP RAGE)Axial MRI (MP RAGE)

�� HighHigh--resolution resolution

T1W sequenceT1W sequence

�� Used in preUsed in pre--

operative operative

planning with 3D planning with 3D

reconstructionreconstruction

Treatment: Surgery

PACS, BIDMCAxial Head MRI (MP RAGE)

Rationale: Gross Total ResectionRationale: Gross Total Resection

�� Balancing maximal Balancing maximal cytoreductioncytoreduction vs. preservation of neurologic functionvs. preservation of neurologic function

�� Because of diffuse tumor infiltration of grossly normal brain, Because of diffuse tumor infiltration of grossly normal brain, ““completecomplete””resectionresection”” not realisticnot realistic

�� Retrospective studies indicate patients with Retrospective studies indicate patients with gross gross total resections have total resections have longer median survival compared to those with subtotal resectionlonger median survival compared to those with subtotal resection

�� Due to therapeutic benefit vs. selection bias for those with lesDue to therapeutic benefit vs. selection bias for those with less extensive s extensive tumors?tumors?

�� Decreases mass effects (edema, hydrocephalus, impending Decreases mass effects (edema, hydrocephalus, impending herniationherniation))

Linskey, http://neurosurgery.uci.edu/articles/iomr.shtml

Treatment: Surgery

ImageImage--guided Surgical Planningguided Surgical Planning

Gross Total Resection: A Stereotactic ApproachGross Total Resection: A Stereotactic Approach

�� Frameless, imageFrameless, image--guided guided neuronavigationneuronavigation system displays location of system displays location of

surgical instruments and tumor superimposed on presurgical instruments and tumor superimposed on pre--operative MR or CT operative MR or CT

imagesimages

�� Imaging updated Imaging updated intraoperativelyintraoperatively using U/S, CT or MRIusing U/S, CT or MRI

Waterford, http://www.informatik.umu.se/~jwworth/3ApplicationAreas

Treatment: Surgery

IntraoperativeIntraoperative MRIMRI

Overview of Management: Adjuvant Overview of Management: Adjuvant ChemoradiationChemoradiation

Therapy (CRT)Therapy (CRT)


Rationale for Adjuvant therapyRationale for Adjuvant therapy

�� High recurrence rate with gross total resection alone, due to inHigh recurrence rate with gross total resection alone, due to infiltrative nature filtrative nature of tumorof tumor

�� Adjuvant whole brain RT (WBRT) shown to improve survival in at lAdjuvant whole brain RT (WBRT) shown to improve survival in at least 3 east 3 randomized trials in 1970srandomized trials in 1970s

�� Representative trial from Brain Tumor Study Group: median survivRepresentative trial from Brain Tumor Study Group: median survival al increased from 14 to 36 weeks with addition of adjuvant WBRT to increased from 14 to 36 weeks with addition of adjuvant WBRT to surgical surgical resectionresection

�� Additional survival benefit when chemotherapy added to RTAdditional survival benefit when chemotherapy added to RT

�� TemozolomideTemozolomide (oral (oral alkylatingalkylating agent) is current standard agent for agent) is current standard agent for adjuvant chemotherapy in GBMadjuvant chemotherapy in GBM

�� Phase III trial in which 573 patients with GBM randomized to invPhase III trial in which 573 patients with GBM randomized to involvedolved--field field RT (60 RT (60 GyGy in 30 fractions) versus the same RT plus concomitant then in 30 fractions) versus the same RT plus concomitant then adjuvant adjuvant temozolomidetemozolomide

�� Adjuvant Adjuvant temozolomidetemozolomide increased overall survival from 12.1 months to increased overall survival from 12.1 months to 14.6 months14.6 months

�� Adjuvant Adjuvant temozolomidetemozolomide 22--year survival increased from 10% to 26%year survival increased from 10% to 26%

Treatment: Adjuvant Chemoradiation Therapy (CRT)

Treatment: Adjuvant Chemoradiation Therapy (CRT)

Imaging in Radiotherapy (RT) PlanningImaging in Radiotherapy (RT) Planning

�� Improvements in imaging have translated into increased accuracy Improvements in imaging have translated into increased accuracy of of radiotherapyradiotherapy

�� PostPost--op Day 1 imaging obtained to assess for extent of resection and op Day 1 imaging obtained to assess for extent of resection and for RT for RT planningplanning

�� ThinThin--slice (<3mm) slice (<3mm) CTCT +/+/-- contrast contrast for treatment planningfor treatment planning

�� PostPost--op MRIop MRI fused with this for definition of target volume fused with this for definition of target volume

�� T2 or FLAIR abnormalityT2 or FLAIR abnormality contoured as contoured as clinical target volume (CTV)clinical target volume (CTV), with , with assumption that edematous region is at risk for microscopic tumoassumption that edematous region is at risk for microscopic tumor r extension. extension.

�� Compared with preCompared with pre--op MRI to ensure postop MRI to ensure post--op changes such as op changes such as hemorrhage not confused with tumor hemorrhage not confused with tumor

�� This volume targeted to 45This volume targeted to 45--50 50 GyGy..

�� PostPost--contrast T1 contrast T1 images define images define gross tumor volume (GTV)gross tumor volume (GTV). If gross . If gross complete resection, then resection cavity is GTV. complete resection, then resection cavity is GTV.

�� Boost to GTV for total dose of 60 Boost to GTV for total dose of 60 GyGy..

�� Can also calculate CTV as GTV + 2 cm marginCan also calculate CTV as GTV + 2 cm margin

�� Commonly used method of fractionated (conventional) RT, with totCommonly used method of fractionated (conventional) RT, with total dose of 60 al dose of 60 GyGyadministered in daily doses of 1.8administered in daily doses of 1.8--2 2 GyGy dosesdoses�� Principle that small does of radiation impart greatest damage toPrinciple that small does of radiation impart greatest damage to rapidly proliferating rapidly proliferating

tumor cells, as normal cells can repair tumor cells, as normal cells can repair sublethalsublethal levels of DNA damagelevels of DNA damage

�� Use of crossUse of cross--sectional images in 3 planes to create 3Dsectional images in 3 planes to create 3D--planningplanning

�� Radiation dose to tumor and normal tissue calculated in 3D, alloRadiation dose to tumor and normal tissue calculated in 3D, allowing design of wing design of treatment plans that treatment plans that limit dose to normal tissue e.g. brainstemlimit dose to normal tissue e.g. brainstem

Treatment: Radiotherapy

33--Dimensional Conformal RT (3DDimensional Conformal RT (3D--CRT) PlanningCRT) Planning

BrainstemBrainstem

GTVGTV

CTVCTV

Radiation Oncology, BIDMC

3D3D--CRT Planning Continued:CRT Planning Continued:

3D3D--Reconstruction of PatientReconstruction of Patient


http://www.varian.com/us/oncology/radiation_oncology/clinac/clinac_21ex23ex.html

BrainstemBrainstem

GTVGTV

CTVCTV

Radiation Oncology, BIDMCRadiation Oncology, BIDMC

Linear Linear

Accelerator Accelerator

(LINAC) (LINAC)

used to used to

deliver RTdeliver RT

3DRT Planning Continued:3DRT Planning Continued:

3D Reconstruction of Patient3D Reconstruction of Patient

�� Critical structures such as Critical structures such as eyeseyes, , optic nerveoptic nerve, optic , optic chiasm, and chiasm, and brain stembrain stem demonstrateddemonstrated



BrainstemBrainstem

GTVGTV

CTVCTV

IntensityIntensity--Modulated RT (IMRT)Modulated RT (IMRT)

�� Specialized 3DSpecialized 3D--CRT technique whereby radiation intensity is varied across each CRT technique whereby radiation intensity is varied across each treatment field treatment field to maximize radiation dose to tumor and minimize dose to normal to maximize radiation dose to tumor and minimize dose to normal tissuetissue�� Thus ideal for tumors that abut uninvolved radiationThus ideal for tumors that abut uninvolved radiation--sensitive structures (e.g. eyes, optic nerves, optic sensitive structures (e.g. eyes, optic nerves, optic

chiasm, brainstem)chiasm, brainstem)

�� Complexity of RT planning requires adaptation of the hardware ofComplexity of RT planning requires adaptation of the hardware of linear accelerators, skilled linear accelerators, skilled physicist support, and increased planning/delivery timephysicist support, and increased planning/delivery time


BrainstemBrainstem

GTVGTV

CTVCTV


Stereotactic Stereotactic RadiosurgeryRadiosurgery (SRS)(SRS)

�� Role not established in GBMRole not established in GBM

�� Single large dose of radiation to small, Single large dose of radiation to small, preciselyprecisely--defined targetdefined target

�� Invasive stereotactic head frame placed Invasive stereotactic head frame placed followed by CT or MRI to plan treatment followed by CT or MRI to plan treatment relative to landmarksrelative to landmarks

�� Achieved by Achieved by multiple nonmultiple non--parallel beamsparallel beamsconverging on targetconverging on target


Stereotactic Stereotactic RadiosurgeryRadiosurgery (SRS): Continued(SRS): Continued

�� PhotonPhoton--based radiation (based radiation (LinacLinac, Gamma Knife, , Gamma Knife, CyberknifeCyberknife®®) or proton) or proton--basedbased

�� N.B. N.B. CyberknifeCyberknife®® uses mobile linear accelerator that adjusts to patient positionuses mobile linear accelerator that adjusts to patient positionbased on realbased on real--time xtime x--ray camerasray cameras

�� Thus no head frame requiredThus no head frame required


CyberknifeCyberknife®®

http://www.accuray.com/Products/Cyberknife/index.aspx

BrachytherapyBrachytherapy

�� Role not established in GBMRole not established in GBM

�� BrachyBrachy = = ‘‘nearnear’’ in Greek; refers to in Greek; refers to placement of radiation source placement of radiation source within bodywithin body

�� Permits delivery of large RT Permits delivery of large RT dose to tumor with rapid falldose to tumor with rapid fall--off in surrounding tissuesoff in surrounding tissues

�� Radioisotope seeds include Radioisotope seeds include 125125I or I or 192192IrIr

�� Sources loaded into Sources loaded into stereotacticallystereotacticallyplaced catheters, or placed catheters, or intraoperativelyintraoperatively after resectionafter resection

�� GliaSiteGliaSite RT system: RT system: intracavitaryintracavitarydevice implanted after resection of device implanted after resection of tumor: solution of tumor: solution of 125125I injected into I injected into closed catheter balloon, which closed catheter balloon, which inflates to fill resection cavity to inflates to fill resection cavity to deliver in doses of 40deliver in doses of 40--60 60 GyGy 55--10 10 mm from the balloon surface.mm from the balloon surface.

Placement of implant catheters

CT showing 3 implant catheters with 192Ir dummy

sources in place

Injection of catheter balloon in GliaSite RT System


Chin et al.

Chin et al.

http://www.gliasite.com/radiation-therapy/gliasite-what-to-expect.htm

Overview of Management: FollowOverview of Management: Follow--UpUp


�� PostPost--treatment followtreatment follow--up by MRI and up by MRI and

history/physical examhistory/physical exam

�� Normal postNormal post--resection changesresection changes at 10 at 10

and 12 months with Case 2and 12 months with Case 2

�� Limitations with conventional contrastLimitations with conventional contrast--

enhanced MRI or CTenhanced MRI or CT

�� Combinations of abnormal enhancement Combinations of abnormal enhancement

patterns (e.g. multiple lesions, corpus patterns (e.g. multiple lesions, corpus

collosumcollosum involvement) help distinguish involvement) help distinguish

necrosis from tumor progressionnecrosis from tumor progression

�� Use of MRS, perfusion MRI, and PETUse of MRS, perfusion MRI, and PET**

developingdeveloping

Axial Head MRI (T1)

10 months post-resection

Axial Head MRI (T1)

12 months post-resection

Follow-Up

Patient 2: Patient 2: s/ps/p Resection and Adjuvant CRTResection and Adjuvant CRT

PACS, BIDMC

PACS, BIDMC

*A Note on PET*A Note on PET

��1818FF--FDGFDG--PET not commonly used PET not commonly used in primary evaluation of GBM in primary evaluation of GBM

�� High grade High grade gliomasgliomas have have similar uptake to normal grey similar uptake to normal grey matter, thus matter, thus obscuredobscured

�� Arguably may be used to Arguably may be used to distinguish tumor recurrence distinguish tumor recurrence from benign enhancing scar from benign enhancing scar tissue or radiation necrosistissue or radiation necrosis

�� Under development: radiotracers Under development: radiotracers correlating with cell proliferationcorrelating with cell proliferation

�� Thus low background in Thus low background in normal brain normal brain

�� ThymidineThymidine analog, 3analog, 3’’deoxydeoxy--33’’--[[1818FF]Fluorothymidine (FLT): ]Fluorothymidine (FLT): uptake correlates to Kiuptake correlates to Ki--67 67 indexindex

Schmitter, http://gamma.wustl.edu/pt043te113.html

Follow-Up

GBM recurrence detected by FDGGBM recurrence detected by FDG--PETPET

Overview of Management: RecurrenceOverview of Management: Recurrence


Sites of RecurrenceSites of Recurrence

�� GBM spreads most commonly by: GBM spreads most commonly by:

�� 1) 1) Direct local extensionDirect local extension, along white matter tracts , along white matter tracts

�� 2) 2) CSF CSF pathways in <2%pathways in <2%

�� 3) 3) SubependymalSubependymal spread even more uncommon, correlates with spread even more uncommon, correlates with poor prognosis poor prognosis

�� 4) 4) HematogenousHematogenous spread most rare, causing dense spread most rare, causing dense osteoblasticosteoblasticbone lesionsbone lesions

�� Wide margin of resection not often possible due to Wide margin of resection not often possible due to proximity to eloquent brain, but even when possible, proximity to eloquent brain, but even when possible, failure occurs most commonly at resection marginfailure occurs most commonly at resection margin

�� Recall diffuse infiltrative nature of tumorRecall diffuse infiltrative nature of tumor

Recurrence

Patient 2: Recurrence Patient 2: Recurrence

at 14 monthsat 14 months

�� 2 new lesions 2 new lesions suspicious for GBM suspicious for GBM recurrence on recurrence on conventional MRI:conventional MRI:�� 1) 1) 4 cm lesion4 cm lesion in in R R frontal lobefrontal lobe abutting abutting central central sulcussulcus

�� 2) New 2) New 1.6x2.0 cm 1.6x2.0 cm lesionlesion in in L parietal lobeL parietal lobetracking back through tracking back through white matterwhite matter

Axial Head MRI (T1): C+ Axial Head MRI (FLAIR)

Lesion 1

Lesion 2

Recurrence: Imaging

PACS, BIDMC

PACS, BIDMC

Axial Head MRI (T1): C+ Axial Head MRI (FLAIR)

Patient 2: Diffusion Tensor MRI (DTI)Patient 2: Diffusion Tensor MRI (DTI)

�� Extent of directionality of water Extent of directionality of water diffusion can be expressed as a diffusion can be expressed as a fractional anisotropy (FA) valuefractional anisotropy (FA) value�� Water flows along axons in white Water flows along axons in white mattermatter

�� Lesion 2Lesion 2 in L parietal lobe in L parietal lobe causes disruption of white causes disruption of white matter tractmatter tract�� Disruption of white matter tract Disruption of white matter tract potential early sign of recurrencepotential early sign of recurrence

�� Lesion 1Lesion 1 visiblevisible

Recurrence: Imaging

PACS, BIDMC

PACS, BIDMC

Axial Head MRI (DTI)

Axial Head MRI (DTI)

Arterial Spin Arterial Spin LabellingLabelling (ASL)(ASL)

�� ““Endogenous contrast agentEndogenous contrast agent””: :

�� HH220 protons in arterial blood 0 protons in arterial blood

labeled by perturbing their labeled by perturbing their

magnetization with RF pulsesmagnetization with RF pulses

�� Thus nonThus non--invasiveinvasive

�� Higher blood flow and blood Higher blood flow and blood

volume in volume in R frontalR frontal and and L L

parietalparietal recurrencesrecurrences

Recurrence: Imaging

PACS, BIDMC

Axial Head MRI (ASL)

Axial Head MRI (ASL)

Treatment of RecurrenceTreatment of Recurrence

Surgical resection if possible, or biopsy of suspicious lesion

Residual tumor<4-6 cm

Residual tumor>4-6 cm

Necrosis from“treatment effect”

SRS (<4 cm)

Brachytherapy(<6 cm)

Retreatment withRT (3DCRT, IMRT)

Wafer chemotherapy

2nd line chemotherapy(PCV, BCNU, CPT-11)

Retreatment withRT (IMRT)

Further resection

Steroids

Recurrence

Fiveash et al.

Example: Treatment of Multifocal Recurrence with SRS

3

1

2

11


Overview of Management: Salvage and Overview of Management: Salvage and

PrognosisPrognosis


Prognosis in GBM: A Role for Imaging?Prognosis in GBM: A Role for Imaging?

�� Clinical indicators of poor prognosis: Clinical indicators of poor prognosis: �� Extent of necrosisExtent of necrosis

�� Younger age Younger age

�� KarnofskyKarnofsky Performance Status <80Performance Status <80

�� Presence of tumor cystsPresence of tumor cysts

�� 2005 study by Pope 2005 study by Pope et al. et al. in AJNR: Findings on conventional MRI in AJNR: Findings on conventional MRI correlate with survival in GBMcorrelate with survival in GBM�� Edema, Edema, multifocalitymultifocality, and satellite lesions associated with shortened , and satellite lesions associated with shortened

survivalsurvival

�� Presence of nonPresence of non--contrastcontrast--enhancing tumor (likely regions of lower grade enhancing tumor (likely regions of lower grade tumor without necrosis) associated with increased survivaltumor without necrosis) associated with increased survival

�� Studies with Perfusion MRI:Studies with Perfusion MRI:�� Contrast transfer coefficient (Contrast transfer coefficient (KKtranstrans, a reflection of blood flow and , a reflection of blood flow and

endothelial permeability) predicts length of survival in highendothelial permeability) predicts length of survival in high--grade grade gliomasgliomas

Patient OutcomesPatient Outcomes�� Patient 1:Patient 1:

�� Doing well Doing well s/ps/p gross resectiongross resection

�� Will commence adjuvant Will commence adjuvant chemoradiationchemoradiation

(3D(3D--CRT and CRT and temozolomidetemozolomide))

�� Patient 2:Patient 2:

�� Recurrent lesion in R frontal lobe to be Recurrent lesion in R frontal lobe to be

resectedresected, followed by SRS to resection bed, followed by SRS to resection bed

�� Second recurrent lesion in L parietal lobe Second recurrent lesion in L parietal lobe

will be treated by SRSwill be treated by SRS

Axial MRI: T1 C+

PACS, BIDMC

PACS, BIDMC

SummarySummary

�� GBM is the most common primary brain malignancy of adultsGBM is the most common primary brain malignancy of adults

�� DiagnosisDiagnosis is by CT and MRI (other imaging techniques developing)is by CT and MRI (other imaging techniques developing)

�� Defining features of rimDefining features of rim--enhancement, necrosis, and hemorrhageenhancement, necrosis, and hemorrhage

�� Also extensive edema and mass effectAlso extensive edema and mass effect

�� Classic Classic ““butterflybutterfly”” appearance, but can be appearance, but can be ““multiformemultiforme””

�� Tissue diagnosisTissue diagnosis at surgical resection or by stereotactic biopsyat surgical resection or by stereotactic biopsy

�� Stereotactic guidance for both procedures relies on CT or MRIStereotactic guidance for both procedures relies on CT or MRI

�� Perfusion MRI, MRS, PET developing for Perfusion MRI, MRS, PET developing for

�� Standard treatmentStandard treatment is gross resection if possible, followed by adjuvant is gross resection if possible, followed by adjuvant chemoradiationchemoradiation therapytherapy

�� Close Close followfollow--up up by MRI (other imaging techniques developing)by MRI (other imaging techniques developing)

�� Treatment for Treatment for recurrencerecurrence varies varies

�� Very poor prognosis, which may be predicted by imagingVery poor prognosis, which may be predicted by imaging

AcknowledgementsAcknowledgements

Dept. of Radiology, BIDMC:Dept. of Radiology, BIDMC:�� GethinGethin Williams, MD, PhDWilliams, MD, PhD

�� David Hackney, MDDavid Hackney, MD

�� Peter Lee, MDPeter Lee, MD

�� AartiAarti SekharSekhar, MD, MD

�� Maria Maria LevantakisLevantakis

Dept. of Radiation Oncology, BIDMC:Dept. of Radiation Oncology, BIDMC:�� Frank WangFrank Wang

�� Stephanie SullivanStephanie Sullivan

�� Jason FieldsJason Fields

�� LiaLia HalaszHalasz, MD, MD

K Mak

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