penn radiology the roots of radiological excellence tumor or treatment? stay tuned… educational...
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PENN RADIOLOGY
THE ROOTS OF
RADIOLOGICAL
EXCELLENCE
The Evolving Landscape of Post-Therapy Brain Tumor Imaging
Jeffrey Ware, MD, Ronald Wolf, MD, PhD, Harish Poptani,
PhD, Donald O’Rourke, MD, Suyash Mohan, MD
Neuroradiology Division
Department of Radiology
University of Pennsylvania
ASNR 2015 ANNUAL MEETING CHICAGO, IL APRIL 25 – APRIL 30, 2015
Tumor or treatment? Stay tuned…
Educational Exhibit: eEdE-62 Presentation Number: 673
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Perelman School of Medicine at University of Pennsylvania Penn Radiology
Disclosure Statement
Neither the authors nor their immediate family members
have a financial relationship with a commercial
organization that may have a direct or indirect interest in
the content
Baltimore, Maryland
Perelman School of Medicine at University of Pennsylvania Penn Radiology
Background
• Improvements to the standard
treatment of brain gliomas are
resulting in prolonged survival and
better overall outcomes
• New treatments are also bringing
about new and complex imaging
manifestations
This exhibit reviews key concepts in neuro-oncologic imaging essential to accurate radiological assessment in the perioperative and postoperative setting
• Preoperative planning Preoperative mapping Risk-benefit assessment
• Post-therapy imaging Perioperative infarct Pseudoprogression True progression Radiation necrosis Pseudoresponse Treatment response criteria
• Emerging therapies Laser-induced thermal therapy Vaccine and immunotherapies Tumor-treating fields
Outline
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Extent of Resection
Maps of language cortex (left) and white matter tracts
(right) overlaid on anatomic images depict the anatomic
relationship of tumor to nearby eloquent structures
1Sanai N, et al (2011) An extent of resection threshold for newly diagnosed glioblastomas. J Neurosurg 115:3–82McGirt MJ, et al. (2009) Association of surgically acquired motor and language deficits on overall survival after resection of glioblastoma ultiforme. Neurosurgery 65:463–469
• Preoperative mapping of eloquent
cortex and white matter tracts with
fMRI and diffusion tractography,
respectively, allows more informed
surgical planning
• Mortality benefits of
cytoreduction1 can be more
accurately weighed against
morbidity of postoperative
neurologic deficits2
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Perelman School of Medicine at University of Pennsylvania Penn Radiology
Cytoreduction vs. Postoperative Deficits
Preoperative MRI in a 57 year-old man with GBM. Diffusion tractography (DTI) of the corticospinal tract (CST) superimposed on anatomic images
FLAIR & DTI T1+C & DTI T1+C & DTI
Close proximity of tumor to the right CST
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Perelman School of Medicine at University of Pennsylvania Penn Radiology
Early follow-up MRI shows thick, nodular enhancement about the posterior and medial margin of the resection cavity, consistent with residual neoplasm which was unable to be resected due to proximity to the CST. The patient did not experience new neurologic deficits following surgery.
T1+CFLAIR T1
Follow-up MRI
Early recurrence/True Progression (TP)
Subsequent follow-up MRI
FLAIR T1+C
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Cytoreduction vs. Postoperative Deficits
Preoperative MRI in a 44 year-old man with GBM. DTI of the CST and fMRI of hand motor areas superimposed on anatomic images
show proximity of tumor to eloquent structures
T1+C FLAIR & fMRI FLAIR & DTI
Postoperative MRI shows complete resection of enhancing
tumor, however the patient developed new right-sided
weakness and aphasia
T1+C
Postoperative tractography was performed, demonstrating the left CST remained intact
The patient experienced near-complete functional recovery, as the
symptoms were due to a supplementary motor area syndrome
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Preoperative Mapping: Benefits
Eloquent cortical mapping (fMRI)1
Tractography for operative planning & intraoperative navigation (DTI)2,3
1Petrella JR., et al., “Preoperative fMRI Localization of Language and Motor Areas: Effect on Therapeutic Decision Making...” Radiology (2006)2Wu JS, et al. “Clinical Evaluation and Follow Up Outcome of DTI Based Functional Neuronavigation,” ‐ ‐ Neurosurgery (2007)
Smaller craniotomy
Reduced duration of surgery
Selection of more aggressive surgical strategy
Greater extent of resection
Reduced duration of surgery
Decreased seizure incidence
Improved postoperative motor performance
Higher median survival in high grade gliomas
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Post-Therapy Imaging
Early postoperative MRI – within 24H
(maximum 72H) of surgery Assess extent of resection & residual tumor Identify perioperative ischemia – include DWI
Indications for follow-up imaging Assess prognosis of postoperative neurologic
deficits Before chemotherapy and/or radiation Change in clinical status Routine surveillance
Techniques Conventional MRI Diffusion MRI MR perfusion and permeability MR spectroscopy Positron emission tomography (PET)
Post-therapy imaging overview at the University of Pennsylvania
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Preoperative images show enhancing & non-enhancing components of a recurrent glioma, which underwent re-resection
Preoperative
Postoperative Follow up
T1+C
T1+C T1+CT1DWI
DWI FLAIR
Perioperative Ischemia
Recognition of perioperative infarct is important to avoid misclassification of enhancement in an evolving infarct as recurrent
neoplasm on follow-up imaging
Immediate postoperative images reveal new restricted diffusion adjacent to the resection cavity, indicating a perioperative infarctOn follow-up, gyriform enhancement about the resection cavity represents an evolving subacute infarct rather than recurrent tumor
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Perelman School of Medicine at University of Pennsylvania Penn Radiology
Temozolomide (TMZ) and MGMT
• TMZ induces tumor cell death by causing
DNA damage
• MGMT (O-6-methylguanine-DNA
methyltransferase) is involved in DNA
repair
• Tumor cells expressing a silencing MGMT
promoter methylation exhibit inhibited
DNA repair and are more sensitive to TMZ
• MGMT promoter methylation is associated
with improved survival with TMZ treatment
• Pseudoprogression (PsP) – refers to
clinical & radiologic manifestations of an
exaggerated but favorable treatment
response
• On MRI, manifests as progressive edema
and enhancement, thereby mimicking true
tumor progression
• Occurs in the early post-treatment period
(<6 months)
Mechanisms Pseudoprogression (PsP)
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Pseudoprogression
Follow-up MRI in a patient status post recent chemoradiation for glioblastoma shows new focal enhancement adjacent to the resection cavity
T1+CFLAIR
Pre-radiation
Follow up
Distinguishing PsP from true progression is critical to avoid discontinuing effective therapy, as PsP represents a favorable treatment response
?Does this represent true tumor progression or pseudoprogression?
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Perelman School of Medicine at University of Pennsylvania Penn Radiology
PsP vs. True ProgressionConventional MRI
Clinical evaluation and conventional MRI have significant limitations in distinguishing
treatment effects from early tumor progression (EP)
Most conventional MRI features are
not specific to either PsP or EP1
1Young RJ, et al. Potential utility of conventional MRI signs in diagnosing pseudoprogression in glioblastoma. Neurology. 2011; 31;76(22):1918-24.
T1+C images obtained immediately following tumor
resection (left), and at 4 and 8 months following
resection (middle and right, respectively) show
progressive nodular enhancement about the
resection cavity with subependymal extension
Progressive subependymal enhancement, however, is
relatively specific for true tumor progression
The findings proved to represent tumor progression at re-resection
.
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Perelman School of Medicine at University of Pennsylvania Penn Radiology
PsP vs. True ProgressionMR Perfusion
TP
PsP
TUMOR• High blood volume (rCBV)
due to high vascular
density• High vascular
permeability (Ktrans) due to
immature neovasculature
PsP• Lower blood volume
(rCBV) due to relative
absence of
neoangiogenesis
MR perfusion measurements of blood volume differ significantly between PsP and TP (right). There is some overlap, however, due to pitfalls and the fact that
treatment effects may coexist with residual/recurrent tumor.
Pitfalls• Low rCBV in tumor may result from
necrosis & edema resulting in vessel
compression and subsequent
hypoperfusion
• High rCBV in PsP may result from
aneurysm, telangiectasia, vascular
elongation, or endothelial proliferation
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Perelman School of Medicine at University of Pennsylvania Penn Radiology
PsP vs. True ProgressionMR Perfusion
rCBV Ktrans vpT1+C
PsP
TP
ADC
MR perfusion measurements can aid in distinguishing pseudoprogression from true tumor progression. Note areas of relatively higher cerebral blood volume
(3rd column) and permeability (5th column) in the case of true progression.
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PsP vs. True Progression
Post-op
FLAIRT1+C rCBV
3 month Follow up
Progressive edema and enhancement about the resection
cavity is concerning for recurrent glioma
rCBV remains low, however, suggesting pseudoprogression
Baltimore, Maryland
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H&E (10X): Reactive brain tissue, hyalinized vessels
H&E (20X): Reactive brain tissue, hyalinized vessels
Final Pathology Diagnosis: Predominantly treatment effect with small proportion (<10%) of residual glioma
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MR Spectroscopy
Normal Brain Glioma
Glial tumors demonstrate a higher choline peak and a lower N-acetylaspartate (NAA) peak compared to normal brain
MR spectroscopy (MRS) allows characterization and quantification of certain metabolites within a region of interest
ChoNAA
NAACho
Courtesy: Gaurav Verma
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Perelman School of Medicine at University of Pennsylvania Penn Radiology
MR Spectroscopy – EPSI
3D mapping of choline-to-creatinine ratio in a
patient with a glioma
Multislice echo-planar spectroscopic imaging sequences (EPSI) utilize very short echo times to construct a high-resolution metabolite map of the entire brain from a single 15 minute examination
Courtesy: Gaurav Verma
Baltimore, Maryland
Perelman School of Medicine at University of Pennsylvania Penn Radiology
MR Spectroscopy – EPSIMetabolite Maps
Cho/Cr
Cr
Cho/NAA
NAA
Cho
Courtesy: Gaurav Verma
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Perelman School of Medicine at University of Pennsylvania Penn Radiology
MR Spectroscopy – EPSI
T1+CFLAIRSegmentation
Enhancing
Immediate
Peritumoral
Distant
Peritumoral
Overlaying MRS data on anatomic segmentations allows metabolite profiles of different regions (tumor, peritumoral, and distant peritumoral) to be assessed and compared
Courtesy: Gaurav Verma
EPSI
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Perelman School of Medicine at University of Pennsylvania Penn Radiology
PsP vs. True ProgressionMR Spectroscopy
True Progression Pseudoprogression
Distant Peritumoral
ImmediatePeritumoral
Enhancing
Cases of true progression show higher choline across all three regions, and particularly in the enhancing region
Courtesy: Gaurav Verma
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Perelman School of Medicine at University of Pennsylvania Penn Radiology
PsP vs. True ProgressionIntegration of Multiparametric Imaging
Post-op
4 month follow-up
FLAIR T1+C
rCBV Ktrans Vp
Follow up MRI reveals progressive enhancement adjacent to the glioma resection cavity Perfusion parameters rCBV, Ktrans, and Vp are elevated. Spectroscopy demonstrates an elevated Cho/NAA. Integrated findings are highly concerning for true progression.
NAA
Cho
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H&E (2.5x): Residual/recurrent glioma
H&E (20x): Residual/recurrent glioma
p53 Ki-67
Final Pathology Diagnosis: Predominantly (75%) recurrent/residual glioma
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Perelman School of Medicine at University of Pennsylvania Penn Radiology
PsP vs. True ProgressionDifferentiation – Summary
Specific clinical & imaging features do, however, greatly influence the likelihood that
imaging findings in the post-treatment setting represent either PsP or tumor progression
Predictor Pseudoprogression True progressionClinical symptoms No new symptoms New neurologic symptoms
MGMT promoter status Methylated Un-methylated
Lesion number Single Multiple
Enhancement pattern Rim-enhancement, central necrosis Solid, nodular, subependymal
MR perfusion Low, stable, or decreasing rCBV High or increasing rCBV
MR diffusion High ADC (necrosis) Low ADC (cellularity)
MR spectroscopy Depressed Cho, Cr, NAA peaksHigh lipid/lactate
High Cho/Cr High Cho/NAA
PET Low metabolic activity High metabolic activity
Pseudoprogression remains a clinical diagnosis which requires integration of clinical data and radiologic findings; thereby
necessitating a team-based approach including radiologists, neurosurgeons, and neuro-oncologists
No single predictor has sufficiently high sensitivity and specificity to reliably differentiate PsP from true progression on a routine basis
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Perelman School of Medicine at University of Pennsylvania Penn Radiology
Radiation Necrosis (RN)
• White matter hypoperfusion and
necrosis resulting from radiation-
induced vasculopathy
• In contradistinction, PsP represents
treatment effect on tumor and blood-
brain barrier and should replace the
outdated term early radionecrosis
• Progressive edema and
enhancement, thereby mimicking true
tumor progression
• Occurs months to years following
therapy
• Classic “soap bubble” or “swiss
cheese” MRI appearance, however no
imaging features are widely
accepted as specific for RN, which
remains a pathologic diagnosis
Mechanisms Imaging Features
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Perelman School of Medicine at University of Pennsylvania Penn Radiology
Radiation Necrosis (RN)FLAIRT1+C
rCBV
NAACr
Cho
Lipid/lactate
Follow up MRI (bottom row) reveals progressive enhancement and edema about the resection cavity
The corresponding region, however, demonstrates relatively low rCBV. MR spectroscopy reveals a high lactate peak, low Cho/NAA, and a relative decrease in all normal metabolites. Integrated findings suggest radiation necrosis rather than progressive neoplasm.
Advanced MR techniques hold the potential to better characterize RN, but this remains an area of active research
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Perelman School of Medicine at University of Pennsylvania Penn Radiology
Antiangiogenic Therapy
• Glial tumors rely on dysregulated
angiogenesis, leading to the formation
of abnormal, permeable blood vessels
• Antiangiogenic therapy refers to
antibody-mediated inhibition of vascular
endothelial growth factors (VEGF)
• Inhibition of VEGF results in vascular
normalization (↓ vessel diameter, ↓
permeability, and basement membrane
thinning)
• Antiangiogenic therapy results in rapid
reduction of enhancement and edema
• Little survival benefit without
concomitant cytotoxic therapy
• May promote the development of an
invasive, non-enhancing phenotype
• Pseudoresponse (PsR) – progression
of non-enhancing tumor despite ↓
enhancement and vessel permeability
Mechanisms Imaging Manifestations
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Pseudoresponse
Pre-Avastin
Post-Avastin 1
Post-Avastin 2
T1+C FLAIR rCBV
Pre-therapy scan shows an enhancing mass in the right temporal lobe
Following initiation of antiangiogenic therapy, there is marked decrease in enhancement and adjacent edema
Subsequent MRI shows increasing T2 signal and rCBV adjacent to the lesion despite minimal enhancement, suspicious for progression of the non-enhancing tumor component
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Perelman School of Medicine at University of Pennsylvania Penn Radiology
Treatment Response Criteria
1Macdonald DR, et al. Response criteria for phase II studies of supratentorial malignant glioma. Journal of Clinical Oncology 8, 1277–1280 (1990)2Wen PY, et al. Updated Response Assessment Criteria for High-Grade Gliomas: Response Assessment in Neuro-Oncology Working Group. Journal of Clinical Oncology 28, 1963–1972 (2010)
McDonald Criteria1
• Most widely used guideline• Relies on the product of largest
diameters of enhancing tumor
Key Limitations
• Enhancement is not specific to tumor• Doesn’t account for non-enhancing
tumor• Doesn’t account for multifocality• Doesn’t address PsP or PsR
RANO Criteria2
(Response Assessment in Neuro-Oncology)
• Both clinical and imaging components• Enhancing and non-enhancing tumor• Measurable and non-measurable disease• Accounts for PsP and PsR
First progression following therapy (<12 weeks)• New enhancement outside radiation field• Pathologic confirmation of progression
First progression following therapy (>12 weeks)• New lesion outside treatment field• Increase in size of ≥ 25% (accounting for steroids)• Increase in non-enhancing tumor on anti-
angiogenic RX• Clinical deterioration not otherwise explainedRANO Criteria should be considered when evaluating
glioma treatment response
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Emerging Therapies
Laser-Induced Thermal Therapy
Vaccine & Immune-Based
Therapy
Tumor-Treating Fields
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Laser-Induced Thermal Therapy
30 year old woman with a non-enhancing right frontal mass lesion, rCBV is not elevated
FLAIR T1+C FLAIR/rCBV
Norred SE, & Johnson JA. Magnetic Resonance-Guided Laser Induced Thermal Therapy for Glioblastoma Multiforme: A Review. BioMed Research International 2014, 1–9 (2014)
Laser ablation was elected over craniotomy and was performed at the time of stereotactic biopsy, which confirmed the diagnosis of WHO grade II glioma. MRI images confirm fiber placement within the lesion and are subsequently used to monitor tissue heating
• Optical fiber introduced into tumor is
used to deliver direct laser energy,
inducing thermal damage &
necrosis
• Less invasive treatment approach
• Performed concurrently with MRI Confirm correct fiber location Real-time monitoring of
tissue heating
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Perelman School of Medicine at University of Pennsylvania Penn Radiology
Vaccine & Immune Therapies
Ongoing clinical trials for recurrent GBM:
• Vaccines against tumor-specific antigens
(rindopepimut, HSPPC-96)
• Stimulated autologous dendritic cells pulsed with
immunogenic tumor antigens (ICT-107)
• Redirected autologous T-cells engineered to
target tumor-specific moieties (CART-EGFRvIII)
Experimental treatments are resulting in
new and complex imaging manifestations
in the post-treatment setting Surveillance examinations in a patient with recurrent GBM on a vaccine therapy show nodular enhancement and elevated rCBV, suggesting tumor progression
T1+C rCBV
6 months
12 months
Biopsy, however, revealed a predominance of necrosis
80% necrosis
60-70% necrosis
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Perelman School of Medicine at University of Pennsylvania Penn Radiology
Tumor-Treating Fields
Novel therapeutic methodology• Direct application of a non-uniform electric field • Disrupts mitotic activity within actively dividing cells• Preferentially induces apoptosis within tumor cells
Courtesy: NovaCare
1Wong ET et al. Response assessment of NovoTTF-100A versus best physician’s choice chemotherapy in recurrent glioblastoma. Cancer Medicine. 2014 Jun;3(3):592–602.
In a phase III clinical trial for recurrent GBM1, demonstrated equivalent efficacy and less toxicity when compared to chemotherapy
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Perelman School of Medicine at University of Pennsylvania Penn Radiology
Conclusions
• RANO criteria should be considered to
evaluate treatment response
• Pseudoprogression: Common Suspect with of enhancing lesion ~ 3
months More often seen with methylated MGMT Improved overall survival MR perfusion and spectroscopy can help
differentiate from true progression
• Pseudoresponse: Rapid decrease in contrast
enhancement with a high response rate Progression of non-enhancing tumor
component Modest effects on overall survival
• Emerging brain tumor therapies are
resulting in new and complex imaging
patterns in the post-treatment setting
Advanced multi-parametric imaging techniques hold promise for improved characterization of post-treatment patterns, however this remains an active area of research & will likely require more prospective testing & standardized quantitation
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Perelman School of Medicine at University of Pennsylvania Penn Radiology
Acknowledgements
• Gaurav Verma• Sumei Wang• Sulaiman Sheriff• Andrew Maudsley• R21 Grant: 1R21CA170284• EPSI Development Group
PENN RADIOLOGY
THE ROOTS OF
RADIOLOGICAL
EXCELLENCE
PENN RADIOLOGY
THE ROOTS OF
RADIOLOGICAL EXCELLENCE
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