PENN RADIOLOGY THE ROOTS OF RADIOLOGICAL EXCELLENCE Tumor or treatment? Stay tuned… Educational...

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

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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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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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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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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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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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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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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

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Perelman School of Medicine at University of Pennsylvania Penn Radiologyp53 Ki-67

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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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


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MR Spectroscopy – EPSIMetabolite Maps

Cho/Cr

Cr

Cho/NAA

NAA

Cho


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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


EPSI

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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


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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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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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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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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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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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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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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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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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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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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

THANKS FOR VIEWING OUR EXHIBIT!

[email protected]@uphs.upenn.edu

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