STATE OF THE ART PROSTATE MR IMAGING

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STATE OF THE ART PROSTATE MR IMAGING
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STATE OF THE ART PROSTATE MR IMAGING

• DYNAMIC CONTRAST-ENHANCED MRI (DCE-MRI)
• LYMPHOTROPIC SUPERPARAMAGNETIC NANOPARTICLES
  ENHANCED MRI
• MR SPECTROSCOPIC IMAGING (MRSI)

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ENDORECTAL COIL FOR HIGH-RESOLUTION ANATOMIC
ANALYSIS

• PROSTATE GLAND
• PROSTATE CAPSULE
• SEMINAL VESICLES
• NEUROVASCULAR BUNDLES
• DENONVILLIERS FASCIA
• PARARECTAL LYMPH NODES

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BLOOD FROM RECENT BIOPSY

• COMPLICATES INTERPRETATION OF MR ANATOMIC IMAGING
• COMPLICATES INTERPRETATION OF MRSI
• COMPLICATES INTERPRETATION OF DCE-MRI

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PELVIC MRI

• LYMPH NODE ANALYSIS
• VASCULAR DISEASE
• OTHER MASSES

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DYNAMIC CONTRAST-ENHANCED MRI

• Anatomic imaging provides only one index of
  biologic activity
• Some therapies, such as antiangiogenic and
  vaccines therapies, are expected to be cytostatic
  and thus may not produce objective responses in
  tumor size

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DYNAMIC CONTRAST-ENHANCED MRI

• DCE-MRI -- acquisition of serial MR images
  before, during, and after the administration of
  an IV contrast agent
• Resulting signal intensity measurements of the
  tumor reflect a composite of tumor perfusion,
  vessel permeability, and the volume of the
  extravascular-extracellular space
• DCE-MRI, in conjunction with traditional MRI,
  provides functional and detailed morphologic
  information in the same study

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DYNAMIC CONTRAST-ENHANCED MRI

• DCE-MRI has been employed for tumor detection,
  characterization, staging, and therapy monitoring
• Cancers demonstrate typical enhancement kinetics
  rapid and high amplitude wash-in followed by a
  relatively rapid wash-out. This pattern can be
  used to distinguish malignant masses from benign
  lesions or normal tissue, which enhance slowly
  and washout slowly

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DYNAMIC CONTRAST-ENHANCED MRI -- FALSE POSITIVES
AND NEGATIVES

• Microscopic disease may still be present even
  when DCE-MRI shows no evidence of tumor
• Some malignant processes can mimic benign
  contrast kinetics, and some benign processes
  (e.g., inflammation) can mimic malignant contrast
  kinetics
• It is thus important to have histopathologic
  correlation at the initial study to determine the
  particular contrast kinetics of a tumor

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DYNAMIC CONTRAST-ENHANCED MRI

• Monitoring of cancer therapy is another important
  role of DCE-MRI
• DCE-MRI provides direct and early evidence of a
  therapeutic effect by demonstrating changes in
  the enhancement curves (slower initial
  enhancement, decreased amplitude, slower
  wash-out)
• Failure of particular areas of the tumor to
  respond to therapy implies the presence of
  resistant clones

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DYNAMIC CONTRAST-ENHANCED MRI

• Tumors with higher initial permeability often
  respond better to chemotherapy than tumors with
  lower permeabilities, as it is possible to
  deliver more cytotoxic therapy to these lesions
• More permeable tissues may be better oxygenated
  and therefore initially more radiosensitive
• Changes on DCE-MRI may be non-predictive the
  therapy may induce physiologic changes in the
  tumor without affecting patient survival

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DYNAMIC CONTRAST-ENHANCED MRI

• Angiogenesis is now considered one of the major
  events that must occur if a tumor is to grow
  beyond several millimeters in diameter
• If tumors are to grow beyond this size, they must
  induce surrounding vessels to create neo-vessels,
  i.e., angiogenesis

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DYNAMIC CONTRAST-ENHANCED MRI

• Angiogenic inhibitors reduce both the number of
  vessels (especially nonfunctional vessels) and
  their permeability on DCE-MRI
• Some therapies, such as antivascular endothelial
  growth factor antibody, are specifically directed
  against a growth factor, VEGF, and are thought to
  regulate vascular maturation, and thus
  permeability
• Such changes are predicted to occur early after
  treatment

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DYNAMIC CONTRAST-ENHANCED MRI

• More conventional therapies can also be monitored
  with DCE-MRI because vessel loss is a final
  common pathway for many therapies
• Cytotoxic chemotherapy and vaccine immunotherapy
  result in changes in enhancement kinetics within
  a tumor

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DYNAMIC CONTRAST-ENHANCED MRI

• Therapeutic radiation can also be monitored
  because decreased vascularity is anticipated with
  successful treatment early after therapy
• A form of angiogenesis induced by radiation
  fibrosis may be seen months after initial
  therapy, leading to paradoxical increases in
  vessel permeability
• Local therapies, such as cryotherapy and
  radiofrequency ablation, can also be monitored
  with DCE-MRI

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DYNAMIC CONTRAST-ENHANCED MRI

• Prostate gland is particularly difficult to
  evaluate
• Heterogeneous gland with its central regions
  prone to hyperplastic changes and tumors, both of
  which display a range of angiogenesis
• The peripheral zone is normally relatively
  hypovascular
• Low grade tumors also tend to be relatively
  hypovascular and thus are difficult to detect
  against the background of normal contrast
  enhancement

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DYNAMIC CONTRAST-ENHANCED MRI

• Nonetheless, contrast-enhanced MRI using rapid
  bolus techniques have been reported to be more
  sensitive to tumors and are a useful adjunct to
  T2-weighted scans in tumor localization and
  staging.

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LYMPHOTROPIC SUPERPARAMAGNETIC NANOPARTICLES
ENHANCED MRI

• NANOPARTICLES WITH IRON OXIDE CORE ARE SLOWLY
  EXTRAVASATED FROM THE VASCULAR SPACE INTO THE
  INTERSTITIAL SPACE
• TRANSPORTED TO LYMPH NODES VIA LYMPHATICS

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LYMPHOTROPIC SUPERPARAMAGNETIC NANOPARTICLES
ENHANCED MRI

• NANOPARTICLES INTERNALIZED BY MACROPHAGES IN
  LYMPH NODES
• INTRACELLULAR IRON-CONTAINING NANOPARTICLES CAUSE
  CHANGES IN MAGNETIC PROPERTIES DETECTABLE BY MR
  IMAGING

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LYMPHOTROPIC SUPERPARAMAGNETIC NANOPARTICLES
ENHANCED MRI

• MRI PERFORMED BEFORE AND 24 HOURS AFTER IV
  ADMINISTRATION OF THE NANOPARTICLES
• NODAL INFILTRATION BY TUMOR CAUSES LESS MAGNETIC
  SUSCEPTIBILITY CHANGE

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LYMPHOTROPIC SUPERPARAMAGNETIC NANOPARTICLES
ENHANCED MRI
Sensitivity
Specificity
Accuracy
PPV
NPV
Per Patient
Per Individual Lymph Node
LN Short Axis 5-10 mm
LN Short Axis lt 5 mm
N ENGL J MED 2003 3482491-2499
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COMBINED ANATOMIC AND METABOLIC IMAGING OF
PROSTATE CANCER -- MRI/3D MRSI

• MRSI PROVIDES A NON-INVASIVE METHOD OF DETECTING
  SMALL METABOLITES WITHIN THE CYTOSOL OR IN THE
  EXTRACELLULAR SPACES OF THE PROSTATE GLAND
• PERFORMED IN CONJUNCTION WITH HIGH RESOLUTION
  ANATOMIC IMAGING

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COMBINED ANATOMIC AND METABOLIC IMAGING OF
PROSTATE CANCER -- MRI/3D MRSI

• INITIAL HUMAN STUDIES HAVE FOCUSED ON MRI/MRSI ON
  1.5 T SYSTEMS
• VALUE OF THIS COMBINED APPROACH HAS BEEN SHOWN IN
  THE LITERATURE
• WHILE ALREADY VALUABLE, COMBINED MRI/MRSI IS
  STILL IN ITS INFANCY. DRAMATIC IMPROVEMENTS IN
  SPATIAL RESOLUTION, CHEMICAL SPECIFICITY, AND
  BIOLOGIC INFORMATION ARE POSSIBLE

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RADIOLOGIC TESTS FOR PROSTATE CANCER?

• LOCAL STAGING (FOR EXAMPLE, EXTRACAPSULAR
  EXTENSION OR SEMINAL VESICLE INVASION) BY TRUS
  AND MRI IS FELT TO BE IMPORTANT -- DETERMINES
  WHETHER THE PATIENT GETS CURATIVE LOCAL THERAPY
  OR PALLIATIVE SYSTEMIC THERAPY
• LOCATION AND EXTENT OF CANCER WITHIN THE PROSTATE
  GLAND IS BECOMING INCREASINGLY IMPORTANT DUE TO
  THE EMERGENCE OF FOCAL PROSTATE CANCER THERAPIES,
  AND FOR THE SELECTION AND RISK STRATIFICATION OF
  PATIENTS IN CLINICAL TRIALS

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MRI Methods

• Multi-planar high-resolution T2 weighted images
  are acquired through the prostate and surrounding
  structures in order to assess the location,
  spatial extent, and spread of prostate cancer.

• T1 weighted images are acquired through the
  prostate gland and pelvis in order to assess for
  the presence of post-biopsy hemorrhage within the
  prostate gland and metastases to pelvic bones and
  lymph nodes.

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MRI Staging of Prostate Cancer

• MRI alone has good accuracy in detecting seminal
  vesicle invasion (96).

Radiology 1994193703-709
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MRI Lacks Specificity for Localizing Cancer
within the Prostate
High Resolution MRI has demonstrated good
sensitivity (79) but low specificity (55) in
determining tumor location due to a large number
of false positives.
Radiology 1994193703-709
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MRSI Metabolic Identification of Prostate Cancer
Prostate Cancer
Creatine
Creatine
3.0
PPM
2.0
2.5
Cancer
Healthy
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Interpretation of Combined MRI/MRSI Data
The output of the MRI/MRSI exam are arrays of
0.3cc spectra and corresponding high resolution
anatomic images.

The interpretation of the data requires a
knowledge of what constitutes a useable spectra,
how spectra change with zonal anatomy and age,
and other complicating factors such as
post-biopsy hemorrhage, and contamination from
surrounding tissues.
Portion of the 3-D MRSI spectral array
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Contamination from Different Tissues Within the
Prostate
creatine
Choline
Citrate
Prostate Cancer
A voxel containing both healthy glandular tissue
and cancer may look like this elevated choline
to creatine but normal levels of citrate
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Complications to the Interpretation of Prostate
Spectra
Post-biopsy artifact
T1 WI
At the time of this previous study, biopsy
hemorrhage was observed in 28 of patients studied
Radiology 1998206785-790
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Appearance of Spectra In Regions of Hemorrhage
Patients have demonstrated both metabolic atrophy
and changes in their metabolite levels in regions
of extensive hemorrhage, particularly early after
biopsy
3 weeks after biopsy
tumor
atrophy
Cho Cr PA
tumor
tumor
citrate
atrophy
atrophy
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Hemorrhage Induced Changes in Healthy Tissue
A
T1 weighted MRI
CC/C0.81
Choline
4 weeks after biopsy
Citrate
CC/C0.22
12 weeks after biopsy
Choline
Citrate
By requiring elevated choline be present when
there is hemorrhage can reduce over-calling cancer
Li, ISMRM 2002
5.0
3.5
4.0
3.0
PPM
2.0
2.5
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MRI/MRSI Data Summary
Up to 1024 spectra per study - Need for summary
images
MRSC/UCSF - Proton MRS Study
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Assessment of Cancer Aggressiveness (Grade)
Neoplasia 20002(1-2) 166-169
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STAGING PREDICTION OF ECEROC Analysis (187
patients)
1
Sensitivity
0.75
0.5
MRI/MRSI
0.25
TRUS
Biopsy
0
0
0.25
0.5
0.75
1
1 - Specificity
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Localization of Cancer to a Sextant of the
Prostate by MRI/MRSI
MRI/MRSI data can be combined to provide both
high specificity or sensitivity in localizing
cancer to a prostatic sextant depending on the
clinical question.

• A specificity of up to 91 was obtained when both
  MRI and MRSI were positive for cancer. Add
  positive sextant biopsy results - 98.

• A sensitivity of 95 was obtained when MRI or
  MRSI were positive for cancer. With the addition
  of positive sextant biopsy, the sensitivity
  remains high at 94.

• A significant (Plt0.05) improvement in overall
  accuracy ( 80) over MRI and biopsy alone.

Journal Urology 2000, 164(2) 400-404 Radiology
1999 213473-480
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MRI/MRSI Current Clinical Uses

• Therapeutic Selection - individualized therapy (
  60 of patients)

• Cancer Diagnosis - men with rising PSA but
  negative biopsies ( 10 of patients)

• Therapeutic Monitoring ( 30 of patients)
• Early identification of failure
• Time course of response

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Individualized Therapeutic Selection
C

• MRI/MRSI concordant for a large volume of
  aggressive cancer with spread outside the capsule
  and seminal vesicle invasion

Cho
Cr

• Brachytherapy alone not appropriate

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Clinical Application MR Targeted, TRUS-Guided
Biopsies
The sensitivity of TRUS guided biopsy is reduced
in large prostates and when the cancer is located
in difficult locations such as the apex of the
gland or in the anterior or lateral aspects of
the gland
PSA - 12 ng/ml Two prior negative biopsies
Journal Urology 2000, 164(2) 400-404
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The addition of the metabolic information
provided by MRSI becomes even more important
after therapy since the contrast between healthy
tissue and cancer is reduced on MRI
Monitoring Therapy Radiation Therapy
Tumor
Pre-Therapy
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MRSI has Demonstrated the Ability to Identify
Cancer Metabolically after Therapy
Atrophy or Necrosis
Radiology 1996 200489-96
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Successful Therapy Complete Metabolic Atrophy
Pre-therapy
Post-therapy
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Unsuccessful External Beam Radiation Therapy
Cancer
Cancer
Atrophy
Cancer
A T2-weighted MR image and spectral array taken
from the midgland of a 55-year-old prostate
cancer patient with a current PSA of 0.6 ng/ml
who had IMRT in June of 2000. Note the metabolic
atrophy consistent with effective therapy in the
right side of the gland, and residual metabolism
on the left side of the gland. The presence of
cancer in the left lateral aspect of the prostate
gland was subsequently confirmed by ultrasound
guided biopsies.
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Unsuccessful Hormone Deprivation Therapy
21 months of combined hormone deprivation therapy
- PSA - 0.4
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Time Course of Metabolic Response to Brachytherapy
red abnormal metabolism
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Time-Course of Metabolic Recovery After Cessation
of Therapy
77 year old patient Gleason 34 1 year of
combined Lupron and Casodex PSA at time of scan -
0.4 ng/ml
Metabolic Atrophy
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CONCLUSIONS

• MRI/MRSI HAS BEEN ESTABLISHED AS A POWERFUL
  IMAGING TECHNIQUE FOR PRE- AND POST-TREATMENT
  ANALYSIS
• GREAT PROMISE FOR LYMPHOTROPIC SUPERPARAMAGNETIC
  NANOPARTICLES TO ASSESS LYMPH NODE METASTASES
• DCE-MRI IS RELATIVELY NEW IN THE EVALUATION OF
  PROSTATE CANCER, AND ITS CLINICAL UTILITY IS YET
  TO BE DETERMINED