Focussed therapy and imaging in prostate cancer

1. FOCALTHERAPY
&
IMAGING IN PROSTATE CANCER
DR. PRATEEK LADDHA
SENIOR RESIDENT
DEPARTMENT OF UROLOGY
CMC LUDHIANA

2. Introduction
■ In an era of increasing prostate cancer incidence and stage
migration toward earlier disease, appropriate management of
the disease requires assessment of the risk of clinical
significance of the disease.
■ Minimally invasive therapies are increasingly being
investigated as an alternative.
■ Prostate cancer is relatively slow growing, with doubling times
for local tumors estimated at 2-4 years.
■ Some prostate cancers prove to be so small, low-grade, and
noninvasive that they appear to pose little risk to the patient,
and are considered indolent.

3. ■ A review suggests that 49% of men undergoing RP have pathological
features in the RP specimen consistent with an insignificant or indolent
cancer (organ-confined cancer < 0.5 mL, no Gleason Grade 4 or 5
component).
Steyerberg EW, Roobol MJ, Kattan MW, van der Kwast TH, de
Koning HJ, Schroder FH. Prediction of indolent prostate
cancer: validation and updating of a prognostic nomogram. J
Urol 2007;177:107e112

4. RATIONALE FOR FOCALTHERAPY FOR
PROSTATE CANCER
INCREASED NUMBER OF CASES BEING
DIAGNOSEDWITH LOCALIZED, LOW
RISK , LOW GRADE PROSTATE CANCER
PSA
Screening
Increasing
life
expectancy
RADICAL PROSTATECTOMY (RP) OR
RADIATIONTHERAPY (RT)

5. Biopsy Strategies to Detect Small
Prostate Cancers
■ Two competing reasons have contributed to the need for the
accurate diagnosis of small prostate tumors.
– most patients with indolent cancers are better served by
expectant management. Epstein and colleagues
demonstrated that tumors with a volume 3 had an indolent
course with a positive predictive value of 95%. Based on
this observation, a number of groups have published their
experience with active surveillance with selective delayed
intervention for prostate cancer
■ PSA doubling time >4 years,
■ PSA density 50% cancer involvement, and
■ Gleason pattern >3. Using these stricter criteria, there were no
prostate cancer-related deaths at 10 years,

6. – High risk features may harbor high grade, and
therefore high risk, disease. Patients with findings of
■ low free PSA (0.75 ng/ml/year,
■ high grade PIN, and
■ atypia with a prior negative biopsy may in fact harbor a
small focus of high grade disease (Gleason score >7), and
this has been found to be as high as 14%

7. ■ The new prostate-imaging technology that fuses MRI with
real-time, three-dimensional ultrasound appears to offer a
more exacting method to obtain biopsy specimens from
suspicious areas within the organ.
■ The new technology may be most beneficial for patients who
fall into one of two categories:
– those who had prior negative biopsies but have persistently
elevated prostate-specific antigen (PSA) levels
– "active surveillance" patients — those with low-risk prostate
cancers who are being carefully monitored over time to see if
their cancer progresses or becomes more aggressive.
■ Researchers found that targeted biopsy was about five times
more likely to find cancer than non-targeted, systematic
biopsy.

8. Targeted biopsy
■ Targeted biopsy refers to direct tissue sampling of suspicious
areas, as opposed to the older method of random, systematic
sampling in use since the 1980s.
■ The new method employs sophisticated MRI (magnetic
resonance imaging) technology, to visualize prostate cancer,
and fusion of the MR images with realtime ultrasound.
■ The result is a 20-minute procedure, done in the clinic under
local anesthesia, much more accurate than the older method
of prostate biopsy because of biopsy targeting.

9. MR US FUSION GUIDED
BIOPSY
■ Benefit in patient with active surveillance
– Confirm low volume low grade disease
– Follow lesions of over time
■
Improved risk stratification for prostate cancer using MR
imaging
■
FocalTherapy
– Allows targeting ,treatment and follow up of only the cancer
and leaves the normal prostate and nerves untouched.

10. 3DMB
■ Procedure andTechnique
■ With the patient in the dorsal lithotomy position, a transrectal ultrasound probe
mounted on a stepper is attached to a standard 5-mm brachytherapy template
grid secured against the perineum.
■ A Foley catheter may be placed in the urethra to aid in identifying the urethra
and assess for hematuria before completing the procedure. Biopsies are
obtained at 5 mm intervals from the apex to the base, laterally to medially, and
anterior to posterior until the entire gland has been sampled using a standard
18-guage automated biopsy gun. Midline biopsies are obtained posterior to the
urethra to avoid urethral injury.

12. ADVANTAGES
3DMB is a safe and effective method to
grade, stage, and locate tumor.
The self embedding procedure of
biopsy cores can help to gain a
maximum of information on cancer
localization within the prostate.
better match tumor burden with
appropriate treatment selection,
thereby minimizing treatment-related
morbidity and potentially improving
clinical outcomes
DISADVANTAGES
3DMB is more time and resource
intensive than standard office based
TRUS biopsies.
Operating room, anesthesia,
duration of procedure, and number
of samples obtained all add to its
expense.
One tertiary care institution reported
that average cost of performing the
procedure in an outpatient surgery
setting was $5,000 to $6,000 dollars

13. Contrast-Enhanced
Ultrasonography
ADVATAGES
■ portability
■ lack of nephrotoxic
contrast agents
■ multi-repeatable
technique.
■ low costs compared with
other imaging modalities
DISADVANTAGES
■ user dependency
■ long learning curve.
■ 3D imaging is available,
mostly ultrasound is still
performed in 2D.
■ growing obesity in the
society, also the limited
tissue penetration poses a

14. FOR PROSTATE CANCER
■ TRUS is the classical ultrasound technique for prostate imaging, and
enables a detailed visualization of the prostate. However,
■ PCa is hard to detect with standard grayscaleTRUS.
■ The classical signs for malignancy are hypoechoic lesions, vesicular
asymmetry, and capsular irregularity; however, only 11–35% of the
malignancies are visible on grayscaleTRUS
■ hypoechoic lesions seen, only in 17–57% of the cases malignancy is
present
■ TRUS is mainly used for volume measurement and guidance of
systematic biopsies.
■ In conclusion, in the diagnosis of PCa, transrectal grayscale ultrasound
is lacking accuracy; therefore, an urgent improvement of TRUS is
needed.

15. COMPUTERISED USG
SOFTWARES
■ Automated Urologic
Diagnostic EXpert system
(AUDEX)
■ computerized transrectal
ultrasound (C-TRUS)
■ use algorithms based on refl
ected raw and visual ultrasound
data, and
■ compute locations where
probability of PCa is high.
■ They show higher PCa detection
results in comparison with
regular grayscaleTRUS.
■ However, the results are not suf
ficient to rule out systematic
biopsies

16. Doppler
■ PCa induces neovascularization, which results in a disturbed perfusion of
malignant tissue compared to normal prostate tissue
■ Sen et al. compared color Doppler with grayscale US in targeted biopsies in 40
patients.
■ Respectively, they show a difference in sensitivity of 88.2 vs. 73.5% and
specificity of 66.6 vs. 33.3%.
■ Power Doppler ultrasonography (PDU) increases the sensitivity for detection
of blood fl ow compared to color Doppler.
■ A comparison between PDU imaging and systematic biopsies has been
performed by Sakayra et al. andTakahashi et al.
■ A sensitivity between 77 and 90% was seen, with a specificity of 75–88%
introduction of contrast-enhanced
ultrasound (CEUS), improved low
blood flow imaging is possible and
microvascular changes Can be
visualized

17. CEUS
■ contrast agent is a solution of
gas- filled microbubbles with a
diameter in the order of
micrometers, smaller than red
blood cells, and stabilized with a
biocompatible shell.
■ Compatible with:
– Cryoablation
– HIFU
In 2005, a comparison between contrastenhanced harmonic imaging targeted biopsies and
systematic biopsies was performed by Halpern et al. Biopsies were performed in 301 patients.
CEUS-targeted biopsies were two times more likely to fi nd cancer compared to systematic
biopsies in patients with PCa. However, targeted biopsies missed 20% of cancers, which were
detected by systematic biopsies alone. They concluded that although the detection rate of
carcinoma is higher with CEUS-guided biopsies, systematic biopsies are still needed

18. Prostate elastography

19. GENERAL DEFINITIONS
■ Focal therapy (FT)
– An anatomy-based (zonal) treatment strategy (e.g. targeting a quadrant, a lobe or
both lobes sub-totally)
■ Targeted FT
– A lesion-based focal treatment strategy targeting the identified tumors plus a safety
margin The aim of (targeted) FT for PCa Eradication of all significant cancer(s) Subtotal
ablation Any ablation where less than the whole gland is treated
■ Extended - hemiablation
– An ablation where one lobe is completely treated plus a margin of the other lobe
regardless of shape Index lesion The single dominant lesion in terms of grade and size
where grade is more important. There can be only 1 index lesion. The term index lesion
itself may be of limited use in the context of FT. It is more important to have an
overview of all significant lesions that warrant treatment rather than a single defined
index lesion
■ Salvage
– FT Salvage FT refers to the situation where FT is applied to the prostate after whole-
gland therapy, or in the same region of the prostate as previous FT. The prostate gland
has to be in place

20. FocalTherapy
■ Many prostate tumors are detected at a very
early stage when they are small and are
confined to one region of the prostate gland.
■ These tumors cannot be felt in a digital rectal
exam. They may be slow growing and pose
little immediate risk to a patient's life.
■ However, because it can be difficult to predict
which tumors will become life threatening,
patient or surgeon may want to eliminate a
clinically localized early-stage tumor rather
than pursue active surveillance.

21. ■ Focal therapy is a general term for a variety of
noninvasive techniques for destroying small tumors
inside the prostate — leaving the gland intact and
sparing most of its normal tissue.
■ In appropriate situations, focal therapy can offer
several advantages for men with early prostate
cancer:
– Focal therapy can effectively destroy specific
areas of cancer within the prostate while
preserving normal prostate tissue and function.
■ Side effects of focal therapy — including changes in
urinary and sexual function — are often temporary
and may be less severe than those associated with
more-aggressive treatments.

22. ■ Because focal therapy causes minimal injury to the prostate
gland, it does not preclude further treatment with radical
prostatectomy, radiation therapy, or additional focal treatment
to another part of the gland, if necessary. Cancer that returns
after radiation therapy may be treated with focal therapy.
■ Focal therapy is often performed on an outpatient basis or with
a single overnight hospital stay.

24. ■ When considering targeted focal ablation, the main
focus at diagnosis is to determine:
– (1) the three-dimensional cancer location within the
gland,
– (2) cancer volume, and
– (3) biologic potential (e.g., which aggressive foci
require immediate therapy, while other indolent foci
may be able to be followed or treated with a
chemopreventive agent).
■ The challenge is how to define the clinically significant
PCa focus based upon its natural biologic history
tempered with patient life expectancy. Further
research will be required to understand the biologic
potential of each of the individual PCa foci within a
cancerous gland

25. Types of FocalTherapy
■ Thermal focal therapies, use either heat or cold to destroy
tumors, include:
– Focal Cryoablation
– High-Intensity FocusedUltrasound (HIFU)

26. Thermal FocalTherapies
FOCAL CRYOABLATION
A needle-thin probe delivers a
solution that surrounds the
tumor and kills it by freezing
it to a very low temperature.
Because focal cryoablation
targets only a small area
within the prostate, it also has
fewer side effects than other
cryoablation techniques,
which freeze the entire
prostate gland.
HIFU
Uses the energy of sound
waves, directed to the tumor
with the help of MRI scans, to
superheat and eliminate small
tumors. HIFU is an attractive
focal therapy approach
because it is relatively
noninvasive. The effectiveness
of this treatment is monitored
in real time, using MRI to
measure the temperature
within the prostate during
therapy.

27. Cryoablation

28. HIFU

29. NONTHERMAL FOCAL
THERAPIES
IRREVERSIBLE
ELECTROPORATION
(IRE)
This nonthermal ablation
technique uses a device called
the NanoKnife® to pass an
electrical current through the
tumor.
The electricity creates very
tiny openings (called pores) in
tumor cells, leading to cell
death.
Ultrasound or CT is used to
focus the current precisely on
the tumor, sparing blood
vessels and other tissues.
VASCULARTARGETED
PHOTODYNAMIC
THERAPY (VTP)
A drug that destroys tumor cells and the
blood vessels that support them is given
intravenously and moves to the inside
of the tumor.
The drug is activated by exposing it to
light of a very specific color
(wavelength), which is delivered to the
tumor site with specially designed fibers
placed within the prostate.
The photoactive substance can then
directly target the vessel supplying
tumor, closing it off and leading to the
destruction of the tumor.

30. IRE

31. PDT

32. MRI Guided Focal Laser
Ablation of Prostate Cancer
■ The prostate is anesthetized with local anesthesia just as is
done prior to a prostate biopsy.
■ The technique is performed under local anesthesia in the MRI
machine.
■ The region of interest harboring the prostate cancer is
identified and a laser fiber is introduced directly into the
prostate cancer under MRI guidance.

33. ■ MRI is highly temperature sensitive. Therefore, the temperature of the
critical structures adjacent to the prostate including the rectum, urinary
sphincter, and erectile nerves are monitored in real time so it is extremely
rare to have any collateral damage to these structures.
■ The temperature of the ablation site within the region of interest known
to harbor prostate cancer is also monitored in real time to optimize
destruction of the indexed lesion of the cancer.
■ At the completion of the procedure, contrast is administered to show that
the region of interest has been successfully ablated.

34. Summary

35. Figure 3
Urology Practice 2014 1, 156-164DOI: (10.1016/j.urpr.2014.05.003)
Copyright © 2014 American Urological Association Education and Research, Inc. Terms and Conditions

36. Conclusions Phase I and II studies of targeted focal therapy for
prostate cancer have demonstrated safety and efficacy.With
improved imaging, new MRI-TRUS fusion targeted biopsies and
standardized patient selection criteria, phase III study is under
way, perhaps setting the stage for a new era of prostate cancer
therapy for many individuals.
Moving Forward the State of the Art in Prostate Cancer
Treatment: Targeted Focal Therapy
Crawford, E. David et al.
Urology Practice , Volume 1 , Issue 3 , 156 - 164

37. ■ Thank you