Transcript in Focal Therapy for Prostate Cancer

Image-Guided Therapy for Prostate
Cancer: The focal approach
Rafael Sanchez-Salas, MD
Department of Urology
L’Institute Mutualiste Montsouris
Paris, France
Disclosures
• Olympus, EDAP-TMS, HistoScanning, Intuitive
• Ecole Européen de Chirurgie; Paris, France
Agenda
• Image-Guided Therapy in Urology
• Diagnosis of Prostate Cancer and Selection for Focal Therapy
• Imaging in Localized Prostate Cancer
• Prostatic Biopsies: Available Techniques and Approaches
• Available Ablation Energies to Treat Prostate Cancer
• Surveillance After Focal Therapy
• Summary
Image-guided Therapy for Prostate Cancer:
Quo Vadis?
Urology
and
technology
Imaging
and
ablatives
techniques
Stage
migration
and risk
stratification
Image-guided Therapy for Prostate Cancer
Alea iacta est
Active
Surveillance
FOCAL
THERAPY
Radical Options
Focal Therapy for PCa:
Level of Evidence of Current Recommendations
for Common Practice
Agenda
• Image-Guided Therapies
• Diagnosis of Prostate Cancer and Selection for Focal Therapy
• Imaging in Localized Prostate Cancer
• Prostatic Biopsies: Available Techniques and Approaches
• Available Ablation Energies to Treat Prostate Cancer
• Surveillance After Focal Therapy
• Summary
Diagnosis of Prostate Cancer and Selection
for Focal Therapy
PSA
PCA3
PSA selection:
Before 2010, low-risk PCa
patients were considered for FT.
Therefore PSA <10 ng/mL
de la Rosette et al., J Endourol. 2010
proPSA
Cancer aggressiveness and
volume?
Selection for focal therapy?
More recently, extension to
intermediate risk.
Most prefer PSA <15 ng/mL
van den Bos, et al. Eur Urol. 2014
Walz et al, SIU-ICUD 2015
Diagnosis of Prostate Cancer and Selection
for Focal Therapy
Overall characteristics of patients included in currently published and ongoing trials on focal
therapy in the primary setting:
•56% low-risk disease
•36% intermediate-risk disease
•8% high-risk disease
•Mean PSA: 3.76–24 ng/mL
•Median age: 56.5–73 yrs
Valerio M, et al. Eur Urol 2015
Reports from Expert Consensus Meetings
Tumor
Focality
Age & Life
Expectancy
• No age threshold
• Life expectancy >10
yrs
• Multifocal cancer
should not
preclude focal
therapy
Risk
FOCAL
THERAPY:
INDICATIONS
Tumor Volume
• No consensus
regarding a minimum
tumor volume for FT
• Intermediate
risk (GS 3+3,
3+4)
Alternatives to Focal
Therapy
•Active surveillance
•Surgery
•Radiotherapy
Prostate
Volume
• No longer an
issue
van den Bos et al., Eur Urol. 2014
Donaldson et al., Eur Urol. 2015
Ahmed et al., BJU Int. 2012
Algaba et al., J Endourol. 2010
?
Focal Ablation Targeted to the Index Lesion in Multifocal
Localised Prostate Cancer: a Prospective Development Study
56 patients treated with HIFU–index lesion
ablation
At 12 mo:
- 80.8% patients had histological absence of
clinically significant cancer
- 85.7% had no measurable PCa
(biopsy and/or mpMRI)
- 3.6% patients had clinically significant
disease in untreated areas not detected at
baseline
Ahmed H, et al. Eur Urol. 2016
Agenda
• Image-Guided Therapies
• Diagnosis of Prostate Cancer and Selection for Focal Therapy
• Imaging in Localized Prostate Cancer
• Prostatic Biopsies: Available Techniques and Approaches
• Available Ablation Energies to Treat Prostate Cancer
• Surveillance After Focal Therapy
• Summary
Imaging in Localized Prostate Cancer: mpMRI
• Increases significant cancer detection.
• High Negative Predictive Values in MRI accuracy studies.
de Rooij M, et al. AJR Am J Roentgenol. 2014
Hambrock, et al. Radiology. 2011
Accuracy of Multiparametric MRI for Prostate Cancer
Detection: A Meta-Analysis
526 patients—The pooled data showed a specificity of 0.88 (95% CI, 0.82–0.92) and sensitivity of 0.74
(95%CI, 0.66–0.81) for prostate cancer detection.
de Rooij M, et al. AJR Am J Roentgenol. 2014
The Role of Magnetic Resonance Imaging (MRI) in Focal Therapy
for Prostate Cancer: Recommendations from a Consensus Panel.
• mpMRI is the optimal approach for focal therapy.
- High-quality machine (3T with/without endorectal coil or 1.5T with endorectal coil)
- Judged by an experienced radiologist.
• mpMRI has sufficient potential to detect a lesion of ~0.5 mL with sensitivity as
well as specificity of ~90%.
Muller BG, et al. BJU Int. 2014
Imaging in Localized Prostate Cancer: mpUS
Gray Scale
Elastography
Histoscanning
Contrast-enhanced Ultrasound
Doppler Imaging
Looking into the future
Muller BG, et al. Curr Opin Urol. 2014
Multiparametric Ultrasound of the Prostate: Adding
Contrast Enhanced Ultrasound to Real-Time Elastography
to Detect Histopathologically Confirmed Cancer
100 patients with biopsy-proven PCa underwent pre-operative TR mpUS combining real-time
elastography and contrast-enhanced ultrasound.
Real-time elastography detected prostate cancer with 49% sensitivity and 73.6% specificity.
It would suggest that the HS protocol requires further refinement before clinical implementation.
The multiparametric approach decreased the false-positive value of real-time elastography
alone from 34.9% to 10.3% and improved the positive predictive value of cancer detection from
65.1% to 89.7%.
Brock M, et al. J Urol. 2013
Imaging in Localized Prostate Cancer: mpUS
Combined data on sensitivity and specificity of the different US modalities
Muller BG, et al. Curr Opin Urol. 2014
Imaging in Localized Prostate Cancer:
Combined imaging
Combined PET/MRI may provide adequate tissue contrast and help to
enhance the clinical assesment of patients with MRI invisible PCa
Barret et al SIU-ICUD 2015
Park H et al, J Nucl Med. 2012
Agenda
• Image-Guided Therapies
• Diagnosis of Prostate Cancer and Selection for Focal Therapy
• Imaging in Localized Prostate Cancer
• Prostatic Biopsies: Available Techniques and Approaches
• Available Ablation Energies to Treat Prostate Cancer
• Surveillance After Focal Therapy
• Summary
Prostatic Biopsies:
Available Techniques and Approaches
• Standard 12-core TRUS biopsy
– Cancer detection rate: 44%
• Final specimen analysis:
–
–
–
–
–
30–40% of the patients were upgraded from their initial biopsy.
Greater extracapsular disease.
Seminal-vesicle involvement.
Lymph-node involvement.
Positive margin rates compared with those who were not upgraded.
Clinical decision making and choosing the right treatment
Tilki, et al. Urol Oncol. 2011
Prostatic Biopsies:
Available Techniques and Approaches
Systematic
trans-rectal
biopsy
Transperineal
mapping
template
prostate
biopsy
Multi-parametric MRI–
targeted biopsy
120 patients submitted to mpMRI +
Fusion-targeted biopsy (FTB) + Saturation
biopsy (SB). All of them were then treated
with radical prostatectomy (RP).
Combined FTB and SB detected 97%
of all significant PCa (sPCa) lesions
and was superior to mpMRI (85%), FTB
(79%), and SB (88%) alone (p<0.001
each).
Radtke JP, et al. Eur Urol. 201
1,003 men submitted to mpMRI + Fusion-targeted biopsy (FTB) + standard biopsy (SB).
170 were then treated with RP.
• FTB diagnosed 30% more high-risk cancers.
• FTB combined with SB led to an additional diagnosis of 22% of mostly low-risk cancers.
• The predictive accuracy of FTB in differentiating low- vs. intermediate- vs. high-risk cancers was
greater than SB.
Siddiqui MM, et al. JAMA. 2015
Prostatic Biopsies:
Available Techniques and Approaches
• MRI-TRUS–guided fusion-targeted biopsy
– Increased detection of high-risk PCa.
– Decreased detection of low-risk PCa.
– Anterior tumors detection.
Baco, et al. Eur Urol. 2015
Mozer, et al. BJU Int. 2015
Siddiqui, et al. JAMA. 2015
294 patients submitted to mpMRI + TPM.
All patients had systematic biopsies + fusion-targeted cores.
• Sampling efficiency was in favor of MRI fusion biopsy with 46.0% of targeted biopsy vs. 7.5% of
systematic TPM detecting Gleason score 7 or greater cancers.
• To diagnose 1 Gleason score 7 or greater cancer, 3.4 targeted and 7.4 systematic biopsies were
needed.
Radtke JP, et al. J Urol. 2015
Agenda
• Image-Guided Therapies
• Diagnosis of Prostate Cancer and Selection for Focal Therapy
• Imaging in Localized Prostate Cancer
• Prostatic Biopsies: Available Techniques and Approaches
• Available Ablation Energies to Treat Prostate Cancer
• Surveillance After Focal Therapy
• Summary
Available Ablation Energies
FREEZING
EFFECT
Cryotherapy
HEAT
EFFECT
RADIATION
PHOTO
SENSITIZER
HIFU
EBR with microboost
LASER
Brachytherapy
Photodynamic therapy
ELECTRIC
EFFECT
Electroporation
Microwave thermotherapy Proton therapy
Radiofrequency ablation
Nanoparticles
thermotherapy
Cyberknife
Jácome-Pita FX, et al., Ecancermedicalscience. 2014;8:435.
De la Rosette et al. SIU-ICUD 2015
Ideal Energy: Definition
Effective
mechanism
• To eradicate known cancer
Easy
application
• To preserve uninvolved tissue
• To preserve genitourinary
function
Re-doable
TRIFECTA
Cost and
availability
Morbidity
Prostate
anatomy
De la Rosette et al, SIU-ICUD 2015
Clinical Results
Follow-up
Biopsy recurrence
(treated side)
Potency
Continence
BDFS (nadir + 2 ng/mL) for low and
intermediate risk
Complications
CRYOTHERAPY
HIFU
15–70 months
1–10 years
4%
1–10%
65–90%
95%
95 – 100%
90–100%
Around 80%
65–75%
Urinary retention,
Rectal fistula
Hematuria,
Dysuria,
Rectal pain and tear
Marien A, et al. Urol Oncol. 2014
IRE—Prospective Studies
Multicenter phase I-II trial
Single-center prospective NEAT trial
16 patients treated with IRE without curative
intent
20 patients treated with IRE
First results on histo-pathologic outcomes of
IRE:
- No viable tissue was seen within the ablation
zone.
- Fibrinoid necrosis of the neurovascular bundle
was observed in 13 patients.
- Denudation of the urothelium of the prostatic
urethra in 9 patients.
•IRE confers low-risk of genitourinary toxicitiy.
•Median PSA significantly dropped to 1.7 ng/mL.
•No residual cancer found at MR-targeted
biopsy in 61.1%.
•2 patients deserved further treatment (RP and
focal HIFU).
van der Bos W, et al. J Urol. 2016
Valerio M, et al. EAU Munich 2016
®
TOOKAD —Phase
III Trial
120 pts randomized to VTP vs. 250 randomized to AS
- PSA ≤10
- 1–3 positive cores and ≤5mm CCL
- GS 3+3
- cT up to cT2a
VTP
AS
Cancer progression
28%
58%
Pts underwent
radical therapy
6%
29%
Pts with negative
biopsies at 24 mos
49%
14%
- No difference in terms of IPSS and IIEF.
- Slightly higher Grade 2 complications in VTP group.
Emberton M. EAU Munich 2016
“A la Carte” Model
Sivaraman A, Barret E. Eur Urol. 2016
Agenda
• Image-Guided Therapies
• Diagnosis of Prostate Cancer and Selection for Focal Therapy
• Imaging in Localized Prostate Cancer
• Prostatic Biopsies: Available Techniques and Approaches
• Available Ablation Energies to Treat Prostate Cancer
• Surveillance After Focal Therapy
• Summary
Follow-up Modalities in Focal Therapy for Prostate
Cancer: Results from a Delphi Consensus Project
• Follow-up length—minimum 5 years
• Modalities to include—mpMRI + biopsies + assessment of EF, QoL, LUTS, UC
• PSA every 3 mos in the first year and every 6 mos thereafter
• mpMRI at 6 mos and 1 yr and every year thereafter
• 12-core + TRUS biopsy combined with targeted biopsy (MRI fusion) at 1 yr and
thereafter if suspicion on imaging
Muller BG, et al. World J Urol 2015
Surveillance
After
Focal
Therapy:
PSA, Derivatives, and other Molecular Markers
• There is currently not enough data describing the
course of serum PSA post-focal therapy with long-term
prognosis:
Recommendation: Record post-treatment PSA levels
including density, nadir, and other kinetics for future research
purposes.
Follow-up:Role of mpMRI
• Useful for monitoring both treated and untreated zones
after focal therapy.
• Minimum requirements:
– 3 T mpMRI
– 1.5 T mpMRI + endorectal coil
• Follow-up times:
– First mpMRI at 6–12 months after treatment
– Optimal frequency—not known. Should be determined by patient factors and
resource availability.
Likely that in patients with low risk, imaging can be infrequent.
– Positive mpMRI should lead to targeted biopsy.
Polascik et al, SIU-ICUD 2015
Role of Biopsy: Mandatory
recommendations:
 mpMRI should be part of any focal therapy program and should trigger
targeted biopsy if suspicious.
 Little published data to inform optimal FU bx regimen.
mpMRI + possible fusion biopsy
Systematic biopsy
Treated area
Mandatory biopsy at 3–6 months
with 4–6 cores
12–24 months and again at 5
years
-
Untreated area
12–24 months and again at 5
years
12–24 months and again at 5
years
Muller GB, et al. World J Urol. 2015
Valerio M, et al. Eur Urol. 2015
Success/Failure in the Treated Zone
• Immediate or technical ablative success: depends on the operator’s
assessment.
• Intermediate- to long-term success: eradication of all aggressive or
clinically significant disease.
Definition of success and failure within the treated zone
•NO RESIDUAL CANCER
•Small volume GS 3+3
•Very small volume (<0.2 cc or
<7 mm in diameter) GS 3+4
• Significant volume ( ≥0.2 cc or 7
mm diameter)
• GS 3+4 (Prognostic Grade Gr 2)
Polascik et al, SIU-ICUD 2015
:
Success/Failure in the Untreated Zone
– Low-risk disease in the untreated zone should be monitored
with standard of care AS protocols.
Definition of Failure in the Untreated Zone
Development of any foci of clinically significant cancer requiring
further therapy (foci developed within 12–18 months—probably
selection failure)
Polascik et al, SIU-ICUD 2015
Agenda
• Image-Guided Therapies
• Diagnosis of Prostate Cancer and Selection for Focal Therapy
• Imaging in Localized Prostate Cancer
• Prostatic Biopsies: Available Techniques and Approaches
• Available Ablation Energies to Treat Prostate Cancer
• Surveillance After Focal Therapy
• Summary
Summary
• Improved imaging has drastically changed the PCa pathway
– Diagnosis
– Treatment decision and planning
– Outcomes control
• Focal therapy trials are at the early stage of clinical development
– The majority of evidence on common practice for focal therapy comes from
experts’ consensus opinion (LE 4)
• What is still needed to make focal therapy an accepted segment of
standard therapy?
– Solid academic effort
• Phase II and III trials with an effective trial design
• Oncological, functional, and quality of life outcomes
Ongoing Trials
Contact/Principal
Investigator
Trial number
Setting
Intervention
Patients
Primary outcome
Ahmed H, Emberton M
NCT01726894
Primary
Focal treatment with nanoknife™
Low to intermediate risk
Safety Profile
de la Rosette J
NCT01835977
Primary
Focal treatment with nanoknife™
Low to intermediate risk
Safety profile
NCT01194648
NCT00987675
NCT01226576
Primary
Primary
Primary
Focal HIFU
Focal HIFU
MRI-guided HIFU
Low to intermediate risk
All risks
Low to intermediate risk
Cancer Control
Safety Profile
Safety profile
NCT00928603
NCT00877682
NCT00774436
NCT02459912
Primary
Primary
Primary
Primary
Focal Cryoablation
Focal Cryoablation
Focal Cryoablation
Focal Cryoablation
Low risk
Low to intermediate risk
Low risk
Low to intermediate risk
Safety profile
Cancer Control
Cancer Control
Potency rate
NCT02632669
NCT01913197
Primary
Primary
Hemi gland focal LDR brachytherapy
MRI guided brachytherapy
Low-risk
Low to intermediate risk
Safety profile
Safety profile
NCT02600156
NCT02200809
Primary
Primary
Focal laser ablation
MRI-guided focal laser ablation
Low to intermediate risk
Intermediate risk
Cancer control
Cancer control
IRE
HIFU
Emberton M, Ahmed H
Ahmed H
Yatim J
Cryotherapy
Guazzoni G
Ward J
Eastham J
Katz A, Kosinski K
Brachytherapy
Jamieson C, Langley S
Quinn S
Laser Ablation
Sathre C, Woodrum D
Bomers J, Fütterer J
ClinicalTrials.gov
For Image-Guided Therapy in PCa . . .
. . . the die is CAST