prostate focal therapy: what’s on the horizon?
TRANSCRIPT
All Rights Reserved, Duke Medicine 2007
Current State of Prostate Focal Therapy
• Patient Selection
• Focal Ablation – Technology and Technique
• Follow-up/ Surveillance after Focal Therapy
• Long Term Outcomes
All Rights Reserved, Duke Medicine 2007
Patient Selection: Evolution in Consensus De la Rosette 2010 (48) Ahmed 2012 (49) Donaldson 2015 (50) Tay 2016 (51) Goal Eradication of all cancer Eradication of all cancer Eradication of clinically
significant cancer Eradication of clinically significant cancer
Cancer Determination
Overall TMB TMB and mpMRI TMB or systematic + mpMRI mpMRI + systematic biopsy
mpMRI Can be recommended at state of art centers
Recommended No clear recommendation Recommended as far as possible
Biopsy of suspicious lesion
- To be studied Recommended Recommended, MRI-TRUS Fusion Biopsy
Biopsy of non-suspicious area
- TMB Recommended Recommended, at least 12 core TRUS biopsy
Disease Factors
Risk Group Low to moderate risk - Intermediate Intermediate Maximum grade - - - 4+3 Maximum size T2a clinically or T2b
radiologically - No agreement Up to 1.5 ml or 3 ml if not
crossing midline; up to 20% of prostate volume or 25% if crossing midline
Residual Disease Permissible
None None 3+3 up to core length 5mm 3+3 up to core length 1mm
Patient Factors
Age/ Life Expectancy At least 10 year life expectancy
NA Not a primary determinant; best suited to life expectancy >10 years and not <5 years
According to major guidelines. No upper or lower limit whereby focal is contraindicated
Sexual Function Effect unknown, counselling recommended
NA NA Important, but not the only indication for choosing focal therapy
All Rights Reserved, Duke Medicine 2007
Patient Selection: today’s pitfalls
12 Core Biopsy
TTMB
mpMRI + Fusion Bx
Selecting unilateral disease for hemi-ablation: 88.4% sensitivity, 34% specificity
Higher detection rate Invasive Needs OR Complications
Reader dependent Fusion biopsy has many moving parts High NPV but consensus still points towards need for systematic biopsy
All Rights Reserved, Duke Medicine 2007
mpMRI
• Reader-dependent – Lesion identification – Excluding extra-capsular
extension
• Fusion Biopsy – Dependent on quality of
fusion
5
Tay KJ, Gupta RT, Brown AF, Silverman RK, Polascik TJ. Defining the Incremental Utility of Prostate Multiparametric Magnetic Resonance Imaging at Standard and Specialized Read in Predicting Extracapsular Extension of Prostate Cancer. Eur Urol. 2016;70(2):211-3.
All Rights Reserved, Duke Medicine 2007
Newer Imaging Modalities
• PSMA-linked small molecules for imaging – Evolution of radiolabels: 68G vs 18F (lower positron emission
energy leading to greater contrast/ resolution)
• Multiparametric Ultrasound – Development of advanced elastography techniques
All Rights Reserved, Duke Medicine 2007
68Ga-PSMA–PET–MRI of a 50-year-old patient who had a rising serum PSA value (16 ng/ml at imaging) and two tumour-negative previous biopsy samples
Maurer, T. et al. (2016) Current use of PSMA–PET in prostate cancer management Nat. Rev. Urol. doi:10.1038/nrurol.2016.26
PSMA-PET-MRI Fusion
All Rights Reserved, Duke Medicine 2007
PSMA-PET-MRI Fusion
• 68G-PSMA-PET-MRI with Fusion Biopsy – 16 cases, 6 histologically confirmed PCa of 7 suspicious cases – Storz et al
• 18F-DCFBC CT-PET with MRI Fusion – 13 cases, PET was less sensitive than MR (0.17 vs 0.39) but more
specific (0.96 vs 0.89) – Rowe et al
All Rights Reserved, Duke Medicine 2007
Matched B-mode, acoustic radiation force impulse (ARFI) and histologic prostate images of patient A. The first row shows an axial view (regular imaging plane) of the prostate; the second and third rows are two parallel coronal views. The axial imaging ...
Liang Zhai, Thomas J. Polascik, Wen-Chi Foo, Stephen Rosenzweig, Mark L. Palmeri, John Madden, Kathryn R. Nightingale Acoustic Radiation Force Impulse Imaging of Human Prostates: Initial In Vivo Demonstration Ultrasound in Medicine & Biology, Volume 38, Issue 1, 2012, 50–61 http://dx.doi.org/10.1016/j.ultrasmedbio.2011.10.002
Acoustic Radiation Force Impulse (ARFI) Imaging
All Rights Reserved, Duke Medicine 2007
Acoustic Radiation Force Impulse (ARFI) Imaging
• Early study suggests good correlation between ARFI Index of Suspicion (IOS) and PIRADS score.
12
Liang Zhai, Thomas J. Polascik, Wen-Chi Foo, Stephen Rosenzweig, Mark L. Palmeri, John Madden, Kathryn R. Nightingale Acoustic Radiation Force Impulse Imaging of Human Prostates: Initial In Vivo Demonstration Ultrasound in Medicine & Biology, Volume 38, Issue 1, 2012, 50–61 http://dx.doi.org/10.1016/j.ultrasmedbio.2011.10.002
All Rights Reserved, Duke Medicine 2007
Focal Ablation Technology
• Cryo – 8 cohort studies, 1 registry report (COLD) • HIFU – 4 cohort studies • Laser – Phase I/ II • VTP – Phase I/ II,III • IRE – Phase I/ II • Brachytherapy • SBRT • Gold nanoparticles • Water Vaporization
All Rights Reserved, Duke Medicine 2007
Comparison of Outcomes Between Preoperatively Potent Men Treated with Focal Versus Whole Gland Cryotherapy in a Matched Population Mendez, M.H., et al., J Endourol, 2015
• FT vs. WG – matched comparison of 634 men • All D’Amico low risk • Median FU: 58.3 months
Treatment Oncological outcomes(BCR free
survival)*
Erectile function (recovery of function)**
Continence Urinary retention Fistula
WG Phoenix: 80.1% ASTRO: 82.1%
46.8%
98.7% 6 months: 7.3% 12 months: 1.9% 24 months: 0.6%
1
FT Phoenix: 71.3% ASTRO: 73%
68.8% 100% 6 months: 5% 12 months: 1.3% 24 months: 0.9%
1
* All P≥ 0.1; ** P=0.01
Mendez, M.H., et al., Comparison of Outcomes Between Preoperatively Potent Men Treated with Focal Versus Whole Gland Cryotherapy in a Matched Population. J Endourol, 2015. 29(10): p. 1193-8.
All Rights Reserved, Duke Medicine 2007
Matched comparison in intermediate risk prostate cancer
0.00
0.25
0.50
0.75
1.00
200 122 80 47 28 12 5 2 1 1 1Partial200 112 72 53 39 28 15 9 3 3 0Whole Gland
Number at risk
0 12 24 36 48 60 72 84 96 108 120analysis time
Whole Gland Partial
Biochemical Progression Free Survival (ASTRO)
0.00
0.25
0.50
0.75
1.00
200 138 91 57 37 18 7 3 2 1 1Partial200 152 104 78 59 40 20 8 3 2 0Whole Gland
Number at risk
0 12 24 36 48 60 72 84 96 108 120analysis time
Whole Gland Partial
Biochemical Progression Free Survival (Phoenix)
• Matched 200 pairs of WG and partial ablation • Intermediate risk PCa • BPFS following partial ablation - not significantly inferior than BPFS post WG • Better sexual fx at 12 months post partial ablation (successful intercourse)
WG – 26.6% Partial - 45.5%
All Rights Reserved, Duke Medicine 2007
Treatment Adjuvants
• Ablation Sensitizers – Thermophysical adjuvants – Chemotherapeutics – Pro-inflammatory cytokines or vascular-based agents – Immunomodulators – Neutraceuticals
18
All Rights Reserved, Duke Medicine 2007
Thermo-physical adjuvants
• Altering the cell environment may enhance the efficacy of cryoablation due to eutectic crystal formation.
19 Han B, Bischof JC. Direct cell injury associated with eutectic crystallization during freezing. Cryobiology. 2004;48(1):8-21.
All Rights Reserved, Duke Medicine 2007
Chemotherapeutic Adjuvants
20
Lung Tumors grafted onto mice. Chemotherapeutic agent: Venorelbine ditartrate
Forest V, Peoc'h M, Campos L, Guyotat D, Vergnon JM. Benefit of a combined treatment of cryotherapy and chemotherapy on tumour growth and late cryo-induced angiogenesis in a non-small-cell lung cancer model. Lung Cancer. 2006;54(1):79-86.
All Rights Reserved, Duke Medicine 2007
Immunomodulators
• TRAIL (Tumor necrosis factor-related apoptosis-inducing ligand) – Directly activates apoptotic pathways at elevated subfreezing
temperatures but not by freeze concentration.
• TNF-alpha – Shown to destroy tumors at the edge of the freeze zone.
21
All Rights Reserved, Duke Medicine 2007
Follow-up/ Surveillance
• Unaddressed issues
– Have we attained sufficient quality in imaging to omit systematic biopsies at follow-up?
– What is the necessary frequency/ follow-up schedule for mpMRI/ fusion biopsy or systematic biopsy?
– What is the role of PSA at follow-up?
All Rights Reserved, Duke Medicine 2007
SIU-ICUD Consensus Statement 2015
• Definitions of Failure: – Treated zone: small volume PGG1 or very small volume PGG2
(<0.2ml) acceptable – Untreated zone: any foci of clinically significant cancer
• PSA – Insufficient long term data – To be collected for research purposes
24
All Rights Reserved, Duke Medicine 2007
SIU-ICUD Consensus Statement 2015
• mpMRI – 3T or 1.5T w/ ERC – At least once 6-12 months after treatment – Periodically thereafter
• Biopsy
25
MRI/ Fusion Biopsy Systematic Biopsy
Treated Area Mandatory biopsy at 3-6 months MRI at 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
All Rights Reserved, Duke Medicine 2007
SIU-ICUD Consensus Statement 2015
• Retreatment – Cause of cancer persistence or recurrence in the treated zone is
multifactorial.
– Patients should not be precluded from any of the standard prostate cancer treatment options, including additional focal therapy if clinically appropriate.
– Focal therapy can be performed in the salvage setting when the reasons for initial failure can be clearly identified and corrected.
26
All Rights Reserved, Duke Medicine 2007
Moving Forward
• Evaluation of long term oncological outcomes – Recurrence on mandatory biopsy – Mortality – Failure/ need for salvage treatment
• Randomized Trials or development of a Multicenter Focal Therapy Registry to capture outcomes in a standardized manner?
28