prostate focal therapy: what’s on the horizon?

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Prostate Focal Therapy: What’s on the Horizon?

Thomas J Polascik, MD FACS

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


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


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


mpMRI

•  Reader-dependent –  Lesion identification –  Excluding extra-capsular

extension

•  Fusion Biopsy –  Dependent on quality of

fusion

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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.


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


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


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


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


Acoustic Radiation Force Impulse (ARFI) Imaging

•  Early study suggests good correlation between ARFI Index of Suspicion (IOS) and PIRADS score.

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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


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


Focal Ablation Technique


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%

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FT Phoenix: 71.3% ASTRO: 73%

68.8% 100% 6 months: 5% 12 months: 1.3% 24 months: 0.9%

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* 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.


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%


Anterior Gland Ablation


Treatment Adjuvants

•  Ablation Sensitizers –  Thermophysical adjuvants –  Chemotherapeutics –  Pro-inflammatory cytokines or vascular-based agents –  Immunomodulators –  Neutraceuticals

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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.


Chemotherapeutic Adjuvants

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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.


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.

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Neutraceuticals: Vit D as a cryosensitizer

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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?


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

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•  mpMRI –  3T or 1.5T w/ ERC –  At least once 6-12 months after treatment –  Periodically thereafter

•  Biopsy

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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



•  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.

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Long Term Outcomes

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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?

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»  Thank You

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prostate focal therapy: what’s on the horizon?

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