Focal Therapy for Prostate Cancer

Focal Therapy for Prostate Cancer

Scott Eggener, M.D.Professor of Surgery- Urologic Oncology and Radiology

University of ChicagoTwitter: @uroegg

University of California – Los Angeles State-of-the-Art Urology 2021

Insightec (advisory)Francis Medical (advisory)

Profound Medical (advisory and investigator)Steba (unpaid)

Focal/ablative therapy

Relevant Disclosures

Prostate Preservation: Outline

• The Quintessential Organ Preservation

• Why You Shouldn’t Immediately Dismiss The Concept

• Ideal Candidate

• Oncologic efficacy

• Functional outcomes

• Future

The Quintessential Organ Preservation

Quintessential Organ Preservation: Don’t Biopsy or Treat When Not Necessary

• Not everyone needs to be screened (age, health, risk profile, patient desire)

• Minimize unnecessary biopsies by using:- free PSA, PSA density, etc- novel serum/urine/tissue biomarkers- MRI

• Know when to stop screening

• Appropriate use of active surveillance

Why You Shouldn’t Immediately Dismiss The Concept of Prostate Focal Therapy

Unimaginable

Progress

Hypothesis: Past is Prologue

Urologic Oncology: Heretical Ideas Now Standard of Care Options

• Laparoscopic or robotic surgery

• Active surveillance for prostate cancer

• Monitoring complete response after chemotherapy for testicular cancer

• Enucleation vs conventional partial nephrectomy

Surgical Oncology: Anti-Halstedian Ideas Now Standard of Care Options

• Liver metastases: wedge resection vs. lobectomy

• Primary melanoma: 1 cm vs. 3 cm margin

• Stage I NSCLC: wedge resection vs. lobectomy

• Pancreatic neuroendocrine: enucleation vs. formal resection

• Low rectal cancer: sphincter-sparing surgery

Breast vs Prostate “Focal” Therapy

Breast Cancer Prostate CancerRadical surgery

Halsted mastectomy (1890’s)

Millin retropubic prostatectomy(1940’s)





First report of focal therapy 1930’s 1995 (focal cryotherapy)






Single-center series 1960’s 2000’s







First RCT reported 1972 2017







First RCT reported 1972 2017

Focal therapy in 2019 60% 1% (?)

First Brachytherapy of Breast Tumor

1925 19901956 1970 19901980

Case Series N=127)

1st Positive RCT

Milan, ItalyN=701

1981

NIH Consensus Statement

1990

Case Series (n=97)

1971

Largest RCTNSABP-B6

N=2163

1985

1955 - 1981

1937 1972

1st RCTGuy’s Hospital, UK

(N=370)

1st Case SeriesLumpectomy + XRT

(n=127)

1954

1st Breast Conservation Case Series

(Brachytherapy +/- surgery) n=250

Widespread UsePioneers Early Adopters RCTs

1935 1945

Case Series (N=265)

1964

1967

Evolution of Breast Cancer “Focal” Therapy

Slide courtesy of Craig Labbate

1st ConceptFocal HIFUCase Series

N=10

Pioneers Early Adopters

1995 20201995 2000 2005 2012 2014 2016 2018

1995

Phase III RCTPDT vs. Active Surveillance

(N=404)

2017

HIFU(N=625)

2018

1st FocalCryoablationCase Series

N=92002 20122006

1st Focal PDTCase Series

N=6HIFUN=20

2011

PDTN=56

Focal Vs. Whole GlandCryotherapy

N = 3172015

Phase I/II Large Registries or Multicenter Series

Evolution of Prostate Cancer “Focal” Therapy

Slide courtesy of Craig Labbate

Breast vs Prostate “Focal” Therapy: False Analogy??

• But all breast cancer lumpectomy patients get radiation also!!!

• But prostate cancer is multifocal!!

Reference: Fisher et al, NEJM, 2002

Local recurrence

Randomized trial of 1851 women: (lumpectomy) versus (lumpectomy + RT) versus (radical mastectomy)

Breast vs Prostate “Focal” Therapy: Impact of Radiation

Breast vs Prostate “Focal” Therapy: Multifocality

Breast cancer: 60-65% of women with invasive breast cancer have secondary (or tertiary) lesions at

mastectomy

Reference: Tot, Cancer, 2007; Holland, Cancer, 1985

Prostate cancer: multifocal in 60 – 85 %

Ideal Candidate for Prostate Focal Therapy

What is the Appropriate Patient for Focal Therapy?


- Not Gleason 6 (GG1)

Gleason 6 (Grade Group 1)

1) 0.28% ECE at prostatectomy (n=2,500; Anderson, Eur Urol, 2017)

2) Never SVI at prostatectomy (n=2,500; Anderson, Eur Urol 2017)

3) Never mets to lymph nodes (n=14,000; Ross, Am J Surg Path, 2014)

4) Following RP, 15-yr cancer mortality < 1% (Eggener, J Urol, 2011)

5) Not aware of anyone ever having a met/dying from pure Gleason 6 (GG1)

Ask Yourself……Which is Gleason 6 (GG1)?

Merriam-Webster Dictionary Definition

Benign: of a mild type or character that does not threaten health or life

Malignant: a malignant tumor of potentially unlimited growth that expands locally by invasion and systemically by metastasis

My Opinion: Gleason 6 (GG1) Is an Indolent Neoplasm Rarely Requiring Treatment (INeRRT)



- Gleason pattern 4

Swedish Active Surveillance: Expected vs Observed Mortality

Reference: Rider et al, Eur Urol, 2013

Intermediate-RiskLow-Risk

• 76,000 Swedish men from 1991-2009 untreated“managed without curative intent”

High-Risk Regional Mets

Increasing risk

Reference: Sauter et al, Eur Urol, 2016

BCR Based on Amount of Pattern 4

~9,600 men having surgery at Martini Klinik with pathologic Gleason 7



- Gleason pattern 4

- High-quality MRI +/- re-staging biopsy

At Experienced MRI Centers: ’negative’ MRI typically denotes < 10% risk of Gleason ≥ 7 on biopsy

• UCLA: 217 men with MRI fusion biopsy (prior negative biopsy)– 9% with Gleason ≥ 7

• NYU: 75 men with MRI fusion biopsy (mixed cohort)– 1.3% with Gleason ≥ 7 on biopsy

• Italian: 107 men with standard biopsy (elevated PSA)– 3.8% with Gleason ≥ 7 on biopsy

• U of Chicago: 180 men with MRI fusion biopsy (mixed cohort)– 2% rate of Gleason 7 or higher

How Reliable is a ‘Negative’ MRI? (biopsy outcomes)

Reference: Filson, Cancer, 2016; Wysock, BJU, 2016; Porpiglia, Eur Urol, 2017; Rodriguez (submitted), Meng, Urology, 2018

Tumor > 2 cm: 22% not detected

Reference: Johnson, Eur Urol, 2019

Gleason ≥ 4+3: 25% missed

Of solitary ‘clinically significant‘ lesions: 17% missed

588 consecutive men with mpMRIbefore prostatectomy at UCLA

CAVEATconsecutive series, not men

deemed eligible for focal therapy

How Reliable is a ‘Negative’ MRI? (prostatectomy outcomes)

High-Grade Cancer at Autopsy

Autopsies in 220 Caucasian (Russia) and 100 Asian (Japan) men who died of causes besides prostate cancer

~10-20% of all dead men have previously undetected “high-grade” cancer

Reference: Zlotta, JNCI, 2013

Asian (n=100) Caucasian (n=220)

Age: mean (range) 68 (24-89) 62 (22-80)

Any cancer 35% 37%

% cancers Gleason 7-10 51% 23%



- Gleason pattern 4


- Technically amenable location with minimal risk of morbidity

Location, Location, Location

• Urethral sphincter

• Cavernosal nerves

• Urethra

• Rectum (rare)



- Gleason pattern 4


- Technically amenable location with minimal risk of morbidity

- Informed consent

• Not risk-free• Unknown intermediate or long-term outcomes• Requires commitment to post-ablation surveillance and biopsy• May include significant financial toxicity

Informed Consent

Reference: Tay et al, Prostate Cancer and Prostatic Diseases, 2017

Patient Selection for Focal Therapy of Prostate Cancer in the Era of Active Surveillance: Delphi Consensus Project

• MRI is standard imaging tool (92%)• Systematic biopsy, even if MRI negative (90%)• PSA < 10 ng/ml (100%); no consensus on PSA 10 – 20 ng/ml or PSAD• MRI foci < 1.5 cm (90%)• Gleason ≤ 4+3 (GG 3) (80%)• Untreated Gleason 6 (GG 1) is acceptable but no consensus on tumor

volume• Gleason 3 + 4 (GG 2), when it can be completely ablated, is the ‘sweet

spot’

Efficacy: Oncologic Outcomes

• 625 men with focal HIFU at 9 centers in the UK from 2006 – 2015

• Rigorous training/mentorship

• Re-treatment allowed; 112 (18%) had repeat HIFU

• 85% were intermediate/high-risk

HIFU Hemi-Ablation

Reference: Guillamier et al, Eur Urol, 2018

HIFU Hemiablation: Failure-Free Survival


All patients: 88% ‘failure-free’ at five years ‘Failure-free’ by D’Amico Risk

‘Failure’ = local salvage therapy or metastases

Vascular-Targeted Photodynamic Therapy• Developed by Weizmann Institute, private foundation, and Steba Biotech (TOOKAD)

• Treatment (unilateral or bilateral) guided by software with judgement from urologist

• Laser fibers inserted transperineally into prostate to cover treatment zone

• Padeliporfin (4 mg/kg IV over 10 minutes)

• Drug activated by light within treatment zone from the laser fibers

Reference: Azzouzi, Lancet Oncology, 2017

Vascular-Targeted Photodynamic Therapy

• 413 men with low-risk prostate cancer randomized to PDT vs surveillance- 1st patient enrolled 2011

• 47 European centers

• Two separate primary endpoints:– Treatment failure: cancer progression (to higher risk category)– Absence of cancer


PDT

n=206

ActiveSurveillance

n=207Progression 28% 58%

Radical Rx 6% 29%

Neg Bx @ 2yr 49% 14%

Results - Progression


Results

Time to Progression

PDT

Surveillance

PDT 4 year Follow-Up:Time to Whole-Gland Therapy

Reference: Gill, J Urol, 2018

• Whole-gland therapy at 4 years: 24% vs 53% (HR 0.31)

- surgery in 80%- radiation in 14%- whole-gland ablation in 5%

Time to whole-gland therapy

Functional Outcomes: Urinary

• Focal HIFU at 9 centers in the UK from 2006 – 2015

• 421 with baseline questionnaire: - 313 responded at 1 - 2 years (97% pad-free)- 247 responded at 2 - 3 years (98% pad-free)

HIFU Hemiablation: Incontinence


HIFU Hemiablation: IPSS

Reference: Ahmed et al, Lancet Oncol, 2012

IIEF (left) and IPSS (right)Photodynamic Therapy: IPSS


IIEF (left) and IPSS (right)Photodynamic Therapy: Urinary Function


Absolute increase in Grade 1-2 incontinence: 5%

Functional Outcomes: Erectile

• 111 men with low-intermediate risk prostate cancer at 10 centers in France between 2009-2015

• Erectile function: 95% within 3 points of baseline IIEF

HIFU Hemiablation: Erections

Reference: Rischmann et al, Eur Urol, 2016

IIEF (left) and IPSS (right)Photodynamic Therapy: Erectile Function


IIEF (left) and IPSS (right)Photodynamic Therapy: Erections


Grade 1: no medsGrade 2: oral medications work

Absolute increase in Grade 1-2 ED: 27%

Prostate Cancer Focal therapy: Future

OutlineFocal Therapy Modalities: Ten and Counting……

• High-intensity focused ultrasound (HIFU)• Cryotherapy• Vascular-targeted photodynamic therapy (PDT)• Focal brachytherapy • Irreversible electroporation (IRE)• MR-guided transurethral ultrasound ablation• MR-guided focal laser ablation (FLA)• Convective water vaporization• Injectable cytotoxin• Partial prostatectomy

FDA Public Workshop (2018) on Focal Therapy for Localized Prostate Cancer

• Multidisciplinary roundtable with FDA leadership

• Discussion of optimal randomized clinical trial designs

• Encouraged inclusion of men with Gleason 7 (GG2)

• Feasible regulatory endpoint: delay or eliminate surgery/XRT

REF: Weinstock, J Urol, 2019

Prostate Focal Therapy Clinical Trials

I am aware of at least 5 ongoing and upcoming randomized trials of focal therapy vs active

surveillance (1 trial vs surgery)

ClinicalTrials.Gov ”focal therapy” and “prostate cancer”: 68 listings

Focal Therapy: Breast Cancer

1976:“As more and more conservative studies ripen, as more

and more concerned physicians observe the adverse effects of

excessive treatment, as more and more women become armed with knowledge, mastectomy, in early

breast cancer, may become as old-fashioned as bloodletting.” Vera Peters

Focal Therapy: Breast Cancer

Focal Therapy: Prostate Cancer

2021: “As more and more conservative studies ripen, as more and more

concerned physicians observe the adverse effects of excessive treatment, as more and more men become armed

with knowledge, prostatectomy or radiation in early prostate cancer, MAY

become as old-fashioned as bloodletting.” Scott Eggener

Focal Therapy: Prostate Cancer

Conclusions

• Prostate focal therapy is worthy of study

• Patient selection is critical

• Clinical trials have been completed and many are ongoing

• DATA will determine: worthwhile, worthless, or somewhere in between?

Conclusions: #1

ConclusionsConclusions: #2

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Focal Therapy for Prostate Cancer