Active Surveillance in Intermediate-Risk

Prostate Cancer: PRO

Larry Goldenberg, CM, OBC, MD, FRCSC

Professor, UBC Dept of Urologic Sciences

Director of Development and Supportive Care, Vancouver Prostate Centre

Vancouver, BC, Canada

Financial and Other Disclosures

• Off-label use of drugs, devices, or other agents: None

• Data from IRB-approved human research is presented

I have the following financial interests or

relationships to disclose: Disclosure code

No financial relationships N

Road Map

• Not all intermediate risk cancers are the same

• We all agree that “high-intermediate” require Rx

• Favourable intermediate risk cases require more

stringent followup protocol (eg MRI), but deferred

therapy is not dangerous

• Ultimately, it comes down to a particular man’s

risk threshold (comfort zone)?

What we know so far: AS

• AS is underutilized

• Patient selection and buy-in is critical

• 25-50% of patients will progress, usually in first 3 to 5 years

• Death due to CaP on AS is 1- 2.4%

• Death due to non-CaP causes is 15-20 times more likely

• Triggers for intervention are not clearly validated

Why not AS for intermediate risk cancer??

• The inability to accurately predict the biological behavior of a cancerin a given individual (Biology vs Histology)

• “CYA”: If you recommend aggressive therapy, then…..

– If the disease progresses, you have done everything possible

– If the disease does not progress, you have cured the patient

Achilles Heel of AS:

Missed High Grade Cancer

Gleason 6

Gleason 8

Today's metastasis was once

organ-confined cancer

It Should Not be a Slippery Slope to IMMEDIATE RP

Dr Klotz

What about the Bunny Rabbits?

Firstly, not all Rabbits are the same!

Risk stratification definitions have changed over time!

Definition: Original AUA/D’Amico-NCCN

• Low Risk: PSA <10, GS≤6, T1/2a

• Intermediate: PSA 10-20, GS=7, T2b

• High Risk: PSA >10, GS>7, T2c/3

• Overweights T-stage

• Does not distinguish 3+4 vs. 4+3

• Does not account for many important variables

All Intermediate risk: “The same, but not the same”?

Definition: CAPRA?

• Low Risk: 0 – 2

• Intermediate Risk: 3-5

• High Risk: 6-10

New NCCN:

• Very low risk: T1c, GG1, 3 or fewer of 12 cores, 50% or less core volume and

PSAD <0.15 ng/ml

• Low Risk: PSA <10, GG1, T1/2a

• Favourable Intermediate: Major pattern grade 3 and less than 50% positive biopsy

cores, with 1 intermediate risk factor, including T2b/c, Grade Group 2 or PSA 10-

20.

• Unfavourable Intermediate: > 1 intermediate risk factor, Grade group 3

• High Risk: PSA >10, GS>7, T2c/3

Quantitative Gleason Score (qGS)

Reese A et al. Cancer, epub 2012.

Pathologists are restratifying (Grade groups):

So we agree that not all intermediate risk cancers are the same and

indeed there is a “Klotz grey zone”

Not all Intermediate Risk are equal

• % of Gleason Pattern 4 (Stamey and McNeal, 1980’s)

• Scattered vs Clustered Grade 4 on a background of Grade 3

• Continuous vs Discontinuous tumour involvement

• Cribriform/Glomeruloid pattern vs poorly formed/fused vs a mix

• Total tumour involvement of a core

• Pathologist interobserver agreement is approximately 74% with greatest

discrepancy differentiating 3 and 4

• Gleason 3+4 without cribriform and intraductal = prognosis of 3+3

(Kweldam et al, Mod Path, 2016)

J Urol, Sept, 2017

Comparison of Outcomes of GG1 And GG2

8095 RPs: GG1 or GG2, PSA≤10, ≤T2a

Gearman et al, J Urol, 2018

GG1 GG2

OC 94% 83%

N1 0.3% 1.8%

XRT postop 3.1% 8.5%

BCR 10 yrs 89% 81%

PFS 10 yrs 99% 96%

Aghazeda et al, J Urol, 2018

N-3,686 RP patients

15%

27%

48%

n

Göteborg Trial: Stopping Active Surveillance

Godtman et al, Eur Urol, 2012

UBC VPC: 1993 – 2014

• 915 men initially Rx with AS

• 651 men met strict inclusion criteria

• Confirmatory biopsy within 18m

• Minimum 6 months f/u, intention to treat

curatively

• Outcomes : – Cessation of AS

– Cancer progression (Repeat Biopsy, PSADT)

– Radical prostatectomy outcomes

– PSA recurrence

– CSM and OM

AS Patient Characteristics at diagnosis

2014

Predictors of Progression

Minimal GP 4 on biopsy is associated

with low-risk tumour in RP specimen

Huang, Taneja et al. AJSP, 2014

Clinical outcomes following deferred RPx

2014

Intermediate risk tumour:

Significant or insignificant?

The “Holy Grail” of Treating Prostate Cancer Today

• To differentiate the biologically significant

cases from the insignificant, and to avoid the

morbidity of treatment whenever possible.

Risk Calculators

• Milan Calculator (Gandaglia et al,

https://onlinelibrary.wiley.com/doi/abs/10.1111/bju.14391)

• Canary Calculator (https://canarypass.shinyapps.io/biopsy_nomogram/)

• ERSPC (PRIAS) calculator (http://www.prostatecancer-riskcalculator.com/active-surveillance-

and-prias-study)

Biomarker Assays and Genomic Classifiers

MRI may be the best “biomarker”

• MRI is very promising*

– to ensure better sampling of prostate (current)

– to reduce number of biopsies needed (future)

* But is it the standard of care yet?

Defining Boundaries in Prostate Cancer

13 to 30% missclassification Delayed intervention Anxiety

45-70% avoid early Rx Preserve Q of L

Balance: probability of dying from untreated- or delayed Rx against chances of having to live with the complications of Rx

Do you feel lucky, Punk?

Risk Threshold - Individualize

CHOICES

Summation

• Not all intermediate risk cancers are the same

• We all agree that “high-intermediate” require Rx

• We have the tools today to better risk stratify and

followup: serum/urine biomarkers, mp-MRI,

radiopharmaceuticals and genomic classifiers

• Ultimately, what is a particular man’s risk

threshold (comfort zone)? His choice!!

Thankyou