PSA andPROSTATE CANCER

Dr Kiran Hazratwala

Urologist

FORMATPSA

Refinements of PSA

Prostate cancer – Natural history

Investigate Localised Prostate cancer

Options of treatment of localised cancer

Active surveillance vs Active intervention

Case studies.

1-Assessment of Risk

Demographic – Age, race, medical health /longevity

History to rule out confounders

Family History

DRE – to compliment the PSA value

Investigations – MSU and Ultrasound (comorbid illness will take precedence)

2- PSASerum Protease – Kallikrien family of proteins

Functions in semen liquefaction

Half life is 3 days

Prostate Specific not disease specific

Very non-specific as a test

Imperfect screening test BUT best we have

DO NOT RELY SOLELY on it

PSA FALSE POSITIVE

PSA REFINEMENTSAimed at decreasing unnecessary biopsies

Age adjusted ranges

PSA Velocity

PSA density

PSA free : total ratio

Age adjusted PSA

AGE (years) Age specific reference (ng/ml)

40-4950-5960-6970-79

0 – 2.5 0 – 3.50 – 4.50 – 6.5

PSAV and PSADPSAV – describes rate of change slope of line of

regression assumes a linear relation of PSA /TIMETraditionally was > 0.75 ng/ml/yrNow MVA > 0.5 ng/ml/yr (Loeb et al AUA 2006)

PSAD – Ratio of PSA level to size on TRUSPSAD of > 0.15 warrant a biopsy!!!!! Reliability is questionable due to variation in

measurements.

PSA FREE:TOTAL ratioMost PSA is bound to ACT or MG

CaP cases have a lower free component

Improves spec for CaP detection in PSA 4-10 ng/ml where risk overall is 25%

Threshold is controversial BUT its use is agreed

f/t ratio < 15% - warrant Biopsy Risk 28-56%15-25% - consider biopsy Risk12-19%>25% - may avoid Bx if DRE normal Risk 8%

How best to use it ?Multiple guidelines exist – NCCN guide here

NCCN

A national recommendation

Single PSA test as a predictor for the long term risk of CaP around mid 40s

PSA > 0.65 ng/ml further PSA testing should be considered as per Australasian CaP SymposiumPSA level (ng/ml) Action needed

<0.65 0.65 – 1 >1

Low risk repeat test in mid 50sPSA test every 2-4 yrsAnnual PSA to assess PSAV

To test or NOT to test??The PSA testing debate between the US and

Euro

Individualize the debate to patients

Whats good for the economist is not always good for patient

Use risk adapted approach

PLCO (US trial)Controversy continues over PSA testing for

prostate cancer, Canada

Still Confusion about the Usefulness of PSA-screening, USA.

Does cancer screening save lives? Not nearly as many as you might guess

PLCO Methods 1993 – 2001

76,693 men aged 55-74 years enrolled at 10 sites

Screened: Annual PSA for 6yrs + DRE for 4yrs

Control: “usual care”

PSA >4ng/ml “considered positive for prostate cancer”

Analysis – based on intent to screen comparison of mortality between groups

Results -- BaselineScreening group

44.0% previous PSA test

Control group44.1% previous PSA test

PLCO Screened group – 85% compliance, 15% didn’t

have a PSA

Control group – contamination40% first year52% sixth yearDRE 41-46%

So 85% testing vs. 52% testing

Study terminated at 7 yrs – effect starts 7-9yrs

Concerns/explanation for results

44% of EACH group already had prior PSA

15% of “screened” group didn’t get screened

52% of “control” group were screened

Low biopsy compliance.

Too short follow up Only 67% have reached 10year follow-up (ERSPC: 12 year lead time)

Too few events (174 deaths from 76,693 men)

ERSPC: European Randomized Study of Screening for Prostate Cancer

182,000 men, 7 centres – different procedures for each site.

Men 50-74years old

Screened group: PSA+DRE every 4yrs (range 2-7)

Any PSA >3-4 (10 in Belgium) sextant biopsies

Primary outcome death

Prostate Cancer Deaths214 prostate cancer deaths in screening group

326 in control group

27% reduction for those who underwent screening (20%as intention to screen)

Adjusted rate ratio 0.80 in screened groupCI: 0.67 to 0.95Rates diverged after 7-8 years

ERSPC Prostate Cancer Deaths

7yrs PLCO review time point

ERSPC 9years median follow-up

Conclusions20-27% reduction in death from prostate cancer

in screened group

Rate of over diagnosis estimated at 50% in screening group.

Need to screen 1068 men and treat 48 men to prevent one prostate cancer deathBreast cancer (781) Colorectal cancer (1250)

What is Active Surveillance?

Conservative management option for localised prostate cancer

• Active intervention has not been ruled out whereas Watchful Waiting generally implies observation until necessary to commence hormonal therapy

• Men on AS may

–Ultimately have active intervention

–Change over to Watchful Waiting protocol

–Continue on the AS protocol

Criteria for Offering Active Surveillance

• Patient Factors

– Age, comorbidity • PSA

– Absolute levels • Upper thresholds vary from <10 up to <20 ng/mL – PSA density – Pre-diagnosis PSAV and PSADT not usually addressed

• DRE – Clinically impalpable or at most any T2 disease

• Gleason Score – Gleason !6 or !7

– Absence of any high grade cancer – 3+4 vs 4+3 not generally addressed where GS 7 allowed

• Biopsy Core parameters – Less than 3 biopsy cores involved – No more than 50% involvement of any core

Criteria for Departure From AS• Patient Factors

– Patient request for treatment or watchful waiting – Development of co-morbidity and move to watchful waiting

• PSA

– Absolute threshold level – PSADT/PSAV

• DRE – Local progression

• Repeat Biopsy parameters – Presence/absence of cancer in 2ndbiopsy – Increased numbers of positive cores – Increased % core involvement – Increased Gleason score – Any presence of high grade cancer

IF A/S is CONSIDERED

Predictors of Progression

• Univariate analysis p-value. • Positive second biopsy 0.002 • PSA (baseline) 0.012 • PSAD (baseline) 0.034 • Clinical Stage >T1a 0.053 • Predicted 5 year PFP (baseline) 0.102 • Gleason score (baseline) 0.241• PSA doubling time 0.300 • Clinical stage (baseline) 0.479 • No. of positive cores (1st biopsy) 0.590 • Proportion of cores positive (1st biopsy) 0.988

PRIAS StudyCriteria for inclusion:

1.Histologically proven carcinoma of the prostate

2.patient should be fit for curative treatment 3.PSA-level at diagnosis ! 10 ng/mL 4.PSA density (PSA D) less than 0,25.Clinical

stage T1C or T2 6.Appropriate biopsy sampling (see ‘biopsy

protocol’) 7.Gleason score 3+3=6 (or less) 8.One or 2 cores invaded with prostate

cancer 9.Participants be willing to attend the follow-

up

Case 1Mr R B 58 yrs

Medically well

No FHx of CaP

DRE = benign moderately enlarged prostate

PSA 4.1 ug/l

PSA repeat 4.7ug/l

Case 1 cont’dBiopsy

PROSTATE TRUS BIOPSIES X 12: - PROSTATIC ADENOCARCINOMA, GLEASON SCORE 6

(3 + 3), PRESENT IN ONE CORE (RIGHT BASE LATERAL)

- FOCAL PERINEURAL INVASION - NO EVIDENCE OF VASCULAR INVASION OR

EXTRAPROSTATIC EXTENSION.

Options??ASLDR BRACHYSurgeryAny other options!!!! Obviously there are 4 !!!!

Case 1 cont’dRepeat biopsy

PROSTATE TRUS BIOPSIES: - GLEASON SCORE 3 + 4 = 7 PROSTATIC

ADENOCARCINOMA INVOLVING SEVEN BIOPSY SITES; RIGHT LOBE - PERINEURAL INVASION IDENTIFIED - NO EVIDENCE OF EXTRAPROSTATIC EXTENSION

Options now?? Its easy answer now….. Ok next case

Case 2 Mr R S 65 yrs old

Medically well

Nil FHx of CaP

DRE – Significantly enlarged benign prostate

PSA

2007 2008 2009 2011

2.4 2.1 3.4 4.7

Case 2 cont’dBiopsy – Prostate volume 75cc

1 - 12. PROSTATIC TRUS BIOPSIES: - PROSTATIC ADENOCARCINOMA OF ACINAR /

USUAL TYPE; - ONE BIOPSY POSITIVE FOR CARCINOMA,

SPECIMEN 8 LEFT BASE MEDIAL,MICROSCOPIC FOCUS < 5%, < 1MM;

- GLEASON SCORE 3 + 3 = 6; - NO PERINEURAL INVASION; - NO EXTRAPROSTATIC EXTENSION

Options?? ASSURGERY OR LDR BRACHYTHERAPY!!!

Case 2 cont’dActive surveillance put in place Aug 2011

PSA Nov 2011 – 4.3

PSA Mar 2012 – 6.3

PSA June 2012 – 7.6

PSA Aug 2012 – 5.7

Time for Protocol biopsy on PRIAS study

Case 2 cont’dRepeat biopsy

12 Tissue core2 cores positive for Adenocarcinoma ProstateRight Apex lateral and left base medial3+3=6 Gleason score 5 and 20% of each core +ve respectivelyNo perineural inv or Extraprostatic extension

OPTIONS now???

Case 2 –Yeah last slide !!Opted for continued AS

PSA Dec 2012 – 4.6

PSA Mar 2013 – 5.1

Where to from here!!!!!!!!