Where are we with PSA screening?  

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THE GOALS OF CANCER SCREENING

‘Detect a cancer at an early stage when it is treatable and curable’

Devita, 6th Edition, Chapter 25, Rimer, Schildkraut &Hiatt

#1 CANCER IN MEN (1/7), #3 CAUSE OF CANCER DEATH (1/27) >50 yr 40% have Prostate cancer on Autopsy

Prostate  Specific  An;gen  

•  Liquefac;on  of  Semen  •  Leaks  into  circula;on  when  there  is  disrup;on  of  the  glandular  architecture  

•  PCa  doesn’t  make  more  PSA,  it  just  leaks  out  more  – BPH,  Prosta;;s,  Urethral  instrumenta;on,  PCa,  Bx  

PSA

•  Normal <4.0 ng/ml •  PSA Velocity:

•  if 4-10: 0.75ng/ml/yr •  if <4: 0.4ng/ml/yr

•  PSA Density: >0.15ng/ml (based on TRUS) •  Free/Total: <10% = Inc Sp

RISK%GROUP% PSA% STAGE% GLEASON%

LOW$ <10$ T1C,$T2a$ ≤6$INTERMEDIATE$ 10620$ T2b$ =7$HIGH$ >20$ ≥T2c$ ≥8$

Options for Treatment •  Watchful waiting •  Active Surveillance •  Radical Prostatectomy

– Open – Laparoscopic – Robotic

•  Radiation – External beam – Brachy – Brachy + External Beam

Active Surveillance - Results

Klotz 2011

Radical  Prostatectomy  

overall survival cancer specific survival St

ephe

nson

et a

l JCO

200

9

Radical  Prostatectomy  •  Old  fashioned  (=  standard  of  care)    

–  “Radical  Retropubic  Prostatectomy”  (RRP)  

•  The  New  Wave  –  “Robo;c  Assisted  Laparoscopic  Prostatectomy”  (RALP)  

•  Why  the  change?  –  Tradi;onally  a  technically  challenging  opera;on  

•  Significant  func;onal  impairment  if  done  poorly  

–  Tradi;onally  associated  with  high  blood  loss  –  Urologists  with  new  tools  want  to  make  their  name  – Marke;ng  $$$$  Marke;ng  $$$$  Marke;ng  !!!!  

RP  vs  RT  

Cancer  Specific  Mortality  

Group   Time     RRP   RT     WW  Tewari   Gleason  

8+    4  years     13.4%     16.8%     43%  

 Albertson    

High-­‐risk      10  years   10%   20%   30%  

TREATMENT   PROS   CONS  

WATCHING   No  Treatment  related  side  effects   Pain  and  suffering  from  metasta;c  disease    

Ac;ve  Surveillance  

Limit  overtreatment  of  low  risk  disease  

May  miss  the  window  for  Cure  

RRP   Can  achieve  a  cure  Able  to  assess  defini;ve  pathology,  Avoids  side  effects  of  radia;on  

Surgical  morbidity  50%  ED  rate,  5%  Incon;nence  

Rate  

EBRT   Min  ;me  off  work,  min  early  side  effects,    

Late  toxicity  to  the  bladder,  Secondary  Cancer  development,  No  pathology  obtained  to  guide  follow  up,  PSA  can  be  hard  to  

follow  aher  due  to    

Brachy   Min  ;me  off  work,  min  early  SE,  less  late  ED  

Severe  BPH  effects,  Prostate  Fistulas,  Urethral  Strictures,  PSA  

bounces,  no  Pathology  

The Changing Face of Prostate Cancer

Cooperberg MR, et al. J Urol 2007;178:S14-S19

23.8 26.2 31.5

45.8 47.4 45.0

13.1

24.0 23.7

23.5 27.2 29.9

38.5

39.2 38.4

28.0 23.0 23.2 24.6

10.7 6.4 2.7 2.4 2.0

0

20

40

60

80

100

<1990 1990–94 1995–99 2000–01 2002–03 2004–07

Low

% o

f pat

ient

s

Risk distribution by year of diagnosis

Intermediate High Advanced

49% Decline in Mortality

Prostate cancer mortality per 100,000 men

aged 50-84 years

FDA Approves PSA Screening

1975 1986 1991 2009

100 80

60

40

20

0

49%

Probability of eventually developing or dying of prostate cancer by PSA at age 60

Mid-life PSA levels strongly predict long-term risk of prostate cancer morbidity.

Vickers A, Cronin A, Björk T, Manjer J, Dahlin A, Bjartell A, Scardino P, Ulmert D and Lilja H. BMJ 2010; Sep 14;341:c4521. .

US Preventive Services Task Force 2012

¡  “recommends against PSA-based screening for prostate cancer”

¡  the benefits of prostate cancer screening do not outweigh the harms of diagnosis and treatment of prostate cancer

¡  grade D recommendation: ¡  “There is moderate or high certainty that the service has

no bet benefit or that the harms outweigh the benefits.”

Canadian Task Force 2014

CMAJ Oct 27, 2014

¡ enhanced survival

¡ less suffering with disease progression

¨  false positives ¨  overdetection

¨  overtreatment

Level 1 Evidence 2014

Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO)

European Randomized Study of Screening for Prostate Cancer (ERSPC)

Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO)

¡  10 U.S. Centers

¡  1993-2001

¡  76,693 men

¡  “usual care” vs. annual screening ¡  DRE for 4 years, PSA for 6 years

Andriole et al. NEJM 360:1310-19, 2009 Andriole et al. JNCI 104:125-132, 2012

PLCO – 13 year follow-up

Screened Usual Care

# cancers 4250 3815

relative risk 1.12 (95% CI 1.07 to 1.17)

# deaths 158 145

relative risk 1.09 (95% CI 0.87-1.36)

Andriole et al. JNCI 104:125-132, 2012

¡ 85% compliance for screening....

¡ .... but also 52% in control group! (at least)

¡ 40% screened within 3 years prior to entering study

Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO)

Andriole et al. NEJM 360:1310-19, 2009

European Randomized Study of Screening for Prostate Cancer (ERSPC)

¡ 7 European countries

¡ 182,000 men

¡ age 50-74 (core group 55-69)

¡ screening q 4 yrs vs. no screening

¡ median follow-up 13 years

Schroeder et al. NEJM 2009;360(13):1320-1328 Schroeder et al. Lancet Aug 7, 2014

ERSPC - Results ¡  82% of screening group underwent screening

¡  incidence of prostate cancer ¡  screened: 9.55 cases/1000 person years (n=7408)

(evidence for overdetection; ratio 1.57)

¡  control: 6.23 cases/1000 person years (n=6107)

¡  risk of death from prostate cancer: ¡  21% relative reduction in screened group (355 vs. 545)

¡  absolute risk reduction 1.28 deaths per 1000 men

¡  therefore number needed to screen 781

¡  number needed to detect to save one life: 27

Schroeder et al. NEJM 2009;360(13):1320-1328 Schroeder et al. Lancet Aug 7, 2014

Cumulative Risk of Death from Prostate Cancer

Schroeder et al. Lancet Aug 7, 2014

Göteborg Subgroup ¡  10,000 men randomized to screening +

10,000 matched controls in population

¡ mean follow-up 14 years

¡  44% relative reduction in rate of death from prostate cancer in screened group versus control

¡  to save one death from prostate cancer: ¡  number needed to screen: 273

¡  number needed to diagnose: 12

Hugosson,  The  Lancet,  2010  

Göteborg Subgroup

Hugosson,  The  Lancet,  2010  

Why USTFPS Grade D? ¡ mixes ERSPC, PLCO and prior smaller studies

together as equivalent and came to conclusion that screening has no or only small benefit with respect to prostate cancer specific survival

¡ carefully analyzed harm incurred by screening: ¡  false positive tests with unnecessary evaluation ¡ over-diagnosis ¡ adverse effects of treatment

Criticism of Task Force ¡  no prostate cancer expertise on task force

¡ Over-estimation of harm

¡ many studies showing fewer adverse effects ignored

¡  Canadian context: active surveillance

¡ Under-estimation of benefit

¡ mixed poor trials indiscriminately with ERSPC

¡  did not consider living with metastatic disease

¡  no consideration of time of follow-up

¡  no screening trial will ever show overall survival benefit

CTFPHC

PSA SCREENING

SURVIVAL BENEFIT

OVER TREATMENT

How can we decrease overtreatment?

Prognosis

Diagnosis Treatment

BC GU Tumour Group ¡  The Genitourinary Cancer Tumour Group of the BC Cancer Agency and the

Vancouver Prostate Centre are recommending PSA testing for asymptomatic men who are well informed and wish to pursue early diagnosis of prostate cancer.

¡  There is evidence from randomized controlled trials that mortality decreases with PSA screening for the early detection of prostate cancer and its treatment.

¡  The decision to use PSA for the early detection of prostate cancer should be individualized. Patients should be informed of the known risks and benefits of early detection of prostate cancer with PSA testing.

¡  Early detection of prostate cancer should be linked to a treatment algorithm that includes discussion and prioritization of active surveillance for men with low risk prostate cancer.

Position statement 2010

Canadian Prostate Cancer Screening Guidelines ¡ Offer screening to healthy men age 50 with ≥ 10-year life expectancy ¡  Age 40 years if family history of PCa or African descent ¡  Consider baseline PSA between ages 40–50 as potential marker of

future risk and need for screening

¡ Annual screening is standard, but studies suggest that every 2–4 years is beneficial

¡  Initial screening should include DRE and PSA ¡  PSAV, PSAD, and PSA free:total may improve sensitivity and

specificity

¡  PSA ≥ 4.0 ng/mL = increased risk of PCa ¡  TRUS-guided biopsy required to obtain Dx

Izawa J, et al. Can Urol Assoc J 2011;5:235-40 PSAD = PSA density; PSAV = PSA velocity

Cease and desist at age 75?

Competing risks: age, co-morbidities, aggressiveness of prostate cancer

vs.

Risk calculator http:www.compass.fhcrc.org/edrnnci/bin/calculator/main.asp

Risk calculator http:www.compass.fhcrc.org/edrnnci/bin/calculator/main.asp

CaP Screening Summary

¡ discuss risks and benefits of screening with patient

¡ do not screen if <10 yr life expectancy

¡ individualized patient decision

¡ consider multiple factors rather than just one PSA threshold

Take Home Message about screening

¡  Prostate cancer screening is worthwhile, but:

¡  not every man needs annual PSA

¡  not every elevated PSA needs a biopsy

¡  not every positive biopsy needs treatment

¡  not every treatment results in impotence or incontinence