SABOR January 2004

1
Prevention Of Prostate Cancer Is This The Way To
Go?
Per-Anders Abrahamsson Chairman
Professor Department of Urology Malmö University
Hospital, Sweden
2
Strategy to Reduce Mortality In Prostate Cancer

• Prevention
• Early diagnosis of prostate cancer

3
Agents of Interest to Prevent Prostate Cancer

• 5-alpha-reductase inhibitors
• Selenium
• vitamin E
• vitamin D
• cyclooxygenase-2 inhibitors
• Lycopenes
• green tea

4
Complementary preventive Medicine In Prostate
Cancer
Up to 50 of patients have used CAM CAM sales
exceeds 2.5 billion in the US

• Herbal medicine
• green tea
• garlic
• Micronutrient supplements
• lycopenes and other carotenoids
• selenium
• vitamin E
• vitamin D
• Dietary measures
• soy protein and plant fibers
• reduction in dietary fat

5
Vitamin E (Alpha-tocopherol)The ATBC Study

• 29,133 Finnish male smokers 50-69 years old
  randomized
• (1)alpha -tocopherol only
• (2)beta -carotene only
• (3) alpha-tocopherol plus beta-carotene
• (4) placebo
• Evaluated incidence of lung cancer and other
  cancers

6
Vitamin E (Alpha-tocopherol)The ATBC study
1985-93

• Supplementation with alpha-tocopherol had no
  effect on lung cancer incidence but did
• reduce the incidence of prostate cancer by 34
  (95 CI, 14-48)
• Lung cancer effect disappeared in follow-up, but
  prostate prevention persisted

7
Ongoing Trials

• SELECT
• Selenium, Vitamin E, Both, or Placebo
• 8,100 men in each arm
• 7-12 years of follow-up planned
• APPOSE - Australian Prostate Cancer Prevention
  Trial Using Selenium
• 200 µg/day selenium vs placebo
• 2000 high risk men in each arm

8
PREVENTION

• Until recently
• Not possible for many years to come
• But the PCPT data may ultimately change this
  scenario !?

9
A European Consensus Conference

• The Implications of the PCPT in terms of Clinical
  Practise
• Paris,
• December 19, 2005

Abrahamsson Teillac, Eur Urol, June 2006
10
The Prostate Cancer Prevention Trial - Study
design
Enrollment
18,882 men randomized
n9423 Placebo
n9459 Finasteride
Annual DRE And PSA for Seven years
End-of-study Biopsy regardless Of PSA and DRE
End-of-study Biopsy regardless Of PSA and DRE
Study Group
11
Gleason Score Total Number of Cancers
Thompson IM, et al. New Engl J Med
2003349215-24
12
Initial Thoughts on Grade

• Observations made in letter to Editor of NEJM
  immediately after publication
• Risk of high-grade cancer did not increase over
  time
• If inducing HG cancer, the relative risk should
  increase over time It did not.

13
What Are the Potential Reasonsfor an Increased
Grade?
Was it due to an alteration in tumour grade,
caused by finasteride?
14
What Are the Potential Reasons for an Increased
Grade?

• Hormonal pathologic effect probably not
• Ascertainment artifact
• Reduced gland volume with finasteride
• Better sampling of gland
• More accurate grading (which is often
  higher)

15
Gland Volume Artifact Hypothesis
Assume no change in tumour with treatment
Result in Placebo Gleason 33
Result in Finasteride Gleason 34
Gleason 4
Gleason 3
16
Corrolary to Volume Artifact- How close is your
grade to true grade
Finasteride higher grade but more accurate
grading
Placebo greater risk you missed the correct
grade
17
What Happens to Gleason Score From Biopsy to
Prostatectomy -
more commonly goes up.
Sometimes goes down
35
24
15
11
8
5
2
From Bostwick DG. Amer J Clin Path 102(Suppl
1)S38, 1994
18
How Does Our Hypothesis Play Out?

• Finasteride
  Placebo
• Any ? at RP 47/192 (24.5) 83/272
  (30.5)
• No change 107/192 (55.7) 155/272
  (57.0)
• Any ? at RP 38/192 (19.8) 34/272
  (12.5)

19
If You Had a HG Tumour at Prostatectomy, What Was
the Likelihood that Biopsy Missed It?

• Placebo 50.0
• Finasteride 29.7

20
Gland Volume Bias

• There appears to have been some sort of bias in
  detection of high-grade disease
• Most likely rationale gland volume
• Recently verified by Kulkarni J Urol 175505,
  2006

21
Gleason Score End-of-Study BiopsiesNumber of
Cancers
Not graded Finasteride n4, Placebo n12
22
PSA Performance?

• Studied men in placebo and finasteride arms of
  PCPT
• All had a biopsy and a PSA within one year of
  biopsy
• Sensitivity and AUC for PSA compared between
  finasteride and placebo

Thompson IM, AUA, Atlanta, 2006
23
ROCs
AUCs Cancer versus no Cancer Finasteride .757,
placebo .681, p lt.001 Gleason gt 7 Finasteride
.838, placebo .781, p.003 Gleason gt 8
Finasteride .886, placebo .824, p.071
24
The Prostate Cancer Prevention Trial
Implications For Clinical Practice
A European Consensus MeetingParis, December 19,
2005
Co-Chairmen Pierre Teillac Per-Anders
Abrahamsson
25
Consensus Meeting Panelists
From left to right Jørgen Nordling, Manfred
Wirth, Pierre Teillac, Per-Anders Abrahamsson,
David Crawford (key note speaker on the PCPT
data), Christopher Chapple, Adrian Joyce,
Clement-Claude Abbou, Jean-Louis Misset, Andrea
Tubaro, Eduardo Solsona. Professor Pierre
Teillac, France Professor Per-Anders Abrahamsson,
Sweden Professor Clement Claude Abbou, France.Mr
Christopher Chapple, United Kingdom Mr Adrian
Joyce, United Kingdom. Professor Jean-Louis
Misset, France Professor Jørgen Nordling,
Denmark. Dr Eduardo Solsona, Spain Professor
Andrea Tubaro, Italy. Professor Manfred Wirth,
Germany
26
PCPT Background and Overview of Results (1)

• Largest Chemoprevention study ever reported in
  the urological community and reports for the
  first time that medical intervention may reduce
  the incidence of diagnosed prostate cancer to a
  clinically meaningful extent (level 1b evidence)

27
PCPT Background and Overview of Results (2)

• This study was initiated and funded by the
  National Cancer Institute for the National
  Institutes of Health of the USA
• The results showed that finasteride reduced the
  risk of developing prostate cancer by 25
  compared to placebo (24.4 placebo vs. 18.4
  finasteride)

28
PCPT Background and Overview of Results (3)

• However, the ?nasteride-treated group was found
  to have a higher proportion of high-grade cancer
  (6.4) compared with the placebo group (5.1)
• This increased prevalence was probably due to a
  detection bias caused largely by the reduction in
  prostate volume in patients on finasteride
  compared with patients on placebo
• This resulted in an improved detection at biopsy
  of high grade cancer in the finasteride group

29
Implications for PCa Chemoprevention

• For men who are concerned about prostate cancer,
• It may be appropriate to discuss chemoprevention
  with finasteride
• In doing so, it is important to highlight both
  the benefits and potential side effects
  associated with long-term treatment

30
Implications for PCa Chemoprevention

• More data on health economic analyses are
  required before recommending widespread
  chemoprevention with finasteride

31
What Do You Tell the Patients?

• Brief description of data from the trial
• That finasteride is not licenced for PCa
  prevention, but that the PCPT demonstrates a
  reduction in risk
• That the results are controversial
• That finasteride may makes sense in patients at
  higher risk of PCa