This document discusses screening and biopsy for prostate cancer. It provides information on: 1. The imperfect nature of PSA screening and the risks of overdiagnosing low-grade prostate cancer through unnecessary biopsies and overtreatment. 2. Factors that can help determine the likelihood of finding cancer on biopsy for men with elevated PSA levels, such as prostate size, family history, and PCA3 urine tests. 3. Imaging options like MRI that may improve accuracy and allow targeted biopsies to avoid unnecessary procedures.

1. V. Screening and Biopsy
PCRI Mentor Class 2012
Mark Scholz MD
Executive Director, Prostate Cancer Research Institute
Medical Director, Prostate Oncology Specialists

2. In The Ideal World….
Prostate cancer screening tests would detect
high-grade cancer while failing to detect low-
grade disease
Treatment would eliminate prostate cancer
100% of the time without any side effects
Money would grow on trees…..

3. Siegel, CA 62:10, 2012
*Estimates are rounded to the nearest 10 and exclude basal and squamous cell skin cancers and in situ carcinoma
except urinary bladder

4. Siegel, CA 62:10, 2012

5. Good and Bad Types Basketball
Players
of Prostate Cancer
Various
Types of
Cats

6. Fifteen-Year Prostate Cancer Mortality Timeline
“The Bad Type”
200,000 men diagnosed late 90’s
80% 13% 7%
Local Therapy Hormone Therapy Active Surveillance
35% Relapse Hormone Resistance
occurs in 50%
70% have 70% die from
Hormone Bone metastasis prostate cancer
Treatment occur in 80%
28,000 in 2012
6

7. PSA Screening Totally Changed The Picture
Siegel, CA 62:10, 2012
Increased Diagnosis of Mostly
Low-Grade Prostate Cancer
Initiation of
PSA Testing
in 1987

8. PSA Screening Every Four Years
in 180,000 European Men
Schroder, New England Journal 366:981,2012
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Risk
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of
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Death
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Annual PSA Screening in 75,000
Men In the United States
Andriole, New England Journal 360:1310, 2009

10. Annual PSA Screening in 75,000 Men
In the United States
Andriole, New England Journal 360:1310, 2009

11. Lower Mortality Since PSA Screening Initiated in 1987
Hoffman, New England Journal 365:2013, 2012
Extra New Cases
Of Prostate Cancer
Diagnosed
Initiation of
PSA Testing
Earlier Diagnosis
of High-Grade
Prostate Cancer

12. U.S Preventive Services Task Force
• The magnitude of harms from screening (e.g., falsely
high PSA, psychological effects, unnecessary biopsies,
over diagnosis of indolent tumors) is “at least small.”
• The magnitude of treatment-associated harms (i.e.,
adverse effects of surgery, radiation and hormonal
therapy) is “at least moderate”—particularly because
of overtreatment among men with low-grade disease.
• The 10-year mortality benefit of PSA-based screening
is “small to none.”
• The overall balance of benefits and harms results in
“moderate certainty that PSA-based screening … has
no net benefit.”

13. PSA Screening Definitely Saves Lives,
But What about Over-Diagnosis?
• Prior to PSA (1987) 1 of 41 men died of PC (2.4%)
• In 2009, with screening and early treatment, the risk of
dying from PC is 1 of 53 (1.9%)
• However, this improved survival come at a price:
– 200,000 men are diagnosed annually instead of 90,000
– One million men have prostate biopsies annually
– 48 men get unnecessary treatment for each life saved by therapy
– Tens of thousands of men diagnosed with Low-Risk prostate cancer
undergo unnecessary treatment with a negative impact on sexual &
urinary function

14. Since the “Approval” of Active Surveillance in 2007
Surgery is……..UP!
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15. Foolish Proposals for Slowing the Rush
to Overtreatment
1. Stop PSA testing altogether, the ostrich approach
– PSA is an inexpensive test that’s proven to saves lives; it
is here to stay
1. Simply stop over-treating by resolving to do more
active surveillance?
– The doctors who do biopsies and make the diagnosis
are action oriented, i.e., they are surgeons
– The general populace, when confronted with the shock
of a cancer diagnosis, naturally assumes prostate
cancer just as deadly as other cancers. Surgical removal
seems like the most logical way to proceed

16. Slowing the Onslaught
of Overtreatment
Stop Doing Mindless Biopsies
On Uninformed Patients
With PSA Between 4 to 10

17. Random Biopsy Finds
“Too Much” Low-
Grade Cancer
Points of
needle entry
Posterior View Prostate

18. Risks of Prostate Biopsy
• 1% risk of infection serious enough to require
hospitalization
• 1% risk of bleeding serious enough to require
transfusion
• Erectile dysfunction (with repeated biopsy)
• Changes in urinary function
• Biopsy does not appear to spread cancer

19. Biopsy Induced Erectile Dysfunction
Fujita, J. Urol, 182:2664, 2009

20. 20-Core Saturation Biopsy
Klein, J. of Urol. 184:1447, 2010
• Increased urinary symptoms that persisted 3
months after the biopsy
• Erectile dysfunction problems that resolved
one month after the biopsy (also with
standard biopsy)

21. Risks of Diagnosing of Low-Grade Cancer
• Unnecessary treatment:
– Impotence, incontinence, Peyronie’s disease,
Climactauria, Strictures
• Emotional meltdown:
– Heart Attack, Suicides
– Depression, anxiety
• Permanent change in self-image
• Insurance issues

22. Frightened to Death by a Cancer Diagnosis
New England Journal 366:14, 2012
Increased Risk of Suicide Prostate Skin Lung
First 3 Months 200% 40% 1100%
Months 3 to 12 100% 0% 500%
After One Year 100% 40% 200%
Fatal Heart Attack
First 3 Months 180% 20% 1100%
Months 3 to 12 40% 0% 400%
After One Year 0% 0% 60%

23. Chance of Cancer Diagnosis with
a Six-Core Biopsy and Normal PSA
Thompson, JNCI 98:529, 2006
PSA Level Cancer Diagnosis Rate
1 – 2 17%
2 – 3 24%
3 – 4 27%

24. Risk of Immediate Biopsy
• More than 20% chance of diagnosing low-grade
prostate cancer
• When diagnosed, the risk of unnecessary
treatment is 90%
• With surgery the risk of:
– Impotence is 50%
– Incontinence after surgery is 7%
– Peyronie’s disease is 16%
– Climacturia is

25. We Know that…
• The goal is not to diagnose all prostate cancer
– Most men over 50 harbor microscopic prostate cancer
– Shall we just biopsy everyone over 40 regardless of PSA?
– Shall we remove the prostates of all men over 40?
• The main goal is detecting and treating high-grade
cancer
• PSA is an imperfect test
– Varies widely from day to day as a result of human
physiology, recent sexual activity, infections, etc.
– PSA levels under 10 predict prostate gland size much better
than prostate cancer. Men with big prostate glands are
being discriminated against!

26. Very First Step: Recheck PSA
• PSA checked on separate days
– Up to 30% Stamey, J. of Urol. 155:1977, 1996
– Up to 20% Brawer, J. of Urol. 157:2183, 1997
• If PSA > 2.5 then:
– 23% were normal the following year
– 20% were normal the following two years
– 18% were normal the following three years
Ankerst, J. of Urol. 181:2071, 2009

27. Test of PSA Stability When Tested
Annually for 5 Years
Eastham, JAMA 289:2695,2003

28. X
X Xxxx
Digital Rectal X X
X Xx
Xx X
Examination X
X
X
X
X X
X X
X X
X X
X X
X X
X X
X X
X
X
X
X
X
X

29. Digital Rectal on Subsequent Testing
Ankerst, J. of Urol. 181:2071, 2009
• 70% of abnormal DRE became normal
the following year, even in patients with
prostate cancer
• More than half of those that became
normal remained normal in subsequent
years

30. Poor Predictive Value of an
Abnormal Rectal Examination
Catalona J. of Urol. 161:835, 1999
PSA Level % Diagnosed
0-1 5%
1 – 2.5 14%
2.5 - 4 30%

31. PSA “Velocity,” A Rising PSA Over Time
Loeb, J. of Urol. 178:2348, 2007
• 0.4 per year with PSA between 0 and 4
detects cancer more frequently
• 0.75 per year with PSA between 4 and 10
detects cancer more frequently.
• 2.0 per year detects cancers associated
with higher mortality –Next slide….

32. Low-Risk… But Fast PSA Velocity
D’Amico NEJM 351:125,2004
PSA Less than 2 More than 2
Velocity point /year points / year
# of Men 703 213
7-Year Death
0% 6.9%
Rate
Important Caveat: Percentage core biopsy was not
evaluated or reported in this study

33. Percent “Free” PSA
• Poor man’s substitute for measurement of
prostate size
• Percentage can range from 3% to 35%
• A high percentage (over 25%) signals BPH
• Low percentage (less than 10%) signals a small
prostate gland
• Percentages between 10% and 25% don’t
signal anything

34. Prostate Cancer Prevention Trial
Google: PCPT Risk Calculator
Thompson, JNCI 98:529, 2006
• Calculates the overall risk of prostate cancer
and the risk of high-grade prostate cancer at
biopsy
• Elements of the calculation:
– PSA, race, age, Body mass index (BMI), DRE, Prior
biopsy (yes/no), Family history, Proscar

35. Google: “PCPT Risk Calculator”
• Age 57
• BMI (are you fat?) Height 75” Weight 175’
• Race Caucasian
Risk of any type of
• PSA 4.0 prostate cancer on
• Rectal exam Normal biopsy = 35%
• Family History Negative
• Digital Rectal Normal Risk of High-Grade
prostate cancer = 6%

36. PCA-3 Urine Test
“More Accurate than Free PSA”
Haese European Urology 54:1081, 2008
• Not influenced by prostate size
• Measured after mild prostate massage
• “Normal” range is less than 35
• Used as a “cross check” for men with elevated
PSA who want to delay biopsy

37. PCA-3 of “35”
de la Taille, J. of Urol. 185:2119, 2011
• More accurate than PSA
• Higher PCA-3 levels associated with:
– Gleason 7 or greater
– 33% positive cores or greater
– High grade vs. low grade cancer

38. PCA3 Assay Sensitivity and
Specificity
at Various Cutoffs
Deras, Journal of Urology 179:1587, 2008
PCA3 % Sensitivity % Specificity
10 85 32
“Normal” 20 71 56
30 56 70
40 49 78
60 33 89
“Abnormal”
80 22 94
100 18 95
Sensitivity measures the proportion of actual positives which are correctly identified
Specificity measures the proportion of negatives which are correctly identified

39. PCPT Calculator: Example with PCA-3
• Age 57
• PCA-3 12
• BMI (are you fat?) Height 75” Weight 175’
• Race Caucasian
• PSA 4.0 Risk of any type of
• Rectal exam Normal prostate cancer: 35%
• Family History Negative with PCA-3: 29%
• Digital Rectal Normal
Unfortunately, when the PCPT calculator incorporates PCA-3
it does not provide a estimate for High-Grade disease

40. The More You Look, The More You
Find: Repeated 6-Core Biopsy in 10,000
Men Screened for PSA Over 3.0
Zackrisson, J. Urol, 171:1500, 2004
Biopsy Number Number Percentage
Biopsied Positive Positive
First 1,725 402 23%
Second 706 124 18%
Third 307 36 12%
Fourth 103 9 9%
Fifth 13 0 0%

41. Four Additional Factors Indicating a
Positive Biopsy is More Likely
1. Smaller prostate gland—under 30 cc
2. Less urinary symptoms—AUA score of 7 or less
• Porter Urology 63:90, 2004
1. Testosterone level below the normal range
– Positive biopsy
• Rhoden J. of Urol. 179:1742, 2008
– Positive surgical margins at time of surgery
• Teloken J. Urol, 174:2178, 2005
• Massengill J. Urol, 169:1670, 2003
1. Abnormality detected by imaging with
ultrasound or MRI

42. AUA
SYMPTOM
SCORE
QUESTIONAIRE

43. Men with Big Prostates, Rejoice
Abd, Urology 77:541, 2011
• Men with a prostate volume of 30-60 cc are
25% as likely to have prostate cancer as a man
with a prostate < 30cc
• Men with a prostate volume > 60 cc are 10%
as likely to have prostate cancer as a man with
a prostate < 30cc

44. Factors Predicting a Positive Biopsy
When PSA is Between Two and Nine
Fleshner, Urology 69:103, 2007
• Smaller prostate
• Increasing age
• Higher PSA
• Hypoechoic lesion on ultrasound

45. Color Doppler Ultrasound
• Accurately determines prostate size
• Detects hypo-echoic and hyper-vascular areas
that can be monitored with sequential scans
or targeted with biopsy
• A fifteen-minute outpatient procedure
performed in the doctor’s office

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47. Imaging with 3T Multiparametric MRI
Turkbey, J. of Urol. 186:1818,2011
• Multiparametric = 4 scans in one
– T2 weighting, Diffusion, Contrast, Spectroscopy
– Accurately determines prostate size
• 3T MRI multiparametric imaging is:
– 90% accurate at detecting significant cancer
– 90% accurate at ruling out significant cancer
• 60 to 90 minute scan with rectal probe
• Abnormalities can be monitored or targeted
with biopsy

48. Theoretical Risks of Delaying a Biopsy
1. Failure to detect a high-grade prostate
cancer early enough to achieve a cure
2. Allowing high-grade disease to progress to a
more advanced stage leading to more
aggressive treatment than what would have
been necessary with earlier diagnosis

49. Some Reasons Why the Danger of a Delaying the
Diagnosis of High-Grade Disease May Be Small
• By the time cancer is diagnosed it has already
been present for many years
• Even high-grade prostate cancers can grow fairly
slowly (PSA screening every 4 years saved lives)
• Rare forms of rapidly growing high-grade disease
may be incurable anyway
• Technological progress may ultimately make
incurable cancers curable over the next 10 years
• Modern scans are pretty good at detecting
progressive high-grade cancer

50. Balance the Risk of Immediate
Biopsy with the Risk of Further Surveillance
1. Gather and evaluate information:
– PCPT Calculator: PSA, DRE, Age, Race, and Family history
– Urine PCA-3
– PSA velocity only helps if sequential PSA levels rise quickly
– Factor in:
• Urinary symptoms determined by AUA score
• Low testosterone levels
• Measurement of the prostate size
• Imaging of the gland with color doppler or MRI
1. Very carefully consider the irreversible perils of:
– The very common scenario of diagnosing low-grade disease
– The less common scenario of delaying the diagnosis of high-grade
disease

51. Valuable Information from Biopsy:
Gleason score and Percentage Cores Positive
• Challenges interpreting Gleason Score:
– It can be misread by unskilled pathologists
– Biopsy can miss high-grade disease resulting in falsely
low scores
• Percentage Cores Positive:
– The percentage of positive biopsy cores predicts
future cancer relapse and cancer progression just as
well as Gleason score
– The optimal number of cores for initial random biopsy
is eight

52. Risk of “Misread” Gleason
Epstein, J. of Urol. 179:1335, 2008

53. Risk of “Wrong” Gleason from Random Biopsy
Compared to Surgical Gleason (1000 Patients)
Narain, The Prostate 49:185, 2001
Biopsy Prostatectomy Gleason Score
Gleason Six Seven 8-10
Score
Six 55% 41% 4%
Seven 43% 67% 20%
8-10 8% 45% 47%

54. Risk of Missing High-Grade Cancer
Freedland, Urology, 69:495, 2007
• Increased by:
– Higher PSA levels
– Higher percentage of core biopsies positive
– Obesity
– Bigger prostate
• Fleshner, J Urol, 175:505, 2006
• Reduced by:
– Seeing lesion on imaging
• Fleshner, J Urol, 175:505, 2006
– Taking 8 or more core biopsies
– Having Gleason 3 + 4

55. Predicting Biopsy Under-Grading
Stackhouse, J. Urol. 182:118, 2009

56. Percentage Cores Predicts Early Relapse
after Surgery in Men with PSA < 10
Aronson, J. Urol, 171:2215, 2004
Gleason Score
Cores Six or Less 3+4 4+3 or
Positive More
< 20% 8% 13% 21%
20-40% 12% 20% 31%
>40% 19% 30% 45%

57. Percentage Core Biopsy Predicts
Relapse
• Multivariate DeWolf, J. of 476 men age 61, PSA 5.8
Analysis Urol, 171:1492, 2004
– >28% cores positive = 3.6 times higher risk of relapse
– Gleason 7 = 3.9 times higher risk of relapse
– Gleason 8-10 = 12 x higher risk of relapse

58. A High Percentage of Positive Cores Predicts
Cancer Metastases in After Surgery
Roehrborn, J. Urol, 171:2209, 2004
Gleason Score % Patients in Median % of
From Biopsy Each Gleason Core Biopsies
Category Positive
4-6 66% 17%
7 28% 33%
8-10 6% 50%

59. Optimal Number of Biopsy Cores
• Random biopsy
– 8 core biopsies finds cancer as well as 12 cores
Abd, Urology 77:541, 2011
• Targeted biopsy
– Image-directed plus 6-core finds 95% of what a
random 10-core biopsy finds
Fleshner, J. Urol, 179-1321, 2008

60. Random Biopsy, Six vs. Twelve Cores
Al-Ghamdi J. Urol. 179:1332, 2008
• 679 men with median PSA 5.3 and age 62
• With 6 cores: 179 cancers found (26% men)
• With 12 cores: 240 cancers found (35% men)
Gleason Six Twelve Number Percent
Grade Core Core Increased Increase
Total 179 240 61 9%
Six or less 146 193 47 7%
7 or more 33 47 14 2%

61. Recommendations for PSA Screening
• Start PSA testing at age 40 to establish a
personal “normal level” rather than comparing
to the general population i.e., PSA > 2.5 or >4
• To optimize PSA testing:
– Abstain from sexual activity for 48 hours
– Ensure no urinary symptoms of prostate infection
– For ongoing testing, use same lab for consistency
• Men with low levels of 1 or less can get PSA
checks every 3-4 years in their 40’s

62. What Should Trigger a Biopsy?
• Persistently elevated PSA with a small prostate
(<30cc) without another reason for PSA rise
• An abnormal DRE that can’t be attributed to a benign
etiology (such as calcification) after scanning with
ultrasound
• An elevated PCA-3 level
• An abnormality seen with color Doppler or MRI
suggestive of underlying high-grade cancer
• An informed patient who is more concerned about
missing high-grade disease than dealing with the
consequences of being diagnosed with a low-grade
prostate cancer

63. Conclusions
• PSA screening saves lives
• Overtreatment is inevitable when mindless
biopsies are performed on an uninformed
populace
• An elevated PSA should trigger both education
and further testing with PCA-3 and prostate
imaging
• While not perfect, biopsy core percentage and
biopsy Gleason both yield very powerful
information about cancer status