1. Management of low Risk Pca:
Laurence Klotz
Professor of Surgery
Sunnybrook Health Sciences Centre
University of Toronto

2. Management of low risk prostate
cancer--outline
Natural history
The problem (overdiagnosis-overtreatment)
Pathologic definition of clinically insignificant disease
Active surveillance
 Rationale
 Technique
 Results (oncologic and QOL)
 5 ARIs
The pitfalls (under- and over-grading)
Focal therapy

4. US Preventive Services Task Force
summary on PSA screening
10/2011:
 …small to no reduction in 10 year prostate
cancer-specific mortality; harms related to false-
positive test results, subsequent evaluation, and
therapy, including overdiagnosis and
overtreatment.
…optimal screening intervals and PSA
thresholds remain uncertain.
The Task Force recommends against PSA-based
screening……a Grade D recommendation.

5. Over Treatment of Prostate Cancer is Common
Study Age, Follow No. Needed to Treat
yrs Up, yrs
Prostate Cancer
Metastases
Death
ERSPC Mean 9 48 22
(Schroder, N Engl J 61
Med 2009)
Goteborg Mean 14 15 __
(Hugosson, Lancet 56
Oncol 2010)
SPGS-4 Mean 15 17 8
(Bill Axelson, N Engl J 65
Med 2011)
Subgroup Absolute 33 20

6. Management of Favorable Risk Prostate Cancer in the
US
Hamilton AS et al, BJU Int 2010 (Data from SEER)

7. Prostate cancer: Known in 2012
39% mortality reduction; accounts for 20% of overall
cancer mortality reduction in men
Early detection responsible for 50% of this
Screening healthy, young men with PSA reduces
prostate cancer mortality by 20-45%
Risk: overdetection and overtreatment
Detection and treatment currently too tightly linked

8. 02/23/13

9. 2009: Natural history of untreated Gleason 6 and 7 Pca:
Lu-Yao GL, Albertsen PC, JAMA. 2009 Sep 16;302(11):1202-9.
Years 0 10 0 10 0 10 0 10

10. • N=23,910
• 12,000 Gleason
2-6
• Risk of Pca
death after RP in
men age 60-69:
0.2% at 20 years
(although
significant PSA
failure rate)

11. •50% moderate -big
ED problem
•24% incontinence
problem

13. Definition of clinically insignficiant prostate
cancer: Stamey TA et al. Cancer (suppl)1993;71(3):933
139 cystoprostatectomy
Lifetime risk of specimens
prostate cancer dx
(pre PSA) 8%
55/139 (40%)
had prostate
cancer
8% of 139=11 patients considered clinically significant
Volume of largest 11 pts. cancers was 0.5-6.1 cc

14. Over diagnosis in ERSPC about 50%
 Screening until 70
with 1 year interval --
49% over diagnosis
 Screening until 70
with 2 year interval in
48% over diagnosis
Screening until age
75 q 4 yrs--57% over
diagnosis
1 yr 2 yrs 4 yrs
Interval
EAM Heijnsdijk et al. BJC 2009

15. Stamey 1982 Wolter et al, ERSPC
•8% incidence of clinical Pca •Diagnosis rate in unscreened
•8% (11) of 139 cysto- arm 50% of that in screened
prostatectomy specimens had > arm
0.5 cc Gleason 3 or some 4 •Volume of 325 RP Cancers
•4/3πr3 =1.0cc diameter sphere •Threshold volume = 1.3 cc
(1.4 cc diameter sphere)
1 cm
02/23/13

16. Watchful Waiting versus Surveillance
Watchful Active
Waiting Surveillance
Primary aim Avoid Individualize
treatment management
Patient /Tumor Limited life Fit for radical
Characteristics expectancy/ treatment/
advanced localized
disease disease
Treatment Delayed Early
Timing
Treatment Palliative Curative
intent

17. The issues:
Who is eligible?
 Role of volume, PSA, grade
 Is there a lower age limit?
 Role of other biomarkers, ie PCA3
 Template/mapping biopsies vs systematic, perineal vs TRUS
 Imaging—MRI, U/S
Follow up strategy:
 Frequency of biopsy, targeting, technique
Triggers for intervention?
 Volume, grade, PSA kinetics, imaging, other
Interventions: Dietary/micronutrient/statins/5 ARI

18. For Whom is Surveillance a Safe Management
Option?
Favorable
Risk

19. National Comprehensive Cancer Network Practice
Guidelines
RECURRENCE RISK EXPECTED INITIAL
RISK SURVIVAL THERAPY
Very Low Active
<20yr Surveillance
(Epstein Criteria) Preferred
Low Risk 1) Active
Surveillance
>10yr 2) Radiotherapy
(D’Amico Criteria)
3) Radical
Prostatectomy
Mohler et al, J Natl Compr Canc Netw. 2010

20. Triggers for intervention in
surveillance series
Klotz Carter Van As 2007 Van den Soloway Dall-Era
2010 2007 Bergh 2010 2010 2008
PSA DT < 3 yrs < 3 yrs
PSA Velocity < 1 ng/ml/yr < 0.75
ng/ml/yr
Grade Gl 4+3 Gl 7 or > 2 4+3 or > Gl 7 or > 2 Gl >=7 Gl >=7
progression cores or 50% core cores or > 2
>50% core cores
Clinical >50% > T2
progression increase
in mass

21. Distribution of PSA doubling times on surveillance.
25
20
% Median 7 years
15
10
5
0
<1 2 3 4 5 6 7 8 9 10 10-15 20 30 40 50 100 >100
02/23/13
PSA Doubling time

22. Follow-up
 Toronto (same as PRIAS)
 DRE/PSA every 3 months for 2yrs, then every 6 months
 Biopsy 6-12 months after enrollment, then every 3-4yrs
 Multi-institutional (Univ Miami, Univ British Columbia; MSKCC;
Cleveland Clinic)
 DRE/PSA every 6-12 months
 Biopsy 18 months after enrollment, then every 1-3yrs
 Johns Hopkins
 DRE/PSA at 6 month intervals
 Biopsy annually until age 75yrs

23. •290 men on AS (Epstein criteria)
•35% developed path progression (beyond Epstein)
•PSA kinetics not predictive of adverse biopsy
findings or RP pathology
Biopsy
RP
02/23/13

24. •305/453 men whose disease was stable by all criteria
•No metastasis, no radical intervention, no upgrading to > 3+4

25. Systematic Review of Pretreatment PSA Velocity and Doubling Time As PCA Predictors.
Vickers A J Clin Oncol 27:398-403. 2008
• Studies with > 200 patients
Author Study Performance of PSA velocity vs PSA
Eggener 995 neg initial bx PPV Velocity 3% higher
Djavan 559 Bx result Worse AUC
Sun 120780 Ca screen Worse AUC (Verification bias)
Moul 11861 Ca screen Worse AUC
Carter 980 Ca death long term Velocity AUC 0.75 vs PSA 0.74
Berger 4800 Ca screen Velocity 0.87 vs PSA 0.65 (VB)
Whittemore 320 Ca death long term Worse AUC
Loeb 6844 Ca screen AUC 0.83 vs 0.81 (VB)
Thompson 5519 Bx in PCPT No difference
Verification bias (VB): Men not having a biopsy assumed to be cancer free
“…little evidence that pretreatment PSA velocity or doubling time are of value for
early-stage prostate cancer….. no justification for the use of PSA dynamics in the
clinical setting or as an inclusion criterion for clinical trials”

26. 1.0
0.8
Survival distribution function
0.6
0.4
62% free of intervention
at 10 years
0.2
0.0
0 2 4 6 8 10 12 14
Surveillance Survival (years)
02/23/13

27. Overall Mortality (probability)
0.0 0.2 0.4 0.6 0.8 1.0
0
2
4
6
32% at 10 years
Time (years)
8
10
12
14

28. 1.0
0.8
Cause Specific Mortality (probability)
10 year PCa mortality 3%
0.6
All PSA DT ≤ 1.6 years
•5/452 patients
0.4
0.2
0.0
0 2 4 6 8 10 12 14
Time (years)
3.7 5.2 5.3 8.7 9.6
02/23/13

30. Summary of active surveillance studies
Author N Median pT3 in RP OS CSS
F/U mo pts
Van As Eur Uro 326 22 8/18 44% 98 100
Carter J Urol 407 41 10/49 98 100
20%
PRIAS 533- 48 4/24 17% 90 99
2000
Soloway 99 45 0/2 100 100
Roemeling 278 41 89 100
Khatami 270 63 Not 100
stated
Klotz JCO 452 73 14/24 82 97 @
(58%) 10 yrs
Total 2130- 43 90 99.7
4000

31. • NNT 15; 7 for men < 65 yrs

32. Low Risk Disease
1.0
0.8
Cause Specific Mortality (probability)
0.2 0.4 0.0 0.6
0 2 4 6 8 10 12 14
Time (years) Active surveillance

33. HR 18.6
02/23/13

34. No difference in any measure of psychological functioning
Between RP and WW group at 12 years

35. Watchful Waiting and QOL in the Physicians' Health Study
Kasperzyk JL, Sanda M, J Urol 186 (5) 1862-7, 2011
% with moderate or
WW Any Treatment 2-Sided p Value⁎
severe symptoms
No. pts 121 1,085
Incontinence: 3.5 10.0 0.024
Nocturia: 27.6 21.3 0.118
Frequency/urgency: 16.1 15.0 0.761
Decreased stream 21.8 13.0 0.011
Fatigue: 12.2 8.9 0.272
Impotence: 67.9 78.2 0.015
Decreased libido 55.7 47.2 0.099

36. Active surveillance and health-related QOL: results of the Finnish arm of a
prospective trial
Vasarainen H et al, BJU Int Epub 1 NOV 2011
RAND-36 score Inclusion After 1 year on AS P value
Physical functioning 91 (13.6) 90 (12.9) 0.608
Role physical 81 (34.2) 89 (25.7) 0.010
Role emotional 82 (32.6) 88 (29.0) 0.052
Vitality 76 (15.7) 76 (16.0) 0.582
Mental health 81 (14.9) 81 (14.1) 0.696
Social functioning 91 (14.4) 93 (14.0) 0.279
Body pain 90 (15.6) 87 (18.7) 0.149
General health 65 (15.2) 65 (16.3) 0.780
N=75

37. Toronto Program Johns Hopkins Program
Low Risk (70%) Very Low Risk (80%)
Klotz et al, J Clin Oncol 2010 Tosoian et al, J Clinc Oncol
(in press 2011)

38. Major Limitations of Current Paradigm:
Misclassification of Risk

39. Missed significant cancers are
usually anterior
WHY:
TRUS biopsy usually directed posteriorly
Evidence:
RPs performed on surveillance candidates
MRI findings
02/23/13

40. Biopsy Missed Tumors
(Anterior/Base/Apex)
30%
70%
Copyright ©Radiological Society of North America, 2007 Choi, Y. J. et al. Radiographics 2007;27:63-75

41. •48/450 men on surveillance having RP
•65% OC
•16/450 (5% of cohort) had non organ-
confined disease at RP)
•100% with tumor volume > 1.0 cm were
anterior
02/23/13

42. •Negative predictive value
for ‘clinically significant’
PCa 95-98%

43. MRI Impacting Management
 65 yr old, PSA 5, one core positive for Gleason 6 (right)
 MRI: Large tumor in right anterior prostate with gross extra-
capsular extension
• Trigger for intervention/targeted biopsy

45. •25% of surveillance
candidates
•Condordance between
GU pathologists for
these lesions 27%
McKenney J, Carroll P
J Urol 2011 186 (2), pg.
465-469

46. Modified Gleason scoring 2005:
Grade inflation
Reference Traditional Gleason Modified Gleason
Helpap Gleason 6 48% 22%
Gleason 7 26% 68%
Billis Gleason 6 68% 49%
Gleason 7 26% 39%
Helpap B Virchows Arch 2006 Dec;449(6):622-7
Billis A J Urol. 2008 Aug;180(2):548-52

48. Time to progression for patients with low- and
intermediate-risk prostate cancer on surveillance.
• 90 men with intermediate risk disease
• 1/3 had Gleason 7, 2/3 PSA > 10
• No diffrence in any outcome compared to low risk
Cooperberg M R et al. JCO 2011;29:228-234
©2011 by American Society of Clinical Oncology

49. •50 men, mean age 69 with Gleason 7
•44 with 3+4, 6 with 4+3
•21 had otherwise favourable parameters
(PSA < 10, PSAD < 0.2, < 3 pos cores)
•29 unfavourable parameters

50. Biomarkers in active surveillance
Challenge: Interrogation of microfocal Gleason 6 in
PZ to reveal occult high grade anterior cancer
‘Cancerization’—is it real
PCA3: Does not appear to correlate with higher grade
cancer
Aureon: Systems pathology approach—promising
Many others in development
Mitochondrial deletion assay
SNPs
Gene expression panel

51. The controversies
 Role of Gleason 3 volume: (LK: main importance as a risk factor for
higher grade disease)
 PSA Kinetics: A flag, not a reliable trigger
 Grade: Significance of small volume 4 (LK: not an automatic trigger
for treatment)
 Role of PCA3: (LK: Jury out--major unmet need for effective
biomarker)
 Template/mapping biopsies vs systematic, perineal vs TRUS (LK:
Interesting but major resource implications)
 Concern about urosepsis; consider prebiopsy micro screen
 Imaging—MP MRI: (LK: increasing role for ‘problem patients’; needs
validation; ideally in all new Pca pts.)

52. We need to communicate a difference
message.
02/23/13

53. Tsunami of information: physicians, media, friends
Treatment outcomes Medical labyrinth
PANIC
Loss of autonomy Evidence based approach
Guidelines

54. Carey map
of Africa
‘ 1805 ‘Evasive anterior cancer’
1 cm
‘Pseudo-disease’
02/23/13
Favorable but significant

55. • 302 patients on surveillance randomized between dutasteride and
placebo
Relative Risk Reduction 44.3% 57.4%%
P = 0.009 P = 0.007
REDEEM: DS Figure 7.1, Table 7.4

56. The controversies
Role of Gleason 3 volume: (LK: not important)
PSA Kinetics: A flag, but not a reliable trigger
 Grade: Significance of small volume 4 (LK: not be an
automatic trigger for treatment)
Role of PCA3: (LK: Jury out--major unmet need for effective
biomarker)
Template/mapping biopsies vs systematic, perineal vs TRUS
(LK: Interesting but major resource implications)
 Concern about urosepsis; consider prebiopsy micro screen
Imaging—MP MRI: (LK: increasing role for ‘problem patients’;
needs validation; ideally in all new Pca pts.)

57. Current approach
AS offered to all Gleason 6, PSA ≤ 10 (accepted by most)
Serial PSA as guide only
Confirmatory biopsy within 1 year, targeting
anterior/anterolateral horn
Repeat biopsy q 3-5 years (age, risk tolerance, PSA) to 80
MP MRI for PSA DT < 3 years or volume increase or
3+minor element 4
Treat if significant Gleason 4 or unequivocal lesion > 1 cm
on MRI

58. Focal Therapy
Not all cancer has the potential to
progress to invasive and metastatic
cancer
Novel imaging and precision biopsy
can identify those lesions that are
likely to progress
Selective therapy to Clinically
Significant lesions alone will be as
effective as whole-gland treatment
and carry less harm

59. Focal cryotherapy for localized prostate cancer: a report
from the national Cryo On‐ Line Database (COLD) Registry
BJU International
pages no-no, 28 OCT 2011 DOI: 10.1111/j.1464-410X.2011.10578.x
http://onlinelibrary.wiley.com/doi/10.1111/j.1464-410X.2011.10578.x/full#f3

60. Focal Cryo Outcomes
Urinary continence (pad-free) 98.4%
Maintenance of spontaneous erections 58.1%
Prostate biopsy performed in 164/1160 (14.1%)
Positive in 43 (26.3%) of those suspected of cancer
recurrence
Positive in 3.7% (43/1160) of treated patients.

62. HIFU Focal Therapy Series
Muto et al (2008) Barret (2009) Ahmed et al Ahmed/
(retrospective) (retrospective) (2011) Emberton
(prospective (2011)
IRB trial) (prospective
IRB trial)
No. 29 12 20 42
Therapy Hemiablation Hemiablation Hemiablation Focal-HIFU
- Unilateral
- Bilateral
Biopsy TRUS Biopsy TRUS Biopsy Template Template
Mean PSA (ng/ml) 5 (range 2-25) <10 <15 <15
Gleason Score </=8 </=7 </=7 </=7
Potency ? ? 95% 90%
Incontinence ? 0% 5% 0%
Disease Control 76.5% (biopsy) 58% (10 years) 10% (any
cancer)
0% significant
cancer)
(Biopsy)

63. 63

64. 64

65. 65

66. Surveillance
Microfocal
Gleason 6 or
older patients Radical
Treatment
Most Gleason ≥ 7
Focal Therapy
Gleason 6, larger
volume (>1cm),
unilateral
02/23/13

67. Low risk prostate cancer:
Conclusions
Gleason pattern 3 very low metastatic potential
 ?Pseudo-cancer
 Main issue is missed higher grade cancers
Surveillance ‘a’ standard of care
 Safe in intermediate time frame
 RR Other Cause to PCa Mortality 19:1
 Validation of intervention triggers a priority
Increasing acceptance in North America
Epidemiology, screening studies
natural history
An evolving strategy (MRI, biomarkers)
Complementary to focal therapy—Brachy/Cryo/HIFU/Laser