1. To Screen or Not to Screen: That is the Question………
New Guidelines for Prostate Cancer Diagnosis: The Global perspective
Gabriel P. Haas, MD. FACS
Medical Director,
Astellas Scientific and Medical Affairs
This is not an Astellas sponsored presentation and the opinions expressed are my own

2. New Guidelines for Prostate Cancer Diagnosis: The Global perspective
Preguntas:
Usan PSA por detecion temprano de Pca?
Familiares con recommendaciones de USA para NO USAR PSA?
Acceptan estos recommendaciones en Portugal?

3. BREAKING NEWS !!! USPSTF PANEL RECOMMENDS AGINST PROSTATE CANCER SCREEING WITH PSA (MAY 2012) PIVOT TRIAL PUBLISHED IN NEW ENGLAND JOURNAL OF MEDICINE (367:203, 2012) JULY 2012: “RADICAL PROSTATECTOMY HAS NO SURVIVAL BENEFIT OVER OBSERVATION”

4. Estimated New Cancer Cases and Deaths By Sex, United States, 2011
From Siegel, R. et al.
CA Cancer J Clin 2011;0:caac.20121v1
Copyright ©2011 American Cancer Society

5. Generaliztions about prostate cancer__clinical issues
INTRODUCTION
Generaliztions about prostate cancer__clinical issues
PCA is very common
PCA left untreated or treated late can be deadly
Early detection with PSA leads to diagnosis of PCA at much earlier stage
Early detection with PSA PROBABLY leads to decreased mortality

6. EPIDEMIOLOGY
PCA starts in 20’s and 30’s and may take decades to be clinically detectable
Prevalence of PCA is MUCH HIGHER than clinical cases
Early detection with PSA DOES lead to detection of some (many) clinically insignificant cancers
Characterization of early prostate cancer is difficult because only diagnosed cancers can be studied – undiagnosed cancers are UNKNOWN

7. Lifetime Risk of Developing or Dying From Prostate Cancer*
Risk Ratio
Developing Histologic Prostate Cancer (Autopsy)
42%
11.7
Developing Clinical Prostate Cancer
16.7%
4.4
Dying from Prostate Cancer
3.6% 1
* For a 50 year old American man.
Modified from Scardino PT Urol Clin N Am 1989 and Human Path 1992

11. Incidence of Prostate Cancer by World Region
North America 92.39
Australia/New Zealand 46.70
Caribbean 42.35
Western Europe 39.55
Northern Europe 34.70
Southern Africa 31.03
Middle Africa 29.58
Tropical S. America 28.05
Central America 24.77
Western Africa 23.85
Temperate S. America 22.86
Micronesia/Polynesia 21.22
Southern Europe 16.91
Eastern Africa 16.75
Eastern Europe14.06
Japan 8.51
Western Asia 7.11
Melanesia 6.04
S.E. Asia 5.85
Other Eastern Asia 5.37
Northern Africa 5.13
S. Central Asia 4.53
China 1.08

12. Prostate Cancer, USA Year Incidence Prevalence Mortality 2010 217,730?
32,050
2003
220,900
28,900
2001
198,100
31,500
1999
179,300
37,000
1996
317,000
41,400
1994
200,000
38,000
1990
106,000
30,000
1985
86,000
24,000
1976
64,000
20,000
Despite the fact that some primary care doctors argue that most prostate cancer is not clinically significant, this opinion is unfortunately wrong.
Over a quarter of a million cases of prostate cancer are diagnosed every year.
Deaths due to prostate cancer, account for 14% of all cancer deaths. This doesn’t count men that have prostate cancer and get hit by a car this is deaths specifically related to prostate cancer.
This is not a trivial disease
Putting this into numbers we all can relate to this means that 1 in 6 men will develop prostate cancer in their lifetime. Or, more pointedly 3 of you in this room are likely to develop prostate cancer in your lifetime and one of you, if left untreated has a 50% chance of dying from it.
But if you can beat the odds you can give yourself up to an 80% chance of being cured

14. PSA Level(ng./ml) % Prostate Ca
0-0.5
6.6%
10.1%
17.0%
23.9%
26.9%

15. Rise in Incidence After PSA, 1988
Dramatic rise in incidence as prevalent cases are culled (2.5X)
Sustained rise in incidence as earlier cancers are detected (1.5X)

16. Reduction in Prostate Cancer Mortality After PSA
40% decline in PCA mortality
45 to 70% of the observed decrease in mortality “attributable” to PSA screening
Jemal A, et al. CA Cancer J Clin 2010; 60:
Etzioni R, et al. Cancer Causes Control 2008;19:

20. Screening for Prostate Cancer
Does it save lives?
Does it lead to OVERDETECTION?
Does it lead to unnecessary treatment?

21. AUA Guidelines 2009 (New Guidelines at AUA, May 2013)
Well informed men aged 40 and over who have a life expectancy of at least 10 years should be offered PSA and DRE to establish a base line and follow-up should be individualized
The decision as to whether to do a biopsy or not should not rely only on the PSA reading(s) but should take into account a range of other factors such as free and total PSA, PSA velocity and density, age of the patient, family history, ethnicity/race, other illnesses/diagnoses, general health and previous biopsy history

22. American Cancer Society 2012 (2/27/12)
The ACS recommends that men make an informed decision with their doctor about whether to be tested for prostate cancer. Starting at age 50 men with more than 10 years of life expectancy should talk to their doctor about the pros and cons of testing so they can decide if testing is right for them.
If they are African American or have a father or brother who had prostate cancer before age 65, men should have this talk with a doctor starting at age 45.
If men decide to be tested, they should have PSA with/without DRE
How often they are tested should depend on their PSA level
If PSA < 2.5 ng/ml, may be tested every 2 years
If PSA > 2.5 ng/ml, recommend annual testing

23. Screening: NCCN Guidelines
For men with life expectancy of > 10 years
Life expectancy is comprised of age and comorbidity
Have a risk/benefit discussion
“Shared decision-making”
Offer baseline DRE and PSA at age 40
If PSA < 1, recheck in 5 years
Median PSA for a man in his 40s is about 0.75
If PSA > 1 or patient is African-American or +FH, offer annual screening
Consider biopsy if PSA > 2.5 or rate of rise is > 0.35 ng/mL per year

24. NY Times: Health Section 2012
U.S. Panel Says No to Prostate Screening for Healthy Men
By GARDINER HARRIS
Healthy men should no longer receive a PSA blood test to screen for prostate cancer because the test does not save lives over all and often leads to more tests and treatments that needlessly cause pain, impotence and incontinence in many
US Preventive Services Task Force, May, 2012

25. For every 1000 men treated for PCa
US Preventive Services Task Force critiques Screening for Prostate Cancer
For every 1000 men treated for PCa
5 die of complications
10-70 experience complications but survive
develop long-term complications
Impotence
Incontinence
Increased Morbidity
Complications of biopsy (68 events/10,000 biopsies)
Psychological consequences
Complications of overtreatment

26. US Preventive Services Task Force critiques Screening for Prostate Cancer
Main concern: Too many of the patients who are diagnosed have clinically insignificant cancers which do not need treatment and therefore should not be diagnosed
GRADE ‘D’ Recommendation:
Evidence is AGAINST screening
Harms outweigh benefits

27. N Engl J Med 360:1310, 2009
N Engl J Med 360: 1320, 2009

28. Comparison of ERSPC and PLCO studies
ERSPC (Europe) PLCO (USA)
Control 89,353 38,350
Screening 72,890 38,343
Age
PSA screening interval 4 yr (87% men) 1 yr (6 yr period)
PSA indication for biopsy >3-4 ng/ml >4 ng/ml
Compliance for PSA test 82% 85%
PCA detected Control 4,307 (4.8%) 2,974
Screening 5,990 (8.2%) 3,452
Follow-up 15 yr 10 yr
PCA death rate ratio
(95% CI, ) (95% CI, )

30. Limitations of the studies
ERSPC (EU) PLCO (USA)
PSA test prior to the study ? 43%
PSA test compliance 82% 85%
PSA test in controls ? 52%

31. ERSPC: PROS AND CONS Absolute risk difference: 0.71 deaths/1000
For each cancer death prevented, 48 cancer cases need to be detected AND treated – 1410 men need to be screened
OVERDETECTION % of cancers detected by screening would not be detected in the men’s lifetime

32. ERSPC

33. ERSPC 162,243 men randomized Screening q 2-4 years vs. usual care
PSA > 3 ng/ml
Sextant biopsies
Compliance in screening group 82%
Screening in the control group ?? (20%)
11 years of follow up (median)
Detection was higher in screening group
6963 cases vs. 5396, or cumulative incidence of 9.6% vs. 6.0%

34. At 11 years, 299 prostate-cancer deaths in screening group and 462 in the control group.
Rate ratio 0.79, 95% confidence interval , p=0.003.

35. ERSPC Screening  21% reduction in prostate-cancer death*
To save 1 life:
Number needed to screen: 1055
Number needed to detect: 37
* Up to 29% reduction if corrected for noncompliance in the screening arm and contamination of the control arm.

36. How does prostate cancer screening efficacy compare with screening for other common cancers?

37. Breast Cancer Screening (Mammogram)
9 randomized trials with 650,000 participants
Relative risk reduction of 22% at 14 years
Number needed to screen: 1792
S Fletcher. Screening for Breast Cancer. UpToDate.com; accessed January 14, 2010
LL Humphrey. Summary of the Evidence for Breast Cancer Screening. Ann Intern Med 2002;137:344-6

38. Colon Cancer Screening
5 randomized trials (at least)
Relative risk reduction of 15-21% at 8-13 years
Number needed to screen: 1173
BD Boggs. How does colonoscopy compare with fecal occult blood testing as a screening tool for colon cancer. JFP 2005; 54(11)
Towler  BP, Irwig  L, Glasziou  P, Weller  D, Kewenter  J. Screening for colorectal cancer using the faecal occult blood test, hemoccult.  Cochrane Database Syst Rev 2000;(2):CD
Pignone  M, Rich  M, Teutsch  S, Berg  AO, Lohr  KN. Screening for colorectal cancer in adults at average risk: a summary of the evidence for the U.S. Preventive Services Task Force.  Ann Intern Med 2002;137:132–141.

39. Screening for Prostate Cancer: Comparison with Other Cancers
Similar risk reduction
Similar number needed to screen
AND
Two recent studies suggest that appropriately targeted screening may improve these figures substantially for prostate cancer…

40. Goteborg Planned analysis of one site of the ERSPC Differs in that
Randomization occurred before invitation to participate
Younger at randomization (median 56 years)
Lower PSA threshold for biopsy (2.5)
High compliance with screening (76%) and follow-through (93%)
Negligible contamination in the control group (est. 3%)
Higher PCa mortality
Longer follow up (median 14 years)
Hugosson et al, Lancet Oncol 2010

41. Goteborg
Rate ratio for death from PCa among the screening group was 0.56 ( , p=0.002)
Number needed to invite to screen 293 and number needed to treat 12 to prevent one PCa death.
Hugosson et al, Lancet Oncol 2010

42. PLCO Sub-set Analysis of Healthy Men
Sub-set analysis of men with no comorbidities (that
predict cardiovascular or
cancer mortality)
Adjusted hazard ratio for
screening group vs.
unscreened group was 0.56
( ), p=0.03.
Number needed to treat to
prevent one PCa death at
10 years was 5.
No Comorbidities
One or more Comorbidities
Crawford et al, JCO 2011

43. Summary of Randomized Trial Data
PLCO
Flawed due to contamination of the control arm
ERSPC
21% relative risk reduction
1055 needed to screen; 37 needed to treat
Screening is more beneficial
In younger, healthier men
As follow up lengthens
Targeted screening reduces NNS to ~300 and NNT to 10 or 12.

44. A good screening test? Sensitive Specific Non-invasive and safe
Detects a common condition
Detects a harmful condition
Detects a condition that has effective treatment
Treatment works better in early stages
Cost-effective
Benefits outweigh harms

45. PSA a good screening test?
Sensitivity at 4.0 ng/ml = 75%
Specificity at 4.0 ng/ml = 25%
Non-invasive and safe yes/ but leads to biopsy/treatment?
Detects a common condition yes
Detects a harmful condition yes, but also indolent ca
Detects a condition that has an effective treatment, yes,
Treatment works better in early stages, yes, but only if needed to be treated
Cost-effective debated
Benefits outweigh harms debated

46. Efforts to Improve Test Characteristics of PSA
Age-adjusted PSA
PSA velocity : 0.75 ng/ml or 0.35 ng/ml
PSA density : 0.15
PSA doubling time : less clear in pre-tx evaluation
Free PSA : < 18%
OTHER MARKERS?
Improved biopsy regiments
Improved Radiologic Guidance and Identification of Significant Cancers (MRI fusion, etc)

47. Decision Tree of Prostate Cancer Screening, Diagnosis and Treatment
PSA
+/-
DRE ?

48. Decision Tree of Prostate Cancer Screening, Diagnosis and Treatment
PSA
+/-
DRE
Prostate
Biopsy
(type of biopsy) ? ?

49. Decision Tree of Prostate Cancer Screening, Diagnosis and Treatment
PSA
+/-
DRE
Re-Biopsy?
Prostate
Biopsy
(type of biopsy) ? ? ?

50. Decision Tree of Prostate Cancer Screening, Diagnosis and Treatment
Active
Surveillance
PSA
+/-
DRE
Prostate
Biopsy
(type of biopsy)
Re-Biopsy?
Surgery
Radiation
Other
HIFU
Focal therapy
Hormones ? ? ? ?

51. Screening Summary There are potential benefits
Reduction in morbidity due to progressive disease
20-40% prostate-cancer specific survival benefit
More likely to benefit younger, healthier patients
There are potential harms
False-positive test leading to other tests
Detection of indolent prostate cancer leading to unnecessary treatment
Screening decisions must
Balance potential benefits and potential harms
Involve the patient – “shared decision-making”

52. Benefits AND Harms Potential benefits
20%-40% relative risk reduction in prostate cancer mortality (i.e., from 3 or 4% to a little less)
Potential harms: For every one life saved…
Between 300 and 1000 men have to undergo screening
Between 10 and 40 men have to undergo treatment
Indiscriminate treatment of low-risk disease
Estimates indicate over one million extra men have undergone treatment in the US due to PSA screening to save at most 56,000 lives
Albersten JNCI 2009

53. Leads us to… LATIN AMERICA…. AFRICA…. ASIA…..
The issues are different:
PSA use very limited
Prostate cancer presents in advanced form
Mortality from prostate cancer is 50-80%
Effective treatment is unavailable
RESOURCES, RESOURCES ,RESOURCES

54. Age-standardized rate (world) of PCA GLOBOCAN 2008
Incidence Mortality Ratio
(per 100,000) (incid./mortality)
World
USA
Canada
Congo
Kenya
Senegal
Tanzania
Uganda
Portugal

55. CONCLUSIONS Prostate Cancer Screening
Prostate cancer mortality is dropping in Western Countries
Trials to PROVE that screening saves lives are very expensive
Methodologies and follow up different
Very little difference may be detected in societies where PSA use has been pervasive
However, in Portugal, recommendations from US may not be applicable