1. Prostate Cancer screening
Mahmoud Abdelsalam MD/PHD
Medical Oncologist, Moncton Hospital
Professor in IM dept. Dalhousie University, Canada
Director of Clinical Trial Moncton, Canada

2. Disclosure Consultancy: Merck, Novartis, Astellas, BMS, Roche,
Ad. Board: Amgen, Pfizer, Johnson, Merck, Novartis
Grants: Roche, Amgen, Johnson, Astellas

3. Objectives
List risk factors for prostate cancer, and discuss relative strength
Discuss potential prevention strategies
Discuss benefits and risks of prostate cancer screening, including expected survival rates
Counsel patients about primary treatment options for local disease
Recommend systemic therapy for advanced cancer.

4. Canadian Cancer Statistics 2015

5. Canadian Cancer Statistics 2015

6. Canadian Cancer Statistics

7. Risk Factors for Prostate Cancer
Age – Rare before 40; 65% over the age of 65
Race - More common in African-American men; more likely diagnosed at advanced stage; 2x more likely to die of the disease; less common in Asian-American and Hispanic-American men than non-Hispanic whites.
Family History - 1st degree relatives, father, brother
Nationality - North America and NW Europe vs Asia, Africa, Central and South America
Genetics – BRCA1 and BRCA2 increase risk, but account for very small percentage of prostate cancer. Lynch syndrome??
Obesity, Diet, Exercise, prostatitis, STDs, Vasectomy – not much effect, BUT…….

9. Life time dying from cancer prostate
Risk of dying from cancer prostate is around 3 %
Once metastatic disease developed, there is no cure.
Prior to PSA screening only 25% of prostate cancer presented confined to prostate vs. 91% since

10. Screening Should you screen at all?
What age should you start and stop screening?
Does PSA-based screening lead to decrease in risk of death from prostate cancer?
What are the advantages and disadvantages of screening?
Canadian guidelines?

11. Screening
Two large trials done recently looking at survival benefit from screening:
PLCO screening trial (U.S.) and ERSPC screening trial (European)
These two RCT were largely basis for Canadian Task Force on Preventive Health Care (CTFPHC) recommendations.

12. European Randomized Study of Screening for Prostate Cancer (ERSPC)
Main endpoint: prostate cancer (PC) mortality
Ages: 50-74, core age group yrs (n=162,387)
Screen interval 4 years (87%) or 2 years (13%)
Sextant (lateral) biopsy recommended for PSA ≥3.0 ng/ml or ≥4.0 ng/ml
With ancillary tests: DRE, F/T ratio for PSA 3-4 ng/ml
Schröder. ECCO 2009; Teaching Lecture:

13. ERSPC screening trial (European)
European Randomized Study of Screening for Prostate Cancer
182,000 men randomized
Ages included
Median f/up of 9 years there was 20% reduction in CaP deaths in screened group
41 % reduction in metastases at presentation

14. Prostate cancer mortality – Intention to screen analysis
Relative risk (RR) of PC death 0.80
(95% CI: , P=0.04), 20% relative reduction
Absolute risk reduction: 7 per 10,000 men screened
NNS: (95% CI: )
NNT: 48 (in excess of control group)
Schröder. ECCO 2009; Teaching Lecture:

15. Göteborg Screening Trial
Göteborg randomized population-based prostate screening trial
20,000 men randomized
Ages included (median 56)
Median follow-up 14 years
Found 44% risk reduction in CaP specific death in screened group
NNT analysis revealed that 293 men needed to be screened and 12 men need to be diagnosed in order to prevent 1 death
Hugosson et al. Mortality results from the Göteborg randomised
Population-based prostate-cancer screening trial.
Lancet Oncol 2010;11:

16. Lancet Oncology, published online July 1, 2010
The independent Göteborg arm of the European trial, the largest and longest study, showed a 44% reduction in death from prostate cancer over 14 years, demonstrating the importance of following the patients long enough before concluding that there is no benefit to screening. And the costs, in terms of number of patients needed to screen and to treat, were much lower.
Over 14 years PSA testing increased the number of cancers detected by 50% but reduced the risk of dying of prostate cancer by 44% in all men and 56% in screened men. The number needed to screen to prevent one death was 293, and number needed to diagnose or treat was 12.

17. 5 treated tp prevent one death
In a follow-up Markov analysis, the European team estimate the benefits of screening over the lifetime of the participants. Now only 98 men needed to be screened and 5 diagnosed (3 were treated; the other 2 were watched) to avoid 1 death from prostate cancer.
5 treated tp prevent one death

18. Caveats – ERSPC
The 20% reduction in rate of death due to prostate cancer underestimates true effect since some controls were also screened (“contamination”) and some assigned to screening did not get screened (“noncompliance”), but …
Model-based adjustment to correct for contamination only indicates that screening reduces mortality by 27%, and …
Model-based adjustment to correct for both contamination and noncompliance indicates that screening reduces mortality by 31%
Roobol MJ, et al., Eur Urol 2009:56(4);

19. More Caveats – ERSPC
Initial data analysis indicates need to screen 1410 men and treat 48 with cancer to save 1 life, but …
Further modeling* indicates numbers needed to screen (NNS) & treat (NNT) to prevent 1 prostate cancer death decrease over time:
Definition: The number needed to screen (NNS) is the number of people who would need to be screened to prevent one person from dying.
(Similarly for the number needed to treat,
abbreviated NNT.)
NNS is computed by taking the reciprocal of the difference between the fraction of people who die in the screening arm and the fraction of people who die in the control arm.
* Loeb S et al., J Clin Oncol 29(4): , 2011

20. The prostate, lung, colon, ovary cancer screening trial (PLCO) (Andriole et al, NEJM 2009)
RCT of screening versus “general care” control group, to show 20% mortality reduction
n=76,693 men aged 55-74
PSA testing yearly for 6 years, DRE year 1-4
Biopsy for PSA >4.0 ng/ml or abnormal DRE
Andriole et al. New Engl J Med 2009;360:
Schröder. ECCO 2009; Teaching Lecture:

21. PLCO – results Follow-up 7 years
Compliance with PSA testing 85%, compliance with biopsy indication ± 40%
In the screen and control arm 85% and 52% of men were PSA tested
Cancer detection: S arm 2.86 (7.4%), C arm 2.32 (6.1%), rate ratio 1.22
Deaths from PC: S arm 2.0/10.000, (50 deaths), C arm 1.7/10,000 (44 deaths)
Rate ratio 1.13, 95%CI , NS
Andriole et al. New Engl J Med 2009;360:
Schröder. ECCO 2009; Teaching Lecture:

22. PLCO trial flaws Significant rates of screening in “control” arm
52% contamination (men were screened prior to study)
Relatively low rate of biopsy in men who had “abnormal” screening results in screen arm
Less than 50% of men in screened arm with indication had biopsy done
Short follow-up (less than 10 yrs)

23. Does PSA Screening Reduce Prostate Cancer Mortality?
PLCO: No
ERSPC: Yes, but at high cost
The two largest screening trials were not mature when the USPSTF analyzed the results. The USPSTF combined several very different screening trials in their meta-analysis, inappropriately underestimating the benefit of screening. And they did not understand the time-sensitive nature of prostate cancer, i.e., the potential harms of screening can be shown almost immediately, but the benefit – avoiding death from prostate cancer – can take many years to become apparent.
In the US PLCO trial there was no benefit to screening because so many men had already been screened when they entered the trial.
The European trial showed a 20% reduction in death from prostate cancer, but the cost was high in terms of men screened and cancers detected and treated.
Over 9 years, PSA screening reduced deaths from prostate cancer by 20% but was associated with a high risk of over diagnosis: 1410 men would need to be screened and 48 additional cases would need to be diagnosed or treated to prevent one death from prostate cancer.

24. Findings: Benefits of Screening with PSA
Study
(country)
Study Characteristics
PSA Threshold
Contamination (rate of screening in control group)
Prostate cancer mortality
Relative Risk
(95% C.I.)
All-Cause Mortality
Absolute Effect
(per 1000 men screened)
GRADE Quality of Evidence*
PLCO†
U.S. population
RCT
76,693 men
age 55-74, annual PSA screening for six years and DRE annually for four years
14 year follow-up
4 ng/ml
52%
1.09
( )
0.96 ( )
No effect
moderate
ERSPC‡
(Finland, Sweden, Italy, Netherlands, Belgium, Switzerland and Spain)
162,243 men
Age (core group 55-69)
PSA every 4 years
13 year follow-up
Most sites 3.0 ng/ml
20%
Core gp: 0.79
( )
All ages:
0.83 ( )
Core gp: 1.00 ( )
All ages: 1.00 (0.98 – 1.02)
1.28 fewer deaths per 1,000 men screened
Description: This is a standard GRADE table summary of the two major clinical trials on PSA screening for prostate cancer (PLCO and ERSPC). It displays the key outcome measures for each of these trials (prostate specific and all-cause mortality relative risk and absolute effect).
*Grading of Recommendations, Assessment, Development and Evaluation (GRADE) rates the continuum of quality of evidence in four categories of high, moderate, low or very low – see evidence review for complete assessment of study quality
†Prostate, Lung, Colorectal and Ovarian Screening Study
‡European Randomized Study for Screening for Prostate Cancer (published online August 7, 2014)

25. Screening Problems with both studies
Short follow-up <10 years (mortality from CaP is very low in first 10 years)
Subset analysis not done for high risk men (i.e. those with +FH, AA)
Contamination level is high specially in PLCO trial
Compliance was low

26. Findings: Harms of Screening with PSA
The main harms of screening identified were:
Harms of biopsy
Harms of over-diagnosis
False positives
Cost

27. Complications Following Prostate Biopsy
Loeb S, Carter HB, Berndt SI, Ricker W, Schaeffer EM. Complications after prostate biopsy: data from SEER-Medicare. J Urol 2011;186:
Nam RK, Saskin R, Lee Y, Liu Y, Law C, Klotz LH, Loblaw DA, Trachtenberg J, Stanimirovic A, Simor AE, Seth A, Urbach DR, Narod SA. Increasing hospital admission rates for urological complications after transrectal ultrasound guided prostate biopsy. J Urol 2010;183:
Pinkhasov GI, Lin YK, Palmerola R, Smith P, Mahon F, Kaag MG, Dagen JE, Harpster LE, Reese CT, Raman JD. Complications following prostate needle biopsy requiring hospital admission or emergency department visits - experience from 1000 consecutive cases. BJU Int 2012;110:

28. OVER DETECTION
Of all screen-detected cancers, an estimated 10-56% would not have become apparent or caused symptoms in the patients’ lifetimes, and the lead time for diagnosis is estimated at 5-12 years.

29. Risks of Screening
Screening detects cancers that do not threaten the patient’s life.
Finding such cases cannot be avoided at present.
When screening the general population for PCa by PSA, over 50% of the PCa’s detected will be minimal cancers (Draisma 2003).
As immediate treatment of these has not been shown to be beneficial, detection and diagnosis of some tumors may be unnecessary and counter-productive, as in some patients there will be treatment-associated morbidity (and, rarely, even mortality).

30. PIVOT (Prostate cancer Intervention Versus Observation Trial)
Randomized men ≤75yrs old to radical prostatectomy vs. expectant management with all-cause mortality as primary end-point
731 men studied
Median f/up 10 years
Different than Scandinavian trial
looked at same thing, but now in PSA screening era
Wilt et al. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med, 367, 2012
Bill-Axelson A et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med, 364, 2011

31. PIVOT (Prostate cancer Intervention Versus Observation Trial)
Found 47% (171/364) men died who had surgery vs. 49.9% (183/367) in observation arm
5.8% (21) men who had surgery died from CaP or treatment vs. 8.4% (31) in observation arm
Essentially NO Difference between groups
Surgery associated with ↓ all-cause mortality in men with PSA>10 and possibly in intermediate or high-risk tumors
Wilt et al. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med, 367, 2012
Bill-Axelson A et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med, 364, 2011

32. ProtecT (Prostate testing for cancer and Treatment)
RCT of treatment effectiveness in UK
Opened 2001 and closed 2008
111,000 men randomly assigned to surveillance, radiation, or surgery
Primary end-point will be CSS at 10yrs
With numerous secondary end-points including QOL analyses
Donovan et al. Prostate testing for cancer and treatment (ProtecT) feasibility study. Health Technol Assess 2003; 7:14

33. Use of Watchful Waiting among U. S
Use of Watchful Waiting among U.S. Patients with Localized Prostate Cancer by Risk Category ( )
Low
Intermediate
High
Cooperberg MR, Broering JM, Carroll PR. Time trends and local variation in primary treatment of localized prostate cancer. J Clin Oncol 2010; 28:

34. Findings: Additional Harms of Screening
Not all men who screened above threshold had a biopsy
Some men who screen positive on the first round could be diagnosed with prostate cancer on a subsequent round
Some men will have multiple biopsies
‡ ‡ Kilpelainen TP, Tammela TL, Roobol M, et al. False-positive screening results in the European Randomized Study of Screening for Prostate Cancer. Eur J Cancer 2011;47:

35. Causes of false positive PSA

36. Why Has Diagnostic Progress Not Resulted In Greater Long-Term Survival Rates?
Death rate is comparatively low considering prevalence
• Lifetime risk of diagnosis: 1 in 6
• Lifetime risk of death: 1 in 33
• 5-year survival rate: 98%
Diagnostic and therapeutic advances have improved quality of life, but not necessarily the years of life
• Risk is tied to age
- All ages: 17.7 cases per 100,000
- Age 75 to 84: 248 cases per 100,000
- Over 85: 591 cases per 100,000
Prostate cancer cells are generally less aggressive with increasing age, suggesting “many prostate cancers detected in routine practice may be clinically unimportant”
Sources: Mayo Clinic.com. Prostate Cancer Guide. Available at:
Thompson IM, Pauler DK, Goodman PJ, Tangen CM, Lucia MS, et al. Prevalence of prostate cancer among men with a prostate-specific antigen level ≤4.0 ng per milliliter. NEJM. 2004;350:

37. Canadian Task Force on Preventive Health Care
Screening for Prostate Cancer with the Prostate Specific Antigen (PSA) Test: Recommendations 2014
Canadian Task Force on Preventive Health Care

38. Summary of the Recommendations Clinicians and Policy Makers
For men aged less than 55 years of age, we recommend not screening for prostate cancer with the prostate-specific antigen test.
(Strong recommendation; low quality evidence)
Basis of the recommendation
The CTFPHC based this recommendation on the low incidence of prostate cancer and prostate cancer mortality, and the lack of evidence for benefit of screening in this age group, as well as the evidence of harms.
The strong recommendation implies that the CTFPHC is confident the harms of screening and subsequent testing/treatment outweigh the benefits.

39. Summary of the Recommendations Clinicians and Policy Makers
For men aged years, we recommend not screening for prostate cancer with the prostate specific antigen test.
(Weak recommendation; moderate quality evidence)
Basis of the recommendation
The CTFPHC placed a relatively low value on a small and uncertain potential reduction in the risk of prostate cancer mortality and a relatively higher value on the risk of harms associated with diagnosis and treatment due to false positive results and overdiagnosis.
The weak recommendation against screening implies that the harms of screening and subsequent testing/treatment probably outweigh benefits, but uncertainty exists.

40. Summary of the Recommendations Clinicians and Policy Makers
For men aged 70 years and older, we recommend not screening for prostate cancer with the prostate-specific antigen test.
(Strong recommendation; low quality evidence)
Basis of the recommendation
The CTFPHC based this recommendation on the lower life expectancy and the lack of evidence for benefits of screening in this age group, as well as the evidence of harms.
The strong recommendation implies that the CTFPHC is confident the harms of screening and subsequent testing/treatment outweigh the benefits.

41. USPSTF To Downgrade PSA Screening From "I" to "D" — As In "Don't Do It"
U.S. Preventative Service Task Force recommended NOT to use PSA to screen for prostate cancer
Based on meta-analysis of available literature
ABSTRACT Background: Prostate specific antigen-based screening can detect prostate cancer in earlier, asymptomatic stages, when treatments might be more effective.
Purpose: To update the 2002 and 2008 U.S. Preventive Services Task Force evidence reviews on screening and treatments for prostate cancer.
Data Sources: MEDLINE (2002 to July 2011), the Cochrane Library Database (through the 2nd quarter of 2011) and reference lists.
Study Selection: Randomized trials of PSA-based screening; randomized trials and cohort studies of prostatectomy or radiation therapy versus watchful waiting for localized prostate cancer; and large (n>1000), uncontrolled observational studies of perioperative harms.
Data Extraction: Investigators abstracted details about the patient population, study design, data analysis, and results and assessed quality using predefined criteria.
Conclusions: After about 10 years, PSA-based screening results in small or no reduction in prostate cancer-specific mortality and is associated with harms related to subsequent evaluation and treatments, some of which may be unnecessary.
The Cancer Letter, Oct. 7, 2011

42. Current Screening Guidelines from Major U.S. Organizations
Stanley H. Weiss, MD, FACP, FACE
PSA Testing: Pitfalls & Utility
Current Screening Guidelines from Major U.S. Organizations
American Urological Assoc Best Practice Statement
Individual decision for those with 10yr life expectancy
Baseline PSA at 40
PSA at subsequent intervals based on PSA level and risk factors
American Cancer Society
Advises against routine screening
PSA should be offered as option
Age 45 in those with risk factors (FH, AA)
Age 40 in those at highest risk (multiple family members or a family member diagnosed at a young age)
US Preventive Services Task Force
Do not screen routinely over age 75
Inadequate evidence regarding younger ages
Current (October 2011) recommendation against PSA-based screening of any asymptomatic men
2011 October 29 — The Prostate Net® Symposium 42

43. Presented By Mark Stein at 2014 ASCO Annual Meeting
Slide 44
Presented By Mark Stein at 2014 ASCO Annual Meeting

44. Prostate Cancer—Indolent vs. Aggressive?
Low Risk
PSA < 10
Gleason score ≤6
Intermediate Risk
PSA 10-20, Gleason 7 or Gleason 6 with PSA >10
High Risk
PSA > 20, Gleason 8-10

45. TREATMENT OPTIONS FOR PROSTATE CANCER
At Diagnosis
Curable
Watch +/- hormones
Watch +/- treat for cure later
TREAT NOW for cure
Non-Curable

46. Active Surveillance Watch, and if need be treat for cure later
Means watching PSA and re-biopsy of prostate every 1-2 years
Go on to curative Rx if PSA jumps quickly, urinary symptoms, or biopsy shows worsening cancer
Best for men with very slow growing cancers whose life expectancy is less than 15 years.

47. Low-risk prostate cancer
Cancer is VERY LIKELY restricted to the prostate gland
Must have T2 (or less) and PSA <10 and Gleason Score 6 (or less)
Expect 80-95% chance of cure with treatment
Active surveillance is good option for many

48. Low-risk prostate cancer T1/T2 and PSA<10 and GS<7
Therapy
Surgery
Seed implant
External Radiotherapy
Surveillance

49. Treatments of Localized Prostate Cancer
The primary treatments reviewed:
Radical Prostatectomy
Radiation Therapy
Androgen Deprivation Therapy (ADT)
Combination Therapy

50. Treatment for cure: operation
Radical prostatectomy – removes the prostate and seminal vesicles
Has a specific side effects
Related to major operation
Urinary incontinence 5-10%
Erectile dysfunction 30-70%
Bladder neck stricture 10%
Is an excellent option in a situation where prostate cancer cells are likely restricted to the prostate gland
Removing the prostate gland provides much more information about the aggressiveness and extent of cancer
Radiotherapy can be used after surgery if it looks like cancer is likely left behind in the surgical bed or if PSA begins to rise in follow up

51. Treatment of cure: Radioactive seeds in prostate
Also called Low Dose Rate or Seed Brachytherapy
Best for men with early disease when cancer cells likely in prostate gland of just beyond capsule
Very high cure rates similar to operation when done by an experienced specialist
“Simple” outpatient procedure
General anaesthetic
Rapid return to normal activity
Men appear happy with this treatment

52. Findings: Benefits of Treatment
Some treatments were found to reduce the risk of prostate cancer-specific mortality, although the quality of evidence was variable.
Prostatectomy was the only treatment with high QoE
Hormone therapy alone was found to produce an increased risk of prostate cancer-specific mortality.
Very limited and low QoE to support a reduction in the risk of all-cause mortality for the following treatments:
Prostatectomy
Radiation Therapy
Combination Therapy (Radiation and Hormone Therapy)

53. Management of CRPC

54. How to Improve screening benefits
High Risk
Family History
Age
PSA velocity
PSA Density
PCA 3 (non-coding mRNA molecule that is believed to be prostate specific)
Risk Score

55. Considerations for High Risk Populations
High risk populations include men of black ethnicity or men with a family history of prostate cancer.
Men of black ethnicity were included in the USA studies, however, the results are not broken down by risk level or risk factor. Instead, the studies provide results for the male population as a whole.
Therefore, there is currently no trial data to suggest that men at high risk should be screened differently from men in the general population.
Clinicians may wish to discuss the benefits and harms of screening in men at high risk, with explicit consideration of their values and preferences.

56. Screening Smarter: How to Increase the Benefits and Reduce the Risks of Screening for Prostate Cancer
Risk-adjust screening by age and PSA (reduce false positives)
Reduce false positive PSA results by repeating (verifing) positives and by adding additional markers (4 kallikrein panel or -2(pro)PSA) (reduce indications for biopsy)
Active surveillance for low-risk cancers (reduce harms of unnecessary therapy)
Refer patients who need treatment to high-volume physicians or centers (reduce harm of necessary therapy)

57. Memorial Sloan-Kettering Cancer Center 2010 Guidelines Risk-adjusted Screening for Prostate Cancer
Begin PSA testing at age 45
For men age
PSA ≥ 3 ng/ml : consider biopsy
PSA > 1 but < 3 ng/ml : return for PSA every 2-4 years
PSA <1 ng/ml : return for PSA in 5 years or at age 50 or 60, whichever comes first
For men age 60 – 70
PSA > 1 but < 3 ng/ml : return for PSA every two years
PSA < 1 ng/ml : no further screening
For men age 71 or higher
No further screening

58. Stanley H. Weiss, MD, FACP, FACE
PSA Testing: Pitfalls & Utility
SEE:
2011-Oct-29
2011 October 29 — The Prostate Net® Symposium 58

59. Stanley H. Weiss, MD, FACP, FACE
PSA Testing: Pitfalls & Utility
Example:
2011-Oct-29
2011 October 29 — The Prostate Net® Symposium 59

60. A Novel Urine Exosome Gene Expression Assay to Predict High-grade Prostate Cancer at Initial Biopsy
we compared the urine exosome gene expression assay with biopsy outcomes in 499 patients with prostate-specific antigen (PSA) levels of 2 to20 ng/mL.
the urine exosome gene expression assay plus SOC was associated with improved discrimination between GS7 or greater and GS6 and benign disease: AUC 0.77 (95% CI, ) vs SOC AUC 0.66 (95% CI, ) (P < .001).
Independent validation in 519 patients Urine exosome gene expression assay plus SOC AUC 0.73 (95% CI, ) was superior to SOC AUC 0.63 (95% CI, ), (P < .001).
JAMA Oncol March 31st, 2016 online

61. Conclusions
Prostate Cancer screening using PSA is controversial with evidence of ?? Reduced mortality.
Long term follow-up is needed to prove mortality reduction.
Harms related to screening, biopsy, treatment and cost should be considered.
Guidelines do not encourage routine screening.

62. Conclusions (continued)
High Risk Group Screening?????
Smarter screening??????
Other screening tests??????
Risk adjusted models??????