Reducing the Harm of Prostate Cancer Screening: Repeated Prostate-Specific Antigen Testing Objective: To determine if repeating a prostate-specific antigen (PSA) test in men with an elevated PSA level is associated with a decreased risk of prostate biopsy and cancer diagnosis. Conclusion: Routinely repeating a PSA test in patients with an elevated PSA level is independently associated with decreased risk of prostate biopsy and prostate cancer diagnosis. Men with an elevated PSA level should be given a repeated PSA test before proceeding to biopsy.

1. Khushboo Gandhi, MD
PGY1, Internal Medicine Residency Program
St. Luke’s Hospital
1st February, 2016

2. ● Serum PSA and DRE - to screen prostate cancer for >20 years
● PSA screening:
○ Allows earlier detection of prostate cancer - widely used in North America - decrease in the incidence of locally advanced prostate
cancer, metastatic prostate cancer, and prostate cancer death.
○ Also increased the detection of low-risk cancers that are unlikely to cause a patient harm
● US Preventive Services Task Force and Canadian Task Force on Preventive Health Care - Recommend against PSA screening.
○ Based on the observation - to prevent one prostate cancer death many men would be exposed to unnecessary prostate biopsy and
treatment
○ Based on the European Randomised Study of Screening for Prostate Cancer
At 13 years of follow-up, 781 men need to undergo PSA screening and 27 cancers need to be detected to prevent 1 prostate
cancer death.
● PSA elevation: Prostate cancer, Infection, Physical activity, Sexual activity
● Variation in PSA concentrations: Normal biological fluctuation or analytic (laboratory assay) differences
● PSA is sensitive but not specific for detecting prostate cancer, especially when levels are moderately elevated between 4-10 ng/ml
● Measures that render PSA testing more specific for prostate cancer and reduce overdiagnosis.
○ PSA velocity
○ Free to total PSA ratio
○ Age-specific PSA thresholds
○ Race-specific thresholds
Background:

3. Prostate cancer diagnostic center:
● Established in 2008 as a referral site to serve a region of over 1 million people in Canada
● Purpose - centralize the diagnosis and evaluation of patients at risk for prostate cancer based on elevated PSA levels or abnormal prostate
examination results.
● All patients referred to the center were asked to undergo a repeated PSA test before assessment.
● The purpose of this study - to determine if routinely obtaining a repeated PSA test in men with an elevated screening PSA level is
associated with a decreased risk of prostate biopsy and cancer diagnosis.
Background

4. Study setting and population:
● Cohort of men with an elevated PSA level ( >4 ng/mL) referred to the Ottawa Regional Prostate Cancer Assessment Center (CAC) in
Ottawa, Ontario, Canada, was reviewed.
● All patients seen at this clinic from April 1, 2008, through May 31, 2013, were eligible for inclusion.
● All patients are asked to undergo a repeated PSA test at the same laboratory where the referral PSA test was performed before
consultation.
Study Protocol:
● Exclusion criteria:
If repeated PSA test was missing or performed more than 3 months after the referral PSA test
If they had a previous prostate biopsy or prostate cancer diagnosis
If their consultation was more than 3 months after repeated PSA testing
If their referral PSA level was not between the predefined study PSA range of 4 - 10 ng/mL
Patients and methods:

5. Patients and methods
● Patient characteristics and outcomes were prospectively recorded. Including Patient age, DRE findings, and PSA values
● DRE classified as normal or abnormal - abnormal DRE results did not necessarily indicate a suspicion of malignant disease
● Transrectal ultrasound-guided prostate biopsies:
1. Performed in the CAC by highly experienced radiologists.
2. All prostate biopsies within 1 year of the initial consultation were included in analyses.
3. Biopsies obtained more than 1 year after the initial consultation were excluded.
● Repeated PSA values - classified as normal (<4 ng/mL) or abnormal ( >=4 ng/mL).
Adjusted and Unadjusted risk of undergoing a prostate biopsy - Compared
Patients with a normal result on repeated PSA testing
Expressed as RR with 95% CI
Patients with an abnormal repeated PSA result
Unadjusted and adjusted associations between
Normal repeated PSA test result
Incidence of prostate cancer
Gleason score of 7 or higher

6. Sensitivity analyses:
● Different PSA threshold may be used by clinicians
● To account variability - Preplanned sensitivity analyses
○ 2 additional PSA thresholds
■ lower threshold of 2.5 ng/mL or higher as abnormal.
■ Age specific PSA thresholds
● 50-59 years - >= 3.5 ng/ml
● 60-69 years - >= 4.5 ng/ml
● >= 70 years - >= 6.5 ng/ml
● Biopsy is the most common method of cancer diagnosis
○ Subgroup analysis only men who underwent biopsy.
○ Determined association between repeated PSA test results and cancer diagnosis
● SAS software
● All test were 2 sided and P< 0.05 considered statistically significant

7. Results:
2834 Patients referred to
prostate cancer assessment
center (2008-2013)
661 Excluded
● 571 Repeated PSA test performed
>3 mo after referral PSA
● 55 Missing repeated PSA test
● 18 Consult >3 mo after repeated
PSA test
● 17 Previous prostate cancer
diagnosis
2173 Referral with abnormal
DRE and/or abnormal PSA
results
905 Excluded
● 418 Referral PSA >= 10 ng/ml
● 487 Referral PSA < 4 ng/ml
1268 included in study cohort
● 11 Attending physicians
○ 9 Urologists
○ 2 Family physicians experienced in prostate cancer assess.

8. Results
Normal result on repeated PSA testing < 4 ng/ml 315 (24.8%) /1268
Normal repeated PSA level Abnormal repeated PSA level
Mean age Lower 61.5 +/- 8.2 65.2 +/- 8.2 P< 0.001
Mean referral PSA level Lower 5.5 +/- 1.4 6.6+/- 1.4 P< 0.001
Use of prostate biopsy 89/315 594/953
Less likely to have diagnosis of cancer 8.3% 35.3%

9. Results
Sensitivity Analyses:
PAS threshold 2.5 ng/ml (n=1516)
Normal results on repeated PSA testing Vs Abnormal 160 patients (11 %)
Decreased risk of prostate biopsy RR = 0.32; 95% CI, 0.23-0.45
Decreased risk of cancer diagnosis RR = 0.19; 95% CI, 0.10-0.37
Age specific threshold (n=1116)
Normal results on repeated PSA testing Vs Abnormal 333 patients (30 %)
Decreased risk of prostate biopsy RR = 0.34; 95% CI, 0.25-0.46
Decreased risk of cancer diagnosis RR = 0.34; 95% CI, 0.25-0.46
Gleason score of 7 or higher RR = 0.28; 95% CI, 0.18-0.44
Subgroup of men who underwent prostate biopsy
Normal repeated PSA level Vs Abnormal
Less likely to have cancer diagnosis RR = 0.52; 95% CI, 0.37-0.72

10. Discussion:
● The US Preventive Services Task Force, the Canadian Task Force on Preventive Health Care and other guidelines have
recommended against routine PSA testing.
● Major reason - harm associated with unnecessary prostate biopsies initiated by false-positive PSA test results.
● Data indicate - Routinely repeating a PSA test in patients with a moderately elevated PSA concentration (<10 ng/mL) prevents many
prostate biopsies and is associated with lower risk of prostate cancer diagnosis.
● 315 of the 1268 patients (24.8%) had a normal PSA level on repeated testing
○ lowered risk of undergoing prostate biopsy by 60%.
● Men who had a normal result on repeated PSA testing
○ Approximately 80% less likely to have a diagnosis of prostate cancer and Gleason score of 7 or higher.
Other studies:
● One study examined blood samples from 972 men in a colon cancer randomized trial and found that approximately 50% of patients with
moderately elevated PSA levels had a normal subsequent PSA test result. In 65% of those patients, the PSA levels remained normal 1 year
later.
● In a cohort study of 101 patients with lower urinary tract symptoms and an elevated PSA level, 35% had a normal level on repeated PSA
testing, and of those, the PSA level remained normal in 82% at 2 years of follow-up

11. Discussion
Related study:
The authors reviewed the Northern Ireland Cancer Registry (n=7052; mean age, approximately 70 years) between 1994 and 2003.
● 38% (2664) of patients with a PSA level between 4 and 10 ng/mL had another PSA test result that was less than 4 ng/mL
○ 321 (12%) had a prostate biopsy
○ 74 (3%) had a diagnosis of cancer
○ only 21(<1%) had a Gleason score of 7 or higher.
● Authors concluded - Normalized PSA level did not rule out prostate cancer
● Study did not specifically address the impact of an immediate repeated PSA test
● Supports the prognostic value of a normal result on repeated PSA testing
● In the placebo arm, 27% of men with a PSA level between 3.3 and 4.0 ng/mL had cancer diagnosed on per-protocol end of study biopsy
● Given this information
○ Normal repeated PSA result does not rule out the presence of prostate cancer or the subsequent development of prostate cancer.
○ Repeating a PSA test will avoid or delay many prostate biopsies in patients whose PSA level may have been transiently elevated

12. Discussion
Limitations:
● Primarily examined patients whose referral PSA level was between 4 - 10 ng/mL
● Sensitivity analyses (PSA threshold of 2.5 ng/mL and age-specific thresholds) yielded consistent results, but could comment on patients
whose referral PSA level is below these thresholds or above 10 ng/mL
● Abnormal DRE result did not necessarily imply that the physician was concerned that the patient had a prostate tumor
● Race and family history of prostate cancer were not consistently documented; unable to adequately assess the impact of repeated PSA
testing on high-risk subgroups
● Do not know the prevalence of prostate cancer in patients who did not undergo biopsy
Author’s Conclusion:
● A significant proportion of patients with an elevated serum PSA concentration will have a normal PSA concentration when retested.
● Normal result on repeated PSA testing was associated with a lower risk of undergoing biopsy, cancer diagnosis, and Gleason score of 7 or
higher within 1 year of referral.
● Findings indicate that routine repeated PSA testing influences patient management and should be adopted by physicians who make
decisions regarding prostate biopsy.
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13. Canadian Task Force on Preventive Health Care
Screening for Prostate Cancer:
● For men aged less than 55 years, we recommend not screening for prostate cancer with the prostate-specific antigen test.
(Strong recommendation; low quality evidence)
● For men aged 55–69 years, we recommend not screening for prostate cancer with the prostate-specific antigen test.
(Weak recommendation; moderate quality evidence)
● For men 70 years of age and older, we recommend not screening for prostate cancer with the prostate-specific antigen test.
(Strong recommendation; low quality evidence)
The U.S. Preventive Services Task Force (USPSTF)
● Recommends against prostate-specific antigen (PSA)-based screening for prostate cancer.

14. Guideline Statement 1:
The Panel recommends against PSA screening in men under age 40 years.
Guideline Statement 2:
The Panel does not recommend routine screening in men between ages 40 to 54 years at average risk.
For men younger than age 55 years at higher risk (e.g. positive family history or African American race), decisions should be individualized.
Guideline Statement 3:
Panel strongly recommends shared decision-making for men age 55 to 69 years that are considering PSA screening based on a man's values
and preferences.
Weigh the benefits of preventing prostate cancer mortality in 1 man for every 1,000 men screened over a decade against the known potential
harms associated with screening and treatment.
The greatest benefit of screening appears to be in men ages 55 to 69 years.
Guideline Statement 4:
To reduce the harms of screening, a routine screening interval of two years or more may be preferred over annual screening
Preserve the majority of the benefits and reduce overdiagnosis and false positives.
Can be individualized by a baseline PSA level.
Guideline Statement 5:
The Panel does not recommend routine PSA screening in men age 70+ years or any man with less than a 10 to 15 year life expectancy.
Some men age 70+ years who are in excellent health may benefit from prostate cancer screening.
American Urology Association Guidelines: