UNIVERSITY OF CALGARY

UNIVERSITY OF CALGARY
Prostate Specific Antigen Testing and Prostate Specific Antigen Velocity for the Screening of
Prostate Cancer
by
William Wayne Gorday
A THESIS
SUBMITTED TO THE FACULTY OF GRADUATE STUDIES
IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE
DEGREE OF MASTER OF SCIENCE
GRADUATE PROGRAM IN MEDICAL SCIENCE
CALGARY, ALBERTA
MAY, 2015
© William Wayne Gorday 2015
Abstract
Prostate specific antigen (PSA) testing for the screening of prostate cancer is
controversial with medical and governmental organizations issuing contradictory statements
regarding its use. My research looked at the utilization of the PSA test for the screening of
prostate cancer in Calgary, Alberta for 2011 and if sociodemographic factors influenced the rate
of testing. I studied whether PSA velocity is better than a single PSA test in predicting prostate
biopsy outcome and if sub-dividing Gleason score 7 prostate cancers improves the predictive
ability of PSA tests. My research found that PSA testing does not follow official guidelines in
younger men and that certain sociodemographic factors do influence the rate of PSA testing. I
found that PSA velocity is not better than the PSA test in predicting prostate biopsy diagnosis
and that sub-dividing Gleason score 7 prostate cancers can increase the clinical utility of the PSA
test.
1
Preface
The following publications and presentation are based on work found in the thesis.
1. Gorday W, Sadrzadeh H, de Koning L, Naugler C. Association of sociodemographic
factors and prostate-specific antigen (PSA) testing. Clinical Biochemistry, 2014.
2. Gorday W, Sadrzadeh H, de Koning L, Naugler C. Prostate-specific antigen velocity
is not better than total prostate-specific antigen in predicting prostate biopsy
diagnosis. Submitted to Clinical Biochemistry
3. Gorday W, Sadrzadeh H, de Koning L, Naugler C. Association of sociodemographic
factors and prostate-specific antigen testing. Poster presentation, University of
Pathology, Department of Pathology and Laboratory Medicine Annual Residents‟ &
Graduate Students‟ Research Day, 07 Nov 2014.
2
Acknowledgements
I would like to thank my thesis committee members Dr. Christopher Naugler, Dr.
Lawrence deKoning and Dr. Hossein Sadrzadeh for their time and effort in ensuring the success
of this thesis. Specifically I would like to acknowledge my thesis supervisor Dr. Christopher
Naugler, whose original ideas, guidance and support made this project possible. I would also like
to thank Calgary Laboratory Services, Dr. Jim Wright and Dr.Amy Bromley for creating and
supporting the Pathologists‟ Assistant program.
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Table of Contents
Abstract .......................................................................................................................... 1
Preface ............................................................................................................................ 2
Acknowledgements ......................................................................................................... 3
Table of Contents ............................................................................................................ 4
List of Tables .................................................................................................................. 6
List of Figures and Illustrations ....................................................................................... 7
List of Symbols, Abbreviations and Nomenclature .......................................................... 8
CHAPTER ONE: INTRODUCTION .............................................................................. 9
1.1 Production and Function of Prostate Specific Antigen ........................................... 9
1.2 Background of Prostate Specific Antigen Testing ................................................ 10
1.3 Findings of the Prostate, Colorectal and Ovarian Cancer trial and the European
Randomised Study of Screening for Prostate Cancer .......................................... 12
1.3.1 Limitations of the Prostate, Colorectal and Ovarian Cancer trial and the European
Randomised Study of Screening for Prostate Cancer .................................... 14
1.4 Recommendations Regarding Prostate Specific Antigen Testing ......................... 16
1.5 Background of Prostate Specific Antigen Velocity .............................................. 17
1.6 Recommendations Regarding Use of Prostate Specific Antigen Velocity ............. 19
1.7 Prostate Cancer Statistics ..................................................................................... 20
1.8 Research significance and Contributions.............................................................. 21
CHAPTER TWO: ASSOCIATION OF SOCIODEMOGRAPHIC FACTORS AND
PROSTATE-SPECIFIC ANTIGEN (PSA) TESTING .......................................... 24
2.1 Introduction ......................................................................................................... 24
2.2 Methods .............................................................................................................. 26
2.2.1 Ethics statement .......................................................................................... 26
2.2.2 Study population and data sources ............................................................... 26
2.2.3 Statistical Analysis ...................................................................................... 27
2.3 Results ................................................................................................................ 28
2.4 Discussion ........................................................................................................... 40
2.5 Conclusion .......................................................................................................... 44
CHAPTER THREE: PROSTATE-SPECIFIC ANTIGEN VELOCITY IS NOT BETTER
THAN TOTAL PROSTATE-SPECIFIC ANTIGEN IN PREDICTING PROSTATE
BIOPSY DIAGNOSIS. ........................................................................................ 45
3.1 Introduction ......................................................................................................... 45
3.2 Methods .............................................................................................................. 47
3.2.1 Ethics statement .......................................................................................... 47
3.2.2 Study population and data sources ............................................................... 47
3.2.3 Statistical Analysis ...................................................................................... 48
3.3 Results ................................................................................................................ 50
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3.4 Discussion ........................................................................................................... 60
3.5 Conclusion .......................................................................................................... 63
CHAPTER FOUR: CONCLUSION AND FUTURE RESEARCH ................................ 64
4.1 Conclusion .......................................................................................................... 64
4.2 Other PSA derived screening tests and Future Biomarkers ................................... 68
4.2.1 Other PSA derived screening tests ............................................................... 68
4.2.2 Future Biomarkers ....................................................................................... 70
REFERENCES ............................................................................................................. 74
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List of Tables
Table 1: PSA testing by age group for the city of Calgary in 2011 ............................................. 28
Table 2: Frequency of PSA testing of the male population in the City of Calgary for 2011 ........ 29
Table 3: Likelihood of receiving a PSA test based on sociodemographic factors ....................... 30
Table 4: Summary of median values for age, total PSA before biopsy and PSA velocity ........... 51
Table 5: Percentage of Gleason scored prostate cancers ............................................................. 52
Table 6: Areas under the curve (AUC) for different PSA velocity calculation methods ............. 53
Table 7: Areas under the curve for multivariable models ........................................................... 58
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List of Figures and Illustrations
Figure 1: Hot spot map of PSA testing rates Calgary, Alberta.................................................... 32
Figure 2: Hot spot map of PSA testing rates Calgary, Alberta.................................................... 33
Figure 3: Hot spot map of PSA testing rates Calgary, Alberta.................................................... 34
Figure 4: Hot spot map of PSA testing rates Calgary, Alberta.................................................... 35
Figure 5: Hot spot map of median household income Calgary, Alberta ...................................... 36
Figure 6: Hot spot map of people with university education Calgary, Alberta ............................ 37
Figure 7: Hot spot map of sociodemographic variable 'Black' Calgary, Alberta ......................... 38
Figure 8: Hot spot map sociodemographic variable 'Aboriginal Métis' Calgary, Alberta ............ 39
Figure 9: Receiver operator characteristic curves for all PSA velocity calculations and PSA
value closest to prostate biopsy for Benign vs. All Prostate Cancers .................................. 54
Figure 10: Receiver operator characteristic curves for all PSA velocity calculations and PSA
value closest to prostate biopsy for Benign+Gleason 5-6 Prostate Cancers vs. Gleason 710 Prostate Cancers ........................................................................................................... 55
Figure 11: Receiver operator characteristic curves for all PSA velocity calculations and PSA
value closest to prostate biopsy for Benign+Gleason 5-7(3+4) Prostate Cancers vs.
Gleason 7(4+3)-10 Prostate Cancers .................................................................................. 56
7
List of Symbols, Abbreviations and Nomenclature
Abbreviations
PSA
PLCO
ERSPC
NCCN
DRE
LIS
ROC
AUC
TRUS
TMPRSS2-ERG
miRNA
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Definition
Prostate-Specific Antigen
Prostate Lung Colorectal and Ovarian Cancer trial
European Randomised Study of Screening for
Prostate Cancer
National Comprehensive Cancer Network
Digital Rectal Exam
Laboratory Information System
Receiver Operator Characteristic Curve
Area Under the Curve
Transrectal Ultrasound
Transmembrane Protease, Serine 2-ETS fusion
microRNA
Chapter One: Introduction
1.1 Production and Function of Prostate Specific Antigen
The prostate gland is composed of fibromuscular stroma, and embedded within the
stroma are tubuloacinar glands 1. These glands contain a tall columnar to pseudostratified
columnar epithelium, which produces a slightly acidic fluid that contributes to sperm viability
and motility. Prostatic fluid contributes to 25% of the total volume of semen and contains
glycoproteins, prostaglandins and enzymes. The prostatic fluid is held until ejaculation at which
point the fibromuscular stroma contracts and the fluid is released into the prostatic urethra.
Found within the prostatic fluid is a clinically important molecule called prostate-specific antigen
(PSA). PSA is a 34 kDa serine protease and a member of the kallikrein family. PSA is first
translated as an inactive precursor and then converted to an enzymatically active form by human
kallikrein 2 2. PSA liquefies the seminal coagulum by cleaving the proteins semenogelin I,
semenogelin II and fibronectin, thereby aiding in sperm motility 1,2. The active form of PSA can
form complexes in the semen and serum with α1-antichymotrypsin, protein C inhibitor and α2macroglobulin 2,3. Therefore, PSA is heterogeneous existing in a precursor form, a free
enzymatically active form and a form bound to other molecules. PSA expression is found in both
normal and neoplastic prostatic tissue, although the expression can decrease in prostate cancers
that are poorly differentiated 4. PSA can also be found in low levels outside the prostate in
paraurethral and anal glands 3. It has also been detected in the serum of women with breast
cancer, lung cancer and uterine cancer 4,5. Normally the prostatic epithelium secretes PSA into
ducts which drain into the urethra. However, if there is a disruption to the normal architecture of
these cells as seen in prostate cancer, benign prostatic hyperplasia and prostatitis, the PSA can
9
diffuse into the surrounding stroma and small blood vessels thereby entering the circulation at
increased levels 4.
1.2 Background of Prostate Specific Antigen Testing
Human PSA was first identified in 1970 by Ablin, Soanes, Bronson and Witebsky 6,7.
These authors discovered two proteins that were unique to the human prostate. The first antigen
was identified as prostatic acid phosphatase, which had already been described by Kutscher and
Wolbergs in 1935 while the second antigen required further characterization 6,7. In 1979 Ming C.
Wang and Tsann Ming Chu isolated and characterized the second antigen, which they originally
called „prostate antigen‟. Through additional research it was believed that the antigen was
specific to the prostate and the term „prostate-specific antigen‟ was coined 7. Building upon the
work of Wang and Chu, Lawrence D. Papsidero (1981) demonstrated that PSA was present in
the serum of men with prostate cancer 8. This paved the way for studies involving PSA as a
biomarker for prostate cancer and in 1987, Stamey et al. published a paper in The New England
Journal of Medicine titled “Prostate-Specific antigen as a Serum Marker for Adenocarcinoma of
the Prostate” 9.
Stamey et al. (1987) reported that serum PSA levels increased as the clinical stage of the
prostate cancer increased and that the serum PSA level was proportionate to the estimated
volume of the tumour. The authors also found that the serum PSA level dropped to undetectable
levels (half life of 2.2 days) after radical prostatectomy for prostate cancer and that it could be
used to monitor the response to radiotherapy or to detect recurrent disease. However, Stamey et
al. also found that serum PSA levels could be increased in the absence of cancer due to benign
prostatic hyperplasia, prostate massage and after needle biopsy 9. While the authors proved that
PSA is a more sensitive biomarker for prostate cancer than prostatic acid phosphatase, they also
10
demonstrated that it lacked specificity. The authors noted that the poor specificity of PSA would
limit its ability to be used as a prostate cancer screening test. Despite this, follow up studies
demonstrated that serum PSA could be useful as an early detection test for prostate cancer
compared to the digital rectal exam which was the current method of early prostate cancer
detection at the time 10,11. Catalona et al. (1993) demonstrated that serial screening with the PSA
test almost doubled the number of organ confined prostate cancers at first detection compared to
screening by the digital rectal exam 12. While the specificity of PSA in this study was better than
the specificity of the digital rectal exam, it was still low ranging from 37% to 63%, depending on
the age group studied. Consistent with these findings, Brawer et al. (1992) concluded that PSA
testing improved the early detection of prostate cancer compared to the digital rectal exam alone,
nevertheless they cautioned that randomized clinical trials were necessary to conclude whether
early detection by PSA screening would decrease prostate cancer mortality rates 11. Despite the
lack of specificity and randomized controlled trials the FDA approved PSA as a blood test for the
screening of prostate cancer in 1994 and since then, it has become one of the most highly utilized
tumour marker tests available 5. After the introduction of the serum PSA test for prostate cancer
screening, it was hypothesised that there should be a resulting increase in the incidence of
prostate cancer. Also, the new cases being diagnosed should be at a younger age, earlier stage on
average and there should be a reduction in mortality 13. Some of these predictions were
demonstrated by Jacobsen et al. (1995) who studied prostate cancer data from Olmsted County,
Minnesota from 1983 through 1992 13.
The serum PSA test was adopted by the Olmsted County medical profession in 1987 so
the data set allowed the researchers to analyze the changes in prostate cancer diagnosis before
and after the introduction of the serum PSA test. The authors found that there was a twofold
11
increase in prostate cancer incidence from 1987 to 1988 and a 3.4 fold increase from 1987 to
1992. The incidence of prostate cancer in the 70 years and older age group initially increased but
began to decline after 1990. The authors noted that this decline was probably due to the depletion
of undiagnosed prostate cancers in this age group as well as an expected shift from detection at
older ages to younger ages as the serum PSA test detects the disease earlier in its course. As a
result of earlier detection, the study demonstrated that fewer men were presenting with advanced
and metastatic disease. Interestingly, the authors also identified an increasing trend of aggressive
treatment for prostate cancer which included an increase in the number of radical prostatectomies
and radiation treatments. This fact highlights one of the controversies which surrounds the PSA
test as a screening test for prostate cancer. At the time of the Jacobsen et al. (1995) study, there
was insufficient data to comment on whether aggressive treatment of organ confined or early
stage prostate cancer would decrease mortality rates. A major reason to have a screening
program for cancer is to reduce the mortality and morbidity associated with the disease which
should offset the costs associated with the screening program. Treating men unnecessarily
increases morbidity and is an inefficient use of health care resources. Two large randomised
trials, the Prostate, Colorectal and Ovarian Cancer trial (PLCO) and the European Randomised
Study of Screening for Prostate Cancer (ERSPC) set out to analyze whether PSA screening
actually improved patient outcomes.
1.3 Findings of the Prostate, Colorectal and Ovarian Cancer trial and the European
Randomised Study of Screening for Prostate Cancer
The Prostate, Colorectal and Ovarian Cancer trial (PLCO) was a randomized controlled
trial that included 76,685 men between the ages of 55-74 years. The men were recruited between
November 1993 and July 2001 and were randomly placed into a testing group (annual PSA
12
testing or digital rectal exam) and a control group. The screening occurred for six years and
concluded in October 2006 14. Follow up of the patients after seven and ten years showed no
reduction in mortality for the PSA testing group compared to the control group. After thirteen
years of follow up, Andriole et al. found a statistically significant 12% relative increase in the
incidence of prostate cancers but a statistically non-significant decrease in the incidence of high
grade prostate cancer in the PSA testing group 14. The authors found no statistically significant
difference between the cumulative mortality rates from prostate cancer between the screening
group and the control group (usual care with some opportunistic screening). The findings of
increased incidence of prostate cancer in the screening group with no benefit in mortality
reduction is concerning, as some of the men in the screening group were being treated
unnecessarily. In fact, the study found that of the “4250 prostate cancer case patients diagnosed
in the intervention arm, 455 (10.7%) had died of causes other than prostate, lung and colorectal
cancer by 13 years” 14. While the PLCO study has not shown any benefit in mortality from
screening for prostate cancer the ERSPC study has.
The ERSPC study began in 1991 and included the Netherlands, Belgium, Sweden,
Finland, Italy, Spain and Switzerland. The study used a total of 182,160 men between the ages of
50 and 74, with 162,388 of the men part of a “predefined core age group” 15. The participants
were randomly placed into a screening group which received a PSA test every four years and a
control group with no screening. After nine, eleven and thirteen years, follow up studies were
done on the core age group to determine the mortality from prostate cancer. During the most
recent 13 year follow up study the authors found a 21% relative reduction in the risk of death
from prostate cancer for the screening group and an absolute risk reduction of 1.28 prostate
cancer deaths per 1000 men16. The number needed to diagnose decreased over the follow up
13
studies from 48 at 9 years, 35 at 11 years and 27 at 13 years. There was no decrease in mortality
for men that were aged 70 and older and screening did not affect all-cause mortality. Also,
Schroder et al. found that the benefit of reduction in prostate cancer mortality should be
considered against the negative aspect of over diagnosis of low grade or latent prostate cancers
15,16
. The PLCO and ERSPC studies have limitations and their findings have been criticised,
which has continued the ongoing controversy surrounding PSA screening.
1.3.1 Limitations of the Prostate, Colorectal and Ovarian Cancer trial and the European
Randomised Study of Screening for Prostate Cancer
Etzioni et al. describe three limitations that randomized trials can have which must be
considered when using the data as a basis for screening policies 17. The first limitation is that
decisions about screening policy require long term information since screening is conducted over
the patient‟s healthy lifetime and often randomized trials are short term. The prostate cancer
mortality rate in the unscreened population at eleven years follow up for the ERSPC study was
low at 0.5 deaths per 1000 people. The ERSPC study found a significant relative reduction of
21% but since the disease-specific mortality was low the difference in rates was equal to 0.1
deaths per 1000 which meant only 1.07 lives were saved per 1000 men screened. If the study
participants are followed until they die or reach an age where screening is no longer
recommended, the disease-specific mortality should show increases close to the lifetime
probability of death from prostate cancer 17. This means that the number of lives saved per 1000
would increase. The authors also demonstrate that short term analysis can distort the estimates of
screening harm in regards to over diagnosis. In the 2009 follow up study of the ERSPC, they
found that 48 cases of prostate cancer needed to be detected to save 1 life and this figure had
been used to illustrate the high ratio of harm to benefit. However, in the 2011 follow up study of
14
the ERSPC, the number dropped to 37 and when Etzioni et al. applied the ERSPC data to long
term models using US population data, they found that the number of cancers needed to be
detected to save one life was 7.6 17.
The second limitation is that the results of randomized trials can be skewed by the
population and the amount of compliance within the trial groups. The PLCO study found no
reduction in mortality for the screened group but the trial began in 1993, after PSA screening had
been adopted by many areas in the US. This meant that many men in the control group had
already received a PSA test and further review found that 74% of men in the control group
received at least one PSA test during the study, with half being tested every 1-2 years. The
presence of screening contaminated the control group and researchers found that the incidence of
prostate cancer in the control group was 20% higher than the general population, suggesting that
the control group may have been screened more intensively than the general US male population.
Gulati et al. used models to conduct virtual PLCO trials to infer what the impact of the
contamination of the control group was on the results. The authors found the contamination
increased the chance of mortality in the screening group and decreased the power to detect a
difference in mortality between the two groups from 40-70% to 9-25% 18. The population used
for the study and the lack of compliance by the control group limited the conclusions that could
be drawn from the results of the PLCO study, especially the result that there was no difference in
mortality between the intervention arm and the control group.
The third limitation of randomized trials that Etzioni et al. cite is that inferences about
screening benefit from the study are only in regards to the screening rules that were being used in
the study. Screening strategies outside the study, which may improve sensitivity and specificity
of clinically relevant prostate cancers, cannot be assessed based on the trial results. Therefore,
15
the use of age specific PSA level cut offs, PSA velocity, PSA density, free PSA, complexed PSA
and various other forms of PSA or blood analytes in conjunction with total PSA levels cannot be
inferred based on the PLCO and ERSPC data. This being said, governmental and medical
organizations have issued statements regarding the PSA test as a screening test for prostate
cancer depending on how they have interpreted the data from the PLCO and ERSPC trials.
Different interpretations of the results have led to contradictory statements that continue to fuel
the controversy surrounding the PSA test.
1.4 Recommendations Regarding Prostate Specific Antigen Testing
In Alberta, the Toward Optimized Practice group is responsible for recommendations
regarding PSA testing as a screening test for cancer 19. This group does not recommend the PSA
test as a mass population screening test; however, they do encourage individualized screening,
which they define as being initiated by the individual or the physician. They recommend that this
process should begin at the age of 50 for asymptomatic, average risk men with a life expectancy
of 10 years or more and who have been educated about the pros and cons of PSA screening.
Routine screening is not recommended for average risk men aged 40-49; unless, men in this age
group have a family history of prostate cancer or are of African-Canadian descent. The Toward
Optimized Practice group also lists age adjusted PSA values which are considered normal
instead of employing a single PSA cut off for all ages. Serum PSA levels rise as men age and by
using age-adjusted thresholds, the positive predictive value of PSA testing is increased 19. The
Canadian Urological Association supports individualized screening and lists many of the same
guidelines as the Towards Optimized Practice group 20. The Canadian Urological Association
does not list general or age specific cut point values as PSA levels and risk of prostate cancer are
continuous. The Canadian Urological Association also notes that a baseline PSA test for men
16
aged 40-49 can be beneficial to gauge future prostate cancer risk. Prostate Cancer Canada and
the Prostate Cancer Centre recommend baseline PSA testing in men as young as 40 and if the
man is at high risk for prostate cancer, they recommend a discussion with their physician about
PSA testing before the age of 40 21,22. The National Comprehensive Cancer Network (NCCN)
also recommends baseline testing for men between 45 to 49 years of age 23. The NCCN
recommends routine PSA testing every 1-2 years for men 50-70 years of age but unlike other
organizations they do not use age specific cut offs. They list a PSA greater than >3.0 ng/mL as
being a possible indication for prostate biopsy but not absolute. Other organizations, such as the
Canadian Task Force on Preventive Health Care and the U.S. Preventive Services Task Force, do
not recommend PSA testing as a screening test for prostate cancer irrespective of age
24,25
. These
two groups cite the results of the PLCO and ERSPC studies as a major basis for their decision.
The age difference in guidelines and outright contradictory statements creates confusion for
physicians and patients. A study by Tudiver et al. found that 86% of family physicians believed
that various PSA screening guidelines were conflicting 26 and a survey of men by Squiers et al.
reported that only 13% of respondents planned to follow the U.S. Preventive Services Task Force
recommendation 27. In contrast 54% of respondents planned to disregard the recommendation
and would still ask for a PSA test in the future. The current disagreement regarding PSA
screening guidelines by these organizations and the continued use of the PSA test as a prostate
cancer screening tool underlines the need for continued research in this area.
1.5 Background of Prostate Specific Antigen Velocity
PSA velocity is the rate of change in PSA levels over time and this value has been an area
of research with the aim of improving the detection of prostate cancer and clinically significant
prostate cancers. Similar to the PSA test, PSA velocity is controversial in its role as a screening
17
tool for prostate cancer. Carter et al. (1992) were one of the first groups to identify an association
between the rate of increase in serum PSA and prostate cancer 28. The authors found that a PSA
velocity of 0.75 ng/mL per year or greater was a statistically significant predictor of subjects
with prostate cancer versus those with benign prostatic hyperplasia or normal control subjects.
Four years later, Kadmon et al. (1996) published limitations on the use of PSA velocity as a
predictor of prostate cancer 29. The authors noted that while the results of the Carter et al. (1992)
study were valid, they did not represent a true clinical situation. Kadmon et al. used a larger
population sample (265 men versus 54 men), a shorter observation period and analyzed the PSA
values using two different assays. The authors believed this reflected a more realistic clinical
situation. The authors reported physiological fluctuations in the participant‟s serum PSA levels
and that 12.5% of men had a PSA velocity greater than 0.75 ng/mL in a single year. However,
when the PSA levels were considered over a period of two years, only 0.4% of men had a
consistent PSA velocity greater than 0.75ng/mL per year. The authors also found that the
variation between assays was 7.5% and could be up to 15%, which means that a PSA increase in
one year from 5.0 to 5.75ng/mL may not be significant but simply the “background noise of
inter-assay variability” 29. Kadmon et al. concluded that for PSA velocity to be useful, annual
PSA levels for at least two years would be necessary to distinguish between normal serum PSA
fluctuations versus a progressive increase in serum PSA that may be indicative of prostate
cancer. Some prostate cancers are present in men with serum PSA levels below the abnormal
range and PSA velocity may be a tool that could be used to identify these cancers.
A study by Thompson et al. (2004) used data from the Prostate Cancer Prevention Trial
and found that 15.2% of men with a PSA level below 4.0 ng/mL, with a negative digital rectal
exam, had prostate cancer 30. The authors found that out of these prostate cancer cases, 14.9%
18
were given a Gleason score of 7 or higher. Fang et al. (2002) calculated the PSA velocities of 89
men with serial PSA levels between 2.0 and 4.0 ng/mL and found that the PSA velocity could
help assess which men in this lower PSA range were at risk of developing prostate cancer 31.
Beger et al. (2006) assessed the PSA levels of 4272 men over 10 years and found that the PSA
velocity in men with prostate cancer was significantly greater than in those without 32. The
authors also found that the PSA velocity began to increase six years before a prostate cancer
diagnosis and that the levels were increased in the patients with non-organ confined disease.
However, Vickers et al. (2011) evaluated PSA velocity using participants from the Prostate
Cancer Prevention Trial, which biopsied men at the end of the study regardless of their PSA
level 33. This allowed the researchers to look at the utility of PSA velocity in individuals with
low serum PSA levels, since most men are only biopsied if their serum PSA levels are high. The
authors found that the increase in the area under the curve using PSA velocity was small (0.702
to 0.709) and using PSA velocity as an independent predictor for prostate cancer would result in
a large number of unnecessary biopsies. The method used to calculate PSA velocity has been
shown to affect the PSA velocity result as well as the predictive value and may be why there are
disagreements amongst different studies 34.
1.6 Recommendations Regarding Use of Prostate Specific Antigen Velocity
The Towards Optimized Practice group lists PSA velocity as a possible marker for
prostate cancer and notes that a PSA velocity of ≥ 0.75ng/mL/year should raise the suspicion of
prostate cancer, regardless of the absolute PSA. This means that men with a PSA of <4.0 ng/mL
but a PSA velocity of ≥ 0.75ng/mL/year could be recommended for prostate biopsy19. The
Canadian Urological Association 2011 guidelines lists PSA velocity as a marker which may
improve PSA sensitivity. The group gives age specific cut point values; however, they note that
19
PSA velocity has yet to be identified as an independent predictor of prostate cancer 20. The
American Urological Association states that there is limited evidence regarding the use of PSA
velocity as a screening test for the early detection of prostate cancer and therefore, the group
does not make any recommendations35. The National Comprehensive Cancer Network (NCCN)
mentions PSA velocity but notes that panellists could not agree on a specific PSA velocity value
that should trigger a prostate biopsy23. The majority of panellists did agree that a PSA velocity of
≥0.35ng/mL/year could be considered as a factor for prostate biopsy when the PSA level is
<2.0 ng/mL, nevertheless an elevated PSA velocity alone should not be the deciding factor to
biopsy. Because the Canadian Task Force on Preventive Health Care and the U.S. Preventive
Services Task Force do not recommend PSA testing for the screening of prostate cancer they
obviously do not recommend the use of PSA velocity for early detection of prostate cancer.
1.7 Prostate Cancer Statistics
More Canadians will die from cancer (1 in 4) than any other cause and approximately
half of Canadians will be diagnosed with cancer at some point in their lives 36. Prostate cancer is
the most common cancer in men with a lifetime incidence of 1 in 8 and the Canadian Cancer
Society estimates that prostate cancer will account for 24.1% of new cancers in men diagnosed in
201436. However, after adjusting for changes in age over time the incident rate of prostate cancer
has declined by 3.2% a year since 2006 and the mortality rate has been declining since the mid1990s 36. Prostate cancer is the most common cancer in men but it is only the third most common
cause of cancer death (10.0%) in men. Men have a 1 in 28 lifetime probability of dying from
prostate cancer. Lung cancer (27.0%) and colorectal cancer (12.8%) are the first and second most
common causes of cancer death in males respectively. Prostate cancer is most often diagnosed in
60-69 year old men but mortality due to prostate cancer is highest in men 80 years and older.
20
The five year survival ratio for prostate cancer is 96% which is one of the highest of all cancers.
For comparison, the male five year survival rate for lung and colorectal cancer is 14% and 64%
respectively. A meta-analysis was conducted by Leal et al. using 25 studies that determined the
prevalence of histological prostate cancer at autopsy in men who had no previous history of
prostate cancer37. The study found that across ethnic groups Chinese and Japanese men had
significantly lower incidences of prostate cancer compared to Caucasian and African American
men. While African American men had the highest incidences of prostate cancer at autopsy they
were not statistically significant compared to Caucasian men. The study found that prostate
cancer incidence increased along with age with 1-4% of 20-29 year old men and 41-85% of 9099 year old men presenting with histological prostate cancer 37. Histological prostate cancer was
detected in 7-51% of men aged 50-59 (the wide variation is due to ethnicity) who are most likely
to access the PSA test. This is an important problem concerning screen detected prostate cancers
because some of these cancers will never become clinically significant and should not be treated.
One of the major issues is determining which prostate cancers once detected will benefit from
intervention and which prostate cancers represent indolent disease.
1.8 Research significance and Contributions
There continues to be confusion and debate surrounding the utility of the PSA test as a screening
test for prostate cancer. Currently, the Canadian Task Force on Preventive Health Care and the
U.S. Preventive Services Task Force do not recommend the use of the PSA test as a screening
test for prostate cancer; however, it is one of the most commonly ordered blood tests and the
only cancer biomarker specific for males24,25. Normally, early detection is key for the successful
treatment of cancers; however with prostate cancer the issue is complex. The epidemiologic data
demonstrates that many men over the age of 50 with prostate cancer will die from causes other
21
than prostate cancer 20. This means that many men are being biopsied and treated for the disease
unnecessarily, which not only causes undue harm and stress to the individual but is also an
inefficient use of health care resources. Because the PSA test continues to be used as a screening
test for prostate cancer it is important to analyze the data to make informed decisions about PSA
screening and to see if a better screening strategy can be discovered. In my thesis I hope to add to
this area of research by analyzing a large clinical data set which is unique since there is only one
laboratory service provider for all of Calgary, Alberta, Canada. I will provide a detailed account
of PSA testing practices in this major Canadian city and identify variables that may affect access
to the PSA test. I believe such a detailed analysis of PSA testing for a major Canadian city is
novel, as is the use of ArcGIS software to create hot spot analysis maps of PSA testing. Esoteric
statistical tests or complex statistical analyses can be difficult to interpret clinically and even if
statistical significance is found the question of how does this finding relate to clinical practice
and patient care is not addressed. I hope to deal with these limitations through the use of receiver
operator characteristic curve analysis and a focus on clinical value as opposed to pure statistical
significance. I will use receiver operator characteristic curves to determine whether PSA velocity
increases the ability of the PSA test to predict prostate biopsy outcome. At the very least, if I find
poor predictive power under all aspects analyzed, I will have added to the argument that the PSA
test and or PSA velocity should not be used for the detection of prostate cancer.
The objectives for the thesis are as follows:
1.) Provide a detailed account of PSA testing practices in a major Canadian city (Calgary,
Alberta) and identify variables that may affect access to the PSA test. Because of
conflicting recommendations regarding the use of PSA as a screening test it is important
to understand who is being tested.
22
2.) Review the literature concerning PSA velocity and summarize the most common
calculations for PSA velocity. Use receiver operator characteristic curves for each PSA
velocity calculation and compare the areas under the curve to decide which method is
superior.
3.) Determine whether PSA velocity adds to the predictive value of the PSA test in detecting
benign vs. prostate cancer, benign + Gleason score 5-6 prostate cancers vs. Gleason 7-10
prostate cancers and benign + Gleason 5-7 (3+4) prostate cancers vs. Gleason 7(4+3)-10
prostate cancers.
23
Chapter Two: Association of sociodemographic factors and prostate-specific antigen (PSA)
testing
2.1 Introduction
Use of the prostate specific antigen (PSA) test as a screening test for prostate cancer has
been controversial for many years, with ongoing disagreements amongst medical and
governmental organizations. The Toward Optimized Practice group makes recommendations for
PSA testing within the Alberta Health Care system. They do not recommend the PSA test as a
mass population screening test, however they do encourage individualized screening, which they
define as being initiated by the individual or the physician. They recommend that this process
should begin at the age of fifty for asymptomatic, average risk men with a life expectancy of ten
years or more and who have been educated about the pros and cons of PSA screening. Routine
screening is not recommended for average risk men aged 40-49, unless warranted by a family
history of prostate cancer or if the individual is of African-Canadian descent 19. These
recommendations are also echoed by the Canadian Urological Association 20. However other
organizations, such as, the Canadian Task Force on Preventive Health Care and the U.S.
Preventive Task force do not recommend PSA testing as a screening test irrespective of age
24,25
.
Official recommendations change over time which also adds to the confusion 19,20,24,25,38,39. For
example, the 2009 American Urological Association Best Practice Policy, mentions early
detection and risk assessment in men aged 40 and older 40. In an update published in 2013, the
American Urological Association increased the recommended age to 55 and did not recommend
PSA testing over the age of 69 39. A study by Tudiver et al. (2002) found that 86% of Canadian
family physicians believed that various PSA screening guidelines were conflicting 26. However,
most experts agree that the PSA test should not be offered as a mass population-screening tool
24
for prostate cancer due to its poor specificity. At the heart of this debate is whether PSA
screening should be offered at all or used as a discretionary screening test based on the
circumstances of individual patients. To further complicate matters it has been found that the
media can be a major source of information for patients regarding the PSA test 41, and can
convey an overly simplified message, which may oppose medical literature 42. In an environment
of ever changing guidelines and contradictions it is important to understand current PSA testing
patterns. This is not only true for the well-being of the patient but also in the context of health
care cost containment. Cost containment is becoming increasingly important in the health care
system as medical laboratories are looking to improve efficiency, while maintaining high quality
patient care 43. Unnecessary testing not only increases costs and wastes resources but also puts
patients at increased risk of false positive test results and follow up procedures 44,45. To move
forward on addressing issues of efficiency and patient care it is important to understand how
PSA testing patterns have changed over time and what, if any, sociodemographic variables may
influence PSA testing.
While there have been Canadian studies which have examined PSA testing at the
provincial and national level, few have addressed testing patterns at the municipal level 46-48. In
this paper we address this issue by examining the characteristics of all patients undergoing PSA
tests in Calgary in 2011. We hypothesize that the frequency of PSA testing will have increased,
especially in men <50 years of age, compared to earlier studies conducted in Alberta and that
sociodemographic variables such as age, median household income and ethnicity will influence
PSA testing rates.
25
2.2 Methods
2.2.1 Ethics statement
Ethics approval for this study was received from the University of Calgary Conjoint
Health Research Ethics Board (Ethics ID E-25060).
2.2.2 Study population and data sources
PSA test counts were obtained from the Calgary Laboratory Services‟ Laboratory
Information System (LIS) for the 2011 calendar year. For each PSA test, the individual‟s age,
PSA result and date of test was recorded. If an individual had multiple PSA tests in the year, the
individual‟s age at the time of the first test and the PSA value of the first test were used. For
linkage with sociodemographic variables, results were attributed to census dissemination areas
based on the patient‟s postal code. Census dissemination areas, as defined by Statistics Canada,
are the smallest geographical units used for census data. Following linkage to a census
dissemination area, all potentially identifying information was removed from the dataset.
Any individuals residing in a census dissemination area outside of the city limits of
Calgary were excluded. Also, any individuals who received three or more PSA tests from
January 1 to December 31 were removed from the dataset. This was done to eliminate
individuals that may be receiving PSA tests for post prostate cancer care or for reasons other than
routine screening. To control for age we divided the men in each Calgary dissemination area into
five age groups, which matched the age groups used by Census Canada (<40, 40-49, 50-59, 6069 and ≥70). Given that Calgary Laboratory Services is the only testing laboratory in Calgary,
Alberta, the data from Calgary Laboratory Services‟ Laboratory Information System represents a
comprehensive view of PSA testing for the city of Calgary. Total PSA tests were performed on a
Cobas® 8000 (e module) using the Cobas® total PSA assay (Roche diagnostics). The assay is
26
sensitive to 0.003µg/L and with dilution, has an upper limit of 5000µg/L. However, in 2011
Calgary Laboratory Services used a minimum value of 0.02µg/L as a reporting standard, so any
values below this were reported as <0.02µg/L in the LIS. For this study values reported as
<0.02µg/L were changed to 0.01µg/L and included as part of the descriptive statistics analysis.
2.2.3 Statistical Analysis
Test utilization data was linked with the 2011 Canada Census data to infer
sociodemographic variables. The following sociodemographic groups were obtained for analysis
from the 2011 Canada Census for each dissemination area in Calgary: recent immigrant status
(immigrated within the last five years), Aboriginal Métis, Aboriginal First Nations, total visible
minority status, visible minority status „Black‟, male employment rate, education level and
median household income. All sociodemographic variables were analyzed independently. There
were 1590 dissemination areas in Calgary for the 2011 Canada Census. Statistical significance
regarding a correlation with frequency of PSA testing and the sociodemographic variables were
tested using Poisson regression with generalized estimating equations to account for the clustered
nature of the data. Statistical analyses were performed using SAS v. 9.2. Results were
considered statistically significant if the P value was <0.05. To calculate the frequency of testing
for each age group in each dissemination area, the number of individuals that received testing
from that age group were divided by the total number of men in that age group for that
dissemination area. These values were then plotted onto a dissemination area map of Calgary for
each age group using ArcGIS software v.9.3, which then was used to produce hot spot analysis
maps. Hot spot analysis maps were also done for the sociodemographic variables median
household income, university education, black and Aboriginal Métis. The software tool uses the
Getis-Ord Gi* statistic 49 which produces z-scores and identifies statistically significant hot and
27
cold spots depending on how many standard deviations the data in a defined area is removed
from the mean. A z-score >1.96 or < -1.96 is equal to a p-value of <0.05 and a z-score >2.58 or <
-2.58 is equal to a p-value <0.01.
2.3 Results
In 2011, 101,650 individual PSA tests were recorded in our LIS, of which 75,914
individual PSA tests met the inclusion criteria. The median PSA value for included tests was
0.93µg/L and the median age at collection was 58 years. The information for 2011 is
summarized in Table 1.
Table 1: PSA testing by age group for the city of Calgary in 2011
Age Groups
<40
40-49
50-59
60-69
≥70
Total testing population
28
Median PSA
Result µg/L
0.67
0.72
0.87
1.13
1.51
0.93
Number
of Tests
1436
14400
26510
20104
13464
75914
Percent
Tested
1.9
19.0
34.9
26.5
17.7
100
PSA testing rates for each age group are summarized in Table 2.
Table 2: Frequency of PSA testing of the male population in the City of Calgary for 2011
Age group
PSA Tests
25-39
40-49
50-59
1397
14400
26510
Total Male
Population
147440
96310
86460
60-69
≥70
Total male population ≥25
Total male population ≥50
20104
13464
75875
60078
46825
34645
411680
167930
Percent Tested
43
39
18
36
0.95
15
31
Visible minority status „Black‟ (as self reported to Census Canada; RR=0.49, P=0.0002),
and Aboriginal Métis (RR=0.36, P=0.0075) were less likely to receive a PSA test. Total visible
minorities, recent immigrant status (moved to Canada within five years of the census), male
employment rate, and Aboriginal First Nation status were not associated with variations in
testing rate. For every increase of $100,000 in household income there was a statistically
significant increase in PSA testing (RR=1.26, P=<0.0001). Having a university education
(RR=1.42, P=<0.0001) versus no university education was also associated with increased PSA
testing. Compared to the age group ≥70 there was a statistically significant decrease in testing for
all age groups with the exception of the 60-69 age group which had a higher rate of testing. The
sociodemographic associations with PSA testing are summarized in Table 3.
29
Table 3: Likelihood of receiving a PSA test based on sociodemographic factors
Sociodemographic
Variable
Recent Immigrant
Aboriginal Métis
Aboriginal First Nations
Visible Minority Black
Total Visible Minorities
Male Employment rate
University Education
Median Household Income1
Age group <40
Age group 40-49
Age group 50-59
Age group 60-69
Age group ≥70
Parameter
Estimate
0.29
-1.03
-0.02
-0.71
0.01
-0.02
0.35
0.23
-4.26
-0.99
-0.27
0.07
95% Confidence
Limits
-0.23
0.82
-1.79
-0.28
-0.53
0.50
-1.09
-0.34
-0.10
0.12
-0.18
0.14
0.18
0.52
0.18
0.28
-4.32
-4.19
-1.02
-0.95
-0.30
-0.24
0.05
0.10
control
Z score
1.1
-2.67
-0.06
-3.74
0.17
-0.22
4
9.09
-134.16
-55.8
-18.28
5.02
P value
0.27
0.01
0.95
<0.01
0.87
0.83
<0.01
<0.01
<0.01
<0.01
<0.01
<0.01
Relative Risk
0.36
0.49
1.42
1.26
0.01
0.37
0.76
1.08
ArcGIS „hot spot‟ analysis maps were created for the sociodemographic variables that were
found to statistically influence the rate of PSA testing. The ArcGIS „hot spot‟ analysis maps of
1
Per $100,000 CDN increase in household income
30
the age groups 40-49(Figure 1), 50-59(Figure 2), 60-69(Figure 3) and ≥70(Figure 4) show that
there is significant variance in testing rates throughout the city. The age groups 40-49, 50-59 and
60-69 have similar PSA testing patterns. These age groups show pockets of increased testing in
newer neighbourhoods in the northwest and south, with relatively lower testing in the northeast
quadrant of the city. The age group ≥70 also shows increased testing in the northwest quadrant of
the city but reduced testing in the city centre. ArcGIS „hot spot‟ analysis maps of median
household income show pockets of increased median household income aggregating in the
northwest, west and southwest quadrants of the city while households with lower income
aggregate in the central and northeast quadrant of the city (Figure 5). Mapping the
sociodemographic variable university education roughly splits the city in half with a statistically
increased amount of individuals with university education living in the northwest and a
statistically significant amount of individuals without university education living in the northeast
and southeast areas of the city (Figure 6). The sociodemographic variables „Black‟ (Figure 7)
and „Aboriginal Métis‟ (Figure 8) show similar areas of increased numbers in the northeast and
far south of the city. The African Canadian demographic also has a pocket of greater numbers in
the far north end of the city and reduced numbers in neighbourhoods in the northwest and
southwest. There are fewer Aboriginal Métis living in the central or downtown portion of the
city.
31
Figure 1: Hot spot map of PSA testing rates Calgary, Alberta
32
Figure 2: Hot spot map of PSA testing rates Calgary, Alberta
33
Figure 3: Hot spot map of PSA testing rates Calgary, Alberta
34
Figure 4: Hot spot map of PSA testing rates Calgary, Alberta
35
Figure 5: Hot spot map of median household income Calgary, Alberta
36
Figure 6: Hot spot map of people with university education Calgary, Alberta
37
Figure 7: Hot spot map of sociodemographic variable 'Black' Calgary, Alberta
38
Figure 8: Hot spot map sociodemographic variable 'Aboriginal Métis' Calgary, Alberta
39
2.4 Discussion
This paper provides a detailed description of PSA testing patterns for males in the City of
Calgary, Alberta in 2011. The 60-69 age cohort had the highest testing rate at 43%, followed by
men aged ≥70 at 39%. Interestingly, 15% of males aged 40-49 underwent a PSA test, a group
which only has a 0.2% lifetime probability of developing prostate cancer in the next 10 years 50.
Aboriginal Métis and visible minority blacks had a decreased probability of receiving a PSA test
compared to the general population. Conversely, an increase in median household income or a
university education were independently associated with an increased probability of receiving a
PSA test.
Published guidelines for PSA testing in Alberta 19 recommend individualized screening
beginning at the age of 50 for asymptomatic, average risk men with a life expectancy of 10 years
or more and who have made an educated choice about PSA screening. PSA screening may be
offered to younger men who are of black ethnicity or those with a family history of prostate
cancer. However, other organizations at the time the data was collected, such as the Canadian
Task Force on Preventive Health Care and the U.S. Preventive Services Task Force concluded
that the evidence was insufficient to recommend PSA screening for prostate cancer in men over
50 years of age 24,51. Two studies have suggested that looking at the age group just before
guideline cut off is an appropriate way to monitor screening guideline compliance and note that
there should be little to no testing in the age groups preceding the cut off age 52,53. Our finding
that there is testing occurring in younger men suggests that official guidelines at the time were
not being followed in many instances. This being said, in 2009 the American Urological
Association updated its PSA Best Practice Policy, lowering the recommended age of testing from
50 years to 40 years 40. Therefore, it is unclear whether this trend is being driven by patient self40
advocacy, as has been shown in other studies 26,41,54,55 or by organizations such as the American
Urological Association which supported testing in younger men at the time.
Hot spot analysis maps of each age group (Figures 1-4) revealed heterogeneous testing
patterns in the city. The age groups 40-49, 50-59, and 60-69 demonstrated similar testing
patterns and represent the majority of PSA testing done in Calgary. All three of these age groups
had significant areas of relatively increased testing in the northwest and south with significant
areas of relatively decreased testing in the northeast. The area of decreased PSA testing in the
northeast quadrant of the city also overlaps with areas of lower median household income
(Figure 5), lower university education rate (Figure 6), and increased numbers of visible
minorities and Aboriginal Métis (Figure 7 and 8). Therefore, it is not surprising that this area of
the city has a lower PSA testing rate given that multiple sociodemographic variables that
influence the frequency of PSA testing aggregate in this location. Other studies in Canada, the
United States, and England have also identified income, education and increasing social
deprivation as factors that affect the frequency of PSA testing 47,48,56-60. A vitamin D study by
Naugler et al. (2013) mapped sociodemographic variables for each dissemination area in Calgary
and also found similar sociodemographic trends 61. Naugler et al. found that higher education and
income clustered in the northwest and southwest quadrants, while new immigrants and
aboriginal people clustered in the northeast and some inner city neighbourhoods. These authors
included individuals with postsecondary education (not university exclusive), which
demonstrated increased numbers in the south and southwest quadrants. These dissemination
areas correspond to the areas of increased testing that we found for the men aged 40-69 in the
south of Calgary and may help explain the observed testing pattern when combined with the
increased median household income also found in this southern area of the city. Another factor
41
that could explain the difference in PSA testing across the city is access to family physicians. A
study by Bissonnette et al. (2012) used ArcGIS software to map health care accessibility in
Mississauga, Ontario, Canada 62. The study found that there were some neighbourhoods with
high health care access and others with low health care access. The authors also demonstrated
that some neighbourhoods with high recent immigrant populations had lower access to
physicians accepting new patients. In the future it would be beneficial to do a similar analysis for
the city of Calgary and to see if there is an association between reduced PSA testing and access
to health care. Interestingly a study by Quan et al. based on the 2001 Canadian Community
Health Survey found that visible minorities were more likely to visit a general practitioner than
Caucasians but were less likely to undergo PSA testing or other cancer screening tests 63.
Three prior studies have examined sociodemographic factors associated with PSA testing
in Alberta, Canada 46-48. Comparing those studies with ours provides a picture of PSA testing in
Alberta over a fifteen year time period. The earliest study looked at data from a 1996 survey of
Alberta men 46, the second study was based on the Canadian Community Health Survey from
2000-2001 47, and the third study used data from the 2000-2003 Alberta Tomorrow Project 48.
The 1996 study reported that for the age groups 40-49, 50-59 and 60-74 the percentage of men
who had received a PSA test was 4.5%, 13.1% and 22.2% respectively. These values are
considerably lower than our data from 2011; however, at this time the PSA test had only been
available for six years and the study also found that awareness of the PSA test was low with less
than half of men reporting that they had heard of the test. This study also found that out of a
subset of men that had reported hearing of the PSA test, the frequency of testing rose across the
age groups (40-49, 50-59 and 60-74) and was much higher at 16.8%, 32.7% and 49.4%
respectively. Interestingly these values are much closer to our findings and indicate that an
42
increase of public awareness about the existence of the PSA test from 1996 to 2011 may account
for the increase between the two time periods. The 2000-2001 survey used the same age groups
as our study and found that for the province of Alberta, lifetime PSA screening was 14.6%,
31.3%, 39.8% and 40.4%, for the age groups 40-49, 50-59, 60-69 and ≥70, respectively. These
values are very close to the yearly testing rates we report but represent lifetime PSA testing rates
and therefore are likely much lower than our rates.
This finding is in keeping with a study comparing PSA testing in Ontario from 1995 to
2002, which also found an increase in PSA testing 64. Likewise, Melia, Moss and Johns found a
statistically significant increase in PSA testing from 1999 to 2002 in England and Wales 56. The
above studies, as well as studies conducted in the United States and England
56-60,65
, looked at
age and various sociodemographic variables that might influence PSA testing rates. All studies
found that increasing age was associated with increased testing and we found a similar trend with
the exception of the 60-69 cohort which had increased testing compared to the ≥70 cohort. The
reduction in testing in the ≥70 group may be due to guidelines which do not recommend PSA
testing in men whose life expectancy is 10 years or less 19,20. Many prior studies reported
increasing income 47,48,57,60 and education 47,57-60 as independent variables associated with
increased testing although there was variation amongst the studies. Published results associated
with ethnicity or immigrant status were discrepant, from decreased testing 47,56, to no difference
48
, to increased testing 57. This variation may be due to variations in ethnic populations and the
sociodemographic characteristics of those populations. For example, the study conducted by
Eisen et al. was done on a male veteran population and they point out that their minority group
may have higher wages, education and increased access to health care compared to other
minority populations 57. We found that the visible minority status of „Black‟ and Aboriginal
43
Métis status are significant predictors of decreased testing while the Canadian study by Beaulac
et al. 47 did not find Aboriginal or black ethnicity to be predictive of PSA testing. African
ancestry is a known risk factor for prostate cancer and has also been associated with higher
prostate cancer mortality rates 59,66.
There are several weaknesses to our study. Despite our efforts to the contrary our data
undoubtedly contains individuals who are being tested as part of post-prostate cancer care or are
presenting with urological symptoms due to benign prostatic hyperplasia or prostatitis and
therefore the data may not represent a homogenous screening population. We tried to address
this issue by removing anyone that had more than two tests in a calendar year. Likewise, we
could not address the issue of PSA testing for urological symptoms. We were not able to identify
individuals who are being tested annually because of a family history of prostate cancer. Because
we looked at the number of tests in a single year we are not able to comment on the lifetime
incidence of PSA testing.
2.5 Conclusion
Our data suggests that PSA testing patterns did not align with many guidelines for
younger men at the time the data was collected. The results show that the PSA test is not equally
utilized by all males in Calgary, Alberta and its use is positively associated with median
household income, education, and negatively associated with Aboriginal Métis and „Black‟
visible minority status. Understanding current testing patterns is important in assessing the
benefit to harm ratio of PSA testing and for monitoring impact to the health care system. Testing
in younger, lower risk men may shift the harm:benefit ratio further to the harm side biasing
future decisions. This should be considered by physicians, patient advocacy groups and policy
makers when examining the utility of the PSA test as a screening tool.
44
Chapter Three: Prostate-specific antigen velocity is not better than total prostate-specific
antigen in predicting prostate biopsy diagnosis.
3.1 Introduction
Prostate-specific antigen (PSA) velocity has been purported to help differentiate prostate
cancer from benign disease28,67-71. However, other researchers have concluded that PSA velocity
does not increase predictive accuracy when compared to models with other common independent
variables such as family history, age, digital rectal exam (DRE) result and total PSA33,72-76.
Contradictory findings exist not only in the primary literature but also in statements made by
various medical organizations regarding the utility of PSA velocity. The American Urological
Association mentions PSA velocity as a secondary screening tool but does not make a
recommendation for its use35. Other organizations list PSA velocity as a tool for prostate cancer
detection but include references to the debate about its clinical relevance 19,20,23. For instance, the
Canadian Urological Society20 refers to PSA velocity and lists age specific cut offs that improve
sensitivity; however, they caution that some studies have shown that PSA velocity is not an
independent predictor of prostate cancer and it should not be used in isolation to determine the
need for prostate biopsy. Neither the U.S. Preventive Task Force nor the Canadian Task Force on
Preventive Health Care recommends routine PSA testing at all24,51.
Biological and analytical factors can affect PSA levels which can impact the clinical
usefulness of the PSA test and PSA velocity. A study by Soletormos et al. reviewed 27 articles
studying biological variation of the PSA test and found that biological variation in a single PSA
test can vary by 33% with a 1-sided 95% confidence interval77. If the mean of three repeated
PSA tests is used the variation of the 1-sided 95% confidence interval is reduced to 20%. The
45
fact that the individuals „true‟ PSA result can vary has clinical implications if the range crosses a
reported PSA cut off value or mimics an increasing PSA velocity. In some cases external factors
such as fasting times, exercise, sedentary behaviour, ejaculation, prostate manipulation and
hospitalization can affect PSA serum levels but there is disagreement in the literature as to the
amount and clinical significance of these variations78-82. Analytical factors such as the type of
assay used can also affect PSA levels. Semjonow et al. analyzed total PSA levels using seven
different assays and found the different assay methods produced different total PSA values83.
Inter-assay variability has been documented even after calibrating with a standard WHO PSA
reference material and in some cases the variation can impact clinical decisions 84. Inter-assay
variability can be limited by using one biochemistry laboratory that uses a single type of PSA
assay so that results are not being compared between different assays. Intra-assay variability
(inherent variation in the test) is usually small and normally less than the intra-individual
variation. Unlike random biological variation intra-assay variability can be monitored by the
laboratory to ensure that it remains within guidelines85. All of these factors contribute to
variability in the PSA result which means that changes between PSA measurements must be
large enough to differentiate normal variation from pathological variation.
To complicate the issue further, there are many ways to calculate PSA velocity with some
authors demonstrating that the calculation method can affect the PSA velocity value 34,86. Because
of these conflicting findings and recommendations our objective for this study was to provide a
new analysis based on a previously unstudied Canadian cohort of men to determine whether PSA
velocity improved the predictive ability of the PSA test. Many of the previously mentioned
studies looked at the ability of PSA velocity to differentiate between Gleason score 2-6 prostate
cancers (low grade) vs. Gleason score 7-10 prostate cancers (high grade). Gleason score 7
46
prostate cancers have been identified as a heterogeneous group with the 3+4 scored prostate
cancers having a better prognosis than the 4+3 scored prostate cancers87,88. We also wanted to
test whether there was increased predictability if only the 4+3 Gleason 7 cancers were included
in the high grade prostate cancer group. To our knowledge other PSA velocity studies have not
further subdivided the Gleason score 7 group in this manner.
3.2 Methods
3.2.1 Ethics statement
Ethics approval for this study was received from the University of Calgary Conjoint
Health Research Ethics Board (Ethics ID E-25060).
3.2.2 Study population and data sources
This study was conducted in Calgary, Alberta, Canada, a unique setting in that the entire
city is serviced by a single laboratory provider (Calgary Laboratory Services) which means that
the data collected by the laboratory information system is representative of the entire city
population and all PSA tests are done at a central location. The Calgary Laboratory Services‟
Laboratory Information System (LIS) was searched for all biopsies with the term „prostate‟ in the
specimen field from January 1, 2009 to December 31, 2013. Only men with a prostate biopsy
were included for analysis (transurethral resection of the prostate and radical prostatectomy
specimens were excluded). In the case of multiple prostate biopsies on one patient the first
biopsy that reported a Gleason scored prostate cancer was used. If there were multiple prostate
biopsies but no diagnosis of prostate cancer then the last recorded prostate biopsy in the LIS was
used. Individuals with a prostate cancer positive biopsy but a history of prostate cancer prior to
2009 were removed. Subjects were removed if they had a history of prior procedures such as
radiation therapy, cryotherapy, green light laser therapy, catheterization, hormone therapy or
47
treatment with finasteride. Subjects with malignancy other than prostate cancer were also
removed. The patient‟s age at the time of biopsy was recorded. All prostate specific antigen
(PSA) results prior to the prostate biopsy were recorded, with a data-availability start date of
January 1, 2007. In order to be included a patient had to have at least two PSA results separated
by at least three months; however, there were no time restrictions on any remaining PSA tests.
All PSA tests were performed on a Cobas® 8000 (e module) using the Roche diagnostics
Cobas® total PSA assay. The assay is sensitive to 0.003µg/L; however, Calgary Laboratory
Services uses a minimum value of 0.02µg/L for reporting. Any PSA values reported as
<0.02µg/L in the LIS were changed to 0.01µg/L for this study. The repeatability coefficient of
variation for the Cobas® ranges from 1.2%-1.7% and the intermediate precision coefficient of
variation ranges from 1.4%-3.7%.
Subjects were divided into five age groups: 40-49, 50-59, 60-69, 70-79 and 80-89. The
age group 80-89 was used for descriptive statistics but not included in the receiver operator
characteristic curve (ROC) analysis as men in this age group are not routinely subjected to PSA
testing due to competing co-morbidities. Based on prostate biopsy diagnosis the data set was
divided into a benign group (all subjects without a cancer diagnosis), a prostate cancer positive
group (all subjects with a Gleason scored prostate cancer), and a Gleason grade 7-10 group. The
Gleason grade 7 prostate cancers were further subdivided into 3+4 and 4+3 groups. Examples in
the literature have shown that 4+3 Gleason 7 prostate cancers are associated with an increased
lethality compared to their 3+4 counterpart87,88.
3.2.3 Statistical Analysis
Four different PSA velocity calculation methods were chosen based on the most common
calculation methods found in twenty-two published studies 29,31,33,67,70,73-75,89-102. Receiver
48
operator characteristic curves (ROCs) were created for each PSA velocity calculation method.
The resulting area under the curves (AUCs) were compared to determine whether one was
superior to the other in differentiating prostate cancer from benign disease or high Gleason grade
prostate cancer from benign or low Gleason grade prostate cancer. The first PSA velocity
calculation was a “two point PSA” method75,91,97,99 which compared the oldest recorded PSA
result against the PSA result closest to the collection of the prostate biopsy [PSA2PSA1/time(years)PSA2-time(years)PSA1]. The second method calculated PSA velocity as the
slope of a linear regression on all PSA values33,67,70,73,74,89,90,92-95,98-100,102. Linear regression is
based on the formula “y=mx+b” where “m” is the slope (PSA velocity) and “b” is the point at
which the line crosses the „Y‟ axis of a graph. To calculate the slope of all PSA values against
time for each subject a macro was created in Microsoft excel. The third PSA velocity calculation
method used the previous described linear regression method but used the natural log value of
the PSA results33,89,90,96,101. The fourth method used linear regression but was restricted to the last
three or two PSA results before biopsy33,67,70,89,92-95,98,99. Percent change in PSA results were also
evaluated with the percent change between the two PSA values closest to the prostate biopsy
considered, as well as the percent change between the oldest PSA value and the PSA value
closest to prostate biopsy [(PSA2-PSA1)/PSA1 x 100].
Descriptive statistics, binary logistic regression and ROCs were performed using IBM
SPSS Statistics version 19. Statistical comparison between two ROCs and their AUCs was done
using SAS Enterprise version 4.3. Results were considered statistically significant with a p value
less than 0.05. Receiver operator characteristic curves (ROC) and the resulting area under the
curve (AUC) were calculated for each PSA velocity calculation method as well as the PSA value
closest to prostate biopsy, the percent change of the two PSA values closest to the prostate
49
biopsy, and the percent change between the oldest and most recent PSA tests. To assess the
combined predictive ability of PSA velocity with other variables, binary logistic regression
models were constructed using various combinations of the previously described PSA velocity
calculation methods along with the other mentioned independent variables. Receiver operator
curves were then generated based on these models.
3.3 Results
There were 9455 men in the LIS with the term „prostate‟ associated with an anatomic
pathology specimen. After excluding subjects who did not meet the criteria 4622 men who had
received a prostate biopsy and were between the ages of 40-89 were included for the study. Out
of the 4622 men, 2212 had a benign diagnosis (47.9%) and 2,410 men had a diagnosis of prostate
cancer (52.1%). Gleason score 7 was the most common (24.4%), followed by Gleason score 6
(22.4%). Out of the Gleason score 7 prostate cancers 842 (75%) were 3+4 and 286 (25%) were
4+3. There was only one prostate cancer (Gleason score 5) with a Gleason score less than six.
Thirty percent of men had prostate cancer with a Gleason score of 7-10 and 5% of men had a
prostate cancer with a Gleason score of 8-10.
Information on digital rectal exam (DRE) was available for 52% of men and transrectal
ultrasound (TRUS) results were available for 55% of men. Out of the DREs reported 18% had an
abnormal result and 15% had an abnormal TRUS reported. The percentage of abnormal DREs
and TRUS increased as the Gleason score increased. For men with a Gleason score 8-10 prostate
cancer, 43% had an abnormal DRE and 35% had an abnormal TRUS. Of the 4622 men, 7% were
aged 40-49, 31% aged 50-59, 42% aged 60-69, 17% aged 70-79 and 3% aged 80-89. The
majority of men had three or more PSA tests (81%) before their prostate biopsy. The median
values of total PSA and PSA velocity increased along with the age group. The median values of
50
age, total PSA and PSA velocity all increased as the Gleason score increased. Table 4
summarizes these median values for the entire data set as well as the benign group, the prostate
cancer positive group, Gleason score 7-10 group, Gleason score 7(4+3)-10 group and the
Gleason score 8-10 group.
Table 4: Summary of median values for age, total PSA before biopsy and PSA velocity
All data
(n=4622)
Benign
group
n=(2212)
All
prostate
cancers
(n=2410)
Gleason
score 7-10
(n=1372)
Gleason
score
7(4+3
only)-10
(n=530)
Gleason
score 8-10
(n=244)
51
Median
Age
Median
Total
PSA(µg/L)
before
biopsy
Median
PSA
velocity
(µg/L/yr)
2 Point
PSA
method
Median PSA
velocity
(µg/L/yr)
linear
regression 3
PSA values
closest to
biopsy
0.62
Median PSA
velocity
(µg/L/yr)
linear
regression
all logPSA
values
0.89
Median
PSA
velocity
(µg/L/yr)
linear
regression
all PSA
values
0.88
62
6.0
60
5.7
0.77
0.76
0.50
0.17
64
6.3
1.00
1.00
0.71
0.21
66
7.0
1.19
1.18
0.86
0.24
69
9.0
1.73
1.67
1.33
0.30
70
10.3
2.30
2.25
1.85
0.39
0.20
As age increased the percentage of prostate cancers compared to benign disease increased and
the percentage of higher Gleason grade prostate cancers also increased. These findings are
summarized in Table 5.
Table 5: Percentage of Gleason scored prostate cancers
Age group
All data (n=4622)
40-49 (n=326)
50-59 (n=1452)
60-69 (n=1934)
70-79 (n=785)
80-89 (n=125)
%Benign vs. All
Gleason Cancers
Benign
48
68
55
46
34
28
Cancer
52
32
45
54
66
72
%Benign +
Gleason 5-6 vs.
Gleason 7-10
Benign
70
91
81
69
51
37
Cancer
30
9
19
31
49
63
%Benign +
Gleason 5-7(3+4)
vs. Gleason
7(4+3)-10
Benign Cancer
89
11
93
7
87
13
90
10
73
27
61
39
The mean time between PSA tests decreased as the number of PSA tests for the
individual increased. For example, the mean time between the first and second PSA test was 12.7
months and the mean time between the fifth and sixth PSA tests was 5.4 months. The majority of
individuals received ≤5 PSA tests (n=3,499) and had a mean time between PSA tests of 8.6
months. The mean time between PSA tests for the data set was 6.5 months.
Markedly higher AUCs were obtained when 3+4 Gleason 7 prostate cancers were
included in the benign group and 4+3 Gleason 7 prostate cancers were included in the malignant
category (Table 6). In all instances PSA velocity calculations were either very modestly better or
inferior to AUCs obtained by considering only the PSA value closest to the prostate biopsy. The
AUCs for all independent variables are summarized in Table 6. The ROCs used to acquire the
AUCs for Table 6 are demonstrated in Figures 9-11.
52
Table 6: Areas under the curve (AUC) for different PSA velocity calculation methods
Independent
variable
Two point PSA
Linear regression all
PSA values
Linear regression 3
PSA values closest to
biopsy
Linear regression all
logPSA values
PSA value closest to
biopsy
% change- 2 PSA
values closest to
biopsy
% change- oldest PSA
value and PSA value
closest to biopsy
53
Benign vs. All
prostate cancers
Benign + Gleason 5-6
vs. Gleason 7-10
AUC
0.574
0.576
95% CI
0.557-0.590
0.559-0.592
AUC
0.621
0.622
95% CI
0.603-0.639
0.604-0.640
Benign + Gleason 57(3+4) vs. Gleason
7(4+3)-10
AUC
95% CI
0.686
0.660-0.713
0.690
0.664-0.716
0.561
0.544-0.578
0.594
0.576-0.613
0.655
0.628-0.682
0.560
0.544-0.577
0.599
0.581-0.616
0.665
0.640-0.690
0.572
0.555-0.588
0.634
0.616-0.652
0.699
0.672-0.726
0.500
0.483-0.517
0.516
0.498-0.534
0.552
0.525-0.578
0.551
0.534-0.568
0.591
0.573-0.610
0.658
0.631-0.686
Figure 9: Receiver operator characteristic curves for all PSA velocity calculations and PSA
value closest to prostate biopsy for Benign vs. All Prostate Cancers
54
Figure 10: Receiver operator characteristic curves for all PSA velocity calculations and
PSA value closest to prostate biopsy for Benign+Gleason 5-6 Prostate Cancers vs. Gleason
7-10 Prostate Cancers
55
Figure 11: Receiver operator characteristic curves for all PSA velocity calculations and
PSA value closest to prostate biopsy for Benign+Gleason 5-7(3+4) Prostate Cancers vs.
Gleason 7(4+3)-10 Prostate Cancers
56
Receiver operator characteristic curves were constructed using the individuals with a
known DRE (n=2,389) and resulted in similar AUCs for all the variables when comparing
benign vs. all prostate cancers, however there were increases in the AUCs for all variables when
comparing benign+Gleason 5-7(3+4) vs. Gleason 7(4+3)-10. This being said, the PSA value
closest to prostate biopsy still had similar or better AUCs compared to PSA velocity. A separate
analysis was done on individuals with a negative DRE (n=1,948) and the AUCs were either
similar or decreased for all variables; however, the general trend of PSA value closest to prostate
biopsy being comparable or superior to PSA velocity remained.
Receiver operator characteristic curves employing multivariable models revealed
improved AUCs for all outcome variables. However, as Table 7 shows this improvement was
entirely due to the addition of age to the models. The addition of PSA velocity did not improve
prediction for any of the models (all changes between AUCs were non-significant at a p-value of
0.05, nonparametric Delong, Delong and Clarke-Pearson method)103. Including DRE status in
the models further increased the AUCs for all models (0.026-0.033) but did not improve the
performance of PSA velocity. Using the same multivariable models on only the DRE negative
population produced similar or slightly decreased AUCs and again PSA velocity did not improve
the AUCs in this population.
57
Table 7: Areas under the curve for multivariable models
Independent
variables
In ROC model
PSA value closest to
biopsy + Age
PSA value closest to
biopsy + PSA velocity
(log method)
PSA value closest to
biopsy + Age + PSA
velocity(log method)
PSA value closest to
biopsy + Age + PSA
velocity(linear
regression all points)
PSA value closest to
biopsy + Age + PSA
velocity (Two point
PSA method)
PSA value closest to
biopsy + Age + PSA
velocity (linear
regression 3 PSA
values closest to
biopsy)
58
Benign vs. All
prostate cancers
Benign + Gleason 5-6
vs. Gleason 7-10
AUC
0.612
95% CI
0.596-0.629
AUC
0.680
95% CI
0.663-0.697
Benign + Gleason 57(3+4) vs. Gleason
7(4+3)-10
AUC
95% CI
0.767
0.745-0.790
0.570
0.554-0.587
0.635
0.617-0.652
0.712
0.686-0.738
0.613
0.597-0.630
0.682
0.665-0.699
0.774
0.752-0.797
0.612
0.596-0.629
0.680
0.663-0.697
0.768
0.745-0.790
0.612
0.596-0.629
0.679
0.662-0.697
0.767
0.745-0.790
0.613
0.596-0.629
0.681
0.663-0.698
0.768
0.746-0.791
Independent
variables
In ROC model
PSA value closest to
biopsy + Age + DRE
PSA value closest to
biopsy + PSA velocity
(log method) + DRE
PSA value closest to
biopsy + Age + PSA
velocity(log method)
+ DRE
PSA value closest to
biopsy + Age + PSA
velocity(linear
regression all points)
+DRE
PSA value closest to
biopsy + Age + PSA
velocity (Two point
PSA method) +DRE
PSA value closest to
biopsy + Age + PSA
velocity (linear
regression 3 PSA
values closest to
biopsy) +DRE
59
Benign vs. All
prostate cancers
Benign + Gleason 5-6
vs. Gleason 7-10
AUC
0.645
95% CI
0.623-0.667
AUC
0.696
95% CI
0.673-0.719
Benign + Gleason 57(3+4) vs. Gleason
7(4+3)-10
AUC
95% CI
0.793
0.765-0.821
0.594
0.571-0.616
0.655
0.631-0.679
0.745
0.714-0.777
0.645
0.623-0.667
0.698
0.675-0.720
0.801
0.774-0.829
0.645
0.623-0.667
0.696
0.673-0.719
0.795
0.767-0.823
0.645
0.623-0.667
0.696
0.673-0.719
0.794
0.766-0.822
0.645
0.623-0.667
0.696
0.673-0.719
0.794
0.766-0.822
3.4 Discussion
Four different PSA velocity calculation methods were chosen based on the most common
calculation methods found in twenty-two published studies 29,31,33,67,70,73-75,89-102 . Using the AUC
as the comparison metric we conclude that among velocity calculation methods, linear regression
using all PSA values and the much simpler two point PSA method are equally superior to the
other calculation methods. These findings are similar to those of studies done by Yu et al. 86 and
Connolly et al.34. However, we also conclude that PSA velocity measurements in general did not
increase the predictive accuracy as compared to the most recent PSA level before biopsy.
Moreover, when combined in predictive models with age and the most recent total PSA value
before prostate biopsy, PSA velocity contributed non-significant increases to the AUC.
Furthermore, prostate-specific antigen velocity did not improve AUCs over the most recent PSA
level before biopsy in the DRE negative population.
There has been some controversy in the literature regarding the inclusion of Gleason
grade 7 carcinomas in high or low risk categories. Stark et al. and Rasiah et al. showed that these
cancers had an intermediate behaviour between Gleason ≤6 cancers and Gleason ≥8 cancers.
This appears to be due to Gleason 7 carcinomas being composed of 3+4 and 4+3 scores, which
display very different biological behaviour. Markedly improved AUCs were obtained in our
study when we included 3+4 Gleason cases in the benign category and 4+3 Gleason scores in the
malignant category. This suggests that PSA may be a better predictor of biologically aggressive
carcinomas than it is of non-aggressive disease. While studies have shown clinical importance in
subdividing Gleason 7 prostate cancers other studies have demonstrated inter-observer variability
amongst pathologists diagnosing prostate cancer. This inter-observer variability can result in
changes to the Gleason score which may affect the clinical management and prognosis of the
60
patient. A study by Jara-Lazaro, Thike and Tan compared diagnosis from prostate consultations
that were sent for expert second opinion104. The authors reported a discordant rate of 57% (no
kappa value reported) between original diagnosis and the review diagnosis with the majority of
changes resulting in upgrading of the original diagnosis. The most common upgrade occurred
from Gleason pattern 3 to Gleason pattern 4 which resulted in Gleason sum 6 cases being
upgraded to Gleason 7 prostate cancers. Other studies have also found a similar upgrading of
prostate biopsy diagnosis after review by a pathologist subspecializing in urological
pathology105. The vast majority of prostate biopsy diagnosis in my data set were performed by
urology pathologists at a single hospital; however, inter-observer variability has also been
reported amongst urological pathologists. Allsbrook et al. compared the prostate biopsy
diagnosis between 10 urologic pathologists and found that they agreed on 70% of the cases with
a kappa coefficient ranging from 0.56-0.70 (moderate to substantial agreement)106. The
reproducibility of Gleason score amongst urological pathologists is better than general
pathologists vs. urological pathologists; however, in this study the Gleason grades were grouped
into 2-4, 5-6, 7, and 8-10. The agreement amongst 3+4 and 4+3 Gleason 7 prostate cancers was
not considered. A study by Persson et al. compared the reproducibility of Gleason score in
radical prostatectomy specimens between local pathologists and reference pathologists 107. The
authors looked at the inter-observer variability between Gleason score 3+4 and 4+3 and found a
concordance rate of 38% and 42% respectively, which was much lower than the overall
concordance rate of Gleason score 7 (65%). Because of inter-observer variability there is a
possibility that the proportions of Gleason 3+4 and 4+3 prostate cancers in my data set could
differ if reviewed by other pathologists and affect the results.
61
Previous studies have also demonstrated that PSA velocity does not improve predictive
accuracy of prostate biopsy outcome 33,73-75,92. A 2011 study by Vickers et al.33 analyzed men
from the placebo arm of the Prostate Cancer Prevention Trial who received a prostate biopsy at
the end of the study regardless of their PSA value. The majority of men in this study had a PSA
level <2.0 µg/L at biopsy while the median PSA level before biopsy in our study was 6.0 µg/L.
Despite the differences in our study populations the Vickers et al. study also reported very small
increases in the AUC (maximum 0.01) when PSA velocity was added to either log PSA value
only or a model containing log PSA, family history, DRE and prior biopsy. A study by Ulmert et
al. in 2008 used archived plasma samples from men aged ≤50 which were collected six years
apart for a preventive medicine study in Sweden75. Each man had two blood samples collected
and archived during the original study and Ulmert et al. used the two plasma samples to measure
total PSA and calculate the PSA velocity. The men were followed for over 15 years after the last
blood draw (median of 16 years for men with prostate cancer and median of 21 years for men
without prostate cancer) and their prostate cancer status confirmed through the Swedish National
Cancer Registry. This study also concluded that PSA velocity does not increase the predictive
value of total PSA alone.
The major weakness of this study is that our study population comes from a clinical data
base and is not a randomly selected population. In the clinical setting men do not randomly
receive prostate biopsies and are often referred for biopsy if their PSA tests are elevated or
persistently elevated. There may be men in the city of Calgary with low PSA values who have
not been biopsied but have prostate cancer and in these men PSA velocity values may be more
predictive of prostate cancer. However, the previous mentioned Vickers et al. study did look at
men with low total PSA and did not find a benefit for PSA velocity in this population. Inter62
observer variance amongst pathologists assigning Gleason scores could affect the number of
Gleason 3+4 and 4+3 prostate cancers in the data set and is a limitation. Also, although our study
used four of the most common PSA velocity calculation methods found in the literature, there are
other methods with more restrictive criteria regarding the time allowed between PSA tests.
Another weakness is that our data set does not have information regarding predictive risk factors
for prostate cancer such as ethnicity and family history, as well many individuals were missing
information regarding their DRE status.
Prostate-specific antigen velocity risk count has been proposed to help differentiate
between low grade and high grade prostate cancers. The majority of our data set has individuals
with more than 3 PSA tests and would be suited to a future analysis of the prostate-specific
antigen velocity risk count method.
3.5 Conclusion
PSA velocity does not improve the predictive ability of a single PSA measurement,
regardless of the calculation method used. Dividing Gleason 7 prostate cancers into 3+4 (low
grade) and 4+3 (high grade) increases the AUC and may improve the ability of current models to
differentiate between men with low grade prostate cancer vs. those with high grade prostate
cancer.
63
Chapter Four: Conclusion and Future Research
4.1 Conclusion
The thesis explores the utilization of the prostate-specific antigen (PSA) test as a
screening test for prostate cancer and consists of two parts. The first part addresses how the PSA
test is being utilized as a screening test in an environment of ever changing
guidelines19,20,23,24,35,51. Because there are contradictory statements from organizations it is
important to see what the actual PSA testing rates are for the screening of prostate cancer and
whether there are sociodemographic factors which influence those rates. My study found that the
PSA test is being widely used and that certain sociodemographic factors affect the rate of testing.
Men at the time of the study were accessing the PSA test despite recommendations by the
Canadian Task Force on Preventive Health Care and The U.S. Preventive Services Task Force
not supporting its use 24,51. The Alberta guidelines regarding PSA testing suggested
individualized screening begin at the age of 50 unless risk factors such as a family history of
prostate cancer or African Canadian ancestry warrant earlier testing 19. However, we found that
out of the 75,914 PSA tests done in 2011, 20.9% were done on men <50 years of age which
suggests that the Alberta guidelines were not being followed. Comparing our findings with past
PSA test frequency studies suggests that the rate of PSA testing is increasing in Alberta. While
the above organizations likely target the medical community as their audience there are other
groups in Canada and Calgary whose target audience is the general public. These groups
recommend men to get a baseline PSA test at 40 years of age or at least to initiate the discussion
of early detection with their physician 21,22. In Calgary the Prostate Cancer Centre has a “MAN
VAN™” which travels through the city informing the public about early detection for prostate
64
cancer and even offers on site baseline PSA testing 22. Studies have found that patients asking or
requesting screening tests can be the impetus for a family physician to order the tests and that the
media can play as great a role in increasing awareness about PSA testing as a family physician
26,41,54,55
. This might explain the testing in the <40 to 40-49 cohorts and could account for the
increase in testing seen in the other age groups because as this information disseminates through
the general population arguably more men would ask their family physician about the PSA test.
It would be interesting to see if this trend continues into 2016 when the next Canada Census is
done because more time will have passed since the recommendations against PSA testing for
prostate cancer screening were released by the Canadian Task Force on Preventive Health Care
and The U.S. Preventive Services Task Force. A study by Bhindi et al. examined the effects on
prostate biopsy and prostate cancer detection rates in a Toronto, Canada based hospital since the
U.S Preventive Services Task Force recommended against PSA screening
108
. The study found
that there has been a decrease in the amount of prostate biopsies as well as a decrease in the
number of low grade and high grade prostate cancers detected since the recommendation.
However, this was an observational study only and further research is necessary. Our first study
found that the sociodemographic factors of median household income, university education,
Aboriginal Métis, and Black ethnicity influenced the rate of PSA testing. These findings are
significant for future medical planning in Alberta. If the Towards Optimized Practice group
continues to encourage individualized screening it is important to educate the groups who are
under utilizing the PSA test and if the Towards Optimized Practice group chooses to recommend
against the use of PSA screening then it is important to educate the groups who are over utilizing
the PSA test. The above information demonstrates the importance of educating the public about
65
health care guidelines and involving other non-governmental groups if adherence to guidelines is
to be achieved.
The second part of the thesis analyzed the utilization of PSA velocity to improve the
ability of the PSA test to predict prostate biopsy outcome and whether changing what constitutes
a significant Gleason score changes the clinical usefulness of the PSA test. I concluded that PSA
velocity does not increase the area under the curve (AUC) compared to the PSA test alone and
therefore is not a useful tool in predicting prostate biopsy outcome. I found that changing what is
considered an important Gleason score significantly impacts the AUC. For example, the AUC of
the PSA test when comparing benign vs. all prostate cancers was 0.572, which is only slightly
better than random chance at predicting prostate biopsy diagnosis. However, when I changed the
criteria and compared benign+Gleason 5-7(3+4) prostate cancers vs. Gleason 7(4+3)-10 prostate
cancers, the AUC increased to 0.699. A laboratory test with an AUC of 0.7 to 0.9 is considered
useful for particular purposes109. Gleason 6 prostate cancers have a very low chance of ever
becoming metastatic and should be included into the benign category as far as screening is
concerned110,111. Gleason 7 prostate cancers are a heterogeneous group with some patients having
no extra-prostatic extension at radical prostatectomy and showing little risk of biochemical
recurrence, while others demonstrate aggressive pathological features at radical
prostatectomy87,88,112. I showed that improvements are made to the AUC of the PSA test when
Gleason 7 prostate cancers are sub-divided; however, some authors have shown that even within
the 3+4 group there is heterogeneity112,113. A study by Reese et al. modified the Gleason score
and applied the new system to Gleason score 7 prostate cancers113. The authors found that by
using a continuous variable that looked at the percentage of Gleason pattern 4 in the specimen
they could improve risk stratification of Gleason 7 prostate cancers and better subdivide the 3+4
66
group into low and high risk. Improvements in risk stratification for the PSA test and Gleason
score are essential as this can decrease the number of men who are treated unnecessarily. A study
that randomly assigned 731 men with clinically localized prostate cancer into an active
surveillance group and treatment group found no difference between prostate cancer specific or
all cause mortality114. This being said, the study did show improvements in mortality for the
radical prostatectomy group in men with a PSA level higher than 10µg/L demonstrating the
importance of properly risk stratifying the patient before treatment. Unfortunately the answer is
not as simple as increasing PSA cut offs to 10.0 µg/L, as it is not uncommon to find high grade
prostate cancers at PSA levels below 4.0µg/L30. Also it would be beneficial to identify
potentially aggressive prostate cancers as early as possible to increase the positive outcomes for
treatment. Active surveillance is now an option for men with the improvement of nomograms
that can better predict the risk of aggressive prostate cancer. A long term follow up of patients
with favourable risk prostate cancer on active surveillance showed similar mortality rates as
patients who received treatment 115. While active surveillance seems to be a viable option, there
have been mixed reports as to how active surveillance affects quality of life. A study by
Johansson et al. found that men who were under active surveillance reported lower quality of life
compared to men who had received treatment for their prostate cancer 116. However, a systematic
review of the literature concerning quality of life in patients under active surveillance by
Bellardita et al. concluded that most men reported overall high quality of life with no significant
changes to their psychological well being117. The PSA test as a cancer screening test is not
perfect, because it has a high sensitivity but low specificity. This means many men are subjected
to the worry of false positives and follow up tests such as prostate biopsy. There have been
improvements in risk stratifying prostate cancer patients, which should limit the number of men
67
exposed to unnecessary treatments. This being said, further research is needed in identifying
other markers which can reduce the number of false positive screening tests and better identify
early biologically aggressive cancers that benefit from treatment.
4.2 Other PSA derived screening tests and Future Biomarkers
4.2.1 Other PSA derived screening tests
This thesis focused on the PSA test and PSA velocity; however, there are other PSA
derived tests which are briefly discussed below.
PSA density- PSA density is a calculation using the PSA test which is proposed to
increase the specificity of total PSA alone. The idea behind PSA density is that large benign
prostate glands, as seen in benign prostatic hyperplasia, will produce increased levels of PSA 118.
The PSA density accounts for this increase in size by dividing the PSA level by the volume of
the prostate. The volume of the prostate is calculated using measurements obtained during
transrectal ultrasound. Some authors have found that PSA density is an independent predictor of
biochemical recurrence after radical prostatectomy118 and can improve the specificity over PSA
alone at predicting prostate cancer119. However, because PSA density cannot be calculated
without the transrectal ultrasound it increases the cost which limits its usefulness as a screening
test. Also, other studies have shown that while PSA density is a statistically significant predictor
of biochemical recurrence, it does not improve the area under the curve when compared to the
PSA test by itself 120. PSA density is also used to assess men with low risk prostate cancer
(Gleason 6 and Gleason 3+4 cancers) for active surveillance. PSA density has been found to be a
predictor of Gleason scoring upgrade and can be useful for monitoring men under active
surveillance 121.
68
Percent-free PSA- Serum PSA can either be bound to other molecules or unbound (free).
Total PSA measures both of these components, while percent-free PSA is the percentage of free
PSA compared to the total PSA. In the normal prostate PSA is enzymatically processed in the
acini before diffusion occurs into the blood; however, in prostate cancer the polarity of the acinar
cells is lost and PSA can diffuse into the blood before being enzymatically processed 20. The
PSA that has not been enzymatically processed binds more readily to other molecules which
results in less free PSA. The idea is that a lower percent-free PSA puts you at an increased risk of
having prostate cancer and could be used to increase the specificity of total PSA alone especially
in the diagnostic gray zone (PSA level between 4.0 and 10.0 µg/L). The increased specificity
would limit the number of unnecessary prostate biopsies 122. However, like the total PSA test
controversy surrounds the percent free-PSA test with some studies finding that it is beneficial 122124
while other studies have found that it does not increase the ability to detect prostate cancer
over total PSA alone 125,126.
proPSA- free PSA is actually composed of other subforms of PSA such as proPSA 127.
Prostate-specific antigen initially contains a 17 amino acid leader sequence which is partially
cleaved to form proPSA and contains seven more amino acids than mature PSA128. This actually
creates seven different isoforms of proPSA with [-2]proPSA being the most stable form. Like
percent-free PSA studies are determining whether proPSA can be used to distinguish benign
increases in total PSA from prostate cancer, as well as differentiating between aggressive
prostate cancer and indolent prostate cancer. Studies have shown that proPSA has a higher AUC
than percent-free PSA in differentiating benign disease from prostate cancer when the total PSA
is in the „gray zone‟ of 4.0 to 10.0 µg/L 129,130. Beckman Coulter developed an algorithm, which
is called the prostate health index that uses the [-2]proPSA value, the free PSA value and the
69
total PSA value. A systematic review of the literature regarding proPSA and the prostate health
index by Abrate et al. found that proPSA and the prostate health index resulted in the highest
AUCs, improved the accuracy of multivariate models and would decrease the number of
unnecessary prostate biopsies 128. More studies are needed on different populations before
generalizations can be made; however, the proPSA test and prostate health index appear
promising.
PSA doubling time- simply the amount of time it takes the serum PSA level to double
and is usually expressed in months. PSA doubling time is a form of PSA kinetics like PSA
velocity and like PSA velocity there have been mixed results as to whether PSA doubling time
offers increased specificity over total PSA alone in predicting prostate biopsy outcome 89.
However, PSA doubling time has proved beneficial in helping to differentiate local recurrence
from systemic recurrence after treatment for prostate cancer 92.
4.2.2 Future Biomarkers
The detection of prostate cancer and predicting its prognosis continues to be problematic.
Many men receive false positive PSA tests and are referred for follow up treatment. This causes
undue stress to the patient and is also a drain on healthcare resources. Also, many men with
screen detected prostate cancer have indolent disease which should not be treated. Many of these
men have and will be subjected to treatment which negatively impacts their lives and again
wastes healthcare resources. For these reasons it is important that research continues for other
biomarkers that will improve prostate cancer detection and risk stratification. The following are
some non-invasive biomarkers which may improve prostate cancer screening.
70
PCA3 and Transmembrane Protease, Serine 2-ETS fusion (TMPRSS2-ERG)PCA3 is a messenger RNA that is unique to the prostate and is over expressed in prostate cancer
compared to benign tissue131,132. PCA3 can be detected in the urine and studies have found
specificity values ranging from 63%-83% but lower sensitivity values ranging from 65%-67%
131,132
. PCA3 has much higher specificity values than the PSA test and therefore could be used to
reduce the number of false positive tests that are referred for prostate biopsy. PCA3 has been
approved by the FDA for use in the decision making process for men who undergo repeat
prostate biopsies131. There have been mixed results regarding the prognostic ability of PCA3
with the majority of studies demonstrating no statistical correlation between aggressive disease
and increased PCA3 levels. TMPRSS2-ERG is a gene fusion that has been detected in the urine
samples of men with prostate cancer131. The TMPRSS2-ERG fusion has a reported sensitivity of
37%, specificity of 93% and a positive predictive value of 94% 131. Because both PCA3 and
TMPRSS2-ERG have increased specificity over the PSA test a study was conducted where both
of the tests were combined and added to the European Randomised Study of Screening for
prostate cancer risk calculator. This risk calculator includes serum PSA level, DRE status, TRUS
status and prostate volume131. Adding PCA3 and TMPRSS2-ERG to the panel increased the
AUC from 0.799 to 0.842. Both of these markers represent non-invasive tests which can increase
the specificity and AUC of traditional prostate cancer screening tests. More studies are needed to
determine if PCA3 and TMPRSS2-ERG have a prognostic role in differentiating indolent
prostate cancers from aggressive disease.
microRNAs- microRNAs (miRNA) interact with messenger RNAs and can be detected
in biological fluids. Many different miRNAs have been identified in prostate cancer with
miRNA-141 and miRNA-375 being the most promising131,133. Both of these miRNAs were able
71
to differentiate benign patients from prostate cancer patients but what was most exciting is that
they were elevated in patients with aggressive disease and were associated with higher Gleason
scores. There have only been a few prostate cancer miRNA studies and more research is needed
to validate the results and standardize the methodologies if they are to be used in a clinical
setting.
DNA methylation- hypo and hyper DNA methylation has been documented in prostate
cancer and leads to genome instability. Hypomethylation leads to activation of oncogenes and
hypermethylation leads to silencing of tumour suppressor genes132,133. The glutathione Stransferase promoter sequence has been found to be hypermethylated in over 90% of prostate
cancers132 and has a high reported specificity ranging from 86%-100%133. Unfortunately, there
have been problems with detection rates (sensitivity) in biological fluids, with values ranging
from 13% to 76%132,133. Because there is widespread methylation changes to the DNA it would
be possible to do multigene promoter methylation testing which would theoretically improve the
sensitivity of single DNA methylation tests133. More research is needed to improve the testing
technologies of DNA methylation to make it viable for clinical practice.
It is likely that improvements to prostate cancer screening will not come from a single
test but rather a panel of biomarkers. Prostate cancer screening could conceivably begin with a
combination of tests like those proposed by Beckman and Coulter, which uses proPSA, freePSA,
and total PSA128. This combination of tests increases the AUC over the PSA test alone and could
be used as a sensitive panel to identify men at risk for prostate cancer. These at risk men could be
followed up with other non-invasive tests with higher specificity, such as microRNA 141 and
375, which has shown promise in differentiating between benign, indolent and aggressive
disease131,133. This way a group of tests with high sensitivity could catch the vast majority of
72
prostate cancers and the second group of tests with greater specificity could differentiate which
men should be recommended for prostate biopsy. This would limit the number of men being
biopsied unnecessarily and reduce the amount of incidental low Gleason score prostate cancers
that are diagnosed. Unfortunately we are not at this point yet, however the ongoing controversy
of the PSA test and the potential harm which can be caused by screening for prostate cancer
means that new biomarkers are desperately needed.
73
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