2. • Kallikrein family- serine protease
• Produced by prostate ductal and acinar epithelium normally.
• Secreted into prostatic ducts at 2.0 g/L
• Liquefies seminal coagulum
• Normally found in low concentration in serum (ng/mL)
Prostate specific antigen
2
3. • PSA in serum circulates in both bound (complexed) and unbound
(free) forms that can be measured using assays.
• Most detectable PSA in serum (65% to 90%) is bound to α1-
antichymotrypsin (ACT), whereas 10% to 35% of detectable PSA is
unbound or free .
Prostate specific antigen
3
5. A. Screening/Early Detection
B. Diagnosis
C. Staging
D. Prognosis
E. •post surgery
F. •post radiotherapy
G. •post androgen ablation
Clinical Utility of Serum PSA
5
7. 1. Rising incidence and mortality rates.
2. Aging population.
3. Current understanding of etiology and pathogenesis limits the use of
preventive measures.
4. Therapeutic options for metastatic disease are palliative in nature.
5. In the pre-PSA era, only 30-40% of patients presented with localized and
potentially curable disease.
Why Do We Need Early Detection
Programs for Prostate Cancer?
7
8. A. Screening/Early Detection
• The effectiveness of PSA as a screening method for prostate cancer is debated,
• There has been a gradual but steady decline in prostate cancer mortality in the U.S. of
approximately 30%.
Clinical Use of Prostate-Specific Antigen
8
9. • Austrian Study (PSA/DRE began 1989)
• In 1993, state of Tyrol made PSA available
• Organ confined cancer rates increased from 29% to 67% between 1993-
1998
• Metastatic disease decreased from 29% to 6%
(80% reduction)
• 42% reduction expected death rates over 5-year period
Evidence of the
Effectiveness of Early Detection
9
10. • NCI – USA(1996) :
• 6% reduction in mortality
• 7.4% for men < 75 yrs old
• 3.8% for men > 75 yrs old
Evidence of the
Effectiveness of Early Detection
10
11. • Quebec Study (1989)
• Compared prostate cancer mortality rates between PSA-screened and
non-screened groups of age-matched men 45 - 80 years of age.
• Prostate cancer mortality was significantly (3-fold, p<0.01) less in
• PSA-screened (5 of 8137) vs unscreened (137 of 38056) men.
• Concluded that men who do chose to have regular PSA
determinations, have a 3-fold lower risk of dying of prostate cancer.
Evidence of the
Effectiveness of Early Detection
11
12. • Does PSA screening save lives?
• This is what 2 large Trials in the US and Europe set out to
prove.
PSA based screening.
12
15. • Aim: to determine whether with DRE and PSA can reduce mortality from prostate
cancer in men 55-74.
• 16 Nov 1993- 21 May 2012
• Primary end point: Prostate cancer deaths and death rates
• Secondary end points: death from all causes, death rates from all causes, prostate
cancer incidence/rates
15
16. • Eligibility criteria: Men 55-74 yrs
• Exclusion criteria: age < 55 yrs or > 74 yrs, treatment for prostate cancers, known
lung/colorectal/prostate cancers, prior removal of prostate, pts who has taken
finasteride / alopecia treatment for 6 months, > 1 PSA blood test in past 3 yrs.
16
17. • Total 76 685 men
• PSA+DRE: annual PSA testing for 6 years and annual DRE for 4 years; 38 340 men
• Control: usual care, which sometimes included opportunistic screening; 38 345
men
17
19. • The European Randomized Study of Screening
for Prostate Cancer ( ERSPC)
• Main end point: Prostate Cancer mortality
• Ages 50-74, N=(182,000 subjects)
• Screen interval 4 years (87%), 2 year (13%)
• Sextant biopsy recommended for PSA more>3
(or more>4 ng/ml in some centres)
• Ancillary tests for PSA 3-4 (DRE, F/T ratio)
PSA based screening.
19
20. • Relative risk (RR) of PC death (0.80 %) (95% CI, 0.65-0.98,
P=0.04), a 20% relative reduction.
• Absolute risk reduction: 7.1 per 10,000 men
PSA based screening.
20
21. • The 2 large trials have mixed results
• Given the uncertainty that PSA testing results in more
benefit than harm, a thoughtful and broad approach to
PSA is critical.
• Patients need to be informed of the risks and benefits
of testing before it is undertaken.
• The risks of overdetection and overtreatment should
be included in the discussion.
PSA based screening.
21
22. • The AUA recommends PSA screening as well-informed men
who wish to pursue early diagnosis..
• A baseline PSA determination at age 40 years has been suggested
upon which the subsequent screening interval may then be based
.
•
PSA based screening.
22
23. • A screening interval of 8 years might be enough in men with initial
PSA levels < 1 ng/mL
• Further PSA testing is not necessary in men older than 75 years and a
baseline PSA < 3ng/mL because of their very low risk of dying from
PCa
PSA based screening
23
24. Clinical Use of Prostate-Specific
Antigen
The combination of DRE and
serum PSA is the most useful
first-line test for assessing the
risk of prostate cancer being
present in an individual
( Catalona et al, 1994b ; Littrup et al, 1994 ; Stone
et al, 1994 ; Bangma et al, 1995 ; Van Der Cruijsen-
Koeter et al, 2001 ).
B. Diagnosis
24
25. • The level of PSA is a continuous parameter: the higher
the value, the more likely is the existence of Prostate
Cancer .
• This means there is no universally accepted cut-off or
upper limit.
Factors to Be Considered When Using PSA for the
Diagnosis of Prostate Cancer
25
26. Relative Risk of Cancer (95% Confidence Interval)
Baseline PSA (ng/mL) Gann et al, 1995 Antenor et al, 2004
0.0-1.0 1.0 1.0
1.0-1.5 2.2 (1.3-3.6) 4.3 (3.0-5.3)
1.5-2.0 3.4 (1.9-5.9) 8.8 (7.0-10.8)
2.0-3.0 5.5 (3.3-9.2) 14.9 (12.3-18.0)
3.0-4.0 8.6 (4.7-15.6) 23.3 (19.0-28.7)
4.0-10.0 22.2 (12.9-38.2) 38.7 (32.2-46.7)
More than 10.0 145.3 (59.1-357.0) 104.2 (80.0-135.7)
Relative Risk of Subsequent Prostate Cancer
Diagnosis after an Initial Baseline Prostate-
Specific Antigen (PSA)
( Andriole et al, 2005 ; Catalona et al, 1998 ; Crawford et al,
1996 ; Schroder et al, 1998 ; Thompson et al, 2004 26
27. PSA(ng/ml) DRE RISK OF CA
(%)PROSTATE
NORMAL NORMAL 15
NORMAL ABNORMAL 20
4-10 +/- 30
>10 +/- 60-70
Prostate Cancer Detection as a Function of
Serum Prostate-Specific Antigen (PSA) Level
and Digital Rectal Examination (DRE)
27
28. • In summary, both PSA and DRE are used to assess the risk
that prostate cancer is present. The addition of PSA to DRE
increases both the detection rate of prostate cancer and the
detection of cancers with a more favourable prognosis.
28
29. • The choice of a PSA threshold or cut point above which one would
recommend further evaluation to rule out prostate cancer (prostate
biopsy) is controversial
• The use of a PSA threshold of 4.0 ng/mL for men older than 50 years
has been accepted by most clinicians as striking a reasonable balance
between these tradeoffs.
Prostate-Specific Antigen Thresholds
29
30. • Volume-based PSA parameters (with prostate volume determined by
ultrasonography) including
• PSA density (PSA divided by prostate volume),
• complexed PSA density (complexed PSA divided by prostate volume)
• PSA transition zone (PSA divided by transition zone volume)
Volume Based Prostate-Specific Antigen
Parameters
30
31. • PSA is the ratio of the PSA level to the gland volume density of 0.15 or greater
was proposed as a threshold for recommending prostate biopsy in men with PSA
levels between 4 and 10 ng/mL and no suspicion of cancer on DRE or TRUS (
Seaman et al, 1993 ; Bazinet et al, 1994 ; Rommel et al, 1994)
• Although PSA density is an imperfect predictor of cancer, it is an additional
method of risk assessment with potential usefulness for counseling men with
intermediate PSA levels (4 to 10 ng/mL) regarding the need for prostate biopsy or
repeat biopsy if PSA is persistently elevated
PSA DENSITY
31
32. • The free/total PSA ratio (f/t PSA) is the concept most extensively investigated and most
widely used in clinical practice to discriminate BPH from Prostate Cancer.
• The ratio is used to stratify the risk of PCa for men who have total PSA levels between
4 and 10 ng/mL and a negative DRE.
• In a prospective multicentre trial, PCa was found on biopsy in 56% of men with a f/t
PSA < 0.10, but in only 8% of men with f/t PSA > 0.25 .
(Catalona WJ, Partin AW, Slawin KM, et al. Use of the percentage of free prostate-specific antigen to enhance
differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial. JAMA 1998
May 20;279(19):1542-7).
FREE/TOTAL PSA RATIO
32
33. • PSA velocity (PSAV), PSA doubling time (PSADT)
• There are two methods of measuring PSA over time. These are:
• PSA velocity (PSAV), defined as an absolute annual increase in serum PSA
(ng/mL/year)
• PSA doubling time (PSADT), which measures the exponential increase of serum
PSA over time reflecting a relative change .
• These two concepts may have a prognostic role in patients with treated prostate
cancer
Measuring PSA over time
33
34. • PSA velocity is given in ng/ml/year and can be thought of as a prediction: for
example, a patient with a current PSA of 2 ng/ml and a PSA velocity of 0.5
ng/ml/year would be expected to have a PSA of 2.5 ng/ml in 12 months time.
• PSA doubling time is the number of months it would take for PSA to increase two-
fold. The PSA doubling time of our example patient would therefore be 48
months. For patients with relatively constant PSA, such as a change from 6 to 6.1
ng/ml over the course of a year, doubling time become rather unstable and such
patients are normally categorized in terms of “doubling time > 10 years” or
similar
34
35. C. Staging
• Serum PSA levels correlate with the risk of extra-prostatic extension,
seminal vesicle invasion, and lymph node involvement.
• Patients with serum PSA levels of less than 10.0 ng/mL are most likely
to respond to local therapy.
Clinical Use of Prostate-Specific Antigen
35
36. • Routine use of a bone scan is not required for staging asymptomatic men with
clinically localized prostate cancer when their PSA level is equal to or less than
20.0 ng/mL.
• An analysis of 23 studies examining the utility of bone scan found metastases in
2.3% of men with PSA levels <10.0 ng/mL, 5.3% in men with PSA levels from
10.1 to 19.9 ng/mL, and 16.2% in men with PSA levels >20.0 ng/mL.
• Accordingly, bone scans are generally not necessary in patients with newly
diagnosed prostate cancer who have a PSA <20.
(Abuzallouf, S., Dayes, I., and Lukka, H.: Baseline staging of newly diagnosed
prostate cancer: a summary of the literature. J Urol, 171: 2122, 2004)
Clinical Use of Prostate-Specific Antigen
36
37. The majority of recurrences following Radical Prostatectomy or
Radical Radiotherapy for localized prostate cancer are asymptomatic.
Serum PSA is the mainstay of surveillance testing in men who have
undergone therapy for localized prostate cancer
PSA in Prognosis
37
38. • The serum PSA levels should be undectectable after
radical prostatectomy
• The AUA defines biochemical recurrence as an initial PSA
value ≥0.2 ng/mL followed by a subsequent confirmatory
PSA value ≥0.2 ng/mL
• However, a cut-point of 0.4 ng/mL may better predict the
risk of metastatic relapse.
(Stephenson, A.J., Kattan, M.W., Eastham, J.A., et al Clin Oncol, 24:
3973, 2006)
PSA after Radical Prostatectomy
38
39. • Biochemical failure following RT is more complicated, since
there is benign tissue remaining after RT
• ASTRO (American society for radiation oncology) guidelines
on PSA recurrence were revised in 2005 (Phoenix Criteria)
PSA after Radical Radiotherapy
39
40. • PSA rise by ≥2 ng/mL above the nadir PSA is considered the
standard definition for biochemical failure after external
beam RT, regardless of whether or not a patient receives
androgen deprivation therapy.
The Phoenix criteria
40
41. • Serum PSA levels typically fall after RT and can then rise ("bounce") transiently, at
a median of 12 to 18 months after treatment.
• Although these rises (or “benign bounces”) are generally small (<0.8 ng/mL), they
can, on occasion, be as high as 10.0 ng/mL,
• Their cause is uncertain, but they may correspond to infarction and inflammation
of the prostate occurring as a late vascular effect of the radiation
The Phenomenon of PSA Bounce
41
42. • Patients with a PSA bounce are more likely to have biochemical
failure, and a PSA bounce of greater that 1.4 ng/mL has been
associated with biochemical failure, metastases, and prostate cancer
death
The Phenomenon of PSA Bounce
42
43. • Achievement of a low PSA nadir after hormonal therapy has prognostic significance
and has been linked to survival.
• For patients with metastatic disease receiving androgen suppression therapy, failure to
achieve a PSA nadir of <4.0 ng/mL seven months after initiation of therapy is
associated with a very poor prognosis
(median survival: approximately one year)
PSA and Androgen suppression
therapy
43
44. • PSA nadir of <0.2 ng/mL :-relatively good prognosis
(median survival: over six years).
PSA nadirs >0.2 and <4.0 ng/mL: -intermediate prognosis
(median survival of44 months)
(Hussain, M., Tangen, C.M., Higano, C., et aldata from Southwest
Oncology Group Trial 9346 (INT-0162). J ClinOncol, 24: 3984, 2006)
PSA and Androgen suppression therapy
44
45. • For patients with a PSA rise following radical prostatectomy or radiation and no
radiologic evidence of metastases, a PSA nadir of >0.2 ng/mL within eight months of
androgen suppression is associated with a 20-fold greater risk of prostate cancer-
specific mortality.
(Stewart, A.J., Scher, H.I., Chen, M.H., et al J ClinOncol, 23: 6556, 2005)
PSA and Androgen suppression
therapy
45
46. • A PSA nadir of >0.2 ng/mL in the setting of a PSADT of <3 months is ominous.
• Support the prognostic importance of the value of the PSA nadir after androgen
deprivation therapy and suggest that careful PSA monitoring after the initiation of
such therapy can effectively identify those patients with a poor prognosis
PSA and Androgen suppression therapy
46
47. • Elevated serum PSA level has become an important marker of many
prostate diseases
• The effectiveness of PSA as a screening method for prostate cancer is
debated
• There is now evidence from a randomized, controlled trial regarding a
mortality decrease associated with PSA screening
• A baseline PSA determination at age 40 years has been suggested upon
which the subsequent screening interval may then be based .
IN A NUTSHELL
47
48. • PSA and DRE are used to assess the risk that prostate cancer is present
• The use of a PSA threshold of 4.0 ng/mL for men older than 50 years has been
accepted by most clinicians as the prostate specific antigen threshold
• Patients with serum PSA levels of less than 10.0 ng/mL are most likely to respond
to local therapy , bone scans are generally not necessary in patients with newly
diagnosed prostate cancer who have a PSA <20.0
IN A NUTSHELL
48
49. • Serum PSA is the mainstay of surveillance testing in men who have undergone
therapy for localized prostate cancer
• The AUA defines biochemical recurrence as an initial PSA value ≥0.2 ng/mL
followed by a subsequent confirmatory PSA value ≥0.2 ng/mL
• PSA rise by ≥2 ng/mL above the nadir PSA is considered the standard definition for
biochemical failure after external beam RT, regardless of whether or not a patient
receives androgen deprivation therapy.
• A PSA nadir of >0.2 ng/mL in the setting of a PSADT of <3 months is ominous
IN A NUTSHELL
49
50. • For patients with metastatic disease receiving androgen suppression therapy,
failure to achieve a PSA nadir of <4.0 ng/mL seven months after initiation of
therapy is associated with a very poor prognosis (median survival:
approximately one year)
• Patients with a PSADT of <6 months, there is approximately a 10% chance
of a positive bone scan.
• Thus, the use of routine bone scans in the setting of a PSA rise following
local therapy is not justified, particularly for those with a PSADT of >6
months and a PSA value of <10.0 ng/mL.
IN A NUTSHELL
50
