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Interpretation of PSA levels after
radical therapy for prostate cancer
SANCHIA S. GOONEWARDENE, JASPAL S. PHULL, AMIT BAHL AND RAJ A. PERSAD
Prostate-specific antigen plays a role in active surveillance and postoperative monitoring
of prostate cancer patients. The authors discuss PSA screening, and consider some of the
problems involved in interpretation of PSA levels after radical prostatectomy, radical
radiotherapy and brachytherapy.
rostate-specific antigen is an enzyme
P secreted from the prostate gland. The level
of PSA can be affected by infection or trauma,
giving a spuriously high result. However, it can
also be elevated by prostate cancer. The PSA
level correlates with tumour volume and
Gleason score, and has been shown to be an
independent prognostic variable.15
PSA AND PROSTATE CANCER SCREENING
Screening for PSA has been debated over the
years. The risk of prostate cancer increases
with age: 40 per cent of 70-year-old men
have detectable cancer in the prostate at
autopsy.6 To prevent one death from prostate
cancer, 48 screened men need to be treated.7
The concentration of PSA at age 60 predicts
the risk that a man will die from prostate
cancer by the age of 85.7 A PSA level of
<1ng/ml is extremely low risk.
The Prostate, Lung, Colorectal and Ovarian
Cancer screening trial in the USA found
Sanchia S. Goonewardene, MB ChB,
BMedSc(Hons), DipSSC, MRCS, Specialist
Registrar in Urology, Guys and St Thomas
Hospital, London; Jaspal S. Phull, MB ChB,
MRCS, Consultant Urologist; Amit Bahl,
MB BS, MD, DNB, MRCP, FRCR, FFRRCSI,
Consultant Oncologist; Raj A. Persad,
MB BS, FRCS, ChM, FRCS(Urol), FEBU,
Consultant Urologist, University Hospitals
Bristol NHS Foundation Trust
www.trendsinurology.com
Age
(years)
PSA value
(ng/ml)
4050 2.5
5060 3.5
6070 4.5
7080 6.5
Table 1. Average PSA values at different ages
no advantage to screening at a median
follow-up of seven years. The overall
conclusion is that screening is not supported
by the evidence base. Average PSA varies
according to age (Table 1). The criteria for a
transrectal ultrasound (TRUS) biopsy are if
the PSA increases above the patients age-
specific range, or if there is a large increase
in PSA, eg >5ng/ml, with no alternative
explanation such as an infection.
PROSTATE CANCER MANAGEMENT:
RISK STRATIFICATION
Partin et al. developed tables to predict
pathological outcome at surgery based on
serum PSA, clinical stage and Gleason score on
biopsy.8 Using the same clinical parameters,
DAmico defined low-, intermediate- and
high-risk categories to predict biochemical
recurrence following treatment.9 This has been
adopted in the National Comprehensive Cancer
Network guidelines for prostate cancer.10
For treatment purposes, patients with
prostate cancer can be stratified into one of
three groups: low-, intermediate- or high-
risk (Table 2). Low- and intermediate-risk
patients are the most suitable for radical
treatment. High-risk patients may be
considered, but only if the outcome is
considered to be sufficiently curative.
Staging investigations, MRI of the prostate
and bone scans are required in only the
intermediate- to high-risk group.
ACTIVE SURVEILLANCE
Localised prostate cancer is defined as cancer
confined to the prostate gland (T1-2), not
breaching the prostatic capsule. Men with
low-risk localised prostate cancers, suitable
for radical treatment, may first be offered
active surveillance, to reduce overtreatment.
After identifying patients at low risk of dying
from prostate cancer, an active surveillance
programme monitors patients for aggressive
tumours that can develop as time progresses.
Surveillance is composed of PSA testing
every three months, a six-monthly review
with a digital rectal examination (DRE), an
annual TRUS biopsy and MRI. This should
include at least one re-biopsy.
When to re-biopsy and role of MRI in
active surveillance
When to re-biopsy is a difficult question, as
there is no set PSA level as a trigger point.
General trends are examined in conjunction
with prostate volume and DRE results.
There has also been debate as to whether
immediate re-biopsy is the way forward. Up
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Risk PSA (ng/ml)
Low <10
Intermediate 10-20
High >20
Table 2. Risk stratification for prostate cancer
to 27 per cent of patients who underwent
immediate repeat biopsy were upgraded
and/or upstaged.11 Thirty per cent of patients
will be reclassified at the first repeat biopsy
at one year.12 If the time taken for the PSA to
double is within two years, this may be
grounds for disease progression, requiring
re-staging with MRI and TRUS biopsy. When
the re-staging results are received, patients
would again be put into low-, intermediate-
and high-risk groups, often with upstaging
of disease, eg Gleason 34 or disease present
in >50 per cent of cores, requiring active
treatment. For re-biopsy, transperineal
template biopsies should also be considered.
As part of this procedure up to 40 cores of a
prostate can be taken for analysis, giving a
much stronger diagnostic ability.
MRI continues to have a growing role as part
of active surveillance. A negative MRI study
has a high negative predictive value and high
specificity for upgrading with subsequent
immediate confirmatory biopsy in low-risk
prostate cancer patients.13 In contrast, a
positive MRI study has a very high sensitivity
for upgrading. Importantly, a negative MRI is
very common within an active surveillance
population13,14 and might represent true
clinically insignificant disease. However, there
is still a dearth of studies in this area.
Active surveillance is not recommended for
men with high-risk localised prostate cancer.
If higher-risk features are detected during
surveillance, these men are encouraged to
undergo definitive therapy. However, clinical
parameters do not determine patient risk
with perfect accuracy (eg some patients
with high-grade disease may be misclassified
as low risk due to undersampling), and a
legitimate concern is that some men will lose
the window of curability during monitoring.
TRENDS IN UROLOGY & MENS HEALTH JULY/AUGUST 2014
Gleason DRE
6 T2a
7 T2b
8 T3a
Not surprisingly, there is a lack of general
agreement on patient selection and triggers
for intervention.
LOCALISED PROSTATE CANCER
Men with localised prostate cancer on active
surveillance with evidence of disease
progression (rise in PSA level or adverse
findings on biopsy) should be offered radical
treatment.15 Radical prostatectomy or radical
radiotherapy (conformal) can be offered to
men with intermediate-risk localised prostate
cancer.15 It should be offered to high-risk
cases only when there is a realistic prospect
of long-term disease control.15 Adjuvant
hormonal therapy is recommended for a
minimum of two years in men receiving
radical radiotherapy for localised prostate
cancer who have a Gleason score of 8.15
LOCALLY ADVANCED PROSTATE CANCER
Locally advanced prostate cancer covers a
spectrum of disease, from a tumour that has
spread through the capsule of the prostate
(T3a) to large T4 cancers that may be invading
the bladder or rectum or have spread to
pelvic lymph nodes.15 Neoadjuvant and
concurrent luteinising hormone-releasing
hormone agonist therapy is recommended for
three to six months in men receiving radical
radiotherapy.15 Adjuvant hormonal therapy is
recommended for a minimum of two years
in men receiving radical radiotherapy for
locally advanced prostate cancer who have
a Gleason score of 8.15
PSA POST-RADICAL THERAPY
Radical interventions include surgery
(robotic, laparoscopic or open), radiotherapy
or brachytherapy. All men who have had
radical treatment should have their PSA
levels checked six weeks following treatment,
at least every three months for the first two
PROSTATE DISEASE
31
years and then at least once or twice a year
thereafter. After at least two years, men with
a stable PSA who have had no significant
treatment complications should be offered
follow-up outside hospital (eg in primary
care) or as part of a survivorship programme.
PSA nadir
The PSA nadir (nPSA) is the lowest PSA level
post-therapy. This will be reached at varying
rates depending on the intervention. Detectable
PSA levels after organ-sparing radical therapies
may not always herald treatment failure. The
PSA level after definitive treatment is a
powerful predictor of outcome in the absence
of clear confounding pathologies.
PSA post-radical prostatectomy
The PSA should be less than 0.1ng/ml after
radical prostatectomy. Once the prostate has
been removed, the serum PSA should decay
to undetectable levels. This is a reassuring
measure of complete resection, reinforced
by histopathological results. Ultrasensitive
assays can detect PSA to a level of 0.01ng/ml.
A detectable PSA reflects an incomplete
resection or occult metastases. Following
radical prostatectomy, several studies
have used <0.2ng/ml as the standard
definition of an unrecordable reading.
Biochemical recurrence with a PSA of
>0.2ng/ml was identified in 19 per cent of
patients postoperatively.16 There have been
no reported cases of recurrence in men with
a nPSA of <0.01ng/ml.17
The nPSA is usually achieved within four to six
weeks after radical prostatectomy. If the PSA
post-radical prostatectomy starts rising, eg to
0.20.4ng/ml, urgent referral to a urologist is
necessary, as at this point the cancer may
have recurred and the patient would be a
candidate for salvage radiotherapy. If the PSA
increases to >4ng/ml, for example, there is a
chance the tumour may have become locally
advanced/advanced, at which point hormone
therapy is the only option.
This is often a challenge for both GPs and
urologists. A rising PSA may be difficult to
interpret. While it may be indicative of
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low-volume recurrence, alternatively, early
intervention with hormone therapy if
metastases are present may result in
castrate-resistant disease. Compounding
factors are early recurrence (within two years
of surgery), a high Gleason score and a rapid
PSA doubling time.
PSA post-radical radiotherapy
The prostate gland remains in situ after
radical radiotherapy. Production of PSA
can be expected, at a lower rate. It may
take months for tumour cells to die post-
radiotherapy. The majority of the decay
occurs within the first year.18,19 It is not
possible to distinguish between local and
distant metastases in men with elevated
PSA post-radiotherapy.
Alcantara et al. showed that a PSA level of
2ng/ml at 12 months is an independent
predictor of outcome. The rates of distant
metastases at 10 years were 4 per cent (PSA
2ng/ml) or 19 per cent (PSA >2ng/ml).20
Horwitz et al. (2005) studied this cohort post-
radiotherapy. Biochemical failure was defined
as 23ng/ml greater than nPSA or two
consecutive rises of at least 0.5ng/ml. This was
more sensitive and specific for distant failure.21
In 2006 the Phoenix Consensus Conference
recommended a new definition of
biochemical failure: a PSA rise of 2ng/ml
above nPSA.22 This is also applicable to
men who have had adjuvant androgen
deprivation therapy as part of their
radiotherapy protocol.23 So, for example, a
patient with low-risk disease and an initial
post-radiotherapy PSA of 0.1ng/ml who
presented again one year later with a PSA of
6ng/ml (greater than nadir + 2) would be
restaged and regraded.
PSA post-brachytherapy
Transperineal brachytherapy is usually
reserved for patients with lower-risk
organ-confined disease, who have few
urinary symptoms and up to 50ml prostate
volumes.24 There seems to be evidence to
support defining biochemical failure in terms
of three consecutive rises, the Phoenix
www.trendsinurology.com
criteria or even a rise above an absolute
PSA. Potters et al. used both the Phoenix and
nadir + 2 definitions. They demonstrated 81
and 77 per cent biochemical freedom from
recurrence at 12 years, respectively.12 Zelefsky
et al. categorised the nPSA into ranges. They
found that a nPSA <0.5ng/ml was associated
with up to 92 per cent PSA relapse-free
survival at eight years follow-up.25
Khaksar et al. used both the three consecutive
PSA rises and the nadir + 2 definitions of
biochemical failure: a nPSA <0.5ng/ml was a
suitably representative target.26
Zelefsky et al. used an arbitrary nPSA at three
years after treatment.25 The definition of the
nPSA following brachytherapy is complicated
by the phenomenon of the PSA bounce. It is
characterised by a PSA rise followed by a
decay in PSA to the original level or below.
The exact mechanism is not fully understood.
A target PSA of 0.5ng/ml was associated
with the lowest biochemical failure
rates during the follow-up periods. For
subgroups within the studies, higher PSA
nadirs were clearly associated with poorer
outcomes. The time to the nPSA after
brachytherapy may be extremely variable.
In the context of brachytherapy (which is
ultimately intraprostatic radiotherapy), the
three consecutive rises and nadir + 2
definitions of biochemical failure have been
compared. Studies have shown that the
sensitivity and specificity for the nadir + 2
definition (Phoenix) were 72 and 83 per cent,
versus 51 and 81 per cent for three PSA rises.24
CONCLUSION
PSA is a multispecific agent, used for both
diagnostic and monitoring purposes. It
plays a role in active surveillance and
monitoring of patients postoperatively.
A clear definition of biochemical relapse
is available post-radical radiotherapy.
Post-radical prostatectomy, any detectable
PSA should be treated with suspicion,
and in the context of the final histology,
preoperative parameters and the rate of rise.
For brachytherapy, no standard definition of
biochemical relapse has been agreed.
Declaration of interests: none declared.
REFERENCES
1. Kuban DA, El-Mahdi AM, Schellhammer PF.
Prostate specific antigen for pretreatment
prediction and posttreatment outcome after
definitive irradiation for prostate cancer. Int J
Radiat Oncol Biol Phys 1995;32:30716.
2. Lee WR, Hanks GE, Schultheiss TE, et al.
Localized prostate cancer treated by external
beam radiotherapy alone: serum prostate
specific antigen outcome. J Clin Oncol 1995;
13:4649.
3. Russell KJ, Boileau MA. Current status of
prostate specific antigen in the management
of prostatic cancer. Semin Rad Oncol 1993;
3:15468.
4. Zagars GK, Pollack A. Radiation therapy for T1
and T2 prostate cancer: prostate-specific
antigen and disease outcome. Urol 1995;
45:47683.
5. Zietman A, Coen J, Shipley W, et al. Radical
radiation therapy in the management of
prostatic adenocarcinoma: the initial prostate
specific antigen value as a predictor of
treatment outcome. J Urol 1994;151:6405.
6. Haas GP, Delongchamps NB, Jones RF, et al.
Needle biopsies on autopsy prostates:
sensitivity of cancer detection based on true
prevalence. J Natl Cancer Inst 2007;99:14849.
7. Schroder FH, Hugosson J, Roobol MJ, et al.
Screening and prostate-cancer mortality in a
randomized European study. N Engl J Med
2009;360:13208.
8. Partin AW, Pound CR, Clemens JQ, et al. Serum
PSA after anatomic radical prostatectomy: the
Johns Hopkins experience after 10 years. Urol
Clin North Am 1993;20:71325.
9. DAmico AV, Moul J, Carroll PR, et al. Cancer-
specific mortality after surgery or radiation
for patients with clinically localized prostate
cancer managed during the prostate-specific
antigen era. J Clin Oncol 2003;21:216372.
10. Mohler J, Bahnson RR, Boston B, et al. NCCN
clinical practice guidelines in oncology: prostate
cancer. J Natl Compr Canc Netw 2010;8:162200.
Continued on page 34
TRENDS IN UROLOGY & MENS HEALTH JULY/AUGUST 2014
Goonewardene PSA levels_Layout 1 15/07/2014 14:15 Page 4

PROSTATE DISEASE
34

11. Berglund RK, Masterson TA, Vora KC, et al. Pathological upgrading and
upstaging with immediate repeat biopsy in patients eligible for active
surveillance. J Urol 2008;180:19647.
12. Potters L, Morgenstern C, Calugaru E, et al. 12-year outcomes following
permanent prostate brachytherapy in patients with clinically localized
prostate cancer. J Urol 2008;179(5 Suppl):s204.
13. Vargas HA, Akin O, Afaq A, et al. Magnetic resonance imaging for
predicting prostate biopsy findings in patients considered for active
surveillance of clinically low risk prostate cancer. J Urol 2012;188:17328.
14. Somford DM, Hoeks CM, Hulsbergen-van de Kaa CA, et al. Evaluation of
diffusion-weighted MR imaging at inclusion in an active surveillance
protocol for low-risk prostate cancer. Invest Radiol 2013;48:1527.
15. NICE. Prostate cancer: diagnosis and treatment. Clinical guideline 175,
January 2014.
16. Freedland SJ, Humphreys EB, Mangold LA, et al. Risk of prostate cancer-
specific mortality following biochemical recurrence after radical
prostatectomy. JAMA 2005;294:4339.
17. Nakamura M, Hasumi H, Miyoshi Y, et al. Usefulness of ultrasensitive
prostate-specific antigen assay for early detection of biochemical failure
after radical prostatectomy. Int J Urol 2005;12:10504.
18. Zagars GK, Pollack A. The fall and rise of prostate-specific antigen.
Kinetics of serum prostate-specific antigen levels after radiation therapy
for prostate cancer. Cancer 1993;72:83242.
19. Zagars GK, Pollack A, Kavadi VA, von Eschenbach AC. Prostate-specific
antigen and radiation therapy for clinically localized prostate cancer. Int J
Radiat Oncol Biol Phys 1995;32:293306.
20. Alcantara P, Hanlon A, Buyyounouski MK, et al. Prostate-specific antigen
nadir within 12 months of prostate cancer radiotherapy predicts
metastasis and death. Cancer 2007;109:417.
21. Horwitz EM, Thames HD, Kuban DA, et al. Definitions of biochemical
failure that best predict clinical failure in patients with prostate cancer
treated with external beam radiation alone: a multi-institutional pooled
analysis. J Urol 2005;173:797802.
22. Roach M 3rd, Hanks G, Thames H Jr, et al. Defining biochemical failure
following radiotherapy with or without hormonal therapy in men
with clinically localized prostate cancer: recommendations of the
RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat Oncol Biol
Phys 2006;65:96574.
23. Buyyounouski MK, Hanlon AL, Eisenberg DF, et al. Defining biochemical
failure after radiotherapy with and without androgen deprivation for
prostate cancer. Int J Radiat Oncol Biol Phys 2005;63:145562.
24. Ash D, Flynn A, Batterman J, et al.; ESTRA/EAU Urological Brachytherapy
Group; EORTC Radiotherapy Group. ASTRO/EAU/EORTC recommendations
on permanent seed implantation for localized prostate cancer. Radiother
Oncol 2000;57:31521.
25. Zelefsky MJ, Kuban DA, Levy LB, et al. Multi-institutional analysis of long-
term outcome for stages T1-T2 prostate cancer treated with permanent
seed implantation. Nat Clin Pract Urol 2007;4:6501.
26. Khaskar SJ, Laing RW, Henderson A, et al. Biochemical (prostate-specific
antigen) relapse-free survival and toxicity after 125I low-dose-rate
prostate brachytherapy. BJU Int 2006;98:121015.

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