CANCER DIAGNOSIS CLINICAL PRACTICE GUIDELINES:
Every man should have an annual PSA and DRE starting at forty years of age even though
current guidelines suggest fifty as appropriate. Men at risk due to race or a
family history of prostate cancer (brothers, fathers),1-3
and men with a family history of breast cancer (mothers, sisters, aunts)1,4-6
should begin annual screening at age 35. Racial factors also contribute to risk
of prostate cancer. Black men seem to have the highest incidence of prostate cancer,
followed by Hispanic men.
U.K. National Cancer Programme guidelines
advise that a PSA of 3.0 and over at any age should be investigated to rule out
prostate cancer (PC), although some prostate cancer experts advocate 2.0 as being
A first step in an investigation of an elevated PSA
should be the determination of the free PSA percentage.
Blood sampling for PSA determinations, done at least three months apart,
and by the same laboratory using the same testing procedure, is necessary to establish
PSA velocity (PSAV) and PSA doubling time (PSADT). The validity of such determinations
is increased if such testing involves at least three determinations over an 18-month
span of time. However, a progressive and serial increase in PSA values should
raise flags of concern that prostate cancer is present and a greater degree of
vigilance is mandatory.
- A free PSA percentage of over 25% is associated with a low risk of prostate cancer.
- A free PSA percentage of under 15% is associated with a higher risk of prostate cancer.7
- A benign cause of an elevated PSA and a correspondingly low free PSA percentage could be prostatitis.
Four to six weeks of ciprofloxacin or similar antibiotic should be prescribed
prior to recommending a biopsy if prostatitis symptoms are noted and/or if expressed
prostatic secretions (EPS) are consistent with prostatitis. At the end of the
antibiotic therapy, a repeat PSA determination should be made. If there is significant
lowering of the PSA, an element of prostatitis is most likely present. The PSA
value after antibiotic therapy will more aptly reflect the status of the patient
in the situation where PC is subsequently established. It should also be emphasized
that although the PSA may significantly decrease after antibiotic therapy, it
is still important to do further PSA testing at regular intervals to determine
if a serial progressive rise in PSA is occurring. It is the nature of the PSA
kinetics, i.e. change in PSA over time, that is very helpful in discerning whether
or not a malignant process is likely present.
- BPH (benign prostate hyperplasia) does not cause a low free PSA percentage. It may cause an elevated PSA, however. Therefore, in the case of an
elevated PSA but a high free PSA percentage (equal to or greater than 25%), an estimate of gland volume by DRE or via transrectal ultrasound of the
prostate may reveal findings consistent with a diagnosis of BPH. A general rule of thumb is that an accurate gland volume (best determined by transrectal
ultrasound of the prostate) x 0.066 will equal the amount of benign-related PSA. Therefore, assuming only the presence of BPH, a 60-gramme or 60 cubic centimetre
prostate is entitled to secrete approximately 3.96 ng of PSA into the blood.
A PSA value that bounces up and down is more indicative of a benign
process than a malignant process.
- A PSAV that exceeds 0.75 ng/ml/yr is associated with a higher probability of PC.8
- A PSADT of less than 12 years is associated with a higher probability of PC.
A PSA that shows a persistent rise
over time, particularly three consecutive rises, three months apart is suspicious
for PC regardless of the level of the PSA. As mentioned above, gland volume in
cubic centimetres (cc) multiplied by 0.066 yields the amount of PSA produced by
the benign-related epithelial cell population of prostate cells. Any amount of
PSA in excess of this should be considered to be produced by a malignant process,
until proven otherwise. Systematic biopsies of the prostate under ultrasound guidance,
however, must be considered mandatory when clinical &/or laboratory findings suggest
the possibility of prostate cancer.
An approach using biological detection
techniques such as those described above would eliminate advanced presentations
of PC. Annual screening in this manner presents us with an opportunity to detect
localised PC in over 95% of men.9 Such statistics offer
an outstanding chance for a curative approach to this disease.
involving these profiling techniques allows the patient-physician team to discern
the very slow growing (indolent) presentations of PC that may be monitored using
watchful waiting as opposed to the standard PC cases for which local treatments
typically result in long term biological non-evidence of disease. Most importantly,
attention to PSA kinetics accomplished by monitoring the PSA and PSA derivatives
such as free PSA percentage, PSADT, PSAV and other calculations, should result
in an almost total disappearance of highly aggressive presentations of PC. It
is the latter that is associated with rapidly progressive disease and fatalities.
These opposite extremes in the clinico-pathological nature of PC, i.e.
the indolent "pussycats" variants versus the aggressive "tigers" ones, are important
to differentiate due to the highly different evaluation and management recommendations
advised for each circumstance.
INDOLENT VERSUS AGGRESSIVE PC
("PUSSYCATS" VERSUS "TIGERS")
Pussycats in general, have low PSA
values (under 10) and long doubling times (greater than 24 months and often 48
months or longer), as well as low PSA velocities (0.75 ng/ml/yr ± 10%). If a biopsy
is done on a patient with a PSA that is under 10, the Gleason score often turns
out to be (3,3). Depending on the calculated tumour volume, clinical stage, PSA
doubling time, and other factors, these objectified biologic parameters may allow
many such patients to be candidates for objectified observation ("watchful waiting").
Of course, these patients are also candidates for any of the currently available
local therapies. Patients who choose to monitor their illness rather than seek
immediate local therapy must be cognisant of the significance of change over time,
or trend. They need to be aware that if manifestations of disease progression
become evident, reevaluation of their situation is warranted. In such circumstances,
consideration must be made for some form of local treatment-before the window
of opportunity for successful local therapy is lost.
Tigers in general,
have high PSAs (over 10), OR very low PSAs associated with very aggressive, high
Gleason score [(4,3), (4,4), (4,5), (5,4), (5,5)] cancers. These are very dangerous
because they often escape investigation for long periods of time since the PSAs
appear to be in the so-called normal range. Investigating all PSAs at 2.0 and
over will help to catch these prostate cancers while they are still organ-confined
and treatable with local therapies. The probability of spotting these low PSA/high
Gleason score cancers is enhanced if patients and doctors monitor PSA levels over
time. Such a practice will detect persistent increases in PSA, even if the absolute
value of PSA is very low. High Gleason score cancers often have reverted to such
a primitive state that they no longer secrete PSA into the blood. Checking the
serum for elevations in other markers such as CGA (Chromogranin A), NSE (Neuron
Specific Enolase), CEA (Carcino-Embryonic Antigen) and PAP (Prostatic Acid Phosphatase)
is important to discern PC activity secondary to de-differentiated tumor cell
populations. Although many physicians consider PAP to be an obsolete test, three
contemporary peer-reviewed publications have concluded that PAP testing is of
major prognostic value in the newly diagnosed man with PC.10-12
Therefore, in cases designated as "tigers", the normal guidelines
for PSA velocity and doubling time may not be applicable. However, the concept
of slope or trend in a biomarker of disease activity remains valid, and any biomarker
elevation should be tracked at regular intervals to determine the presence of
abnormal growth of primitive tumor cell clones.
If we scientifically observe the biological manifestations of prostate health
or disease, we can detect PC at a time when currently available therapies are
most likely to cure the most common malignancy facing man. If we ignore these
biological communications that are red flags to alert us to the presence of a
threat to our life, a vital opportunity to change the course of an illness is
missed. The loss of life, productivity, and the extreme costs to the health care
system-all of which result from a late-stage diagnosis of this disease-should
provide impetus for all of us to be proactive when it comes to an early diagnosis
of a malignant condition. This fundamental concept has been heralded for many
malignances, such as cancer of the cervix, lung cancer, colorectal malignancy
and breast cancer. When will we make the same connection when it comes to men
with PC?13 Aren't the almost 100,000 lives lost each
decade in the U.K. too great a price to pay?
PHYSICIANS AND PATIENTS:
In the U.K. and on the Web:
Prostate Cancer Charity is a source of good prostate cancer literature and has
an excellent helpline. Address: 3 Angel Walk, London W6 9HX. Confidential Helpline
Tel. +44 (0)845 300 8383, Web site: www.prostate-cancer.org.uk.
Prostate Research Campaign, UK, 10 Northfields Prospect, Putney Bridge Road,
London SW18 1PE. Tel. +44 (0)208 582 0248. Web site: http://www.prostate-research.org.uk/.
The Prostate Cancer Research Institute
(PCRI) Web site at http://www.pcri.org. This
site has a wealth of information including the Prostate Cancer Address Book, which
lists expert prostate cancer physicians, software tools, and articles and downloadable
issues of the publication PCRI INSIGHTS.
Us TOO! INTERNATIONAL at http://www.ustoo.org/.
This is the world's largest independent, charitable network of education and support
groups for men with prostate cancer and their families, with groups worldwide.
"A Primer on Prostate Cancer, The Empowered Patient's
Guide" by Stephen B. Strum, MD, FACP and Donna Pogliano, Second Edition, copyright
2005, now also available in the German language. The Primer is available at web
booksellers such as www.amazon.com,
http://www.barnesandnoble.com, and www.lefprostate.org.
It can also be ordered through the Life Extension Foundation (+1-866-820-7457)
and at Barnes & Noble, Borders, and other fine bookstores everywhere. This is
an in-depth guide about prostate cancer that presents a comprehensive approach
to the diagnosis, evaluation and selection of therapies currently available to
the prostate cancer patient. It consists of 368 pages of fully indexed text with
168 full color graphics to enhance a clear understanding of prostate cancer. It
is intended to bring the patient-partner-physician team involved with prostate
cancer from a basic understanding of this disease to a highly sophisticated level
Working together, we can achieve vast inroads into
the diagnosis, evaluation and treatment of this illness.
- Cerhan JR, Parker AS, Putnam SD, et al: Family history and prostate cancer risk in a
population-based cohort of Iowa men. Cancer Epidemiol Biomarkers Prev 8:53-60, 1999.
- Hayes RB, Liff JM, Pottern LM, et al: Prostate cancer risk in U.S. blacks and whites with a family history of
cancer. Int J Cancer 60:361-4, 1995.
- Isaacs SD, Kiemeney LA, Baffoe-Bonnie A, et al: Risk of cancer in relatives of prostate cancer probands. J Natl Cancer
Inst 87:991-6, 1995.
- Bennett KE, Howell A, Evans DG, et al: A follow-up study of breast and other cancers in families of an unselected
series of breast cancer patients. Br J Cancer 86:718-22, 2002.
- Ford D, Easton DF, Bishop DT, et al: Risks of cancer in BRCA1-mutation carriers. Breast
Cancer Linkage Consortium. Lancet 343:692-5, 1994.
- Goldgar DE, Easton DF, Cannon-Albright LA, et al: Systematic population-based assessment of cancer risk
in first-degree relatives of cancer probands. J Natl Cancer Inst 86:1600-8, 1994.
- Ito K, Yamamoto T, Ohi M, et al: Free/total PSA ratio is a
powerful predictor of future prostate cancer morbidity in men with initial PSA
levels of 4.1 to 10.0 ng/mL. Urology 61:760-4, 2003.
- Ito K, Yamamoto T, Ohi M, et al: Usefulness of prostate-specific antigen velocity
in screening for prostate cancer. Int J Urol 9:316-21, 2002.
- Labrie F, Candas B, Cusan L, et al: Diagnosis of advanced or noncurable prostate
cancer can be practically eliminated by prostate-specific antigen. Urology 47:212-7, 1996.
- Moul JW, Connelly RR, Perahia B, et al: The contemporary
value of pretreatment prostatic acid phosphatase to predict pathological stage
and recurrence in radical prostatectomy cases. J Urol 159:935-40, 1998.
- Dattoli M, Wallner K, True L, et al: Prognostic role of serum prostatic acid phosphatase
for 103Pd-based radiation for prostatic carcinoma. Int J Radiat Oncol Biol Phys
- Han M, Piantadosi S, Zahurak ML, et al: Serum acid phosphatase
level and biochemical recurrence following radical prostatectomy for men with
clinically localized prostate cancer. Urology 57:707-11, 2001.
- Labrie F, Candas B, Dupont A, et al: Screening decreases prostate cancer death:
first analysis of the 1988 Quebec prospective randomized controlled trial. Prostate