GH7P54LQFUGI

PROSTATE –QUEST FOR EARLY

DIAGNOSIS

ANIL BATTA

Introduction:--

Prostate cancer is a frequent cause of death in men.

Unfortunately, the majority of prostate cancers have
spread beyond the gland when first diagnosed using
the conventional detection method, digital rectal
examination. Prognosis is poor and treatment
options are limited to palliative therapy with late
stage disease. With no curative therapy for
advanced prostate cancer available currently or in the
foreseeable future, the most promising alternative for
improving the prognosis of patients with prostate cancer is
to enhance early detection.

WAY TO DIAGNOSIS EARLY:--

The most useful tumour marker for prostate cancer

at present is prostate-specific antigen (PSA). PSA is
a glycoprotein that is almost exclusively produced in
the prostate. The major forms that presently can be
determined in human serum are the uncomplexed,
free form (f-PSA, MW ~33 kD) and a complex of f-
PSA with  1-antichymotrypsin (MW ~100 kD). Both
forms represent the main fraction of total PSA (t-
PSA) that can currently be identified in human
serum (1-3).
The determination of prostatic acid phosphatase
(PAP) does not add clinically useful information to
PSA measurement, and is therefore not
recommended (4,5).

Screening and diagnosis

The use of PSA for the detection of prostate cancer
leads to an earlier diagnosis and probably more
curable stages of the disease are detected. On the
other hand, knowledge of the natural history of early
lesions suggests that indiscriminate use of PSA will lead
to overdiagnosis and overtreatment in some cases (6).
Information on the effectiveness of treatment is

currently unavailable, and no evidence exists that

early diagnosis and treatment will lead to an
improvement of disease-related and overall mortality
(7,8). Despite these uncertainties it is proposed that
use of the PSA test should not be withheld from
symptomatic men and those who wish to be
examined for the presence of prostate cancer.
Application to the general population should depend,
however, on the results of prospective randomized
studies showing that early detection and treatment
can decrease prostate cancer mortality (9). Since
the positive predictive value (number of positive
tests in patients with the disease divided by the total
number of tests performed) of PSA in screening
populations is disturbingly low (~30%) it is
necessary to enhance the specificity of the tumour
marker (10-13).

URGENCY FOR EARLY TREAMENT:--

Possible ways to increase the specificity of t-PSA in
the diagnosis of prostate cancer may include
determination of t-PSA/prostate volume-ratio (14-
16), use of age-specific reference ranges (17-19) or
measurement of serial t-PSA increase over time (PSA
"velocity" or "doubling time") (20-22) but evidence
is as yet inconclusive or the application is of limited
use in daily practice. The use of age-specific
reference ranges cannot be recommended yet, since
no trials are available showing the efficacy of
prostate biopsies for age-specific PSA decision points
of concentrations lower than 4 ng/ml. For highly
selected sub-populations, the free to total PSA ratio
may hold most promise to enhance the specificity of
PSA for detecting prostate cancer (1-3, 23-27) but
considerable further research is required.

Despite well documented drawbacks, t-PSA

determinations can be recommended
in symptomatic men, if the diagnosis of prostate
cancer alters the treatment decision. In the absence
of studies documenting that early detection of
prostate cancer does more good than harm it may
be reasonable to restrict PSA testing
in asymptomaticindividuals to those who agree to
undergo prostate biopsy in case of elevated t-PSA
levels and have a life expectancy of more than ten
years (28, 29). At this time, there is no evidence to
encourage the widespread use of PSA testing or the
introduction of population based screening to detect
prostate cancer (7).

BIOCHEMICAL MARKERS:--
To assure a valid recognition of the presence or
absence of cancer suspicion, the characteristics and
assay-specific reference ranges of available PSA
assays (of which there are now more than eighty)
should be distributed by the producer of the assay.
Every laboratory report should contain the name of
the assay used and a valid reference range,
specifically generated for this assay to enable the
physician in charge of interpreting the results to
draw correct conclusions (30-32). Ethnic or regional
differences between reference range populations
need to be considered (33, 34).
Digital rectal examination does not influence the
concentration of t-PSA to a clinically significant
extent in most of the studies published, but the
serum concentration of f-PSA can probably be
increased by manipulation of the prostate such as
digital rectal examination (35) or following
ejaculation (36), resulting in "free to total" PSA
ratios typical of those seen in benign prostatic
hyperplasia in prostate cancer patients. To avoid
such misleading results, blood should be drawn prior
to digital rectal examination and the time interval
since the last ejaculation should be noted. Although
evidence exists that changes in f-PSA concentrations
occur within several hours after drawing of the blood
sample (37-39), no recommendations for the
optimal time interval before processing can be given
currently and it is proposed to use the same pre-
analytical conditions that were applied in generating
the reference values of the assay used (37).
Medication with anti-androgenic effect (e.g. LHRH
agonists or 5-alpha-reductase inhibitors) can lead to
low t-PSA concentrations although prostate cancer is
present.

EARLY DIAGNOSIS & TREATMENT:-

Following the diagnosis and treatment of prostate
cancer, t-PSA is a valuable tool for determining the
prognosis of a patient in the absence of anti-
androgen treatment. If anti-androgen treatment has
been initiated, t-PSA does not always reflect the
behaviour of the tumour.

Knowledge of post-treatment t-PSA values can

enhance quality of life if they indicate absence of
residual disease, but conversely can lead to
diminished well-being in otherwise asymptomatic
patients who can anticipate the clinical progress of
the disease by rising t-PSA values months or even
years prior to the appearance of symptoms. The
possible drawbacks of t-PSA determinations
following treatment should always be weighed
against the therapeutic means that can be offered to
the patient in case of rising t-PSA values.

f-PSA has not been shown to offer clinically relevant

prognostic information and should therefore not be
determined during follow-up of prostate cancer (40).

BRIEF CONCLUSION:--
 t-PSA is clearly the best marker available for
prostate cancer but must be used in conjunction
with digital rectal examination. Although almost
tissue-specific, it is not disease-specific. There is
considerable overlap in t-PSA concentrations
between patients with organ-confined prostate
cancer and patients with benign prostatic
hyperplasia. Conversely, approximately 25% of
patients with prostate cancer show no elevation of
serum t-PSA and must be diagnosed by other
methods, e.g. digital rectal examination. Increased
serum PSA concentrations and/or abnormal digital
rectal examination can only raise the suspicion of
prostate cancer..

REFERENCES

1. Stenman UH, Hakama M, Knekt P, Aromaa A,

Teppo L, Leinonen J: Serum concentrations of
 prostate specific antigen and its complex with
alpha1-antichymotrypsin before diagnosis of
prostate cancer. Lancet 344: 1594-1598, 1994.
2. Lilja H, Christensson A, Dahlen U, Matikainen MT,
Nilsson O, Pettersson K, et al: Prostate-specific
antigen in serum occurs predominantly in complex
with alpha-1-antichymotrypsin. Clin Chem 37: 1618-
1625, 1991.
3. Christensson A, Björk T, Nilsson O, Dahlen U,
Matikainen M, Cockett ATK, et al: Serum prostate
specific antigen complexed to alpha 1-
antichymotrypsin as an indicator of prostate cancer.
J Urol 150: 100-105, 1993.
4. Wirth MP, Frohmüller HGW: Prostate specific
antigen and prostate acid phosphatase in the
detection of early prostate cancer and the prediction
of regional lymph node metastases. Eur Urol 22: 27-
32, 1992.
5. Kontturi M: Is acid phosphatase (PAP) still justified
in the management of prostatic cancer? Acta
Oncol 30: 169-170, 1991.
6. Stamey TA, Freiha FS, McNeal JE, Redwine EA,
Whittemore AS, Schmid HP: Localized prostate
cancer. Relationship of tumour volume to clinical
significance for treatment of prostate cancer.
Cancer 71 Suppl. 3: 933-938, 1993.
7. 7 Selley S, Donovan J, Faulkner A, Coast J, Gillatt
D: Diagnosis, management and screening of early
localised prostate cancer. Health Technol Assess 1:
No. 2, 1997.
8. Australian Health Technology Advisory Committee:
Prostate cancer screening. Canberra, Australian
Health Technology Advisory Committee, 1996.
9. Schröder FH, Boyle P: Screening for prostate
cancer - necessity or nonsense? Eur J Cancer 29A:
656-661, 1993.
10. Babaian RJ, Miyashita H, Evans RB, von
Eschenbach AC, Ramirez EI: Early detection program
for prostate cancer: results and identification of
high-risk patient population. Urology 37: 193-197,
1991.
11. Catalona WJ, Richie JP, Ahmann FR, Hudson MA,
Scardino PT, Flanigan RC, et al: Comparison of
digital rectal examination and serum prostate
specific antigen in the early detection of prostate
cancer: results of a multicenter clinical trial of 6,630
men. J Urol 151: 1283-1290, 1994.
12. Dorr VJ, Williamson, Stephens RL: An evaluation
of prostate -specific antigen as a screening test for
prostate cancer. Arch Intern Med 153: 2529-2537,
1993.
13. Schröder FH, Bangma CH: The European
randomized study of screening for prostate cancer
(ERSPC). Brit J Urol 79 Suppl.: 68-71, 1997.
14. Veneziano S, Pavlica P, QuerzŠ R, Nanni G,
Lalanne MG, Vecchi F: Correlation between prostate-
specific antigen and prostate volume evaluated by
transrectal ultrasonography: usefulness in diagnosis
of prostate cancer. Eur Urol 18: 112-116, 1990.
15. Babaian RJ, Miyashita H, Evans RB, Ramirez EI:
The distribution of prostate specific antigen in men
without clinical or pathological evidence of prostate
cancer: relationship to gland volume and age. J
Urol 147: 837-840, 1992.
16. Benson MC, Whang IS, Olsson CA, McMahon DJ,
Cooner WH: The use of prostate specific antigen
density to enhance the predictive value of
intermediate levels of serum prostate specific
antigen. J Urol 147: 817-821, 1992.
17. Oesterling JE, Jacobsen SJ, Chute CG, Guess HA,
Girman CJ, Panser LA, et al: Serum prostate-specific
antigen in a community-based population of healthy
 men - Establishment of age-specific reference
ranges. JAMA 270: 860-864, 1993.
18. Paul R, Breul J, Hartung R: Prostate-specific
antigen density and age-specific prostate-specific
antigen values: the solution of prostate cancer
screening? Eur Urol 27: 286-291, 1995.
19. Etzioni R, Shen Y, Petteway JC, Brawer MK: Age-
specific prostate-specific antigen: a reassessment.
Prostate Suppl. 7: 70-77, 1996.
20. Carter BC, Pearson JD, Metter EJ, Brant LJ, Chan
DW, Andres R et al: Longitudinal evaluation of
prostate-specific antigen levels in men with and
without prostate disease. JAMA 267: 2215-2220,
1992.
21. Gann PH, Hennekens CH, Stampfer MJ: A
prospective evaluation of plasma prostate-specific
antigen for detection of prostatic cancer. JAMA 273:
289-294, 1995.
22. Schmid HP: Prostate specific antigen doubling time
in diagnosis and follow-up of patients with prostate
cancer. Tumour Marker Update 8: 71-77, 1996.
23. Catalona WJ, Smith DS, Wolfert RL, Wang TJ,
Rittenhouse HG, Ratliff TL, et al: Evaluation of
percentage of free serum prostate-specific antigen
to improve specificity of prostate cancer screening.
JAMA 274: 1214-1220, 1995.
24. Catalona WJ, Partin AW, Slawin KM, Brawer MK,
Flanigan RC, Patel A, et al: Use of the percentage of
free prostate-specific antigen to enhance
differentiation of prostate cancer from benign
prostatic disease. JAMA 279: 1542-1547, 1998.
25. Stenman UH, Leinonen J, Alfthan H, Rannikko S,
Tuhkanen K, Alfthan O: A complex between
prostate-specific antigen and alpha 1-
antichymotrypsin is the major form of prostate-
specific antigen in serum of patients with prostatic
cancer: assay of the complex improves clinical
sensitivity for cancer. Cancer Res 51: 222-226,
1991.

Tumour markers in prostate cancer

The most useful tumour marker for prostate cancer
at present is prostate-specific antigen (PSA). PSA is
a glycoprotein that is almost exclusively produced in
the prostate. The major forms that presently can be
determined in human serum are the uncomplexed,
free form (f-PSA, MW ~33 kD) and a complex of f-
PSA with  1-antichymotrypsin (MW ~100 kD). Both
forms represent the main fraction of total PSA (t-
PSA) that can currently be identified in human
serum (1-3).
The determination of prostatic acid phosphatase
(PAP) does not add clinically useful information to
PSA measurement, and is therefore not
recommended (4,5).

Screening and diagnosis

The use of PSA for the detection of prostate cancer
leads to an earlier diagnosis and probably more
curable stages of the disease are detected. On the
other hand, knowledge of the natural history of early
lesions suggests that indiscriminate use of PSA will
lead to overdiagnosis and overtreatment in some
cases (6). Information on the effectiveness of
treatment is currently unavailable, and no evidence
exists that early diagnosis and treatment will lead to
an improvement of disease-related and overall
mortality (7,8). Despite these uncertainties it is
proposed that use of the PSA test should not be
withheld from symptomatic men and those who wish
to be examined for the presence of prostate cancer.
 Application to the general population should depend,
however, on the results of prospective randomized
studies showing that early detection and treatment
can decrease prostate cancer mortality (9). Since
the positive predictive value (number of positive
tests in patients with the disease divided by the total
number of tests performed) of PSA in screening
populations is disturbingly low (~30%) it is
necessary to enhance the specificity of the tumour
marker (10-13).

REFERENCES

1. Stenman UH, Hakama M, Knekt P, Aromaa A,

Teppo L, Leinonen J: Serum concentrations of
prostate specific antigen and its complex with
alpha1-antichymotrypsin before diagnosis of
prostate cancer. Lancet 344: 1594-1598, 1994.
2. Lilja H, Christensson A, Dahlen U, Matikainen
MT, Nilsson O, Pettersson K, et al: Prostate-specific
antigen in serum occurs predominantly in complex
with alpha-1-antichymotrypsin. Clin Chem 37: 1618-
1625, 1991.
3. Christensson A, Björk T, Nilsson O, Dahlen U,
Matikainen M, Cockett ATK, et al: Serum prostate
specific antigen complexed to alpha 1-
antichymotrypsin as an indicator of prostate cancer.
J Urol 150: 100-105, 1993.
4. Wirth MP, Frohmüller HGW: Prostate specific
antigen and prostate acid phosphatase in the
detection of early prostate cancer and the prediction
of regional lymph node metastases. Eur Urol 22: 27-
32, 1992.
5. Kontturi M: Is acid phosphatase (PAP) still
justified in the management of prostatic cancer?
Acta Oncol 30: 169-170, 1991.
6. Stamey TA, Freiha FS, McNeal JE, Redwine EA,
Whittemore AS, Schmid HP: Localized prostate
cancer. Relationship of tumour volume to clinical
significance for treatment of prostate cancer.
Cancer 71 Suppl. 3: 933-938, 1993.
7. 7 Selley S, Donovan J, Faulkner A, Coast J, Gillatt
D: Diagnosis, management and screening of early
localised prostate cancer. Health Technol Assess 1:
No. 2, 1997.
8. Australian Health Technology Advisory
Committee: Prostate cancer screening. Canberra,
Australian Health Technology Advisory Committee,
1996.
9. Schröder FH, Boyle P: Screening for prostate
cancer - necessity or nonsense? Eur J Cancer 29A:
656-661, 1993.
10. Babaian RJ, Miyashita H, Evans RB, von
Eschenbach AC, Ramirez EI: Early detection program
 for prostate cancer: results and identification of
high-risk patient population. Urology 37: 193-197,
1991.
11. Catalona WJ, Richie JP, Ahmann FR, Hudson MA,
Scardino PT, Flanigan RC, et al: Comparison of
digital rectal examination and serum prostate
specific antigen in the early detection of prostate
cancer: results of a multicenter clinical trial of 6,630
men. J Urol 151: 1283-1290, 1994.
12. Dorr VJ, Williamson, Stephens RL: An evaluation
of prostate -specific antigen as a screening test for
prostate cancer. Arch Intern Med 153: 2529-2537,
1993.
13. Schröder FH, Bangma CH: The European
randomized study of screening for prostate cancer
(ERSPC). Brit J Urol 79 Suppl.: 68-71, 1997.
14. Veneziano S, Pavlica P, QuerzŠ R, Nanni G,
Lalanne MG, Vecchi F: Correlation between prostate-
 specific antigen and prostate volume evaluated by
transrectal ultrasonography: usefulness in diagnosis
of prostate cancer. Eur Urol 18: 112-116, 1990.
15. Babaian RJ, Miyashita H, Evans RB, Ramirez EI:
The distribution of prostate specific antigen in men
without clinical or pathological evidence of prostate
cancer: relationship to gland volume and age. J
Urol 147: 837-840, 1992.
16. Benson MC, Whang IS, Olsson CA, McMahon DJ,
Cooner WH: The use of prostate specific antigen
density to enhance the predictive value of
intermediate levels of serum prostate specific
antigen. J Urol 147: 817-821, 1992.
17. Oesterling JE, Jacobsen SJ, Chute CG, Guess HA,
Girman CJ, Panser LA, et al: Serum prostate-specific
antigen in a community-based population of healthy
men - Establishment of age-specific reference
ranges. JAMA 270: 860-864, 1993.
18. Paul R, Breul J, Hartung R: Prostate-specific
antigen density and age-specific prostate-specific
antigen values: the solution of prostate cancer
screening? Eur Urol 27: 286-291, 1995.
19. Etzioni R, Shen Y, Petteway JC, Brawer MK: Age-
specific prostate-specific antigen: a reassessment.
Prostate Suppl. 7: 70-77, 1996.
20. Carter BC, Pearson JD, Metter EJ, Brant LJ, Chan
DW, Andres R et al: Longitudinal evaluation of
prostate-specific antigen levels in men with and
without prostate disease. JAMA 267: 2215-2220,
1992.
21. Gann PH, Hennekens CH, Stampfer MJ: A
prospective evaluation of plasma prostate-specific
antigen for detection of prostatic cancer. JAMA 273:
289-294, 1995.
22. Schmid HP: Prostate specific antigen doubling
time in diagnosis and follow-up of patients with
 prostate cancer. Tumour Marker Update 8: 71-77,
1996.
23. Catalona WJ, Smith DS, Wolfert RL, Wang TJ,
Rittenhouse HG, Ratliff TL, et al: Evaluation of
percentage of free serum prostate-specific antigen
to improve specificity of prostate cancer screening.
JAMA 274: 1214-1220, 1995.
24. Catalona WJ, Partin AW, Slawin KM, Brawer MK,
Flanigan RC, Patel A, et al: Use of the percentage of
free prostate-specific antigen to enhance
differentiation of prostate cancer from benign
prostatic disease. JAMA 279: 1542-1547, 1998.
25. ranges for prostate-specific antigen in black
men. N Engl J Med 335: 304-310, 1996.
26. Collins GN, Martin PJ, Wynn-Davies A, Brooman
PJ, O'Reilly PH: The effect of digital rectal
examination, flexible cystoscopy and prostatic biopsy
on free and total prostate specific antigen, and the
free-to-total prostate specific antigen ratio in clinical
practice. J Urol 157: 1744-1747, 1997.

Author has been Senior

Resident in PGIMER,
Chandigarh .He is now
working as Associate Professor
in the department of
BIOCHEMISTRY Baba Farid
University of Health Sciences,
Faridkot Punjab India for the
last 13 Years.