Tumour markers in prostate cancer

8/7/2019 Tumour markers in prostate cancer

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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


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examination. Prognosis is poor and treatment

options are limited to palliative therapy with late

stage disease. With no curative therapy foradvanced 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 E1-antichymotrypsin (MW ~100 kD). Bothforms represent the main fraction of total PSA (t-


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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 thatearly diagnosis and treatment will lead to an

improvement of disease-related and overall mortality


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(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 beexamined 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 treatmentcan 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


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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, sinceno 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-PSAdeterminations can be recommended

in symptomatic men, if the diagnosis of prostate


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cancer alters the treatment decision. In the absence

of studies documenting that early detection of

prostate cancer does more good than harm it maybe 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 tenyears (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


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the assay used and a valid reference range,

specifically generated for thisassaytoenable the

physician in charge ofinterpretingthe resultstodraw correctconclusions(30-32). Ethnicorregional

differencesbetween reference range populations

need tobe considered (33, 34).

Digitalrectalexamination doesnotinfluence theconcentration oft-PSA toaclinicallysignificant

extentin mostofthe studiespublished, butthe

serum concentration off-PSA can probablybe

increased bymanipulation ofthe prostate suchas

digitalrectalexamination (35) orfollowing

ejaculation (36), resultingin "free tototal" PSA

ratiostypicalofthose seen in benign prostatic

hyperplasiain prostate cancerpatients. Toavoid

suchmisleadingresults, blood should be drawn prior

todigitalrectalexamination and the time interval

since the lastejaculation should be noted. Although


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evidence exists that changes in f-PSA concentrations

occur within several hours after drawing of the blood

sample (37-39), no recommendations for theoptimal 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


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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 weighedagainst 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 bedetermined during follow-up of prostate cancer (40).

BRIEF CONCLUSION:--


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t-PSA is clearly the best marker available for

prostate cancer but must be used in conjunction

with digital rectal examination. Although almosttissue-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 prostatichyperplasia. 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, TeppoL, Leinonen J: Serum concentrations of prostate


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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, Bjrk 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, Frohmller HGW: Prostate specific antigenand prostate acid phosphatase in the detection of

early prostate cancer and the prediction of regional

lymph node metastases. Eur Urol 22: 27-32, 1992.


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5.Kontturi M: Is acid phosphatase (PAP) still justifiedin 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.Schrder FH, Boyle P: Screening for prostate cancer- necessity or nonsense? Eur J Cancer 29A: 656-661,

1993.


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10.Babaian RJ, Miyashita H, Evans RB, vonEschenbach AC, Ramirez EI: Early detection program

for prostate cancer: results and identification ofhigh-risk patient population. Urology 37: 193-197,

1991.

11.Catalona WJ, Richie JP, Ahmann FR, Hudson MA,Scardino PT, Flanigan RC, et al: Comparison ofdigital 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 evaluationof prostate -specific antigen as a screening test for

prostate cancer. Arch Intern Med 153: 2529-2537,

1993.

13.Schrder FH, Bangma CH: The Europeanrandomized study of screening for prostate cancer

(ERSPC). Brit J Urol 79 Suppl.: 68-71, 1997.


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14.Veneziano S, Pavlica P, Querz R, Nanni G,Lalanne MG, Vecchi F: Correlation between prostate-

specific antigen and prostate volume evaluated bytransrectal 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 menwithout 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


15/26

men - Establishment of age-specific reference

ranges. JAMA 270: 860-864, 1993.

18.Paul R, Breul J, Hartung R: Prostate-specificantigen 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, ChanDW, 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: Aprospective evaluation of plasma prostate-specific

antigen for detection of prostatic cancer. JAMA 273:

289-294, 1995.


16/26

22.Schmid HP: Prostate specific antigen doubling timein 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


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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 E1-antichymotrypsin (MW ~100 kD). Bothforms 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


18/26

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 bewithheld from symptomatic men and those who wish

to be examined for the presence of prostate cancer.


19/26

Application to the general population should depend,

however, on the results of prospective randomized

studies showing that early detection and treatmentcan 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 screeningpopulations 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, TeppoL, Leinonen J: Serum concentrations of prostate

specific antigen and its complex with alpha1-

antichymotrypsin before diagnosis of prostate

cancer. Lancet 344: 1594-1598, 1994.


20/26

2.Lilja H, Christensson A, Dahlen U, Matikainen MT,Nilsson O, Pettersson K, et al: Prostate-specific

antigen in serum occurs predominantly in complexwith alpha-1-antichymotrypsin. Clin Chem 37: 1618-

1625, 1991.

3.Christensson A, Bjrk T, Nilsson O, Dahlen U,Matikainen M, Cockett ATK, et al: Serum prostatespecific antigen complexed to alpha 1-

antichymotrypsin as an indicator of prostate cancer.

J Urol 150: 100-105, 1993.

4.Wirth MP, Frohmller HGW: Prostate specific antigenand 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 justifiedin the management of prostatic cancer? Acta

Oncol 30: 169-170, 1991.


21/26

6.Stamey TA, Freiha FS, McNeal JE, Redwine EA,Whittemore AS, Schmid HP: Localized prostate

cancer. Relationship of tumour volume to clinicalsignificance 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 earlylocalised 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.Schrder FH, Boyle P: Screening for prostate cancer- necessity or nonsense? Eur J Cancer 29A: 656-661,

1993.

10. Babaian RJ, Miyashita H, Evans RB, vonEschenbach AC, Ramirez EI: Early detection program

for prostate cancer: results and identification of


22/26

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 6,630men. J Urol 151: 1283-1290, 1994.

12. Dorr VJ, Williamson, Stephens RL: An evaluationof prostate -specific antigen as a screening test for

prostate cancer. Arch Intern Med 153: 2529-2537,

1993.

13. Schrder FH, Bangma CH: The Europeanrandomized study of screening for prostate cancer

(ERSPC). Brit J Urol 79 Suppl.: 68-71, 1997.

14. Veneziano S, Pavlica P, Querz R, Nanni G,Lalanne MG, Vecchi F: Correlation between prostate-

specific antigen and prostate volume evaluated by


23/26

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.


24/26

18. Paul R, Breul J, Hartung R: Prostate-specificantigen density and age-specific prostate-specific

antigen values: the solution of prostate cancerscreening? 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: Aprospective evaluation of plasma prostate-specific

antigen for detection of prostatic cancer. JAMA 273:

289-294, 1995.

22. Schmid HP: Prostate specific antigen doublingtime in diagnosis and follow-up of patients with


25/26

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 blackmen. N Engl J Med 335: 304-310, 1996.

26. Collins GN, Martin PJ, Wynn-Davies A, BroomanPJ, O'Reilly PH: The effect of digital rectal

examination, flexible cystoscopy and prostatic biopsy

on free and total prostate specific antigen, and the


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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.

Tumour markers in prostate cancer

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