Prostate cancer

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.

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 a 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).

Increasing the specificity for prostate cancer detection and population based screening

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 asymptomatic individuals 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).

Technical aspects

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.

Follow-up and therapy monitoring

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).

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. The diagnosis of prostate cancer requires histopathological verification by prostate biopsy, preferably guided by transrectal ultrasound, before any kind of treatment is initiated.

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