Education and debate

ABC of Urology: UROLOGICAL MALIGNANCY--1: PROSTATE CANCER

Symptoms and signs

The symptoms and signs of prostate cancer are initially closely similar to those of benign prostatic hyperplasia--obstruction of the urethra by the malignant gland may lead to hesitancy, poor urinary flow, intermittent flow, post-micturition dribbling, and incomplete emptying. Secondary bladder instability may ensue and give rise to urinary frequency, nocturia, and urgency.

 Haemospermia

 * Patients with haemospermia often present
 to their general practitioner thinking that they
 may have cancer

 * Haemospermia is usually related to non-
 specific inflammation of the prostate and
 settles spontaneously

The patient may also present with haematuria, typically reporting that the blood appears at the beginning of an otherwise clear urinary stream. Although this suggests a cause localised to the lower urinary tract, all such patients should be investigated and managed along the lines described for patients with haematuria (see next article in the series).

 Onset

 * Prostate cancer typically proceeds
 insidiously

 * Men often present late with advanced
 disease and symptoms resulting from bony
 metastasis or from anaemia of chronic disease

Investigations of patients with suspected prostate cancer

Investigations begin in the same way as for patients with benign prostatic hyperplasia--a full history of the main symptoms, followed by a thorough clinical examination and digital rectal examination. There are few clinical signs in early prostate cancer, but digital rectal examination will often detect an early lesion. In prostate cancer either the normal smooth surface of the prostate may be replaced by a hard nodule or the gland itself may be enlarged, hard, and "craggy" to the touch. The normal midline sulcus may be lost.

The serum prostate specific antigen level should be established. Normal ranges depend on the assay used.

 Normal ranges for prostate
 specific antigen

 Polyclonal assay   0-2.5 ng/ml
 Monoclonal assay   0-4 ng/ml

Whether to proceed with a transrectal ultrasound examination and biopsy has been the subject of much debate, but current recommendations suggest that most men with either an abnormal finding on digital rectal examination or a raised prostate specific antigen value should have a transrectal biopsy with ultrasound guidance. This recommendation should be considered in the context of the individual patient, and elderly or frail men with no other signs of cancer may be successfully managed by close observation. Biopsy is not without complications (particularly infection and bleeding), and this should be remembered when considering a biopsy. The rise in prostate specific antigen over time can also be used to discriminate between benign prostatic hyperplasia and prostate cancer, and a value rising by more than 0.75 ng/ml a year has been suggested as the cut off point for these two conditions.

View larger version (123K): [in this window] [in a new window]   Technique of transperineal prostate biopsy. The operator guides the needle into the prostate with finger placed in rectum.

View larger version (129K): [in this window] [in a new window]   Transrectal ultrasound scan showing prostate cancer (arrow) bulging anteriorly through prostate capsule.

Screening for prostate cancer

Several problems have beset the widespread acceptance of screening. Firstly, the correct protocol has yet to be established. Digital rectal examination as a screening tool relies heavily on the experience of the examiner. If digital rectal examination alone is used, one third of patients diagnosed with prostate cancer will have incurable disease. Transrectal ultrasonography, when used alone, has low positive and negative predictive values and so is not recommended as a screening tool--it should be reserved for guiding the urologist's needle during biopsies. Determining the prostate specific antigen level remains the most useful tool for screening, and several recent studies have confirmed its specificity.

 Screening

 * The value of screening for prostate cancer
 has been much debated by urologists

 * Proponents cite as justification the fact that
 the incidence of prostate cancer is rising by
 3% a year

 * Prostate cancer is now the second
 commonest cause of death from cancer in
 men in northern Europe

Secondly, one of the concerns about routine screening for prostate cancer is that either (a) it may detect patients who have prostate cancer that has spread beyond the prostate capsule (and is thus incurable) or (b) small tumours that will be clinically unimportant during the lifetime of the patient may be discovered, the treatment of which may cause appreciable morbidity. At postmortem examination about one third of men aged over 75 years will have clinically unimportant microscopic foci of cancer in the prostate that cannot be detected by current methods. However, cancers detectable by determination of prostatic specific antigen level may differ from these unimportant cancers.

Thus screening with use of prostatic specific antigen values seems to have the potential to detect clinically important disease.

 Differences between cancers detectable with
 prostate specific antigen value and clinically
 unimportant cancers not detectable till postmortem
 examination

 * Cancers that are detectable by use of prostate specific antigen values
 may be more likely to be clinically relevant

 * Cancers detected by use of prostate specific antigen values are
 frequently either poorly differentiated or spread widely throughout the
 prostate

 * Most cancers detected by use of prostate specific antigen values will be
 reclassified to a higher clinical stage when removed at radical
 prostatectomy

Management of prostate cancer Localised disease

Patients in this group comprise those with clinically inapparent disease (stage T1 in the tumour, node, metastases (TNM) classification system) and those with palpable disease confined to the prostate (stage T2).

View larger version (155K): [in this window] [in a new window]   Diagrams showing first two stages of prostate cancer: T1--clinically inapparent cancer; T2--palpable disease confined to prostate.

Many men are discovered to have prostate cancer after histopathological examination of prostate chips removed during a transurethral prostatectomy for bladder outflow obstruction, presumed to be due to benign prostatic hyperplasia.

Patients with a life expectancy of less than 10 years and stage T1a disease are probably best managed by regular follow up, as few such cancers will progress over the next 10 years. Higher stage disease in these patients (but still localised to the prostate) should be managed by radiotherapy or hormonal therapy. Patients whose life expectancy is more than 10 years should be given the choice of either radical prostatectomy or radiotherapy, although stage T1a disease can initially be managed by surveillance.

Radical prostatectomy is associated with an impotence rate of 30-60%, although impotence is less common when nerve sparing approaches are used. Urinary incontinence (incidence of 5-15%) may respond to drugs, although implantation of an artificial urinary sphincter may be needed.

Radiotherapy in localised disease (stage T1 or T2) is the preferred treatment for older patients and those whose health status or grade of tumour precludes curative surgery. Impotence is a side effect in up to 60% of patients, but 15 year disease-free survival rates of up to 85% have been achieved.

Locally advanced disease

In patients with locally advanced disease (stage T3) the emphasis is not to cure as most men will have occult metastatic disease. The preferred treatment for these patients is radiotherapy, although radical prostatectomy is sometimes performed as a salvage procedure when radiotherapy fails.

View larger version (148K): [in this window] [in a new window]   Diagrams showing third and fourth stages of prostate cancer: T3--locally advanced disease, with tumour extending beyond prostate capsule; T4--disseminated disease, showing metastasis to femur.

Disseminated disease

Most patients with disseminated disease (stage T4) are treated with hormonal therapy, although the correct time to start such treatment remains unclear. Symptomatic men should begin treatment immediately, whereas those without symptoms may be spared treatment until symptoms develop.

Hormonal therapies are based on the suppression of testosterone production or competition with its effects. Cyproterone acetate is an antiandrogen which acts by preventing the active metabolite of testosterone--dihydrotestosterone--from binding to intracytoplasmic protein complexes within the prostate cell and thus reduces prostatic cell growth. Luteinising hormone-releasing hormone agonists, such as goserelin, act by initially stimulating the release of gonadotrophins by the pituitary, before causing an inhibition. For this reason an antiandrogen should be given before the use of a luteinising hormone-releasing hormone agonist to prevent the transient stimulation of tumour growth. On occasions such tumour stimulation may lead to compression of the spinal cord by bone metastases or to urinary retention.

Bilateral subcapsular orchidectomy is as effective as either of the above treatments and removes the need for continued therapy. However, many men find the thought of surgical castration unpalatable.

Recent advances

 Recent advances in management of prostate cancer

 Intracrinology                                                      Apoptosis

 * Intracrinology is the study of the synthesis of active steroids   * Apoptosis describes a complex mechanism of programmed
 in peripheral target tissues                                        cell death by which effete cells are removed from a tissue

 * It has recently been shown that the adrenal may be the source     * The regulatory pathways of apoptosis may be switched off in
 of inactive steroid precursors, which are converted into active     malignant tissues
 metabolites in the prostate
                                                                     * Removal of androgens by medical or surgical castration
 * Studies have shown that medical or surgical castration            induces androgen dependent prostate cancer cells to undergo
 remove serum testosterone, but dihydrotestosterone levels in        apoptosis, but most patients relapse when androgen
 the prostate are less affected, showing the importance of           independent cells become the dominant cell type
 adrenal androgens
                                                                     * Radiation and certain cytotoxic drugs may achieve their
 * The combination of medical castration and inhibition of action    beneficial effects by inducing apoptosis in this androgen
 of dihydrotestosterone together (maximal androgen blockade)         independent cell population
 has been shown to produce a small improvement in response
 rates in some patients with prostate cancer

 Key references

 Catalona WJ. Management of cancer of the prostate. N Engl J Med
 1994;331:996-1004

 Steiner MS. Role of peptide growth factors in prostate cancer. Eur Urol
 1995;27(suppl 2):9

 Andriole GL, Gerber GS. Screening for prostate cancer: American view.
 Current Opinion in Urology 1993;3:373-6

 Boyle P, Alexander FE, Standaert B, Denis L. Screening for prostate cancer.
 In: Hendry WF, Kirby RS, eds. Advances in urology/andrology. Vol 6.
 Edinburgh: Churchill Livingstone, 1993

 Bentvelsen FM, Schroder FH. Modalities available for screening of prostate
 cancer. Eur J Cancer 1993;29A:804-11

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Papatsoris, A. G, Anagnostopoulos, F. (2008). Men's behaviour towards prostate cancer screening. Postgrad. Med. J. 84: 57-59 [Full text]  
• Del Mar, C B, Glasziou, P. P (1996). ABC series may be anachronistic in era of evidence based medicine. BMJ 313: 880-880 [Full text]  
• Hehir, M., Walker, L. (1996). Article on prostate cancer should have adhered to agreed staging terminology. BMJ 313: 492-492 [Full text]