Prostate cancer is one of the most common and controversial conditions treated by urologists. No uniform opinion exists regarding diagnosis or treatment for any stage of the disease, even within institutions. In this Section we review the ‘non-controversial’ aspects of pathology, epidemiology, and clinical presentation of prostate cancer, followed by the more controversial topics of diagnosis, treatment, and the rationale for the differences between management protocols.

Prostate cancer is a major cause of morbidity and mortality in men over 45 years old worldwide. In the United States it ranks second as a cause of cancer deaths in men, with an estimated lifetime risk for clinical diagnosis of 8 per cent. Median age for clinical diagnosis is 72 years. The autopsy prevalence however is much higher and is directly proportional to age, with an overall rate of about 30 per cent in men over 50 years of age. Most of these lesions found at autopsy are well differentiated and of very low volume (<1 mm³).

There are marked geographical and racial differences in the incidence of prostate cancer. North Americans (especially African Americans) and Western Europeans have higher rates than average and Orientals living in the East have lower rates. Interestingly, the autopsy prevalence is fairly constant worldwide. Emigration from a low incidence to a high incidence country results in an intermediate level of risk, suggesting the involvement of environmental factors in the aetiology.

Prostate cancer is endocrine dependent and requires testosterone to develop and grow. Eunuchs never develop prostate cancer, and men with low testosterone due to other conditions have low rates. Diet is also an important risk factor. There is a positive correlation between prostate cancer rates and high dietary fat intake. High fat intake may result in promotion of endocrine-sensitive tumours and increase the available prostatic testosterone. First-degree relatives of prostate cancer patients have an eight-fold increased risk of prostate cancer, especially if the cancer develops at a young age (<60 years).

Malignant tumours of the prostate can arise from epithelial or non-epithelial cells. Adenocarcinoma represents over 95 per cent of all epithelial tumours, which are the most common in adult men. Transitional cell carcinomas may arise as a direct extension from a bladder tumour or may develop solely in the prostate from its own transitional epithelium. Squamous cell carcinomas are the rarest epithelial tumours but are seen more frequently after external beam radiotherapy of adenocarcinoma. In children, non-epithelial tumours, especially rhabdomyosarcomas, predominate.

Several grading systems attempt to classify adenocarcinomas by their risk for progression. The most popular is the Gleason system, which assigns a category from 1 to 5 based on degree of differentiation, gland formation, and the relationship of cancer cells to stroma, determined by the low power microscopic appearance. The Gleason score is the sum of the two most common patterns, ranging therefore from 2 (most well differentiated) to 10 (most poorly differentiated). While simple and reproducible, there is no consideration of cytological appearance or anaplasia. The Gleason score correlates linearly with stage of disease, but most overlap is found in intermediate grades, in which treatment selection is most difficult. Other grading systems consider cellular morphology as well as glandular pattern. The most commonly used of these are the Mostofi, Gaeta, and Mayo systems. None has a distinct prognostic advantage over the standard Gleason score.

Recently, the use of flow cytometry to determine DNA ploidy has become an important prognostic tool. Cells with an abnormal chromosome number (aneuploid) have a higher risk of recurrence and progression. Patients with diploid untreated, localized disease (stage B) have a 90 per cent 6-year survival. Survival drops to 40 per cent for those with aneuploid tumours. The Mayo clinic reported aneuploidy in 63 per cent of tumours which recurred following treatment but in only 8 per cent of tumours that remained stable.

Apart from grade, the single strongest predictor of tumour progression and metastasis is tumour volume. Most clinically significant tumours have a volume greater than 5 mm³ while most incidental tumours found at autopsy are less than 1 mm³

The search for predictors of tumour progression in an individual patient is of key importance in treatment selection. Other markers currently under investigation are nuclear roundness, cell motility, character of tumour cell borders, lymphocytic/blood vessel infiltration, oncogene expression, and the presence of growth factors and receptors.

Prostate cancer can spread locally via the entrance to the seminal vesicles or vasa deferentia, which may produce ureteral obstruction in 10 to 35 per cent of patients. Rectal invasion is rare. Primary lymphatic drainage is via the internal iliac, perivesical, external iliac, obturator, and presacral nodes. The secondary field includes inguinal, common iliac, and para-aortic nodes. Bloodborne spread to bone is common: bone metastases occur in 85 per cent of patients who die of prostate cancer. Common sites are the axial skeleton, proximal femur, pelvis, ribs, sternum, skull, and humerus. Soft tissue metastases also occur, primarily in liver and lung. Most patients with distant spread also have positive nodes.

The first staging system for prostate adenocarcinoma, and still the most popular in North America, is the American Urologic System devised by Whitmore and later modified by Jewett and Catalona (Table 1) 466.

The International Union Against Cancer system (TNM) has been updated in 1992 and is reproduced in Table 2 467. This TNM-based system is used worldwide, but is more popular in Europe.

For many years, prostate cancer could only be diagnosed by digital rectal examination, prostatic acid phosphatase levels, and transperineal biopsy. There has recently been a proliferation of new diagnostic modalities that have improved (and complicated) diagnosis and monitoring.

Digital rectal examination has been the mainstay of prostate cancer detection for decades; however, it has significant limitations. Signs of malignancy include gland asymmetry, induration, and hard nodule formation. In asymptomatic men, digital rectal examination has a positive predictive value for cancer of 6 to 50 per cent; this is both operator and referral population dependent. Only 30 to 40 per cent of tumours detected in this way are truly confined to the prostate; conversely, up to 40 per cent of cancers less than 1.5 cm in size are missed. Since only the peripheral zone is accessible to digital rectal examination, tumours confined to the central or transitional zones will all be missed.

Prostatic acid phosphatase is produced by the lysosomal fraction of epithelial prostate cells and is present in the blood of patients with stage C and D prostate cancer. Levels are also elevated in pancreas cancer, breast cancer, osteosarcoma, Gaucher's disease, and deep vein thrombosis. There is a 7 to 15 per cent false-negative rate, especially in anaplastic tumours, and a 7 to 20 per cent false-positive rate. Prostatitis, rectal examination, and urethral catheterization can all elevate prostatic acid phosphatase levels. Immunohistological identification of the enzyme allows the prostatic origin of a metastasis to be determined.

The discovery of prostatic specific antigen has revolutionized the early detection and monitoring of prostate cancer. This glycoprotein serine protease liquefies the seminal coagulum and is 100 per cent specific to the prostate. Its serum half-life is about 2.5 days. There are several assays available, each with its own normal range. The two most popular are Hybritech's Tandem R (normal 0–4 ng/ml) and the Yang PROS-check (normal 0–2.5 ng/ml). In this Section, all values quoted will be for the Hybritech assay.

Both benign and malignant prostate cells produce prostatic specific antigen, but malignant cells produce roughly 15 times more per gram of tissue. Moderate elevation of this enzyme may, therefore, be due to a large benign gland, a small malignant one, or a combination of the two. Less than 15 per cent of patients with pure benign prostatic hypertrophy have a prostatic specific antigen level above 10 ng/ml and almost none have a level above 20 ng/ml. Any form of prostatic manipulation will temporarily elevate prostatic specific antigen levels, but only biopsy or surgery will change the value.

Prostatic specific antigen level is directly proportional to the stage and Gleason grade of tumours. However, significant overlap exists, making predictions for individual patients difficult. Nevertheless, 94 per cent of patients with prostate cancer and a prostatic specific antigen level below 10 ng/ml will have disease confined to the prostate. In diagnosing prostate cancer, sensitivity and specificity will depend on the cut-off point chosen, and the prevalence of the disease in the patient population. Taking 10 ng/ml as cut-off, the sensitivity is only 35 per cent; this increases to 70 per cent if the cut-off is lowered to 4 ng/ml. Increasing sensitivity will lower specificity: roughly 75 per cent of men with a level between 4 and 10 ng/ml have benign enlargement alone.

Prostatic specific antigen is the most powerful test for monitoring therapy of prostate cancer. Following radical prostatectomy, persistently elevated levels suggest residual or metastatic disease. Following radiotherapy, an increasing level correlates with positive biopsies and the development of metastases. In stage D disease, this test has a false negative rate of less than 5 per cent, and levels are inversely proportional to survival time. The level at 6 months after starting hormonal therapy is the best predictor of response.

Transrectal ultrasound with 5 to 7 MHz transducers can give detailed images of prostatic zonal anatomy. Most peripheral zone tumours appear hypoechoic (Fig. 1) 1595 due to replacement of stroma by tumour. As a screening tool, however, transurethral ultrasound is limited by the fact that only one-third of hypoechoic lesions are cancer and that up to 40 per cent of prostate cancers are isoechoic and therefore not detected. This method will, however, detect twice as many tumours as digital rectal examination alone. Staging localized lesions with transrectal ultrasound results in the same over- and understaging as is seen with digital rectal examination.

The primary advantage of transrectal ultrasound is its ability to guide a biopsy needle directly, either to an area of suspicion (nodule, seminal vesicle) or to perform six spaced ‘mapping’ biopsies, as advocated by Stamey.

CT scans can show prostatic size and contour but have an accuracy of only 65 per cent in assessing extracapsular spread. CT is used primarily to assess enlargement of lymph nodes and has an accuracy of 75 per cent in predicting nodal metastasis. The use of CT for staging prostate cancer patients has decreased since the availability of prostatic specific antigen (see above).

MRI gives better images of the prostate and seminal vesicle than does CT and can differentiate malignant nodules, but like digital rectal examination and ultrasound frequently understages capsular invasion. The use of endorectal coils may improve its sensitivity and specificity in the near future.

Nuclear bone imaging remains the best technique for detecting bone metastases, with a false negative rate of less than 2 per cent. Since a prostatic specific antigen level below 20 ng/ml is associated with a negative bone scan in 97 per cent of patients, some centres now omit the scan. However, this practice is not widely accepted and at the very least a baseline scan should be obtained in all patients with a diagnosis of prostate cancer.

Until the 1980s, the standard biopsy technique was the transperineal approach, under general or regional anaesthetic. With the development of spring loaded biopsy guns and ultrasound, transrectal biopsy is now simple, safe, and can be performed on an outpatient basis without anaesthetic. The patient has an enema the night before and is given oral antibiotics (usually a sulphonamide or a quinolone). Transrectal ultrasound allows accurate needle placement in a nodule, seminal vesicle, or set mapping locations. Six spaced core biopsies can accurately assess tumour volume, can upstage stage A disease in the case of peripheral zone involvement, and can predict extracapsular extension when tissue contralateral to a known lesion is also positive for cancer. The risk of diagnosing clinically insignificant ‘incidental’ carcinoma is small; if confirmatory biopsies are used, only 1.4 per cent of cancers so found are smaller than 0.5 cm³.

Whether and how to screen for prostate cancer is probably the most controversial issue in urological oncology, with far ranging medical and economic consequences. Why screen for prostate cancer? In many countries it is the number one or two cancer killer of men. A newborn male has a 10 per cent chance of developing prostate cancer and roughly a 3 per cent chance of dying from it. Relying on symptoms or digital rectal examination, a minority of patients present with curable localized disease. On the other hand, two-thirds of prostate cancers never present clinically and in those that do, 60 to 75 per cent of patients die of something else. Most importantly, there is no accurate means of predicting which tumours will remain quiescent and which will become locally or systemically aggressive. If the screening tests used detect a significant number of tumours that would not shorten the patient's life, the morbidity and mortality of treatment could be worse than the disease.

The best way to settle the issue is with a randomized trial. This has not yet been done and will need thousands of men and many years of follow-up to reach a conclusion. In the meantime, screening must be considered as experimental, as any other unproven drug or surgery, with the potential for both benefit and harm.

The best potential screening combination of the current modalities is digital rectal examination and prostatic specific antigen level, performed annually in men between 50 and 70 years of age (over 40 years in those with a positive family history). If both of these are normal, transrectal ultrasound has a positive predictive value of less than 10 per cent, making its routine use unnecessary and costly. Catalona and colleagues screened 10212 men using prostatic specific antigen alone and found 10 per cent to have a level above 4.0 ng/ml. In patients with a level between 4 and 10 ng/ml, 26 per cent had prostate cancer, of which 73 per cent were organ confined. In the patients found to have prostate cancer with a normal digital rectal examination and an abnormal prostatic specific antigen level (i.e. those that would have been missed without screening), 90 per cent were of clinically significant volume or grade (stage A2-B) and 77 per cent were pathologically organ confined. If both of these tests were positive, only 54 per cent were organ confined. Therefore, screening with prostatic specific antigen can detect preclinical lesions of sufficient stage to warrant treatment. However, whether routine screening can decrease morbidity and prolong life can only be answered by a randomized trial.

The basic investigation of a patient with biopsy proven prostate cancer includes complete history, physical examination, haemoglobin, prostatic specific antigen, prostatic acid phosphatase, liver function tests, bone scan, and CT scan of pelvic nodes. If these confirm localized disease, the treatment chosen should alter the natural history of the disease and decrease morbidity and mortality. Treatment choice depends on the stage, grade, and volume of the tumour, and the patient's (biological) age.

In some cases, the risk of cancer progression in the patient's lifetime is so low that no intervention is warranted. Most would agree that this applies to men over 80 years old with localized disease and to men over 60 with stage A1 disease. Some European centres also advocate observation for patients with well and moderately differentiated A2 and B disease. Adolfsson and colleagues found that in patients with T1–2 disease, the 10-year local progression rate was 72 per cent, the rate of metastasis was 23 per cent, and the rate of death from prostate cancer death was 8 per cent. Johansson and colleagues followed 223 patients with T0–2 disease and reported a 10-year disease specific survival of 87 per cent and progression-free survival of 53 per cent (most patients however received hormonal therapy on progression). While similar to progression rates after other forms of therapy, these patients were not representative of those that undergo radiotherapy or radical prostatectomy. In general, they were older, had lower volume of disease, lower grade (some diagnosed by cytology alone) and neither prostatic specific antigen nor prostatic acid phosphatase was measured, which would underestimate progression. The application of these findings to men with life expectancies greater than 10 years must therefore be made with caution and with full disclosure of the limitations of the data to the patient.

External beam radiotherapy is an effective treatment for many men with confined (stage A/B) and locally invasive (stage C) prostate disease. Standard therapy is 5000 cGy over 5 weeks to the pelvis with a further prostate boost of 2000 cGy over 2 weeks. Local control can be achieved in 80 to 95 per cent of patients overall. In those with stage A and B disease, 5, 10, and 15-year survival rates are 80, 60, and 37 per cent respectively. In stage C disease, this drops to 60, 35, and 22 per cent respectively.

In most European centres, external beam radiotherapy is the primary treatment for localized prostate cancer in all men less than 80 years old. In North America, it is usually first choice therapy only in men between 70 and 80 years old. The primary concern in using this treatment in men with a life expectancy above 15 years is the high rate of prostatic specific antigen elevation after treatment. Stamey reported on 183 patients, treated with external beam radiotherapy: only 11 per cent had undetectable levels of prostatic specific antigen at 5 years. Although levels decreased in 80 per cent of patients, they began to rise after 1 year in 50 per cent. A rising level of prostatic specific antigen is associated with positive post-radiation biopsy and local recurrence.

Major complications of external beam radiotherapy occur in about 10 per cent of patients and 2 per cent require surgical intervention. Complications include impotence (25–30 per cent), urethral strictures (3 per cent), proctitis (1.3 per cent), and small bowel fistula (<1 per cent). Many patients develop early and self-limited diarrhoea and radiation cystitis.

Salvage radical prostatectomy is possible in patients with positive prostatic biopsies after external beam radiotherapy, but with an increased complication rate (rectal injury 10 per cent, incontinence 10–64 per cent). Only 30 per cent of patients have a normal level of prostatic specific antigen after salvage surgery.

In patients with positive margins after radical prostatectomy, external beam radiotherapy can reduce local recurrence rates from 30 per cent to 5 per cent, but there is no demonstrated benefit to patient survival.

Radical prostatectomy refers to the complete surgical removal of the prostate and seminal vesicles. As originally performed, either retropubically or perineally, there was a high complication rate, particularly for impotence and incontinence. In the early 1980s, Walsh and Donker performed a detailed neuroanatomical study of the region and modified the retropubic approach to spare the neurovascular bundles responsible for erection (Figs 2, 3) 1596,1597. Improved attention to anatomical detail also has improved continence and positive margin rates.

Preoperatively patients should receive a bowel preparation (in case of rectal perforation), prophylactic antibiotics and antithrombotic therapy (compression stockings preferred). Anaesthetic can be a full general or epidural. The surgical position is low lithotomy and a Foley catheter is inserted, followed by an examination under anaesthesia.

bilateral diagnostic pelvic lymph node dissection (internal iliac and obturator nodes),

division of puboprostatic ligaments,

control of dorsal venous complex (potential source of troublesome bleeding),

division of urethra, sparing the neurovascular bundle (dorsolateral to urethra) if free of tumour,

division of rectourethralis muscle and lateral prostatic pedicle (medial to neurovascular bundle),

blunt dissection posteriorly between prostate and rectum,

division of vesicoprostatic junction with identification and preservation of ureteral orifices,

dissection of seminal vesicles, removed with the specimen,

reconstruction of bladder neck,

vesicourethral anastomosis with 6–8 circumferential absorbable sutures,

drainage of bladder and perivesical space

Recent technical improvements have greatly reduced the morbidity of radical prostatectomy, especially the incidence of impotence and incontinence. The mortality rate is less than 1 per cent. Impotence affects 20 to 60 per cent of patients, depending on patient age and tumour stage. More than 50 per cent develop transient stress incontinence but only 2 per cent develop total incontinence. Bladder neck stricture (5 per cent), rectal perforation (<1 per cent), lymphocele (5 per cent), deep vein thrombosis (10 per cent), and pulmonary embolism (1 per cent) also occur. Obturator nerve injury, abscess, and ureteral obstruction are rare complications.

Results depend on the stage of disease (both clinical and pathological) and the experience of the surgeon (there is a steep ‘learning curve’). Overall, patient survival after surgery for clinically localized disease is 80 per cent at 5 years, 70 per cent at 10 years, and 50 to 60 per cent at 15 years. There is a 10 to 15 per cent local recurrence rate as gauged either by biopsy or prostatic specific antigen levels.

Patients with stage A disease have high rates of potency and disease control. Patients with a classic ‘B1’ nodule have results mirroring normal life expectancy (up to 75 per cent 15-year survival in young patients). However those with B2 or B3 lesions have high rates of capsular penetration or seminal vesicle involvement (40–60 per cent upstaged to C1 or D1). Most B2–3 lesions with positive margins are poorly differentiated and associated with a presurgical serum prostate specific antigen level over 10 ng/ml. Some centres offer surgery to stage C patients, and if the nodes are negative, up to 25 per cent may be downstaged to true stage B. If the lesion is small (C1) and well differentiated, survival rates similar to stage B are seen. Recently, some groups have tried preoperative ‘downstaging’ of stage C lesions with hormonal therapy, but the early published results are very disappointing.

The Mayo Clinic among others have advocated simultaneous radical prostatectomy and hormonal therapy for stage D1 disease. They report 5-year progression-free rates of 86 per cent and survival equal to that of age-matched controls, especially for those with diploid tumours. These patients were highly selected, having low volume nodes, small primary lesions, and a high socioeconomic class. This combined treatment has not been compared to hormonal ablation alone in these patients. Some advocate ‘prophylactic’ radical prostatectomy in D1 disease to prevent the need for further local disease control, although only 30 per cent of D1 patients treated with hormones alone eventually require prostatectomy.

The results achieved at specialist centres with radical prostatectomy and external beam radiotherapy are similar in patients with localized prostate cancer. Unfortunately, patients are seldom comparable between studies for age, stage, grade, and follow-up. The only completed randomized trial comparing the two treatments from the Veterans Administration group favoured radical prostatectomy, but the study had methodological flaws. Until such a trial is completed, patients must be given the three options of therapy, regardless of the local ‘favourite’. In patients with an expected life-span of less than 5 years (i.e. those more than 80 years old), observation is warranted. In patients with a 5- to 10-year expected life-span external beam radiotherapy gives similar results to surgery with less morbidity. For patients under 70 years old with an expected life-span of more than 15 years, surgery is likely to be superior, given the data showing persistent prostatic specific antigen elevation with time following radiotherapy. In patients with clinical stage B but a very high risk of capsular penetration (large volume, contralateral biopsy positive, poorly differentiated), radiotherapy may be preferred.

The favourable response of prostate cancer to androgen ablation was first described by Huggins in 1941 and it has remained the treatment of choice for metastatic disease. About 80 per cent of patients with metastatic prostate cancer have a measurable response to endocrine therapy, with a mean duration of response of 2 to 3 years, although some patients may have a much longer response. Eventual progression of disease is due to growth of androgen independent cell populations. The response of an individual cannot be predicted before treatment, but negative prognostic factors include low pretreatment testosterone, bone pain, elevated serum alkaline phosphatase, and low performance status. Early treatment of asymptomatic patients does not prolong survival compared with delayed treatment (when symptoms occur), although early treatment does delay progression and in all probability decreases overall morbidity.

The gonads produce about 95 per cent of the circulating androgens under the central control of the pituitary gland and hypothalamus (Fig. 4) 1598. The adrenals supply the remaining 5 per cent, although it is controversial whether adrenal androgens alone can support the growth of prostate cancer cells. Most circulating testosterone is bound to sex steroid binding globulin. Free testosterone is converted to the active form in the prostate, dihydrotestosterone, by the enzyme 5&agr;-reductase. It is not clear whether prostate cancer responds only to dihydrotestosterone or whether testosterone can be used directly. Clinical androgen ablation can be achieved by interfering with any step of androgen production.

Bilateral scrotal orchiectomy is simple, safe, and produces castrate levels in about 3 h. The main side effects are gynaecomastia, impotence, and hot flushes. Anaesthesia may be general, regional, or local. If a normal appearing scrotum is important to the patient then subcapsular orchiectomy (preserving the tunica albuginea), epididymal sparing (sew the epididymis to itself as an ‘autoprosthesis’), or implantation of a synthetic testicular prosthesis are appropriate options.

Exogenous oestrogen is believed to block androgen metabolism at several levels: feedback pituitary luteinizing hormone suppression (most important), direct testicular androgen suppression, increased sex steroid binding globulin levels, increased prolactin levels, and direct tumour suppression (clinical relevance doubtful). In addition to the side-effects of orchiectomy, diethylstilboestrol at doses necessary to produce castrate testosterone levels (3–5 mg/day), is associated with increased cardiovascular complications and deaths. Daily doses of 1 to 2 mg do not have cardiovascular side-effects but do not reliably produce castrate levels, although symptomatic improvement often still occurs. Although largely supplanted by newer drugs, diethylstilboestrol is currently the least expensive medical therapy, and very low doses are being studied in trials of combination therapy.

Administration of LHRH analogues results in a flare of testosterone after about 3 days, but testosterone levels then drop paradoxically to castrate levels after 2 weeks due to down-regulation of pituitary receptors and decrease of luteinizing hormone stores. The clinical effect is equivalent to orchiectomy or diethylstilboestrol. There is a lower incidence of gynaecomastia and fluid retention but a higher incidence of hot flushes. In addition, unless the early ‘flare’ period is covered by diethylstilboestrol or an antiandrogen, there is danger of tumour expansion leading to spinal cord compression or ureteral obstruction. LHRH analogues are available as daily subcutaneous injection, nasal spray, or as a monthly depot injection.

Pure antiandrogens such as flutamide block binding of dihydrotestosterone and testosterone to the androgen receptor. Use of pure antiandrogens is the only hormone treatment that preserves libido and potency, but the potential for increasing testosterone levels precludes their use as monotherapy, apart from the asymptomatic patient in whom potency is a major issue. Side-effects include gynaecomastia, flushing, and diarrhoea.

Cyproterone acetate is a synthetic progestational agent that blocks the dihydrotesterone receptor but also has central gonadotropin blocking effects, making it particularly helpful in patients with hot flushes on other therapy. The central effect may be lost with prolonged use.

Ketoconazole, an antifungal agent, is an imidazole derivative that inhibits P450 enzymes and cholesterol production, resulting in ablation of both testicular and adrenal androgens. It is the most rapid medical treatment, with castrate testosterone levels being achieved by 8 h at a dose of 400 mg 8-hourly. Primary side-effects are nausea, gynaecomastia, impotence, pruritus, elevation of liver enzyme levels, and, rarely, an Addison crisis (responsive to glucocorticoids).

Prednisone at 15 mg per day can decrease dihydrotestosterone levels in castrate men with a reported 20 per cent objective improvement in D3 disease.

Since the initial remarkable results of Labrie, there has been much interest in total androgen blockade whereby both testicular and adrenal androgens are ablated. Typical regimens combine orchiectomy or LHRH analogues with a pure antiandrogen. The American National Cancer Institute study comparing a LHRH analogue with or without flutamide showed a statistically significant increase in time to progression and a reduction in mortality for total androgen blockade, although only by 3 months. Similar results were seen in a Canadian trial with an improved survival time of 5 months. European studies however have shown delayed disease progression but no survival benefit. These studies are not yet fully mature with respect to survival. Subset analysis suggests that patients with low disease burden and good performance status benefit most from total androgen blockade.

Due to the eventual emergence of androgen resistant tumours in patients treated with hormonal therapy, newer treatments are constantly being evaluated. The most promising include suramin, which blocks growth factors and decreases binding of tumour growth factor-&agr;; estramustine phosphate which has some oestrogenic effect but also produces mitotic arrest in tumours; and diphosphonates, which inhibit bone mineralization and resorption, producing symptomatic relief of bone metastases. Cytotoxic chemotherapy has produced very disappointing results to date. The most promising agents have been Adriamycin and 5-flurouracil.

When metastatic prostate cancer progresses despite hormonal therapy, the median survival rate is under 1 year. In this case, the therapeutic options are limited. If compliance with medical castration is unsure, the patient should undergo bilateral orchiectomy. If total androgen blockade has not been used, an antiandrogen to block adrenal testosterone can be added, but the evidence for a benefit is slight. Some patients on total androgen blockade benefit from withdrawal of the antiandrogen. While secondary hormonal responses are variable and short lasting, the most useful agents have been estramustine phosphate and ketoconazole.

This devastating complication must always be considered in prostate cancer patients with back pain or decreased lower limb sensation. Both radiation and decompressive laminectomy have high rates of palliation.

Local extension may commonly impinge on the trigone causing obstructive uropathy. Antegrade or retrograde stenting is the procedure of choice followed by hormone therapy if not already begun.

If not controlled, consultation with a cancer pain speciality team is helpful. In cases of intractable pain, local radiotherapy and/or oral prednisone may be considered.

The following are the recommendations of the author and represent an approach that in 1992 would be considered somewhat conservative in North America and aggressive in Europe. Each treatment choice is recommended to the patient as the author's preference: however all treatment options with their risks, benefits, and the strength of the data supporting them are given as alternatives.

Transrectal ultrasound and biopsy of peripheral zone, should be undertaken. If this is positive, treat as stage B; otherwise, monitor with serial measurement of prostatic specific antigen and digital rectal examination. Radical prostatectomy should be performed in patients under the age of 70 if prostatic specific antigen levels increase and in any patient under 60 with a strong family history or elevated serum prostatic specific antigen levels.

If no metastases are detected and the patient is under the age of 70, radical prostatectomy is recommended, with external beam radiotherapy as second choice. Between the ages of 70 and 80, external beam radiotherapy is preferable. Over the age of 80 monitoring alone with hormonal therapy for progression is suitable.

A patient with stage B2 disease and a normal contralateral biopsy should be treated as B1. Radical prostatectomy should be offered to those with stage B3 disease only if it is well differentiated and the prostatic serum antigen level is below 15 ng/ml. Otherwise, radiotherapy should performed be due to the high rate of positive margins following surgery.

External beam radiotherapy is recommended. Patients with C2 disease or those with C1 that is poorly differentiated and/or with a prostatic serum antigen level above 20 ng/ml should first undergo diagnostic pelvic lymph node dissection to exclude the high probability of metastatic disease.

Asymptomatic patients with stage D0 or D1 disease should be offered early or delayed endocrine therapy. Symptomatic patients should receive endocrine therapy immediately. Those who are sexually active and have a low volume of disease could be offered monotherapy with a pure antiandrogen. Otherwise, the first-line therapy is bilateral orchidectomy or depot LHRH analogue with antiandrogen cover for the flare period. If the patient has a low disease burden and a good performance status, antiandrogen therapy should be maintained to achieve total androgen blockade. In emergency (spinal cord compression, thromboembolism) bilateral orchidectomy or ketoconazole therapy should be instituted.

Adequate pain control must be ensured. If medical compliance is questionable, bilateral orchidectomy is applicable; otherwise ketoconazole, estramustine phosphate, or prednisone could be used. If the patient is young and has a good performance status, enrolment in a chemotherapy trial may be warranted.

Adolfsson J, Carstensen J. Natural course of clinically localized prostate adenocarcinoma in men less than 70 years old. J Urol 1991; 146: 96–8.

Bagshaw MA, Cox RS, Ramback JE. Radiation therapy for localized prostate cancer. Urol Clin N Am 1990; 17: 787–802.

Béland G, et al. Total androgen ablation: Canadian experience. Urol Clin N Am 1991; 18: 75–82.

Canadian Task Force on the Periodic Health Examination. Periodic health examination, 1991 update: 3. Secondary prevention of prostate cancer. Can Med Assoc J 1991; 145: 413–28.

Carter BS, Beaty TH, Steinberg GD, Childs B, Walsh PC. Mendelian inheritance of familial prostate cancer. Proc Natl Acad Sci USA 1992; 89: 3367–71.

Catalona WJ, et al. Measurement of prostate-specific antigen in serum as a screening test for prostate cancer. N Engl J Med 1991; 324 1156–61.

Chodak GW, Vogelzang NJ, Caplan RJ, Soloway M, Smith JA. Independent prognostic factors in patients with metastatic (stage D2) prostate cancer. JAMA 1991; 265: 618–21.

Crawford ED, et al. The effect of digital rectal examination on prostate-specific antigen levels. JAMA 1992; 267:2227–8.

Gerber GS, Chodak GW. Routine screening for cancer of the prostate. J Natl Cancer Inst 1991; 83: 329–35.

Hinman FJ. Screening for prostatic carcinoma. J Urol 1991; 145:126–9.

Huggins C, Hodges CV. Studies on prostatic cancer. 1. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res 1941; 1: 293–7.

Johansson JE, Adami HO, Andersson SO, Berström R, Holmberg L, Krusemo UB. High 10-year survival rate in patients with early, untreated prostatic cancer. JAMA 1992; 267: 2191–6.

Kane RA, et al. Prostate-specific antigen levels in 1695 men without evidence of prostate cancer. Findings of the American Cancer Society National Prostate Cancer Detection Project. Cancer 1992; 69: 1201–7.

Kozlowski JM, Ellis WJ, Grayhack JT. Advanced prostatic carcinoma. Early versus late endocrine therapy. Urol Clin N Am 1991; 18: 15–24.

Lange PH, Ercole CJ, Lightner DJ, Fraley EE, Vessella R. Value of serum PSA determinations before and after radical prostatectomy. J Urol 1989; 141: 873–9.

Lee F, et al. Prostate cancer: comparison of transrectal US and digital rectal examination for screening. Radiology 1988; 168: 389–94.

McNeal JE, Bostwick DG, Kindrachuk RA, Redwine EA, Freiha FS, Stamey TA. Patterns of progression in prostate cancer. Lancet 1986; 1: 60–3.

Partin AW, et al. Prostate specific antigen in the staging of localized prostate cancer: Influence of tumor differentiation, tumour volume and benign hyperplasia. J Urol 1990; 143: 747–52.

Paulson DF, Moul JW, Robertson JE, Walther PJ. Postoperative radiotherapy of the prostate for patients undergoing radical prostatectomy with positive margins, seminal vesicle involvement and/or penetration through the capsule. J Urol 1990; 143: 1178–82.

Shoskes DA, Perrin RG. The role of surgical management for symptomatic spinal cord compression in patients with metastatic prostate cancer. J Urol 1989; 142: 337–9.

Silverberg E, Lubera JA. Cancer statistics. CA-Cancer J Clin 1988; 38: 5–22.

Stamey TA, Kabalin JN, Ferrari M. Prostate specific antigen in the diagnosis and treatment of adenocarcinoma of prostate III. Radiation treated patients. J Urol 1989;141: 1084–7.

Stamey TA, et al. Prostate specific antigen in the diagnosis and treatment of adenocarcinoma of prostate II. Radical prostatectomy treated patients. J Urol 1989; 141: 1076.

Stamey TA, Yang N, Hay AR, McNeal JE, Freiha FS, Redwine E. Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. N Engl J Med 1987; 317: 909–16.

Terris MK, McNeal JE, Stamey TA. Detection of clinically significant prostate cancer by transrectal ultrasound-guided systematic biopsies. J Urol 1992; 148: 829–32.

Walsh P. The role of radical prostatectomy in the management of prostatic cancer. Cancer 1987; 60: 526–37.

Walsh PC, Donker PJ. Impotence following radical prostatectomy: insight into etiology and prevention. J Urol 1982; 128: 492–7.

Walsh PC, Jewett HJ. Radical surgery for prostate cancer. Cancer 1980; 45: 1906–11.

Walsh PC, Lepor H, Eggleston JC. Radical prostatectomy with preservation of sexual function: anatomical and pathological considerations. Prostate 1983; 4: 473–85.