Treatment of carcinoma of the prostate

Natural history of prostate cancer

T1 and T2

The progression rate of well-differentiated ha prostate cancer is very low, being about 10—14 per cent after 8 years

For moderately differentiated tumours the rate is about 20 per cent, but for T1b tumours the rate is in excess of 35 per cent

Similar rates of progression (20—30 per cent) are found for T2 disease

T3 and T4 (MO)

About 50 per cent progress to bony metastases after 3—5 years

M1

The median survival of men with metastatic disease is about 3 years

Prostatic biopsy

If there is suspicion of prostate cancer, because of either local findings, a raised PSA or metastatic disease, then a transrectal biopsy using an automated gun with appropriate antibiotic cover is indicated. Several cores may be needed to make a diagnosis. The incidence of sepsis from transrectal biopsy increases if more than three biopsies are taken. If there are associated symptoms of BOO then either:

  a TURP can be performed which will provide diagnostic material and symptomatic relief;

  transrectal biopsy can be carried out. If the diagnosis is positive and there is locally advanced disease, then hormone ablation can provide good symptomatic relief without the need for operation.

Early disease

Curative treatment can only be offered to patients with early disease (T1a, Tlb, T1c and T2). The treatment of patients with advanced disease (T3, T4 or any MO) is only palliative.

Radical prostatectomy

Radical prostatectomy is only suitable for localised disease (T1 and T2) and should only be carried out in men with a life   expectancy of >10 years. Exclusion of metastases would -require a negative bone scan, chest X-ray and a serum PSA <20 nmol/ml. It is a major surgical procedure and should only be performed by experienced surgeons when there is a high chance of cure. It results in a high incidence of impo­tence, but a low incidence of severe stress incontinence (<5 per cent) which may require the fitting of an artificial urinary sphincter. It involves removal of the prostate down to the distal sphincter mechanism in addition to the seminal vesicles (Fig. 66.23). The bladder neck is reconstituted and anastomosed to the urethra. Recent modifications to this operation by Professor Patrick Walsh of the Johns Hopkins Hospital in Baltimore have led to the realisation that careful dissection in early stage disease can lead to preservation of the neurovascular bundles which lie behind the prostate. This modification has led to the preservation of erectile function in about 60—70 per cent of cases.

Pelvic lymph node dissection

Pelvic lymph node dissection is carried out immediately prior to radical prostatectomy when radical treatment is being considered. In some centres this was combined with the open open implantation of 125j seeds, although with recent surgical modification of radical prostatectomy this is now only rarely performed.

Radical radiotherapy for early prostate cancer

Radical radiotherapy to the prostatic bed and pelvic lymph nodes rather than radical surgery has tended to be the treatment of choice in the UK for locally confined prostate cancer. The survival rates in the treatment of T1 to T2 disease are not greatly different from radical prostatectomy, although histological evidence of persistent tumour is found within the prostate in about 30 per cent of treated patients. Patients with locally advanced disease (T3) may be treated by radiotherapy, but most urologists treat such patients by means of androgen ablation. The treatment requires the patient to attend hospital on a daily basis for between 4 and 6 weeks. Some local complications are inevitable, namely irritation of the bladder with urinary frequency, urgency and sometimes urge incontinence and similar problems affecting the rectum with diarrhoea and, occasionally, late radiation proctitis.

Advanced disease

There is still debate about the timing of androgen ablation treatment in patients with locally advanced or metastatic disease without symptoms. The options are androgen deprivation at diagnosis or careful review, reserving active treatment for the later development of symptoms. Patients with local or general symptoms should be offered androgen deprivation.

Orchidectomy

Orchidectomy is performed to carry out androgen ablation in the treatment of locally advanced (T3 or T4) disease or of metastatic disease. In 1941 prostate cancer was shown to be responsive to such treatment by Charles Huggins — the only urologist to win the Nobel Prize. Bilateral orchidectomy, whether total or subcapsular, will eliminate the major source of testosterone production.

Hypophysectomy and adrenalectomy

These treatments are no longer carried out. In the past, patients who had initially responded to hormone treatment but subsequently relapsed were thought to have a small chance of obtaining further relief if a hypophysectomy was performed.

General radiotherapy

General radiotherapy for symptomatic metastases is an excellent form of palliative treatment often producing dramatic pain relief in men with- hormone-relapsed prostate cancer. More recently, hemibody irradiation has been shown to decrease symptoms in men with widespread bony metastases.

Strontium

Strontium is now being employed as a bone-seeking isotope which delivers effective radiotherapy to metastatic areas. It appears to be as effective as hemibody irradiation in the treatment of men with metastatic hormone-relapsed disease.

Medical forms of androgen ablation

Medical forms of androgen ablation have been available since the discovery of stilboestrol. Initially there was great enthu­siasm for this treatment and Honvan® (phosphorylated diethylstilboestrol) could be given intravenously. Both treatments are effective in producing regression of prostate cancer, but are associated with significantly increased thrombotic complications and cardiovascular mortality. Even if stilboestrol is used at a dose of 1 mg three times a day complications can occur. Other hormones that have been tried include progestogens and Provera®.

The other commonly available treatment to reduce testosterone levels to the castrate range is LHRH agonists. These agents initially stimulate hypothalamic LHRH receptots, but because of their constant presence (rather than the normal diurnal rhythm) they then down-regulate them, resulting in cessation of pituitary LH production and hence a decrease in testosterone production. In the first 10 days or so serum testosterone levels may increase and it is wise to give flutamide, bicalutamide (Casodex) or Cyproterone acetate for this period. LHRH agonists may be given by monthly or 3 monthly depot injection.

Other treatments have become available recently which block the androgen receptor. Cyproterone acetate also has some progestogenic effect, whilst flutamide and bicalutamide are pure antiandrogen. In general, oral monotherapy has not been shown to be as good as LHRH agonists or orchidectomy.

Complete androgen blockade

Complete androgen blockade has been advocated as being likely to result in increased life expectancy and an increased time to progression in a fitter subgroup of men with advanced prostate cancer. The concept is that of abolishing the testicular secretion of testosterone by means of orchidectomy or the use of LHRH therapy and then inhibiting the effects of adrenal androgenic steroids by means of androgen receptor blockade with flutamide, bicalutamide (Casodex) or the use of cyproterone acetate. Recent overviews of randomised trials do not confirm earlier reports of effectiveness.

Cytotoxic agents in the treatment of these elderly men have proved disappointing, but whether this is because the tumour is inherently insensitive or because these elderly men will not tolerate effective doses is uncertain.

Summary of treatment

1.      Incidentally diagnosed T1a and T1b disease. For men in their 70s conservative treatment would usually be the correct approach. Radical surgical treatment might be con­sidered in the younger (<65 years) man with this form of the disease, although even in this group some men will elect to pursue a conservative course when counselled about risks versus benefits.

2. Localised T2 disease. In younger fitter men (<65 years), this may be treated by radical prostatectomy or radical radiotherapy. Watchful waiting remains an option — par­ticularly for more elderly patients. In the elderly patient with outflow obstruction transurethral resection with or without hormone therapy is indicated. The benefit of radi­cal treatment over a conservative approach is likely to be at most 25 per cent, given that progression to metastatic disease is in this order of magnitude after 10 years.

3. Locally advanced T3 and T4 disease. These patients are at significant risk of disease progression. Early androgen ablation is favoured if close follow-up is not possible. For the sexually active a careful conservative approach with the adoption of androgen ablation when symptoms arise is reasonable.

4. Metastatic disease. Once metastases have developed the out­look is poor. For patients with symptoms there is no dilemma; androgen ablation will provide symptomatic relief in over two-thirds of the patients. For patients with asymptomatic metastases the timing of treatment is less clear.

There are few hard and fast rules in the treatment of this cancer, but the surgeon should avoid making the patients worse through creating more complications as a result of treatment than the disease would have caused in its own right.