The management of prostate cancer

Summary
Prostate cancer is the most common malignancy in Australian men. Localised prostate cancer may be treated with radical prostatectomy, radiotherapy or watchful waiting. In the absence of information from randomised trials, no approach is clearly superior. For patients with metastatic disease, androgen deprivation is the mainstay of treatment. Bilateral orchidectomy and luteinising hormone releasing hormone agonists are the major first-line treatments, and yield identical results. Ultimately, most patients develop hormonally insensitive disease. In these patients, radiotherapy or the use of the radioisotope, strontium-89, may relieve symptoms.

Introduction
Prostate cancer is the most common malignancy and the second most common cause of cancer deaths in Australian males. It has long been taught that men die with prostate cancer rather than from it. However, 25% of men who have prostate cancer die from the disease, whilst many more experience substantial morbidity. The incidence has risen over the past decade, although this increase may be partly due to more frequent diagnosis, following heightened community awareness and the introduction of tests such as the measurement of serum prostate specific antigen (PSA) (see 'Prostate specific antigen' Aust Prescr 1993;16:37-9).

The management of prostate cancer is determined by the stage and the degree of differentiation of the disease. The modified Whitmore and Jewett staging system is used widely (Table 1). Differentiation is commonly reported as a Gleason score, which is based on the predominant histological appearance of the tumour. The Gleason score is a single number between 2 (low grade, well differentiated) and 10 (high grade, poorly differentiated) and correlates with prognosis.

Early prostate cancer (stages A and B)
The optimal treatment for early stage disease is controversial. This controversy exists because of a lack of well designed and executed clinical trials. Although trials have been planned or commenced, the results will not be available for some years, and current clinical decision making will continue to be based on incomplete and inadequate information.

Those patients who have focal (stage A1), well differentiated cancers rarely have progression of their tumour. Their risk of cancer-related death is 4% at 10 years. These patients are therefore commonly followed without treatment. By contrast, patients with stage A2 or B tumours have a far higher risk of cancer-related death (10-65% at 10 years, dependent upon the degree of differentiation). Management options include radical prostatectomy, radiotherapy or observation (watchful waiting). Typically, the results for surgery are better than those for patients treated with radiotherapy or observed without treatment. However, the selection of younger, healthier patients for prostatectomy could account for these findings, rather than any real difference between the management approaches.

Decisions regarding treatment must take into account the patient's general condition, as well as the likely adverse effects of treatment. Watchful waiting is usually reserved for those patients who are older, with a life expectancy (independent of their prostate cancer) of less than 10 years and/or who have well differentiated tumours. For those patients who are to receive curative treatment, the different adverse effects of surgery and radiotherapy may assist the decision -making process. Radical prostatectomy is associated with a slightly higher incidence of both incontinence and impotence than radiotherapy (although with prolonged follow-up after radiotherapy, the incidence of impotence increases). Radiotherapy may also result in radiation-induced bowel damage. Trials which are currently planned or ongoing should provide data to assist a rational choice of therapy.

Locally advanced prostate cancer (stage C)
It is questionable whether patients with locally advanced disease are able to be cured using currently available treatment. These men are not candidates for surgical resection and treatment is usually with radiotherapy or with hormonal ablation. However, occult spread to lymph nodes or distant sites is often present, particularly in those men with adverse prognostic features, such as a high Gleason score ( >7) or a very high PSA. These patients develop symptomatic metastatic disease despite adequate control of the local disease in the prostate. Newer approaches to the management of stage C disease include the early introduction of hormonal ablation in those patients whose tumours have poor risk features, and the use of initial hormonal therapy in patients with bulky disease, followed by radiotherapy or, in some cases, attempted surgical resection. Clinical trials evaluating the benefits of these strategies are still under way.

Metastatic prostate cancer (stage D)
Up to 50% of patients with prostate cancer present with established metastatic disease, while others develop metastatic disease during the course of their illness. The mainstay of treatment for metastatic prostate cancer since the 1940s has been androgen ablation.

In men, the major source of circulating androgens is the testicles, with a small component (<5% of the total) being produced by the adrenal glands. Several techniques of androgen ablation are possible, including orchidectomy, the use of luteinising hormone releasing hormone (LHRH) agonists and the use of antiandrogens. Oestrogens are no longer commonly used to suppress androgen production because of their cardiovascular adverse effects.

Traditionally, androgen deprivation (irrespective of the method used to achieve it) has been used when symptoms of metastatic disease develop, thus avoiding the associated adverse effects for as long as possible. However, several studies have suggested, indirectly, that early treatment of metastatic disease may offer a survival advantage. This issue is now being addressed directly in a large randomised trial. The problem of how best to treat patients with asymptomatic metastatic (or locally recurrent) disease is increasing in frequency, due to the use of PSA for monitoring after attempted curative treatment. Until more data are available, decisions about early versus delayed hormonal therapy must be made by balancing the adverse effects (particularly impotence) and the cost of treatment against the theoretical, but as yet unproven, gains in survival.

Bilateral orchidectomy
Bilateral orchidectomy is the gold standard for androgen ablation in men with prostate cancer. It results in a rapid and permanent decrease in circulating testosterone levels. A dramatic improvement in the symptoms of metastatic prostate cancer can occur within a few hours or days. Overall, 70-80% of men with metastatic prostate cancer respond to orchidectomy, with a decrease in symptoms, shrinkage of tumour masses and a fall in the concentrations of PSA. The median duration of response is approximately 18 months and the median duration of survival is 24-36 months.

The major adverse effects of orchidectomy are impotence, hot flushes and, occasionally, mild breast tenderness. In addition, the thought of castration does not appeal to many men and, when asked their preference in clinical trials, a majority choose treatment with a LHRH agonist. The major advantages of orchidectomy are the rapid onset of its effects and the reduction in the need for repeated visits for treatment. This improves compliance, and, relative to LHRH agonists, orchidectomy is inexpensive.

LHRH agonists
Production of androgens by the Leydig cells in the testes is dependent upon stimulation by luteinising hormone (LH). LH is released by the pituitary gland in response to the pulsatile secretion of LHRH by the hypothalamus. The continuous presence of LHRH has the opposite effect; it prevents the release of LH from the pituitary, and consequently abolishes testicular androgen production. Two LHRH agonists are available in Australia, goserelin, an implant, and leuprorelin, a depot injection. Both provide continuous release of the drug for approximately one month.

The efficacy of LHRH agonists is identical to that of orchidectomy, although the onset of action is slower. A flare reaction may occur at the start of treatment, with an increase in pain and the size of tumour masses. This is of particular relevance in patients with incipient spinal cord compression, which can be precipitated by such a flare. In order to prevent this, patients with extensive metastatic disease should be treated with an antiandrogen such as flutamide for the first two weeks of LHRH agonist therapy.

LHRH agonists have a similar adverse effect profile to that of orchidectomy. The additional disadvantages are their high cost and the need for continuous monthly treatments. Advantages include theoretical reversibility and the avoidance of castration. In practice, testicular atrophy probably follows prolonged LHRH administration.

Antiandrogens
Antiandrogens block the effects of androgens by displacing them from androgen receptors. The two classes of antiandrogens are the steroidal antiandrogens (e.g. cyproterone acetate) and the non-steroidal antiandrogens (e.g. flutamide). These drugs are not commonly used as first-line monotherapy in the hormonal management of prostate cancer. Randomised trials have shown a shorter duration of response in patients treated with flutamide compared to those treated with goserelin. Such trials have not been carried out using cyproterone acetate (although it is known to produce results identical to those achieved with oestrogens).

The adverse effects of flutamide are gynaecomastia, diarrhoea and abnormalities of liver function tests. Potency and libido may be retained with this drug. Cyproterone acetate does not usually produce diarrhoea, but otherwise has similar adverse effects. In addition, like some other steroidal compounds, it exhibits cardiovascular toxicity such as venothromboembolism (although to a lesser extent than with oestrogens).

The major use of the antiandrogens has been as part of total androgen blockade. In addition, they are often used as second -line hormonal therapy, after disease progression occurs in patients previously treated with orchidectomy or a LHRH agonist. The results of such second-line hormonal therapy are disappointing. Responses occur in only 20-25% of patients with a median duration of less than 6 months.

An interesting phenomenon that occurs with flutamide is the withdrawal response. This occurs in patients who have been treated with, and have responded to, flutamide. Following progression of their disease, responses are observed in a small proportion of patients when flutamide is ceased. This is a useful manoeuvre in patients who have disease progression while receiving total androgenic blockade including flutamide.

Total androgenic blockade
Total androgenic blockade (TAB) refers to the combined use of an antiandrogen with either a LHRH agonist or orchidectomy. The rationale is to block the effects of the circulating adrenal androgens which remain after orchidectomy or treatment with LHRH agonists. Several randomised trials have demonstrated a slight prolongation of survival for patients treated with TAB when compared to LHRH agonists or orchidectomy alone, without an increase in toxicity. In the subgroup of patients with low volume metastatic disease, the improvement in survival is more marked, with an approximate 20 month increase in median survival. Studies of these patients are under way to try to confirm this benefit. There is no basis for the use of TAB in patients with high volume metastatic disease (>5 bony metastatic sites, or bony metastases outside the axial skeleton).

External beam radiotherapy
In addition to its role in the management of localised prostate cancer, radiotherapy plays an important part in the management of metastatic disease, particularly when this has become refractory to hormonal ablation. It provides rapid and effective relief from bone pain. Radiotherapy can be used to treat localised lesions, or to treat larger areas using hemi-body irradiation. Even relatively short courses of radiotherapy, or on occasions, single fractions, may provide substantial relief of pain.

Strontium-89
Strontium-89 is a radioisotope that mimics the behaviour of calcium. After intravenous injection, it is taken up and incorporated into bone with preferential retention in areas of sclerotic metastases. Strontium-89 is an emitter of beta radiation, so patients do not pose a radiation hazard and do not require isolation after treatment as the range of beta radiation in tissue is only 1-2 mm.

The place of strontium-89 in the management of metastatic prostate cancer is not yet clear. Its major use is in patients with widespread bone pain, due to hormonally refractory disease. The alternative to strontium-89 in these patients is hemi-body radiation. Whilst the two approaches have similar efficacy in relieving pain (and in survival), there is a lower rate of development of new sites of bone pain in men treated with strontium-89.

Further reading
Dearnaley DP. Cancer of the prostate. Br Med J 1994;308:780-4.

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

Chodak GW, Thisted RA, Gerber GS, Johansson JE, Adolfsson J, Jones GW, et al. Results of conservative management of clinically localized prostate cancer. N Engl J Med 1994;330:242-8.