Treatment of early-stage prostate cancer

The reason the patient can be offered the prospect of choice in determining what therapy he should have for early-stage disease is that observation, radiotherapy and radical surgery have all been shown to offer the patient with good or moderate histology tumours the same overall chance of long-term survival. The advantages of surveillance include a better quality of life and absence of treatment side effects but this may be offset by the anxiety of living with untreated cancer and the need for regular follow-up. For patients, with poor histology, surgery offers a marginally better survival chance than radiotherapy. The survival advantage is minimal. There has, however, been no randomized comparison of these three options involving significant patient numbers; and so this subject remains a matter for vociferous debate. A recent study of approximately 600 patients randomized to receive either watchful waiting or radiotherapy showed a better outlook for treated patients. The outlook for patients with low-grade Gleason 3 + 3 tumours is so good that in many ways this tumour group should be regarded as not being a malignant tumour. NICE, the most venerable body, advocate surveillance alone for patients with Gleason 3 + 3 tumours.

In the early 1990s, investigations were initiated into the value of hormonal therapy given in addition to radiotherapy and surgery. No advantage to such “neoadjuvant” hormonal therapy has been found in those patients proceeding to radical surgery. In contrast, a number of randomized studies have shown an advantage to neoadjuvant hormonal therapy in patients receiving radiotherapy. The majority of studies have found a decreased risk of local relapse with hormonal therapy, and two major trials reported improved survival. There is controversy as to the suitable duration of treatment with adjuvant hormonal therapy.

Brachytherapy is a radiotherapy technique where the local intensity of radiation is increased by the implantation of radioactive seeds or wires (see Figure 3.11). This technique has been applied to localized prostate cancer. Up to 100 iodine-125 or palladium-103 radioactive seeds are permanently implanted directly into the prostate via transperineal needles under general or spinal anaesthetic. Excellent results have been claimed, but not proven in any randomized trial. Recent publications have shown that the incidence of major side effects of brachytherapy is the same as for conventional radiation, and the efficacy of brachytherapy is no doubt similar to conventional radiation treatment. Brachytherapy has additional side effects to radiotherapy and these include a 12% instance of urethral stricture requiring surgical intervention.

Treatment of locally advanced or metastatic prostate cancer

When patients have locally advanced, that is T3 or T4, prostate cancer or metastatic disease (Figures 14.3 and 14.4), the first-line treatment involves the use of hormonal therapy (see Figure 3.27). Urological surgeons have been heard to advocate radical surgery for T3 tumours, but 5-year “cure” rates are around 50% and so the authors of this book recommend systemic hormonal therapy or radiotherapy for this patient group. Again, this area is one of considerable debate and controversy.

Hormonal therapy for prostate cancer condition was first described in the 1940s, when the disease was found to be dependent upon testosterone. For this reason, the first treatments offered in the 1940s were orchiectomy, that is, removal of the testes or oestrogen therapy.

The results of treatment were first analysed in the 1960s by the Veterans Administration Cooperative Urological Research Group (VACURG). In their studies, the VACURG randomized patients to treatment with oestrogens or placebo, or with orchiectomy or placebo, respectively. The overall survival of patients treated or untreated was the same, but there was an excess mortality rate from cardiovascular deaths in the oestrogen-treated group. The reason for this is that oestrogens cause an increased coagulability of blood and increased blood volumes.

Because orchiectomy is barbaric and oestrogen therapy is associated with morbidity and mortality, medical treatments for this condition have been sought which are not so invasive and have no side effects. The most effective of these treatments, which has the least morbidity associated with its use, is a group of compounds called the gonadotropin-releasing hormone (GnRH) agonists. These include leuprorelin acetate, goserelin acetate and buserelin. These are currently given subcutaneously by monthly or 3-monthly injection. When treatment with GnRH agonists is started, there is a transient surge in luteinizing hormone (LH) before the levels fall, and this can lead to an initial rise in testosterone and flare of disease. Anti-androgens, such as flutamide and bicalutamide, can cover this flare by directly inhibiting the androgen receptor. Some doctors advocate continuing treatment with this combination or maximal androgen blockade of GnRH agonist plus anti-androgen. The evidence is overwhelming for the use of these agents in combination; survival is improved, osteoporosis is prevented and a chance is provided for an anti-androgen withdrawal response.

Prostate cancer is very responsive to endocrine treatment and 80% of patients improve subjectively. After an average period of approximately 1 year, however, most patients with metastatic cancer on presentation have PSA evidence of relapse. When biopsies from patients with recurrent tumour are examined and compared with biopsies on presentation, it is striking that up to 50% will show androgen receptor mutations. This is in contradiction to the situation in breast cancer, where hormone receptor amplification is the most commonly observed change. Over 700 mutations of the androgen receptor have been described, and these changes are a clue to the probable reason for the response to second-line hormonal therapy. This response is transient and is thought to occur because the mutation has led the tumour to depend upon the anti-androgen as a growth factor. The usual first approach to this is the addition of an anti-androgen to the GnRH agonist if initial treatment was GnRH monotherapy. Conversely if the first-line treatment was maximal androgen blockade, second-line treatment is the withdrawal of anti-androgen therapy, where cessation of anti-androgen treatment will lead to a response in up to 40% of patients.

Subsequent biochemical or clinical disease progression is usually described as hormone-refractory disease or castrate-resistant disease. An increasing number of approaches are available for hormone-refractory prostate cancer including interfering with the androgen pathway with oral abiraterone or enzalutamide, and intravenous taxane chemotherapy (docetaxel and cabazitaxel). Abiraterone inhibits androgen synthesis in both the testes and adrenal glands by inhibiting the CYP17 enzymes, 17,20-lyase and 17-α-hydroxylase. Corticosteroid replacement therapy is necessary for patients treated with abiraterone. Enzalutamide inhibits androgen receptor signalling. Chemotherapy is increasingly popular in patients with prostate cancer. Taxanes are the only chemotherapy agents that have been shown to significantly prolong overall survival in men with castrate-resistant prostate cancer. Unfortunately, because there are so many more urologists than oncologists in the United Kingdom, only limited numbers of men with prostate cancer are offered chemotherapy. A recent study has shown that only one man in seven who might be suitable for treatment with chemotherapy receives it. This is attributed to the reluctance of urologists to refer patients to oncologists. One can only speculate and wonder as to the psychological causes of this difficulty.

Until recently, men with prostate cancer represented a rather passive but extremely brave group of individuals who accepted their fate. The last two decades have seen significant changes in the way that men deal with their cancers and prostate cancer has now become, quite rightly, politicized with the cause championed to good effect.

The large number of men with advanced prostate cancer and the relatively prolonged natural history of the illness mean that palliative care plays an essential role. Moreover, the high frequency of metastases to bones reinforces the importance of palliative radiotherapy for pain control, bisphosphonates to reduce skeletal events and orthopaedic surgery for the management of pathological fractures (see Figure 3.6). Metastatic spinal cord compression is a relatively common occurrence in late-stage disease (Figure 14.5).

Prognosis for small bulk localized disease

Prognosis for metastatic and large bulk localized disease