Castration-sensitive phase
The principle behind treatment in the castration-sensitive phase is to abolish the stimulation of cancer cells by inhibiting testicular testosterone production and thereby reducing androgen levels in the blood: so-called androgen deprivation therapy (ADT). Surgical or medical castration are suitable forms of androgen deprivation therapy (Fig. 1). Anti-androgen therapy, which blocks androgen receptors, is generally not recommended as monotherapy for metastatic prostate cancer, but may be considered by a specialist in the event of pronounced side effects of castration therapy (2, 3). Treatment in this phase is initiated in the specialist health care service and can be continued in the primary health care service.
Surgical castration, orchiectomy, should be used if a very rapid reduction in testosterone levels is required (2, 3). A therapeutic decrease in testosterone levels is achieved from day one. However, orchiectomy has become less relevant following the introduction of medical castration.
Medical castration with analogues of gonadotropin-releasing hormone (luteinising hormone-releasing hormone, LHRH) – goserelin and leuprorelin (Zoladex, Eligard, Enanton, Procren) – is the most widely used systemic first line treatment of metastatic prostate cancer (2). The drugs are injected monthly or every 3 – 6 months.
Gonadotropin-releasing hormone analogues initially increase testosterone levels, which may cause an acute exacerbation of the clinical condition known as a flare reaction (3). This is seen particularly in cases of widespread bone metastases or urinary tract obstruction. A fall in serum testosterone to castrate level (< 0.7 – 1.7 nmol/l) is first achieved after 2 – 4 weeks. During this period, anti-androgen therapy with bicalutamide tablets (Casodex) should be used to counteract flare.
An alternative option is the gonadotropin-releasing hormone antagonist degarelix (Firmagon), which yields castrate levels of serum testosterone after three days without a flare reaction (3). The gonadotropin-releasing hormone antagonist is administered as monthly injections and may cause irritation at the injection site.
During androgen deprivation therapy, the PSA level should be checked by a general practitioner every 3 – 6 months, and the patient referred back to a specialist if levels increase. If testosterone is not at the castrate level, it may be appropriate to switch to another gonadotropin-releasing hormone analogue or to perform orchiectomy. Discontinuing anti-androgens during androgen deprivation therapy may trigger a withdrawal response in which the PSA level falls (seen in 15 – 20 % of patients) (7).
When selecting treatments, quality of life must be balanced against side effects. Typical side effects of castration therapy include decreased libido, erectile dysfunction, hot flushes, loss of vitality, depression, and cognitive impairment as well as metabolic changes (osteoporosis, metabolic syndrome). In our experience, patients that have been well informed in advance accept these side effects, but in a few individuals they may be serious and troublesome.
The general practitioner has an important role to play in detecting and preventing some of these side effects. Blood pressure, blood glucose levels and serum lipids should be checked annually. Bone density measurements and pharmaceutical prophylaxis of osteoporosis should be considered if androgen deprivation therapy is used over several years (3). Patients must be encouraged to follow the Norwegian Directorate of Health’s recommendations regarding diet and physical activity (8).
There are alternatives to conventional androgen deprivation therapy that should be considered within the specialist health care service and discussed with certain patients: total androgen blockade (androgen deprivation therapy combined with anti-androgens) and intermittent androgen deprivation. The use of these options is dependent on the disease course and symptoms (3).
Two studies have shown that early use of docetaxel (Taxotere) in combination with androgen deprivation therapy in the castration-sensitive phase increases survival in patients with metastatic prostate cancer compared to androgen deprivation therapy alone (5, 6). These studies revealed an average survival benefit of 14 and 15 months respectively in the groups that received docetaxel in addition to androgen deprivation therapy. In both studies, the largest effect was seen in those with the most advanced disease.
Induction therapy with docetaxel should be considered within three months of initiation of castration therapy in most patients with newly diagnosed metastatic prostate cancer (3). Chemotherapy should be administered at an outpatient oncology clinic under the direction of an oncologist.