Mario Di Martino
University “Federico II” Naples
In western countries, prostate cancer is currently the most prevalent form of cancer and the second leading cause of cancer death in men.(1) Radical prostatectomy and radiation therapy are the primary options for localised disease. Prostate cancer growth is androgen-dependent,(2) and the standard primary treatment for advanced disease is based on androgen suppression by reducing the levels of circulating androgens and inhibiting their effects at organ level. However, this form of treatment has limited efficacy, and refractory disease due to resistance to further hormonal manipulation occurs eventually. Since androgen suppression is rarely curative, different combinations of antiandrogens with other drugs, including chemotherapy, are under evaluation in an attempt to improve treatment outcome. Furthermore, in addition to increasing survival, preservation of quality of life is important.
The selection and timing of hormonal therapy are based on physician expertise and informed decision-making by the patient. Survival rates are low in the case of hormone- resistant disease. Thus, preventing the onset of hormone resistance and new methods of treatment are important areas of research.
Androgen ablation is effective in more than 90% of patients (including late-stage disease). In patients unfit for surgery, primary hormonal therapy is considered a useful treatment option for localised and locally advanced prostate cancer.(3) Due to limited clinical data, it is still unclear whether mono- or combination therapy should be selected in these cases.
Evidence has emerged on the role of neoadjuvant and adjuvant hormonal therapy in addition to local surgery and radiotherapy, and several trials are ongoing on alternative forms of hormonal therapy (intermittent therapy). Neoadjuvant therapy has been used to decrease the rate of positive margins and could help improve patient outcome after radical prostatectomy. Seven randomised trials demonstrated that neoadjuvant therapy reduces the positive margin rates for clinical intracapsular stage; data for locally advanced disease are less convincing.(5,6)
The goal of adjuvant therapy is to target residual microscopic foci of cancer following local primary treatment. The Medical Research Council has carried out a large randomised clinical trial on the best timing for adjuvant therapy.(7) Patients treated immediately showed a significant benefit in all-cause and cancer mortality compared with patients receiving delayed treatment (62% vs 71%; p<0.001). These results are similar to those obtained in metastatic patients.(8)
Several studies have investigated intermittent hormone blockade to evaluate the reduction in side-effects resulting from androgen deprivation, the improvement in quality of life in advanced disease and the delay in hormone resistance.(9) These studies suggested that intermittent androgen ablation might produce a long-lasting reduction in serum testosterone levels. Randomised trials are currently in progress to determine the impact of intermittent therapy on survival and biological costs.
However, hormone therapy is associated with adverse effects, limited efficacy and duration, and high costs. Decreased libido and/or potency might have a major impact on treatment decision.
Luteinising hormone-releasing hormone (LHRH) analogues such as leuprorelin acetate, goserelin, triptorelin and buserelin act by inhibiting LH production, thus suppressing production of testosterone and dihydrotestosterone (DHT)(10) after an initial “flare-up” controlled by early antiandrogen treatment. The use of LHRH analogues does not cure prostate cancer or prolong median survival, but it improves symptoms in 60–80% of patients and delays clinical progression.(11)
Meta-analysis on survival rates showed no difference between LHRH analogues and surgical orchidectomy, with better results and fewer withdrawals being observed in advanced disease compared with antiandrogen monotherapy.(12) Some researchers are in favour of early treatment.(7)
Antiandrogen therapy achieves androgen deprivation by antagonising the binding of androgen to the androgen receptor and by inhibiting androgen receptor activation. There are two types of antiandrogens: steroidal (cyproterone acetate) and nonsteroidal (flutamide, nilutamide or bicalutamide). Steroidal antiandrogens have progestational properties; their central and peripheral action at pituitary gland and prostate levels decreases testosterone and LH levels, with loss of libido and potency. Nonsteroidal antiandrogens act only at glandular level; they increase serum testosterone, which is often transformed into oestrogens by aromatases (unfortunately, this can lead to gynaecomastia).
Flutamide was the first antiandrogen used in monotherapy (250mg three times a day). Only in one study was there no difference between flutamide and orchidectomy regarding time to cancer progression and overall survival.(13) The effects of bicalutamide 50, 100 and 150mg/day have been compared with castration in several studies. In more than 1,000 patients, bicalutamide 50mg/day was inferior to castration for time to treatment failure, time to disease progression and median survival.(14) The bicalutamide Early Prostate Cancer Program, in which 8,113 patients have been enrolled, is currently investigating the value of bicalutamide 150mg/day as immediate therapy, either as immediate or as adjuvant to primary curative treatment in localised and locally advanced disease.(15) The trial is ongoing, and the bicalutamide- treated group shows a significant reduction in the risk of objective progression at three years of follow-up. The use of nilutamide as monotherapy has been studied in a single trial of 26 untreated patients with metastatic disease, showing partial response in 38.5%, a median progression-free survival time of nine months and a median survival time of 23 months.(16)
Cyprotherone acetate (CPA) monotherapy has been used in many studies, including EORTC protocol 30761, which compared CPA 250mg/day with diethylstilboestrol (DES) 3mg/day.(17) There was no difference in time to cancer progression or overall survival in both nonmetastatic and metastatic patients. However, clinical trials comparing CPA monotherapy with castration or complete androgen blockade (CAB) did not fulfil the statistical requirements for contemporary equivalence studies.
Complete androgen blockade
CAB aims at inhibiting all circulating androgens, including adrenocorticoids. This method combines surgical orchidectomy or use of an LHRH agonist with the use of an antiandrogen. In the past, many studies have shown a survival advantage for patients treated with CAB.(18,19) Recently, however, a large randomised trial reported no survival difference between CAB and orchidectomy alone in 1,387 patients with metastatic prostate cancer,(20) and some advantages with the use of orchidectomy in terms of quality of life and pharmacoeconomics.(21) CAB is an established treatment option for patients with locally advanced and metastatic prostatic cancer. It is considered palliative; it is likely to affect quality of life, body strength and fat distribution, and can lead to hair loss, hot flushes and lower bone density in the long term.
Recently, there has been increased interest for the use of low doses of oestrogens. The use of oestrogens leads to biochemical and clinical remissions in first- and second-line therapy, although they also cause significant toxicity. (22–24) Oestrogens are effective in inducing remission as standard first-line therapy, and also appear to be effective in second-line therapy. No studies have yet addressed quality of life and psychological aspects associated with oestrogen therapy.
Chemotherapy is used only as palliative treatment in patients with hormone-refractory disease. Recent data are available regarding the use of adjuvant chemotherapy in prostate cancer. Mitoxantrone was evaluated in 96 patients with stage T3 disease,(25) who were randomised to receive hormonal therapy with an LHRH agonist and flutamide, with or without four cycles of adjuvant mitoxantrone. Patients who received adjuvant mitoxantrone had a higher initial objective response rate (95% vs 53%) and median survival time (80 months vs 36 months) compared with patients treated with hormonal therapy alone. No survival advantage of mitoxantrone was observed in metastatic patients. Chemotherapy is not used in hormone-refractory disease, as no single agent or combination therapy has been shown to prolong survival. However, new drugs and drug combinations have led to significant palliation of symptoms and improvements in quality of life in symptomatic patients with metastatic disease. Agents such as estramustine, doxorubicin and mitomicin have been used as monotherapy or in combination with standard hormonal therapy. New promising agents, such as etoposide, vinblastine, paclitaxel and, recently, docetaxel and mitoxantrone, have demonstrated significant palliation in approximately half of the patients with symptoms, but their use is limited. Moreover, evidence suggests a survival benefit in patients who respond to treatment with taxanes.(26)
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