Overview of Current Treatment Strategies in Prostate Cancer

1. Introduction 

Prostate cancer is one of the most common cancers in men and the second most common cause of cancer death. Despite its prevalence, the natural history of the disease is still relatively unknown, with many aspects of its progression being poorly understood. In clinical terms, prostate cancer can be divided into a spectrum of categories, based on the degree of progression:

Each of these disease categories, and the current thinking regarding the optimum treatment at each stage will be discussed.

2. Incidental disease 

Around 5% of patients are diagnosed as having what is termed ‘incidental’ or ‘subclinical’ disease at their first visit. This can be subdivided into two categories: insignificant or significant disease. Although the definition of ‘insignificant’ disease is the subject of debate at present, it is generally considered to be a tumour volume of 0.5 ml or less having no Gleason score of 4 or 5.

Treatment choice for patients with insignificant disease will depend on both patient and tumour characteristics. In elderly patients or in those with a low-grade or small volume tumour, treatment may comprise active surveillance of the patient—‘watchful waiting’—and delaying treatment with androgen deprivation. For other patient types urologists may consider active treatment.

At the author’s unit, at the Ospedale di Circolo, Varese, Italy, around 2000 patients with prostate cancer have been treated over the last decade. Of these, around 4% were diagnosed as having insignificant disease. This subgroup of patients was analysed in a non-randomised study (unpublished data). Patients with insignificant disease were divided into two groups: ‘watchful waiting’ or ‘active treatment’ with radical prostatectomy or radiotherapy. The difference in progression rates between the two groups was highly significant: 35% in the watchful waiting group and only 8% in the active treatment group; mortality was the same in each group. It was also observed that many of the patients who underwent radical prostatectomy were subsequently found to have significant disease. The conclusion that can be drawn from this study is that insignificant disease should be observed carefully and treated appropriately.

3. Localised disease 

At first presentation, the majority of patients (50–58%) are found to have localised disease confined within the prostate capsule.

Standard treatments for localised prostate cancer include surgery, radiation therapy (external beam or brachytherapy), or active surveillance/observation (‘watchful waiting’). If the surgical option, radical prostatectomy, is chosen, this can be combined with neoadjuvant hormonal therapy, or alternatively adjuvant hormonal therapy or radiotherapy. Radiotherapy can also be combined with hormone treatment. Radiotherapy can be used in patients who are considered unfit for radical prostatectomy. Watchful waiting can be the selected option in elderly patients who have a short life expectancy.

Three factors influence the choices of therapy described above:

In localised disease, if the patient has a prostate-specific antigen (PSA) value greater than 20, a Gleason score greater than 7, perineural invasion or positive surgical margins they can be considered to be ‘high risk’. In this case, there are two possibilities for treatment, either watchful waiting or adjuvant treatment.

4. Biochemical failure 

‘Biochemical failure’ in prostate cancer after the first definitive therapy is characterised by a rising PSA profile and is an early surrogate of treatment failure. To date, there is no common consensus on the definition of biochemical failure. Some patients, even after a successful radical prostatectomy with negative margins, show persistent or rising PSA. In the case of radiotherapy, the consensus statement of the American Society for Therapeutic Radiology and Oncology (ASTRO) defines biochemical failure after radiotherapy as an increase in PSA of more than three times the nadir [1].

There has been considerable discussion about the meaning of the rising PSA after first definitive therapy: does it indicate a recurrence of local disease or progression to systemic disease? This has important implications for the way the patient is subsequently treated: either locally or systemically. Again, there is the option of early or delayed treatment.

5. Extracapsular extension 

Another special category of prostate cancer is extracapsular extension or seminal vesicle involvement. The lymph nodes may be dissected during the radical prostatectomy and in some cases micrometastases are found. Treatment in these cases may involve watchful waiting and monitoring the PSA or alternatively immediate androgen deprivation with either a GnRH agonist, an antiandrogen or complete androgen blockade. Adjuvant hormonal therapy is indicated when there is lymph node involvement. When using androgen deprivation, either continuous or intermittent treatment can be considered.

The optimal timing of the initiation of antiandrogen therapy in prostate cancer is controversial. Messing et al. demonstrated that in immediate treatment was superior to delayed treatment for patients with minimal residual disease after radical prostatectomy in terms of survival and reducing the risk of recurrence [2]. Ninety-eight men who underwent radical prostatectomy with pelvic lymphadenectomy and who had nodal metastases were randomised to receive either immediate antiandrogen therapy (a GnRH agonist or bilateral orchiectomy) or observation until disease progression. After a median follow-up of 7.1 years 7/47 men who received immediate treatment had died compared to 18/51 in the observation group (p=0.02). At the time of the last follow-up, 77% of men in the immediate treatment group and 18% in the observation group had no evidence of disease recurrence (p<0.001). Fig. 1 shows progression-free survival in the two treatment groups.

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Fig. 1. Kaplan–Meier estimates of progression-free survival [3]. Reproduced with permission of New England Journal of Medicine.

When there is seminal vesicle involvement it is known that the risk of disease progression is increased. In a review of the published literature and also the Mayo Clinic database, Zincke et al. concluded that early adjuvant hormonal therapy after radical prostatectomy had a significant impact on time to progression and cause-specific survival in patients with seminal vesicle invasion and limited lymph node disease [3].

In a study by See et al. bicalutamide 150mg was given as adjuvant therapy after the initial treatment (standard care with radiotherapy, radical prostatectomy or watchful waiting) [4]. The study was a combination of three randomised, double-blind, placebo controlled clinical trials in 8113 men with localised or locally advanced (T1–T4, Nx/N0, M0) prostate cancer. Patients were randomised to receive 150mg bicalutamide daily or placebo, in addition to standard care. The primary end points were time to objective progression and overall survival. At this initial analysis of the study results, treatment with bicalutamide provided a highly significant reduction of 42% in the risk of objective progression compared with standard care alone (p<0.0001). However, a large number of patients stopped treatment due to severe and painful gynaecomastia.

However some recent unpublished information suggests that at a median follow-up of over 5 years a trend for an increase in the number of cumulative deaths in patients receiving monotherapy with bicalutamide 150mg when compared with patients who received placebo can be observed (25.2% vs. 20.5%). This is not observed in the group of patients with advanced disease [unpublished data]. The Canadian Health Authorities have withdrawn the approval for antiandrogen monotherapy with bicalutamide for the treatment of localised prostate cancer [5]. Several European countries have also withdrawn approval for bicalutamide for this indication.

At the recent European Association Urology (EAU) meeting in 2003, Schroeder et al. reported the results of the European Association for Research and Treatment of Cancer (EORTC) 30846 study comparing immediate versus delayed hormonal treatment in patients with node-positive disease after surgery [6]. No differences between the two groups were found in terms of specific mortality or survival. The results of this study are interesting as they are in contrast to other studies showing that immediate treatment is more effective.

An MRC study in the UK compared immediate and delayed treatments and found that in M0 patients, mortality was significantly less with immediate treatment [7]. One criticism of the study was that a large number of patients in the delayed treatment group were not treated once their disease had progressed, which could introduce a potential bias.

6. Adjuvant radiotherapy 

There is a lack of randomised studies investigating the optimal timing of adjuvant radiotherapy—either immediate or delayed. The indication for adjuvant radiotherapy is when there is evidence of extracapsular extension or if the patient has a Gleason score of greater than 7 and local relapse [8]. In a retrospective review of the literature, Lennernas et al. found that adjuvant radiotherapy improves local control especially if the treatment is started as soon as the PSA starts to increase [9]. The conclusions that can be drawn from this is that earlier the adjuvant radiotherapy, the lower the PSA recurrence.

7. Neoadjuvant hormonal therapy and surgery 

There are many published studies investigating neoadjuvant therapy and surgery as treatment for prostate cancer. Soloway et al. showed that the incidence of positive margins was decreased if neoadjuvant hormonal therapy was used [10], however 5-year results did not demonstrate any improvement in survival [11].

A study in Italy showed similar results. A significant decrease in positive margins with neoadjuvant maximal androgen blockade (MAB) compared to surgery alone, although survival data have yet to be reported [12].

Japanese investigators have reported downstaging to pT0 status (no residual tumour) in 16% of patients after neoadjuvant hormonal therapy of more than 3 months [13]. If the neoadjuvant treatment is extended for longer than 3 months, previously considered to be the standard, there seems to be an even greater decrease in the incidence of positive margins [14], [15]. This suggests that the optimal duration of neoadjuvant therapy is greater than 3 months.

8. (Neo)adjuvant hormonal therapy and radiotherapy 

There are two older studies showing improved local control, disease progression and survival in patients treated with adjuvant hormonal therapy in addition to radiotherapy in locally advanced prostate cancer [16], [17]. A study of neoadjuvant hormonal therapy with brachytherapy in locally advanced disease showed that hormonal manipulation improved the biochemical outcome for those at high-risk and those with an initial PSA of greater than or equal to 10ng/ml, but not for those with intermediate-risk features [18]. EORTC currently has a study ongoing comparing adjuvant hormonal therapy for either 6 months or 3 years, plus radiotherapy, and the results are awaited with interest.

9. Guidelines for treatment in locally advanced disease 

The European Consensus Guidelines for the treatment of locally advanced disease have recently been published [19]. Treatment can be divided into the options summarised in Table 1.

Table 1. The European Consensus Guidelines for the treatment of locally advanced disease: treatment options [18]

	⋅	Hormonal therapy alone
		∘ Maximal androgen blockade
		∘ Antiandrogen monotherapy
		∘ Continuous GnRH agonist
		∘ Intermittent androgen deprivation
	⋅	Hormonal therapy in combination with surgery
		∘ Neoadjuvant treatment
		∘ Adjuvant treatment
		∘ Immediate versus deferred treatment
	⋅	Hormonal therapy in combination with radiotherapy

Treatment choice will depend on patient and tumour characteristics. Watchful waiting can be considered if the patient does not have a long life expectancy (<5–10 years), or if they are asymptomatic with no Gleason 4 or 5. Active treatment is recommended if they have a longer life expectancy and the tumour is not high risk.

More recently, a European Consensus Group has also published recommendations for the treatment of locally advanced disease [20]. They concluded that there was no overall consensus as to the standard of care in clinically apparent, locally advanced prostate cancer. It was agreed, however, that hormonal therapy represented a valid treatment in these patients. Treatment practices and regimens were found to vary considerably between European countries, but GnRH analogues are widely used, either alone or in combination with antiandrogens.

10. Advanced disease 

On initial investigation, around 30% of patients are found to have advanced disease and 25% will be found to have progressed on follow-up. The median survival after progression to advanced disease is only 2.5 years. Hormone therapy is generally considered to be the main treatment for advanced prostate cancer. Depending on their treatment history, this group of patients can be divided into two categories: hormone naı̈ve or hormone resistant.

In Europe, the use of surgical castration is considered in patients in whom a rapid fall in testosterone needs to be achieved and comorbidity is high. Studies have compared the use of GnRH agonists and MAB achieved by GnRH agonist plus antiandrogen and found that MAB was superior to GnRH agonist alone in term of progression-free survival, particularly in those patients with a good prognosis [21], [22]. The Prostate Cancer Trialists Collaborative Group (PCTCG) have undertaken a meta-analysis of randomised trials of MAB in advanced prostate cancer and concluded that MAB improved 5-year survival by 2–3% when added to androgen suppression therapy [23].

The EORTC and South Western Oncology Group (SWOG) have a common study ongoing to investigate continuous versus intermittent androgen suppression. Preliminary results suggest that there is no difference in outcomes between the two treatment groups [24].

Antiandrogen monotherapy showed no difference in survival compared to castration in M0 patients [25], although it appears to be less effective than castration when metastases are present [26]. A Scandinavian group has recently published a study comparing intravenous estrogen with MAB and found no difference between treatment groups in terms of time to biochemical or clinical progression and overall or disease-specific survival [27]. However, it is expected that estrogen-treated patients would experience a greater degree of side effects.

11. Hormone-resistant prostate cancer 

Prostate cancer cells are heterogeneous in their sensitivity to androgens. Cells can range from androgen-dependent, through androgen sensitive to androgen independent. In clinical terms, there are two categories within this group: those patients still sensitive to hormones and those insensitive to hormones. Failure of hormone therapy is detected by a rising PSA, and this can signify androgen-independent growth or inadequate androgen suppression. It is generally accepted that once the cancer has become hormone resistant, androgen deprivation should be maintained with a second-line therapy to eliminate adrenal androgens [28]. Paradoxically, withdrawal of the antiandrogen component can also results in disease improvement in patients who have failed on combined androgen blockade [29]. There are some indications for third-line endocrine treatments, such as estrogens, ketoconazole or glucocorticoids.

12. Chemotherapy 

Results with the use of chemotherapy in advanced prostate cancer are mixed. New combinations are being investigated which show promising results with acceptable toxicity.

13. Treatment strategies under investigation 

Various new options are being investigated for the treatment of prostate cancer. Studies with the use of GnRH antagonists have shown that castrate levels are reached quickly and there is no testosterone surge [30]. However, these compounds have no effect on hormone-refractory disease [31].

Other compounds that are being evaluated include bisphosphonates in patients with bone metastases and also those with high-risk disease, anti-apoptotic drugs, such as sulindac, vitamin D, and endothelin antagonists, which are thought to delay the time to progression. Gene therapy is still in the experimental stages but may offer an option in the future.