The Role of Hormonal Therapy in the Treatment of Locally Advanced Prostate Cancer—Regional Perspectives: Europe

1. Introduction 

In Europe, prostate cancer is the second most frequent cause of cancer death in men. Data from 23 European countries demonstrate an increase in incidence and mortality rates in elderly patients, and a significant upward trend in incidence in the younger and middle-aged groups [1]. Due to improved screening and diagnosis there is a trend towards the detection of tumours at earlier stages, however, despite this, up to 30–35% of men with prostate cancer cannot be cured by either radical prostatectomy or radiotherapy alone. Commonly, PSA relapse occurs following localised therapy and this usually signals the progression to systemic disease.

2. Survival versus quality of life 

Whether or not to treat with androgen suppression therapy at the initial stage following PSA recurrence is controversial, due to the adverse effects associated with such treatment. The majority of presenting patients are relatively young and otherwise healthy with a good life expectancy, therefore the treatment of PSA-only recurrence requires approaches that not only improve survival, but also preserve their quality of life.

Traditional hormonal therapies comprise androgen ablation using bilateral orchiectomy, estrogens or LHRH agonists with or without antiandrogens. Other treatment regimens including intermittent hormonal therapy, 5α-reductase inhibitors, and antiandrogens alone or in combination with 5α-reductase inhibitors have also been of interest in recent years. These drugs may preserve potency and have fewer side effects than traditional hormonal therapy, but the long-term efficacy and survival benefits are unknown.

There is a lack of randomised studies investigating the optimal timing of the initiation of hormonal therapy for PSA-only recurrence, therefore the timing of treatment should be individualised to take into account the patient’s preference (balancing the benefits versus the side effects) as well as the aggressiveness of disease and the objectives of therapy. Patients with a high Gleason score, lymph node involvement, a short progression-free interval after local therapy, and a rapidly rising PSA should be considered for early rather than deferred treatment due to the high likelihood of early symptomatic metastatic disease in these patients.

In terms of balancing risks and benefits, there are parallels in other areas of oncology. Very few women with high-risk breast cancer refuse adjuvant chemotherapy and/or tamoxifen despite severe side effects and an often only modest survival benefit. This indicates that these women are willing to sacrifice their quality of life for the potential gain associated with therapy. Does this view also apply in men with prostate cancer?

3. Clinical trials of adjuvant hormonal therapy 

In contrast to the breast cancer field, there are only a few prospective, randomised studies investigating adjuvant hormonal therapy in patients with prostate cancer.

3.1. With radiotherapy 

Bolla and co-workers [2] reported the results of the European Organisation for Research and Treatment of Cancer (EORTC) protocol 22863: 415 patients with locally advanced disease were randomly assigned to receive radiotherapy alone or radiotherapy plus immediate androgen suppression. An LHRH agonist was started on the first day of irradiation and continued for three years. Median follow-up was 66 months. Overall survival at 5 years was significantly different between the treatment groups: 62% in the radiotherapy-only group and 78% in the combined-treatment group (p<0.001) (Fig. 1). Disease-free survival at 5 years was 74% versus 40% in these two groups, respectively (p<0.001).

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Fig. 1. Kaplan–Meier estimates of overall survival by treatment group [2]. Reproduced with permission of Lancet.

The Radiation Therapy Oncology Group (RTOG) protocol 92-02 was a prospective, randomised trial of androgen suppression and external beam irradiation in patients with locally advanced prostate cancer [3]. All men received LHRH agonists and antiandrogens two months before and during radiation, and were randomised to no further therapy or 24 months of additional LHRH agonists. The median follow-up was 4.8 years. The group who received long-term androgen deprivation showed significant improvement in disease-free survival compared to those who received no further therapy (54% vs. 34%).

3.4. Antiandrogens 

In the Early Prostate Cancer Program, patients with localised or locally advanced disease were randomised to receive 150mg bicalutamide or placebo in addition to standard therapy (radical prostatectomy, radiotherapy or watchful waiting) [7]. Antiandrogen monotherapy was found to reduce the risk of objective progression by 42% after a median follow-up of three years (Fig. 2). Follow-up is ongoing to determine potential survival benefits of this treatment. Meanwhile the Canadian Health Authorities have withdrawn the approval for antiandrogen monotherapy with bicalutamide for the treatment of localised prostate cancer since there was a trend to a higher mortality rate in the bicalutamide group compared to the placebo group (25.2% vs. 20.5%) after a median follow up of 5.4 years [8]. Several European countries have also withdrawn approval for bicalutamide for this indication.

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Fig. 2. Risk of objective progression in patients treated with bicalutamide plus standard therapy compared to placebo plus standard therapy [7]. Reproduced with permission of Journal of Urology.

4. Which patients could benefit from an adjuvant treatment? 

Early adjuvant hormonal therapy would be beneficial in men with poor prognostic factors such as pelvic lymph node metastases, a high Gleason score, or invasion of the seminal vesicles and who are at high risk of systemic progression. Adjuvant radiotherapy would be beneficial in patients with positive margins and a low risk of systemic progression.

5. Unanswered questions and disadvantages of adjuvant hormonal therapy 

There are still many unanswered questions relating to hormone therapy, in particular the optimal timing for initiation and the optimum duration once treatment is initiated. There is currently no consensus regarding the duration of adjuvant hormonal therapy. The disadvantage of giving long-term hormonal therapy is that it is expensive and patients may experience side effects that adversely affect their quality of life.

Often, it is difficult to differentiate between local and systemic relapse. Therefore, the physician may have problems deciding on the most appropriate therapy in cases of PSA-only recurrence.

Recently, it has been demonstrated that cells of the LNCaP human prostate cancer cell line whose growth had initially been suppressed by bicalutamide, underwent mutation of the androgen receptor (AR) and became resistant to the drug. The same AR mutation has recently been discovered in recurrent prostate cancer samples from patients treated by combined androgen blockade therapy with bicalutamide. These data support the hypothesis that androgen receptor mutation is one mechanism of bicalutamide resistance [9]. It is also possible that antiandrogen monotherapy with bicalutamide induces androgen receptor mutation which may accelerate the development of androgen-independent prostate cancer.

6. The need for alternative treatments 

Klein and co-workers [10] screened more than 500 bone marrow, blood and lymph node samples from 474 patients with breast, prostate and gastrointestinal cancers for single disseminated cancer cells by immunocytochemistry with epithelial-specific markers. Irrespective of cancer type, they saw an unexpectedly high genetic divergence in minimal residual cancer. They conclude that tumour cells leave the primary tumour at an early stage. These cells are genetically very unstable. The selection acting on this very heterogeneous cell population during systemic cancer progression finally results in the expansion of tumour cells with a relatively stable genome. Investigation of the CGH profiles of single tumour cells of a man with prostate cancer and bone metastases showed that these cells had nearly identical chromosomal alterations indicating that they derived from a common progenitor cell.

The extreme heterogeneity in minimal residual cancer is a problem for all adjuvant therapies that rely on a single agent. Therefore, alternative treatments or combinations of traditional therapies should also be considered in the adjuvant therapy of prostate cancer.

7. Future developments 

Despite the advances that have been made in the diagnosis and treatment of prostate cancer, there are still many challenges to overcome, and new treatment options and regimens are constantly being sought.

Intermittent hormonal therapy, where hormone therapy is discontinued after the PSA returns to normal and then resumed when PSA begins to rise, is a promising new approach that could improve quality of life and possibly delay the emergence of hormone resistance.

Multimodal therapy combining two or more treatment options is the subject of great interest. Hormonal therapy combined with surgery or radiation in certain patients with locally advanced or N1 prostate cancer improves local control and possibly survival.

The use of chemotherapy and hormone combinations earlier in high-risk, localised prostate cancer may eventually improve clinical outcome by decreasing the risk of systemic relapse. The use of chemotherapy and hormone combinations in metastatic and high-risk disease is also an area of active research. The taxanes, estramustine in combination with taxanes, carboplatin or etoposide are promising chemotherapeutic drugs for hormone-refractory prostate cancer.

Importantly, understanding the mechanism of emergence of hormone resistance will help in devising strategies to prolong androgen dependence and in identifying new therapeutic targets.

The role of molecular-targeted therapies, such as Herceptin, Iressa and others, is an area of active clinical research and will hopefully benefit patients in the future.