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

3.1. Radical prostatectomy alone 

Mian et al. reported that radical prostatectomy alone in patients with a Gleason score of >8 resulted in disease-free survival in 81% after 5 years and 68% after 7 years; 79% had no evidence of biochemical failure after 5 years [3].

3.2. Radical prostatectomy plus neoadjuvant hormonal therapy 

Neoadjuvant hormonal therapy for 3 months prior to radical prostatectomy has been investigated in seven Phase III studies. They reported a decrease in positive margins of around 50% but no change in PSA recurrence [4], [5].

The results of the study by Gleave et al. suggested that neoadjuvant hormonal therapy of more than 3 months duration was necessary for the optimum effect [6]. Their study showed that there was ongoing biochemical and pathological regression between 3 and 8 months of total androgen blockade with leuprorelin and flutamide. Serum PSA continued to decline after 3 months and reached an undetectable level after about 7 or 8 months of therapy (Fig. 1). An assessment of pathologic tumour stage, showed that after 8 months of hormonal therapy there were some patients with P0 disease, suggesting that in some cases hormonal therapy could be potentially curative. The incidence of positive margins was lower in the 8-month compared to the 3-month group (12% versus 23%, respectively, p=0.01).

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Fig. 1. Changes in PSA following 3 and 8 months of neoadjuvant hormonal therapy [6]. Reproduced with permission of Journal of Urology.

A comparison of the University of British Columbia and Canadian Uro-oncology Group studies shows that PSA-free survival is better after 8-months of neoadjuvant hormonal therapy compared to 3 months [7]. However, there is no survival advantage or PSA recurrence data to suggest that the longer therapy is superior.

A study by Meyer et al. also supports the benefits of longer than 3 months duration of neoadjuvant hormonal therapy prior to radical prostatectomy [8]. They found that treatment with antiandrogen alone for any duration, or the combination of an antiandrogen and a LHRH analogue for 3 months or less were not associated with any improvement in survival compared to radical prostatectomy alone. However, patients receiving combined therapy with the antiandrogen and a LHRH analogue for more than 3 months had a significantly lower risk of PSA failure than those treated with radical prostatectomy alone (hazard ratio 0.52).

3.3. Radical prostatectomy plus adjuvant radiotherapy 

The value of post-operative external beam radiation therapy after radical prostatectomy for pT3 disease has been debated for some time. It is unclear whether there is any value in giving radiotherapy to high-risk patients. There are no randomised clinical trials reported yet that can confirm this hypothesis, although some are ongoing.

Investigations of longer-term follow-up of adjuvant radiation therapy have shown benefits for adjuvant treatment: 89% with no evidence of disease after 5 years in the adjuvant treatment group versus 55% in the control group [9].

Early post-operative radiotherapy may reduce the risk of PSA recurrence following radical prostatectomy and should be considered if there is adverse pathology.

3.4. Radical prostatectomy plus adjuvant hormonal therapy and radiotherapy 

Radiotherapy combined with neoadjuvant or adjuvant hormone therapy appears to show some treatment synergy.

Bolla et al. investigated long-term hormone therapy and radiation therapy in T1–T4 disease and found improved overall survival; this was the first localised prostate cancer study to demonstrate a survival advantage with this regimen [10].

Results of the Radiation Therapy Oncology Group (RTOG) 8531 study show 65% versus 42% of patients with no evidence of progression in the hormone-treated group versus the adjuvant radiation only group, but there was no difference in disease-free or overall survival [11].

An important study that the RTOG are currently undertaking is investigating high-risk patients after radical prostatectomy. Patients are randomised to radiotherapy, total androgen blockage or both. Results are yet to be reported.

3.5. Chemotherapy combinations 

Another subject of interest is the introduction of chemotherapy earlier in disease management and studies are ongoing to investigate various chemotherapy options and combinations including taxanes, estramustine and mitoxantrone.

Wang et al. investigated the combination on an LHRH analogue and flutamide with and without mitoxantrone in 96 patients with advanced disease. In localised disease, there was a significantly higher objective response and longer survival in the mitoxantrone-treated group. There was no advantage in the addition of chemotherapy in metastatic disease.

Another ongoing study by the Southwest Oncology Group (SWOG) 9921 is investigating survival rates in men with risk features who have undergone radical prostatectomy Patients are randomised to treatment with hormone therapy (biclutamide and goserelin acetate) with or without mitoxantrone.

3.6. Adjuvant hormonal therapy 

Several studies have been undertaken to assess the benefits of adjuvant hormonal therapy following definitive treatment with either surgery or radiation.

Prayer-Galetti and colleagues found a 25% advantage in disease-free survival at 5 years for patients with locally advanced prostate cancer treated with LHRH agonist adjuvant therapy after radical prostatectomy [12].

The bicalutamide Early Prostate Cancer (EPC) trial recruited patients from centres in Scandinavia, Europe and North America [13]. Patients received either bicalutamide 150 mg or placebo as adjuvant therapy following primary therapy (radical prostatectomy or radiotherapy), or as immediate therapy in men who would otherwise have been managed by watchful waiting (initiation of therapy only if symptoms or signs of progression occurred). Primary endpoints were progression-free survival and overall survival.

The side effects with bicalutamide (breast pain) were a significant problem. The incidence of objective progression in the observation group was significantly lower than in the bicalutamide-treated group, although a high proportion of patients did progress with this treatment. It could be argued that the patients who failed on bicalutamide were hormone refractory.

However more recent data from a planned second analysis of the EPC results showed that at a median follow-up of 5.4 years in patients with localised prostate cancer otherwise managed by watchful waiting and bicalutamide 150 mg therapy, there was a trend towards accelerated deaths compared to that of the placebo-treated group [196 (25.2%) deaths vs. 174 (20.5%) deaths, HR=1.23, 95%CI 1.00, 1.50] [unpublished data]. This trend was mostly associated with localised disease in patients at low risk of disease progression.

The RTOG 8610 trial investigated total androgen blockade plus radiation therapy versus radiation therapy alone in 500 patients with cT3 disease and found an improvement in cancer-specific survival at 8 years (Table 2) [14]. Improvements were seen between the follow-up points at 5 years and 8 years suggesting that a longer follow-up is needed to confirm treatment effects.

Table 2. Study RTOG 8610: total androgen blockade ± radiation therapy [14]

	⋅	500 patients with cT3 disease
	⋅	Total androgen blockade (4 months) + EBRT vs. EBRT alone
	⋅	Local control: 84% vs. 71% at 5 years
	⋅	PSA recurrence 46% vs. 21% at 5 years
	⋅	Improved cancer-specific survival at 8 years 70% vs. 52% (best in patients with Gleason scores 2–6)

The RTOG 9413 trial is investigating whole pelvic or prostate only radiotherapy with neoadjuvant or adjuvant hormone therapy using total androgen suppression. The best results have been achieved with whole pelvic radiation and neoadjuvant hormonal therapy [15].

3.7. Investigational strategies: radical prostatectomy or radiotherapy plus chemohormonal therapy 

Multimodality therapy with dual or triple combinations of treatment is continuing to be investigated.

Chemotherapy alone for the treatment of prostate cancer has a very poor response rate. The rationale for combining chemohormonal therapy with radiotherapy is as follows:

RTOG 9902 is currently investigating hormone therapy plus radiotherapy versus hormone therapy plus radiotherapy plus chemotherapy with paclitaxel, estramustine and etoposide for localised, high-risk prostate cancer and results are awaited.

3.8. Hormone therapy alone 

Brawer and colleagues undertook a study of hormone therapy alone in high-risk T3/T4 prostate cancer patients and found results similar to those in the Bolla radiotherapy plus hormone therapy trials [9] with cause-specific survival of 95% after 5 years [16].