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

1. Introduction 

Since there is a considerable lack of data on the management of prostate cancer in Asia, two key sources were utilised in the development of this paper:

The study by Akaza et al. [2] showed that the treatment of prostate cancer in Asia is influenced by several factors, including:

2. Cultural and philosophical factors and differences 

There is a popular concept in Asia that preservation of life is a more important goal than improvement in the quality of life. Many of the undesirable effects of therapy, such as reduced libido and sexual function, are often not discussed with patients. Little research has been conducted so far in Asia and therefore Western literature has to be extrapolated for Asian patients, which may not be appropriate.

Many patients with prostate cancer die at home without receiving any medical attention. In many cases, Death Certificates are not issued and autopsies not undertaken, especially in Muslim countries where those who die are buried the same day.

Economics play a big role in prostate cancer management and choice of therapy as there are very poor health care systems in many countries.

In terms of morbidity and mortality, data are limited but show a great variation between counties. The highest morbidity is reported for Japan and the lowest for China; the highest mortality is reported for Japan and the lowest for Korea (Table 1).

Table 1. Prostate cancer morbidity and mortality per 100,000 males in various Asian countries [2]

		Morbidity	Mortality
	China	4.5	2.36
	Japan	16.1	8.2
	Korea	3.87	1.8
	Singapore	13	5
	Taiwan	12.36	4.78

There are also variations in the stage-specific ratio of prostate cancer. In countries except for Japan the highest percentage of patients are Stage IV (32–73%) whereas in Japan the highest percentage are Stage II (69%) (Table 2).

Table 2. Stage-specific ratio of prostate cancer in various Asian countries [2]

		Stage
		I	II	III	IV
	China	5.6	25.7	21.5	47.2
	Indonesia	2	20	5	73
	Japan	2	69	19	10
	Korea	10	15	5	70
	Singapore	28	20	20	32
	Taiwan	10	20	30	40

Reproduced with permission of Japanese Journal of Cancer Chemotherapy.

To improve diagnosis and staging in Asian countries there are prostate awareness campaigns and digital rectal examination (DRE) screening. For example, every Father’s Day in the Philippines is designated as National DRE Day. Improvements have also been achieved in recent years by advances in abdominal and transrectal ultrasound, measurement of PSA (although this is not used for screening), gun biopsy needles which are smaller in diameter, and the transrectal ultrasound-guided sextant biopsy technique. Pathologists have also improved their reading and standardisation, especially Gleason grading. Bone scans, computerised axial tomography and magnetic resonance imaging also help in diagnosis.

3. Management of locally advanced prostate cancer in Asia 

In Asia, treatment of the prostate cancer patient is individualised based on assessment of the biological potential of the disease, the life expectancy of the patient and the preferences of the patient. The consensus that was developed from a review of the literature performed for the Asian Consensus Conference concluded that androgen deprivation improved survival of patients with locally advanced prostate cancer and neoadjuvant hormonal therapy reduced radiation field size and hence treatment-related morbidity [3], [4], [5].

The role of adjuvant hormonal therapy for locally advanced prostate cancer is currently being evaluated. Preliminary findings showed no survival advantage but significant disease-free interval for patients receiving immediate orchiectomy [6].

Another consensus point from the Asian Consensus Conference was that in patients with T3 disease, while the mainstay of treatment is systemic androgen deprivation therapy, local therapy in the form of radical prostatectomy with adjuvant radiotherapy, hormonal treatment, or radiotherapy with hormonal adjuvant therapy may offer some benefit [7], [8]. Neoadjuvant hormonal therapy before radical prostatectomy is not recommended as there are no proven benefits [9].

In node-positive disease, radiotherapy combined with hormonal therapy has been shown to benefit long-term survival but the extent of contribution from the local therapy remains unclear [10].

Radical prostatectomy with adjuvant hormonal therapy is advocated by some groups who have reported good long-term survival [11], [12].

4. Philippine survey of the management of locally advanced prostate cancer 

A survey has been undertaken of 94 of the 210 urologists in the Philippines regarding their management of locally advanced prostate cancer [unpublished data]. Antiandrogens are used by 88%, LHRH agonists by 66%, orchiectomy by 61% and external beam radiation by 75%. The use of radical prostatectomy is quite low (21%) (Table 3). The main factors that are considered when choosing treatment are age of the patient and cost. Other factors are co-morbid conditions, the patient’s fear of surgery, Gleason grade and PSA level.

Table 3. Treatment patterns of urologists in the Philippines (unpublished data)

	94 urologists (total 210)
	LHRH agonists	66.3%
	Antiandrogens	88.4%
	Total androgen blockade	32.6%
	Orchiectomy	61.0%
	Radical prostatectomy	21.0%
	External beam irradiation	75.8%

5. Hormonal manipulation in prostate cancer 

Since early 1940s, hormonal manipulation has been an effective modality and a mainstay of treatment in prostate cancer. Its potential value as an adjuvant to definitive treatment modalities, such as surgery and radiotherapy, remains controversial. There is a paucity of long-term, prospective, randomised studies that have addressed the issue of adjuvant hormonal manipulation in prostate cancer.

Androgen ablation therapy provides a well-tolerated method for inducing prostate cancer cell death and tumor regression [13]. Apoptosis or programmed cell death occurs in normal, benign hyperplastic and malignant prostatic epithelial cells with any procedure that results in castrate levels of testosterone [14]. The benefits of hormonal therapy in this situation are mainly that it reduces the size of the prostate gland and the tumor rather than its control of minimal residual disease after radiotherapy.

The timing of hormone therapy in patients with advanced prostate cancer remains controversial. Although evidence from the Veterans Administration Cooperative Urological Group (VACURG) data indicated the potential benefit of immediate hormone treatment in terms of time to progression and disease-specific survival, it also supported the possibility of deferred treatment. Since publication of these studies in the 60s and 70s, the concept and dogma has been that early hormonal therapy slowed disease progression but did not prolong survival. Data from more recent studies using androgen ablation in early disease plus the availability of newer, better tolerated hormone therapies may demonstrate that the survival and welfare of patients with advanced prostate cancer would be considerably better with immediate hormone therapy rather than deferred treatment.

There are indications that radiotherapy and cryosurgery can be highly effective when directed at relatively small tumour targets and thus hormone therapy is beneficial in this setting in terms of reducing the tumour volume.

Within Asian countries the actual choice of hormonal therapy may be dictated by economics. Orchiectomy is less costly than a course of hormonal therapy and the patient’s choice may be influenced by what he can afford.

6. Adjuvant hormonal therapy 

While radical prostatectomy provides high cure rates for localized prostate cancer, success rates are much lower at 25% for locally advanced disease [15]. External beam irradiation has been considered the gold-standard treatment resulting in a median survival as long as 5 years [16]. Some controlled clinical trials have failed to demonstrate the value of prophylactic hormonal therapy with diethylystilbestrol, orchiectomy or both in patients treated with external radiotherapy [17], [18], [19]. However, another study of 277 patients found metastases were delayed significantly compared with radiotherapy alone [6].

An EORTC Phase III study (22863) undertaken in 1997 compared radiotherapy plus adjuvant hormonal therapy with radiotherapy plus observation in 415 patients [3]. The results showed an 85% disease-free state after 5 years in combination group compared to 48% in radiotherapy alone group (Fig. 1).

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

7. Immediate versus delayed antiandrogen therapy 

Messing and co-workers undertook a study in 98 men post radical prostatectomy with pelvic lymphadenectomy found to have nodal metastases [20]. They were randomised to receive either immediate antiandrogen therapy with goserelin or orchiectomy, or follow-up until disease progression. Patients were assessed quarterly for the first year and the year then semiannually. The median follow-up was 7.1 years. In the antiandrogen group 7 out of 47 men died compared with 18 out of 51 in observation group (p=0.02). The cause of death was prostate cancer in 3 men in immediate-treatment group and in 16 in observation group (p<0.01). At last follow-up, 36 men in immediate-treatment group (77%) and 9 men in observation group (18%) had no evidence of recurrent disease including undetectable serum PSA (p<0.001). The authors concluded that immediate antiandrogen therapy after radical prostatectomy and pelvic lymphadenopathy improves survival and reduces the risk of recurrence in patients with node-positive prostate cancer.

8. Neoadjuvant hormonal therapy 

Short-term hormonal therapy with flutamide and goserelin before and during irradiation plus long-term hormonal therapy with goserelin after external irradiation showed advantages over external irradiation alone in terms of local control, decreased incidence of distant metastases and progression-free survival [21].

Up to two-thirds of clinically confined tumors are understaged, with positive margin rates of 30–60% reported after radical prostatectomy [22], [23]. Routine PSA screening results in earlier detection and thus increases the amount of T1c disease found and the probability of organ confined disease. However, higher tumor stage, Gleason’s grade and pre-operative PSA correlate with an increased risk of positive margins and PSA recurrence [24].

Although not focusing specifically on locally advanced disease, Gleave et al. undertook a study in 547 men with T1b, T1c and T2 prostatic adenocarcinoma requiring radical prostatectomy [25]. Patients were given monthly 7.5mg leuprorelin and 250mg flutamide every 8hours for 3 months pre-operatively or the same treatment for 8 months. The groups were equivalent in terms of demographics, clinical stage, Gleason grade and baseline PSA. When changes in DRE were investigated, there were no differences between the two treatment groups regarding prostate enlargement, size, palpable tumor or consistency at baseline and after two months. Pre-operatively, the group treated for 8 months has smaller gland size, less palpable tumours and a higher percentage with normal consistency.

Serum PSA decreased at similar rates in the two treatment groups during first three months of neoadjuvant hormonal therapy decreasing 83%, 98% and 99% after 1, 2 and 3 months respectively. A gradual further 57% decrease in mean serum PSA was observed between the third and eighth month in the 8-month treated group. Almost twice as many patients had undetectable pre-op PSA nadir <0.1 in the 8-month compared with the 3-month treated group. In terms of pathological stage, the 8-month group was reported to have less positive margins, a higher rate of organ-confined tumors, a higher proportion of small volume or microfocal disease, a lower incidence of positive lymph nodes.

There are various indications for androgen deprivation before interstitial brachytherapy including an initial prostate volume >50ml, treatment length >5.5cm, a Gleason’s score of 8–10, a pretreatment PSA >10, elevated Gleason’s and PSA, median lobe hypertrophy and pubic arch interference. A study has shown a mean volume reduction of 33% after a 3.7-month average duration of androgen deprivation [26]. A greater reduction is seen in patients with a larger prostate volume and with longer deprivation duration. LHRH agonists alone are found to be more effective than total androgen blockade.

9. Conclusions 

Cultural and philosophical factors must be considered in the management of prostate cancer in Asia. Progress in the management of locally advanced prostate cancer has been impeded by the VACURG studies published in the 60s and 70s. There should be a focus on evaluating the use of neoadjuvant and adjuvant use of hormones in the primary management of prostate cancer especially radical prostatectomy and external beam irradiation. Large, randomised clinical trials must be undertaken to determine the efficacy of the newer modes of androgen ablation used as neoadjuvant and adjuvant therapy to external beam irradiation and radical prostatectomy. It is vital that Asian countries are part of this global survey as the incidence of prostate cancer has been rising over the years because of improvement in diagnosis.