How the Addition of Hormones Improves Outcome: Hormone Therapy and Radiotherapy

1. Introduction 

In term of mechanisms by which we can investigate how hormone therapy can affect patients who undergo radiation therapy, data are limited, however it is possible to obtain information from the following sources, but there are a variety of unanswered questions about each option:

Animal studies in the Shionogi mouse model have shown that if hormonal therapy is allowed to take effect, then lower doses of radiation are required to eliminate the tumour [1]. A higher dose of radiation was needed in animals immediately after orchiectomy compared to giving radiation once maximal regression of the tumour had occurred.

A study by Kuhn et al. investigated the reduction in PSA in patients treated with an LHRH analogue alone or an LHRH analogue plus an antiandrogen. In the antiandrogen group, there was an immediate drop in the PSA, whereas with the LHRH agonist alone, there was a delay in this reduction until the testosterone reached castrate levels (Fig. 1). In terms of the effect on the tumour cells, it is likely that at least for the first month of NHT you would also need to use an antiandrogen to ensure maximal regression of prostate volume and tumour volume [2].

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Fig. 1. Reduction in PSA with LHRH + antiandrogen or LHRH alone [2]. Reproduced with permission of New England Journal of Medicine.

2. Dosage of radiation and hormone therapy 

Radiation therapy can be given in a number of ways:

•External beam radiation therapy (EBRT): there is a huge variation of doses, from 70–90Gy.

•Brachytherapy: the target dose varies with the isotope: for 103Pd 124GY and for 125I 145–160Gy.

There is a difference in the way the radiation is given between these two options and this has led to the debate: are lower doses over a longer period of time better than higher doses for a shorter period of time? Also, what is the impact of hormonal therapy in these two cases?

Data in the literature show that 3–4 months of hormonal therapy reduces prostate volume by 25–54%.

Stone and Stock treated 145 patients with NHT (LHRH agonists plus flutamide) for 3 months before and 3 months after seed implant. The reduction in prostate volume ranged from 2–62% with a mean of 35% [3]. They also reported that patients who had smaller prostates at the outset had a mean reduction of 29% whereas those who had large prostates at the outset had a mean reduction of 41% (p<0.05).

The advantages of using hormonal therapy to reduce the prostate in patients being treated with brachytherapy are: larger glands require more activity, that pubic arch interference can be minimized, urinary symptoms and retention can be reduced and there will be a lower seed costs (a smaller prostate will need fewer seeds implanted).

In a study by McNeely [4], radiation doses were found to increase in patients receiving 125I in large prostates:

•<25cc: median D90 = 157Gy;

•25–50cc: median D90 = 161Gy;

•50 cc: median D90 = 171Gy.

Doses above 160Gy are associated with a higher degree of radiation side effects.

3. Neoadjuvant and concommitant hormone therapy 

The advantages of using neoadjuvant and concomitant hormonal therapy in patients undergoing brachytherapy are that it may reduce the likelihood of relapse. This rationale is based on EBRT data. Hormonal therapy has been shown to reduce tumour volume, which may increase the effectiveness of the radiation therapy. There is also a theory that the combination may be better than either treatment alone—the theory of apoptotic synergism.

A study has compared patients treated with brachytherapy alone or brachytherapy plus 6 months of an LHRH analogue plus an antiandrogen, 3 months before and 3 months after the implant [5]. All patients were categorised as intermediate to high risk (Gleason score ≥7 or PSA >10). Results showed that the intermediate-risk patients had better freedom from biochemical failure than high-risk patients (Fig. 2a). Similarly, those who received hormone treatment had better freedom from biochemical failure than those who did not receive hormones (Fig. 2b). Intermediate-risk patients treated with hormonal therapy had a 94% freedom from biochemical failure after 4 years, suggesting that this group is the ideal patient population to receive short-term hormonal therapy in combination with brachytherapy. No advantage was found of using hormonal therapy in low-risk patients.

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Fig. 2. (a) Freedom from biochemical failure in intermediate-risk and high-risk patients [5]. Reproduced with permission of International Journal of Radiation Oncology and Biological Physics. (b) Freedom from biochemical failure in patients treated with hormone therapy versus no therapy [5]. Reproduced with permission of International Journal of Radiation Oncology and Biological Physics.

Other studies have not shown this advantage when using hormonal therapy although different protocols have been employed.

We know from the literature that if a patient has radiation therapy and there is persistent local disease, most patients will progress. Cancer-specific survival at 5 years is 15% for disease that progresses compared to 80% for non-progression, so it is important that local disease is eliminated [6].

Biopsies on 296 patients 2 years after brachytherapy showed that in high-risk patients (those with Gleason 7 or above), 6 months of hormonal therapy significantly reduced the time to progression. However, radiation treatment was also important: a multivariate analysis showed that radiation dose and hormone therapy were both highly significant predictors of a positive biopsy [7]. In contrast, Gleason score, PSA and stage were not significant predictors of local control.

4. Treatment of high-risk patients 

Patients with T3 disease are the most difficult to control. Studies of patients with PSA values >20ng/ml treated with radiotherapy alone show very poor freedom from biochemical failure rates. One study showed a zero freedom from biochemical failure after 10 years [8].

Sylvester and co-workers have investigated a combination of brachytherapy and radiotherapy with and without hormonal therapy and showed no difference in progression-free survival (Sylvester, unpublished data). However, this was not a randomised study and the duration of hormonal therapy was short.

The conclusions drawn from recent clinical studies is that in order to treat high-risk patients effectively, it is necessary to take multimodal approach. A study by Stock and Stone reported at the American Society for Therapeutic Radiology and Oncology (ASTRO) meeting in 2002 investigated 131 high-risk patients. To be considered ‘high-risk’ the patients had to have disease in the seminal vesicles detected by biopsy or a Gleason score of 8–10 or a PSA ≥20ng/ml or two or more of the following: PSA ≥10, stage ≥T2b, Gleason score of 7. The median follow-up was 45 months and the ASTRO definition of PSA failure was used. Two-thirds of the patients were T2b or greater, the mean PSA was 22 and two-thirds had Gleason score of 7 or above.

Treatment consisted of the following:

•neoadjuvant hormonal therapy for 3 months—an LHRH agonist plus an antiandrogen;

•partial brachytherapy implant—seminal vesicles were implanted if positive;

•2-month break—continued hormonal therapy;

•3D conformal external beam—median: 45Gy;

•total duration of hormonal therapy: 8–9 months.

The hormonal therapy was continued throughout and stopped after the radiation was completed.

Results showed the 6-year overall freedom from biochemical failure was 88%. The freedom from failure was no different when patients were analysed according to their starting PSA value (<10, 10–20 or >20ng/ml) however if stratified by Gleason score (<6, 7 or 8–10), there was a difference: those with the lowest Gleason score had the highest freedom from failure (97%).

This can be compared to studies on radical prostatectomy patients. Grossfeld et al. looked at survival in patients with Gleason 8–10 stratified by either PSA <20ng/ml or PSA ≥20ng/ml [9]. Median follow-up was 36 months and the likelihood of remaining disease free was found to be greater in the lower PSA group (40% versus 20%). This is in contrast to the Stock and Stone radiation study described above where there was no difference between the high and low PSA groups (75% versus 79%).

Sofer et al. looked at time to progression after radical prostatectomy in relation to seminal vesicle involvement and found that a higher percentage of seminal vesicle-negative patients were progression-free after 120 months compared to seminal vesicle-positive patients [10]. Again this is in contrast to the Stock and Stone radiation study where the involvement of seminal vesicles had no influence on progression.

The results of these various studies raise several questions that need further exploration: Why is there a difference between the seminal vesicle positive patients in the Sofer study where the success rate was about 35% and those in the Stock and Stone study, where the success rate was much higher at 75%? The other issue is that a 75% success rate indicates a 25% failure rate—how best can we manage these patients? Biopsies undertaken during the study indicate that they were all systemic, rather than local, failures.

5. Optimal duration of hormonal therapy with radiation 

It has been established that for NHT, the optimal duration is 3 months, for concomitant therapy it is 3–6 months, but what is the optimum for AHT?

Bolla et al. showed an advantage of radiation plus adjuvant hormonal therapy over radiation therapy alone after 3 years, however this does not necessarily mean that 3 years is the optimum duration [11].

Roach et al. undertook a meta-analysis of all the Radiation Therapy Oncology Group (RTOG) trials with the aim of determining the optimal use of hormone therapy in high-risk prostate cancer [12]. This was a difficult task as there is a considerable amount of data over a long period of time using different radiation doses, which makes the validity of the results questionable.

The investigators divided patients into four risk groups depending on their Gleason score and T stage. As was expected, the lowest risk patients did least well in terms of disease free survival after radiotherapy alone. The use of long-term hormonal therapy improved overall survival (28% versus 44%) and disease-specific survival (42% versus 69%) compared to radiotherapy alone. It was concluded that there is a benefit in using long-term hormonal therapy in high-risk patients. What is not clear is when this hormonal therapy should be started.

6. Hormonal therapy and morbidity 

A few recent studies have shown that hormonal therapy increases the incidence of urinary retention compared to brachytherapy alone, although this is difficult to explain. However Terk et al. found that it was urinary symptoms before brachytherapy that influenced subsequent urinary retention and not the hormonal therapy [13].

In terms of sexual function it has been shown that men who received hormonal therapy before brachytherapy had a worse preservation of potency than brachytherapy alone. Hormonal therapy also has a negative impact on quality of life outcomes.

Stock et al. have found that while both radiation and hormone therapy have a slight negative impact on potency, it is the pre-treatment sexual potency that predicts post-treatment potency and is not an effect of the hormone therapy [14].

7. Conclusions and unmet needs 

For the future it will be important to determine using randomised, controlled trials if brachytherapy is equivalent in efficacy to external beam radiation therapy. Other issues that need clarification are the use of dose escalation (EBRT + brachytherapy or IMRT) and whether hormone therapy can enhance local control. In the PSA era, does hormone therapy change the way the patient needs to be monitored? As higher doses of radiation are now being used to treat patients compared to several years ago, biochemical control has improved. It is therefore difficult to compare recent and older trials. Long-term studies are necessary with radiation therapy to truly determine which patients are failing and how best to manage them.