How the Addition of Hormones Improves Outcome: Hormone Therapy Alone in Locally Advanced Prostate Cancer

1. Introduction 

There is currently a great deal of interest in multimodality therapies for the treatment of locally advanced prostate cancer. In the light of this ongoing research it could be questioned whether there is a role for a treatment with hormone therapy alone. Although once reserved for the management of metastatic prostate cancer, hormone therapy is being used increasingly to treat lower stages of disease.

CaPSURE™ (Cancer of the Prostate Strategic Urologic Research Endeavor) is a longitudinal observational study of prostate cancer patients that aims to support the decision-making process of physicians. Created in 1995, the CaPSURE™ database has enrolled more than 10,000 patients and provides one of the most extensive sets of data available on prostate cancer. They regularly publish their findings.

One of these studies was undertaken to assess patterns of hormone monotherapy use in a contemporary cohort of 1485 men newly diagnosed with prostate cancer. Of these, 20% received hormone therapy alone. Most of them had non-metastatic disease—clinical stage T3 or below, a PSA value of less than 20ng/ml and a Gleason score of less than 8 [1].

A second study also suggested that a large number of patients with localised disease received hormone therapy alone [2]. Harlan et al. investigated the factors associated with the choice of initial therapy for localised disease and found that 10% received hormone therapy alone as their first treatment.

However there are a limited number of published papers on the use or hormone therapy alone in locally advanced non-metastatic prostate cancer. A search of Medline (June 2003) revealed:

2. What is advanced disease? 

Hormone therapy has traditionally been used for the treatment of advanced (i.e. metastatic) disease. Although there is no universally accepted definition, a recent consensus meeting [3] summarised usually accepted definition of advanced prostate cancer (Table 1). It is also known that a high number of positive biopsies (>50%) is often associated with a locally advanced stage (pT3a-b) [4].

Table 1. A consensus definition of advanced prostate cancer

	⋅	T4, pT3b disease
	⋅	T3 (even if 5–10% are pT2)
	⋅	PSA >20ng/ml

In this paper, the pN+ status will not be considered as locally advanced but as disseminated disease, and therefore will not be specifically discussed.

Various tools are now available to help predict the evolution of the disease including those of D’Amico, Partin’s tables and Kattan’s nomograms. These tools give different answers (expected risk of biological progression at 5 of 7 years, or expected final pathological report) and could be helpful counseling patients.

3. Guidelines and recommendations 

There are various published recommendations and guidelines for the use of hormone therapy in prostate cancer, most of them concerning unfit patients or men with a short life expectancy. The cancer committee of the French Urological association [1] considered hormonal therapy only as a viable option for T3 patients with a life expectancy less than 10 years, and for T4 patients.

The European Association of Urology updated its guidelines in 2003 [2] and recommend the use of hormone therapy alone in localised disease if a patient has a life expectancy of less than 10 years, is unfit for a local treatment, or has high-risk features with a Gleason score ≥8. In locally advanced disease hormone therapy is recommended if the life expectancy is less than 10 years, the PSA value is >25ng/ml, or in large, symptomatic T3–4 disease.

The American Urological Association has also published guidelines but only on clinically localised prostate cancer and these have not been updated since 1995 [3].

The National Comprehensive Cancer Network published guidelines in 2002 recommending the use of hormone therapy alone for patients with a life expectancy of less than 5 years and a T3a or Gleason score greater than 7 or PSA greater than 20ng/ml. They also included T3b disease or N1 on CT scan or M1 disease.

4. Clinical studies of hormone therapy 

Before the era of routine PSA measurement, two authors reported on the use of hormone therapy alone in patients with non-metastatic disease. Fellows et al. in a randomised trial found no difference in overall survival in 277 patients with T2–4 disease when orchiectomy was combined with radiotherapy compared to the two treatments alone; however there was a delay in metastatic progression when castration was added to radiotherapy [5]. Dupont et al. treated 115 patients with T2–4 disease with maximal androgen blockade (MAB) (flutamide plus medical castration) and found a median overall survival of 7.9 years (69.7% overall survival at 5 years) [6].

More recently, Fowler et al. investigated 200 patients with T3–4 disease (Nx, M0) treated with hormonotherapy alone [orchiectomy (39%), LHRH (52%) or MAB (8%)]. Five-year cancer-specific survival was 92% and overall survival 59% [7]. Only 5% of the patients had local bothersome symptoms.

In the study by Akaza et al., 178 patients with T1-3 disease (N0, M0) were randomised to receive an LHRH analogue alone or combined with SAA (chlormadinone). Five-year cancer-specific survival was 93%/89% and overall survival was 72%/64% respectively [8].

In summary, using hormone therapy alone, the cancer specific survival at 5 years is clearly above 90%. Therefore it cannot be considered only as a short-term, palliative treatment modality. But when using hormonal therapy alone, there are several questions that need to be addressed:

5. Early versus delayed treatment 

The conclusions of the Veterans Administration Cooperative Urological Group (VACURG) studies are still debatable in terms of whether early treatment is better than delayed. A Medical Research Council trial in 1997 showed a survival advantage of early treatment in M0 patients only: 42% overall survival in patients treated immediately versus 30% when treated was deferred [9].

Cancer-specific survival was significantly better with immediate compared to delayed treatment at 5+ years. These results were updated two years later and the survival advantage had disappeared [10]. Despite this, there were less severe complications in the early-treated patients (ureteral obstruction, bone fractures, spinal cord compression).

Schroeder et al. reported the results of the EORTC study 30846 at the American Urological Association (AUA) meeting in 2003 in which they compared immediate versus delayed treatment in pN+ patients. The trial was closed early and as result was underpowered however with a median follow-up of 8.7 years the hazard ratio was found to be not significant. The author however concluded that there was a trend in favour of early treatment [11].

Another EORTC trial (30891) has closed (1,000 patients recruited) and results comparing early versus delayed treatment in locally advanced disease are awaited.

To summarise, for hormone therapy alone there is still no clear answer as to whether early is better than delayed treatment. However, with combined modalities (radiotherapy or surgery plus hormone therapy), results suggest that early treatment is superior.

Firstly, the study by Messing et al. suggested that early hormonal treatment (castration or LHRH analogue) is better than delayed in pN+ patients who have undergone radical prostatectomy [12]. After a median follow up of 7.1 years, the overall and specific survival was better in the immediate-treated group. This was updated at this year’s AUA meeting, with the same conclusion [13].

The RTOG 8531 study reported by Pilepich at ASCO 2003 found that with radiotherapy, immediate hormonal therapy is better than hormonal treatment delayed until recurrence [14].

Finally, it is often the patient’s request to receive early hormonal treatment if the choice is given [15].

6. Maximal androgen blockade or monotherapy? 

Multiple studies have been undertaken to assess the relative merits MAB (medical or surgical castration plus anti-androgen) or monotherapy. The answer is still unclear.

Eisenberger et al. found no difference in overall survival in patients treated with either MAB (fluatmide plus orchiectomy) or orchiectomy alone [16]. However two meta-analyses have suggested that MAB is better [17], [18], even if the observed differences in survival are very small, leading to a questionable practical significance of these findings.

7. Anti-androgen monotherapy 

Concerning monotherapy with the steroidal anti-androgen cyproterone acetate (CPA), the EORTC study 30761 (locally advanced or metastatic disease) found no difference in efficacy between CPA and diethylstilbestrol however CPA was found to be to be associated with fewer adverse events [19]. Another study has found no difference in efficacy between CPA and MAB [20]. Similarly, a study with a flutamide monotherapy found no difference compared to MAB [21].

Considering monotherapy with bicalutamide 150 mg, only two significant randomised trials have been published so far.

Iversen et al. reported the results of 2 pooled studies comparing bicalutamide versus orchiectomy or LHRH agonist in T3-4 M0 patients. There was no difference in overall survival (median survival: 65.3/69.9 months respectively) with a median follow-up of 6.3 years [22]. Boccardo et al. found no difference in survival between patients treated with bicalutamide monotherapy versus an LHRH agonist plus flutamide, however there was a non-significant trend in favour of MAB for progression-free survival [23].

It should be noted however that very recently some concerns have been raised regarding the safety of anti-androgen monotherapy for the treatment of localised prostate cancer. This will be published in detail in the literature in the near future.

For 5α-reductase inhibitors, only feasibility studies have been undertaken; no clinical response results have been reported.

8. Intermittent therapy 

The use of intermittent therapy is the subject of considerable debate. It is based on the fact that apoptosis secondary to androgen withdrawal happens only in differentiated cells; this differentiation requires androgens. Theoretically, an ‘off-treatment period’ where the hormone treatment is withdrawn, may have quality of life benefits for the patient. This remains to be proven in clinical trials.

Most series include multiple stages and are retrospective, each using a different modality, mainly MAB. Follow-up ranges between 7 and 64 months and the off-treatment period is up to 50% of a cycle.

It is clear now that intermittent hormone therapy does not induce an early hormone resistance.

We also know that intermittent treatment leads to an intermittent castration if the on-treatment period is less than 8 months. Finally, after an initial 8 months castration, the M0 patients that will have the most prolonged off treatment periods (more than 20 months) are those with a low Gleason score (≤7), a low initial PSA, and a nadir during castration <0.1ng/ml [24].

The only published randomised comparison was presented at the AUA meeting in 2002. Intermittent therapy was found to improve progression-free survival after 3 years in M0 patients but not M+ patients [25].

An unusual intermittent modality was reported by Labrie and colleagues. Fifty-seven patients with locally advanced disease were treated with MAB which was then stopped and the patients followed-up after cessation of treatment [26]. They found that the longer the initial castration, the lower the relapse rate after cessation: 10% if greater than 5 years but 100% if less than 1 year. At relapse, all the patients responded if treatment was resumed.

9. Castration and side effects 

However, early castration can be associated with several problems: a decreased quality of life [27], (depression, libido, impotence, fatigue), altered cognitive functions, decreased bone mineral density: fractures and bone pain [28].

Finally, ‘early’ hormonal treatment could lead to a non-metastatic hormone-resistant state. Once a patient has become hormone resistant, there is no effective second-line treatment in terms of survival.

Whether quality of life is improved with intermittent treatment is still the subject of debate and clinical trials have not given a definite answer. However, the longer the off-treatment period, the more pronounced the impact on quality of life.

Bicalutamide monotherapy also leads to significant side effects, namely gynaecomastia and breast pain. In terms of overall quality of life, there was no significant difference between bicalutamide and castration although there was a trend in favour of castration [29].

10. Conclusions and unmet needs 

We urgently need an internationally accepted definition of locally advanced disease and a practical and usable definition of concomitant diseases and their impact on survival. In healthy young men, research has shown that the addition of hormone therapy to radiotherapy is better than radiotherapy alone. However the real role of radiotherapy in association with hormone therapy is still unclear and the results of ongoing trials are awaited (TPA 023, RTOG 0011, NCIC-SWOG, MRC 2633) in terms of survival and quality of life benefits. The advantage of intermittent compared to continuous hormone therapy is also still to be proven.

In sick or older patients who are asymptomatic, the best timing for hormone therapy (early versus delayed) and the best hormone therapy (combined, monotherapy with LHRH or with anti-androgen) remains to be defined. In symptomatic patients hormonal therapy is the accepted standard treatment.