To understand hormone suppression, we need to understand how normal growth is promoted in prostate tissues. Androgens, having a molecular structure containing 19 carbon atoms, are hormonal steroids enzymatically derived from the precursor molecule cholesterol. Androgens are responsible for the development of secondary male characteristics and are directly involved in the health and growth of prostatic tissue.

In males, androgens are produced by the testes and by the adrenal gland. The testes are the only direct source of substantial amounts of testosterone, while the androgens produced by the adrenal gland —androstenedione, dehydroepiandosterone and dehydroepiandosterone sulfate— are hormone precursors that end up enzymatically converted to testosterone and dihydrotestosterone in prostatic and peripheral tissues.2 The adrenal gland also produces a minuscule amount of testosterone, but the amount is negligible as compared to testicular output.

Prostate epithelium is made up of three different types of cells. The largest portion is made of secretory epithelial cells. There are also basal epithelial cells and endocrine-paracrine cells. Not much is known about the endocrine-paracrine cells, their function and androgen sensitivity. The normal secretory epithelial cells are sensitive to androgens while the basal cells do not require androgens to grow and can survive without it. Basal cells are believed to be the stem cells of the prostate or cells that generate secretory epithelial cells.3, 4

The cause of prostate cancer is not well understood yet, but scientists know it starts from an ancestral cell that, probably in the past, started a program of abnormal reproduction. The malignant transformation of a cell happens through the accumulation of genetic mutations within the cell.  Interpreting these genetic changes in the future using the Human Genome Project5, will provide the key to understand the processes at the root of human cancers.

In interpreting the pathway of disease progression, the ancestral cell has now grown into an accumulation of daughter cells that have become more and more aggressive and differ vastly from the original ancestral cell and its characteristics. As these cells dedifferentiated, their androgen sensitivity could possibly change and they might become androgen-insensitive or even androgen-hypersensitive.2   In either case or perhaps by other pathways, these cells can have the potential to grow in the absence of androgens. On the other hand, if the cancer started with androgen-insensitive basal cells, this phenotype can be the very aggressive prostate cancer that never responds to androgen to support its growth, and consequently will not respond to androgen suppression.6

The key to prostate cancer hormonal suppression response is based on the actual stage of cellular composition (degree of dedifferentiation and androgen-dependence) of the tumor load at diagnosis. Prostate cancer is heterogeneous and multifocal. Based on its genetic mutations, each cancer can respond differently to androgen deprivation. This is why they observe such variability in the results from hormone suppression treatment. Prostate cancer’s diagnostic process is through transrectal ultrasound (TRUS) guided biopsies. In surgical series, there is a great variability between diagnostic biopsy results and pathology results of prostate specimens, resulting in up to 45% understaging to 32% overstaging of tumor grade.7 This alone can be a serious handicap in the diagnostic process and treatment decision.8,9 Correlation could improve if biopsy samples were taken based on prostate volume and directed at established targets in a pattern, with properly identified samples per target area. At this point in time, the vast difference in biopsy results and final pathology results are being mostly ignored, probably as dictated by cost factors. Treatment decisions made under this uncertainty umbrella are a major cause of treatment failure. Patients ultimately pay the price for lack of good reliable diagnostic information and a clearer picture in reference to the all-important true molecular stage of each individual’s state of cancer progression.

Androgen deprivation results in marked morphological changes in prostatic tissue, including increased cell death or apoptosis and lower cancer cell proliferation rates. Unfortunately, because of the heterogeneity of prostate cancer, the response to androgen deprivation is variable in many patients and very much dependent on the particular stage of genetic mutations of the different identified and unidentified tumors present in the patient's prostate or other metastatic sites.

As mentioned, the magnitude of these changes is quite variable, with high-grade tumors —poorly differentiated— responding the least to androgen suppression. This seems to be the reason for the 20% of patients not responding or having only partial response to hormone ablation. The other 80% of patients achieve a response, which can last from a few months to a few years. Unfortunately, with time many patients develop more aggressive tumor phenotypes which are resistant to hormone ablation and thus fail therapy.6

Hormone suppression for advanced prostate cancer ... a reality
When a patient is diagnosed with advanced disease or when definitive treatment fails as demonstrated by a multiple rise in PSA level, hormone suppression is the primary treatment option. It is widely recognized that this form of treatment is palliative and at this stage of the disease is never curative.
The major therapeutic methods to induce androgen suppression include the following:
1.    Castration or orchiectomy (surgical removal of testes).
2.    Medical castration induced by luteinizing hormone releasing hormone (LHRH) agonists or antagonists.
3.    Medical castration induced by estrogen or estrogen analogs.
4.    Medical castration induced by antiandrogens and with/without alpha-reductase inhibitor combination with LHRH agonists or antagonists.
5.    Medical castration induced by secondary hormonal manipulations such as ketoconazole with or without glucocorticoids. 6.    Medical castration induced by combinations of all of the above methods. It is not the intent here to do a review of these options or their comparative efficacy. It should suffice to note that all these options can reduce testosterone to castrate levels and consequently induce the morphological changes mentioned above.

t is obvious that surgical castration conveys irreversibility and its use should be limited to those in need of a sudden reduction of testosterone to avoid compression fractures or to very advanced cases of prostate cancer as a practical solution to the inconvenience of periodic injections, if so desired. What is interesting is to clarify the different action mechanism of some of these options:
1.    Orchiectomy: Elevated LH (luteinizing hormone) and FSH (follicle-stimulating hormone) and decreased testosterone (T) and dihydrotestosterone (DHT). No effect on the adrenal gland output.
2.    LHRH agonists and antagonists: Inhibition of LH secretion. Decrease of T and DHT. No effect on adrenal gland output.
3.    Estrogen or estrogen analogs: Inhibition of LH secretion. Promotion of synthesis of sex-hormone binding globulin (SHBG) by the liver, reducing the amount of bioavailable testosterone to target tissues, 5-alpha-reductase inhibition, interference with both T and DHT binding with androgen receptor (AR). DNA polymerase inhibition.
4.    Antiandrogen monotherapy: Increases testosterone and LH while not affecting adrenal output. Alpha-reductase inhibitors reduce the amount of DHT, but increase testosterone.
5.    Ketoconazole: Inhibits both testicular and adrenal androgen output by blocking cytochrome P-450, therefore plasma testosterone decreases, while plasma LH increases.

There is no question that hormonal suppression can be a very effective form of treatment for early stages of advanced disease. Even in very advanced disease, hormonal suppression can offer pain reduction and an improvement in the quality of life in those patients in which bulky tumors affect natural functions. There is a significant survival difference in advanced disease in relation to the number of metastatic lesions present.
 
Labrie et al10 reported significantly longer survival (8+ years) in patients with 1 to 5 bone lesions as compared to those with 6 to 10 bone lesions (3.6 years) and disseminated disease (1.76 years). This supports the notion of early suppression over a delayed application.

Hormone suppression for early prostate cancer...  a possibility
If early hormone suppression works to provide pain palliation, extend survival and in general improve quality of life for advanced prostate cancer patients, why not use it in earlier stages of cancer?It seems a logical extension, but this conclusion is not based on any supportive clinical trials and is very much opposed for economic reasons. Hormonal suppression with the modern array of available drugs is a costly proposition and presently the only reversible form of hormonal treatment.
From a survivor’s viewpoint, every man diagnosed with an aggressive prostate cancer should consider hormonal suppression for a finite period of time prior to any definitive treatment or as in an intermittent suppression protocol. The suppression period should not be too extensive, causing irreversible changes in the testosterone producing glands and permanent side effects, or too short, failing to institute all the morphological cellular changes necessary to make the treatment more effective. This treatment period might be variable depending on the patient's PSA response to deprivation. Those achieving an undetectable PSA nadir rapidly, might be treated for shorter periods and those with more resistance to achieve an undetectable PSA nadir, might have to be treated for longer periods of time or treated with more active protocols. From literature reviews, the minimum period needed is approximately eight to nine months of suppression.11 This minimum period is needed to institute all the necessary changes to potentially improve treatment results.

This process serves many purposes. It is a process that must be carefully monitored. A rapid response to hormone suppression might provide valuable information about the androgen dependent/androgen independent composition of the tumor load. Those who do not respond well might benefit from more effective forms of treatment in a more expeditious manner. Close observation gives men and their physicians time to ascertain the individuality of the case, and gives patients time to learn what is ahead in the treatment selection that fits them the best.

This is a costly process; it causes uncomfortable and possibly irreversible side effects. These must be addressed and understood before the initiation of therapy and last, but not least, it causes changes in the prostate such as gland volume reduction and tissue fibrosis that might make some treatment procedures more difficult to perform (such as surgery or brachytherapy). Anyone can see why this treatment modality has not been readily accepted for treating earlier stages of prostate cancer. In spite of all the opposition, this is something that needs to be studied and considered as potentially beneficial for selected groups of patients.

The potential benefit of combined therapies in borderline diagnostic cases should not be ignored. It is very possible that those opposed to this form of therapy for early stage prostate cancer will be surprised with the end results of future studies. Furthermore, what seems costlier now is in effect more efficient treatment with less relapses and significant future cost avoidance.

There is no question that hormone suppression in early prostate cancer is controversial and seldom used, but there is a major need to investigate the effects of this treatment in improving survival. It seems that neoadjuvant therapy applied to radiotherapy increases the time to recurrence. This translates to improved survival29. Studies at different institutions have produced similar results. More comprehensive studies are needed, but in the case of hormone suppression before, during and after radiation treatment of the prostate there has been a synergistic survival benefit demonstrated by the combination treatment which cannot be obtained by either treatment applied separately.12, 13, 14 Some have questioned whether radiation therapy contributed significantly to these outcomes and whether it is clinically necessary. There is nevertheless a study done at MD Anderson that seems to answer this question. Sagars GK et al14, showed that monotherapy with androgen deprivation treated patients had 58% failure rate at 5 years while those on combined therapy (RT + HT) had a 10% failure rate.

Results of neoadjuvant hormone suppression treatment prior to surgery have not demonstrated any survival improvement results in spite of a 20% to 30% reduction of positive margins15 and capsule penetration.16   Typically, surgical patients were treated for only three months prior to surgery.15, 16 The suppression period seems to be critical. More studies, utilizing more prolonged suppression periods, are necessary to compare results with radiation treatment preceded by hormone suppression, where survival was impacted. Gleave and co-workers17 in Canada have tried longer periods of hormone suppression prior to surgery with improved results after 5 years of follow-up. A randomized study is underway to verify the efficacy of longer suppression periods prior to surgery.

Early versus delayed hormonal suppression ... the evidence for early treatment.
Hormonal suppression has been the mainstay of treatment for advanced forms of prostate cancer. Although early clinical studies suggested that major improvements and even sporadic cure could occur, later randomized prospective investigations showed that hormonal treatments were palliative rather than curative. The real question then became one of comparing quality of life issues with survival potential in utilizing hormonal suppression as early or delayed treatment.As a result of the data generated by Veterans Administration Cooperative Urologic Research Group showing high toxicity in patients treated with estrogen therapy, delayed hormonal suppression has been accepted as standard practice. Reanalysis of those data using cancer-specific deaths showed improved cancer-specific survival with early hormonal therapy in selected patients diagnosed with early stages of advanced disease. A large and growing body of clinical data now suggests a superior benefit to early hormonal therapy.18,19 Aside from the survival benefit, it is now well established that early hormonal treatment significantly delays the onset of disease progression, which may correlate with an improved quality of life.20, 21

In a recent randomized study by the U.K. Medical Research Council Prostate Cancer Working Party Investigators Group, results demonstrated a 32% survival benefit with early hormonal suppression over delayed suppression, and at the same time pathological fracture, spinal cord compression, ureteric obstruction and development of extra-skeletal metastases were twice as common in deferred patients.22    Improving quality of life is thus an important issue in applying hormonal suppression at an early stage of advanced disease.

In another randomized clinical trial, Messing EM and co-workers,23 compared immediate and delayed treatment in patients who had minimal residual disease after radical prostatectomy. RESULTS: After a median of 7.1 years of follow-up, 7 of 47 men who received immediate antiandrogen treatment had died, as compared with 18 of 51 men in the observation group (P=0.02). The cause of death was prostate cancer in 3 men in the immediate-treatment group and in 16 men in the observation group (P<0.01) and the researchers concluded: Immediate antiandrogen therapy after radical prostatectomy and pelvic lymphadenectomy improves survival and reduces the risk of recurrence in patients with node-positive prostate cancer.

Granfors et al28reported the results of 91 patients with clinically localized prostate cancer who were treated for pelvic-confined prostate cancer. Patients had surgical lymph node staging and were then randomized to receive definitive external-beam radiotherapy or combined orchiectomy and radiotherapy. Patients who received radiation alone without hormonal treatment were treated with androgen ablation at clinical evidence of disease progression. Results were reported at a median follow-up of 9.3 years. Clinical progression was observed in 61% of patients treated with radiotherapy alone and in 31% of patients who received combined treatment (P=.005). Mortality was 61% and 38%, respectively, and cause-specific mortality was 44% and 27%, respectively (P=.06), in groups 1 and 2. Differences in favor of combined treatment were mainly seen in lymph node positive tumors. Node-negative tumors showed no significant difference in survival rates. The authors concluded the progression-free, disease-specific, and overall survival rates for patients with prostate cancer and pelvic lymph node involvement are significantly better after combined androgen ablation and radiotherapy than after radiotherapy alone. These results strongly suggest that early androgen deprivation is better than deferred endocrine treatment for these patients28

Bolla et al29 reported results of 415 patients with locally advanced prostate cancer. Patients were randomized to receive radiation therapy alone or radiotherapy plus immediate treatment with goserelin for 3 years. The median follow-up was 45 months. Kaplan-Meier estimates of overall survival at 5 years were 79% in the combined-treatment group and 62% in the radiotherapy group (P=.001). The proportion of surviving patients who were free of disease at 5 years was 85% in the combined-treatment group and 48% in the radiotherapy-alone group (P<.001). The authors concluded adjuvant treatment with goserelin when started simultaneously with external-beam radiation improved local control and survival in patients who had locally advanced prostate cancer.

For many years, there has been published evidence that demonstrates that the lower the tumor burden the better the response to hormone suppression. This was clearly demonstrated by Crawford ED et al24 in 1989. In this study, men were stratified by the degree of their cancer progression at diagnosis. The response to combined suppression was as follows:

1. Advanced disease with major symptoms such as bone pain, weight loss etc. responded
for only 8.5 months.
2. Advanced disease with minor symptoms, responded for 15.4 months.
3. Advanced disease limited to lymph nodes, responded for 4 years.

In this study done more than a dozen years ago, 10% of the patients in the No. 1 category were still responding after 4 years while 35% of the patients with disease limited to lymph nodes were still responding after 10 years. This is a clear indication that hormonal response is directly proportional to the degree of disease progression at the time of diagnosis and that each patient’s disease can elicit a different response to treatment.

Why would any one advise men with advanced disease to postpone hormone suppression until they become less responsive is beyond understanding, but this is what happens in many instances. The take home message here for patients presented with the option to save hormone suppression for a rainy day is that they should stop and think before they blindly accept that this treatment invariably fails in one to two years. No one should be deprived of hope in the treatment of advanced prostate cancer. Don't let anyone, physician or layman confuse you on this issue. Don't allow an old myth to detract from your quality and extension of life if you decide to be treated as early as possible.

Intermittent hormonal suppression... A valiant try to postpone androgen-independence
To understand intermittent androgen suppression (IAS) it is necessary to understand the morphological changes induced in a normal prostate by androgen suppression. Within days, at the very onset of hormone ablation either by chemical or medical castration, there are significant changes in the prostate including cell death and reduced cell's proliferation rates as mentioned previously.The theory behind intermittent hormone suppression is based on the fact that progression to androgen-independence is an adaptive process secondary to androgen withdrawal. This phenomenon appears to be related to an alteration of the ratio of stem cells in the population of tumor cells.6 When intermittent therapy is applied, progression after cessation would be caused by hormone-sensitive cells and resumption of hormonal suppression might then lead to a prolonged progression-free survival time.The molecular mechanisms and genetic changes that lead to the progression of prostate cancer during hormone suppression are not very well defined and need more direct research for proper characterization. It is known that an increased copy number of chromosomes 7, 8 and X may be associated with recurrent prostate cancer. There is also a high level amplification of the androgen receptor (AR) that contributes to proliferation. In IAS, the AR might be turned on and off during the on and off cycles, with the net result of postponement of androgen-independence.

Dr. Liao's group in Chicago25 discovered that some of these androgen-independent cells are, in fact, very sensitive to testosterone and can be killed by exposure to small amounts of the androgen. Liao explained how this could happen. For testosterone to act on a cell, the cell must have receptors that allow the hormone to bind to it. They found that during androgen ablation, the number of receptors on the cancer cells increased greatly (this is the amplification mentioned above). Once that had happened, the effect of testosterone on the cancer cells, for reasons not yet understood, resulted in the production of proteins that dictate cell death instead of growth. These supersensitive cancer cells could be killed in the laboratory studies by small amounts of testosterone, suppressing the growth of the prostate tumors. At this point in the cancer's growth, anti-testosterone therapy becomes counterproductive, allowing the tumors to grow instead of suppressing them. Dr. Liao's group also discovered that in addition to killing advanced prostate cancer cells, testosterone made the cells that had become androgen-independent once again dependent on the hormone for their growth. These androgen-dependent tumors could then be treated once again by androgen ablation therapy, just as Dr.Huggins had demonstrated half a century ago.

Therefore, as Dr. Liao suggested, a more effective treatment for advanced prostate cancer may be a repeated cycling of therapies. That is, first blocking testosterone, then when the cells become hormone independent but sensitive to its killing effects, administering it in small amounts, then blocking it once more when the cancer cells again become dependent on testosterone for their growth..

This is basically what the original IAS protocol of the Vancouver group attempted to do back in 1993. The protocol followed by Goldenberg, Bruchovsky, Akakura et al26 concluded:
1. Whether intermittent androgen suppression (IAS) will enhance progression free survival or overall survival will have to be determined in future randomized clinical trials.
2. IAS does provide improved quality of life characterized by a possible recovery of sexual function and a general sense of well being during off-treatment periods.
3. Affords the possibilities of the prolongation of androgen-dependent state of the tumor, reduced treatment cost, less cumulative drug toxicity, and the potential for alternating with other treatment modalities, such as cytotoxins, antiangiogenic agents, or gene therapy.

More trials are needed to elucidate the efficacy of IAS, but at least we know that even though this trial could not demonstrate an overall improvement in survival, at least it demonstrated an improvement in the quality of life during the off-treatment periods. The potential to postpone refraction as experienced by Bruchovski et al. in animal studies27 is there. Dr. Liao's study25 seems to be a confirmation and complement of that possibility.

SUMMARY
As a newly diagnosed patient with prostate cancer, it is important to understand all treatment options. Basic prostate cancer-specific research is urgently needed to answer the dilemma presented by prostate cancer at this point in time. Namely, the lack of more precise diagnostic tools or more widespread application of those presently available, could distinguish aggressive disease which needs to be treated from disease that could be left untreated or treated with less invasive treatments. DNA microarrays that detect genes that distinguish aggressive variances of prostate cancer from more indolent forms are being developed. Molecular rather than histological identification of tumors would be a great advancement in separating the “tigers” from the “pussycats.”

Understanding the basics about hormonal suppression and learning the things that it can do and those that it cannot do based on the true stage of disease progression, can go a long way in helping those diagnosed with localized disease, and others diagnosed with more advanced stages in arriving at a treatment/no treatment decision. Hopefully, disease awareness will prevail and such informed and knowledgeable patients will create back pressure in the system that will generate a more widespread understanding of prostate cancer in the general population and in both the general practitioners and specialists that deal with prostate cancer diagnosis and treatments.

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