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An Historical Appreciation of Treatment
for Advanced Prostate Cancer

Last Revised November 25, 1995

Introduction | The discovery of hormonal therapy | The VACURG studies | The development of LHRH agonists | The work of Ferdinand Labrie | Did combined hormonal therapy really work? |


Many people find it useful to understand the way in which treatments for advanced prostate cancer have evolved over recent decades. So this is a brief introduction to that evolution.

The discovery of hormonal therapy

In the late 1930s and early 1940s there were no effective treatments for advanced prostate cancer other than pain management. We understood little about the evolution of this disease and little about the endocrine mechanisms which caused the spread of the disease initially within the prostate and later throughout the body. Our appreciation of the nature of prostate cancer was limited.

Then, in the early 1940s Dr Charles Huggins and his colleagues at the University of Chicago started to investigate the biochemical mechanisms which led to the spread of prostate cancer. They quickly recognized the critical role of the male sex hormone, testosterone, in stimulating the growth of prostate and prostate cancer cells. As a consequence, they became the first group of physicians to treat a patient with advanced prostate cancer with so-called "hormonal" therapy: they gave patients an orchiectomy.

An orchiectomy or surgical castration removes the primary source of testosterone in man. As a consequence, the amount of testosterone in the body is reduced to about 5-10% of its original level. Huggins and his colleagues discovered not only that they could reduce the painful symptoms of prostate cancer, they also appeared to be able to slow the progression of the disease. Several years later Huggins was awarded the Nobel Prize for medicine for these and related discoveries.

Throughout the 1940s and 1950s, the work started by the Chicago group was continued in Chicago and in various other centers across America. Among the most interesting developments were an increasing appreciation of the role of the so-called hypothalamic-pituitary-adrenal axis (made up of three of the key endocrine glands) in the growth and development of the prostate and prostate cancer. This led to the discovery that other forms of hormone therapy could be used instead of surgical castration in order to counteract the effects of testosterone. By far the most important of these was the use of female sex hormones or estrogens such as diethylstilbestrol (DES). For over 30 years the two standard forms of treatment for patients with advanced prostate cancer were castration or DES.

However, a number of other developments in the management of advanced prostate cancer can also be traced back to the early work of Huggins and his colleagues. Among the more important of these developments was the recognition that the adrenal androgens had a role in the growth of prostate cancer. Bilateral adrenalectomy or removal of the adrenal glands was a relatively rare but accepted procedure in attempts to slow the progression of prostate cancer in patients who were failing standard hormone therapy. Some would consider that this form of therapy was the earliest type of combined hormone therapy.

The Veterans Administration Cooperative Urology Research Group studies

The mid 1960s saw the first attempts to expand and formalize the treatment of advanced prostate cancer through the use of randomized clinical trials. The largest such trials comprised two studies planned and carried out by the Veterans Administration Cooperative Urological Research Group (VACURG), a relatively informal group of physicians working in VA hospitals. The studies carried out by this group were, for their time, highly significant, despite later suggestions of major flaws in their design.

The VACURG group was interested in two primary questions. (1) Was orchiectomy + 5 mg of DES as good or better for the treatment of advanced prostate cancer than orchiectomy alone or 5 mg of DES alone? (2) What was the best dose of DES for treatment of advanced prostate cancer. However, it is important to realize that an additional result of the VACURG studies was the careful review and classification of tissue from over 2000 prostates which led to the Gleason grading system.

It is unnecessary for us to go in detail into the complexities of the VACURG studies. Suffice it to say that they definitively documented that DES treatment at high doses (5 mg/d) is associated with severe cardiovascular side effects which could lead to death in a relatively large number of men at risk for cardiovascular disease. In addition, they argued that their studies showed that there was no benefit to early hormonal therapy for prostate cancer. The latter claim has now been partially discredited, leading to newer trials designed to reassess the putative value of early hormonal therapy. The first trial which may be large enough and well enough designed to answer this question will report its results in 1996.

The development of LHRH agonists

The association of DES with important cardiovascular side effects was a stimulus to research on new agents which could replace DES for the hormonal treatment of prostate cancer. These agents needed to have different effects on the endocrine cascade. However, the end result had to be the same: they had to block the effects of testosterone on the prostate which could stimulate the growth of prostate cancer cells.

The new agents which met these criteria were the luteinizing hormone releasing hormone (LHRH) agonists. These synthetic biochemicals mimic the effects of a hormone called luteinizing hormone releasing hormone. This natural hormone is made by the pituitary and acts on the hypothalamus to stimulate the release of a second hormone called luteinizing hormone (LH). Luteinizing hormone then stimulates the production of testosterone. By flooding the body with synthetic LHRH agonist molecules, one stops the body from producing the natural LHRH molecule. As a result, there is no stimulation of LH release and so no stimulation of testosterone production. The clinical use of LHRH agonists is a classic example of using a biochemical "feedback" system to block the production of the normal end product of a specific biochemical pathway.

In a major clinical trial conducted in the early 1980s, it was shown that a daily injection of one of these LHRH agonists (leuprolide acetate) could produce the same effects on patients with advanced prostate cancer as 3 mg/d of DES -- but without the risk of cardiovascular side effects. Several other LHRH agonists have now been developed by different pharmaceutical companies. Two of them are in relatively common use for the treatment of prostate cancer in the US. Others are available in other parts if the world.

The work of Ferdinand Labrie

With the availability of the LHRH agonists, researchers and clinicians turned their attention to ways in which they could offer improved methods for the treatment of advanced prostate cancer. One of these researchers was a Canadian physician named Ferdinand Labrie.

Dr Labrie returned to some of the earlier work of Huggins and his colleagues and came to the conclusion that, once one had successfully blocked the effects of testosterone on prostate cancer, there were still the adrenal androgens available which could be converted into testosterone with the same impact. Although the adrenal androgens comprise only 5-10% of the normal complement of male hormones, there was sufficient experimental data to support Dr Labrie's beliefs. Luckily for Dr Labrie, there was also another new pharmaceutical available which appeared to have the effect that he sought, at least in animal models. That pharmaceutical was flutamide -- the first nonsteroidal antiandrogen.

Flutamide and the other nonsteroidal antiandrogens work by blocking the effects of DHT directly on the synthesis of new protein in the prostate cell. As explained above, DHT is formed from testosterone and the adrenal androgens. Labrie therefore argued that by giving an LHRH to block testosterone production and a nonsteroidal antiandrogen to block the effect of any DHT on the synthesis of prostatic proteins, he had developed a potentially superior form of treatment for advanced prostate cancer. He carried out clinical trials of this new combination therapy and published results which have been debated to this day. According to Labrie, in those first clinical trials, he was able to show a significant survival benefit in some 80% of his patients. Although these trials were not randomized nor were they blinded, the result was a small flood of patients across the border from America to Montreal to be treated by Dr Labrie's new method. American prostate cancer specialists were not happy about this turn of events.

Did combined hormone therapy really work?

As told by at least one leading urologist involved in the clinical studies, the American prostate cancer establishment set out to prove Labrie wrong. In 1984 they initiated what came to be known as National Cancer Institute Intergroup trial 0036, and this trial demonstrated exactly the opposite of their expectation. This trial is discussed in more detail in a section on combined hormonal therapy. However, the trial clearly showed that patients who received an LHRH agonist and flutamide had a median survival advantage over those who received only the LHRH agonist.

Several other studies have since been carried out on the use of so-called combined hormonal therapy (CHT) or maximal androgen deprivation (MAD) in the treatment of patients with advanced prostate cancer. We still do not have final and conclusive evidence of its clinical value, although the amount of data supporting this form of therapy continues to accumulate.

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The content in this section of the Phoenix 5 site was originally developed by CoMed Communications (a Vox Medica company) as part of The Prostate Cancer InfoLink. It is reproduced here with the permission of Vox Medica.

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