The Journal of Steroid Biochemistry and Molecular Biology
ReviewMajor impact of hormonal therapy in localized prostate cancer—death can already be an exception
Introduction
Prostate cancer is the most frequently diagnosed cancer and the second cause of cancer death in men in North America [1]. In fact, one out of eight men will be diagnosed with prostate cancer during his lifetime. At such a rate, prostate cancer will kill more than 3,000,000 men among the male population presently living in the United States, while more than 200,000 men die annually worldwide from prostate cancer. The medical and social consequences of this disease are comparable to those of breast cancer in women. Prostate cancer is thus a major challenge in urgent need of significant improvement in diagnosis and treatment.
Section snippets
Prostate cancer deaths are decreasing
Death rates from prostate cancer have dropped by 17% in the United States between 1994 and 2003 (Fig. 1). This decrease in prostate cancer death coincides with the routine use of the prostate specific antigen (PSA) test. These numbers are those estimated or predicted by the American Cancer Society. This decrease in prostate cancer death is a major improvement since it corresponds to a decrease of 6002 deaths from prostate cancer in 2003 compared to 1994. This decrease in cancer deaths can only
Two equally important sources of androgens in men
An important advance in our understanding of the biology and endocrinology of prostate cancer and its impact on cancer treatment is the observation that humans and some other primates are unique among animal species in having adrenals that secrete large amounts of the inactive precursor steroids dehydroepiandrosterone (DHEA), its sulfate DHEA-S, and some androstenedione (4-dione), which are converted into potent androgens in a large series of peripheral tissues, including the prostate (Fig. 2).
Medical castration with LHRH agonists
While the experiments performed in the rat were simply suggestive of an inhibitory effect of LHRH agonists on testicular functions, we discovered in 1979 that men are exquisitely sensitive to the inhibitory action of an LHRH agonist. We then studied the effect of administering the LHRH agonist buserelin to a patient suffering from stage B prostate cancer. Thus, in the first prostate cancer patient treated with an LHRH agonist, the 500-μg dose of the LHRH agonist administered intranasally twice
Combined androgen blockade in advanced disease
The first treatment shown to prolong life in prostate cancer is the combination of an LHRH agonist (blocker of androgen secretion by the testes) with a pure antiandrogen such as flutamide, nilutamide or bicalutamide (at the proper dose, namely at least 150 mg daily). When associated with castration which eliminates the androgens of testicular origin, these compounds sometimes called nonsteroidal antiandrogens block the action of the androgens produced locally in the prostate [2], [36], [37], [38]
Today, prostate cancer can be diagnosed at the clinically localized stage in more than 95% of cases
Despite the progress achieved in the treatment of advanced or metastatic prostate cancer using LHRH agonists [35], [56] and especially with combined androgen blockade [36], [37], [39], [40], [45], [46], [47], [48], it is well recognized that the only possibility of a significant reduction in prostate cancer mortality is the treatment of localized disease [57]. It is reasonable to suggest that the observed decrease in deaths from prostate cancer is due to earlier diagnosis with serum PSA [58],
Death from prostate cancer is reduced by two-thirds by screening and early treatment
In analogy with other cancer types, it is believed that our efforts should be concentrated on the diagnosis of prostate cancer at an early stage in order to be able to use curative therapies. Definitive proof of the benefits of screening for prostate cancer can only be obtained from prospective and randomized studies comparing the incidence of death from prostate cancer in a group of men screened and treated early versus a group of men receiving standard medical care. Accordingly, the Laval
Monotherapy with an LHRH agonist decreases cancer deaths by at least one third in localized or locally advanced disease
Despite the recent advance in the treatment of metastatic prostate cancer using LHRH agonists [35], [56] or surgical castration in association with a pure antiandrogen [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], it is well recognized that the only means of achieving an important reduction in prostate cancer mortality is treatment of localized disease [57]. In fact, it is reasonable to suggest that the recently observed decline in prostate cancer mortality
The high probability of a cure of localized prostate cancer by combined androgen blockade
Despite the important advance observed with monotherapy (LHRH agonists) in localized prostate cancer, namely a one third to two-thirds reduction in deaths from prostate cancer, can we achieve better results? Based upon the observation that 50% of androgens are left in the prostate after castration alone, it is reasonable to suggest that better results can be achieved with the combination of an LHRH agonist and a pure antiandrogen.
With long-term treatment of localized prostate cancer with
Conclusion: death from prostate cancer can already be an exception
While showing the particularly high efficacy of hormonal therapy in localized prostate cancer, the present data clearly indicate that long-term treatment somewhat similar to the 5 years of Tamoxifen in breast cancer, is required for optimal control of prostate cancer. Great caution should be taken, however, about the interpretation of serum PSA that must be used as surrogate marker. In fact, serum PSA rapidly and easily decreases to undetectable levels under androgen blockade although the
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