Review
Major impact of hormonal therapy in localized prostate cancer—death can already be an exception

https://doi.org/10.1016/j.jsbmb.2004.10.011Get rights and content

Abstract

For about 50 years, androgen blockade in prostate cancer has been limited to monotherapy (surgical castration) or high doses of estrogens in patients with advanced disease and bone metastases. The discovery of medical castration with LHRH agonists has led to fundamental changes in the endocrine therapy of prostate cancer. In 1979, the first prostate cancer patient treated with an LHRH agonist received such treatment at the Laval University Medical Center. A long series of studies have clearly demonstrated that medical castration with an LHRH agonist has inhibitory effects on prostate cancer equivalent to those of surgical castration. The much higher acceptability of LHRH agonists has been essential to permit a series of studies in localized disease. Based upon the finding that the testicles and adrenals contribute approximately equal amounts of androgens in the human prostate, the combination of medical (LHRH agonist) or surgical castration associated with a pure antiandrogen (flutamide, nilutamide or bicalutamide) has led to the first demonstration of a prolongation of life in prostate cancer, namely a 10–20% decreased risk of death according to the various metaanalyses of all the studies performed in advanced disease. In analogy with the other types of advanced cancers, the success of combined androgen blockade in metastatic disease is limited by the development of resistance to treatment. To avoid the problem of resistance to treatment while taking advantage of the relative ease of diagnosis of prostate cancer at an “early” stage, the much higher acceptability of LHRH agonists has permitted a series of studies which have demonstrated a major reduction in deaths from prostate cancer ranging from 31% to 87% at 5 years of follow-up in patients with localized or locally advanced prostate cancer. Most importantly, recent data show that the addition of a pure antiandrogen to an LHRH agonist in order to block the androgens made locally in the prostate leads to a 90% long-term control or probable cure of prostate cancer.

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

References (107)

  • X.-F. Huang et al.

    Molecular characterization of a first human 3 (alpha-beta)-hydroxysteroid epimerase

    J. Biol. Chem.

    (2000)
  • B. Bélanger et al.

    Comparison of residual C-19 steroids in plasma and prostatic tissue of human, rat and guinea pig after castration: unique importance of extratesticular androgens in men

    J. Steroid. Biochem.

    (1989)
  • B. Schmitt et al.

    Combined androgen blockade with nonsteroidal antiandrogens for advanced prostate cancer: a systematic review

    Urology

    (2001)
  • J.F. Caubet et al.

    Maximum androgen blockade in advanced prostate cancer: a meta-analysis of published randomized controlled trials using nonsteroidal antiandrogens

    Urology

    (1997)
  • G.A. Dijkman et al.

    Long-term efficacy and safety of nilutamide plus castration in advanced prostate-cancer, and the significance of early prostate specific antigen normalization

    J. Urol.

    (1997)
  • M. Plante et al.

    Stimulatory effect of synthetic progestins currently used for the treatment of prostate cancer on growth of the androgen-sensitive Shionogi tumor in mice

    J. Steroid. Biochem.

    (1988)
  • M. Laufer et al.

    Complete androgen blockade for prostate cancer: what went wrong?

    J. Urol.

    (2000)
  • F. Labrie et al.

    Diagnosis of advanced or noncurable prostate cancer can be practically eliminated by prostate-specific antigen

    Urology

    (1996)
  • F. Labrie et al.

    Downstaging of early stage prostate cancer before radical prostatectomy: the first randomized trial of neoadjuvant combination therapy with Flutamide and a luteinizing hormone-releasing hormone agonist

    Urology

    (1994)
  • J. Laverdiere et al.

    Beneficial effect of combination therapy administered prior and following external beam radiation therapy in localized prostate cancer

    Int. J. Radiat. Oncol. Biol. Phys.

    (1997)
  • F. Labrie

    Androgen blockade in prostate cancer in 2002: major benefits on survival in localized disease

    Mol. Cell. Endocrinol.

    (2002)
  • F. Labrie et al.

    Can combined androgen blockade provide long-term control or possible cure of localized prostate cancer?

    Urology

    (2002)
  • T. Makinen et al.

    Prostate cancer screening within a prostate specific antigen range of 3 to 3.9 ng/ml: a comparison of digital rectal examination and free prostate specific antigen as supplemental screening tests

    J. Urol.

    (2001)
  • C.H. Bangma et al.

    The value of screening tests in the detection of prostate cancer. Part I: Results of a retrospective evaluation of 1726 men

    Urology

    (1995)
  • P. Lodding et al.

    Characteristics of screening detected prostate cancer in men 50 to 66 years old with 3 to 4 ng/ml. Prostate specific antigen

    J. Urol.

    (1998)
  • N. Faure et al.

    Inhibition of serum androgen levels by chronic intranasal and subcutaneous administration of a potent luteinizing hormone-releasing hormone (GNRH) agonist in adult men

    Fertil. Steril.

    (1982)
  • W.B. Peeling

    Phase III studies to compare goserelin (Zoladex) with orchiectomy and with diethylstilbestrol in treatment of prostatic carcinoma

    Urology

    (1989)
  • R.G. Middleton et al.

    Prostate Cancer Clinical Guidelines Panel Summary report on the management of clinically localized prostate cancer. The American Urological Association

    J. Urol.

    (1995)
  • T. Granfors et al.

    Combined orchiectomy and external radiotherapy versus radiotherapy alone for nonmetastatic prostate cancer with or without pelvic lymph node involvement: a prospective randomized study

    J. Urol.

    (1998)
  • T.H. van der Kwast et al.

    Prolongued neoadjuvant combined androgen blockade leads to a further reduction of prostatic tumor volume: three versus six months of endocrine therapy

    Urology

    (1999)
  • A. Jemal et al.

    Cancer Statistics 2003

    CA Cancer J. Clin.

    (2003)
  • F. Labrie et al.

    Complete androgen blockade for the treatment of prostate cancer

  • C. Labrie et al.

    Androgenic activity of dehydroepiandrosterone and androstenedione in the rat ventral prostate

    Endocrinology

    (1988)
  • F. Labrie et al.

    Endocrine and intracrine sources of androgens in women: inhibition of breast cancer and other roles of androgens and their precursor dehydroepiandrosterone

    Endocr. Rev.

    (2003)
  • I. Dufort et al.

    Characteristics of a highly labile human type 5 17beta-hydroxysteroid dehydrogenase

    Endocrinology

    (1999)
  • G. Pelletier et al.

    Immunoelectron microscopic localization of 3β-hydroxysteroid dehydrogenase and type 5 17β-hydroxysteroid dehydrogenase in the human prostate and mammary gland

    J. Mol. Endocrinol.

    (2001)
  • M. El-Alfy et al.

    Localization of type 5 17β-hydroxysteroid dehydrogenase, 3β-hydroxysteroid dehydrogenase and androgen receptor in the human prostate by in situ hybridization and immunocytochemistry

    Endocrinology

    (1999)
  • W.M. Geissler et al.

    Male pseudohermaphroditism caused by mutations of testicular 17β-hydroxysteroid dehydrogenase 3

    Nat. Genet.

    (1994)
  • P. Nokelainen et al.

    Expression cloning of a novel estrogenic mouse 17 beta-hydroxysteroid dehydrogenase/17-ketosteroid reductase (m17HSD7), previously described as a prolactin receptor-associated protein (PRAP) in rat

    Mol. Endocrinol.

    (1998)
  • K.C. Cheng et al.

    Molecular cloning and expression of rat liver 3 alpha-hydroxysteroid dehydrogenase

    Mol. Endocrinol.

    (1991)
  • I. Dufort et al.

    Isolation and characterization of a stereospecific 3β-hydroxysteroid sulfotransferase (pregnenolone sulfotransferase) cDNA

    DNA Cell. Biol.

    (1996)
  • R. Horton

    Dihydrotestosterone is a peripheral paracrine hormone

    J. Androl.

    (1992)
  • I. Dufort et al.

    Human types 1 and 3 3 alpha-hydroxysteroid dehydrogenases: differential lability and tissue distribution

    J. Clin. Endocrinol. Metab.

    (2001)
  • S. Andersson

    Steroidogenic enzymes in skin

    Eur. J. Dermatol.

    (2001)
  • F. Labrie et al.

    Physiological changes in dehydroepiandrosterone are not reflected by serum levels of active androgens and estrogens but of their metabolites: intracrinology

    J. Clin. Endocrinol. Metab.

    (1997)
  • P.I. Mackenzie et al.

    The UDP glycosyltransferase gene superfamily: recommended nomenclature update based on evolutionary divergence

    Pharmacogenetics

    (1997)
  • E. Levesque et al.

    Isolation and characterization of the UGT2B28 cDNA encoding a novel human steroid conjugating UDP-glucuronosyltransferase

    Biochemistry

    (2001)
  • A. Bélanger, J. Couture, S. Caron, R. Roy, Determination of non-conjugated and conjugated steroid level in plasma and...
  • D. Turgeon et al.

    Relative enzymatic activity, protein stability, and tissue distribution of human steroid-metabolizing UGT2B subfamily members

    Endocrinology

    (2001)
  • O. Barbier et al.

    Cellular localization of uridine diphosphoglucuronosyltransferase 2B enzymes in the human prostate by in situ hybridization and immunohistochemistry

    J. Clin. Endocrinol. Metab.

    (2000)
  • Cited by (17)

    • Essential Intracrine Androgenic Action in Lung Development for Both Sexes

      2018, Journal of Steroid Biochemistry and Molecular Biology
      Citation Excerpt :

      Flutamide blocked the action of endogenous androgens, showing the important contribution of androgens for obtaining normal lung structures. The authenticity and the purity of the tested flutamide lot were confirmed after the experiment and the pure antiandrogenic characteristic of this molecule is well characterized [25]. Circulating androgen levels are too low for androgen receptor activation in postnatal females from birth onwards and postnatal males starting at PND 5 [10].

    • Development, validation and application of a stable isotope dilution liquid chromatography electrospray ionization/selected reaction monitoring/mass spectrometry (SID-LC/ESI/SRM/MS) method for quantification of keto-androgens in human serum

      2013, Journal of Steroid Biochemistry and Molecular Biology
      Citation Excerpt :

      The efficacy of abiraterone acetate in CRPC patients confirms the Geller hypothesis that these prostate tumors are still androgen dependent [26]. In CRPC, the tumor either acquires the ability to conduct de novo androgen biosynthesis from cholesterol or utilizes the circulating depot of adrenal androgens as precursors for T and DHT to drive tumor proliferation and metastasis [9,10,27–29]. The efficacy of ADT and the molecular mechanism of resistance to those therapies can be better assessed if sensitive methods such as those described here were applied to the patient.

    • Molecular mechanisms of steroid receptor-mediated actions by synthetic progestins used in HRT and contraception

      2011, Steroids
      Citation Excerpt :

      Similarly, the contraceptive use of DRSP combined with EE, has also been shown to useful in the treatment of mild acne as well as premenstrual dysphoric disorder [9]. In contrast, anti-androgenic activity can cause detrimental effects such as hot flushes, loss of libido, bone loss and osteoporosis [199]. Thus progestins with anti-androgenic activity such as DNG, DRSP and TMG may cause similar side-effects in women.

    • Synthesis and biological activity of ferrocenyl derivatives of the non-steroidal antiandrogens flutamide and bicalutamide

      2011, Journal of Organometallic Chemistry
      Citation Excerpt :

      Prostate cancer is a major societal problem which affects one man in eight and is the cause of 200,000 deaths per year worldwide [1].

    View all citing articles on Scopus
    View full text