Current status and prospects of androgen depletion therapy for
Hideyuki Akaza, Department of Urology,
University of Tsukuba, Tsukuba, Ibaraki, Japan
It is said that the prostate was histologically acknowledged as an independent organ for
the first time in the mid-nineteenth century. No organ termed the prostate is indicated
even in the world-renowned drawing of anatomy by Leonard da Vinci (1452 – 1519). It
was in 1941 that androgen depletion therapy (ADT) was reported as effective against
prostate cancer. For this achievement, Dr. Huggins received a Nobel Prize 25 years later
in 1966. At that time, most patients with prostate cancer who received ADT were in
progressive stage. As such, Dr. Huggins himself observed that recurrence was noted in
many cases after several years of remission. ADT was therefore classified as a palliative
treatment. Since PSA was discovered in 1979, the rate of detection of early-stage
prostate cancer has rapidly improved. Subsequently, in 1983, the method of anatomical
prostatectomy was reported by Walsh, and established the concept of radical treatment of
prostate cancer. To be more precise, it became accepted that localized prostate cancer
(LPC) and locally advanced prostate cancer (LAPC), the rate of detection of which
sharply increased thanks to PSA screening, should be aggressively treated by radical
methods including prostatectomy and radiotherapy. However, the conclusion that ADT is
a palliative method of treatment reached half a century ago is still accepted at present.
As a result, this concept has been applied even to LPC and LAPC, and few careful clinical
studies have been performed 1). Despite the progress in ADT, including the
establishment of theoretical grounds for maximal androgen blockade (or combined
androgen blockade; MAB or CAB) and the development of a new nonsteroidal
antiandrogen preparation, there has been little change in the concept of ADT as a palliative
method of treatment of progressive prostate cancer, either.
(II) Current status of ADT
The Prostate Cancer Treatment Guideline was published by the Japanese Urological
Association in 2006 2). As a member in charge of the drug therapy section of this edition,
the author would like to report the current status of ADT by citing the abstract of the
overview of this section.
“At present, there is no chemotherapy superior to endocrine therapy for the treatment of
prostate cancer. Though the proximal effects of various endocrine therapies are
remarkable, there is a limit to their indication since the effects of treatment persist for only
for 2 to 3 years in progressive cases and because of the onset of sex-related adverse
reactions including erectile dysfunction (ED) and decreased libido.
The most generally applicable endocrine therapy is monotherapy with luteinizing
hormone-releasing hormone (LH-RH) agonist or antiandrogen preparation, or concomitant
treatment with these 2 drugs. In treatment with LH-RH agonist, concomitant
administration of an antiandrogen preparation should be considered if urinary tract
obstruction caused by flare-up phenomenon associated with a transient increase in
testosterone in the initial stage of administration, ostealgia due to a metastatic lesion,
spinal compression, etc. are anticipated. The efficacy of LH-RH agonist is considered
equivalent to that of castration. However, the efficacy of monotherapy with antiandrogen
preparation is reported to be less than that of LH-RH, though no significant difference was
observed. On the other hand, antiandrogen preparations induce fewer sex-related adverse
reactions. Monotherapy with nonsteroidal antiandrogen preparations has therefore been
reported to be useful, depending on patient status. When the usefulness of bicalutamide
as auxiliary therapy was investigated in LPC or LAPC in patients undergoing radical
surgery, radiotherapy, and cautious observation of clinical course, prolongation of PSA
doubling time and decrease in objective risk of progression were observed. At present, a
large-scale investigation of prolongation of survival period is proceeding. In another
investigation, whether chemo-endocrine therapy is more effective in treating Stage IV
prostate cancer than endocrine monotherapy alone is being examined.
The down-staging effect of neo-adjuvant hormonal therapy (NHT) is manifested as a
decrease in frequency of cases with a positive resected stump or lymph node metastasis.
Many randomized controlled studies (RCT) have confirmed the efficacy of NHT.
However, since no clear evidence that NHT can improve survival rate has been obtained,
(VI) Future of ADT
A considerable number of malignant tumors are not localized to the organs of primary
onset, and have already metastasized (clinically or microscopically) at the time of
diagnosis. Furthermore, surgery sometimes fails to completely extirpate LPC and LAPC,
resulting in subsequent local recurrence and remote metastasis. Systemic therapy is thus
important in the treatment of cancer. In the case of prostate cancer, ADT is a powerful
means of systemic treatment. Thanks to the success of a large-scale prostate cancer
prevention trial (PCPT) 8) using the 5α reductase inhibitor finasteride, safe endocrine
therapy that can maintain QOL has become possible. The establishment of more
powerful methods of ADT without impairment of QOL is expected not only for patients
with progressive prostate cancer but also for LPC and LAPC, through the development of
new antiandrogen preparations and molecular target drugs.
It is important to promote basic and clinical research based on the understanding that cure
of prostate cancer is almost always possible with current ADT if progression to the
hormone independent prostate cancer can be avoided.
1) Akaza H. Trends in primary androgen depletion therapy for patients with localized and
locally advanced prostate cancer: Japanese perspective. Cancer Sci. 2006;97:243-7.
2) The Prostate Cancer Treatment Guideline 2006 edited by Japanese Urological
Association. KANEHARA & CO., LTD. 2006.
3) Mulrow C, Langhome P, Grimshaw J. Integrating heterogeneous pieces of evidence in
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4) Fleming C, Wasson JH, Albertsen PC, et al. A decision analysis of alternative
treatment strategies for clinically localized prostate cancer. Prostate Patient Outcomes
Research Team. JAMA. 1993;269:2650-8.
5) Miller DC, Gruber SB, Hollenbeck BK, et al. Incidence of initial local therapy among
men with lower-risk prostate cancer in the United States. J Natl Cancer Inst.
6) Loblaw DA, Virgo KS, Nam R, et al. Initial hormonal management of
androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2006 update
of an american society of clinical oncology practice guideline.
J Clin Oncol. 2007;25:1596-605. Epub 2007 Apr 2.
7) Albertsen PC, Hanley JA, Fine J. 20-year outcomes following conservative
management of clinically localized prostate cancer. JAMA. 2005;293:2095-101.
8) Ankerst DP, Thonpson IM. New answers from the Prostate Cancer Prevention Trial on
the chemoprevention of prostate cancer. Arch Ital Urol Androl. 2006;78:154-6.