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,
the results of analysis of long-term prognosis in each of these trials are awaited.
Endocrine therapy is opted for in treating stage III-IV prostate cancer, and life-prolonging
effects of it have been observed. Endocrine therapy is sometimes performed in
combination with surgery and radiotherapy in stage III cases. Particularly since the
report on the results of a RCT that survival period was prolonged more by concomitant
radiotherapy and endocrine therapy than by radiotherapy alone, there has been much
expectation regarding the efficacy of concomitant treatment. However, there are
problems in this regard, including the selection of appropriate patients, the appropriate
time for initiation of endocrine therapy, the duration of treatment, and others. In general,
the standard treatment for progressive prostate cancer with metastasis is ADT by surgical
or medical castration. Since 40% of the androgen present in prostate gland cells appears
to be derived from the adrenals, MAB was found to be useful due to inhibition of
androgen from the testes and adrenals via castration (orchiectomy or LH-RH agonist
administration) in combination with nonsteroidal antiandrogen preparation administration.
Though MAB has been a generally accepted method of treatment of progressive prostate
cancer, whether it can improve long-term prognosis in comparison with castration alone
has been a subject of recent discussion. According to the results of a meta-analysis
recently performed, there is little difference in 2-year survival rate between MAB and
monotherapy (castration or LH-RH agonist alone), though 5-year survival rate was
significantly higher with MAB. However, since the difference in survival rate is small, it
appears that true clinical benefit should be determined considering adverse reactions, QOL,
and cost. At present, the results of further research demonstrating the validity of MAB
are awaited. Recently, the results of a double-blind study that compared MAB
monotherapy using bicalutamide as antiandrogen preparation with LH—RH agonist
monotherapy were reported. Findings indicated a definite effect on time to progression.
Even when recurrence of cancer is observed, discontinuation of antiandrogen preparation
alone can in some cases transiently inhibit the progress of disease (antiandrogen
withdrawal syndrome). PSA decreased in 14 - 60% and a clinical effect was observed in
0 - 25% of patients with discontinuation of antiandrogen preparation, or combination
with hydrocortisone. However, PSA reduction is reported to persist for only for 2 to 4
months, in general.
The above findings do not differ notably from those noted in the guidelines of the EAU or
NCI-PDQ. However, the EAU and NCI-PDQ guidelines take a somewhat negative
stance regarding use of ADT in the treatment of LPC and LAPC.
The current issues in use of ADT concern the following 3 points: 1) Though their
number is still small, clinical studies based on new concepts (effects of MAB and
intermittent androgen blockade therapy, etc.) are being performed. Depending on the
results of these studies, new conclusions regarding the role of ADT may be reached. 2)
ADT is generally employed in Japan to treat LPC and LAPC (Fig. 1), and MAB is used in
many cases (Fig. 2). This tendency is definitely on the increase in the United States, as
well (Fig. 3). 3) This choice of treatment is inconceivable if treatment method is selected
according to the guidelines. Why, then, does it exist?
JUA 2007 Debate Prostate Cancer University of Tsukuba
(Int JU, 2005)
T1~T4T1~T3 w/o meta
JUA PC Registration 2005
JUA PC Registration 2005
Prostate cancer registration data provided by the Japanese Urological Association are
shown in this graph.
Types of initial treatment as of 2000 for newly diagnosed patients are summarized.
PADT was selected for 56.94% of cases of T1 through T4 disease. For T1 through T3,
PADT was still selected for 45.90% of cases.
Cancer Registration Committee of the Japanese Urological Association.
Clinicopathological statistics on registered prostate cancer patients in Japan: 2000 Report
from the Japanese Urological Association.
Int J Urol. 2005;12:46-61.