Contemporary Hormonal Management of Advanced Prostate Cancer

Contemporary Hormonal Management of Advanced Prostate Cancer

ABSTRACT: The traditional definition of “advanced” prostate cancer includes only patients with widespread osteoblastic or soft-tissue metastases (clinical or pathologic stage T any N any M1; or stage D2). Current evidence indicates that this definition should be broadened. Because many patients with T3 disease or local lymph node metastases progress to distant metastases, the concept of advanced prostate cancer should also include stages C and D1 (T3, T4, and any T N1). Furthermore, based on pretreatment prostate-specific antigen (PSA) levels, many men treated for clinically localized disease will progress rapidly and, depending on their age and general health, should be included in the advanced-disease category. Also, using prognostic marker modeling with PSA, tumor grade, and other factors, recurrences can be predicted even earlier in many cases. This may be particularly significant in light of recent clinical data indicating that early androgen ablation therapy delays disease progression and improves survival in patients with advanced (M0 or M1) disease. The luteinizing hormone-releasing hormone (LHRH) agonists have become the preferred method of androgen ablation in patients with advanced prostate cancer. Use of an LHRH agonist, alone or combined with an antiandrogen, is more acceptable to many patients than orchiectomy and lacks the potential cardiotoxicity associated with estrogens. Combined hormonal therapy remains controversial but may provide a modest survival benefit, especially in men with minimal metastatic disease. Intermittent hormonal therapy has great appeal, particularly because of the potentially deleterious effects of long-term hormonal therapy; however, its efficacy has yet to be proven.[ONCOLOGY 12(4):499-508,1998]

Early in 1997, the American Cancer Society estimated that over
334,500 new cases of prostate cancer would be diagnosed in 1997 in
the United States.[1] This incidence figure was later adjusted
downward to approximately 210,000 cases as a result of the culling
effect of the PSA screening era. If one accepts the assumption that
most men with non-organ-confined prostate cancer have advanced
disease, then perhaps 60%, or over 100,000 men, will require care for
advanced prostate cancer in this year alone.

Since its introduction in 1941,[2] endocrine manipulation by means of
orchiectomy or medical hormonal therapy has remained the mainstay of
treatment for metastatic adenocarcinoma of the prostate. The
availability of new options for hormonal therapy has engendered
controversies regarding not only the preferable forms and timing of
treatment but also the very definition of “advanced”
prostate cancer. These controversies have led some to propose a
revised definition of advanced disease. This new definition
incorporates recently acquired knowledge about prostate cancer and
may influence the treatment and monitoring of various manifestations
of advanced disease.

Contemporary Definition of Advanced Prostate Cancer

The term “advanced prostate cancer” is synonymous with
“incurable” to most patients and clinicians.[3]
Traditionally, the definition of advanced prostate cancer has
referred only to disease stage and has included only symptomatic
stage D2 disease with bony or soft-tissue metastases. However,
patients with extracapsular disease are at increased risk of dying
from prostate cancer compared with patients with localized
disease.[4] Because a majority of patients with extracapsular disease
are otherwise healthy and have no competing morbidity, stages D1
(regional lymph node involvement), T4 (tumor is fixed or invades
adjacent structures other than the seminal vesicles),[5] and T3
(tumor has extended through the prostatic capsule)[5] should be
included in the revised definition of advanced prostate cancer for
most men.

When both clinical and pathologic staging are assessed, T3 disease,
in particular, represents a large percentage of the prostate cancers
being treated. Approximately one-half of patients with clinically
confined T2 cancers are found on pathologic assessment to have T3
cancers.[3,6] Moreover, a 34% incidence of extracapsular extension is
noted, even in tumors identified because of elevated
prostate-specific antigen (PSA) levels (so-called stage T1c disease).[7]

Patients with a persistent elevation of PSA after prostatectomy or
radiation therapy, as well as those with high PSA levels without
evidence of metastases, should also be included in the definition of
advanced disease in most cases. Prostate-specific antigen is a
sensitive marker for monitoring response to therapy.[8-10] After
radical prostatectomy, PSA should fall to undetectable levels; a
postoperative rise in PSA indicates the presence of residual tumor.
Prostate-specific antigen testing also is the best method available
for monitoring patients after radiation or androgen deprivation
therapy; a post-radio-therapy nadir value < 1.0 ng/mL or < 0.5
ng/mL indicates a good prognosis.[11]

Recent work with prognostic markers has enabled the selection of men
at high risk for disease recurrence after treatment of clinically
localized prostate cancer. Partin et al studied clinical stage B2
patients undergoing radical prostatectomy and was able to select a
subgroup of men at very high risk of recurrence using an equation
based on pretreatment PSA, surgical Gleason sum, and organ-confinement

Our Department of Defense Center for Prostate Disease Research (CPDR)
group has also created and validated a radical prostatectomy
recurrence model that appears to be useful for all patients.[13] The
equation, given in Table 1, uses
four prognostic factors—PSA, Gleason sum, pathologic stage, and
race—to derive a risk of recurrence. In the CPDR study, the
high-risk group had a 55.5% chance of recurrence at 3 years and an
84.8% chance at 5 years. In our opinion, at least this group may be
considered to have advanced prostate cancer, and this can be
determined in the immediate postoperative period.

Aside from these equations using traditional prognostic markers, our
group and others are using newer markers, such as molecular
biomarkers, to establish risk of recurrence and progression to
advanced disease. For example, we found that all patients whose
radical prostatectomy specimen overexpressed the p53 tumor-suppresser
gene protein and the bcl-2 oncogene developed disease
recurrence within 5 years of surgery.[14] Similar prognostic models
are being developed for irradiated patients.

To summarize, the current definition for advanced prostate cancer
should include not only men with widespread osteoblastic metastases,
weight loss, and urinary obstruction but also patients with a
substantial risk of disease progression and death from prostate
cancer, even those who have no symptoms (Table

Treatment Options for Advanced Prostate Cancer

Androgen ablation therapy has been the mainstay of treatment for
stage D2 metastatic prostate cancer for over 50 years.[2] Treatment
options include orchiectomy, luteinizing hormone-releasing hormone
(LHRH) agents, and combination hormonal therapy, which adds an oral
nonsteroidal antiandrogen to the testicular ablation. Estrogens are
rarely used currently because they may cause cardiovascular toxicity.[15]

LHRH Agonists
The use of LHRH agonists has become the preferred method of androgen
ablation. In their depot formulations, LHRH analogs are easily
administered, rapidly produce castrate serum levels of testosterone,
and are not associated with increased cardiovascular risk. Although
none of the currently available monotherapies for advanced prostate
cancer offers the prospect of a cure, all symptomatic patients with
stage D disease should receive hormonal therapy to improve quality of
life and relieve symptoms.[16] Open, multicenter studies in patients
with stage D2 prostate cancer have demonstrated that treatment with
the depot formulations of the LHRH agonists were associated with an
objective tumor response (no progression); normalization of, or at
least a 50% decrease in, PSA; and improvement in or stabilization of
both local disease status and overall performance status in nearly
all patients.[17,18]

Orchiectomy vs Medical Hormonal Therapy
Although the outcome of orchiectomy is equivalent to that of LHRH
agents, most patients now prefer monthly, quarterly, or every-4-month
LHRH injections to the prospect of castration. Past study has shown
that patients prefer LHRH agonists to orchiectomy[19] because of the
psychological implications of loss of the testicles.

In the late 1990s, an additional concern for patients is that
hormonal therapy should be reversible. Even though the efficacy of
intermittent hormonal therapy (see below) is as yet unproven,
patients have expressed a desire for this approach, should it be
proven efficacious, or should hormonal therapy side effects become troublesome.

Combination Hormonal Therapy
Cancer progression during androgen deprivation therapy may be
explained by inadequate suppression of adrenal androgens or by the
development of androgen-independent tumor cell populations. It
appears that the late 1990s will bring continued debate regarding the
clinical value of combination hormonal therapy. Since the initial
reports of this approach in the early 1980s, the value of adding an
antiandrogen to testicular androgen deprivation has been debated.

Because low levels of dihydroxytestosterone produced by the adrenal
glands may continue to stimulate androgen-sensitive cells, the use of
an antiandrogen, either in addition to an LHRH agonist or after
bilateral orchiectomy, may offer an advantage over monotherapy. There
is some evidence that combination therapy improves response and
survival rates.[20-23] The National Cancer Institute (NCI) study
0036, European Organization for Research and Treatment of Cancer
(EORTC) study 30853, Canadian Anandron Study, and Multinational
Nilutamide Study all showed a survival benefit of 7 to 15 months with
combination hormonal therapy.[24] However, the recently reported NCI
intergroup trial 0105 of orchiectomy and flutamide (Eulexin) vs
orchiectomy and placebo showed no survival benefit from the addition
of an antiandrogen to orchiectomy.[25]

Furthermore, even two meta-analyses of combined hormonal therapy
studies came to different conclusions. The first analysis, published
in the Lancet, [26] found minimal benefit from the use of
combination hormonal therapy (2- to 3-month survival advantage); yet,
a recently published second meta-analysis found a clear benefit of
this approach (7.3- to 7.6-month survival benefit).[24]

In all of the studies included in these meta-analyses, most of the
patients were men with late advanced metastatic disease. The benefit
of combination hormonal therapy in earlier advanced disease may be
less controversial. For example, in patients with minimal metastatic
disease, both the NCI 0036 and EORTC 30853 studies showed a more
pronounced survival advantage for combination hormonal therapy.
However, the minimal-disease subgroup in NCI 0105 did not show a
survival benefit from combination hormonal therapy with orchiectomy.[25]


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