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Hormonal Approaches in the Treatment of Bony Metastase

Hormonal Approaches in the Treatment of Bony Metastase

ABSTRACT: Hormonal therapy for prostate cancer designed to reduce testosterone levels has been employed for decades and provides objective remission rates of 40% to 60% and subjective response rates of 60% to 85%. Orchiectomy, as well as pharmacological androgen deprivation strategies such as diethylstilbestrol (DES), luteinizing hormone-releasing hormone (LHRH) agonists, and antiandrogens all provide similar clinical responses, but there are differences in safety and tolerability. Although advances have been made, the optimization of hormonal therapy of advanced metastatic prostate cancer remains challenging. Recent trials demonstrate a clinical benefit to combination antiandrogen/LHRH agonist therapy, especially in patients with minimal disease. As promising as these results appear, hormonal manipulation eventually ends in relapse and quality of life and pain relief remain important goals that must be addressed with alternative modalities.[ONCOLOGY 8(Suppl):9-14, 1994]

Introduction

Prostate cancer has recently surpassed lung cancer as the most
common malignancy among American men[1]. In fact, the disease
represents nearly 28% of all male cancers and has an annual incidence
of more than 130,000 cases[1,2 ]. If detected and treated during
the earliest stages (A1 or A2; see Table 1), survival rates can
range from over 80% to close to 98%. Initiation of treatment immediately
upon prostate cancer diagnosis has even been suggested.3 Only
one-quarter or less of patients are diagnosed early enough to
benefit from this level of therapeutic success[1].

Diagnosis/Prognosis

Prostate-specific antigen (PSA), a single-chain glycoprotein produced
by prostatic epithelial cells, appears to be a more accurate diagnostic
tool for prostate cancer than the digital rectal exam (DRE)[2].
Recent data demonstrate that the rate of false positive DREs is
as high as 87% and the detection rate was as low as 1% to 2% in
another early study. In contrast, the detection rate is over 30%
in patients presenting with a normal DRE and a PSA more than 10
ng/mL. One of the most sensitive diagnostic indicators of prostate
cancer is a positive DRE in the presence of elevated PSA, capable
of detecting 53% of prostatic neoplasms.

PSA in Treatment Evaluation

Aside from diagnosis, the determination of serum PSA has made
possible the assessment of a variety of treatments employed at
both ends of the prostatic disease spectrum[4-6]. Earlier studies
suggested that PSA is a clinically useful prognostic indicator
of therapeutic responses to surgery (ie, radical prostatectomy)
and radiotherapy. More recent data demonstrate that serum PSA
also has a role in the evaluation of endocrine therapy in patients
with benign prostatic hyperplasia (BPH) or those in the advanced
stages of prostate cancer.

In the assessment of BPH patients, serum levels of PSA have been
found to positively correlate with prostatic volume (r = 0.876;
P less than 0.05) following treatment with the antiandrogen, flutamide
(Eulexin)[5]. Similarly, PSA decreases of greater than 50% following
one month of luteinizing hormone-releasing hormone (LHRH) agonist
(goserelin) therapy have been found to be prognostic for disease
stabilization in patients with stage D1 or D2 prostate cancer[6].

Treatment Selection

Disease progression remains a concern even if prostatic adenocarcinoma
is diagnosed early[1]. Tumor progression has been estimated to
occur within 4 to 8 years in 16% of A1 cases while another 26%
progress within 10 years. An even higher proportion of cases of
stage A2 prostate cancer (ie, one-third) progress after the first
4 years. The high survival rates observed during untreated stage
A1, the more progressive nature of stage A2, and the difficulty
of distinguishing between the two has led to controversy regarding
the wait-and-see approach that has recently been adopted for the
management of early diagnosed patients[2,3]. Although systematic
studies are lacking, it has been suggested that the administration
of aggressive hormonal therapy at the time of diagnosis may provide
clinical benefits to those who are still in the early course of
the malignancy[3].

In contrast to early, more focal disease, the need for aggressive
surgical, radiotherapeutic, chemotherapeutic, or hormonal approaches
is clearcut in the one-half of prostate patients that have stage
B or C disease[1,2]. Regardless of the availability of these treatment
options, mortality remains high. For example, the 5-year survival
rate among patients with stage C prostate cancer is 40% to 60%
despite radiotherapy. Five-year survival rates are even lower
for stage D malignancy--less than 20% for patients who remain
untreated. Evidence suggests that survival among the latter population
rarely improves with treatment. Unfortunately, about 25% of patients
present with stage D disease. These advanced prostatic tumors
are associated with the second highest mortality rate of all cancers
in males, responsible for 13% of cancer fatalities among men in
this country (35,000 deaths).

Hormonal Therapy

Aside from its controversial use as prophylaxis or in the management
of patients with early disease, hormonal therapy has been an established
palliative therapy for stage D prostate cancer for decades[1,2,7-10].
In fact, it has been suggested that therapy be initiated as soon
as possible following prostate cancer diagnosis[7]. Overall, primary
hormonal therapy produces an objective remission rate of 40% to
60% and even higher (60% to 85%) rates of subjective responses[8].

Regardless of documented efficacy, many clinical questions regarding
the optimization of hormonal treatment remain unanswered. For
instance, there appears to be little consensus on the best agent
to administer, the best time to initiate treatment, or the use
of combination hormonal therapies or adjunctive chemotherapy[2,8,11].
The remainder of this review will address some of these issues
and focus on the rationale of androgen deprivation in patients
with advanced metastatic prostate adenocarcinoma, as well as comparisons
of the mechanisms of action, efficacy, and safety of therapeutic
options for androgen deprivation.

Rationale--The rationale for hormonal therapy began over
50 years ago with the observation that prostatic tumors are often
androgen dependent[12]. Numerous treatments for advanced prostatic
carcinoma have since developed from attempts at manipulating those
components of the hypothalamus-pituitary-testicular-adrenal axis
(Figure 1) involved in the synthesis of testosterone or its active
metabolite, 5-dihydrotestosterone (DHT)[12,13]. Numerous treatments for advanced prostatic
carcinoma have since developed from attempts at manipulating those
components of the hypothalamus-pituitary-testicular-adrenal axis
(Figure 1) involved in the synthesis of testosterone or its active
metabolite, 5-dihydrotestosterone (DHT)[12,13].

It is well known that the release of luteinizing hormone (LH),
the factor responsible for stimulating testicular androgen synthesis,
is activated by the binding of hypothalamus-derived LH-releasing
hormone (LHRH) to pituitary receptors.8 Aside from the regulation
of testosterone levels provided by these hormones, both androgens
and estrogens provide negative feedback control. The basis of
both established and novel hormonal prostate cancer treatment
is the surgical or biochemical disruption of this integrated system
(Table 2)[11].

Therapeutic Options

Orchiectomy

Approximately 90% of the total daily androgen production of 5
to 10 mg occurs in the testes[8]. Therefore, surgical removal
of the latter is seemingly the most straightforward method of
androgen deprivation and has been considered the method of choice
for treating metastatic prostate cancer for many years[2,8,9,15-17].
Orchiectomy results in an approximate 95% decrease in blood androgen
levels in many patients and rates of temporary disease regression
of 20% to 57%. Surgery has many benefits--a relatively favorable
safety profile, immediate testosterone suppression, efficacy that
is independent of patient compliance, and low cost. However, it
is not without disadvantages--impotence, a high incidence of hot
flashes (30% to 40%), and an adverse psychological impact. It
is not surprising that approximately 50% to 90% of patients with
advanced disease prefer the idea of medical as opposed to surgical
castration[8,18].

In addition to these difficulties, it has been observed that the
extent of reduction of testosterone levels is not dramatic in
all patients undergoing orchiectomy[15]. Besides the testes, the
adrenals are capable of producing an additional 0.4 mg androgens/day
(mostly in the form of dehydroepiandrosterone or androstenedione,
which are ultimately converted to testosterone and DHT)[8]. Testosterone
levels that are sufficient to stimulate the in vitro proliferation
of human prostatic cancer cells may remain in many castrated patients
due to adrenal synthesis.

One early study of 27 patients confirmed the involvement of adrenal
androgens in prostate cancer progression following orchiectomy.
Plasma testosterone dropped from a mean value of 452 ng/100 mL
to 28 ng/100 mL in 17 prostate cancer patients, but dropped to
only a mean value of 137 ng/100 mL in the remaining 10 patients[15].
The latter group also developed adrenal-derived androstenedione
levels that were more than two-fold higher than baseline values
by 10 days post-surgery (Figure 2). Further treatment with dexamethasone
resulted in adrenal suppression and a further significant drop
in testosterone levels in these patients.

Patients with a poor physiologic response to castration also experienced
a poorer clinical response than those with lower post-orchiectomy
androgen levels. This contribution of adrenal androgens to testosterone
levels in some castrated patients has given rise to attempts to
achieve total androgen ablation with the addition of pharmacological
therapies to orchiectomy[10,17].

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