Hormonal Approaches in the Treatment of Bony Metastases

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.

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].

Pharmacological Approaches

Estrogens--Estrogen administration in males results in feedback inhibition of both LH release and testosterone production[8]. This observation has been the basis for the most established pharmacological strategy for androgen ablation in patients with advanced prostatic carcinoma, diethylstilbestrol (DES) administration[9]. Daily doses of 1 to 3 mg of DES have been found to decrease serum testosterone to castrate levels in most patients. This dosage range also minimizes cardiovascular risks (ie, phlebitis, thrombosis, angina, ischemia) that have been observed with higher (ie,

5 mg/day) DES doses[8]. However, some investigators have reported that even 3 mg DES results in a relatively high rate of drug discontinuance (21%) due to cardiovascular and other adverse effects, including nausea/vomiting (16%), and breast tenderness/gynecomastia (49%).9,16 Feminization, hot flashes, fluid retention, and impotence have also been associated with estrogen[1,2].

LHRH agonists--Chronic administration of LHRH analogues produces an initial androgen surge followed by dramatically reduced testosterone levels via a down regulation of LHRH pituitary receptors that results in the suppression of LH release[8]. The clinical utility of one LHRH agonist, leuprolide (Lupron), was established early in the development of this class of agents[9,14]. A more recent LHRH analog, goserelin acetate (Zoladex), has produced disease remission in 50% and stabilization in 25% of patients with advanced prostate cancer[18]. In addition, nearly 70% of goserelin-treated patients have reported decreased bone pain and analgesic usage, as well as increased performance status. The availability of the implant and depot formulation allows for a once-monthly dosing schedule for goserelin and leuprolide.

The initial stimulation of pituitary LH release observed at the start of LHRH agonist therapy is associated with flare reactions that result in increased serum testosterone levels over the first 1 to 2 weeks of treatment[14,18]. Clinically, this may translate into transient increases in bone pain, which may need to be treated with analgesics[18]. Chronic administration of both leuprolide and goserelin is also associated with other adverse effects due to sex hormone declines: A high incidence of hot flashes (60% to 80%), as well as impotence and decreased libido, similar in frequency to that observed in patients who have undergone orchiectomy.

Antiandrogens--Antiandrogens are agents capable of competitively blocking testosterone and DHT receptors[12]. Both steroidal [cyproterone acetate, CPA (Androcur); megestrol acetate (Megace)] and nonsteroidal antiandrogens [flutamide (Eulexin); nilutamide; bicalutamide (Casodex)] have been employed in patients with advanced prostatic tumors. It has been suggested that the development of the former as prostate cancer therapies has been hampered by progestational adverse effects such as impotence and decreased libido as well as steroidal effects such as edema and thrombosis. In contrast, nonsteroidal antiandrogens are essentially devoid of these effects. However, they are not without adverse events such as gynecomastia, gastrointestinal disturbances, visual disturbances, and alcohol intolerance[10,17,19].

It should be noted that paradoxical declines in PSA have recently been reported in patients who discontinued flutamide due to disease progression (ie, increases in PSA, appearance of new metastatic sites)[20]. Although the mechanism is unknown, this observation has led to the recommendation that antiandrogen treatment be discontinued well before the initiation of second-line chemotherapy in patients who experience loss of disease stabilization. This will minimize the interpretation of false-positive responses to second-line cytotoxic treatments as clinical successes. Despite this potential complication of antiandrogen therapy, there has been increasing interest in flutamide, nilutamide, and Casodex, especially in combination with LHRH agonists to achieve total androgen blockade[8].

Combination therapy--Although there are differences in their safety and tolerability profiles, numerous comparative studies have found few distinctions between orchiectomy, estrogen, LHRH agonist, and antiandrogen strategies with regard to response or survival rates in patients with metastatic disease[2,9,16,21]. In contrast, accumulating data have demonstrated prolonged periods of overall and progression-free survival with the addition of antiandrogens to LHRH agonist therapy[8,10,19]. Furthermore, adjunctive antiandrogen treatment helps to minimize the flare reaction associated with the initial testosterone surge associated with LHRH analogue administration[10].

In 1985, the National Cancer Institute (NCI) initiated an extensive multicenter study designed to compare leuprolide monotherapy with leuprolide/flutamide combination therapy in patients with previously untreated, confirmed stage D2 prostatic carcinoma[10]. Three-hundred patients received leuprolide/placebo while another 303 were treated with leuprolide/flutamide; the former were crossed-over to combination treatment after the first phase of the study. Initial data published in 1989 have recently been updated and confirm the preliminary published observations.

Initial results demonstrated that combination therapy significantly prolonged survival time by 7 months (P = 0.035) and the period of progression-free survival by almost 3 months (P = 0.039) compared with monotherapy[10]. (Updated 1992 data are presented in Figure 3a). It was also noted that improvements in both overall and progression-free survival associated with combination therapy were more evident when patients were stratified by disease severity. As evidenced by Figures 3b and 4, patients with minimal disease derived the most benefits from the addition of flutamide to their treatment. In this study, disease severity was defined by Eastern Cooperative Oncology Group (ECOG) performance status, which has also been found to be one of the most important indices for predicting response to LHRH agonist (goserelin) monotherapy[22].

The clinical benefits of total androgen blockade were also demonstrated in a recent European Organization for Research and Treatment of Cancer phase III study (EORTC 30853) that compared the survival benefits of bilateral orchiectomy to goserelin/flutamide[19]. Patients who received combination therapy experienced a significantly longer duration of overall survival (34.4 vs 27.1 months, P =0.02) and cancer-specific survival (43.9 vs 28.8 months, P = 0.007) compared with those undergoing orchiectomy. As in the NCI trial, patients with less severe disease (ie, less than five sites of bone involvement or good performance status) appeared to benefit the most from combination therapy.

Remaining Clinical Challenges

Although advances in the development of safe and effective hormonal treatments have resulted in longer periods of disease stabilization and increases in quality of life for patients with ad- vanced prostatic carcinoma, several important clinical challenges remain[8]. For example, the initiation of therapy during early stages, the selection of appropriate candidates for combination therapy, and the efficacy of antiandrogen monotherapy in patients who wish to remain sexually active are all important issues that need to be resolved. Furthermore, hormonal therapy eventually ends in relapse for the vast majority of prostate cancer patients. The return of bone pain, decreases in performance, and declining quality of life must continually be addressed in these patients as well as those for whom first-line hormonal treatment has failed[23]. At this point in the management of the disease, other modalities such as radiotherapy or systemic radiopharmaceuticals must be considered.

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