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.
Prostate cancer has recently surpassed lung cancer as the most common malignancy among American men. 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.
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). 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). 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.
Disease progression remains a concern even if prostatic adenocarcinoma is diagnosed early. 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.
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).
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. Overall, primary hormonal therapy produces an objective remission rate of 40% to 60% and even higher (60% to 85%) rates of subjective responses.
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. 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).
Approximately 90% of the total daily androgen production of 5 to 10 mg occurs in the testes. 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. 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). 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. 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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