1. The relative effectiveness of the available methods for monotherapy: orchiectomy, luteinizing hormone-releasing hormone (LHRH) agonists, and antiandrogens

Monotherapy uses a single drug or a surgical procedure, orchiectomy, for androgen suppression. The following drug classes and agents are included in the assessment: the LHRH agonists (leuprolide, goserelin, and buserelin), the nonsteroidal antiandrogens (flutamide, nilutamide, and bicalutamide), and the steroidal antiandrogen, cyproterone. Each agent was compared to orchiectomy or diethylstilbestrol (DES, 3 mg/d), which was confirmed by our meta-analysis to be equivalent to orchiectomy as a comparator. No trials directly compared the effectiveness of two LHRH agonists or two antiandrogens as monotherapies.

2. The effectiveness of combined androgen blockade compared to monotherapy

For combined androgen blockade, an antiandrogen is used with orchiectomy or an LHRH agonist in order to inhibit simultaneously production of and cellular responses to androgens. The evidence comparing monotherapy to combined androgen blockade was examined in the aggregate (i.e., using any antiandrogen) and by class of antiandrogen (nonsteroidal antiandrogens or cyproterone). In addition, the class of nonsteroidal antiandrogens was examined by agent.

3. The effectiveness of immediate compared to deferred androgen suppression

Three distinct patient populations and treatment settings were considered: (a) androgen suppression initiated at PSA rise in men who have previously undergone definitive therapy for initially localized prostate cancer, (b) androgen suppression as primary therapy in men who are newly diagnosed with locally advanced or asymptomatic metastatic prostate cancer, and (c) long-term androgen suppression initiated at radiotherapy in men with locally advanced or asymptomatic metastatic prostate cancer. For each population and setting, immediate androgen suppression was compared to androgen suppression deferred until signs or symptoms of clinical progression.

The population of interest to this report is men with advanced prostate cancer, including: (1) regional (D1; N+/M0) or disseminated (D2; M1) metastases; (2) locally advanced disease (C; T3-4/N0 or NX/M0); and, only for the third key question, (3) rising PSA, or other signs of progression after definitive therapy for clinically localized disease (A or B; T1-2/N0). Thus, the use of neoadjuvant (short-term) androgen suppression in candidates for definitive treatment of clinically localized disease is outside the scope of this report.

Outcomes of interest are: overall, cancer-specific, and progression-free survival; time to treatment failure; adverse effects; and quality of life. Where available, data on patient preferences are included. We also looked for treatment outcomes that were analyzed by patient subgroups based on prognostic factors such as tumor grade, extent of disease, and performance status. Two supplementary analyses were conducted for each key question: (1) meta-analysis of overall survival at 2 years (questions 1 and 2) and 5 years (questions 2 and 3); and (2) cost-effectiveness analysis.

This introductory chapter provides background information to aid the reader in understanding the clinical context and prior research on the key questions addressed in this evidence report. The following topics are addressed in the introduction:

• Prevalence of prostate cancer and costs of treatment.
• Prostate cancer staging systems.
• Treatment of prostate cancer.
• Description of androgen suppression methods considered in this report.
• Clinical research issues for each key question.

Clinically Localized Disease

Patients with clinically localized prostate cancer, i.e., disease that appears to be confined within the prostatic capsule, are offered definitive therapy (surgery or radiation) or watchful waiting. The American Urological Association Guidelines state that patient preference should guide the decision, as there is presently insufficient evidence to recommend treatment over watchful waiting or to recommend surgery or radiotherapy as the treatment of choice (Middleton, Thompson, Austenfeld et al., 1995). Options for definitive therapy for clinically localized prostate cancer are surgery (radical prostatectomy) or radiation therapy. Radiation may be delivered by external beam or by interstitial brachytherapy, a newer modality. Evidence comparing the long-term outcomes of brachytherapy and external beam radiotherapy is not yet available (Blue Cross and Blue Shield Association, 1997).

Longitudinal data from the Physician Health Study suggested that, for patients with an aggressive tumor, median survival from the initial rise in PSA levels is 13 years (Gann, Hennekens, and Stampfer, 1995). Based on this observation, treatment is frequently recommended for patients who have clinically localized disease and who are in good health, with 10 or more years of life expectancy (Balducci, Pow-Sang, Friedland et al., 1997). However, it is presently unknown whether immediate treatment of clinically localized disease improves survival over that in similar populations managed by watchful waiting and treatment upon progression (Albertsen, 1996; Albertsen, Fryback, Storer et al., 1995; Johansson, Holmberg, Johansson et al., 1997).

At surgery, a substantial proportion of patients is discovered to have more extensive disease: as much as 60 percent of those with clinical T2b lesions (Oesterling, Fuks, Lee et al., 1997). There has been considerable effort to improve techniques of predicting which patients actually have more extensive disease, so that unnecessary surgery can be avoided. A recent nomogram combines information from clinical stage, PSA, and Gleason biopsy grade (Partin, Kattan, Subong et al., 1997). In patients with PSA levels > 10, preoperative bone scan is used to detect metastases.

Because more extensive disease is so frequently discovered at surgery in patients initially diagnosed with clinically localized disease, neoadjuvant therapy has been attempted. In this approach, a short course of androgen suppression is administered for several months before either radical prostatectomy or definitive radiation therapy is performed (Garnick, 1997; Wang and Fair, 1997). When used with radiation therapy, the androgen suppression continues until the course of radiation is completed. The major objective of neoadjuvant androgen suppression is to downstage the tumor by reducing its volume so that it is confined within the prostatic capsule.

Data from pilot studies of neoadjuvant androgen suppression prior to prostatectomy suggest that tumors that appear to be locally advanced by clinical criteria infrequently are converted to organ-confined tumors (Wang and Fair, 1997). On the other hand, several studies reported that the frequency of finding extracapsular extension or positive margins at surgery was reduced in those with clinically localized disease given neoadjuvant androgen suppression (for review, see: Garnick, 1997; Wang and Fair, 1997). However, at present, data comparing long-term survival of patients given neoadjuvant androgen suppression prior to prostatectomy with survival after surgery alone have not been reported from randomized controlled trials.

Data from randomized trials that compare neoadjuvant androgen suppression followed by radiotherapy with radiotherapy alone also are limited (Zietman, Prince, Nakfoor et al., 1997). Interim analysis of results at 6 years of followup from one ongoing trial showed that neoadjuvant androgen suppression significantly improved local control and decreased the development of metastases when compared with radiation therapy alone (Pilepich, Winter, Roach et al., 1998). However, the difference in overall survival between treatment arms did not reach statistical significance.

Some surgeons suggest that shrinking the prostate prior to surgery also may reduce blood loss and other complications of surgery. Radiation therapists propose that neoadjuvant androgen suppression permits more selective targeting of radiation to the prostate, thus preventing collateral damage to surrounding tissues (primarily the bowel and bladder). Reports from several studies show that the prostatic volume is reduced by neoadjuvant androgen suppression (for review, see: Garnick, 1997; Wang and Fair, 1997). This does permit the use of a smaller target volume in treatment planning for patients treated with radiation. However, at present, no data are available from randomized comparative trials of neoadjuvant androgen suppression that demonstrate either reduced blood loss during prostatectomy or reduced collateral damage from radiation therapy.

Locally Advanced Disease

The objectives of treatment for locally advanced prostate cancer (stage C or T3-4/N0 or Nx/M0) include eradication (or at least control) of the primary tumor, prevention or delay of disease progression and the morbidity and symptoms it causes, and increasing the duration of survival (Corn and Hanks, 1997; Frydenburg and Oesterling, 1997; Lee, Hanks, and Schultheiss, 1996; Lerner, Blute, and Zincke, 1996; Oesterling, Fuks, Lee et al., 1997; Perez, 1997). At present, conclusive data from prospective, controlled, randomized studies are lacking to compare the modalities (and their combinations) for treatment of locally advanced prostate cancer. Patient selection bias and other confounding factors preclude reliable conclusions on optimal therapies based on data from single-arm studies of radiotherapy (with or without androgen suppression), surgery (with or without adjuvant radiotherapy or adjuvant androgen suppression), or androgen suppression alone.

The treatment of choice is likely to differ based on prognostic factors such as Gleason score and the degree of extracapsular extension: penetration of the capsule with no tumor at the margins (stage C1), margin involvement (stage C2), or seminal vesicle invasion (stage C3) (Frydenberg and Oesterling, 1997). However, treatment selection usually occurs before the patient's substage is known reliably, since the diagnosis requires pathologic examination on a surgical specimen. For those with higher grade and/or more extensive tumors, a single modality using either radiation therapy, surgery, or androgen suppression alone is generally considered inadequate treatment and not usually recommended (Corn and Hanks, 1997; Frydenburg and Oesterling, 1997; Lee, Hanks, and Schultheiss, 1996; Lerner, Blute, and Zincke, 1996; Oesterling, Fuks, Lee et al., 1997; Perez, 1997). Nevertheless, until data are available from randomized controlled trials, patient preferences regarding the balance of risks from progression and adverse effects will continue to play a major role in treatment selection.

The most frequently recommended treatment for locally advanced disease is external beam radiation, which may be supplemented with adjuvant androgen suppression for several years or more (Corn and Hanks, 1997; Lee, Hanks, and Schultheiss, 1996; Oesterling, Fuks, Lee et al., 1997; Perez, 1997; Pilepich, 1996). Radiation therapy alone is not curative if there are clinically silent regional or distant metastases or if it does not fully eradicate the primary tumor. Nevertheless, successful local control can delay progression and may increase survival duration (Bolla, Bartelink, Gibbons et al., 1997).

For patients with locally advanced disease, radiation is delivered to the tumor by means of an external beam either alone or combined with a boost dose of interstitial brachytherapy (Corn and Hanks, 1997; Lee, Hanks, and Schultheiss, 1996; Perez, 1997). Brachytherapy alone is not usually recommended for these patients (Prestidge, Prete, Buchholz et al., 1998). Evidence is not yet available from randomized trials comparing long-term survival after external beam radiotherapy with or without a brachytherapy boost. Evidence comparing the outcomes of treatment for locally advanced disease using radiation therapy alone with those using radiation combined with adjuvant androgen suppression for several years or more is reviewed in this assessment as part of Key Question 3.

Surgery alone also is unlikely to cure patients with prostate cancer that is judged to be T3 or T4 by clinical criteria. Nevertheless, prostatectomy followed by adjuvant radiation therapy or adjuvant androgen suppression also may be offered to these patients if they are otherwise healthy and have a life expectancy of at least 10 years (Frydenberg and Oesterling, 1997; Lerner, Blute, and Zincke, 1996). The observation that up to 20 percent of those with stage C or T3 tumors by clinical criteria are found to have organ-confined disease by pathologic examination after surgery often is cited as one justification for this approach. In addition, surgery with adjuvant radiation or adjuvant androgen suppression can achieve the clinical objectives of local tumor control. It also permits more definitive evaluation of lymph node involvement and lymph node dissection, if necessary. For patients who select surgical treatment of locally advanced disease, there are no data from randomized comparative trials to determine whether adjuvant therapy should use radiation or androgen suppression.

Salvage Therapy for Local Relapse or Residual Disease

Patients who relapse after treatment with radical prostatectomy for initially localized disease and those discovered to have positive margins at surgery may be offered radiation therapy to the tumor bed for salvage (Corn and Hanks, 1997; Perez, 1997; Zeitman, 1996). Similarly, those who relapse after radiation therapy for clinically localized disease and those whose tumors are not fully eradicated by primary irradiation may be offered radical prostatectomy for salvage (Reiter, Scardino, and Miles, 1996). Androgen suppression is the treatment of choice for those who are not suitable for, decline, or fail salvage therapy. Some clinicians also may recommend the addition of androgen suppression to salvage therapy.

Before the availability of PSA monitoring, clinical signs or symptoms of disease progression were required to identify those who failed definitive treatment for localized disease; presently, biochemical monitoring permits earlier detection. Measurable PSA levels after radical prostatectomy may indicate local treatment failure, metastatic disease, or both (Stamey and Kabalin, 1989). Many of these patients may remain free of symptoms and/or detectable metastases for extended periods of time (Frazier, Robertson, Humphrey et al., 1993). Elevated or increasing PSA levels after radiation therapy also commonly signal local and/or distant treatment failure, but, again, the disease may not be clinically symptomatic (Kuban, El-Mahdi, and Schellhammer, 1995a). A critical question for both groups failing definitive treatment is the optimal timing for initiating androgen suppression.

Metastatic Disease

The management of metastatic prostate cancer, disease that has spread to regional lymph nodes or beyond, takes into consideration age, comorbidities, clinical symptoms, and whether distant metastases or only regional lymph node involvement is present. Androgen suppression is the mainstay of treatment for metastatic prostate cancer (Balducci, Pow-Sang, Friedland et al., 1997). The treatment goals in these patients include preventing or delaying disease progression, preventing or delaying the development of symptoms or their worsening, and increasing the duration of survival.

For many years, when it was thought that the primary source of androgen (90 percent to 95 percent) was testicular, bilateral orchiectomy was the gold standard for effective ablation. A medical approach to obtaining castration levels of serum testosterone was effectively achieved with the administration of DES (Byar and Corle, 1988; Veterans Administration Cooperative Urological Research Group, 1967) or other estrogens, but the risk of cardiovascular complications has tempered their use. Newer drugs, luteinizing hormone-releasing hormone agonists, have been substituted; and orchiectomy may still be used, usually in a modified, subcapsular approach. But castration, whether achieved by surgical or medical means, does not suppress production of the adrenal androgens.

It is now well known that the 5 percent to 10 percent of circulating androgens that originate in the adrenal glands are controlled by the hypothalamus through the anterior pituitary (McLeod, Crawford, and DeAntoni, 1997). Whether the adrenal androgens are important in the growth of prostate cancer and a necessary target of medical suppression has only been hypothesized. The use of combined androgen blockade, which adds antiandrogen therapy to medical or surgical castration, has been advocated as standard therapy for advanced prostate cancer (Caubet, Tosteson, Dong et al., 1997; Debruyne and Dijkman, 1995; Labrie, Dupont, Belanger et al., 1982; Thrasher and Crawford, 1996) but remains the subject of controversy.

Other trials have investigated the intermittent use of androgen suppression therapy, in which treatment is given in response to PSA fluctuations. For example, therapy is administered with rising levels of PSA and withdrawn when PSA levels decrease (Goldenberg, Bruchovsky, Gleave et al., 1995; Klotz, Sogani, and Block, 1997). Obviously, this approach is possible only with medical approaches to androgen suppression. A potential advantage is recovery of sexual function and avoidance of the other adverse consequences of reduced serum testosterone when treatment is temporarily discontinued. There are concerns, however, that disease relapse and/or progression may occur more frequently than with continuous treatment. Long-term data on the outcomes of intermittent androgen suppression also are not yet available (Garnick, 1997; Klotz, Sogani, and Block, 1997; Moul, 1998; Newling, 1997).

Hormone-Refractory Disease

Prostate cancer that does not respond to or that relapses after primary androgen suppression treatment is particularly problematic. Patients who develop hormone-refractory clinical disease may respond to second-line androgen suppression therapies (Ritter, Messing, Shanahan et al., 1992; Small and Vogelzang, 1997). Various methods for secondary hormonal therapy are available, but responses rarely last longer than 6 months and most patients die within 1 year (Mahler, Akaza, Boccardo et al., 1997). Patients unresponsive to androgen suppression may be referred to clinical trials investigating chemotherapy regimens.

Results of various chemotherapy trials have been mixed (Rubben, Dijkman, Ferrari et al., 1997). A recent international committee has concluded that "complete response cannot be achieved by [single-agent] chemotherapy, that a cytostatic drug of first choice is not available, and that a comparative study with quality of life as an end point is urgently needed" (Rubben, Dijkman, Ferrari et al., 1997). Trials of combination chemotherapy are ongoing, as are studies assessing the efficacy of combining cytotoxic therapy and hormonal treatment (Rubben, Dijkman, Ferrari et al., 1997). In one such randomized study, palliation was achieved more frequently, and certain parameters of health-related quality of life were better in patients randomized to mitoxantrone plus prednisone than in those randomized to prednisone alone (Tannock, Osoba, Stockler et al.,1996). However, there was no difference in overall survival.

Production and Action of Endogenous Androgens

Androstenedione and testosterone (and its active metabolite, dihydrotestosterone [DHT]) are produced in the testes, whereas androstenedione and dehydroepiandrosterone (and its sulfate), which are relatively weak androgens, are produced by the adrenal glands (Denis, 1993; Huben and Perrapato, 1991; Vogelzang and Kennealey, 1992). The adrenal androgens undergo further conversion to testosterone and DHT in the peripheral tissues and in the prostate (Denis, 1993). About 95 percent of the circulating plasma testosterone is produced from cholesterol in the Leydig cells of the testes (Huben and Perrapato, 1991; Vogelzang and Kennealey, 1992; Wojciechowski, Carter, Skoutakis et al., 1986). The testes contribute, on average, 5 to 10 mg of testosterone to the daily androgen production, whereas the adrenal cortex contributes 0.4 mg of androgens per day, under the influence of adrenocorticotropin (Denis, 1993).

Approximately 95 percent of testosterone and dihydrotestosterone circulate bound to carrier proteins such as plasma beta-globulin, sex hormone-binding globulin (SHBG, including testosterone-binding globulin [TBG]), and, to a lesser extent, plasma albumin (Huben and Perrapato, 1991; Vogelzang and Kennealey, 1992). Androgens can circulate in the blood as "free" active unbound hormones; however, when bound to the carrier proteins, the androgens are inactive and cannot interact with tissue androgen receptors; approximately 3 percent of the total circulating testosterone circulate in the "free," unbound form (Vogelzang and Kennealey, 1992). Plasma testosterone concentrations in men aged 20 to 60 years are relatively constant, after which there is a steady decrease; this decrease is partly due to the increase in circulating SHBG, which decreases the concentration of free testosterone (Huben and Perrapato, 1991).

Testosterone enters cells by passive diffusion (Vogelzang and Kennealey, 1992; Wojciechowski, Carter, Skoutakis et al., 1986). Once inside the cell, testosterone is converted by the cytoplasmic membrane-bound enzyme 5-alpha-reductase to DHT, its active metabolite; dihydrotestosterone is the most active intracellular form of androgen (Huben and Perrapato, 1991; Vogelzang and Kennealey, 1992). Dihydrotestosterone binds to intracellular receptor proteins, forming a receptor-steroid complex that initiates transcription and protein production after the complex is transported to the nucleus. The proteins produced as a result of this process are believed to affect the growth and function of cells (e.g., prostatic cells, hormone-dependent cancer cells) (Denis, 1993; Vogelzang and Kennealey, 1992; Wojciechowski, Carter, Skoutakis et al., 1986).

The production of androgens in the Leydig cells of the testes is influenced by pituitary luteinizing hormone (LH), the production of which is regulated by the pulsatile release of hypothalamic luteinizing hormone-releasing hormone (Denis, 1993; Huben and Perrapato, 1991; Wojciechowski, Carter, Skoutakis et al., 1986). It is this pulsatile release that exerts the physiologic response of LH production (Denis, 1993; Wojciechowski, Carter, Skoutakis et al., 1986). LH regulates the rate-limiting step of the synthesis of testosterone from cholesterol in the Leydig cells (Wojciechowski, Carter, Skoutakis et al., 1986). This "hypothalamic-pituitary-gonadal" axis of testosterone production allows for interventions at several different points in the axis (Huben and Perrapato, 1991).

Orchiectomy

Bilateral orchiectomy is a relatively safe, albeit irreversible, procedure with low morbidity and associated cost (Vogelzang and Kennealey, 1992; Wojciechowski, Carter, Skoutakis et al., 1986). The surgical approach can be subcapsular or may involve total orchiectomy. The subcapsular approach preserves the scrotum and thus allows cosmetic replacement with prostheses.

Following surgery, circulating concentrations of testosterone fall to castrate levels (i.e., decreasing the total plasma concentration of testosterone to 90 to 95 percent of baseline) within 3 hours (Huben and Perrapato, 1991; Maatman, Gupta, and Montie, 1985; Vogelzang and Kennealey, 1992), providing a rapid and permanent means of androgen suppression. The rapid decline in circulating concentrations of testosterone was once an important advantage of orchiectomy when many patients had disseminated metastases at initial diagnosis and some were at risk for spinal cord compression. Currently, it is very rare to encounter newly diagnosed patients with such an advanced stage of disease.

Because orchiectomy permanently eliminates testicular production of androgens, there are no questions regarding compliance with therapy as there may be with medical approaches to androgen suppression. However, irreversibility can be a disadvantage for orchiectomy if current trials of intermittent androgen suppression show that its long-term efficacy is comparable to that of continuous androgen suppression. Orchiectomy also is poorly accepted by patients because of its psychologic impact (Vogelzang and Kennealey, 1992; Wojciechowski, Carter, Skoutakis et al., 1986). Nevertheless, some patients may prefer a one-time surgical treatment to repeated daily, monthly, or quarterly injections. Furthermore, there is inadequate information for patients to use in making treatment decisions that reliably compares the anticipated effects of different options for androgen suppression with the realities of life during and after treatment.

Diethylstilbestrol

Estrogens are one of the older methods of androgen suppression for advanced prostate cancer. Estrogens block the production of androgens by inhibiting pituitary LH secretion by blocking testosterone binding sites in the hypothalamus, resulting in a decrease in LHRH (Denis, 1993; Huben and Perrapato, 1991; Vogelzang and Kennealey, 1992). They also appear to inhibit directly testosterone synthesis in the testes as well as increasing the amount of circulating SHBG, increasing its binding capacity, thereby decreasing the unbound or "free" fraction of circulating androgens (Denis, 1993; Huben and Perrapato, 1991). Estrogen therapy, is seldom used currently for the treatment of advanced prostate cancer because of the relative risks, most notably cardiovascular, associated with such therapy (Physician Data Query Database, 1998).

A variety of estrogens have been used in the treatment of advanced prostate cancer, but for this report, only DES is of interest. DES was used in nearly all randomized trials that compared LHRH agonists or antiandrogens with estrogen therapy and thus serves, along with orchiectomy, as a common comparator of the relative effectiveness of the newer androgen suppression agents.

Diethylstilbestrol is a synthetic nonsteroidal estrogen (McEvoy, 1997). It can occur as DES base, as the diphosphate ester, or as the disodium salt of the diphosphate ester. One milligram of DES is approximately equivalent to 1.6 mg of DES diphosphate on a molecular basis (McEvoy, 1997).

Diethylstilbestrol has been used in the palliative treatment of advanced prostate cancer (McEvoy, 1997). At daily oral doses of 3 mg or more, DES reduces circulating testosterone concentrations to castrate levels within 7 to 21 days (Vogelzang and Kennealey, 1992).

DES is administered orally as the base or as the diphosphate ester or as an intravenous injection as the disodium salt of the diphosphate ester (McEvoy, 1997). Although DES at 1 mg/d has been prescribed, this level of administration decreases plasma testosterone concentration to castrate levels in only about 70 percent of patients (Huben and Perrapato, 1991). Nevertheless, data from a randomized trial showed that DES treatment at 1 mg/d was equivalent to castration with respect to survival and progression of metastatic disease (Newling, Pavone Macaluse, Smith et al., 1992). Most trials that compared an LHRH agonist or antiandrogen to DES utilized a dose of 3 mg/d. This dosage is preferred to the 5 mg/d dose used in some earlier trials (e.g., Veterans Administration Cooperative Urological Research Group, 1967), since it may provide the best balance of optimal androgen suppression with reduced cardiovascular toxicity (Atala and Amin, 1991; Huben and Perrapato, 1991; McEvoy, 1997; Physician Data Query Database, 1998).

Luteinizing Hormone-Releasing Hormone Agonists

The LHRH agonists were synthesized following determination of the natural gonadotropin-releasing hormone (GnRH) decapeptide structure in 1973 (Huben and Perrapato, 1991; (Wojciechowski, Carter, Skoutakis et al., 1986); modifications in the peptide sequence have resulted in compounds with much longer half-lives than the naturally occurring compound (Huben and Perrapato, 1991). GnRH is a collective term that includes both follicle-stimulating hormone (FSH)-releasing hormone (FSH-RH) and luteinizing hormone-releasing hormone (LHRH) (Wojciechowski, Carter, Skoutakis et al., 1986).

The effects of LHRH agonists on androgen production are thought to be due primarily to "downregulation," or desensitization of pituitary LHRH receptors, causing a suppression in luteinizing hormone release and a resultant decrease in testosterone production (Huben and Perrapato, 1991; Wojciechowski, Carter, Skoutakis et al., 1986). The long-acting analogs can occupy the pituitary LHRH receptors, without changing the affinity of those receptors for LHRH (Wojciechowski, Carter, Skoutakis et al., 1986). It is generally accepted that the pulsatile release of LHRH from the hypothalamus results in its physiologic effect (i.e., LH production), whereas maintenance of a sustained, high concentration of LHRH results in downregulation of the receptors (Wojciechowski, Carter, Skoutakis et al., 1986). The resultant decrease in testosterone production decreases both prostatic and testicular weight (Wojciechowski, Carter, Skoutakis et al., 1986). This type of pharmacologic therapy is sometimes termed "chemical" or "medical" castration, as it essentially results in the same physiologic state as that following surgical orchiectomy (Atala and Amin, 1991)

Serum testosterone may actually increase by as much as 50 percent above baseline when therapy with an LHRH agonist is first initiated (TAP Pharmaceuticals, Inc., 1997a, 1997b, 1997c). Since testosterone production is stimulated, patients may experience a tumor "flare," with a worsening of disease symptoms (e.g., bone pain, dysuria, hematuria, weakness) for the first few days to weeks. As therapy continues, however, serum testosterone will decrease to castrate concentrations (Huben and Perrapato, 1991; Physician Data Query Database, 1998; TAP Pharmaceuticals, Inc., 1997a, 1997b, 1997c; Wojciechowski, Carter, Skoutakis et al., 1986). Concomitant short-term therapy with antiandrogens or estrogens can prevent tumor flare (Physician Data Query Database, 1998). LHRH agonist therapy should be initiated with great caution in patients with impending spinal cord compression due to vertebral metastatic disease or early ureteral obstruction due to tumor involvement of the base of the bladder because of the possibility of tumor flare (TAP Pharmaceuticals, Inc., 1997a, 1997b, 1997c). Some clinicians maintain that LHRH therapy is contraindicated in such patients (Huben and Perrapato, 1991). However, the consequences of tumor flare may no longer be clinically significant, since patients rarely begin treatment with an LHRH agonist at this late stage of disease. LHRH agonists also can cause loss of libido, hot flushes, and impotence (Physician Data Query Database, 1998).

Because these agents are peptides, they are poorly absorbed and are only weakly active following oral administration; therefore, they have been administered as subcutaneous or intramuscular injections, intranasal sprays or drops, or percutaneous and intramuscular depots (Vogelzang and Kennealey, 1992).

Three LHRH agonists (leuprolide, goserelin, and buserelin) are addressed in this report (Table 3).

Table

Table 3. LHRH Agonists.

Antiandrogens

Antiandrogens block the stimulating effect of testosterone on prostate cell growth (Vogelzang and Kennealey, 1992). Antiandrogens can inhibit binding of endogenous androgens to the receptors present in target tissues and/or inhibit androgen uptake (Vogelzang and Kennealey, 1992; Schering Corporation, 1996). Interaction with the androgen receptor results in an unstable antiandrogen-receptor complex that is transient and does not result in androgen-dependent gene transcription and protein synthesis (Soloway and Matzkin, 1993). The relative binding affinity of the antiandrogens for the androgen receptor decreases with time, indicating that the antiandrogen-receptor complex dissociates more readily than the testosterone- or dihydrotestosterone-receptor complex (Soloway and Matzkin, 1993).

Antiandrogens can be divided into two classes-steroidal and nonsteroidal, based primarily on whether the compound exerts hormone-like effects (including estrogenic, progestational, or androgenic activity) (Huben and Perrapato, 1991). The nonsteroidal antiandrogens are generally "pure" antiandrogens, meaning that they have no androgenic steroidal effects (Brogden and Clissold, 1989; Vogelzang and Kennealey, 1992). These were developed to circumvent the steroidal adverse effects associated with the steroidal antiandrogens (e.g., cyproterone acetate, megestrol) (Vogelzang and Kennealey, 1992). Because they block both central (i.e., diencephalic) and peripheral androgen receptors when administered to nonorchiectomized rats, these drugs cause a slow and gradual increase in plasma testosterone due to the increase in LHRH secretion (Soloway and Matzkin, 1993). Increases in LH, testosterone, and estrogen (estradiol) have been reported in patients receiving nilutamide or bicalutamide as monotherapy (Soloway and Matzkin, 1993; Zeneca Pharmaceuticals, 1997). This has led to a clinical reluctance to use the nonsteroidal antiandrogens as monotherapy. In addition, limited clinical study of monotherapy in humans has produced equivocal results (Soloway and Matzkin, 1993).

Three nonsteroidal antiandrogens (flutamide, bicalutamide, and nilutamide) and one steroidal antiandrogen (cyproterone) are addressed in this report (Tables 4 and 5, respectively).

Table

Table 4. Nonsteroidal Antiandrogens.

Table

Table 5. Steroidal Antiandrogens.

Although other steroids with antiandrogenic effects (e.g., medroxyprogesterone acetate, megestrol acetate) have been used in clinical trials as treatment for advanced prostate cancer, none of them is currently used as primary therapy in the United States. Furthermore, none has been used in combination with an LHRH agonist or orchiectomy for combined androgen blockade. Consequently, these drugs and agents used for secondary hormonal therapy (e.g., aminoglutethimide, ketoconazole, spironolactone) are outside the scope of this evidence report.

Relative Effectiveness of Monotherapy Methods

The pioneering work of Huggins (Huggins and Hodges, 1941; Huggins, Stevens, and Hodges, 1941); (Herbst, 1941; (Herbst, 1942), and their colleagues established the clinical benefit of androgen ablation as therapy for men with advanced prostate cancer. During much of the time since these initial discoveries, the goal of androgen ablation has been to delay clinical progression and to palliate symptoms of metastatic disease. For all but the last two decades, surgery (i.e., orchiectomy) and estrogens were the only options available for androgen ablation.

Early placebo-controlled randomized trials conducted by the Veterans Administration Cooperative Urological Research Group (VACURG) compared orchiectomy with the synthetic estrogen, diethylstilbestrol (DES), and with their combination (Byar and Corle, 1988; Jordan, Blackard, and Byar, 1977; Veterans Administration Cooperative Urological Research Group, 1967). This landmark study demonstrated that 5 mg/d of DES reduced the number of deaths due to prostate cancer when compared with placebo or when added to orchiectomy. However, this dose of DES also increased the number of deaths due to cardiovascular disease and, thus, provided no improvement in overall survival. Furthermore, the excess deaths due to cardiovascular toxicity occurred mostly in the first year of treatment with DES, arguing against any benefit from early treatment. A second VACURG placebo-controlled randomized trial compared three dosages of DES and found a similar tradeoff between fewer deaths due to prostate cancer and more early deaths due to cardiovascular toxicity when the highest dose (5 mg/d) was compared with an intermediate dose (1 mg/d).

A newer approach to androgen ablation was developed in the late 1970s. This relied on the use of luteinizing hormone-releasing hormone agonists (e.g., leuprolide, goserelin, or buserelin) to suppress androgen production by the testes (Chrisp and Goa, 1991; Chrisp and Sorkin, 1991; Conn and Crowley, 1991; Plosker and Brogden, 1994; Roila, 1989). Avoiding the adverse psychologic effects of orchiectomy and, thus, increasing patients' acceptance of treatment was proposed as a major advantage of medical castration using LHRH agonists. Many randomized trials have compared the outcomes of treatment with LHRH agonists (e.g., leuprolide, goserelin, or buserelin) with either orchiectomy or DES. However, no studies directly compared one of the LHRH agonists with another drug of the same class when used for monotherapy.

The clinical studies of LHRH agonists also showed that similar endocrine physiologic sequelae of reduced testosterone concentrations resulted from surgical or long-term medical castration. These often may include impotence, loss of libido, gynecomastia, breast pain and tenderness, hot flushes, and/or loss of muscle mass. Additionally, concerns have been expressed regarding the possibility of osteoporosis as a long-term consequence of reduced testosterone concentrations (Daniell, 1997). Consequently, there was interest in developing drugs that prevent the intracellular actions of androgens by blocking their binding to the androgen receptor without reducing testosterone concentrations. Collectively termed "antiandrogens," these may be steroid (e.g., cyproterone, megestrol, or medroxyprogesterone acetates) or nonsteroidal (e.g., flutamide, bicalutamide, or nilutamide) in chemical structure. Antiandrogens are a fourth alternative to orchiectomy, DES, or LHRH agonists for treatment of advanced prostate cancer.

Based on results from clinical and laboratory animal studies, monotherapy with cyproterone acetate appears to be more effective than monotherapy with either megestrol acetate or medroxyprogesterone acetate (Goldenberg and Bruchovsky, 1997; Nicholson and Waxman, 1997; Schroder, 1993). Consequently, cyproterone acetate is the only steroidal antiandrogen that continues to be used alone (albeit outside the United States) for primary hormonal therapy of advanced prostate cancer. However, steroidal antiandrogens have progestational and/or gonadotropic effects in addition to their inhibitory effects at the androgen receptor. In contrast, the nonsteroidal antiandrogens are more selective in their actions at the intracellular androgen receptor, without any gonadotropic or progestational effects. Most of the comparative trials investigating antiandrogens as monotherapy for prostate cancer have utilized either DES or orchiectomy as the control treatments. Several of the antiandrogens also have been compared with an LHRH agonist or with the patients' choice of surgical or medical castration. No trials have directly compared the nonsteroidal and steroidal antiandrogens.

Orchiectomy and DES are the most commonly available comparators for all other monotherapies. Although DES is no longer widely used for hormonal suppression, trials comparing DES to orchiectomy were included in this report to establish the equivalence of DES and orchiectomy when used as the control arm to compare other monotherapies. Our initial meta-analysis established that the hazard ratio for survival after treatment with DES relative to survival after orchiectomy was 0.9726 (95 percent confidence interval 0.756 to 1.252). If DES were not included as a comparator, the evidence basis for this assessment would be less robust. The review would be reduced from 22 trials to 16 trials, and the number of patients would be reduced from more than 5,300 patients to somewhat fewer than 4,500 patients.

To compare the effectiveness of the methods available for monotherapy as primary treatment for advanced prostate cancer, this evidence report will address the following questions:

1.

What is the effectiveness of treatment with an LHRH agonist compared to orchiectomy or DES?

2.

What is the effectiveness of treatment with an antiandrogen compared to orchiectomy or DES?

3.

Is there any difference in effectiveness among the LHRH agonists?

4.

Is there any difference in effectiveness among the antiandrogens?

5.

How do the alternatives available for monotherapy compare with respect to adverse effects?

6.

How do the alternatives available for monotherapy compare with respect to their effects on quality of life and with respect to patient preferences?

Combined Androgen Blockade Compared to Monotherapy

More than 50 years ago, (Huggins and Scott,1945) reported clinical responses to bilateral adrenalectomy in four patients whose cancers had relapsed after orchiectomy. However, three of the four died soon after surgery because methods then available to replace adrenocortical steroid hormones were inadequate (Newling, 1997 ; Thrasher and Crawford, 1996). It is now well accepted that 5 percent to 10 percent of the DHT found in the prostate derives from circulating androgens (other than testosterone) that are produced by the adrenal gland. Neither orchiectomy nor treatment with an LHRH agonist prevents production of adrenal androgens. This is the theoretical rationale for combined androgen blockade. However, it is still controversial whether preventing the stimulation of prostate cancer cells by DHT formed from adrenal androgens adds clinical benefit beyond that of blocking testicular production of testosterone.

Despite the availability of better methods for hormone replacement after adrenalectomy, surgery for ablation of adrenal androgens is no longer used in men with prostate cancer. The antiandrogens are drugs that bind relatively tightly to the androgen receptor. By occupying the binding site, they prevent binding of the endogenous androgens. However, the antiandrogens do not permit the occupied receptor to carry out its normal repertoire of physiologic responses. Combined androgen blockade thus involves the use of either surgery or an LHRH agonist to prevent testicular production of testosterone, together with an antiandrogen to block the action of adrenal androgens.

An initial series of reports from nonrandomized studies generated considerable enthusiasm for this approach, particularly for combining an LHRH agonist with an antiandrogen, which avoided surgery (for reviews, see Hussain and Crawford, 1997; Labrie, Belanger, Cusan et al., 1996; Robertson, Roberson, Padilla et al., 1996; Thrasher and Crawford, 1996). The earliest reported results focused primarily on prevention of the flare reaction that occurred during the first few days of treatment with an LHRH agonist (Labrie, Dupont, Belanger et al., 1982). Subsequently, additional nonrandomized pilot studies reported that men given combined androgen blockade survived longer than historical controls. These observations led to randomized controlled trials to test the hypothesis that men with advanced prostate cancer survived longer after combined androgen blockade than after monotherapy with an LHRH agonist.

The National Cancer Institute (NCI)-sponsored Intergroup trial (INT 0036) was one of the earliest and largest randomized studies to test this hypothesis and reported positive results (Crawford, Eisenberger, McLeod et al., 1989). More than 600 men with stage D2 prostate cancer were treated with either leuprolide plus placebo or leuprolide plus flutamide. Median survival was 6 months longer in the combined treatment arm. Longer followup showed that an additional 3 percent of these patients were alive at 5 years, when compared with those in the control arm.

One concern in generalizing from the results of the Intergroup study (INT 0036) was whether combined androgen blockade only improved survival when compared to the use of an LHRH agonist alone. There was some doubt as to whether LHRH agonists were clinically as effective as orchiectomy, although there were comparable declines in serum testosterone concentration by one month after initiation of treatment. A related concern was whether the flare reaction, which is caused by the use of an LHRH agonist, might also bias the comparison. Consequently, additional trials were conducted to compare survival after orchiectomy with or without an antiandrogen, and to compare survival after orchiectomy alone with survival after an LHRH agonist plus an antiandrogen.

A variety of monotherapies and combinations have been tested. These include either orchiectomy or one of the LHRH agonists (leuprolide, goserelin, or buserelin) used alone in the control arm and used with a nonsteroidal antiandrogen (flutamide, nilutamide, or bicalutamide) or a steroidal antiandrogen (cyproterone) in the other arm. Although results from several of these trials agreed with those of the Intergroup study (INT 0036), most did not find a statistically significant difference in survival between treatment arms. Whether combined androgen blockade improves survival relative to monotherapy remains a matter of controversy.

The NCI also sponsored a second Intergroup trial (INT 0105) as a further contribution towards resolving this controversy. This trial, led by the Southwest Oncology Group, compared orchiectomy alone to orchiectomy plus a nonsteroidal antiandrogen and thus eliminates tumor flare as a potential source of bias. It is the largest trial of combined androgen blockade thus far, with sufficient statistical power to detect a 25 percent improvement in overall survival. Furthermore, the trial design included prospective stratification for major prognostic factors (extent of disease and performance status) and an adequate number of patients in the minimal disease subgroup to permit a test of the hypothesis that patients with minimal disease benefit more from combined androgen blockade than from monotherapy. The results of this trial at a median followup of 50 months have recently been reported (Eisenberger, Blumenstein, Crawford et al., 1998) and are included in this assessment.

Reviews and overviews that addressed the controversy over combined androgen blockade reached differing conclusions. One viewpoint, that the benefits of combined androgen blockade were unproven, was based on the large number of trials with no statistically significant difference between arms compared with the few with a significant difference (e.g., Fitzpatrick, 1996; Goldenberg and Bruchovsky, 1997; Schroder, 1995). Related concerns were the additional economic costs and adverse effects of combination therapy. The case for combined therapy was based on the size of the positive trials and issues related to the design of the negative trials (e.g., Debruyne, 1996; Iversen, 1997; Labrie, Belanger, Cusan et al., 1996; Schellhammer, 1996; Thrasher and Crawford, 1996). These issues included:

• Whether sample sizes were adequate to detect small differences in survival;
• Whether duration of followup was adequate;
• Whether consistent criteria were used to evaluate response or progression;
• Whether patients with locally advanced disease should have been aggregated with those who had metastatic disease; and
• Whether patients should be stratified prospectively for important prognostic factors.

The Prostate Cancer Trialists' Collaborative Group (PCTCG) addressed this controversy by a meta-analysis that combined results from 22 randomized trials with a total of 5,710 patients (Prostate Cancer Trialists' Collaborative Group, 1995). The PCTCG solicited updated individual patient data from all published and unpublished randomized trials that compared any monotherapy with any combination regimen, attempting to exclude trials with confounding factors that could bias the results. For each trial, the number of deaths in the combination arm was compared with the number that would have been expected on the basis of the average survival for all randomized patients using the logrank statistic. The PCTCG analysis used an intention-to-treat approach and had a median followup for all patients of 40 months with 57 percent of patients no longer alive. Crude death rates were 58 percent for monotherapy and 56 percent for combined therapy, with actuarial estimates of survival at 5 years of 22.8 percent and 26.2 percent, respectively. The difference in survival of 3.4 percent (95 percent CI 0 to 7 percent) was not statistically significant.

Potential limitations of the PCTCG meta-analysis have been widely discussed in the literature (e.g., Hussain and Crawford, 1997; Iversen, 1997; Schellhammer, 1996; Thrasher and Crawford, 1996). A threshold issue was whether trials using a nonsteroidal antiandrogen, which selectively blocks the androgen receptor, should be combined with those using a steroidal antiandrogen, which also have progestational and other hormonal effects. Although the PCTCG analysis found no statistically significant heterogeneity of results between these two groups of trials, the validity of pooling data across these trials remained a concern. The trials with cyproterone for combined androgen blockade were consistently negative whereas the trials with nonsteroidal antiandrogens were generally positive, even when the difference was not statistically significant.

A second issue with respect to the PCTCG meta-analysis was whether the results from trials that did not use short-term antiandrogens to block the flare reaction in the control arm should be combined with those that controlled flare or those that used orchiectomy. Trials with orchiectomy as the control did not need to prevent flare, since it only occurs with an LHRH agonist. The following were among the other issues raised:

• Survival was the only outcome collected and subjected to meta-anyalyses;
• Trials that were not mature with respect to followup were included;
• Data were not available from three large trials (including the SWOG INT-0105 trial with 1,371 patients);
• Trials that enrolled patients with and without metastases were included; and
• Analyses of outcomes for subgroups with minimal disease or other good prognostic features were not possible.

A second meta-analysis, restricted to randomized trials that used nonsteroidal antiandrogens in the combination regimen, was reported by Caubet and coworkers, (Caubet, Tostenson, Dong et al. 1997). This meta-analysis excluded studies published only as abstracts, those that did not publish data on survival, and one trial that used short-term cyproterone to control tumor flare in controls receiving an LHRH agonist alone. The analysis utilized two different methods to estimate the log hazard ratio for survival from each trial. Although 13 trials met the inclusion criteria for the meta-analysis, only 9 included the necessary statistical summaries in the published reports to permit estimation of the relative risk by at least one of the two methods. The meta-analyses used a random effects model to generate pooled estimates of the relative risk for survival from each of the two methods used to estimate the log hazard ratios. Both methods of analysis yielded statistically significant relative risks that favored combined androgen blockade (0.78, 95 percent CI 0.67 to 0.90; 0.84, 95 percent CI 0.76 to 0.93). There was also a statistically significant increase in time to progression (relative risk, 0.74; 95 percent CI 0.63 to 0.86) that favored combined androgen blockade.

Note also that a third meta-analysis is less commonly cited in the literature and now may be largely of historical interest because its scope was limited to only one of the nonsteroidal antiandrogens (Bertagna, De Gery, Hutcher et al., 1994). This meta-analysis, which included 7 trials and 1,056 patients, was restricted to double-blind studies that compared orchiectomy with orchiectomy plus nilutamide. The analysis reported that the odds of death were reduced in the combination arm relative to the monotherapy arm but that the difference was not statistically significant. The odds of disease progression were significantly reduced (odds ratio, 0.84; p=0.05).

As of this writing, a planned second cycle for updating the PCTCG meta-analysis is nearing completion. This analysis will be an important contribution to the literature on combined androgen blockade because of the updated data it contains. It includes data from additional trials that were not sufficiently mature at the time of the first analysis (most notably the SWOG INT 0105 study), as well as longer followup from all of the trials in the previous report.

To compare the effectiveness of combined androgen blockade with that of monotherapy as primary treatment for advanced prostate cancer, this evidence report will address the following questions:

1.

Does combined androgen blockade improve outcomes compared to monotherapy using orchiectomy or an LHRH agonist?

2.

Does combined androgen blockade benefit particular subpopulations of patients?

3.

How do combined androgen blockade and monotherapy compare with respect to adverse effects?

4.

How do combined androgen blockade and monotherapy compare with respect to their effects on quality of life?

One analysis will aggregate evidence for combined androgen blockade using any antiandrogen. A second analysis will aggregate evidence for each class of antiandrogen (nonsteroidal or steroidal antiandrogen) separately. To the extent permitted by the evidence, additional analyses will examine the class of nonsteroidal antiandrogens separately by agent (flutamide, bicalutamide, and nilutamide).

Immediate Compared to Deferred Androgen Suppression

Early placebo-controlled randomized trials conducted by the Veterans Administration Cooperative Urological Research Group found that excess deaths due to cardiovascular toxicity occurred mostly in the first year of therapy with DES, arguing against any benefit from early treatment (Byar and Corle, 1988; Jordan, Blackard, and Byar, 1977; Veterans Administration Cooperative Urological Research Group, 1967). Although orchiectomy was not associated with such toxic effects, there was reluctance to perform this surgery until absolutely necessary. The availability of the LHRH agonists, which avoided the cardiovascular risks associated with DES, stirred interest in the potential benefits of earlier androgen suppression. This renewed interest in the hypothesis that earlier treatment might improve survival and other outcomes for patients with advanced prostate cancer.

For asymptomatic patients, an important question is whether androgen suppression should begin early and which clinical observations should trigger the decision to start treatment (Crawford, Fourcade, Iversen et al., 1997; Mazeman and Bertrand, 1996; Schroder, 1989). Put simply, the alternatives are to initiate androgen suppression as soon as it is known that the disease has spread beyond the prostatic capsule, generally referred to as immediate therapy, or to defer therapy until progression is detected. In practice, however, these alternatives vary for patients at different points along the natural course of the disease.

One patient population of interest is those who are treated with definitive therapy (surgery or radiation) for early stage disease and then either are not cured or relapse. Presently, the most likely finding in this group of patients would be either a persistent elevation or a renewed increase in PSA levels. Their alternatives are to begin hormonal therapy immediately after the persistent or renewed PSA elevation is detected or to defer until additional progression is documented. Evidence of progression might include, for example, detection of nodal involvement or metastatic lesions by imaging techniques. Note also that the PSA threshold to trigger the decision for immediate therapy may vary.

A second patient population of interest is those with locally advanced disease at the time of initial diagnosis but without nodal involvement or distant metastases. The alternatives for these patients include radiotherapy with or without androgen suppression, surgery with adjuvant radiotherapy or adjuvant androgen suppression, or androgen suppression alone. Conclusive data are lacking to determine which of these choices provides optimal treatment outcomes, both for the group as a whole and for subgroups defined by the extent of extracapsular invasion and tumor grade (Corn and Hanks, 1997; Frydenburg and Oesterling, 1997; Lee, Hanks, and Schultheiss, 1996; Lerner, Blute, and Zincke, 1996; Oesterling, Fuks, Lee et al., 1997; Perez, 1997).

For those who select radiotherapy for locally advanced disease, it is of interest to determine if adjuvant androgen suppression that begins with radiotherapy and continues for several years or more improves outcomes when compared with androgen suppression that is deferred until additional progression. However, studies that restrict their focus to a direct comparison of these two alternatives leave open the possibility that immediate androgen suppression without radiotherapy may be adequate treatment for locally advanced disease. Furthermore, the benefits of radiotherapy combined with adjuvant androgen suppression may be restricted to patients with higher grade tumors and/or more extensive extracapsular extension.

An additional comparison of immediate to deferred treatment applies to those who select androgen suppression alone or after surgery for locally advanced disease. Except for the minority who select surgical treatment, many of these patients may continue to have elevated PSA levels following the diagnosis of locally advanced disease. For them, possible triggers for beginning deferred therapy might be the development of symptoms, the appearance of nodal or distant metastases, or a higher threshold for PSA levels.

The third population of interest incluYQZFEIz7y diagnosed patients with metastases that are not causing pain or other symptoms. Treatment alternatives for these patients are hormonal therapy immediately upon diagnosis or deferred until symptoms appear. The percentage of patients initially diagnosed at this stage of disease is declining in the United States. This decline may be due to the widespread adoption of screening programs using PSA measurement and/or digital rectal examination. Nevertheless, there were several small nonrandomized studies in patients with stage D1 disease that was detected by pathologic examination after radical prostatectomy (for review, see Mazeman and Bertrand, 1996). Data from these studies suggested a survival benefit from immediate treatment and led to randomized controlled trials to compare the outcomes of immediate and deferred therapy (Medical Research Council Prostate Cancer Working Party Investigators Group, 1997).

A fourth population of interest includes patients with apparently localized disease but at risk for extra-prostatic extension of the tumor based on tumor volume and/or PSA levels. These patients may be considered for brief early treatment with androgen suppression, usually referred to as neoadjuvant therapy. The underlying hypothesis of this approach is that it may shrink the tumor within the confines of the prostatic capsule and thus increase the possibility of cure with definitive therapy. As described previously, studies have been reported on the use of neoadjuvant androgen suppression prior to prostatectomy (e.g., Schulman, 1994; Van Poppel, Ameye, Oyen et al., 1992; Voges, Mottrie, Stockle et al., 1994; for review see Wang and Fair, 1997) or radiotherapy (e.g., Pilepich, Krall, al-Sarraf et al., 1995; Radiation Therapy Oncology Group, 1994; for review, see Zietman, Prince, Nakfoor et al., 1997). However, these patients have not been diagnosed with advanced prostate cancer and thus are outside the scope of the present systematic review.

In patients with locally advanced disease or asymptomatic metastatic cancer, the rationale for immediate hormonal therapy includes the following (Crawford, Fourcade, Iversen et al., 1997):

• A smaller tumor volume may be more easily treated than a larger tumor volume.
• Complications of the tumor, such as pathologic fractures or ureteral obstruction, may be prevented.
• Local progression may be prevented, and the frequency of transurethral resection for relief of obstruction may be reduced.
• Subgroup analyses from some trials of combined androgen blockade suggest patients with minimal disease may derive more benefit than those with extensive disease.

On the other hand, there also are observations and concerns that tend to support deferred therapy. These include:

• Laboratory research suggests early use of androgen suppression may lead to more rapid development of hormone-resistant disease (for brief review, see Mazeman and Bertrand, 1996).
• The longer duration of androgen suppression therapy when patients are treated immediately may substantially reduce the quality of life because they suffer the adverse effects of treatment for longer periods.

The last concern has lead to the concept of intermittent androgen suppression, in which treatment is discontinued once PSA levels decline below a set threshold and then reinstituted if or when PSA levels rise once again (Goldenberg, Bruchovsky, Gleave et al., 1995; Klotz, Sogani, and Block, 1997). This approach allows patients some time free of therapy and may provide a better quality of life. A concern that has been raised, however, is that intermittent therapy may not delay progression or improve survival as effectively as continuous therapy. Randomized trials comparing intermittent androgen suppression with continuous treatment are under way, but no data are available as yet (Garnick, 1997; Klotz, Sogani, Block et al., 1997; Moul, 1998; Newling, 1997).

To compare the effectiveness of immediate versus deferred androgen suppression as primary treatment for advanced prostate cancer, this evidence report will address the following questions, each in a distinct patient population:

1.

Patients: Men who have previously undergone definitive therapy (radical prostatectomy or radiation therapy) for initially localized prostate cancer.
Question: Does initiation of androgen suppression immediately upon a rising PSA improve outcomes compared to initiation of androgen suppression that is deferred until signs or symptoms of clinical progression?

2.

Patients: Men who are newly diagnosed with locally advanced or asymptomatic metastatic prostate cancer and are undergoing primary therapy with androgen suppression.
Question: Does primary androgen suppression initiated immediately at diagnosis improve outcomes compared to androgen suppression deferred until signs or symptoms of clinical progression?

3.

Patients: Men who have locally advanced or asymptomatic metastatic prostate cancer and are undergoing radiation therapy.
Question: Does adjuvant androgen suppression initiated with radiotherapy, and continued for several years or more, improve outcomes compared to radiotherapy alone followed by androgen suppression initiated at signs or symptoms of clinical progression?

These distinct patient populations and treatment settings are considered separately because it is unknown whether findings from one population generalize to another population.