Interventions

Twenty-three of the 27 trials comparing monotherapy with combined androgen blockade were two-arm trials. One of these trials used a 2X2 factorial design but is classified here as a two-arm trial because results of the two monotherapy arms and the two combined androgen blockade arms were pooled after 48 weeks of followup (Schulze, Kaldenhoff, and Senge, 1988). The overwhelming majority of the two-arm studies compared orchiectomy, leuprolide, or goserelin with the same monotherapy plus either flutamide or nilutamide.

Four of the 27 trials were three-arm trials. Three of these trials compared combined androgen blockade using cyproterone as the antiandrogen to two different monotherapy arms (de Voogt, Klijn, Studer et al., 1990; Robinson, Smith, Richards et al., 1995; Thorpe, Azmatullah, Fellows et al., 1996). The fourth compared monotherapy to two combined androgen blockade arms, each with a different dose of nilutamide (Brisset, Boccon-Gibod, Botto et al., 1987).

The 28th trial (n=813) compared four regimens for combined androgen blockade: goserelin with flutamide, goserelin with bicalutamide, leuprolide with flutamide, and leuprolide with bicalutamide (Schellhammer, Sharifi, Block et al., 1997). Nearly all reports from this trial pooled data from each of two arms to compare flutamide with bicalutamide for combined androgen blockade. However, a recent report from this study included separate analyses of outcomes for each of the four arms (Sarosdy, Schellhammer, Sharifi et al., 1998a).

Among the 27 trials comparing combined androgen blockade with monotherapy, the monotherapy was orchiectomy in 14 studies (n=4,156), an LHRH agonist in 12 studies (n=3,733), and orchiectomy or an LHRH agonist in 1 study (Schulze, Kaldenhoff, and Senge, 1988). Only 2 (n=588) of the 14 trials that used orchiectomy as monotherapy combined an LHRH agonist with an antiandrogen in the other arm (Denis, Carnelro de Moura, Bono et al., 1993; Iversen, Christensen, Friis et al., 1990).

Drug treatments were continued until death, disease progression, or withdrawal due to adverse effects in all studies. The 12 trials that compared an LHRH agonist with and without an antiandrogen used the same dose of LHRH agonist in both arms. All used doses, dosage forms, and schedules of administration known to reduce serum testosterone to castrate levels within 2 to 3 weeks after initiation of treatment and to maintain this level while therapy continued. Thus, it is unlikely that variations in the results of individual trials might be attributable to differences in the treatment regimens used for LHRH agonists.

Only 4 of the 12 trials that used an LHRH agonist for monotherapy also used an initial brief treatment with an antiandrogen to control the tumor flare reaction (Bono, DiSilverio, Robustelli della Cuna et al., 1998; de Voogt, Klijn, Studer et al., 1990; Ferrari, Castagnetti, Ferrari et al., 1993, 1996). Thus, the other eight trials may be biased against the monotherapy arm because an antiandrogen was not used to control flare. The flare reaction does not occur when orchiectomy is used as monotherapy. Therefore the 14 trials in which the control arm was orchiectomy alone may provide a better comparison of combined androgen blockade with monotherapy.

All trials with flutamide as the antiandrogen used the same dose (250 mg 3 times per day). All but one of the trials with nilutamide as the antiandrogen used a dose of 300 mg/d. The single exception (Dijkman,Janknegt, De Reijke et al.,1997) and one of three arms in a second trial (Brisset, Boccon-Gibod, Botto et al., 1987) used 150 mg/d. The trials using cyproterone as the antiandrogen varied in dosage, ranging from 100 to 300 mg/d.

Patient Populations

The overwhelming majority of patients in trials of combined androgen blockade had metastatic disease, largely stage D2. Reports from 18 of the 28 trials specified that histologic confirmation of the diagnosis was required. All trials were restricted to patients undergoing primary hormonal therapy. The mean or median age of these patients was between 65 and 75 years. On the whole, these studies were well balanced with regard to stage and, where reported, on the distribution of other prognostic factors.

A substantial number of studies reported the distribution of prognostic factors other than stage, such as tumor grade or presence of symptoms from metastases. However, only four trials provided data that compared treatment arms for one or more primary outcomes after stratifying by prognostic group (Crawford, Eisenberger, McLeod et al., 1989; Denis, Carnelro de Moura, Bono et al., 1993; Eisenberger, Blumenstein, Crawford et al., 1998; Iversen, Christensen, Friis et al., 1990). Two others stated that they completed comparative analyses on subgroups, but did not publish the relevant data (de Voogt, Klijn, Studer et al., 1990; Robinson, Smith, Richards et al., 1995). The lack of reporting of results stratified by prognostic groups is a notable deficiency of this body of evidence.

Enrollment was limited to patients with metastatic disease in 20 trials. Of these, 12 trials enrolled only those with metastases to the bone, soft tissue, or extrapelvic lymph nodes (stages D2 or M1). In the eight trials that also enrolled patients with metastases limited to the pelvic lymph nodes (stages N1 to N3/M0 or D1), the percentage of those not staged as M1/D2 ranged from 3 percent (Namer, Toubol, Caty et al., 1990) to 30 percent (Ferrari, Castagnetti, Ferrari et al., 1996). However, the arms within each of these trials were well balanced for stage of disease.

Of the remaining trials, seven included patients with no evidence of metastases (stages C or T3-T4/N0/M0). The percentage of patients without metastases ranged from 7 percent (Iversen, Christensen, Friis et al., 1990) to 45 percent (Boccardo, Pace, Rubagotti et al., 1993), but the arms within each of these trials also were well balanced for disease stage. The final trial (Schulze, Kaldenhoff, and Senge, 1988) did not provide information on the stage distribution of the randomized patients.

Fourteen trials compared treatment groups for the degree of differentiation of the primary tumor (i.e., tumor grade). Of these, only one (Dijkman, Janknegt, De Reijke et al., 1997) did not include any patients with well--differentiated tumors. Among the others, the percentage of patients in each arm with poorly differentiated, high-grade tumors ranged from less than 20 percent in three trials (Di Silverio, Serio, D'Eramo et al., 1990; Thorpe, Azmatullah, Fellows et al., 1996; Tyrrell, Altwein, Klippel et al., 1991) to 50 percent to 60 percent in three others (Iverson, Christensen, Friis et al., 1990; Namer, Toubol, Caty et al., 1990; Williams, Asopa, Abel et al., 1990). The treatment arms were imbalanced with respect to the percentage of patients with poorly differentiated tumors in only three studies. The imbalance favored combined androgen blockade (53 percent versus 34 percent) in one trial (Namer, Toubol, Caty et al., 1990), whereas it favored the control arm (50 percent versus 63 percent in each study) in the others (Iversen, Christensen, Friis et al., 1990; Williams, Asopa, Abel et al., 1990).

Twenty trials compared treatment groups for the percentage of patients who were symptomatic at study entry. For this report, symptomatic was defined as the presence of pain from skeletal metastases. The proportion of symptomatic patients ranged from less than 30 percent (Denis, Carnelro de Moura, Bono et al., 1993) to almost 80 percent (Crawford, Eisenberger, McLeod et al., 1989). The treatment arms were imbalanced with respect to bone pain at study entry in two studies. The imbalance favored the control arm (42 percent versus 61 percent) in one trial (Brisset, Boccon-Gibod, Botto et al., 1987) and favored the combined androgen blockade arm (64 percent versus 42 percent) in the other (Knonagel, Bolle, Hering et al., 1989).

Twenty-five studies compared treatment arms for the distribution by age; they were uniformly well balanced. Twenty trials compared treatment arms for the number of patients with impaired performance status. In three trials, more patients were impaired in the combined androgen blockade arms (Brisset, Boccon-Gibod, Botto et al., 1987; Fourcade, Cariou, Coloby et al., 1990; Knonagel, Bolle, Hering et al., 1989). Eight studies limited enrollment to those who were newly diagnosed, and five also accepted previously treated patients. Of the five, only two compared arms with respect to the duration of disease, and both were well balanced (Dijkman, Janknegt, De Reijke et al., 1997; Zalcberg, Raghaven, Marshall et al., 1996). Published reports from the remaining 15 trials were silent with respect to this characteristic.

Only six studies compared arms with respect to racial/ethnic distributions and all were well balanced (Crawford, Eisenberger, McLeod et al., 1989; Crawford, Kasimis, Gandara et al., 1990; Dijkman, Janknegt, De Reijke et al., 1997; Eisenberger, Blumenstein, Crawford et al., 1998; Schellhamer, Sharifi, Block et al.,1997; Tyrrell, Altwein, Klippel et al., 1991). Only two studies reported PSA levels at entry (Bono, DiSilverio, Robustelli della Cuna et al., 1998; Dijkman, Janknegt, De Reijke et al., 1997); both were well balanced. No other imbalances between study arms that might have confounded the results were reported.

Outcomes

Efficacy outcomes summarized in the Results section include overall survival, cancer-specific survival, progression-free survival and/or time to progression, and time to treatment failure. Nearly all the trials provided some data on the adverse effects of treatment. However, the specific adverse outcomes that were reported varied markedly among the trials.

Overall survival after monotherapy was compared with survival after combined androgen blockade in 21 studies. The 21 trials included 23 separate comparisons of a monotherapy with a combination regimen and a total of 6,871 patients. An additional trial that compared combined androgen blockade regimens without a monotherapy control group also reported overall survival (Schellhammer, Sharifi, Block et al., 1997).

Overall survival was obtained at the following intervals: 1 year (19 trials), 2 years (20 trials), and 5 years (10 trials). The published Kaplan-Meier curves were used to estimate nearly all of these data. Median overall survival was obtained from 18 trials. These data were provided explicitly in 12 studies and were estimated from the published Kaplan-Meier curves in 6.

Cancer-specific survival was reported in five trials. Time to treatment failure was reported in six trials. Some measure of disease progression was reported in 21 trials. Five trials reported progression-free survival, 1 trial reported the crude progression-free rate without an actuarial analysis, and 15 trials reported time to disease progression. Increase in the serum level of PSA was rarely used as evidence of disease progression.

Nearly all the trials provided some data on the adverse effects of treatment. However, the specific adverse outcomes that were reported varied markedly among the trials. In addition, one randomized trial, a feasibility study of a second trial, and a cross-sectional survey reported on quality of life.

Quality of Study

All studies were randomized controlled trials. Overall study quality was assessed as described in the Methodology section of this report. The meta-analysis comparing overall survival for combined androgen blockade with monotherapy included a sensitivity analysis restricted to studies of higher quality. Studies that blinded patients and investigators to group assignment and that used an intent-to-treat analysis of outcomes were classified as higher quality studies for purposes of sensitivity analysis. Blinding was considered to be not applicable for studies of combined androgen blockade when any arm received orchiectomy. Evidence Table II.1 (see Appendix II) shows whether patients and investigators were blinded to group assignment, and Evidence Table II.3 shows whether withdrawals were documented and whether intent-to-treat analysis was used. Of the 28 trials of combined androgen blockade, 11 were considered higher quality for purposes of sensitivity analysis.

Efficacy Outcomes

Overall Survival

Data on survival were reported by 15 trials, including 5,636 patients, that used nonsteroidal antiandrogens for combined androgen blockade and from 6 trials, including 1,235 patients, that used cyproterone in the combination arms (total n=6,871). Overall, 18 of the 21 trials, including 5,485 patients, found no statistically significant difference in survival between monotherapy and combined androgen blockade (Evidence Table II.2, Appendix II). This group includes the trial recently completed by the Southwest Oncology Group (Eisenberger, Blumenstein, Crawford et al., 1998), which compared orchiectomy plus placebo with orchiectomy plus flutamide and is the largest single trial comparing monotherapy with combined androgen blockade (n=1,382). Median survival was 29.9 months in the control arm and 33.5 months in the combination arm.

Only three trials, including 1,386 patients, reported a statistically significant difference in survival between the monotherapy and combined androgen blockade arms (Crawford, Eisenberger, McLeod et al., 1989; Denis, Carnelro de Moura, Bono et al., 1993; Dijkman, Janknegt, De Reijke et al., 1997). All three trials favored combined androgen blockade, and each utilized a nonsteroidal antiandrogen in the combination arms. There was no survival benefit from combined androgen blockade in any of the six trials that used cyproterone in the combination arm.

Table 11 summarizes pertinent findings from the three trials with significant differences between treatment arms. Dijkman, Janknegt, De Reijke, and coworkers (1997) compared orchiectomy plus placebo with orchiectomy plus nilutamide. Median survival was 3.7 months longer in the combination arm and overall survival was 9 percent greater at both 2 years and 5 years. Crawford, Eisenberger, McLeod, and coworkers (1989) compared leuprolide plus placebo with leuprolide plus flutamide. Median survival was 6 months longer in the combination arm and survival was 7 percent greater at 2 years and 3 percent greater at 5 years. Denis, Carnelro de Moura, Bono, and coworkers (1993) compared orchiectomy with goserelin plus flutamide. Median survival was 7 months longer in the combination arm and survival was 7 percent greater at 2 years and 8 percent greater at 5 years.

Table

Table 11. Survival Data from Studies With Significant Differences.

Of the 18 trials that did not reach statistical significance, 3 reported trends that favored combined androgen blockade. For this report, a trend is defined as Kaplan--Meier curves that differ with 0.05<p<0.20. The recent SWOG/ECOG trial (INT 0105; n=1,382) compared orchiectomy plus placebo to orchiectomy plus flutamide (Eisenberger, Blumenstein, Crawford et al., 1998). Median survival was 29.9 months versus 33.5 months and survival was 62 percent versus 63 percent at 2 years and 28 percent versus 32 percent at 5 years (p=0.14). Beland, Elhilali, Fradet, and coworkers (1990) compared orchiectomy plus placebo with orchiectomy plus nilutamide (n=194). Median survival was 18.9 months versus 24.3 months and survival at 2 years was 38 percent versus 49 percent (p=0.137). Tyrrell, Altwein, Klippel, and coworkers (1991) compared goserelin alone to goserelin plus flutamide (n=569). Median survival was 37.7 months versus 42.4 months and survival was 65 percent versus 72 percent at 2 years and 34 percent versus 42 percent at 5 years (p=0.14). Only one trial found a slight nonsignificant trend that favored monotherapy (Di Silverio, Serio, D'Eramo et al., 1990). This study (n=315) compared goserelin alone to goserelin plus cyproterone; median survival was 30.1 months versus 23.8 months and survival at 2 years was 63 percent versus 49 percent (p=0.26).

Combined Androgen Blockade Compared with Monotherapy in Prognostic Subpopulations

Only four trials compared treatment arms for one or more primary outcomes after stratifying by prognostic group. The first NCI Intergroup study (INT 0036) compared leuprolide alone to leuprolide plus flutamide and reported significantly longer overall survival in the combination arm. Patients in this trial were divided into good or poor prognostic groups based on the extent of disease (limited versus extensive) and ECOG performance status (0-2 versus 3) (Crawford, Eisenberger, McLeod et al., 1989; Eisenberger, Crawford, Wolf et al., 1994). There were large differences in median survival (42 months versus 61 months) and progression-free survival (19 months versus 48 months) that favored the arm given combined androgen blockade in the group with the best prognosis (n=82). Substantially smaller differences between arms were reported for the groups with a poorer prognosis (n=522). However, note that only a small percentage of patients (13.6 percent) met the criteria for the best prognostic group. Because of the small sample size, the investigators did not test these differences for statistical significance.

The second Intergroup study (INT 0105) stratified patients by minimal versus extensive disease and by good versus poor (>3, ECOG scale) performance status, with dynamically balanced randomization with respect to the stratification factors (Eisenberger, Blumenstein, Crawford et al., 1998). Furthermore, the investigators allowed an accrual overrun in order to increase the trial's statistical power in the minimal disease subgroup. Although less than 5 percent of patients in either arm had poor performance status, they reported separate actuarial analyses of overall and progression-free survival for the minimal and extensive disease subgroups of each study arm. There was no statistically significant difference in the median overall (52.1 months) or progression-free (48.1 months) survival for patients in the minimal-disease subgroup treated with orchiectomy plus flutamide when compared with those in the same subgroup treated with orchiectomy plus placebo (51.0 months and 46.2 months, respectively). Thus, this large, adequately powered trial did not confirm the hypothesis regarding a potentially enhanced benefit of combined androgen blockade in a subset of patients with minimal disease.

(Iversen, Christensen, Friis, and coworkers,1990) compared goserelin alone to goserelin plus flutamide and did not report a statistically significant benefit from combined androgen blockade for either overall or cancer-specific survival or for time to progression. These investigators also reported cancer-specific and progression-free survival separately in subgroups with minimal (n=73) and extensive (n=189) disease (Iversen, Rasmussen, Klarskov et al., 1993). There were no statistically significant differences between treatment arms for either outcome in either prognostic subgroup. Again, though, only 28 percent of the patients were in the subgroup with minimal disease.

The European Organization for Research and Treatment of Cancer (EORTC) trial 30853 also compared orchiectomy alone to goserelin plus flutamide and found significantly longer survival in the combination arm (Denis, Carnelro de Moura, Bono et al., 1993). The hazard ratio for death (orchiectomy to combination therapy) was 0.67 for those with WHO performance status 0 (n=108) and 0.79 for those with WHO performance status 2 (n=70). Similarly, the hazard ratios were 0.60 for those with fewer than 5 skeletal lesions on bone scan (n=74) versus 0.84 for those with more than 15 lesions (n=86). However, no confidence intervals were reported for these data, and there were few patients in each subgroup.

Two additional trials reported that they compared the effects of monotherapy and combined androgen blockade for good and poor prognostic groups based on formulas that combined factors shown to have independent prognostic value in proportional hazards analyses (de Voogt, Klijn, Studer et al., 1990; Robinson, Smith, Richards et al., 1995). Neither study included Kaplan-Meier curves for any of the efficacy outcomes that compared treatments for specific prognostic groups. However, both stated that there was no significant effect of combined androgen blockade in either the good or poor prognostic groups.

Comparisons of Different Regimens for Combined Androgen Blockade

The Casodex Combination Study (Schellhammer, Sharifi, Block et al., 1996a, 1996b, 1997) was the only trial that directly compared different regimens for combination therapy. This trial utilized a 2X2 factorial design, with leuprolide and goserelin as the LHRH agonists and flutamide and bicalutamide as the nonsteroidal antiandrogens. Patients in each of the four arms received one of the four possible combinations. Eleven of the 13 reports published by these investigators pooled data on outcomes for all patients given flutamide and for all patients given bicalutamide.

The median overall survival was longer in the group that received an LHRH agonist plus bicalutamide (41 months; n=404) than in the group that received an LHRH agonist plus flutamide (34 months; n=409). However, the hazard ratio for mortality did not achieve statistical significance (0.87; 95 percent CI 0.72 to 1.05; p=0.15). There also was no statistically significant difference between the groups in median times to progression (22 months versus 18 months; hazard ratio, 0.93; 95 percent CI 0.79 to 1.10; p=0.41). At a median followup of 49 weeks, the hazard ratio for time to treatment failure was significantly in favor of those given an LHRH agonist plus bicalutamide (42 percent versus 53 percent; hazard ratio 0.749; p=0.005). After additional followup to a median of 95 weeks, there was only a strong trend in favor of fewer treatment failures among those given an LHRH agonist plus bicalutamide (hazard ratio 0.87; 95 percent CI 0.74 to 1.03; p=0.10).

A recent abstract from this study reported data separately for each of the four study arms (Sarosdy, Schellhammer, Sharifi et al., 1998a). There were no statistically significant differences in survival between the goserelin plus bicalutamide (n=268) and goserelin plus flutamide (n=272) groups or between the leuprolide plus bicalutamide (n=136) and goserelin plus bicalutamide (n=268) groups. There was a significant difference in survival that favored the leuprolide plus bicalutamide group (n=136) over the leuprolide plus flutamide group (n=137) (survival at 4 years: 48 percent versus 32 percent; p=0.008). There also was a significant difference that favored the goserelin plus flutamide group (n=272) over the leuprolide plus flutamide group (n=137) (survival at 4 years: 40 percent versus 32 percent, p=0.047). Of the four combinations, survival was greatest for leuprolide plus bicalutamide and shortest for leuprolide plus flutamide. However, the p values reported were not corrected for multiple comparisons, and the investigators point out that the trial did not have adequate statistical power to support definitive comparisons between the four regimens they tested.

An additional set of exploratory analyses from the Casodex Combination trial (Sarosdy, Schellhammer, Sharifi et al., 1998a, 1998b) pooled data for all patients given goserelin plus a nonsteroidal antiandrogen (n=540) and compared these data to those pooled for all patients given leuprolide plus a nonsteroidal antiandrogen (n=273). The hazard ratio for time to progression was 0.99 (95 percent CI 0.84 to 1.18; p=0.92). The hazard ratio for overall survival was 0.91 (95 percent CI 0.75 to 1.11; p=0.34). Local adverse effects at the site of depot injection were infrequent and occurred no more frequently with one of the LHRH agonists than with the other.

Adverse Events

Using the decision rules described in the Methodology section of this report, the data were pooled across studies that used the same class of intervention. We report two types of evidence on adverse events: adverse events by category and adverse events leading to withdrawal from therapy. Because of the limitations in the evidence, estimates of specific events by category reported here should be viewed with caution. The evidence on adverse events leading to withdrawal from therapy is more reliable. The categories of adverse events of interest are: cardiovascular, endocrine, gastrointestinal, hepatic, and ophthalmologic. These data were pooled across studies that used the same class of intervention. Classes of intervention are: orchiectomy or LHRH agonist plus nonsteroidal antiandrogen and orchiectomy or LHRH agonist plus cyproterone. Not included in the tables, but discussed below, are data from the Casodex Combination trial that compared four regimens of combined androgen blockade and reported on local adverse effects from injection of depot dosage forms for LHRH agonists (Sarosdy, Schellhammer, Sharifi et al., 1998a, 1998b).

The second type of evidence was on adverse events leading to withdrawal from therapy for each of the specific antiandrogens used in combination with chemical or surgical castration. These data are summarized in Evidence Tables II.11-13 (Appendix II).

Quality of Life

A substudy of the recently completed SWOG/ECOG trial (INT 0105) is the only source of data from a randomized controlled trial that compares patients treated with a monotherapy to patients treated with combined androgen blockade with respect to formal measures for quality of life (Moinpour, Savage, Lovato et al., 1997; Moinpour, Savage, Troxel et al., 1998). Data were collected at randomization and at 1, 3, and 6 months after the start of treatment on three treatment-related symptoms (diarrhea, gas pain, and body image), on physical functioning, and on emotional functioning. Patients in this substudy who were treated with orchiectomy plus flutamide reported significantly more diarrhea at 3 months (p<0.001), and worse emotional functioning at 3 and 6 months (p<0.003), than did those given orchiectomy plus placebo. There also were nonsignificant trends toward more problems among those in the combination arm with the following: physical functioning, fatigue, abdominal gas, overall pain, and body image.

A cross-sectional survey used three separate instruments to measure quality of life in patients receiving an LHRH agonist plus flutamide (Albertsen, Aaronson, Muller et al., 1997). However, this study only compared patients who progressed while on combined androgen blockade to those who did not progress. No patients treated with a monotherapy were included. A feasibility study conducted by the EORTC (as part of protocol 30853) included an optional assessment of quality of life at entry and at each followup visit using a validated questionnaire (da Silva, 1993; da Silva and Aaronson, 1988). However, only 63 of the 327 patients randomized to either orchiectomy or goserelin plus flutamide completed the questionnaire at one or more clinic visits (da Silva, Fossa, Aaronson et al., 1996; da Silva, Reis, Costa et al., 1993). Consequently, it was not possible to compare the two treatment arms.

It is noteworthy, however, that the EORTC feasibility study demonstrated marked discrepancies between patients' self-assessments and treating physicians' evaluations of quality-of-life parameters. Other investigators have reported similar discrepancies (Litwin, Lubeck, Henning et al., 1998). Consequently, it is unlikely that a report of more frequent improvement and/or delayed deterioration in subjective parameters assessed by physicians after orchiectomy plus flutamide than after orchiectomy plus placebo (Dijkman, Fernandez del Moral, Debruyne et al., 1995) can be interpreted as evidence of improved quality of life. Also noteworthy is the marked discrepancy between the patients' perceptions collected by the SWOG investigators (Moinpour, Savage, Lovato et al., 1997; Moinpour, Savage, Troxel et al., 1998) and physicians' subjective evaluations reported by Dijkman, Fernandez del Moral, Debruyne et al. (1995) for the identical comparison of treatments.

A few other reports discussed quality of life in relation to the frequency of various disease symptoms and adverse effects of therapy but did not formally attempt to measure quality of life.

Summary

Twenty-seven randomized controlled trials, including 7,987 patients, compared the outcomes of monotherapy with the outcomes of combined androgen blockade. Twenty of these trials used a nonsteroidal antiandrogen in the combined androgen blockade arm; 12 trials used flutamide, 8 used nilutamide, and none used bicalutamide. In seven trials, combined androgen blockade was accomplished with the nonsteroidal antiandrogen agent cyproterone. The monotherapy arm was orchiectomy in 14 trials, an LHRH agonist in 12 trials, and either orchiectomy or an LHRH agonist in 1 trial. In addition, a 28th trial compared four regimens for combined androgen blockade.

Twenty-one trials compared survival after monotherapy to survival after combined androgen blockade (n=6,871). Of these, 20 trials reported overall survival at 2 years, and 10 of these trials also reported survival at 5 years. Twenty-one trials reported some measure related to disease progression: either progression-free survival (5 trials) or time to progression (16 trials). Only five studies reported cancer-specific survival and only six trials reported time to treatment failure.

Conclusions