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Aronson N, Seidenfeld J, Samson DJ, et al. Relative Effectiveness and Cost-Effectiveness of Methods of Androgen Suppression in the Treatment of Advanced Prostate Cancer. Rockville (MD): Agency for Health Care Policy and Research (US); 1999 May. (Evidence Reports/Technology Assessments, No. 4.)

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

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Relative Effectiveness and Cost-Effectiveness of Methods of Androgen Suppression in the Treatment of Advanced Prostate Cancer.

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3Results and Conclusions I: Comparison of Monotherapies

Key Questions

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 a luteinizing hormone-releasing hormone (LHRH) agonist compared to orchiectomy or diethylstilbestrol (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?

Overview of the Evidence

The literature search identified 24 controlled trials that randomized more than 6,600 patients to treatment with different monotherapies for advanced prostate cancer. It is noteworthy that more than 30 years elapsed between the start of the earliest trial (the Veterans Administration Cooperative Urology Research Group [VACURG] studies, begun in 1960) and the latest (Iversen, Tyrrell, Kaisary et al., 1998, begun in 1992). Over that period, new diagnostic techniques were developed, new staging and grading systems were implemented, and methods of monitoring patients for progression and/or relapse were improved.

Three trials directly compared administration of DES with orchiectomy (Peeling and members of the British Prostate Group, 1984; Robinson, Smith, Richards et al., 1995; Veterans Administration Cooperative Urology Research Group, 1967; Blackard, Byar, and Jordan,1973). As discussed in the Introduction section of this report, these trials were analyzed to establish that DES is equivalent to orchiectomy when used as a comparator in trials of LHRH agonists or antiandrogens and thus maximize the evidence basis for this assessment. Most of the 24 trials compared an LHRH agonist or an antiandrogen with either surgical orchiectomy or DES. All studies of LHRH agonists or antiandrogens that used DES in the control arm used a dose of 3 mg/d. A few trials compared an antiandrogen with either an LHRH agonist ( Moffat, 1990; Thorpe, Azmatullah, Fellows et al., 1996) or the patients' choice of surgical or medical castration (Chodak, Sharifi, Kasimis et al., 1995; Iversen and the International Casodex Investigators, 1994; Iversen, Tyrrell, Kaisary et al., 1998; Kaisary, Tyrrell, Beacock et al., 1995). No studies of monotherapy directly compared one of the LHRH agonists with another drug of the same class. The data abstracted from all 24 trials are summarized in Evidence Tables I.1, I.2, I.3,I.4 (Appendix I). A coding key in Appendix I summarizes the coding scheme used to classify the comparisons of interventions that were investigated in the trials abstracted.

Interventions

Ten randomized trials, including 1,908 patients, compared an LHRH agonist with either orchiectomy (comparison codes 2.1, 2.2, 2.3), DES (comparison codes 3.1, 3.2, 3.3), or the choice of orchiectomy or DES (comparison codes 4.1, 4.2, 4.3). There was some minor variability among trials in the doses, schedules of administration, and dosage forms of the LHRH agonists used (daily injection versus depot preparations given monthly, every 3 months, or every 4 months). Nevertheless, in all instances, previous clinical studies that compared doses or dosage forms showed that all the regimens utilized in the 10 trials reliably reduced serum testosterone concentrations to castrate levels by 1 to 3 weeks after treatment was initiated and maintained those levels while treatment continued. Thus, it is unlikely that any differences in dose, schedule, or dosage form might have biased the results of any trial or affected the comparability of results among trials.

Of the 10 trials of LHRH agonists, only 1 investigated leuprolide; this trial compared leuprolide to DES (comparison code 3.1) in 199 randomized patients (The Leuprolide Study Group, 1984). Five studies investigated goserelin: two trials compared goserelin with orchiectomy (comparison code 2.2) in a total of 608 randomized patients (Kaisary, Tyrrell, Peeling et al., 1991; Vogelzang, Chodak, Soloway et al., 1995) and three trials compared goserelin with DES (comparison code 3.2) in a total of 580 patients (Citrin, Resnick, Guinan et al., 1991; Moffat, 1990; Waymont, Lynch, Dunn et al., 1992 ). Four studies investigated buserelin: three trials compared buserelin with orchiectomy (comparison code 2.3) in a combined total of 354 patients (Bruun and Frimodt-Moller for the Danish Buserelin Study Group, 1996; de Voogt, Klijn, Studer et al., 1990; Koutsilieris and Tolis, 1985), and one trial compared buserelin with the choice of orchiectomy or DES (comparison code 4.3) in 167 patients (Huben and Murphy, 1988). All six trials with DES in the control arm used the same dose: 3 mg/d.

A total of 13 randomized trials were identified that included 3,840 patients and compared an antiandrogen with either orchiectomy (comparison codes 5.1 through 5.4), DES (comparison codes 6.1 through 6.4), an LHRH agonist (comparison code 8.1), or the choice of orchiectomy or an LHRH agonist (comparison codes 7.1 through 7.4). Of these, three trials studied the nonsteroidal antiandrogen flutamide: one trial compared flutamide with orchiectomy (comparison code 5.1) in 104 patients (Boccon-Gibod, Fournier, Bottet et al., 1997), and two trials compared flutamide with DES (comparison code 6.1) in a total of 132 patients (Chang, Yeap, Davis et al., 1996; Lund and Rasmussen, 1988). All three trials used the same dose of flutamide, 250 mg three times daily, and both trials with DES in the control arm utilized 3 mg/d.

Five trials investigated the nonsteroidal antiandrogen bicalutamide: one study compared it directly with orchiectomy (comparison code 5.3) in 376 patients (Iversen, Tveter, and Varenhorst, 1996), and four trials compared it with the patient's choice of orchiectomy or an LHRH agonist (comparison code 7.3) in a total of 2,105 patients (Chodak, Sharifi, Kasimis et al., 1995; Iversen and the International Casodex Investigators, 1994; Iversen, Tyrrell, Kaisary et al., 1998; Kaisary, Tyrell, Beacock et al., 1995). Of these five trials, three utilized 50 mg/d of bicalutamide (Chodak, Sharifi, Kasimis et al., 1995; Iversen, Tveter, and Varenhorst, 1996; Kaisary, Tyrell, Beacock et al., 1995) and two utilized 150 mg/d (Iversen and the International Casodex Investigators, 1994; Iversen, Tyrrell, Kaisary et al., 1998). This difference may make it difficult to compare results reported from these trials. No randomized trials investigated the nonsteroidal antiandrogen nilutamide as a monotherapy for advanced prostate cancer.

Five trials investigated the steroidal antiandrogen cyproterone: two studies compared cyproterone with orchiectomy (comparison code 5.4) in 175 randomized patients (Ostri, Bonnesen, Nilsson et al., 1991; Peeling and members of the British Prostate Group, 1984); three studies compared cyproterone with DES (comparison code 6.4) in 432 randomized patients (Moffat, 1990; Pavone-Macaluso, de Voogt, Viggiano et al., 1986; Peeling, 1984); and two studies compared cyproterone with goserelin (comparison code 8.1) in 689 randomized patients (Moffat, 1990; Thorpe, Azmatullah, Fellows et al., 1996). Note that two of these five studies (Moffat, 1990; Peeling, 1984) were three-arm trials and thus each provided data for two of the three comparisons of cyproterone. The dosage of cyproterone varied in these trials, with one utilizing 100 mg/d (Ostri, Bonnesen, Nilsson et al., 1991), one using 250 mg/d (Pavone-Macaluso, de Voogt, Viggiano et al., 1986), and the other three using 300 mg/d (Moffat, 1990; Peeling, 1984; Thorpe, Azmatullah, Fellows et al., 1996). All three trials with DES utilized a dose of 3 mg/d. Nevertheless, the differences in the doses of cyproterone may make it difficult to compare the results reported from these trials.

Three trials directly compared orchiectomy with DES (comparison code 1.0) in a total of 1,302 randomized patients. Of these, the VACURG trial (Blackard, Byar, and Jordan, 1973; Veterans Administration Cooperative Urology Research Group, 1967) utilized a dose of 5 mg/d of DES, whereas two studies (Peeling, 1984; Robinson, Smith, Richards et al., 1995) utilized a dose of 1 mg/d of DES.

Note that the studies with more than two monotherapy arms (Moffat, 1990; Peeling, 1984) are counted more than once in the above listing of trials. Note also that the VACURG trial comparing orchiectomy with DES reported most (but not all) outcomes separately for patients diagnosed in stage III or stage IV. To accommodate the outcomes reported from the VACURG trial, the Evidence Tables (see Appendix I) include three separate listings for the VACURG trial: one for stage III patients (Veterans Administration Cooperative Urology Research Group, 1967), one for stage IV patients (Blackard, Byar, and Jordan, 1973), and one for the combined group (Jordan, Blackard, and Byar, 1977).

Patient Populations

The populations of the trials that compared monotherapies overwhelmingly consisted of patients with metastatic disease, largely staged as either D2 or M1. Only 13 of the 24 trials required histologic confirmation of the diagnosis; an additional 4 accepted cytology for confirmation; and the remainder did not specify a requirement or a method for confirmation. All the trials were restricted to patients who had not undergone previous hormonal therapy for prostate cancer. The mean or median ages of the patients enrolled in these trials ranged from 65 to 75 years.

Seventeen of the 24 trials limited enrollment to patients with metastatic disease. Of these, 16 included only patients with metastases to bone, soft tissue, or extrapelvic lymph nodes (stages D2/M1). One trial also included patients with metastases only to regional lymph nodes but did not provide the distribution of patients by stage within the treatment arms (Peeling, 1984).

Five trials included patients with either locally advanced (stage C/M0) or metastatic disease (Koutsilieris and Tolis, 1985; Lund and Rasmussen, 1988; Moffat, 1990; Pavone-Macaluso, de Voogt, Viggiano et al., 1986; Waymont, Lynch, Dunn et al., 1992). In these five trials, the percentage of patients with locally advanced disease ranged from 15 to 48 percent but was generally balanced across the two treatment arms. The VACURG trial also included patients with either locally advanced (stage III) or metastatic disease but reported nearly all outcomes separately by stage. Finally, one study included only patients with stage C/M0 disease (Iversen, Tyrrell, Kaisary et al., 1998).

Within the individual trials, patient and tumor characteristics at study entry were generally well balanced between arms. The following were among the prognostic factors evaluated: age (19 studies), tumor grade (12 studies), presence or absence of bone pain (14 studies), and performance status (13 studies). In one small study (n=40), there were slightly more patients with poorly differentiated tumors in the arm treated with DES (45 percent) than in the arm treated with flutamide (35 percent) (Lund and Rasmussen, 1988). In another small study (n=29), 43 percent of those treated with buserelin and 100 percent of those treated with orchiectomy had bone pain from metastatic disease at study entry (Koutsilieris and Tolis, 1985). The distribution of patients with bone pain at study entry was imbalanced to a lesser degree in a second study (n=92) of flutamide (56 percent) versus DES (43 percent) (Chang, Yeap, Davis et al., 1996). No other imbalances between study arms that might have confounded the results were reported for these prognostic factors.

Only three studies each reported the distribution of patients within arms with respect to the duration of disease (Chang, Yeap, Davis et al., 1996; The Leuprolide Study Group, 1984; Waymont, Lynch, Dunn et al., 1992), PSA levels at study entry (Boccon-Gibod, Fournier, Bottet et al., 1997; Chodak, Sharifi, Kasimis et al., 1995; Iversen, Tyrrell, Kaisary et al., 1998), or race/ethnic group (Citrin, Resnick, Guinan et al., 1991; Iversen, Tyrrell, Kaisary et al., 1998; Vogelzang, Chodak, Soloway et al., 1995). In one of these studies, there was a significant imbalance (p=0.04) with respect to the percentage of African-American patients in the arm treated with goserelin (36 percent) compared with the arm treated with orchiectomy (24 percent) (Vogelzang, Chodak, Soloway et al., 1995). No other imbalances between study arms were reported.

Only three trials reported one or more of the primary outcomes separately by stage of disease (Iversen and the International Casodex Investigators, 1994; Iversen, Tyrrell, Kaisary et al., 1998; Pavone-Macaluso, de Voogt, Viggiano et al., 1986; Veterans Administration Cooperative Urology Research Group, 1967/ Blackard, Byar, and Jordan, 1973). None of these trials reported actuarial analyses that compared treatment arms with respect to any primary outcomes for subgroups defined by prognostic factors other than stage of disease.

Outcomes

Nearly all (21 of 24) of the studies comparing monotherapies that met the inclusion criteria for this report provided some data on the overall survival of randomized patients. However, the duration of followup was limited, and only six studies reported on survival at 5 years after treatment. Fifteen trials reported outcomes related to disease progression. Four of these studies reported either the actuarial or crude rate of progression-free survival, and the remaining 11 reported time to progression. Only one trial (the VACURG study) reported cancer-specific survival. Eleven trials provided data on 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 substantially among the trials. Two randomized controlled trials and an additional nonrandomized study reported on quality of life.

Quality of Study Design and Conduct

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 the monotherapies 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 overall survival and/or progression-related outcomes were classified as higher quality studies for purposes of sensitivity analysis. Blinding was considered to be not applicable when the treatment was orchiectomy in one of the study arms. Evidence Table I.1 in Appendix I shows whether patients and investigators were blinded to group assignment, whether withdrawals were documented, and whether intent-to-treat analysis was used. Of the 24 trials, 13 were considered higher quality for the purpose of sensitivity analysis.

Results

Efficacy Outcomes

Overall Survival

Evidence Table I.2 in the Appendix summarizes data on overall survival from 21 trials that reported this outcome. For each treatment arm, the tabulated data include the number of patients at risk at the start of the trial, the median overall survival, and actuarial estimates of the percentage of patients alive at 1, 2, and 5 years after study entry. Three trials (Koutsilieris and Tolis, 1985; Lund and Rasmussen, 1988; Ostri, Bonnesen, Nilsson et al., 1991) only reported the crude actual survival and did not provide an actuarial analysis. A fourth trial (Boccon-Gibod, Fournier, Bottet et al., 1997) reported that an actuarial analysis was done and showed no statistically significant difference between the 2 treatment arms. However, the published report did not include the Kaplan-Meier survival curves or other survival data.

For the remaining trials, the final columns of Evidence Table I.2 summarize (when available) the percentage of patients dead in each arm at the time of last published followup (reported by only 12 trials), and the results of statistical analyses. The trials varied considerably with respect to their maturity. Approximately 20 percent or fewer of the patients had reached the trial's main endpoint at the time results were reported from three studies (Chang, Yeap, Davis et al., 1996; Huben and Murphy, 1988; Iversen, Tveter, and Varenhorst, 1996). In two trials, 80 percent to 90 percent of patients had reached the endpoint (de Voogt, Klijn, Studer et al., 1990; Robinson, Smith, Richards et al., 1995). For most of the seven remaining studies for which maturity at the time of reporting could be assessed, from 40 percent to 60 percent of the patients had died.

Data on median survival were available for 15 of the 22 comparisons listed in Evidence Table I.2. Survival ranged from a low of 9 months for 18 patients treated with DES (Ostri, Bonnesen, Nilsson et al., 1991; comparison 5.4) to a high of 67 months for 266 patients treated with orchiectomy (Veterans Administration Cooperative Urology Research Group, 1967; comparison 1.0). Differences between studies are most likely attributable to differences in the patient populations they randomized (e.g., stage III in Veterans Administration Cooperative Urology Research Group, 1967, and M1/D2 patients in Ostri, Bonnesen, Nilsson et al., 1991). Nevertheless, the majority of trials reported median survivals between 20 and 40 months.

Data on the percentage of patients alive at 2 years after randomization was available for 20 of the comparisons. The range for this outcome was 15 percent for 257 patients given a choice of orchiectomy or goserelin (Chodak, Sharifi, Kasimis et al., 1995; comparison 7.3) to 88 percent for 320 patients given bicalutamide (Iversen, Tyrrell, Kaisary et al.,1998; comparison 7.3). This range again appears to reflect differences in the patient populations randomized. In the majority of studies, from just under 50 percent to approximately 75 percent of patients were alive at 2 years.

Data on the percentage of patients alive at 5 years after randomization were available from only six trials. The range for this outcome was 12 percent for 118 patients treated with orchiectomy (de Voogt, Klijn, Studer et al., 1990; comparison 2.3) to 53 percent for 266 patients treated with orchiectomy (Veterans Administration Cooperative Urology Research Group, 1967; comparison 1.0). Two additional trials reported data on survival at 4 years after randomization with a range of 31 percent to 67 percent (Iversen, Tyrrell, Kaisary et al., 1998; Waymont, Lynch, Dunn et al., 1992). Once again, for survival at 4 or 5 years, the differences in range appear to reflect differences in the patient populations randomized.

DES versus orchiectomy

Neither of the two trials that compared survival after orchiectomy with survival after DES (comparison 1.0) found a statistically significant difference in either median survival or the percentage of patients alive at either 2 years or 5 years (Robinson, Smith, Richards et al., 1995; Veterans Administration Cooperative Urology Research Group, 1967; Blackard, Byar, and Jordan, 1973). There also was no difference between treatment arms at 10 years after randomization in the VACURG trial, the only study with this duration of followup.

LHRH agonists versus orchiectomy or DES

None of the nine trials that reported data comparing survival after an LHRH agonist either to survival after orchiectomy (comparisons 2.2 and 2.3) or to survival after DES (comparisons 3.1, 3.2, and 4.3) found a statistically significant difference between the two study arms.

Antiandrogen therapy versus orchiectomy or DES or LHRH agonists

Eight studies compared nonsteroidal antiandrogens as single agents with either orchiectomy (comparisons 5.1 and 5.3), DES (comparison 6.1), or the choice of orchiectomy or an LHRH agonist (comparison 7.3). Four of these eight trials used orchiectomy or DES in the control arms, two of which reported statistically significant improvements in survival that favored the control arms. These ranged from 8 months (p=0.0007; Iversen, Tveter, and Varenhorst, 1996) to 14.7 months (p=0.009; Chang, Yeap, Davis et al., 1996) longer in median survival and an additional 14 to 15 percent of patients surviving at 2 years in the control arms. One trial used flutamide as the nonsteroidal antiandrogen (Chang, Yeap, Davis et al., 1996), and the other study used bicalutamide (Iversen, Tveter, and Varenhorst, 1996). The remaining two trials, both of which used flutamide as the nonsteroidal antiandrogen, reported no significant difference in survival between treatment arms (Boccon-Gibod, Fournier, Bottet et al., 1997; Lund and Rasmussen, 1988).

The remaining four trials compared bicalutamide monotherapy to the choice of orchiectomy or an LHRH agonist (comparison 7.3). Three of the four found no significant difference in survival between the two study arms (Chodak, Sharifi, Kasimis et al., 1995; Iversen, Tyrrell, Kaisary et al., 1998; Kaisary, Tyrell, Beacock et al., 1995). The fourth (Iversen and the International Casodex Investigators, 1994) found a small but statistically significant difference in favor of the control arm (p=0.02).

Trials that compared cyproterone with either orchiectomy (comparison 5.4) or DES (comparison 6.4) found no significant difference in survival between the two study arms.

Cancer-Specific Survival

Among all 24 trials that compared monotherapies, only one report from the VACURG study comparing orchiectomy with DES (Jordan, Blackard, and Byar, 1977) provided data on this outcome. Consequently, Appendix I does not include a table on cancer-specific survival.

Progression-Free Survival and/or Time to Progression

Evidence Table I.3 summarizes the available data on outcomes related to progression; only 15 of the 24 trials comparing monotherapies reported one of these outcomes. Most of the trials used the National Prostate Cancer Project's criteria for progression, which specify an increase in tumor volume by 25 percent or more. However, some trials required an increase by 50 percent in either the size of lesions or the prostate volume to meet their definition of progression.

Of the 15 trials, only two reported actuarial analyses of progression-free survival (Huben and Murphy, 1988; Robinson, Smith, Richards et al., 1995). Two others reported the crude progression-free rate without an actuarial analysis (Bruun and Frimodt-Moller, 1996; Lund and Rasmussen, 1988). The remaining 11 trials reported time to disease progression. However, five of the 11 trials that reported time to progression included death among the indicators of progression when prostate cancer could not be ruled out as the cause of death, whereas the other six trials did not. Because of these marked differences in the definition of progression, these must be treated as different outcome measures that are not readily comparable. Consequently, the number of trials reporting any one outcome related to progression is insufficient to justify a combined analysis. It is also noteworthy that almost none of the 15 trials that reported outcomes related to progression included an increase in the serum level of PSA in their definition of progression.

With few exceptions, the median time to progression or progression-free survival generally varied from approximately 12 to 24 months. From just under 30 percent to approximately 55 percent remained free from progression at 2 years after enrollment in the majority of studies reporting these outcomes.

LHRH agonists versus orchiectomy or DES

As was true for overall survival, no significant differences in progression-related outcomes were found between the treatment arms in four of the five trials that compared orchiectomy or DES with any of the LHRH agonists. The National Prostate Cancer Project Protocol 1700/1700B (Huben and Murphy, 1988), which compared buserelin with the choice of orchiectomy or DES and found a significant benefit in favor of the control arm (p<0.05), was the only exception.

Antiandrogen therapy versus orchiectomy or DES or LHRH agonists

Trials that compared an antiandrogen with either DES or orchiectomy generally found either no difference between the treatment arms or a modest benefit in favor of the control arm (i.e., in favor of orchiectomy or DES).

Particularly noteworthy are the conflicting outcomes of the two identical trials comparing bicalutamide with surgical or chemical castration reported very recently by (Iversen, Tyrrell, Kaisary et al.,1998,). Although study 0306 found a statistically significant benefit in favor of bicalutamide, study 0307 found a benefit in the opposite direction. Based on these conflicting results, the investigators declined to carry out the planned combined analysis for these two trials. It should be added that the two other trials on bicalutamide (Chodak, Sharifi, Kasimis et al., 1995; Kaisary, Tyrell, Beacock et al., 1995) used a dose of 50 mg/d, and the more recent study (Iversen, Tyrrell, Kaisary et al., 1998) used 150 mg/d. This may explain the observation that bicalutamide was less effective than chemical or surgical castration in both of the older studies.

Time to Treatment Failure

Eleven trials (46 percent) reported data on time to treatment failure; these are summarized in Evidence Table I.4. The definitions of treatment failure for the trials included in this table are roughly comparable, in that death from any cause, withdrawal due to adverse reactions or patient decision, and disease progression were considered treatment failures for all of the trials. There were a few slight differences, however, in the criteria for disease progression. Although most of the trials used the National Prostate Cancer Project's criteria for progression, which specify an increase in tumor volume by 25 percent or more, there were some that required an increase by 50 percent in either the size of lesions or the prostate volume.

Median time to treatment failure ranged from a low of 6 months (Kaisary, Tyrrell, Peeling et al., 1991; comparison 2.2) to a high of 26 months (Chang, Yeap, Davis et al., 1996; comparison 6.1). From 24 percent (Waymont, Lynch, Dunn et al., 1992; comparison 3.2) to 55 percent (Chang, Yeap, Davis et al., 1996; comparison 6.1) of the randomized patients remained free from treatment failure at 2 years after enrollment.

LHRH agonists versus orchiectomy or DES

There were no significant differences in the time to treatment failure between treatment arms in trials that compared orchiectomy or DES with LHRH agonists. One trial that compared DES with goserelin (Waymont, Lynch, Dunn et al., 1992) found a trend that almost achieved statistical significance in favor of goserelin (24 percent versus 35 percent survival at 2 years; p=0.06).

Antiandrogen therapy versus orchiectomy or DES or LHRH agonists

Most trials that compared DES or orchiectomy with an antiandrogen found either a benefit in favor of the control arm or no significant difference. Recently, conflicting trends were reported from two identical trials that compared bicalutamide with a choice of orchiectomy or buserelin in patients with stage M0 disease (Iversen, Tyrrell, Kaisary et al., 1998). There was a trend toward increased time to treatment failure in the bicalutamide arm of study 0306 (n=128; hazard ratio 0.66; 95 percent CI 0.42 to 1.04). In contrast, there was a trend toward decreased time to treatment failure in the bicalutamide arm of study 0307 (n=352; hazard ratio 1.24; 95 percent CI 0.96 to 1.61).

Adverse Events

Using the decision rules described in the Methodology section, the data were pooled across studies that used the same class of intervention. Classes of intervention were orchiectomy, DES, cyproterone, LHRH agonists, and nonsteroidal antiandrogens. Since DES is no longer widely used for treatment, adverse events associated with DES are not discussed in this review of evidence. Trials using DES were included in this evidence report to provide a common comparator of efficacy, in addition to orchiectomy, for other monotherapies. As described in the Methodology section, we report two types of evidence on adverse events: adverse events by category and adverse events leading to withdrawal from therapy.

The categories of adverse events of interest are: cardiovascular, endocrine, gastrointestinal, hepatic, and ophthalmologic. However, there were insufficient reports of adverse events within the hepatic and ophthalmologic categories. These data were pooled across studies that used the same class of intervention. Classes of intervention are: orchiectomy, LHRH agonists, nonsteroidal antiandrogens, and cyproterone.

Due to 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. Within the intervention classes of LHRH agonists and nonsteroidal antiandrogens, adverse events leading to withdrawal from therapy are reported by specific agent. These data are summarized in Evidence Tables I.8; I.9; I.10 in Appendix I.

The only study that directly compared two LHRH agonists was a trial comparing different combination regimens without a monotherapy control arm (Schellhammer, Sharifi, Block et al., 1997). Therefore, this study is included in Part II: Combined Androgen Blockade rather than in this section. However, it should be noted that a recent abstract from this trial (Sarosdy, Schellhammer, Sharifi et al., 1998b) provides the only data that compare depot preparations of leuprolide and goserelin for local adverse effects at the injection site. Local pain, reactions, hypersensitivity, or development of a mass at the site of depot injection occurred very infrequently. Furthermore, there were no differences in frequency between patients given leuprolide and those given goserelin.

Adverse Events by Category

Where results collected from package inserts differ noticeably from the evidence from trials meeting this report's eligibility criteria, they are noted below.

Cardiovascular

Evidence Table I.5 (Appendix I) shows that the rate of nonspecified cardiovascular events for all classes of interventions is below 5 percent. The rates of peripheral edema are more variable; LHRH agonists had a rate of 18.4 percent, followed by orchiectomy (12.9 percent) and nonsteroidal antiandrogens (8.6 percent). Embolic events, phlebitis, or venous thrombosis were observed in low proportions (under 5.6 percent) for all classes of interventions. Regarding stroke or transient ischemic attacks, all interventions were at or below 2.9 percent. The rates of angina or myocardial infarction ranged between 3.6 percent and 7.0 percent across interventions. In the package insert for the daily dosage form of leuprolide (see Evidence Table I.12), electrocardiogram (ECG) changes or ischemia were reported in 19.4 percent of patients.

Endocrine

These data are summarized in Evidence Table I.6 (Appendix I). Impotence was reported in 5.3 percent in two studies of nonsteroidal antiandrogens, whereas the rates were somewhat higher for orchiectomy (13.3 percent) and LHRH agonists (20.8 percent). It should be noted that monotherapy arms from studies of combined androgen blockade report strikingly higher rates of impotence: 71 percent for orchiectomy or the LHRH agonists and 66 percent for orchiectomy/LHRH agonist plus a nonsteroidal antiandrogen. Even these rates are lower than that observed in clinical practice, where chemical or surgical castration is virtually always associated with impotence. The discrepancies are probably explained by measurement error and inconsistent reporting within and across trials. One possibility is that trials reporting low rates of impotence did not distinguish between patients who were and were not impotent prior to androgen suppression.

Hot flushes are more common with both orchiectomy (50.8 percent) and LHRH agonists (49.3 percent), compared with nonsteroidal antiandrogens (11.3 percent). Gynecomastia is more frequent with nonsteroidal antiandrogens (37.7 percent), compared with orchiectomy (5.3 percent) and LHRH agonists (4.4 percent). It should be noted that gynecomastia can be prevented by irradiation prior to initiating hormonal therapy. One package insert for the 1-month leuprolide depot reported a rate of 58.9 percent for gynecomastia/breast pain/tenderness. It is unclear how the estimate might be affected by use of prophylactic irradiation.

Gastrointestinal

Evidence Table I.7 (Appendix I) summarizes these data. Nonspecified gastrointestinal adverse events were very similar across interventions (9.1 to 11.8 percent), although the package insert for the 1-month depot formulation of leuprolide reports a rate of 26.8 percent. Nausea/vomiting were reported in about 9 percent in nonsteroidal antiandrogen trials. The rate for LHRH agonists was 4.6 percent and 1.3 percent or less for orchiectomy. Diarrhea was reported as 0 to 6.6 percent across all intervention categories. Gastrointestinal pain was found in 7 percent for nonsteroidal antiandrogens, and 2 percent for orchiectomy. It is commonly thought that flutamide is associated with a high rate of diarrhea, but these data do not confirm this.

Adverse Events Leading to Withdrawal from Therapy

Orchiectomy is an irreversible procedure and is not included in this analysis. The pooled data in Evidence Table I.8 show that, in the single study on the use of leuprolide, the withdrawal rate was 0 percent. The rate for goserelin is 2.0 percent for the 1-month formulation and 1.3 percent for the 3-month formulation, and the rate for buserelin is 4.2 percent. Flutamide has the highest withdrawal rate among nonsteroidal antiandrogens (9.8 percent), and the rate for bicalutamide is 4.0 percent and 6.8 percent for nilutamide. Cyproterone, at 250 mg/d has a rate of 1.2 percent and, at a dose of 300 mg/d, 4.2 percent.

Key Findings

  • Limitations in the evidence on adverse events by category suggest that estimates of specific types of adverse events should be viewed cautiously. The evidence on adverse events leading to withdrawals from therapy is more reliable.
  • The frequency of withdrawal from therapy due to adverse events is the most reliable index reported for comparing the tolerability of the two drug classes. Withdrawals occurred less often among patients treated with an LHRH agonist (0 to 4 percent) than among patients treated with nonsteroidal antiandrogens (4 to 10 percent). The rate of withdrawal from therapy was highest for flutamide.
  • Impotence may be slightly more common in patients receiving orchiectomy or a LHRH agonist, compared with antiandrogen.
  • Hot flushes are substantially more common in patients who are treated with orchiectomy or an LHRH agonist.
  • Gynecomastia is more common in patients receiving nonsteroidal antiandrogens.
  • Nausea/vomiting might be slightly more common with nonsteroidal antiandrogens.

Quality of Life

Only two randomized trials used a standardized and validated instrument (Cleary, Morrissey, and Oster, 1995) to measure quality of life (Chodak, Sharifi, Kasimis, et al., 1995; Iversen, Tyrrell, Kaisary et al., 1998; comparison 7.3). Both compared bicalutamide with the choice of surgical or chemical castration. Treatment with bicalutamide was reported to improve sexual interest and physical capacity from that measured at enrollment by more than was observed for those randomized to surgical or chemical castration (p<0.01). 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 attempt to measure quality of life.

The only other data that compare the effects of monotherapies on quality of life in men with advanced prostate cancer is from a nonrandomized study of 115 men who selected treatment with goserelin and 32 men who selected orchiectomy (Cassileth, Soloway, Vogelzang et al., 1992). Quality of life, as measured by the Functional Living Index: Cancer scale, improved from baseline at both 3 and 6 months in those who selected goserelin (p=0.0001) but did not change from baseline in those who selected orchiectomy (p=0.54 at 6 months). These investigators also reported an improvement in psychosocial measures for those who selected goserelin but no improvement for those who selected orchiectomy. These data must be interpreted cautiously, however, because the study was not randomized and the factors that influenced patient choice of therapy may have biased the results.

Although it is not strictly a measure of quality of life, patient preferences when they were offered a choice between treatments may provide useful information. Two of the four studies on bicalutamide that offered those in the control arm a choice of orchiectomy or an LHRH agonist (comparison 7.3) reported the number who chose each option. Of 285 patients offered this choice in the two trials (Iversen, Tyrrell, Kaisary et al., 1998; Kaisary, Tyrrell, Beacock, et al., 1995), only 87 (30 percent) chose orchiectomy. However, no direct evidence compares patients treated with orchiectomy with those given an LHRH agonist with respect to quality of life. Thus, it is not known whether patient perceptions when contemplating this choice of therapies are borne out by the realities of life after treatment.

Meta-Analysis

Meta-analysis was performed using the methods described in the Methodology section. A table of hazard rates for each arm of each study was constructed (Evidence Table I.13 in Appendix I). Hazard rates for overall survival at 2 years were combined using a random effects model, and all results of the analysis are reported as hazard ratios relative to orchiectomy. A hazard ratio of 1.0 indicates that patients treated with the therapy of interest and patients treated with orchiectomy had an equal chance of death from any cause within 2 years of treatment.

The meta-analysis included data from 18 of the 21 studies listed in Evidence Table I.2 that compared overall survival after two or more monotherapies. One study (Koutsilieris and Tolis, 1985) was omitted because it did not report an actuarial analysis of survival and only included six patients in the control arm. A second trial (Lund and Rasmussen, 1988) was omitted because it reported no mortality in one arm of the study and as a result it was impossible to calculate a hazard ratio. The third trial (Boccon-Gibod, Fournier, Bottet et al., 1997) was omitted because it did not provide data on survival, although it reported no significant difference between study arms at a median of 69 months of followup. Note that two studies included in the meta-analysis (Pavone-Macaluso, de Voogt, Viggiano et al., 1986; Veterans Administration Cooperative Urology Research Group, 1967; Blackard, Byar, and Jordan, 1973) have separate entries for patient subgroups: stage III and stage IV patients in the VACURG study and stage C and stage D patients in the Pavone-Macaluso et al. study.

Table 7 presents the combined estimates for each monotherapy relative to orchiectomy. Results are reported separately for each agent in the classes of LHRH agonists and antiandrogens. Table 8 presents combined estimates by classes of monotherapy. Sensitivity analyses were used to test for heterogeneity of participants and study methods. Table 9 presents the results of the sensitivity analysis for those studies that restricted the subjects to stage D2. Table 10 presents the results of the sensitivity analysis for those studies that were prospectively determined to be of higher quality.

Table 7. Combined Estimates of Treatments for Prostate Cancer - Hazard Ratios Relative to Orchiectomy.

Table

Table 7. Combined Estimates of Treatments for Prostate Cancer - Hazard Ratios Relative to Orchiectomy.

Table 8. Combined Estimates of Treatment Classes for Prostate Cancer - Hazard Ratios Relative to Orchiectomy.

Table

Table 8. Combined Estimates of Treatment Classes for Prostate Cancer - Hazard Ratios Relative to Orchiectomy.

Table 9. Combined Estimates of Treatment Classes for Prostate Cancer-Hazard Ratios Relative to Orchiectomy for Studies of Subjects With Stage D2 Cancer.

Table

Table 9. Combined Estimates of Treatment Classes for Prostate Cancer-Hazard Ratios Relative to Orchiectomy for Studies of Subjects With Stage D2 Cancer.

Table 10. Combined Estimates of Treatment Classes for Prostate Cancer-Hazard Ratios Relative to Orchiectomy for Studies Determined to be of High Quality.

Table

Table 10. Combined Estimates of Treatment Classes for Prostate Cancer-Hazard Ratios Relative to Orchiectomy for Studies Determined to be of High Quality.

These results suggest that none of the treatments is better than orchiectomy and some appear to be less effective. The confidence intervals tend to be quite large as is apparent from the results shown in Figure 1.

Figure 1. Survival at 2 Years, Monotherapies.

Figure

Figure 1. Survival at 2 Years, Monotherapies.

The analysis was repeated, combining the treatments into the broader categories of orchiectomy, DES, LHRH agonists, and antiandrogens. These results are summarized in Table 8.

These estimates have much smaller confidence intervals. The results suggest that DES and LHRH agonists are essentially equivalent to orchiectomy and that the antiandrogens may have slightly higher hazard ratios. The results are shown in Figure 2.

Figure 2. Survival at 2 Years, Monotherapies, by Category.

Figure

Figure 2. Survival at 2 Years, Monotherapies, by Category.

This reduced analysis assumed that the various treatments that were grouped were actually equivalent. To formally test that hypothesis, we calculated the likelihood ratio chi-squared value with 4 degrees of freedom and found it to be 1.268 (p=0.742), indicating that the treatments were not different from each other.

The above analysis was repeated for those studies that restricted the subjects to stage D2. This eliminated six comparisons of monotherapies from four studies (Iversen, Tyrrell, Kaisary et al., 1998; Pavone-Macaluso, de Voogt, Viggiano et al., 1986; Veterans Administration Cooperative Urology Research Group, 1967; Blackard, Byar, and Jordan, 1973; Waymont, Lynch, Dunn et al., 1992).

Note that only the data for stage C patients were eliminated for one of these studies (Pavone-Macaluso, de Voogt, Viggiano et al., 1986). The results of the analysis are shown in Table 9 and are shown graphically in Figure 3.

Figure 3. Survival at 2 Years, Monotherapies, by Category, Stage D2 Patients.

Figure

Figure 3. Survival at 2 Years, Monotherapies, by Category, Stage D2 Patients.

Note that the results are virtually identical to the analysis of all stages except that the confidence bands are slightly wider.

The analysis was also repeated for those studies that were determined to be of high quality, based on whether the trial was double-blinded (except when orchiectomy was one intervention) and whether an intent-to-treat analysis was performed. This eliminated six trials (Bruun, Frimodt-Moller, and the Danish Buserelin Study Group, 1996; Citrin, Resnick, Guinan et al., 1991; Ostri, Bonnesen, Nilsson et al., 1991; Pavone-Macaluso, de Voogt, Viggiano et al., 1986; The Leuprolide Study Group, 1984; Waymont, Lynch, Dunn et al., 1992). The results of the analysis are shown in Table 10 and are shown graphically in Figure 4.

Figure 4. Survival at 2 Years, Monotherapies, by Category, High Quality Studies.

Figure

Figure 4. Survival at 2 Years, Monotherapies, by Category, High Quality Studies.

Again, note that the results are virtually identical to the analysis of all stages except that the confidence bands are slightly wider.

Summary and Conclusions

Summary

Twenty-four randomized controlled trials, including more than 6,600 patients, met the study selection criteria for this report. These trials compared the following monotherapies for androgen suppression in men with advanced prostate cancer:

  • DES versus orchiectomy
  • LHRH agonist versus DES or orchiectomy
  • Nonsteroidal antiandrogen versus DES or orchiectomy or an LHRH agonist
  • The steroidal antiandrogen cyproterone versus DES or orchiectomy or an LHRH agonist

No study directly compared one LHRH agonist to another as monotherapies.

Although DES is no longer widely used for hormonal suppression, trials comparing DES with orchiectomy were included in this report to establish the equivalence of DES and orchiectomy when either is used as the control arm to compare other monotherapies. If DES were not included as a comparator, the evidence basis for assessing the relative efficacy of LHRH agonists and the antiandrogens would be less robust. The review would be reduced from 22 trials, including more than 5,300 patients, to 16 trials, including somewhat less than 4,500 patients.

The population studied was overwhelmingly patients with metastatic disease, largely staged as either D2 or M1. Of the 24 trials, 21 reported either median survival or survival at 2 years after enrollment, or both. Only six trials reported survival at 5 years, and two others reported survival at 4 years.

A meta-analysis combined data from 20 trials on overall survival at 2 years. Meta-analysis was performed using a random effects model. Each drug used for androgen suppression was compared to orchiectomy. A hazard ratio of 1.0 indicates that patients treated with the therapy of interest and patients treated with orchiectomy had an equal chance of death from any cause within 2 years of treatment.

The meta-analysis included two sensitivity analyses. One restricted the analysis to subjects with stage D2/M1 disease; the second was restricted to higher quality trials. A trial was classified as higher quality when it was double-blinded (not required when orchiectomy was one of the treatments) and it reported outcomes based on an intention-to-treat analysis. The sensitivity analyses yielded results consistent with the overall analysis but with wider confidence intervals.

These trials did not provide sufficient information to stratify results by known prognostic factors. Nor did the trials consistently report outcomes other than overall survival, such as cancer-specific or progression-free survival. No trial measured quality of life by a standard instrument.

Conclusions

1. There is no statistically significant difference in survival for patients treated with LHRH agonists compared to patients treated with orchiectomy or DES

  • Ten trials, including 1,908 patients, compared an LHRH agonist either to orchiectomy or to DES. Nine of the 10 reported data on overall survival, and none found a statistically significant difference between treatments. The measures reported were 2-year, 5-year, and median overall survival.
  • The meta-analysis found that 2-year overall survival with LHRH agonists as a class is essentially equivalent to orchiectomy (hazard ratio 1.1262; 95 percent confidence interval 0.915 to 1.386).
  • Evidence on the time to disease progression is consistent with the evidence on survival. Five trials on LHRH agonists reported time to progression. Four of these found no statistically significant difference between the LHRH agonist and orchiectomy or DES, whereas the fifth found a benefit in favor of the choice of orchiectomy or DES.

2. There is no statistically significant difference in survival among patients treated with different LHRH agonists

  • Of the 10 studies of LHRH agonists, one compared leuprolide to DES, five compared goserelin to orchiectomy or DES, and four compared buserelin to orchiectomy or DES. Nine of these trials compared overall survival after an LHRH agonist to that after orchiectomy or DES, and none found a statistically significant difference between treatments.
  • The meta-analysis compared each LHRH agonist to orchiectomy. The three LHRH agonists have similar hazard ratios when compared to orchiectomy: leuprolide, 1.0994 (95 percent confidence interval 0.207 to 5.835); goserelin 1.1172 (95 percent confidence interval 0.898 to 1.390); and buserelin 1.1315 (95 percent confidence interval 0.533 to 2.404). The confidence intervals are widest for leuprolide and narrowest for goserelin, which is a consequence of the number and size of the available studies.
  • Of the five trials of LHRH agonists that reported some measure of disease progression, four reported no statistically significant difference between an LHRH agonist and orchiectomy or DES. One trial on buserelin found a statistically significant benefit in favor of the choice of orchiectomy or DES.

3. The evidence shows a trend toward lower survival after nonsteroidal antiandrogens used as monotherapy than after orchiectomy, DES, or LHRH agonists

  • Eight trials (n=2,717) compared a nonsteroidal antiandrogen to orchiectomy, DES, or an LHRH agonist. Three found a statistically significant difference favoring the control arm; an additional 6 to 15 percent of patients survived at 2 years. The remainder found no significant difference between arms but showed slight trends toward improved survival in the control arms for four of six studies.
  • The meta-analysis found that the hazard ratio relative to orchiectomy was 1.2158 for nonsteroidal antiandrogens as a class (95 percent confidence interval 0.988 to 1.496), compared to 0.9835 for DES (95 percent confidence interval 0.764 to 1.267) and 1.1262 (95 percent confidence interval 0.915 to 1.386) for LHRH agonists.
  • The evidence does not suggest differences between the two nonsteroidal antiandrogens in effect on survival. One trial of flutamide found a statistically significant difference that favored the control arm, whereas two found no significant differences. Two trials of bicalutamide found a statistically significant difference that favored the control arm, whereas three others found no significant differences. There were no trials of nilutamide as monotherapy.
  • The meta-analysis found a hazard ratio compared to orchiectomy of 1.2027 (95 percent CI 0.973 to 1.487) for bicalutamide and 1.9583 (95 percent CI 0.369 to 10.394) for flutamide. However, the confidence interval for flutamide is much wider.
  • The meta-analysis also found a hazard ratio compared to orchiectomy of 1.2005 (95 percent CI 0.592 to 2.433) for the steroidal antiandrogen cyproterone, suggesting that cyproterone is not superior to the nonsteroidal antiandrogens.

4. LHRH agonists and nonsteroidal antiandrogens differ in their adverse effects. The evidence on differences in adverse effects among the agents within each class is limited but does not suggest that one agent is superior to the others

  • The frequency of withdrawal from therapy due to adverse events is the most reliable index reported for comparing the tolerability of the two drug classes. Withdrawals occurred less often among patients treated with an LHRH agonists (0 to 4 percent) than among patients treated with nonsteroidal antiandrogens (4 to 10 percent). The rate of withdrawal from therapy was highest for flutamide.
  • Impotence was more common among patients treated with orchiectomy and LHRH agonists compared to patients treated with nonsteroidal antiandrogens, but the available data are too inconsistent to quantify the difference. It should be noted that the frequency of impotence among men treated with orchiectomy or LHRH agonists was substantially lower in the trials of monotherapy than in the monotherapy arm of trials comparing monotherapy with combined androgen blockade, which suggests differences in how impotence was measured.
  • Hot flushes were more common among patients treated with orchiectomy or LHRH agonists compared to a nonsteroidal antiandrogen (50 percent versus 11 percent). Gynecomastia was more common among patients treated with nonsteroidal antiandrogens than patients treated with an LHRH agonist (38 percent versus 4 percent).
  • Among the LHRH agonists, local pain, reactions, hypersensitivity, or development of a mass at the site of depot injections were very infrequent and occurred as often with leuprolide as they did with goserelin in the only study that directly compared the two.

5. There is insufficient evidence to compare the effects of the various monotherapies on quality of life

  • The large majority of patients prefer to avoid orchiectomy. Approximately 70 percent of patients chose treatment with an LHRH agonist rather than surgical orchiectomy in two trials that offered patients a choice between the treatments and that reported the distribution by choice.
  • One trial reported that bicalutamide improved sexual interest and physical capacity from that measured at enrollment by more than did surgical or chemical castration.

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