| Japanese Journal of Clinical Oncology | Pages |
Goserelin Acetate with or without Antiandrogen or Estrogen in the Treatment of Patients with Advanced Prostate Cancer: a Multicenter, Randomized, Controlled Trial in Japan
Introduction
Patients And Methods
Patient Selection
Methods
Statistics
Results
Patients
Efficacy
Safety
Discussion
Conclusions
Affiliations Of The Authors
References
Goserelin Acetate with or without Antiandrogen or Estrogen in the Treatment of Patients with Advanced Prostate Cancer: a Multicenter, Randomized, Controlled Trial in Japan
Objective: The aims of this randomized, controlled study were to investigate the efficacy and safety of long-term monotherapy with the luteinizing hormone-releasing hormone agonist goserelin acetate compared with both short- and long-term combined androgen blockade. Methods: Patients with advanced prostate cancer (n = 371) were randomized to treatment with goserelin acetate alone or a combination of goserelin acetate plus either long-term or short-term antiandrogen (chlormadinone acetate) or short-term estrogen (diethylstilbestrol diphosphate). Results: There were no significant differences between the treatment groups with respect to objective progression, overall survival or disease-specific survival. Nevertheless, subgroup analysis suggested that patients with minimal disease or a good prognosis might benefit more from combined androgen blockade than other patients. Combined androgen blockade significantly reduced the incidence of disease flare compared with goserelin acetate treatment alone. Conclusions: Neither short- nor long-term combined androgen blockade had a survival advantage over goserelin acetate alone.
Keywords: prostate cancer - antiandrogen - goserelin acetate - chlormadinone acetate - diethylstilbestrol diphosphate
INTRODUCTION
In 1982, Labrie et al. (1) proposed that combined androgen blockade (CAB), the co-administration of an antiandrogen and castration (medical or surgical), would provide more effective treatment for prostate cancer than either treatment alone. Subsequently, some large randomized trials have demonstrated significant survival advantages for patients with advanced prostate cancer treated with CAB in favor of orchidectomy or a luteinizing hormone-releasing hormone (LH-RH) agonist (2-4). However, other similar trials have been unable to confirm these results and the use of CAB remains controversial (5-8).
CAB may reduce the disease flare observed in approximately 3% of patients with advanced prostate cancer after the administration of an LH-RH agonist alone (7). This disease flare is due to an initial elevation of testosterone levels by the LH-RH agonist; therefore, the addition of an antiandrogen or an agent that decreases LH-RH or testosterone production (such as an estrogen) may reduce the initial elevation of testosterone and minimize the time for testosterone levels to reach castration levels, compared with LH-RH agonist alone. This initial flare of disease symptoms may reduce the quality of life of the patient and possibly their subsequent compliance with treatment.
In the early 1990s, chlormadinone acetate (CMA), a steroidal agent, was the only antiandrogen approved in Japan. Chlormadinone acetate has proven anti-tumor effects and, although its efficacy in stage D patients was reported to be poor (9), it has since been shown to result in similar objective responses to flutamide in patients with stage C or D prostate cancer (10). Furthermore, a large clinical trial in Japan observed no serious side effects with long-term CMA use (9).
The aim of this randomized, controlled study was to investigate the efficacy and safety of long-term medical castration compared with long- and short-term CAB. Therapy with goserelin acetate alone was compared with goserelin acetate plus long-term CMA and goserelin acetate plus short-term CMA or short-term diethylstilbestrol diphosphate (DES-DP). In addition, the effect of CAB on the initial flare of testosterone levels and subsequent disease symptoms observed in some patients following LH-RH agonist administration was investigated. Some preliminary results of this trial have been reported in the Japanese Journal of Urological Surgery (11).
PATIENTS AND METHODS
This was a collaborative multicenter study involving 73 institutions in Japan. Patients were enrolled between February 1992 and July 1994 and the trial was completed in December 1996.
Patient Selection
To enter the study, patients had to meet the following eligibility criteria: histologically proven, newly diagnosed, stage C or D prostate cancer; an Eastern Cooperative Oncology Group (ECOG) performance status of grade 0-3 or apparent grade 4 due to bone metastasis; expected survival of 3 months or longer. Patients with active multiple cancer, severe hepatic, renal, cardiovascular or bone marrow complications or pretreatment testosterone levels of <100 ng/dl, as assessed by the Case Investigation Committee, were excluded.
Methods
After signing an informed consent form, patients were randomized to one of four treatment groups with stratification for the clinical stage, degree of histological differentiation and degree of bone metastasis [extent of disease (EOD) grade] (12). The four treatment groups were as follows: (1) goserelin acetate alone; (2) goserelin acetate plus long-term (at least 28 months) CMA; (3) goserelin acetate plus short-term (8 weeks) CMA; (4) goserelin acetate plus short-term (8 weeks) DES-DP. Goserelin acetate (Zoladex, 3.6 mg depot) was administered subcutaneously once every 4 weeks. CMA (Prostal, 25 mg tablet) 50 mg twice daily was given after food in the morning and evening. DES-DP (Honvan, 100 mg tablet) was administered three times daily before each meal, to a total of 300 mg/day [reduced to 100 mg/day if an adverse drug reaction (ADR) occurred].
Disease progression and symptoms, ECOG performance status and routine laboratory tests were evaluated prior to study drug administration, at week 12, at the end of each subsequent year and at study discontinuation. Prostate-specific antigen (PSA) and testosterone were also measured at these time points and additionally after 3 days and 2, 4 and 8 weeks. PSA and testosterone levels were measured collectively at an external institution, using a Markit-M enzyme immunoassay or a DPC radioimmunoassay, respectively. Response was defined according to PSA levels as follows: complete response if elevated PSA levels normalized; partial response if elevated PSA levels were reduced by at least 50%; no change if elevated PSA levels were reduced by <50% or increased by <25%; and progression of disease if elevated PSA levels increased by at least 25% or if previously normal PSA levels increased to an abnormal level. PSA relapse was considered to have occurred if PSA levels reached twice the normal level in patients with a complete response to treatment, PSA was elevated by at least 50% compared with pretreatment values in patients with a partial response to treatment or PSA levels increased by at least 125% of the pretreatment value in patients with no response to treatment.
The evaluation parameters were the anti-tumor effect, progression-free survival, overall and disease-specific survival, overall subjective response, quality of life (results to be reported separately), ADRs and withdrawals due to ADRs. The anti-tumor effect was judged in accordance with `Response Criteria for Urological Cancer Treatment' prepared by the Japanese Urological Association and the Japanese Society of Pathology (13). These criteria are described by Akaza et al. (14) and are similar to those of the World Health Organization (15), except that the Japanese criteria include the evaluation of PSA levels. Subjective symptoms, performance status and status of use of analgesic drugs were combined by the physician to give a measure of the overall subjective response. During the follow-up period, routine laboratory tests were performed and ADRs were reported at 3 month intervals.
Statistics
A total sample size of 420 patients was chosen to provide an 80% probability of detecting a 50% improvement in median survival with CAB at a significance level of 0.05 after a 3-year follow-up period. The primary efficacy analysis was carried out on the per-protocol population. A paired t-test was used to compare pre- and post-treatment testosterone values and the Kruskal-Wallis test was used for the analysis of efficacy. Time to progression and duration of survival curves were calculated using the Kaplan-Meier technique and groups were compared using a log rank test. Subjective response rates were compared using a Mann-Whitney U-test with Bonferroni adjustment for multiplicity. To evaluate time-course changes in PSA and testosterone levels, logarithmic ratios of post- versus pretreatment values at each time point were analyzed using analysis of variance (ANOVA). Treatment groups were compared using Tukey's method for multiple comparisons. In addition, the Mantel-Haenszel test was used to analyze the effect of baseline characteristics on the anti-tumor effect and survival.
RESULTS
Patients
Of 390 enrolled and randomized patients, 388 received treatment. The two patients who did not receive their allocated treatment had been found to have other cancers. A further 17 patients who received treatment were excluded owing to low testosterone levels or active multiple cancer; thus 371 patients were eligible for the evaluation of efficacy (Table 1). Ten of the eligible patients, who did not complete the trial according to protocol, were included in the safety but excluded from the efficacy evaluations. A further eight patients who withdrew during the first 6 weeks of the study without ADRs were excluded from the safety analysis.
Table 1. Trial profile for the four treatment groups
| Goserelin acetate | Goserelin acetate plus long-term CMA | Goserelin acetate plus short-term CMA | Goserelin acetate plus short-term DES-DP | Total | |
| Enrolled and randomized | 98 | 96 | 98 | 98 | 390 |
| Treatment received | 98 | 96 | 98 | 96 | 388 |
| Protocol violations | 7 | 2 | 3 | 7 | 19 |
| Protocol deviations | 2 | 2 | 3 | 3 | 10 |
| Evaluable for safety | 89 | 91 | 94 | 89 | 363 |
| Eligible for efficacy | 91 | 94 | 95 | 91 | 371 |
| Evaluable for efficacy | 89 | 92 | 92 | 88 | 361 |
| Median days of treatment | 464 | 379 | 566 | 429 | 448 |
| (range) | (4-1624) | (16-1771) | (31-1685) | (11-1778) | (4-1778) |
| Reasons for withdrawal: | |||||
| Adverse drug reaction | 0 | 5 | 1 | 10 | 16 |
| Disease progression | 51 | 45 | 38 | 38 | 172 |
| Other reason* | 27 | 30 | 35 | 25 | 117 |
| Prognostic outcome[dagger] | |||||
| Total death | 43 | 45 | 36 | 31 | 155 |
| Cancer death | 34 | 31 | 22 | 26 | 113 |
| Alive | 37 | 40 | 44 | 44 | 165 |
| Lost to follow-up | 9 | 7 | 12 | 13 | 41 |
| Completed trial | 11 | 12 | 18 | 15 | 56 |
The 361 patients who were evaluated for efficacy were in the trial for a median of 448 days (range 4-1778 days). A total of 305 of these patients withdrew from the study due to ADRs (16 patients) disease progression (172 patients) or other reasons (117 patients), including adverse events thought to be unrelated to the trial drug (37 patients), a slight elevation of PSA (below that for a definition of relapse) (20 patients) and lost to follow-up (29 patients). A total of 56 patients remained in the study for the entire treatment period.
The patient groups appeared to be fairly well balanced for all baseline characteristics and potential risk factors (Table 2).
Table 2. Patient demographics and baseline characteristics at randomization among 371 eligible patients
| Number of patients (%) | |||||
| Goserelin acetate alone (n = 91) |
Goserelin acetate plus long-term CMA (n = 94) |
Goserelin acetate plus short-term CMA (n = 95) |
Goserelin acetate plus short-term DES-DP (n = 91) |
Overall (n = 371) |
|
| Age: mean ± SD (years) | 73.7 ± 8.0 | 73.5 ± 7.8 | 73.2 ± 8.2 | 72.2 ± 7.9 | 73.2 ± 8.0 |
| Complication present | 35 (38) | 50 (53) | 46 (48) | 31 (34) | 162 (44) |
| Past history | 36 (40) | 38 (40) | 39 (41) | 40 (44) | 153 (41) |
| Clinical stage | |||||
| C | 23 (25) | 25 (27) | 26 (27) | 24 (26) | 98 (26) |
| D1 | 3 (3) | 2 (2) | 3 (3) | 4 (4) | 12 (3) |
| D2 | 65 (71) | 67 (71) | 66 (69) | 63 (69) | 261 (70) |
| Tumor differentiation | |||||
| Well | 9 (10) | 12 (13) | 14 (15) | 8 (9) | 43 (12) |
| Moderate | 53 (58) | 52 (55) | 51 (54) | 54 (59) | 210 (57) |
| Poor | 29 (32) | 30 (32) | 30 (32) | 29 (32) | 118 (32) |
| ECOG performance status | |||||
| 0 | 52 (57) | 52 (55) | 46 (48) | 59 (65) | 209 (56) |
| 1 | 20 (22) | 32 (34) | 37 (39) | 21 (23) | 110 (30) |
| 2 | 10 (11) | 4 (4) | 9 (9) | 6 (6) | 29 (8) |
| 3 | 7 (8) | 6 (6) | 3 (3) | 4 (4) | 20 (5) |
| 4 | 2 (2) | 0 (0) | 0 (0) | 1 (1) | 3 (1) |
| EOD grade | |||||
| 0 | 28 (31) | 29 (31) | 31 (33) | 29 (32) | 117 (32) |
| 1 | 31 (34) | 29 (31) | 28 (29) | 29 (32) | 117 (32) |
| 2 | 10 (11) | 21 (22) | 25 (26) | 23 (25) | 79 (21) |
| 3 | 8 (9) | 9 (10) | 4 (4) | 5 (5) | 26 (7) |
| 4 | 14 (15) | 6 (6) | 7 (7) | 5 (5) | 32 (9) |
| Testosterone: mean ± SD (ng/dl) | 436 ± 188 | 418 ± 153 | 521 ± 171 | 486 ± 190 | 465 ± 180 |
| PSA: mean ± SD (ng/ml) | 188 ± 425 | 140 ± 270 | 240 ± 504 | 148 ± 274 | 179 ± 383 |
Efficacy
Anti-tumor Effect. Neither short- nor long-term CAB improved the anti-tumor response to treatment at week 12 compared with goserelin acetate alone (Table 3). There were no statistically significant differences between the treatment groups with respect to the response to treatment at 12 weeks or at 1, 2, 3 or 4 years; this included the overall response and the response of the primary lesion, bone metastatic lesions and lymph node metastatic lesions. However, there were some significant differences between the groups in terms of best response, suggesting that CAB with short-term CMA results in an improved response compared with CAB with long-term CMA. Significant differences in the best response between the groups were obtained for the overall response (P = 0.017, Kruskal-Wallis test) and for the response according to bone metastatic lesions (P = 0.019, Kruskal-Wallis test), with the largest differences occurring between the goserelin acetate plus long-term CMA and goserelin acetate plus short-term CMA groups (Table 3). Analysis using the Mantel-Haenszel test showed that the presence or absence of concomitant disease or testosterone values above or below the median value had no influence on the overall anti-tumor effect.
Subgroup analysis, according to baseline characteristics, demonstrated that patients with poorly differentiated cancer showed a poorer response in the goserelin acetate plus long-term CMA group compared with the other three treatment groups, with a statistically significant difference between the treatment groups for the response rate at week 12 (P = 0.022, Kruskal-Wallis test) and best response rate (P = 0.001, Kruskal-Wallis test). Similarly, patients with stage D2 cancer showed a poorer response in the goserelin acetate plus long-term CMA group compared with the other three treatment groups, with a statistically significant difference between the groups for the best response rate (P = 0.001, Kruskal-Wallis test). However, the patient numbers in these subgroups were small (27-65) so these analyses were under-powered.Survival. CAB did not result in a survival advantage compared with goserelin acetate treatment alone. The Kaplan-Meier curve of progression-free survival is shown in Fig. 1. Median progression-free survival times were 23.6 months for goserelin acetate alone, 23.4 months for goserelin acetate plus long-term CMA, 36.4 months for goserelin acetate plus short-term CMA and 36.2 months for goserelin acetate plus short-term DES-DP, with no statistically significant differences between the four groups. Analysis by subgroup, according to baseline characteristics, indicated a difference between the goserelin acetate alone group and the goserelin acetate plus short-term CMA group for EOD grade 1 (1-5 bone metastatic lesions) (P = 0.002, log rank test). However, patient numbers were small (28-31) and the analysis was under-powered.
Median survival was 48.5 months for goserelin acetate alone, 42.4 months for goserelin acetate plus long-term CMA, 51.0 months for goserelin acetate plus short-term CMA and not attainable for goserelin acetate plus short-term DES-DP owing to an insufficient follow-up period (Fig. 2). Three-year survival rates were 65.6, 60.2, 67.9 and 67.2% for the respective groups, with no significant difference between the four groups. Overall survival was also studied for each baseline characteristic by subgroup analysis but no statistically significant differences were observed for any subgroup. Similarly, the disease-specific survival of the 361 eligible patients is shown in Fig. 3. Median disease-specific survival was 52.3 months for patients on goserelin acetate alone, 55.0 months for patients in the goserelin acetate plus long-term CMA group and not attainable for the two remaining treatment groups owing to an insufficient follow-up period. Three-year disease-specific survival rates were 73.0, 70.6, 79.3 and 70.9%, with no significant difference between the four treatment groups. There were also no significant differences between the four groups for disease-specific survival when analyzed according to subgroups. Analysis using the Mantel-Haenszel test showed that the presence or absence of concomitant disease or testosterone values more or less than the median value had no influence on the progression-free, overall or disease-specific 3-year survival rates.
Figure 1. Kaplan-Meier probability of progression-free survival for the four treatment groups. CMA, chlormadinone acetate; DES-DP, diethylstilbestrol diphosphate. Median progression-free survival 378.5 days (range 50-1453 days); n = 172. Log rank test 0.1046.
Figure 2. Kaplan-Meier probability of overall survival for the four treatment groups. CMA, chlormadinone acetate; DES-DP, diethylstilbestrol diphosphate. Median overall survival 664 days (range 16-1650 days); n = 155. Log rank test 0.4324.
Overall Subjective Response. There were no significant differences in the overall subjective response rates between the four treatment groups at week 12, year 1 or year 2. However, a significant difference in the subjective response was observed between the groups at years 3 and 4 (P = 0.008 and 0.048, respectively, Kruskal-Wallis test). At year 3, the subjective response rates were 63.6, 77.8, 50.0 and 68.0% for treatment with goserelin acetate alone, goserelin acetate plus long-term CMA, goserelin acetate plus short-term CMA and goserelin acetate plus short-term DES-DP, respectively. The subjective response was significantly higher in the long-term CMA group than in the short-term CMA group at year 3 (P = 0.0043, Mann-Whitney U-test, significant after Bonferroni adjustment for multiplicity).
Prostate-specific Antigen Levels. Medical castration alone and CAB markedly reduced PSA levels, with response rates (partial response or complete response) exceeding 85% for all four treatment groups after 12 weeks (Table 3). However, CAB reduced PSA levels quicker than goserelin acetate treatment alone. Figure 4 shows the changes in PSA (back-transformed ratio of post- to pretreatment levels) during the first 12 weeks of treatment. After 3 days' treatment, PSA levels had declined compared with mean pretreatment levels in all treatment groups except for the goserelin acetate alone group; PSA levels remained significantly higher in the goserelin acetate alone group compared with the CAB groups until week 4. The reduction in PSA levels in the goserelin acetate plus short-term DES-DP group was significantly greater than for each of the other three treatment groups from 2 to 12 weeks (P < 0.05, Tukey's test). This resulted in significantly more patients (76.8%) who had received goserelin acetate plus short-term DES-DP having normal PSA levels at week 12 compared with each of the other three treatment groups (52.4, 44.8 and 48.9% for the goserelin acetate alone, plus long-term CMA and plus short-term CMA groups, respectively) (P < 0.05, Tukey's test).
Figure 3. Kaplan-Meier probability of disease-specific survival for the four treatment groups. CMA, chlormadinone acetate; DES-DP, diethylstilbestrol diphosphate.Median overall survival 664 days (range 95-1650 days); n = 113. Log rank test 0.4914.
Figure 4. Changes in PSA levels for the four treatment groups (excludes patients with protocol deviations and those patients whose sample for PSA analysis was not taken within a specified period).
Testosterone Levels. A significant elevation of testosterone levels was observed in all four treatment groups at 3 days after initiation of the study compared with the pretreatment mean values (P < 0.01, paired t-test). The mean values (SD) of the log of post-/pretreatment testosterone levels were 2.88 (2.09) for goserelin acetate alone, 1.62 (2.73) for goserelin acetate plus long-term CMA, 1.41 (3.30) for goserelin acetate plus short-term CMA and 1.55 (2.37) for goserelin acetate plus short-term DES-DP. The elevation in the goserelin acetate alone group was significantly greater than in each of the other three groups (P < 0.05, Tukey's test). Thereafter, testosterone levels decreased to a similar level in all of the treatment groups [mean values (SD): goserelin acetate alone, 15.6 ng/dl (8.8); goserelin acetate plus long-term CMA, 11.1 ng/dl (12.6); goserelin acetate plus short-term CMA, 22.2 ng/dl (62.1); goserelin acetate plus short-term DES-DP, 25.9 ng/dl (108.2)].
Safety
Adverse Drug Reactions. CAB with CMA and goserelin acetate alone were well tolerated and resulted in a similar incidence of ADRs. Significantly more ADRs occurred in the goserelin acetate plus short-term DES-DP group than in each of the other three treatment groups (P < 0.05, Tukey's test) at 12 weeks and follow-up (Table 4). At 12 weeks, the incidence of ADRs was 30.3% in the goserelin acetate alone group, 27.5% in the goserelin acetate plus long-term CMA group, 20.2% in the goserelin acetate plus short-term CMA group and 53.9% in the goserelin acetate plus short-term DES-DP group. The most common ADRs occurring in all treatment groups were endocrine disorders, namely hot flushes, breast swelling/tenderness, impotence and loss of libido. The incidence of breast swelling/tenderness was significantly higher in the goserelin acetate plus short-term DES-DP group than in the other three treatment groups (P < 0.05, Tukey's test). There was also a significantly higher incidence of ADRs related to cardiovascular disorders in the goserelin acetate plus short-term DES-DP group compared with the goserelin acetate alone and goserelin acetate plus short-term CMA group (P < 0.05, Tukey's test).
Treatment was discontinued owing to ADRs in 16 patients (five patients in the goserelin acetate plus long-term CMA group, one patient in the goserelin acetate plus short-term CMA group and 10 patients in the goserelin acetate plus short-term DES-DP group) (Table 1). Eight of these ADRs leading to withdrawal were thought to be related to the goserelin acetate treatment; these included a skin rash, numbness of toes and fingers, irritation at the site of administration, bleeding at the site of administration, hepatic dysfunction, elevation of glutamate oxalate transaminase (GOT) and glutamate pyruvate transaminase (GPT) and hot flushes. Each of these ADRs occurred in only one patient, with the exception of bleeding at the site of administration which occurred in two patients. Nevertheless, there were no withdrawals due to ADRs in the goserelin acetate alone group. Four ADRs, each occurring in one patient, were thought to be related to the CMA treatment: epigastralgia, a gastrointestinal disorder, angina pectoris and hepatic dysfunction. In addition, one patient reported edema, which was thought to be related to DES-DP treatment. There was only one death due to an ADR, a patient in the goserelin acetate plus short-term DES-DP group who developed congestive heart failure. Although this symptom was considered to be an adverse reaction to DES-DP, the patient might have died as a result of the prostate cancer.Disease Flare. Compared with goserelin acetate treatment alone, CAB reduced the incidence of disease flare [defined as an aggravation or development of cancer-related symptoms (including difficulty on voiding, urinary retention, hematuria, cancer pain, arthralgia and perineal pain) attributable to a transient testosterone level elevation within 1 week of goserelin acetate administration]. The incidence of disease flare was 7.9% in the goserelin acetate alone group, 3.3% in the goserelin acetate plus long-term CMA group, 4.3% in the goserelin acetate plus short-term CMA group and 1.1% in the goserelin acetate plus short-term DES-DP group, with no significant difference between the treatment groups (Table 4). However, there was a significantly different incidence between the goserelin acetate alone group and the three treatment groups combined [7.9 versus 2.9%, P = 0.048 by Fischer's exact test (one-sided)], indicating that the incidence of disease flare was lower with CAB compared with castration alone. Increased pain was experienced by 11 patients (3.0% of all patients), including five of the 31 patients (16.1%) with EOD grade 4.
DISCUSSION
We are able to present below a full discussion of the final trial results, which was not possible when the preliminary results were reported (11).
Table 3. Response rates (presented as percentage with complete or partial response) at week 12 and best response rates for the four treatment groups
| Goserelin acetate alone (%) (n = 89) | Goserelin acetate plus long-term CMA (%) (n = 92) | Goserelin acetate plus short-term CMA (%) (n = 92) | Goserelin acetate plus short-term DES-DP (%) (n = 88) | P value from analysis of all response categories by Kruskal-Wallis test | |
| Overall | |||||
| At 12 weeks | 41.6 | 33.7 | 43.5 | 48.9 | 0.186* |
| Best response | 59.6 | 44.6 | 68.5 | 56.8 | 0.017[dagger] |
| Prostate | |||||
| At 12 weeks | 20.2 | 17.4 | 19.6 | 22.7 | 0.696 |
| Best response | 37.1 | 33.7 | 37.0 | 44.3 | 0.596 |
| Bone | |||||
| At 12 weeks | 22.2 | 9.5 | 23.8 | 22.0 | 0.070 |
| Best response | 37.1 | 1.5 | 56.3 | 34.9 | 0.019 |
| Lymph node | |||||
| At 12 weeks | 47.4 | 25.0 | 40.0 | 58.8 | 0.078 |
| Best response | 73.7 | 42.9 | 73.3 | 70.6 | 0.155 |
| PSA levels | |||||
| At 12 weeks | 92.9 | 85.1 | 93.3 | 89.0 | 0.001 |
| Best response | 92.9 | 86.2 | 93.3 | 88.0 | 0.167 |
Table 4. Adverse drug reactions at 12 weeks for the four treatment groups
| Goserelin acetate alone (n = 89)n (%) |
Goserelin acetate plus long-term CMA (n = 91)n (%) |
Goserelin acetate plus short-term CMA (n = 94)n (%) |
Goserelin acetate plus short-term DES-DP (n = 89)n (%) |
P value | |
| Endocrine | |||||
| Hot flushes | 7 (7.9) | 4 (4.4) | 4 (4.3) | 5 (5.6) | 0.693 |
| Breast swelling/tenderness | 1 (1.1) | 5 (5.5) | 1 (1.1) | 32 (36.0) | <0.001 |
| Impotence/loss of libido | 11 (12.4) | 8 (8.8) | 5 (5.3) | 10 (11.2) | 0.368 |
| Circulatory | 1 (1.1) | 2 (2.2) | 1 (1.1) | 10 (11.2) | 0.002 |
| Disease flare | 7 (7.9) | 3 (3.3) | 4 (4.3) | 1 (1.1) | 0.149 |
| All adverse drug reactions | |||||
| At 12 weeks | 27 (30.3) | 25 (27.5) | 19 (20.2) | 48 (53.9) | <0.001 |
| At follow-up | 29 (32.6) | 29 (31.9) | 25 (26.6) | 50 (56.2) | <0.001 |
CAB using CMA or DES-DP plus medical castration with goserelin acetate did not result in a survival advantage compared with treatment with goserelin acetate alone. The median progression-free survival for patients in the goserelin acetate alone group was 24 months, which is similar to other large published trials with reported median progression-free survival times of 18 months (7) and 32 months (6). However, the overall median survival rate of 49 months obtained for goserelin acetate treatment alone in our study is longer than that obtained by Boccardo et al. (7) and Tyrrell et al. (6), who observed survival rates of 32 and 35 months, respectively.
In agreement with our study, other investigators have also found no significantly improved survival advantage with CAB treatment compared with LH-RH agonist monotherapy (5-8,16,17). A meta-analysis of 25 randomized trials comparing orchidectomy with CAB concluded that current evidence does not indicate any survival advantage for CAB over orchidectomy (18), although the fairly wide 95% confidence interval (0-7% absolute improvement in 5-year survival) does not preclude a moderate survival benefit.
In contrast, some large trials have reported a significantly improved prognosis with CAB treatment compared with castration alone (2-4). In addition, two meta-analyses found a significant difference in favor of CAB for progression-free survival (19,20) and one of them found a significant improvement in overall survival (20).
Owing to conflicting results, the use of CAB in patients with advanced prostate cancer remains controversial; however, it has been suggested that specific subgroups of patients may benefit more from CAB than other patients. In our study, subgroup analysis indicated a difference in favor of CAB between the goserelin acetate alone group and the goserelin acetate plus short-term CMA group in patients with EOD grade 1. Although this result must be interpreted with caution owing to small patient numbers, other trials have also suggested that patients with minimal disease or a good prognosis may benefit more from CAB than other patients (2,4,21-23). Indeed, Sylvester et al. (24) have suggested that the European Organization for Research and Treatment of Cancer (EORTC) trial 30853 (4) showed a survival benefit for CAB whereas the EORTC trial 30843 (25) did not show such an effect because the survival advantage in the EORTC trial 30853 was limited to patients with a good prognosis (54%). There were fewer such patients (28%) in EORTC 30843 (24). Confirmation of this will require larger trials but this would be difficult to achieve in Japan owing to the low incidence of prostate cancer compared with Western countries. Indeed, the participation of more than 73 institutions was necessary to enrol the target number of patients for this study.
In our study, CAB reduced PSA levels quicker than goserelin acetate treatment alone and DES-DP had a greater effect than CMA on PSA levels. The normalization rate for PSA was significantly higher for the goserelin acetate plus DES-DP group than for the other three treatment groups after 12 weeks. This result is consistent with other studies of CAB versus castration alone (3,6).
Exploratory analysis suggested that the rate of reduction of PSA levels on treatment, PSA levels at week 12 and the PSA response rate at week 12 were predictors of disease-specific survival in all of the treatment groups; however, this requires further clarification. Similarly, Matzkin et al. (26) found that both the nadir PSA level and the percentage decline from the pretreatment level after 12 and 24 weeks' treatment with an antiandrogen or castration predicted the progression-free survival (P < 0.001). Dijkman et al. (3) also found that patients whose PSA levels were normal after 12 weeks treatment with orchidectomy plus placebo or nilutamide had significantly longer median progression-free survival (P < 0.0001) and overall survival (P < 0.0001) than those with elevated PSA levels at 12 weeks. Furthermore, CAB increased the chance of patients having normal PSA levels at 12 weeks compared with orchidectomy alone (3).
In our study, CAB resulted in a significantly lower initial rise in testosterone levels compared with goserelin acetate treatment alone and testosterone suppression remained significantly inferior in the goserelin acetate alone group compared with the long-term CMA group throughout the initial 12 weeks. This was reflected by a significantly higher incidence of disease flare in the goserelin acetate alone group compared with the CAB treatment groups; however, disease flare was not completely suppressed by CAB. Other studies have shown that pretreatment with either synthetic estrogens (27,28) or cyproterone acetate (29,30) or both (31) can prevent LH-RH agonist-induced testosterone surge; therefore, an improved result might have been obtained in our study if the antiandrogen or estrogen had been administered prior to the goserelin acetate depot rather than concomitantly.
Although CAB can be effective for suppressing disease flare, it may also result in an increased incidence of ADRs. ADRs commonly associated with LH-RH agonist therapy (including hot flushes, impotence and loss of libido) developed in all treatment groups. However, combined treatment with DES-DP resulted in a significantly higher incidence of ADRs compared with combined treatment with CMA, largely due to the increased incidence of breast swelling or tenderness and circulatory disorders.
CONCLUSIONS
Neither short- nor long-term CAB induced a survival advantage compared with goserelin acetate treatment alone. Using DES-DP as part of the CAB regimen more frequently decreased PSA levels to normal at week 12 compared with CAB using CMA or goserelin acetate treatment alone, but increased the incidence of ADRs. CAB diminished the initial elevation of testosterone compared with goserelin acetate treatment alone and the incidence of disease flare was significantly higher in the goserelin acetate alone group than the combined treatment groups. Therefore, CMA may be a useful adjunct to goserelin acetate to eliminate the initial disease flare observed in some patients following LH-RH agonist administration. The possibility of treatment modification based on the PSA response is worthy of further investigation.
AFFILIATIONS OF THE AUTHORS
1Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, 2Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki, 3Ibaraki Prefectural University of Health Sciences, Inashiki-gun, Ibaraki, 4Faculty of Medicine, The University of Tokyo, Tokyo, 5Fujieda Municipal General Hospital, Fujieda, Shizuoka, 6Tohoku University School of Medicine, Sendai, Miyagi, 7Chiba University School of Medicine, Chiba, 8Tokyo Kosei-Nenkin Hospital, Tokyo, 9Faculty of Medicine, Kyoto University, Kyoto, 10Nara Medical University, Kashihara, Nara, 11Faculty of Medicine, Kyusyu University, Fukuoka, 12Nagasaki University School of Medicine, Nagasaki and 13Faculty of Medicine, Kagoshima University, Kagoshima, Japan.
References
Received June 10, 1999; accepted August 25, 1999
For reprints and all correspondence: Toshihiko Kotake, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3, Nakamichi, Higashinari-ku, Osaka 537-8511, Japan
Abbreviations: ADR, adverse drug reaction; CAB, combined androgen blockade; CMA, chlormadinone acetate; DES-DP, diethylstilbestrol diphosphate; ECOG, Eastern Cooperative Oncology Group; EOD, extent of disease; EORTC, European Organization for Research and Treatment of Cancer; LH-RH, luteinizing hormone-releasing hormone; PSA, prostate-specific antigen.
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