Japanese Journal of Clinical Oncology 34:20-28 (2004)
© 2004 Foundation for Promotion of Cancer Research
Superior Anti-tumor Efficacy of Bicalutamide 80 mg in Combination with a Luteinizing Hormone-releasing Hormone (LHRH) Agonist Versus LHRH Agonist Monotherapy as First-line Treatment for Advanced Prostate Cancer: Interim Results of a Randomized Study in Japanese Patients
1 Department of Urology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki, 2 Department of Urology, Harasanshin Hospital, Fukuoka, 3 Department of Urology, Kansai Medical University, Osaka, 4 Department of Urology, Shimane Medical University, Izumo, Shimane, 5 Department of Urology, Okayama University Graduate School of Medicine, Okayama, 6 Department of Urology, Nishi-Kobe Medical Center, Kobe, 7 Department of Urology, Tohoku University School of Medicine, Sendai, 8 Department of Urology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, 9 Department of Urology, Kyushu University, Fukuoka, 10 Department of Urology, Nagasaki University School of Medicine, Nagasaki and 11 Department of Biostatistics, School of Health Sciences and Nursing, The University of Tokyo, Tokyo, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Objectives: To evaluate bicalutamide (Casodex) 80 mg as a component of maximum androgen blockade (MAB) in Japanese patients with previously untreated advanced prostate cancer.
Methods: 205 patients with previously untreated stage C/D prostate cancer were randomized (1:1) to receive once-daily bicalutamide 80 mg or placebo, each combined with a luteinizing hormone-releasing hormone (LHRH) agonist. Primary study variables were the 12 week prostate-specific antigen (PSA) normalization (i.e. PSA level 
4 ng/ml) rate, the 12 week overall tumor response rate (proportion with a partial response or better) and the proportion of withdrawals due to adverse drug reactions (ADRs) at follow-up. This interim analysis was undertaken after a minimum of 6 months’ follow-up (median 15 months).
Results: The 12 week PSA normalization rate was 79.4% for MAB and 38.6% for LHRH agonist monotherapy (P < 0.001). The 12 week overall tumor response rate was 77.5 and 65.3%, respectively (P = 0.063). The withdrawal rate due to ADRs was 8.8% and 10.9%, respectively. There were differences in favor of MAB over monotherapy with respect to time to treatment failure (TTTF) (P = 0.038) and time to progression (TTP) (P = 0.016). There have been too few deaths (n = 10) to analyze survival. The profiles of adverse events and ADRs were broadly similar in the two treatment groups.
Conclusion: In Japanese patients with advanced prostate cancer, first-line treatment with bicalutamide 80 mg in combination with an LHRH agonist is superior to LHRH agonist monotherapy in terms of the antitumor response at 12 weeks, and also time to treatment failure and progression, and does not compromise treatment safety. The study is ongoing.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Maximum androgen blockade (MAB), combination therapy of either a luteinizing hormone-releasing hormone (LHRH) agonist or orchiectomy with an antiandrogen, is widely used in Japan for treating advanced prostate cancer. The rationale for MAB is that while castration prevents testicular androgen synthesis, androgens of adrenal origin are largely unaffected and may continue to stimulate the growth of hormone-sensitive prostate cancer cells. The addition of an antiandrogen to castration antagonizes the action of these androgens at the receptor level. Despite this clear theoretical rationale, clinical trial results have been equivocal, although none has shown a significant advantage in favor of castration alone and MAB has been the subject of considerable controversy for at least a decade (1).
A recent Prostate Cancer Trialist’s Collaborative Group (PCTCG) meta-analysis of 27 MAB trials (those begun before 1991 and which therefore used flutamide, nilutamide or cyproterone acetate as the antiandrogen component) found that the magnitude of the 5-year survival benefit for MAB appeared to be influenced by the antiandrogen component, with non-steroidal antiandrogens having an advantage over steroidal compounds (1). Only one large study of MAB, using the steroidal antiandrogen chlormadinone, has been conducted in Japanese patients (2,3). This study found no advantage for MAB compared with goserelin acetate (Zoladex) monotherapy. Given the results of the PCTCG meta-analysis, an evaluation of non-steroidal antiandrogens as a component of MAB for Japanese patients would seem to be warranted. Indeed, a phase III study of flutamide in this setting is under way. Flutamide in the standard dosages used for MAB in Japanese patients (375 mg/day) has, however, been associated with a high incidence of hepatic dysfunction (12–40%), often necessitating treatment withdrawal (4–7). Flutamide therapy may also be complicated by diarrhea in up to 26% of patients (8–10) and may be severe, requiring withdrawal from treatment.
The non-steroidal antiandrogen bicalutamide (Casodex) was approved at a dose of 80 mg once daily for use as monotherapy in Japan in 1999. A phase III trial conducted by Schellhammer and co-workers (9,10) has demonstrated tolerability advantages for bicalutamide over flutamide as a component of MAB in Caucasians, specifically with respect to abnormal hepatic function and diarrhea, and provides a rationale for evaluating bicalutamide as a component of MAB in Japanese subjects. An initial 12 week non-comparative pilot study of bicalutamide 80 mg combined with the LHRH agonist goserelin (Zoladex) showed that combination achieved a high antitumor response (87%) and was well tolerated with no withdrawals due to adverse drug reactions (ADRs) (11). We therefore initiated a large long-term comparative study of bicalutamide-based MAB versus LHRH agonist monotherapy. One of the primary objectives of this study was to examine the safety of bicalutamide-based MAB and accordingly the withdrawal rate due to ADRs was set as a primary variable and the study powered on this basis. The study was also powered to verify the superior efficacy of MAB over monotherapy in terms of the prostate-specific antigen (PSA) normalization rate and overall tumor response after 12 weeks’ therapy.
This paper reports the results from the first full set analysis of our study, including those for the primary study variables, and also interim results on time to treatment failure (TTTF), time to progression (TTP) and survival. This analysis was undertaken after all patients had completed at least 6 months’ follow-up, the minimum follow-up at the first analysis of Schellhammer et al.’s study (9).
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Study Design
This ongoing study has two phases, an initial randomized, double-blind, placebo-controlled phase, followed by an open phase (from September 20, 2002). All data in this paper were obtained under double-blind conditions (data cut-off June 17, 2002).
The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and Good Clinical Practice requirements. The Institutional Review Board at all participating institutions approved the protocol. An Independent Data Monitoring Committee was established to conduct annual interim assessments of the study.
Patients
Patients were recruited at 49 centers in Japan (listed at the end of the paper) between February 2000 and December 2001. Eligibility criteria for the study were: age 
20 years; histologically proven, previously untreated, advanced (stage C or D) prostate cancer; measurable or evaluable lesions; performance status 0–2; baseline PSA level 10 ng/ml; and life expectancy 3 months. Exclusion criteria were: liver enzymes >2.5 times the upper limit of the normal range (ULN); serum creatinine 1.5 ULN; white blood cell count <3000/mm3; hemoglobin (Hb) <10.0 g/dl; platelets <7.5 x 104/mm3; other active malignancy; dyspnea at rest; refractory cardiac failure; and history of hypersensitivity to LHRH or its derivatives or components of the LHRH agonist formulations. All patients provided written informed consent prior to study entry.
Study Treatment
Enrolled patients were randomized in a 1:1 manner to receive either bicalutamide 80 mg or matching placebo once daily. In addition, all patients received an LHRH agonist according to the investigator’s choice, either goserelin acetate 3.6 mg or leuprorelin acetate 3.75 mg, given by subcutaneous depot injection every 4 weeks. The randomized drug number was assigned by EPS (Tokyo, Japan) using a permuted block design with size 4. Random allocation was also performed by EPS using a computer-generated dynamic allocation method (a modified minimization method), taking account of the following factors: center, type of LHRH agonist, clinical stage (C, D1 or D2), age (74 years, 75 years), performance status (0, 1 or 2) and baseline PSA level (<60 ng/ml, 60 ng/ml).
In the event of disease progression in the MAB group, bicalutamide 80 mg was withdrawn and patients monitored for the antiandrogen withdrawal syndrome (these results will be reported on study completion). Subsequent therapy was initiated at the investigator’s discretion. Patients who progressed in the monotherapy group were also treated at the investigator’s discretion, with the addition of bicalutamide 80 mg being one option (second-line responses to bicalutamide 80 mg will be reported on study completion).
Randomized treatment was given in a double-blind manner until September 20, 2002, when the key was broken. Subsequently, patients in the monotherapy group discontinued placebo, whereas in the MAB group bicalutamide 80 mg was continued in an open-label manner. Patients without disease progression or other withdrawal criteria will continue to receive study treatment (LHRH agonist ± bicalutamide 80 mg) until November 2003. All patients will be followed for disease progression and survival until December 2003.
Assessments
Patients were assessed, examined or evaluated for general health and adverse events (AEs) at baseline and 1, 4, 5, 8 and 12 weeks after commencing study treatment, then every 4 weeks until progression (or earlier treatment withdrawal) and then annually for progression (where appropriate) and survival.
The primary lesion and metastatic sites were assessed clinically and by appropriate imaging techniques (scintigraphy, CT, MRI, ultrasound, X-ray) at baseline, 12 weeks and as appropriate (best objective response or disease progression). PSA levels were assayed (radioimmunoassay method) by a central laboratory every 4 weeks until disease progression, with blood sampling performed before any prostatic assessments (biopsy, palpation, ultrasound). Quality of life was assessed using the Japanese version of the Functional Assessment of Cancer Therapy – Prostate (FACT-P) (12), which was completed by the patient at baseline and weeks 1, 5 and 24; the results will be reported in a separate paper (in preparation). Blood samples for routine laboratory tests were collected every 4 weeks until 12 weeks after randomization and then every 12 weeks thereafter.
Details of AEs, including abnormal laboratory data, were recorded at each visit during study treatment and up to 4 weeks after treatment withdrawal. Events for which a causal relationship to the study drug(s) could not be excluded were classified as ADRs.
Statistical Analysis
The primary study variables were the PSA normalization rate [defined as the proportion of patients with a normal (4 ng/ml) PSA level] and overall tumor response rate [defined as the proportion of patients with a partial response or better using the Criteria for Efficacy Evaluation of Non-Invasive Treatment of Prostate Cancer (13)] at 12 weeks and the rate of withdrawals due to ADRs at the time of data cut-off (June 17, 2002). Calculations on the sample size required assumed that these variables would be similar to those observed in previous studies: PSA normalization and overall tumor response as in the pilot studies of MAB using non-steroidal antiandrogens (90 and 75%, respectively) (11,14) and a large study of goserelin monotherapy (50 and 50%, respectively) (2), all of which were conducted in Japanese patients; withdrawals due to ADRs as in a long-term study of bicalutamide-based MAB in Caucasians (5.5%) (9) and long-term studies of goserelin and leuprorelin in Japanese and Caucasian patients (1%) (14–17). The percentage of withdrawals due to ADRs in the MAB group was considered clinically acceptable if the upper limit of the 95% confidence interval (CI) for the difference between the two treatment groups was <12.5%. Based on these assumptions, the required sample size (90% power, two-sided significance level of 0.05) was 200 patients (100 in each treatment group).
All patients who received at least one dose of the randomized drug were included in the analyses. Point estimates and 95% CIs [Newcombe method (18)] were calculated for each of the primary efficacy and safety variables and also for the difference between the two treatment groups. In addition, Fisher’s exact test was used for the primary efficacy variables. In order to avoid the problem of multiplicity and maintain the two-sided significance level of 0.05, the difference in the overall tumor response rate was tested only after a significant difference in PSA normalization rate was observed between the treatment groups. Further analyses of both primary efficacy variables were undertaken with patients stratified by the prognostic factors (center, type of LHRH agonist, clinical stage, age, performance status and baseline PSA level) using the same method.
The secondary study variables included tumor response rates at 12 weeks by lesion site (primary, bone, lymph nodes, PSA response), time to PSA normalization, TTTF, TTP, survival, AEs and ADRs. TTTF was defined as the number of days between the first dose of study treatment (earliest of LHRH agonist or randomized therapy) and the earliest of study treatment withdrawal, disease progression or death. TTP was defined as the number of days between the first dose of study treatment and either disease progression or death. Progression as established using the Japanese Urological Association Criteria, 3rd edition (19). The Cox proportional hazards model, including randomized treatment and with covariates for the prognostic factors, was used for all time to event data. In addition, time to PSA normalization, TTTF and TTP were compared between the treatment groups using the log-rank test. The incidence of AEs and ADRs was calculated.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Patients’ Characteristics
A total of 205 patients were enrolled in this study; 102 were assigned to MAB and 103 to monotherapy. Two patients in the monotherapy group withdrew from the study before commencing randomized treatment owing to deterioration of performance status or failure to attend for hospital visit (Fig. 1) and were excluded from all analyses. Of the remaining patients, 156 (76.8%) received goserelin acetate and 47 (23.2%) received leuprorelin acetate. Patients’ and disease characteristics in the two treatment groups are presented in Table 1. Although the method of randomization ensured balance between the two groups in terms of clinical stage (C/D1, D2) (Table 1), differences in terms of TNM staging were apparent [T4, 14.7% in the MAB group versus 22.8% in the monotherapy group (P = 0.157); N1, 27.5% versus 37.6%, respectively (P = 0.122)]; it was considered unlikely that this difference would bias the results.
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By the data cut-off point, 33 patients (32.4%) in the MAB group and 46 patients (45.5%) in the monotherapy group had discontinued randomized treatment (Fig. 1). All but one of these patients (from the MAB group) continued to be followed for disease progression. Median follow-up in the MAB and monotherapy groups was 465 and 468 days, respectively.
Efficacy
Primary Endpoint
As shown in Table 2, the 12 week PSA normalization rate was significantly higher in the MAB group than in the monotherapy group (79.4% versus 38.6%, P < 0.001). Exploratory analyses showed that in patients with a baseline PSA <60 ng/ml, the rate of PSA normalization at 12 weeks was 95.0% with MAB and 62.2% with monotherapy, whereas in patients with a PSA level 60 ng/ml, the rates were 69.4 and 25.0%, respectively. Thus, the difference between the treatment groups was greater when the baseline level was 60 ng/ml compared with <60 ng/ml (44.4 versus 32.8%). Twelve week PSA normalization rates in patients with C/D1 disease were 89.8 and 42.1%, respectively. The corresponding rates for D2 disease were 65.1 and 34.1%, respectively. Thus, the difference between MAB and monotherapy was greater in C/D1 than D2 disease (47.7 versus 31.0%). Patients aged 75 years also had higher rates of PSA normalization at 12 weeks than younger patients, although the difference in the rate of PSA normalization between the treatment groups was greater in those aged <75 years than those aged 75 years (47.5 versus 34.7%). The choice of LHRH agonist did not influence either the normalization rates or the difference between the treatment groups.
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The 12 week overall tumor response rate was greater in the MAB group than the monotherapy group (77.5 versus 65.3%), although the difference did not achieve statistical significance (P = 0.063; Table 2). Exploratory analyses revealed that in both treatment groups, patients with C/D1 disease and those aged
75 years had higher response rates than those with D2 disease and aged <75 years, respectively.
Secondary Endpoints
When analyzed by lesion site, tumor response rates at 12 weeks at all sites (primary, bone, lymph nodes), and also the PSA response rates, were higher with MAB than monotherapy (Table 3).
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PSA normalization (at any time during follow-up) occurred in 95 (93.1%) patients in the MAB group and 57 (56.4%) in the monotherapy group. The time course of PSA normalization differed (P < 0.001) between the two groups (Fig. 2); the median time to normalization was 8.1 weeks in the MAB group and 24.1 weeks in the monotherapy group. The HR for PSA normalization for MAB relative to monotherapy was 4.09 (95% CI 2.85, 5.88).
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Treatment failure occurred in 33 patients (32.4%) in the MAB group and 46 (45.5%) in the monotherapy group. The median TTTF was 96.1 and 67.7 weeks, respectively, a difference of 28.4 weeks (P = 0.038) (Fig. 3). The HR for TTTF for MAB relative to monotherapy was 0.60 (95% CI 0.38, 0.94). Seventeen (16.7%) patients in the MAB group and 30 (29.7%) in the monotherapy group experienced disease progression (P = 0.016). The Kaplan–Meier plot of TTP is presented in Fig. 4. The median TTP was not reached in either group. The risk of progression during follow-up was reduced by 54% in the MAB group relative to the monotherapy group (HR 0.46, 95% CI 0.25, 0.84; P = 0.011).
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There have been 10 deaths to date, six in the monotherapy group and four in the MAB group. Six of these were due to prostate cancer, four in the monotherapy group and two in the MAB group. There are currently too few events for further analysis of overall or disease-specific survival.
Safety
The median duration of exposure to randomized therapy was 48.2 weeks (range 2.9–115.9 weeks) in the MAB group and 40.1 weeks (range 0.7–112.1 weeks) in the monotherapy group.
Primary Endpoint
Nine patients (8.8%) in the MAB group and 11 (10.9%) in the monotherapy group withdrew owing to ADRs, an estimated difference of –2.1% (95% CI, –10.7%, 6.4%) (Table 2).
Secondary Endpoints
AEs occurred in 90 patients (88.2%) in the MAB group and 84 (83.2%) of those in the monotherapy group, while ADRs were recorded for 61 (59.8%) and 59 (58.4%) patients, respectively (Table 4). The most common AEs in the study population as a whole were hot flushes, nasopharyngitis, abnormal hepatic function, back pain, anemia, pruritus, arthralgia, eczema and constipation. The most common ADRs were hot flushes, anemia and abnormal hepatic function. The profiles of AEs and ADRs were broadly similar in the two groups (Table 4).
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The incidence of hot flushes in the MAB group was lower than in the monotherapy group (18.6 versus 31.7%). A further 2% of patients in the MAB group reported increased sweating, night sweats and ‘feeling hot’. All events relating to hot flushes were mild to moderate in severity (grade 2 or lower). Overall, ADRs relating to abnormal hepatic function were reported by 13.7 and 17.8% of patients, respectively. Two patients in the MAB group had a grade 4 ADR relating to hepatic function, while one patient in each group had a grade 3 ADR. The incidence of anemia (including decreased red blood cell counts, Hb and/or hematocrit) was slightly higher in the MAB group than the monotherapy group (7.8% versus 5.9%). Gynecomastia/breast pain occurred in <2% of patients in each treatment group. Two (2.0%) patients in the monotherapy group experienced urinary retention, presumed to be due to tumor flare. Symptoms related to tumor flare were not seen in the MAB group. Four patients died of conditions unrelated to prostate cancer (pancreatic cancer, gastric cancer, cerebral infarction, accident), two in each treatment group. None of them died during the study treatment period, nor were the deaths considered to be related to study treatment.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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The results presented here demonstrate that after 12 weeks’ therapy, MAB using bicalutamide 80 mg has superior efficacy to LHRH agonist monotherapy. The estimate of the difference in the PSA normalization rate was 40.8% (79.4 versus 38.6%; P < 0.001), and that for overall tumor response was 12.1% (77.5 versus 65.3%; P = 0.063). In both groups, the PSA normalization rate was ~10% lower than expected. This may be due to differences in the distribution of clinical stage and baseline PSA between our patients and those in the studies on which the estimates were based (2,11,14), and also the higher rate of early treatment withdrawal in our study. The overall tumor response rate seen in the monotherapy group was higher than expected, whereas that in the MAB group was in accordance with our expectations and hence the between-group difference just failed to achieve statistical significance (P = 0.063). The higher than expected result in the monotherapy group is probably attributable to the larger (two-fold) proportion of patients with stage C/D1 disease (who are more likely to achieve a partial response than patients with D2 disease) than in the reference study (2). The favorable efficacy results for MAB at 12 weeks are supported by the interim analyses of TTTF and TTP, both of which also favored MAB. The number of deaths, however, is too small to assess survival. Follow-up for both progression and survival is ongoing. Additionally, in the first 24 weeks of the study, symptom-related quality of life improved in both groups, with the MAB group showing the greater improvement (data will be reported in a separate paper, in preparation).
While the overall benefits of MAB appear to be modest in studies conducted to date (1), there is some evidence to suggest that patients with minimal disease derive greater benefit than those with extensive metastatic disease (20–22). Our 12 week PSA normalization rate results provide some support for this hypothesis, with the benefit for MAB being greater in patients with C/D1 disease than those with D2 disease. However, at first glance, this result would appear to conflict with our finding that the benefit of MAB was greater in patients with a baseline PSA level 60 ng/ml (who would be expected to have more advanced disease) than those with a level <60 ng/ml. Examination of the distribution of disease stage within each PSA subgroup reveals that 44.4% of patients with a PSA level 60 ng/ml had C/D1 disease at study entry (30 patients in the MAB group and 26 in the monotherapy group), thereby explaining, at least partly, the apparent contradiction between the exploratory analyses by stage and baseline PSA level.
The only published phase III study of MAB in Japanese patients utilized the steroidal antiandrogen chlormadinone (2,11). In that study, neither short-term MAB (antiandrogen given for 8 weeks) nor long-term MAB demonstrated an advantage over goserelin acetate (Zoladex) monotherapy with respect to the short-term (12 week) antitumor effect (assessed similarly to our study). Furthermore, time to objective progression, overall survival and disease-specific survival showed no difference between the different treatment groups. The difference between the findings of these studies appears to be in accordance with the conclusions of the PCTCG meta-analysis of MAB trials (which did not include bicalutamide studies) (1) that non-steroidal antiandrogens provide greater benefit within the MAB setting than steroidal antiandrogens.
The percentage of withdrawals due to ADRs, the primary safety variable, was lower with MAB (8.8%) than monotherapy (10.9%). These figures were higher than our estimates for both treatment groups (5.5 versus 1%). However, presumably because of the double-blind nature of the study, almost half of the withdrawals in our study (9/20) were actually for low-grade (1 or 2) ADRs. Additionally, a further four of the withdrawals for conditions classified as ADRs under double-blind conditions were for events that are not generally regarded as being causally related to the study drugs (cerebrovascular disease, acute myocardial infarction, atrial fibrillation, alcoholic liver disease).
Overall, the safety profile of MAB therapy was broadly similar to that of monotherapy, with respect to both pharmacological and non-pharmacological events. The effect of bicalutamide on hepatic function was an important consideration in this study as there are several reports that flutamide used in MAB in Japanese patients (dosage 375 mg/day) is associated with a high incidence (12–40%) of impaired hepatic function (4–7). Furthermore, flutamide-related hepatotoxicity appears to occur more frequently in Japanese patients receiving MAB than in Caucasians, despite the 50% reduction in dosage (10). Reassuringly in our study, neither the total number of patients with any abnormal hepatic function test result nor the frequency of elevations of individual enzymes was markedly higher in the MAB group than in the monotherapy group. However, as two grade 4 events did occur in the MAB group, we do recommend periodic testing of hepatic function.
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CONCLUSIONS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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These interim findings show that, when given as first-line treatment for advanced prostate cancer, bicalutamide 80 mg in combination with an LHRH agonist significantly improves the PSA normalization rate at 12 weeks and reduces the risk of treatment failure and disease progression compared with LHRH agonist monotherapy, without compromising tolerability. The study is ongoing.
Study Institutions Listed in Descending Order of the Number of Enrolled Patients
Harasanshin Hospital; Kansai Medical University Hospital; Shimane Medical University Hospital; Nishi-Kobe Medical Center; Okayama University Hospital; Showa University Hospital; Nihon University Itabashi Hospital; Fujieda Municipal General Hospital; Kurashiki Central Hospital; Tokushima University Hospital; National Shikoku Cancer Center; Tokyo Medical University Hospital; Gifu University Hospital; Kanazawa University Hospital; Nara Medical University Hospital; Kobe University Hospital; Kyushu University Hospital; National Nagasaki Medical Center; Hirosaki University School of Medicine and Hospital; Tokyo Women’s Medical University Hospital; Keio University Hospital; Kyoto University Hospital; Osaka University Hospital; Kawasaki Medical School Hospital; Hiroshima University Medical Hospital; Nagasaki University Hospital; Sasebo Municipal General Hospital; Yamagata University Hospital; The University of Tokyo Hospital; Kitasato University Hospital; Teikyo University Ichihara Hospital; University Hospital, Kyoto Prefectural University of Medicine; Osaka City University Hospital; Sapporo Medical University Hospital; Tohoku University Hospital; Niigata University Medical Hospital; Niigata Cancer Center Hospital; Tsukuba University Hospital; The Jikei University Hospital; Kokuho Asahi Central Hospital; Yokohama City University Hospital; Nagoya Daini Red Cross Hospital; Nagoya City University Hospital; Kochi Medical School Hospital; Hokkaido University Medical Hospital; Toranomon Hospital; Chiba University Hospital; Osaka Medical Center for Cancer and Cardiovascular Diseases; Tottori University Hospital.
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FOOTNOTES |
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+ For reprints and all correspondence: Hideyuki Akaza, Department of Urology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba City, Ibaraki 305-8575, Japan. E-mail: akazah{at}md.tsukuba.ac.jp
Casodex and Zoladex are trademarks of the AstraZeneca group of companies.
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REFERENCES |
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Received August 14, 2003; accepted November 27, 2003
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