Two years of bicalutamide monotherapy in patients with biochemical relapse after radical prostatectomy

Two years of bicalutamide monotherapy in patients with biochemical relapse after radical... Abstract Background Salvage treatments for biochemical relapse (BCR) after radical prostatectomy (RP) have several problems in terms of indications or adverse events. We studied the possibility of 2 years of bicalutamide monotherapy for BCR after RP. Methods Patients who showed BCR (prostate-specific antigen (PSA) ≥ 0.2 ng/ml) after RP were recruited. Protocol treatment was planned as 2 years of bicalutamide (80 mg/day) followed by observation. Protocol treatment failure was defined as PSA re-elevation of ≥0.2 ng/ml, clinical progression, any other treatments, or discontinuation or restart of bicalutamide. Primary endpoint of this study is time to protocol treatment failure from initiation of bicalutamide. Results A total of 91 patients were registered between 2003 and 2009. Median age and PSA at initiating bicalutamide were 68 (range, 55–78) years and 0.32 (range, 0.19–7.91) ng/ml. Twenty-four (26.4%) patients could not complete 2 years of bicalutamide mainly due to progression of disease. Of the 91 patients, 2- and 5-year protocol treatment failure-free survivals were 74.6% and 33.0%, with a median follow-up of 76 (range, 11–118) months. Median time from initiating bicalutamide to treatment failure was 43 (95% confidence interval, 33–47) months. High-risk status at RP and time to BCR after RP < 6 months were significant predictors of second BCR. Conclusions Two years of bicalutamide monotherapy should not be recommended as standard management for BCR after RP, but might be feasible for selected patients who do not have high-risk status at RP and short time to BCR. prostate cancer, salvage therapy, bicalutamide, prostatectomy, biochemical relapse Introduction The use of radical prostatectomy (RP) for localized or locally advanced prostate cancer has been increasing, mainly because of increases in the incidence of prostate cancer and the adoption of robot-assisted laparoscopic surgery in Japan. Over 20 000 patients with prostate cancer were estimated to have undergone RP in Japan in 2016 (1). RP has been one of the gold-standard treatments for prostate cancer, but a significant proportion of patients treated with RP unfortunately experience significant disease burden with an elevation of prostate-specific antigen (PSA). Previous studies have reported that around 30% of patients treated with RP experience biochemical relapse (BCR) after RP (2,3). Management for BCR after RP includes salvage radiation therapy (SRT) or salvage hormonal therapy (SHT), but both SRT and SHT show considerable problems in terms of adverse events or indications. The incidence of acute genitourinary and gastrointestinal toxicity with SRT is reportedly over 50% (4). Grade 3 or 4 adverse events are relatively rare, but sometimes persist and can prove resistant to treatment (4–7). Several previous studies have demonstrated that early SRT with lower PSA level was associated with better oncological outcomes (8–10), but overtreatment is also possible in patients with low PSA levels (11). SHT is usually recommended for patients with unfavorable factors (e.g., shorter PSA doubling time, Gleason score 8 or greater, pathological stage T3 or greater) (12,13), but the optimal timing for starting SHT has not been determined, and evidence confirming that SHT can prolong overall survival has been lacking. In addition, long-term hormonal treatment with surgical or medical castration can lead to unfavorable metabolic changes such as weight gain, metabolic syndrome, osteoporosis, diabetes mellitus and cardiovascular disease (14,15). Bicalutamide is an androgen-receptor blocker that works against prostate cancer without suppressing testosterone levels. Few severe adverse events are associated with bicalutamide use, besides gynecomastia, which occurs in up to 70% of patients treated with bicalutamide (13,16–18). In 2006, McLeod et al. showed that 2 years of bicalutamide monotherapy (150 mg) after RP or radiation therapy did not provide any clinical benefit in terms of progression-free survival or overall survival, despite prolonging the time to PSA progression compared to placebo (17), but bicalutamide was administered as an adjuvant in that study, and a substantial proportion of patients were considered to have a low risk of BCR after RP. We considered that 2 years of bicalutamide monotherapy for BCR after RP might offer several advantages, in terms of a lower incidence of adverse events compared to SRT or SHT, and the possibility of avoiding overtreatment by terminating bicalutamide within 2 years. We therefore designed this single-arm prospective study to determine the effects of 2 years of bicalutamide monotherapy for BCR after RP. Methods This study was prospectively designed, and the ethics committees of all participating institutions approved the study procedure. All patients provided written informed consent prior to enrollment. Patients who presented with BCR after RP were recruited from a total of seven institutions (Tohoku University, Hirosaki University, Yamagata Prefectural Central Hospital, Akita City Hospital, Akita University, Akita Kousei Medical Center, Osaki Citizen Hospital). BCR after RP was defined as PSA elevation of ≥0.2 ng/ml after RP, and second BCR was defined as PSA re-elevation of ≥0.2 ng/ml during or after 2 years of bicalutamide monotherapy. Patient characteristics including age, PSA level, clinical stage, Gleason score and D’Amico risk classification (19) before RP, pathological stage, Gleason score and resection margin status after RP, time from RP to BCR, and age and PSA level at initiation of bicalutamide were recorded. Protocol treatment (PT) was set as bicalutamide administered at 80 mg/day for 2 years, then follow-up without any treatment for prostate cancer. PT failure was defined as follows: PSA elevation of ≥0.2 ng/ml, any treatment changes other than bicalutamide monotherapy, discontinuation of bicalutamide due to adverse effects or patient choice during the 2 years of bicalutamide, and PSA re-elevation of ≥0.2 ng/ml, or any treatment for prostate cancer including restarting bicalutamide after completion of 2 years of bicalutamide. Gynecomastia and other Grade 3 or greater adverse events during 2 years of bicalutamide were evaluated according to the National Cancer Institute – Common Toxicity Criteria version 2 (20). Primary endpoint of this study is time to PT failure from initiation of bicalutamide. Secondary endpoints are second BCR free survival from initiation of bicalutamide and adverse events during 2 years of bicalutamide monotherapy. PT failure-free survival from initiation of bicalutamide in all patients and in patients who completed the 2 years of bicalutamide was analyzed using the Kaplan–Meier method. Cox proportion regression analyses were used to develop a predictive model assessing the risk of PT failure and second BCR. All statistical analyses were performed using EZR version 1.35 (Saitama Medical Center, Jichi Medical University) (21), a graphical user interface for R (The R Foundation for Statistical Computing, version 3.3.2). All P values were two-sided, with P < 0.05 considered significant. Results Ninety-one patients who presented with BCR after RP were enrolled in this study between 2003 and 2009. Table 1 shows the characteristics of the 91 patients at the start of 2 years of bicalutamide. Neoadjuvant hormonal therapy was performed in three patients before RP, but no patients underwent any treatments between RP and initiation of bicalutamide. Table 1. Characteristics of the 91 registered patients at start of 2 years of bicalutamide At radical prostatecomy  Median age at operation (years) 68 [range 55, 78]  Median PSA before biopsy (ng/ml) 9.2 [range 4.20, 34.83]  Neoadjuvant hormonal therapy 3 (3.3%)  Damico’s risk classifications   Low 8 (8.8%)   Intermediate 45 (49.5%)   High 38 (41.8%) Pathological results  Gleason score eight or greater 37 (40.7%)  pT3 or greater 61 (67.0%)  Positive resection margin 45 (49.5%)  pN1 1 (1.1%) At start of bicalutamide  Median age at administration (years) 69 [range 56, 79]  Median PSA (ng/ml) 0.32 [range 0.19, 7.91]  Median time to BCR (months) 11 [range 0, 70] At radical prostatecomy  Median age at operation (years) 68 [range 55, 78]  Median PSA before biopsy (ng/ml) 9.2 [range 4.20, 34.83]  Neoadjuvant hormonal therapy 3 (3.3%)  Damico’s risk classifications   Low 8 (8.8%)   Intermediate 45 (49.5%)   High 38 (41.8%) Pathological results  Gleason score eight or greater 37 (40.7%)  pT3 or greater 61 (67.0%)  Positive resection margin 45 (49.5%)  pN1 1 (1.1%) At start of bicalutamide  Median age at administration (years) 69 [range 56, 79]  Median PSA (ng/ml) 0.32 [range 0.19, 7.91]  Median time to BCR (months) 11 [range 0, 70] PSA, prostate-specific antigen; BCR, biochemical relapse. Table 1. Characteristics of the 91 registered patients at start of 2 years of bicalutamide At radical prostatecomy  Median age at operation (years) 68 [range 55, 78]  Median PSA before biopsy (ng/ml) 9.2 [range 4.20, 34.83]  Neoadjuvant hormonal therapy 3 (3.3%)  Damico’s risk classifications   Low 8 (8.8%)   Intermediate 45 (49.5%)   High 38 (41.8%) Pathological results  Gleason score eight or greater 37 (40.7%)  pT3 or greater 61 (67.0%)  Positive resection margin 45 (49.5%)  pN1 1 (1.1%) At start of bicalutamide  Median age at administration (years) 69 [range 56, 79]  Median PSA (ng/ml) 0.32 [range 0.19, 7.91]  Median time to BCR (months) 11 [range 0, 70] At radical prostatecomy  Median age at operation (years) 68 [range 55, 78]  Median PSA before biopsy (ng/ml) 9.2 [range 4.20, 34.83]  Neoadjuvant hormonal therapy 3 (3.3%)  Damico’s risk classifications   Low 8 (8.8%)   Intermediate 45 (49.5%)   High 38 (41.8%) Pathological results  Gleason score eight or greater 37 (40.7%)  pT3 or greater 61 (67.0%)  Positive resection margin 45 (49.5%)  pN1 1 (1.1%) At start of bicalutamide  Median age at administration (years) 69 [range 56, 79]  Median PSA (ng/ml) 0.32 [range 0.19, 7.91]  Median time to BCR (months) 11 [range 0, 70] PSA, prostate-specific antigen; BCR, biochemical relapse. Of the 91 patients who started bicalutamide, 24 (26.4%) experienced treatment failure within 2 years. Reasons for discontinuation of bicalutamide were as follows: second BCR within 2 years of bicalutamide in 15 patients; cessation of bicalutamide in eight patients (due to own choice in four and gynecomastia in four); and other advanced cancer in one patient. Figure 1 shows PT failure-free survival from the initiation of bicalutamide. Two- and five-year PT failure-free survivals in all 91 patients were 74.6% (95% confidence interval (CI), 64.2–82.3%) and 33.0% (95%CI, 23.2–43.1%), respectively, with a median follow-up of 76 months (range, 11–118 months). Median time to treatment failure from initiation of bicalutamide was 43 (95% CI, 33–47) months. The 5-year second BCR-free survival was 37.2%. Figure 1. View largeDownload slide Kaplan–Meier estimate of protocol treatment failure-free survival from start of 2 years of bicalutamide monotherapy in all 91 patients. Figure 1. View largeDownload slide Kaplan–Meier estimate of protocol treatment failure-free survival from start of 2 years of bicalutamide monotherapy in all 91 patients. Figure 2 shows PT failure-free survival in all 62 patients who completed 2 years of bicalutamide treatment and were then followed-up. Five patients who continued bicalutamide beyond the 2 years of the PT were excluded from this analysis. The 5-year PT failure-free survival rate from initiation of bicalutamide was 44.3% (95% CI, 31.6–56.2%). Median survival time to treatment failure from initiation of bicalutamide was 51 (95% CI, 43–65) months. Figure 2. View largeDownload slide Kaplan–Meier estimate of protocol treatment failure-free survival from start of 2 years of bicalutamide in the 62 patients who completed 2 years of bicalutamide monotherapy and were then followed by observation. Figure 2. View largeDownload slide Kaplan–Meier estimate of protocol treatment failure-free survival from start of 2 years of bicalutamide in the 62 patients who completed 2 years of bicalutamide monotherapy and were then followed by observation. Cox proportional hazard analyses predicting PT failure or second BCR were performed. Pathological Gleason score ≥8, pT3 or greater and PSA at initiation of bicalutamide >0.4 ng/ml were excluded from multivariate analyses, as these factors correlated strongly with high-risk status at RP, positive resection margin and time to BCR after RP < 6 months, respectively. Although no factors were associated with PT failure in the 91 patients who started 2 years of bicalutamide in multivariate analysis, high-risk status at RP and time to BCR after RP < 6 months were both significantly associated with second BCR (Table 2). Figure 3 shows the second BCR-free survival according to the number of risk factors based on the analysis. Five-year second BCR-free survivals in patients with zero, one and two risk factors were 41.4%, 45.6% and 7.8%, respectively. Patients with both risk factors (high-risk group and time to BCR after RP < 6 months) showed a significantly higher incidence of second BCR than those with zero or one risk factor (P < 0.001). Table 2. COX proportion hazard analysis predictors of PT failure and second BCR in all 91 patients PT failure second BCR Hazard ratio (95%CI) P value Hazard ratio (95%CI) P value Univariate  Age 70 years or greater 1.38 (0.83–2.3) 0.21 1.36 (0.79–2.36) 0.27  D’Amico high-risk group 1.65 (1.01–2.69) 0.045* 1.73 (1.02–2.93) 0.04*  Pathological Gleason score 8 or greater 1.18 (0.72–1.92) 0.51 1.26 (0.75–2.13) 0.38  pT3 or greater 0.94 (0.56–1.58) 0.82 1.02 (0.58–1.80) 0.96  Positive resection margin 0.94 (0.58–1.52) 0.81 1.05 (0.62–1.75) 0.87  Time to BCR after RP < 6 months 1.51 (0.91–2.52) 0.11 1.98 (1.16–3.36) 0.01*  PSA > 0.4 ng/ml at start of bicalutamide 1.21 (0.74–1.98) 0.44 1.63 (0.97–2.75) 0.07 Multivariate  Age 70 years or greater 1.38 (0.83–2.29) 0.22 1.39 (0.80–2.41) 0.25  D’Amico high-risk group 1.63 (1.00–2.67) 0.05 1.75 (1.03–2.98) 0.04*  Positive resection margin 1.00 (0.61–1.63) 1 1.15 (0.68–1.94) 0.60  Time to BCR after RP < 6 months 1.55 (0.92–2.59) 0.1 2.10 (1.22–3.61) <0.01* PT failure second BCR Hazard ratio (95%CI) P value Hazard ratio (95%CI) P value Univariate  Age 70 years or greater 1.38 (0.83–2.3) 0.21 1.36 (0.79–2.36) 0.27  D’Amico high-risk group 1.65 (1.01–2.69) 0.045* 1.73 (1.02–2.93) 0.04*  Pathological Gleason score 8 or greater 1.18 (0.72–1.92) 0.51 1.26 (0.75–2.13) 0.38  pT3 or greater 0.94 (0.56–1.58) 0.82 1.02 (0.58–1.80) 0.96  Positive resection margin 0.94 (0.58–1.52) 0.81 1.05 (0.62–1.75) 0.87  Time to BCR after RP < 6 months 1.51 (0.91–2.52) 0.11 1.98 (1.16–3.36) 0.01*  PSA > 0.4 ng/ml at start of bicalutamide 1.21 (0.74–1.98) 0.44 1.63 (0.97–2.75) 0.07 Multivariate  Age 70 years or greater 1.38 (0.83–2.29) 0.22 1.39 (0.80–2.41) 0.25  D’Amico high-risk group 1.63 (1.00–2.67) 0.05 1.75 (1.03–2.98) 0.04*  Positive resection margin 1.00 (0.61–1.63) 1 1.15 (0.68–1.94) 0.60  Time to BCR after RP < 6 months 1.55 (0.92–2.59) 0.1 2.10 (1.22–3.61) <0.01* PT, protocol treatment; BCR, biochemical relapse; RP, radical prostatectomy; PSA, prostate-specific antigen; 95% CI, 95% confidence interval. *Statistically significant. Table 2. COX proportion hazard analysis predictors of PT failure and second BCR in all 91 patients PT failure second BCR Hazard ratio (95%CI) P value Hazard ratio (95%CI) P value Univariate  Age 70 years or greater 1.38 (0.83–2.3) 0.21 1.36 (0.79–2.36) 0.27  D’Amico high-risk group 1.65 (1.01–2.69) 0.045* 1.73 (1.02–2.93) 0.04*  Pathological Gleason score 8 or greater 1.18 (0.72–1.92) 0.51 1.26 (0.75–2.13) 0.38  pT3 or greater 0.94 (0.56–1.58) 0.82 1.02 (0.58–1.80) 0.96  Positive resection margin 0.94 (0.58–1.52) 0.81 1.05 (0.62–1.75) 0.87  Time to BCR after RP < 6 months 1.51 (0.91–2.52) 0.11 1.98 (1.16–3.36) 0.01*  PSA > 0.4 ng/ml at start of bicalutamide 1.21 (0.74–1.98) 0.44 1.63 (0.97–2.75) 0.07 Multivariate  Age 70 years or greater 1.38 (0.83–2.29) 0.22 1.39 (0.80–2.41) 0.25  D’Amico high-risk group 1.63 (1.00–2.67) 0.05 1.75 (1.03–2.98) 0.04*  Positive resection margin 1.00 (0.61–1.63) 1 1.15 (0.68–1.94) 0.60  Time to BCR after RP < 6 months 1.55 (0.92–2.59) 0.1 2.10 (1.22–3.61) <0.01* PT failure second BCR Hazard ratio (95%CI) P value Hazard ratio (95%CI) P value Univariate  Age 70 years or greater 1.38 (0.83–2.3) 0.21 1.36 (0.79–2.36) 0.27  D’Amico high-risk group 1.65 (1.01–2.69) 0.045* 1.73 (1.02–2.93) 0.04*  Pathological Gleason score 8 or greater 1.18 (0.72–1.92) 0.51 1.26 (0.75–2.13) 0.38  pT3 or greater 0.94 (0.56–1.58) 0.82 1.02 (0.58–1.80) 0.96  Positive resection margin 0.94 (0.58–1.52) 0.81 1.05 (0.62–1.75) 0.87  Time to BCR after RP < 6 months 1.51 (0.91–2.52) 0.11 1.98 (1.16–3.36) 0.01*  PSA > 0.4 ng/ml at start of bicalutamide 1.21 (0.74–1.98) 0.44 1.63 (0.97–2.75) 0.07 Multivariate  Age 70 years or greater 1.38 (0.83–2.29) 0.22 1.39 (0.80–2.41) 0.25  D’Amico high-risk group 1.63 (1.00–2.67) 0.05 1.75 (1.03–2.98) 0.04*  Positive resection margin 1.00 (0.61–1.63) 1 1.15 (0.68–1.94) 0.60  Time to BCR after RP < 6 months 1.55 (0.92–2.59) 0.1 2.10 (1.22–3.61) <0.01* PT, protocol treatment; BCR, biochemical relapse; RP, radical prostatectomy; PSA, prostate-specific antigen; 95% CI, 95% confidence interval. *Statistically significant. Figure 3. View largeDownload slide Kaplan–Meier estimates of second biochemical relapse-free survival from start of 2 years of bicalutamide in the 91 patients, according to number of risk factors. Figure 3. View largeDownload slide Kaplan–Meier estimates of second biochemical relapse-free survival from start of 2 years of bicalutamide in the 91 patients, according to number of risk factors. Gynecomastia occurred in 75 patients (82.4%). Frequencies of Grade 1 and 2 gynecomastia were 72.5% and 9.9%, respectively. No Grade 3 gynecomastia was encountered, but four of the patients with Grade 2 gynecomastia could not continue bicalutamide. There was no other Grade 3 or greater adverse events other than Grade 4 cerebral infarction in a 70-year old man. Discussion Our single-arm prospective study using 2 years of bicalutamide monotherapy as salvage treatment in patients with BCR after RP showed that about one-third of patients remained disease-free at 5 years after initiating bicalutamide. Previous studies regarding SRT or SHT have reported 5-year BCR-free survival rates of 50–82% (4,22–25), much higher than the findings in this study, despite differences in patient characteristics among studies. These results indicate that 2 years of bicalutamide monotherapy should not be considered as standard treatment for BCR after RP. However, patients who had either none or only one of the risk factors ‘high-risk status at RP’ and ‘time to BCR after RP < 6 months’ displayed relatively favorable BCR-free survival (41–45%) compared to those with both risk factors (7%). Whether this treatment could be feasible in selected patients may thus be worth consideration. Several studies have used bicalutamide as adjuvant or salvage treatment after RP or radiation, but study protocols have varied markedly among these investigations. The bicalutamide Early Prostate Cancer program evaluated the efficacy of bicalutamide at 150 mg/day as immediate hormonal therapy after RP or radiotherapy in 8113 cases of localized or locally advanced prostate cancer, and found that bicalutamide improved progression-free survival (not including BCR) compared to placebo (hazard ratio (HR), 0.85; 95% CI, 0.79–0.91; P = 0.001) (16). The Japanese Clinical Oncology Group 0401 compared radiation plus bicalutamide with bicalutamide alone in patients with BCR (PSA > 0.4 ng/ml) after RP. That study showed that the 5-year treatment failure-free survivals with radiation plus bicalutamide and bicalutamide alone were 69.7% and 57.0%, respectively (HR, 0.56; 95%CI, 0.38–0.82) (26). Only two studies terminated bicalutamide use at 2 years. The Radiation Therapy Oncology Group 9601 performed a double-blinded, placebo-controlled trial between 1998 and 2003, in patients with detectable PSA (0.2–4.0 ng/ml) after RP who were randomly divided to receive radiation with 2 years of bicalutamide or radiation with placebo. Addition of 2 years of bicalutamide was found to significantly increase overall survival. The cumulative incidence of second BCR (PSA > nadir + 0.3 ng/ml) at 12 years was 44.0% in the bicalutamide group, as compared with 67.9% in the placebo group (HR, 0.48; 95%CI, 0.40–0.58; P < 0.001) (27). Trial 23, as one of the components of the bicalutamide Early Prostate Cancer program, also performed a randomized trial, in which 3292 patients with T1b-4, N0-Nx, M0 who had undergone RP were randomized to receive bicalutamide at 150 mg daily or placebo for 2 years in addition to standard care. Although 2 years of bicalutamide as adjuvant to RP did not improve objective progression-free and overall survivals, the risk of PSA progression was decreased by 20% compared with standard care alone (17). Those previous studies demonstrated that adjuvant or salvage treatment with bicalutamide improves PSA progression, but effects on overall survival have not been determined. We consider that several advantages exist to 2 years of bicalutamide monotherapy in patients with BCR after RP. First, bicalutamide does not have severe adverse events other than gynecomastia, which usually resolves spontaneously after termination of bicalutamide, whereas adverse events of SRT or SHT are various and sometimes persistent (4–7,28). Second, bicalutamide has less influence on sexual function. McLeod et al. reported that the incidences of impotence and decreased libido were low with bicalutamide (7.3% and 4.7%, respectively), and similar to those with placebo (6.8% and 1.7%, respectively) (17). Bicalutamide monotherapy might be beneficial for patients who hope to maintain erectile function even after RP. Third, termination of bicalutamide after 2 years represents another important advantage. We started bicalutamide in patients who showed PSA elevation to ≥0.2 ng/ml, and median PSA at initiation of bicalutamide was 0.32 ng/ml. Amling et al. reported that 51% and 38% of patients who reached PSA 0.2–0.29 ng/ml and PSA 0.3–0.39 ng/ml within 3 years after RP did not show any subsequent PSA increase (29). Salvage treatment with low PSA level after RP remains controversial, meaning that it could be associated with favorable oncological outcomes, but there is the possibility of overtreatment for some patients who do not have true recurrence. Therefore, it may be useful to stop bicalutamide for 2 years followed by observation, in terms of avoiding overtreatment, which could not be distinguished when starting bicalutamide. On the other hand, 2 years of bicalutamide monotherapy shows considerable disadvantages. In our study, 2- and 5-year second BCR-free survivals were 82.3% and 37.2%, respectively, much lower than those with SRT or SHT (4,22–25). Bicalutamide monotherapy for BCR after RP seems likely to carry a significant risk of disease progression, particularly in patients with risk factors. Moreover, 82.4% of patients experienced gynecomastia, to the extent where four could not continue bicalutamide. Such disadvantages indicate that 2 years of bicalutamide monotherapy should not be routinely recommended for all patients with BCR after RP. In this study, we found that high-risk status at RP and time to BCR after RP < 6 months were significant predictors of second BCR before initiating bicalutamide. Previous studies have also shown risk factors for salvage treatment after RP or radiation therapy. Stephenson et al. reported that PSA level before SRT, prostatectomy Gleason grade, PSA doubling time, surgical margins, androgen-deprivation therapy before or during SRT, and lymph node metastasis were significant predictors of disease progression after SRT in a multi-institutional cohort of 1540 patients (30). Briganti et al. reported that pathological stage, Gleason score, positive surgical margins and pre-SRT PSA were significantly associated with BCR after SRT in 472 patients who started SRT at PSA < 0.5 ng/ml (24). SHT is usually indicated for patients displaying unfavorable factors such as shorter PSA doubling time or high Gleason score, for whom SRT is considered less likely to achieve disease control (12). Factors for predicting second BCR with salvage treatment using bicalutamide have not been discussed, but may be similar to predictors for SRT. Two years of bicalutamide monotherapy may be a feasible option for selected patients who are candidates for SRT. This study has several important limitations. First, this study used a single-arm design with a very small sample size, meaning that no confirmatory conclusions can be made from this study. Second, endpoints of this study were PT failure or second BCR, and effects of bicalutamide monotherapy on metastasis-free or overall survival were not analyzed, despite the lack of cancer-specific deaths during the study period. Third, we adopted 2 years as a duration for bicalutamide administration based on previous studies with 50 mg or 150 mg of bicalutamide, but the optimal duration and dose of bicalutamide should be examined in further detail. Fourth, we demonstrated possibilities of bicalutamide in maintaining erectile function compared to SRT or SHT, but we do not have any data regarding erectile function. Despite these limitations, this study is the first to examine the effects of 2 years of bicalutamide monotherapy in patients who presented with BCR after RP. The results of this study may be informative when considering management of BCR after RP. In conclusion, 2 years of bicalutamide should not be routinely recommended in patients with BCR after RP. However, it might be optional in selected patients who do not have high-risk status at RP and short time to BCR, whereas careful and close follow up should be needed. Acknowledgements We thank Dr Isao Numata, Dr Norihisa Kizu and Dr Shigeto Ishidoya for their cooperation on data collection. Funding This research received no specific grant from any funding agency in the public, commercial or non-profit sectors. The authors declare no conflict of interests in preparing this article. Conflict of interest statement None declared. Abbreviations BCR biochemical relapse PSA prostate-specific antigen PT protocol treatment RP radical prostatectomy SHT salvage hormonal therapy SRT salvage radiation therapy References 1 The central social insurance medical council . 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Defining prostate specific antigen progression after radical prostatectomy: what is the most appropriate cut point? J Urol 2001 ; 165 : 1146 – 51 . Google Scholar CrossRef Search ADS PubMed 30 Stephenson AJ , Scardino PT , Kattan MW , et al. . Predicting the outcome of salvage radiation therapy for recurrent prostate cancer after radical prostatectomy . J Clin Oncol 2007 ; 25 : 2035 – 41 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Japanese Journal of Clinical Oncology Oxford University Press

Two years of bicalutamide monotherapy in patients with biochemical relapse after radical prostatectomy

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Abstract

Abstract Background Salvage treatments for biochemical relapse (BCR) after radical prostatectomy (RP) have several problems in terms of indications or adverse events. We studied the possibility of 2 years of bicalutamide monotherapy for BCR after RP. Methods Patients who showed BCR (prostate-specific antigen (PSA) ≥ 0.2 ng/ml) after RP were recruited. Protocol treatment was planned as 2 years of bicalutamide (80 mg/day) followed by observation. Protocol treatment failure was defined as PSA re-elevation of ≥0.2 ng/ml, clinical progression, any other treatments, or discontinuation or restart of bicalutamide. Primary endpoint of this study is time to protocol treatment failure from initiation of bicalutamide. Results A total of 91 patients were registered between 2003 and 2009. Median age and PSA at initiating bicalutamide were 68 (range, 55–78) years and 0.32 (range, 0.19–7.91) ng/ml. Twenty-four (26.4%) patients could not complete 2 years of bicalutamide mainly due to progression of disease. Of the 91 patients, 2- and 5-year protocol treatment failure-free survivals were 74.6% and 33.0%, with a median follow-up of 76 (range, 11–118) months. Median time from initiating bicalutamide to treatment failure was 43 (95% confidence interval, 33–47) months. High-risk status at RP and time to BCR after RP < 6 months were significant predictors of second BCR. Conclusions Two years of bicalutamide monotherapy should not be recommended as standard management for BCR after RP, but might be feasible for selected patients who do not have high-risk status at RP and short time to BCR. prostate cancer, salvage therapy, bicalutamide, prostatectomy, biochemical relapse Introduction The use of radical prostatectomy (RP) for localized or locally advanced prostate cancer has been increasing, mainly because of increases in the incidence of prostate cancer and the adoption of robot-assisted laparoscopic surgery in Japan. Over 20 000 patients with prostate cancer were estimated to have undergone RP in Japan in 2016 (1). RP has been one of the gold-standard treatments for prostate cancer, but a significant proportion of patients treated with RP unfortunately experience significant disease burden with an elevation of prostate-specific antigen (PSA). Previous studies have reported that around 30% of patients treated with RP experience biochemical relapse (BCR) after RP (2,3). Management for BCR after RP includes salvage radiation therapy (SRT) or salvage hormonal therapy (SHT), but both SRT and SHT show considerable problems in terms of adverse events or indications. The incidence of acute genitourinary and gastrointestinal toxicity with SRT is reportedly over 50% (4). Grade 3 or 4 adverse events are relatively rare, but sometimes persist and can prove resistant to treatment (4–7). Several previous studies have demonstrated that early SRT with lower PSA level was associated with better oncological outcomes (8–10), but overtreatment is also possible in patients with low PSA levels (11). SHT is usually recommended for patients with unfavorable factors (e.g., shorter PSA doubling time, Gleason score 8 or greater, pathological stage T3 or greater) (12,13), but the optimal timing for starting SHT has not been determined, and evidence confirming that SHT can prolong overall survival has been lacking. In addition, long-term hormonal treatment with surgical or medical castration can lead to unfavorable metabolic changes such as weight gain, metabolic syndrome, osteoporosis, diabetes mellitus and cardiovascular disease (14,15). Bicalutamide is an androgen-receptor blocker that works against prostate cancer without suppressing testosterone levels. Few severe adverse events are associated with bicalutamide use, besides gynecomastia, which occurs in up to 70% of patients treated with bicalutamide (13,16–18). In 2006, McLeod et al. showed that 2 years of bicalutamide monotherapy (150 mg) after RP or radiation therapy did not provide any clinical benefit in terms of progression-free survival or overall survival, despite prolonging the time to PSA progression compared to placebo (17), but bicalutamide was administered as an adjuvant in that study, and a substantial proportion of patients were considered to have a low risk of BCR after RP. We considered that 2 years of bicalutamide monotherapy for BCR after RP might offer several advantages, in terms of a lower incidence of adverse events compared to SRT or SHT, and the possibility of avoiding overtreatment by terminating bicalutamide within 2 years. We therefore designed this single-arm prospective study to determine the effects of 2 years of bicalutamide monotherapy for BCR after RP. Methods This study was prospectively designed, and the ethics committees of all participating institutions approved the study procedure. All patients provided written informed consent prior to enrollment. Patients who presented with BCR after RP were recruited from a total of seven institutions (Tohoku University, Hirosaki University, Yamagata Prefectural Central Hospital, Akita City Hospital, Akita University, Akita Kousei Medical Center, Osaki Citizen Hospital). BCR after RP was defined as PSA elevation of ≥0.2 ng/ml after RP, and second BCR was defined as PSA re-elevation of ≥0.2 ng/ml during or after 2 years of bicalutamide monotherapy. Patient characteristics including age, PSA level, clinical stage, Gleason score and D’Amico risk classification (19) before RP, pathological stage, Gleason score and resection margin status after RP, time from RP to BCR, and age and PSA level at initiation of bicalutamide were recorded. Protocol treatment (PT) was set as bicalutamide administered at 80 mg/day for 2 years, then follow-up without any treatment for prostate cancer. PT failure was defined as follows: PSA elevation of ≥0.2 ng/ml, any treatment changes other than bicalutamide monotherapy, discontinuation of bicalutamide due to adverse effects or patient choice during the 2 years of bicalutamide, and PSA re-elevation of ≥0.2 ng/ml, or any treatment for prostate cancer including restarting bicalutamide after completion of 2 years of bicalutamide. Gynecomastia and other Grade 3 or greater adverse events during 2 years of bicalutamide were evaluated according to the National Cancer Institute – Common Toxicity Criteria version 2 (20). Primary endpoint of this study is time to PT failure from initiation of bicalutamide. Secondary endpoints are second BCR free survival from initiation of bicalutamide and adverse events during 2 years of bicalutamide monotherapy. PT failure-free survival from initiation of bicalutamide in all patients and in patients who completed the 2 years of bicalutamide was analyzed using the Kaplan–Meier method. Cox proportion regression analyses were used to develop a predictive model assessing the risk of PT failure and second BCR. All statistical analyses were performed using EZR version 1.35 (Saitama Medical Center, Jichi Medical University) (21), a graphical user interface for R (The R Foundation for Statistical Computing, version 3.3.2). All P values were two-sided, with P < 0.05 considered significant. Results Ninety-one patients who presented with BCR after RP were enrolled in this study between 2003 and 2009. Table 1 shows the characteristics of the 91 patients at the start of 2 years of bicalutamide. Neoadjuvant hormonal therapy was performed in three patients before RP, but no patients underwent any treatments between RP and initiation of bicalutamide. Table 1. Characteristics of the 91 registered patients at start of 2 years of bicalutamide At radical prostatecomy  Median age at operation (years) 68 [range 55, 78]  Median PSA before biopsy (ng/ml) 9.2 [range 4.20, 34.83]  Neoadjuvant hormonal therapy 3 (3.3%)  Damico’s risk classifications   Low 8 (8.8%)   Intermediate 45 (49.5%)   High 38 (41.8%) Pathological results  Gleason score eight or greater 37 (40.7%)  pT3 or greater 61 (67.0%)  Positive resection margin 45 (49.5%)  pN1 1 (1.1%) At start of bicalutamide  Median age at administration (years) 69 [range 56, 79]  Median PSA (ng/ml) 0.32 [range 0.19, 7.91]  Median time to BCR (months) 11 [range 0, 70] At radical prostatecomy  Median age at operation (years) 68 [range 55, 78]  Median PSA before biopsy (ng/ml) 9.2 [range 4.20, 34.83]  Neoadjuvant hormonal therapy 3 (3.3%)  Damico’s risk classifications   Low 8 (8.8%)   Intermediate 45 (49.5%)   High 38 (41.8%) Pathological results  Gleason score eight or greater 37 (40.7%)  pT3 or greater 61 (67.0%)  Positive resection margin 45 (49.5%)  pN1 1 (1.1%) At start of bicalutamide  Median age at administration (years) 69 [range 56, 79]  Median PSA (ng/ml) 0.32 [range 0.19, 7.91]  Median time to BCR (months) 11 [range 0, 70] PSA, prostate-specific antigen; BCR, biochemical relapse. Table 1. Characteristics of the 91 registered patients at start of 2 years of bicalutamide At radical prostatecomy  Median age at operation (years) 68 [range 55, 78]  Median PSA before biopsy (ng/ml) 9.2 [range 4.20, 34.83]  Neoadjuvant hormonal therapy 3 (3.3%)  Damico’s risk classifications   Low 8 (8.8%)   Intermediate 45 (49.5%)   High 38 (41.8%) Pathological results  Gleason score eight or greater 37 (40.7%)  pT3 or greater 61 (67.0%)  Positive resection margin 45 (49.5%)  pN1 1 (1.1%) At start of bicalutamide  Median age at administration (years) 69 [range 56, 79]  Median PSA (ng/ml) 0.32 [range 0.19, 7.91]  Median time to BCR (months) 11 [range 0, 70] At radical prostatecomy  Median age at operation (years) 68 [range 55, 78]  Median PSA before biopsy (ng/ml) 9.2 [range 4.20, 34.83]  Neoadjuvant hormonal therapy 3 (3.3%)  Damico’s risk classifications   Low 8 (8.8%)   Intermediate 45 (49.5%)   High 38 (41.8%) Pathological results  Gleason score eight or greater 37 (40.7%)  pT3 or greater 61 (67.0%)  Positive resection margin 45 (49.5%)  pN1 1 (1.1%) At start of bicalutamide  Median age at administration (years) 69 [range 56, 79]  Median PSA (ng/ml) 0.32 [range 0.19, 7.91]  Median time to BCR (months) 11 [range 0, 70] PSA, prostate-specific antigen; BCR, biochemical relapse. Of the 91 patients who started bicalutamide, 24 (26.4%) experienced treatment failure within 2 years. Reasons for discontinuation of bicalutamide were as follows: second BCR within 2 years of bicalutamide in 15 patients; cessation of bicalutamide in eight patients (due to own choice in four and gynecomastia in four); and other advanced cancer in one patient. Figure 1 shows PT failure-free survival from the initiation of bicalutamide. Two- and five-year PT failure-free survivals in all 91 patients were 74.6% (95% confidence interval (CI), 64.2–82.3%) and 33.0% (95%CI, 23.2–43.1%), respectively, with a median follow-up of 76 months (range, 11–118 months). Median time to treatment failure from initiation of bicalutamide was 43 (95% CI, 33–47) months. The 5-year second BCR-free survival was 37.2%. Figure 1. View largeDownload slide Kaplan–Meier estimate of protocol treatment failure-free survival from start of 2 years of bicalutamide monotherapy in all 91 patients. Figure 1. View largeDownload slide Kaplan–Meier estimate of protocol treatment failure-free survival from start of 2 years of bicalutamide monotherapy in all 91 patients. Figure 2 shows PT failure-free survival in all 62 patients who completed 2 years of bicalutamide treatment and were then followed-up. Five patients who continued bicalutamide beyond the 2 years of the PT were excluded from this analysis. The 5-year PT failure-free survival rate from initiation of bicalutamide was 44.3% (95% CI, 31.6–56.2%). Median survival time to treatment failure from initiation of bicalutamide was 51 (95% CI, 43–65) months. Figure 2. View largeDownload slide Kaplan–Meier estimate of protocol treatment failure-free survival from start of 2 years of bicalutamide in the 62 patients who completed 2 years of bicalutamide monotherapy and were then followed by observation. Figure 2. View largeDownload slide Kaplan–Meier estimate of protocol treatment failure-free survival from start of 2 years of bicalutamide in the 62 patients who completed 2 years of bicalutamide monotherapy and were then followed by observation. Cox proportional hazard analyses predicting PT failure or second BCR were performed. Pathological Gleason score ≥8, pT3 or greater and PSA at initiation of bicalutamide >0.4 ng/ml were excluded from multivariate analyses, as these factors correlated strongly with high-risk status at RP, positive resection margin and time to BCR after RP < 6 months, respectively. Although no factors were associated with PT failure in the 91 patients who started 2 years of bicalutamide in multivariate analysis, high-risk status at RP and time to BCR after RP < 6 months were both significantly associated with second BCR (Table 2). Figure 3 shows the second BCR-free survival according to the number of risk factors based on the analysis. Five-year second BCR-free survivals in patients with zero, one and two risk factors were 41.4%, 45.6% and 7.8%, respectively. Patients with both risk factors (high-risk group and time to BCR after RP < 6 months) showed a significantly higher incidence of second BCR than those with zero or one risk factor (P < 0.001). Table 2. COX proportion hazard analysis predictors of PT failure and second BCR in all 91 patients PT failure second BCR Hazard ratio (95%CI) P value Hazard ratio (95%CI) P value Univariate  Age 70 years or greater 1.38 (0.83–2.3) 0.21 1.36 (0.79–2.36) 0.27  D’Amico high-risk group 1.65 (1.01–2.69) 0.045* 1.73 (1.02–2.93) 0.04*  Pathological Gleason score 8 or greater 1.18 (0.72–1.92) 0.51 1.26 (0.75–2.13) 0.38  pT3 or greater 0.94 (0.56–1.58) 0.82 1.02 (0.58–1.80) 0.96  Positive resection margin 0.94 (0.58–1.52) 0.81 1.05 (0.62–1.75) 0.87  Time to BCR after RP < 6 months 1.51 (0.91–2.52) 0.11 1.98 (1.16–3.36) 0.01*  PSA > 0.4 ng/ml at start of bicalutamide 1.21 (0.74–1.98) 0.44 1.63 (0.97–2.75) 0.07 Multivariate  Age 70 years or greater 1.38 (0.83–2.29) 0.22 1.39 (0.80–2.41) 0.25  D’Amico high-risk group 1.63 (1.00–2.67) 0.05 1.75 (1.03–2.98) 0.04*  Positive resection margin 1.00 (0.61–1.63) 1 1.15 (0.68–1.94) 0.60  Time to BCR after RP < 6 months 1.55 (0.92–2.59) 0.1 2.10 (1.22–3.61) <0.01* PT failure second BCR Hazard ratio (95%CI) P value Hazard ratio (95%CI) P value Univariate  Age 70 years or greater 1.38 (0.83–2.3) 0.21 1.36 (0.79–2.36) 0.27  D’Amico high-risk group 1.65 (1.01–2.69) 0.045* 1.73 (1.02–2.93) 0.04*  Pathological Gleason score 8 or greater 1.18 (0.72–1.92) 0.51 1.26 (0.75–2.13) 0.38  pT3 or greater 0.94 (0.56–1.58) 0.82 1.02 (0.58–1.80) 0.96  Positive resection margin 0.94 (0.58–1.52) 0.81 1.05 (0.62–1.75) 0.87  Time to BCR after RP < 6 months 1.51 (0.91–2.52) 0.11 1.98 (1.16–3.36) 0.01*  PSA > 0.4 ng/ml at start of bicalutamide 1.21 (0.74–1.98) 0.44 1.63 (0.97–2.75) 0.07 Multivariate  Age 70 years or greater 1.38 (0.83–2.29) 0.22 1.39 (0.80–2.41) 0.25  D’Amico high-risk group 1.63 (1.00–2.67) 0.05 1.75 (1.03–2.98) 0.04*  Positive resection margin 1.00 (0.61–1.63) 1 1.15 (0.68–1.94) 0.60  Time to BCR after RP < 6 months 1.55 (0.92–2.59) 0.1 2.10 (1.22–3.61) <0.01* PT, protocol treatment; BCR, biochemical relapse; RP, radical prostatectomy; PSA, prostate-specific antigen; 95% CI, 95% confidence interval. *Statistically significant. Table 2. COX proportion hazard analysis predictors of PT failure and second BCR in all 91 patients PT failure second BCR Hazard ratio (95%CI) P value Hazard ratio (95%CI) P value Univariate  Age 70 years or greater 1.38 (0.83–2.3) 0.21 1.36 (0.79–2.36) 0.27  D’Amico high-risk group 1.65 (1.01–2.69) 0.045* 1.73 (1.02–2.93) 0.04*  Pathological Gleason score 8 or greater 1.18 (0.72–1.92) 0.51 1.26 (0.75–2.13) 0.38  pT3 or greater 0.94 (0.56–1.58) 0.82 1.02 (0.58–1.80) 0.96  Positive resection margin 0.94 (0.58–1.52) 0.81 1.05 (0.62–1.75) 0.87  Time to BCR after RP < 6 months 1.51 (0.91–2.52) 0.11 1.98 (1.16–3.36) 0.01*  PSA > 0.4 ng/ml at start of bicalutamide 1.21 (0.74–1.98) 0.44 1.63 (0.97–2.75) 0.07 Multivariate  Age 70 years or greater 1.38 (0.83–2.29) 0.22 1.39 (0.80–2.41) 0.25  D’Amico high-risk group 1.63 (1.00–2.67) 0.05 1.75 (1.03–2.98) 0.04*  Positive resection margin 1.00 (0.61–1.63) 1 1.15 (0.68–1.94) 0.60  Time to BCR after RP < 6 months 1.55 (0.92–2.59) 0.1 2.10 (1.22–3.61) <0.01* PT failure second BCR Hazard ratio (95%CI) P value Hazard ratio (95%CI) P value Univariate  Age 70 years or greater 1.38 (0.83–2.3) 0.21 1.36 (0.79–2.36) 0.27  D’Amico high-risk group 1.65 (1.01–2.69) 0.045* 1.73 (1.02–2.93) 0.04*  Pathological Gleason score 8 or greater 1.18 (0.72–1.92) 0.51 1.26 (0.75–2.13) 0.38  pT3 or greater 0.94 (0.56–1.58) 0.82 1.02 (0.58–1.80) 0.96  Positive resection margin 0.94 (0.58–1.52) 0.81 1.05 (0.62–1.75) 0.87  Time to BCR after RP < 6 months 1.51 (0.91–2.52) 0.11 1.98 (1.16–3.36) 0.01*  PSA > 0.4 ng/ml at start of bicalutamide 1.21 (0.74–1.98) 0.44 1.63 (0.97–2.75) 0.07 Multivariate  Age 70 years or greater 1.38 (0.83–2.29) 0.22 1.39 (0.80–2.41) 0.25  D’Amico high-risk group 1.63 (1.00–2.67) 0.05 1.75 (1.03–2.98) 0.04*  Positive resection margin 1.00 (0.61–1.63) 1 1.15 (0.68–1.94) 0.60  Time to BCR after RP < 6 months 1.55 (0.92–2.59) 0.1 2.10 (1.22–3.61) <0.01* PT, protocol treatment; BCR, biochemical relapse; RP, radical prostatectomy; PSA, prostate-specific antigen; 95% CI, 95% confidence interval. *Statistically significant. Figure 3. View largeDownload slide Kaplan–Meier estimates of second biochemical relapse-free survival from start of 2 years of bicalutamide in the 91 patients, according to number of risk factors. Figure 3. View largeDownload slide Kaplan–Meier estimates of second biochemical relapse-free survival from start of 2 years of bicalutamide in the 91 patients, according to number of risk factors. Gynecomastia occurred in 75 patients (82.4%). Frequencies of Grade 1 and 2 gynecomastia were 72.5% and 9.9%, respectively. No Grade 3 gynecomastia was encountered, but four of the patients with Grade 2 gynecomastia could not continue bicalutamide. There was no other Grade 3 or greater adverse events other than Grade 4 cerebral infarction in a 70-year old man. Discussion Our single-arm prospective study using 2 years of bicalutamide monotherapy as salvage treatment in patients with BCR after RP showed that about one-third of patients remained disease-free at 5 years after initiating bicalutamide. Previous studies regarding SRT or SHT have reported 5-year BCR-free survival rates of 50–82% (4,22–25), much higher than the findings in this study, despite differences in patient characteristics among studies. These results indicate that 2 years of bicalutamide monotherapy should not be considered as standard treatment for BCR after RP. However, patients who had either none or only one of the risk factors ‘high-risk status at RP’ and ‘time to BCR after RP < 6 months’ displayed relatively favorable BCR-free survival (41–45%) compared to those with both risk factors (7%). Whether this treatment could be feasible in selected patients may thus be worth consideration. Several studies have used bicalutamide as adjuvant or salvage treatment after RP or radiation, but study protocols have varied markedly among these investigations. The bicalutamide Early Prostate Cancer program evaluated the efficacy of bicalutamide at 150 mg/day as immediate hormonal therapy after RP or radiotherapy in 8113 cases of localized or locally advanced prostate cancer, and found that bicalutamide improved progression-free survival (not including BCR) compared to placebo (hazard ratio (HR), 0.85; 95% CI, 0.79–0.91; P = 0.001) (16). The Japanese Clinical Oncology Group 0401 compared radiation plus bicalutamide with bicalutamide alone in patients with BCR (PSA > 0.4 ng/ml) after RP. That study showed that the 5-year treatment failure-free survivals with radiation plus bicalutamide and bicalutamide alone were 69.7% and 57.0%, respectively (HR, 0.56; 95%CI, 0.38–0.82) (26). Only two studies terminated bicalutamide use at 2 years. The Radiation Therapy Oncology Group 9601 performed a double-blinded, placebo-controlled trial between 1998 and 2003, in patients with detectable PSA (0.2–4.0 ng/ml) after RP who were randomly divided to receive radiation with 2 years of bicalutamide or radiation with placebo. Addition of 2 years of bicalutamide was found to significantly increase overall survival. The cumulative incidence of second BCR (PSA > nadir + 0.3 ng/ml) at 12 years was 44.0% in the bicalutamide group, as compared with 67.9% in the placebo group (HR, 0.48; 95%CI, 0.40–0.58; P < 0.001) (27). Trial 23, as one of the components of the bicalutamide Early Prostate Cancer program, also performed a randomized trial, in which 3292 patients with T1b-4, N0-Nx, M0 who had undergone RP were randomized to receive bicalutamide at 150 mg daily or placebo for 2 years in addition to standard care. Although 2 years of bicalutamide as adjuvant to RP did not improve objective progression-free and overall survivals, the risk of PSA progression was decreased by 20% compared with standard care alone (17). Those previous studies demonstrated that adjuvant or salvage treatment with bicalutamide improves PSA progression, but effects on overall survival have not been determined. We consider that several advantages exist to 2 years of bicalutamide monotherapy in patients with BCR after RP. First, bicalutamide does not have severe adverse events other than gynecomastia, which usually resolves spontaneously after termination of bicalutamide, whereas adverse events of SRT or SHT are various and sometimes persistent (4–7,28). Second, bicalutamide has less influence on sexual function. McLeod et al. reported that the incidences of impotence and decreased libido were low with bicalutamide (7.3% and 4.7%, respectively), and similar to those with placebo (6.8% and 1.7%, respectively) (17). Bicalutamide monotherapy might be beneficial for patients who hope to maintain erectile function even after RP. Third, termination of bicalutamide after 2 years represents another important advantage. We started bicalutamide in patients who showed PSA elevation to ≥0.2 ng/ml, and median PSA at initiation of bicalutamide was 0.32 ng/ml. Amling et al. reported that 51% and 38% of patients who reached PSA 0.2–0.29 ng/ml and PSA 0.3–0.39 ng/ml within 3 years after RP did not show any subsequent PSA increase (29). Salvage treatment with low PSA level after RP remains controversial, meaning that it could be associated with favorable oncological outcomes, but there is the possibility of overtreatment for some patients who do not have true recurrence. Therefore, it may be useful to stop bicalutamide for 2 years followed by observation, in terms of avoiding overtreatment, which could not be distinguished when starting bicalutamide. On the other hand, 2 years of bicalutamide monotherapy shows considerable disadvantages. In our study, 2- and 5-year second BCR-free survivals were 82.3% and 37.2%, respectively, much lower than those with SRT or SHT (4,22–25). Bicalutamide monotherapy for BCR after RP seems likely to carry a significant risk of disease progression, particularly in patients with risk factors. Moreover, 82.4% of patients experienced gynecomastia, to the extent where four could not continue bicalutamide. Such disadvantages indicate that 2 years of bicalutamide monotherapy should not be routinely recommended for all patients with BCR after RP. In this study, we found that high-risk status at RP and time to BCR after RP < 6 months were significant predictors of second BCR before initiating bicalutamide. Previous studies have also shown risk factors for salvage treatment after RP or radiation therapy. Stephenson et al. reported that PSA level before SRT, prostatectomy Gleason grade, PSA doubling time, surgical margins, androgen-deprivation therapy before or during SRT, and lymph node metastasis were significant predictors of disease progression after SRT in a multi-institutional cohort of 1540 patients (30). Briganti et al. reported that pathological stage, Gleason score, positive surgical margins and pre-SRT PSA were significantly associated with BCR after SRT in 472 patients who started SRT at PSA < 0.5 ng/ml (24). SHT is usually indicated for patients displaying unfavorable factors such as shorter PSA doubling time or high Gleason score, for whom SRT is considered less likely to achieve disease control (12). Factors for predicting second BCR with salvage treatment using bicalutamide have not been discussed, but may be similar to predictors for SRT. Two years of bicalutamide monotherapy may be a feasible option for selected patients who are candidates for SRT. This study has several important limitations. First, this study used a single-arm design with a very small sample size, meaning that no confirmatory conclusions can be made from this study. Second, endpoints of this study were PT failure or second BCR, and effects of bicalutamide monotherapy on metastasis-free or overall survival were not analyzed, despite the lack of cancer-specific deaths during the study period. Third, we adopted 2 years as a duration for bicalutamide administration based on previous studies with 50 mg or 150 mg of bicalutamide, but the optimal duration and dose of bicalutamide should be examined in further detail. Fourth, we demonstrated possibilities of bicalutamide in maintaining erectile function compared to SRT or SHT, but we do not have any data regarding erectile function. Despite these limitations, this study is the first to examine the effects of 2 years of bicalutamide monotherapy in patients who presented with BCR after RP. The results of this study may be informative when considering management of BCR after RP. In conclusion, 2 years of bicalutamide should not be routinely recommended in patients with BCR after RP. However, it might be optional in selected patients who do not have high-risk status at RP and short time to BCR, whereas careful and close follow up should be needed. Acknowledgements We thank Dr Isao Numata, Dr Norihisa Kizu and Dr Shigeto Ishidoya for their cooperation on data collection. Funding This research received no specific grant from any funding agency in the public, commercial or non-profit sectors. The authors declare no conflict of interests in preparing this article. Conflict of interest statement None declared. Abbreviations BCR biochemical relapse PSA prostate-specific antigen PT protocol treatment RP radical prostatectomy SHT salvage hormonal therapy SRT salvage radiation therapy References 1 The central social insurance medical council . 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Defining prostate specific antigen progression after radical prostatectomy: what is the most appropriate cut point? J Urol 2001 ; 165 : 1146 – 51 . Google Scholar CrossRef Search ADS PubMed 30 Stephenson AJ , Scardino PT , Kattan MW , et al. . Predicting the outcome of salvage radiation therapy for recurrent prostate cancer after radical prostatectomy . J Clin Oncol 2007 ; 25 : 2035 – 41 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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Japanese Journal of Clinical OncologyOxford University Press

Published: Apr 28, 2018

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