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Background We evaluated patient‐reported outcomes (PRO) during neoadjuvant androgen deprivation therapy (ADT) plus external beam radiation therapy (EBRT) followed by either adjuvant continuous ADT (CADT) or intermittent ADT (IADT) for patients with locally advanced prostate cancer (Pca). Methods A multicenter, randomized phase III trial enrolled 303 patients with locally advanced Pca. The patients were treated with 6 months (M) of ADT followed by 72 Gy of EBRT, and were randomly assigned to CADT or IADT after 14 M. The PROs were evaluated at sic points: baseline, 6 M, 8 M, 14 M, 20 M, and 38 M using FACT‐P questionnaires and EPIC urinary, bowel, and sexual bother subscales. Results The FACT‐P total scores were significantly better (p, The quality of life was significantly favorable in intermittent androgen deprivation therapy (ADT) on FACT‐P total score, physical well‐being and functional score than those is continuous ADT in adjuvant hormone therapy for locally advanced prostate cancer.

Aim The aim was to evaluate the efficacy and safety of abiraterone acetate plus prednisolone in patients with chemotherapy-naïve early metastatic castration-resistant prostate cancer who failed first-line androgen deprivation therapy. Methods Patients with early metastatic castration-resistant prostate cancer with confirmed prostate-specific antigen progression within 1-year or prostate-specific antigen progression without having normal prostate-specific antigen level (, This study investigated efficacy and safety of abiraterone acetate plus prednisolone in chemotherapy-naive early metastatic castration-resistant prostate cancer patients. Abiraterone acetate plus prednisolone proved to be a beneficial treatment option with regards to its higher response rate.

ObjectivesWith novel antiandrogen treatments of varying clinical benefits and risks becoming available, this study investigates how patients with castration-resistant prostate cancer (CRPC) value differences in treatment characteristics.DesignCross-sectional observational study.SettingA discrete choice experiment was conducted. Patients chose between two hypothetical non-metastatic CRPC (nmCRPC) treatments defined by six attributes: risk of fatigue, falls or fracture, cognitive impairment, hypertension, rashes as side effects to treatment and extension of time until cancer-related pain occurs.ParticipantsA total of 137 adult male patients with CRPC with no prior experience with chemotherapy and with Eastern Cooperative Oncology Group status 0–1 were recruited. Patients were excluded if they participated in an investigational programme outside of routine clinical practice, had a clinically relevant medical or psychiatric condition, or diagnosis of visceral/other metastases not related to the prostate, or were otherwise deemed ineligible by the referring physician.Primary outcome measuresRelative preference weights and relative importance of the attributes was estimated by hierarchical Bayesian logistic regression.ResultsAmong the treatment attributes, ‘risk of cognitive impairment as a side effect of treatment’ was the most important attribute (relative importance (RI) (95% CI): 27.47% (24.80% to 30.14%)), followed by ‘extension of time until cancer-related pain occurs’ (RI (95% CI): 17.87% (15.49% to 20.25%)) and the ‘risk of falls or fracture’ (RI (95% CI): 15.99% (14.73% to 17.25%)). The ‘risk of hypertension as a side effect of treatment’ (RI (95% CI): 13.77% (12.73% to 14.81%)) had similar RI as ‘risk of rashes as a side effect of treatment’ (RI (95% CI): 13.17% (12.15% to 14.19%)), followed by the ‘risk of fatigue as a side effect of treatment’ (RI (95% CI): 11.74% (10.75% to 12.73%)).ConclusionsPatients consider the risk of cognitive impairment as a side effect of treatment as the most important attribute in nmCRPC, followed by the extension of time until cancer-related pain occurs, and the risk of falls and fracture. These features should be considered in treatment decision making for nmCRPC in Japan.

Background In the global Phase-3 Selective Prostate Androgen Receptor Targeting with ARN-509 study, apalutamide plus ongoing androgen deprivation therapy (ADT) significantly increased metastasis-free survival (MFS) and improved other clinical outcomes in men with nonmetastatic castration-resistant prostate cancer (nm-CRPC) who were at high risk of developing metastases. In this subpopulation analysis of Selective Prostate Androgen Receptor Targeting with ARN-509 study, the efficacy and safety of apalutamide plus ADT were evaluated in Japanese patients with nm-CRPC. Methods The primary efficacy end point was MFS. Secondary efficacy end points were time to metastasis, progression-free survival, symptomatic progression, initiation of cytotoxic chemotherapy, and overall survival. Safety and pharmacokinetic parameters were also assessed. Results Fifty-five Japanese patients with ongoing ADT were randomized (apalutamide: n = 34, placebo: n = 21). Median treatment duration was 5.7 months in the apalutamide group and 11.0 months in the placebo group. Median MFS was not reached in the apalutamide group (95% confidence interval: 10.97, not estimable) and was 18.23 months (95% confidence interval: 11.04, 18.50) in the placebo group. Secondary end points were improved in the apalutamide group. The safety profile of apalutamide with ADT was comparable with the global population, and no new safety signals were identified in this Japanese subpopulation. Although, apalutamide exposure tended to be higher in the Japanese subpopulation compared with the non-Japanese population, this was likely to be explained by body weight and considered not clinically meaningful. Conclusion In the Japanese subpopulation, treatment with apalutamide with ADT resulted in favorable efficacy outcomes with comparable benefit-risk profile to the global population with nm-CRPC who are at high-risk of developing metastases.

Introduction The incidence of prostate cancer in Japan continues to increase, necessitating the continued development of effective therapies and strategies. Recent advances in treatments have improved the prognosis of metastatic disease and highlighted the importance of treating bone metastases to reduce the incidence of skeletal complications and improve patients’ quality of life. With the increasing number of treatment options that have become available, including bone-targeted therapy with the alpha emitter radium-223 dichloride (Ra-223), Japanese clinicians are faced with making difficult decisions on the choice of optimal treatment strategy. In such situations, guidance based on expert opinions can be beneficial. Methods A panel meeting of 27 Japanese experts in the management of prostate cancer was held to share opinions and to establish consensus recommendations on key clinical questions. Panelists were asked to vote on more than 40 questions pertinent to prostate cancer, and the answers helped guide a comprehensive discussion. Results The panel reached a consensus on key topics related to the optimal treatment strategy for Ra-223 therapy, namely, that patients with symptomatic, metastatic castration-resistant prostate cancer (CRPC) would benefit most from the use of this agent and that this treatment therapy should be provided before chemotherapy. Other topics that achieved consensus included: monitoring for osteoporosis and providing treatment if necessary during androgen deprivation therapy; performing magnetic resonance imaging in the presence of discrepancies in bone scintigram and computed tomography scans; monitoring alkaline phosphatase during CRPC treatment; using osteoclast-targeting in patients with CRPC with bone metastases; and using osteoclast-targeted agents combined with Ra-223. Conclusion These consensus recommendations and the updated information which became available subsequent to the panel meeting included here provide useful information for clinicians to aid in designing optimal treatment strategies for their patients. Funding Bayer Yakuhin Ltd. Electronic supplementary material The online version of this article (10.1007/s40487-018-0088-0) contains supplementary material, which is available to authorized users.

Investigating oncological outcomes in patients registered in the Japanese Prostate Cancer Outcome Study of Permanent Iodine-125 Seed Implantation (J-POPS) in terms of biochemical relapse-free survival (bRFS) by the Phoenix and the newly developed J-POPS definitions, exploration of predictive factors for bRFS, and preliminary verification of pitfalls of prostate-specific antigen (PSA) failure definitions. Between July 2005 and June 2007, 2316 clinically localized patients underwent permanent seed implantation. The primary endpoint was bRFS. One of the secondary endpoints was overall survival (OS). The median age was 69 and performance status was 0 in 99.1% of participants. The median biologically effective dose (BED) was about 180 Gy2. During a median follow-up of 60.0 months, 8.4 and 5.9% had PSA failure by the Phoenix and the J-POPS definitions, respectively. The 5-year bRFSs based on the Phoenix and the J-POPS definitions were 89.1 and 91.6%, respectively. The 5-year OS was 97.3%. According to multivariate analyses, only age affected bRFS based on the Phoenix definition, whereas the risk group and BED independently affected bRFS based on the J-POPS definition. A spontaneous PSA decrease was seen in 91.1% of participants after PSA failure based on the Phoenix definition alone, but in only 22.2% after PSA failure based on the J-POPS definition alone. The world’s largest registration study, J-POPS, consisted of patients with longevity, and a highly quality-controlled BED resulted in excellent bRFS and OS. The high likelihood of PSA bounce by the Phoenix definition should be taken into account, especially in younger patients. NCT00534196.

Background Abiraterone (AA) and enzalutamide (ENZA) are increasingly being used in chemotherapy-naive patients with metastatic castration-resistant prostate cancer owing to efficacy and favorable toxicity. However, the order in which they should be administered has not been determined. Patients and Methods We retrospectively reviewed the records of chemotherapy-naive patients with metastatic castration-resistant prostate cancer who had received sequential treatment with either AA followed by ENZA (AA-ENZA) or the converse (ENZA-AA). Prostate-specific antigen (PSA) response rates (defined as ≥ 50% PSA decline from baseline), first-line progression-free survival (PFS), second-line PFS, combined PFS (defined as first-line PFS plus second-line PFS), and overall survival are compared between the 2 sequence groups. Results A total of 97 patients received sequential treatment with AA and ENZA; 50 patients were in the AA-ENZA group, and 47 patients were in the ENZA-AA group. The PSA response rate to first-line treatment was not significantly different between AA (48%) and ENZA (51%) ( P = .840). However, a significant difference was observed in the PSA response rate to second-line treatment (AA, 6.4% vs. ENZA, 30%; P = .004). The median combined PFS was not significantly different between sequence groups (hazard ratio, 0.71; 95% confidence interval, 0.46-1.08; log-rank P = .105). The order of addition also had no significant effect on median overall survival (hazard ratio, 0.98; 95% confidence interval, 0.64-1.52; log-rank P = .834). Conclusion With the exception of the second-line PSA response, there was no significant difference in clinical outcomes between the AA-ENZA and ENZA-AA groups. Our results might be useful reference in daily practice, especially for patients who do not have a suitable general condition for chemotherapy.

Background Prostate-specific antigen (PSA) flare is a well-known phenomenon in patients with prostate cancer treated with luteinizing hormone-releasing hormone agonist and chemotherapy. However, its incidence and the significance for the clinical outcomes of patients treated with abiraterone acetate (AA) are uncertain. Patients and Methods A multicenter retrospective analysis of chemotherapy-naive patients treated with AA for metastatic castration-resistant prostate cancer (mCRPC) was conducted. The baseline characteristics, treatment history of mCRPC, and serum PSA kinetics during AA treatment were collected. The log-rank test was applied to compare progression-free survival (PFS) between patient groups with a PSA flare according to the different definitions and immediate PSA declines. Results The data from 83 patients were analyzed. An immediate PSA decline of any amount was observed in 59 patients (71.1%). According to the various definitions of PSA flare, its incidence ranged from 6.0% to 10.8%. Although the median interval to the peak PSA level was 0.95 month, regardless of the PSA flare definition, the interval to the PSA nadir showed a wide range of 2.8 to 7.6 months. In PSA flare subgroup, the median PFS in patients with any PSA decline to less than the baseline and > 30% decline from the baseline was 12.4 months. The PFS duration of PSA flare patients did not significantly differ from that of patients with an immediate PSA decline of any amount and immediate > 30% decline without PSA flare. Conclusion The PSA flare phenomenon is not rare event during AA treatment. A PSA decline during AA treatment, with or without a PSA flare, was associated with favorable clinical outcomes. Thus, AA should not be withdrawn early in patients with mCRPC in whom an initial, isolated PSA increase has been observed.

Purpose: To compare prostate contours on conventional stepping transverse image acquisitions with those on twister-based sagittal image acquisitions. Material and methods: Twenty prostate cancer patients who were planned to have permanent interstitial prostate brachytherapy were prospectively accrued. A transrectal ultrasonography probe was inserted, with the patient in lithotomy position. Transverse images were obtained with stepping movement of the transverse transducer. In the same patient, sagittal images were also obtained through rotation of the sagittal transducer using the “Twister” mode. The differences of prostate size among the two types of image acquisitions were compared. The relationships among the difference of the two types of image acquisitions, dose-volume histogram (DVH) parameters on the post-implant computed tomography (CT) analysis, as well as other factors were analyzed. Results : The sagittal image acquisitions showed a larger prostate size compared to the transverse image acquisitions especially in the anterior-posterior (AP) direction (p < 0.05). Interestingly, relative size of prostate apex in AP direction in sagittal image acquisitions compared to that in transverse image acquisitions was correlated to DVH parameters such as D 90 (R = 0.518, p = 0.019), and V 100 (R = 0.598, p = 0.005). Conclusions : There were small but significant differences in the prostate contours between the transverse and the sagittal planning image acquisitions. Furthermore, our study suggested that the differences between the two types of image acquisitions might correlated to dosimetric results on CT analysis.

Background To date, research has not determined the optimal procedure for adjuvant androgen deprivation therapy (ADT) in patients with locally advanced prostate cancer (PCa) treated for 6 months with neoadjuvant ADT and external-beam radiation therapy (EBRT). Methods A multicenter, randomized, phase 3 trial enrolled 303 patients with locally advanced PCa between 2001 and 2006. Participants were treated with neoadjuvant ADT for 6 months. Then, 280 patients whose prostate-specific antigen levels were less than pretreatment levels and less than 10 ng/mL were randomized. All 280 participants were treated with 72 Gy of EBRT in combination with adjuvant ADT for 8 months. Thereafter, participants were assigned to long-term ADT (5 years in all; arm 1) or intermittent ADT (arm 2). The primary endpoint was modified biochemical relapse-free survival (bRFS) with respect to nonmetastatic castration-resistant prostate cancer (nmCRPC) progression, clinical relapse, or any cause of death. Results The median follow-up time after randomization was 8.2 years. Among the 136 and 144 men assigned to trial arms 1 and 2, respectively, 24 and 30 progressed to nmCRPC or clinical relapse, and 5 and 6 died of PCa. The 5-year modified bRFS rates were 84.8% and 82.8% in trial arms 1 and 2, respectively (hazard ratio, 1.132; 95% confidence interval, 0.744-1.722). Conclusions Although modified bRFS data did not demonstrate noninferiority for arm 2, intermittent adjuvant ADT after EBRT with 14 months of neoadjuvant and short-term adjuvant ADT is a promising treatment strategy, especially in a population of responders after 6 months of ADT for locally advanced PCa.

Purpose To report results from our phase I dose-escalation study of stereotactic body radiotherapy (SBRT) using 4 fractions for patients with localized prostate cancer. Materials & methods Fraction sizes of 8 Gy, 8.5 Gy, and 9 Gy were defined as levels 1, 2, and 3. The prescribed dose was delivered to at least 95% of the planning target volume. Image-guided, intensity-modulated radiotherapy was delivered to all patients. Dose-limiting toxicity (DLT) was defined as acute toxicity of Grade 3 or higher. The maximum tolerated dose (MTD) was defined as the level at which ≥30% of patients showed DLT. The recommended dose (RD) was defined to be one dose level below the MTD. If no patients at level 3 showed DLT, level 3 was defined as the recommended dose (RD). Results Nine patients were enrolled in each level. All patients were low or intermediate risk. Median durations of follow-up for patients at levels 1–3 were 48.9 months, 42.6 months, and 18.4 months, respectively. Protocol treatment was completed for all patients. No patient showed DLT at each dose level. Level 3 was therefore designated as the RD for the phase II study. Although most toxicities were Grade 1, genitourinary toxicity was common compared to gastrointestinal toxicity. Three-year biochemical control rate was 90.3%. Conclusion The dose level of 36 Gy in 4 fractions with a 2-day break was tolerable and highly encouraging for SBRT of localized prostate cancer. The phase II trial to confirm the efficacy and toxicity of this treatment is now on going. Trial registration UMIN, UMIN000010236. Registered 13 March 2013.

No standard therapy has been established for localised prostate cancer patients with prostate-specific antigen (PSA) failure after radical prostatectomy (RP).To determine whether radiotherapy ± hormone therapy is superior to hormone therapy alone in such patients.This study is a multicentre, randomised, open-label, phase 3 trial. Patients with localised prostate cancer whose PSA concentrations had decreased to0.1 ng/ml after RP, and then increased to 0.4-1.0 ng/ml, were randomised to the salvage hormone therapy (SHT) group (80 mg bicalutamide [BCL] followed by luteinising hormone-releasing hormone agonist in case of BCL failure) or the salvage radiation therapy (SRT) ± SHT group (64.8 Gy of SRT followed by the same regimen as in the SHT group in case of SRT failure). From May 2004 to May 2011, 210 patients (105 in each arm) were registered, with the median follow-up being 5.5 yr.The primary endpoint was time to treatment failure (TTF) of BCL.TTF of BCL was significantly longer in the SRT ± SHT group (8.6 yr) than in the SHT group (5.6 yr; hazard ratio 0.56, 90% confidence interval [0.40-0.77]; one-sided p = 0.001). Thirty-two of 102 patients (31%) in the SRT ± SHT group did not have SRT treatment failure. However, clinical relapse-free survival and overall survival did not differ between the arms. The most frequent grade 3-4 adverse event was erectile dysfunction (83 patients [80%] in the SHT group vs. 76 [74%] in the SRT ± SHT group). Limitations include the short follow-up periods and surrogate endpoint setting to allow definitive conclusions.Initial SRT prolongs TTF of BCL in patients with post-RP PSA failure, indicating that SRT ± SHT is more beneficial than SHT alone.Patients who have prostate-specific antigen failure after radical prostatectomy benefit from salvage radiation therapy prior to salvage hormone therapy.

The present review summarizes data from studies reporting on health-related quality of life after brachytherapy and competing modalities. There are various therapeutic modalities for localized prostate cancer, including radical surgery, external beam radiotherapy and active surveillance. Advances in surgical and radiation treatment have entered clinical practice in the form of robot-assisted surgery or intensity-modulated radiotherapy. Brachytherapy remains the main treatment option for patients with localized prostate cancer, with 10-year survival data showing favorable outcomes. Because each treatment modality has achieved favorable survival outcomes, focus in determining appropriate treatment has shifted toward health-related quality of life, where each treatment has a different profile and/or adverse symptoms. The development of health-related quality of life assessment tools has allowed the creation of a pool of specific health-related quality of life data across many studies. The present article reviews the impact of brachytherapy and other modalities on quality of life, as well as future directions.

INTRODUCTION AND OBJECTIVES:We evaluated the efficacy and safety of prostate-directed radiotherapy with or without metastasis-directed radiotherapy in de novo oligometastatic patients who underwent...

Background: No standard therapy has been established for patients with prostate-specific antigen (PSA) failure after radical prostatectomy (RP). This study was designed to determine whether radiotherapy ± hormone therapy is superior to hormone therapy alone in such patients. Methods: This multicentre, randomised, open-label, unblinded, phase 3 trial included 36 institutions. Patients with localized prostate cancer [T1-2N0M0) treated by RP, pT0/2/3 and pN0/x] whose PSA concentrations had decreased to

To examine the antitumor activity of zoledronic acid (ZA) combined with androgen deprivation therapy (ADT) for men with treatment-naive prostate cancer and bone metastasis.We enrolled 227 men with treatment-naive prostate cancer and bone metastasis. Participants were randomly assigned (1:1 ratio) to receive combined androgen blockade alone (CAB group) or ZA with combined androgen blockade (CZ group). Time to treatment failure (TTTF), time to the first skeletal-related event (TTfSRE), and overall survival (OS) rates were estimated using the Kaplan-Meier method. Hazard ratios (HRs) were calculated using the Cox proportional hazards model. Median follow-up duration was 41.5 months.Median TTTFs were 12.4 and 9.7 months for the CZ and CAB groups, respectively (HR 0.75; 95 % CI 0.57-1.00; p = 0.051). For men with baseline prostate-specific antigen levels200 ng/mL, median TTTFs were 23.7 and 9.8 months for the CZ and CAB groups, respectively (HR 0.58; 95 % CI 0.35-0.93; p = 0.023). Median TTfSREs were 64.7 and 45.9 months for the CZ and CAB groups, respectively (HR 0.58; 95 % CI 0.38-0.88; p = 0.009). OS was similar between the groups.This study failed to demonstrate that combined use of ZA and ADT significantly prolonged TTTF in men with treatment-naive prostate cancer and bone metastasis. However, it generates a new hypothesis that the combined therapy could delay the development of castration resistance in a subgroup of patients with low baseline prostate-specific antigen values200 ng/mL. The treatment also significantly prolonged TTfSRE but did not affect OS.

Purpose: The aim of this report is dosimetric evaluation for an intraoperative fusion computed tomography (CT) as a superior predictor of 1-month CT based dosimetry in comparison to transrectal ultrasound (TRUS) in permanent interstitial prostate brachytherapy. Material and methods : Data of 65 patients treated with seed implantation were analyzed. All procedures has been performed with patients in the lithotomy position inside the O-arm system. An end-fine probe is used as a landmark to fuse TRUS and O-arm-based CT images. There was no difference in the patient’s position, probe position, and timing of image acquisition between the two imaging modalities. Dose-volume histogram (DVH) parameters such as the dose to 90% of prostate volume (D 90 ) has been analyzed. Results: The area under the curve of the receiver operating characteristic tended to be larger on fusion CT than on TRUS for most DVH parameters (71.85% vs. 59.59% for D 90 ; p = 0.07). Significant relationships between fusion CT and 1-month CT were confirmed using Pearson’s correlation coefficients for most DVH parameters (R = 0.48, p < 0.01 for D 90 ), although the relationship between TRUS and 1-month CT was poor. Large dose reduction (35 Gy for D 90 ) was seen from TRUS to fusion CT, especially in patients with high body weight and small prostate volume. Conclusions : Intraoperative fusion CT appears to have higher predictive power for 1-month CT-based dosimetry than TRUS. A prospective trial using fusion CT-based planning is warranted.

Purpose : To evaluate the prognostic value of prostate-specific antigen nadir (nPSA) after high-dose-rate (HDR) brachytherapy in clinically non-metastatic high-risk prostate cancer patients. Material and methods : Data from 216 patients with high-risk or locally advanced prostate cancer who underwent HDR brachytherapy and external beam radiation therapy with long-term androgen deprivation therapy (ADT) between 2003 and 2008 were analyzed. The median prostate-specific antigen (PSA) level at diagnosis was 24 ng/ml (range: 3-338 ng/ml). The clinical stage was T1c-2a in 55 cases (26%), T2b-2c in 48 (22%), T3a in 75 (35%), and T3b-4 in 38 (17%). The mean dose to 90% of the planning target volume was 6.3 Gy/fraction of HDR brachytherapy. After 5 fractions, external beam radiation therapy with 10 fractions of 3 Gy was administered. All patients initially underwent neoadjuvant ADT for at least 6 months, and adjuvant ADT was continued for 36 months. The median follow-up was 7 years from the start of radiotherapy. Results : The 7-year PSA relapse-free rate among patients with a post-radiotherapy nPSA level of ≤ 0.02 ng/ml was 94%, compared with 23% for patients with higher nPSA values (HR = 28.57; 95% CI: 12.04-66.66; p < 0.001). Multivariate analysis revealed that the nPSA value after radiotherapy was a significant independent predictor of biochemical failure, whereas pretreatment predictive values for worse biochemical control including higher level of initial PSA, Gleason score ≥ 8, positive biopsy core rate ≥ 67%, and T3b-T4, failed to reach independent predictor status. The 7-year cancer-specific survival rate among patients with a post-radiotherapy nPSA level of ≤ 0.02 ng/ml was 99%, compared with 82% for patients with higher nPSA values (HR = 32.25; 95% CI: 3.401-333.3; p = 0.002). Conclusions : A post-radiotherapy nPSA value of ≤ 0.02 ng/ml was associated with better long-term biochemical tumor control even if patients had pretreatment predictive values for worse control.

BACKGROUND Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trial showed the survival benefit for prostate radiotherapy in newly diagnosed prostate cancer patients with a low metastatic burden. The result raises the next question whether additional radiotherapy to metastatic sites could improve the survival in those with a low metastatic burden. METHODS We evaluated the efficacy and safety of prostate-directed radiotherapy (PDRT) with or without metastasis-directed radiotherapy (MDRT) in newly diagnosed oligometastatic patients who underwent combination of high-dose-rate prostate brachytherapy, external beam radiotherapy, and androgen deprivation therapy. Forty patients with bone metastasis and node positive prostate cancer were retrospectively analyzed. Of these, 22 (55%), 3 (7%), and 15 (38%) patients had N1M0, M1a, and M1b, respectively. Eighteen patients (45%) received MDRT to all metastatic sites. All patients initially underwent ≧6 months of androgen deprivation therapy. Oligometastatic disease was defined as presence of five or fewer metastatic lesions. Median follow-up period was 62.5 months. RESULTS Of the 40 patients, the 5-year castration-resistant prostate cancer (CRPC)-free survival rate and cancer-specific survival was 64.4% and 87.9%, respectively. Pre- or post-treatment predictive value including prostate-specific antigen (PSA) at diagnosis ≥20 ng/mL, Gleason grade group 5, positive biopsy core rate ≥51%, PSA nadir level of ≥0.02 ng/mL after the radiotherapy, and no MDRT were significantly associated with progression to CRPC. Patients with MDRT had significantly higher probability of achieving a PSA level of

Abiraterone acetate (AA) is a first-in-class CYP17 (17α-hydroxylase/C17, 20 lyase) inhibitor that is approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). AA prolonged overall survival in both mCRPC patients with or without previously chemotherapy by two randomized Phase III studies (COU-AA-301 and 302 trial). In Japan, AA approved in 2014, similar efficacy and safety of AA are demonstrated. Prostate-specific antigen (PSA) response rates were 60.4% in chemotherapy naive mCRPC patients (JPN-201 study) and 28.3% in post-chemotherapy mCRPC patients (JPN-202 study), respectively. The most common were liver dysfunction and mineralocorticoid-related adverse events such as hypokalemia, hypertension, and edema. Majority of the adverse events were grade 1 or 2 in severity. PSA flare phenomenon observed approximately 10% during AA treatment, which is feature and different from that of enzalutamide. There is no clear answer to sequential androgen receptor-axis-targeted therapy. But, AA to enzalutamide sequence may be better outcome for PSA progression-free survival compared with reverse sequence. Even in elderly patients with mCRPC, if the patients can be treated, they can be safe and obtain the sufficient therapeutic effect. However, there is no report of AA treatment in Japanese elderly mCRPC patients. This review evaluated the use of AA for Japanese mCRPC patients in detail.

Radiotherapy (RT) is one of the most important treatments for prostate cancer. Although RT can kill cancer cells through direct and indirect effects of radiation, it occasionally induces an abscopal effect whereby localized radiation treatment is associated with elimination of metastatic cancer at a distance from the irradiated area. Thus, RT may induce an effective antitumor immune response, although the mechanism involved has remained unclear. The present was designed to evaluate this effect of RT in 36 patients with prostate cancer who provided informed consent prior to enrollment in this clinical trial. Peripheral blood samples were collected periodically after low-dose-rate (LDR) prostate brachytherapy, and lymphocyte subsets were analyzed by flow cytometry. The proportion of activated T cells (CD3+HLA-DR+, CD4+HLA-DR+ and CD8+HLA-DR+) in peripheral blood revealed a gradual and bimodal increase after LDR brachytherapy, whereas memory CD8+ T cells bimodally decreased after treatment. The ratios of activated T cells and regulatory T cells gradually increased after the treatment. Thus, LDR brachytherapy was demonstrated to induce effective immune responses in patients. This increase of activated T cells may contribute to maintenance of remission and reduction of relapse rates.

Background We evaluated a five-tiered Gleason grade groups arising from the 2014 International Society of Urological Pathology consensus conference on prognostic prediction in clinical stage T3a (extracapsular invasion) and T3b (seminal vesicle involvement) prostate cancer undergoing high-dose-rate brachytherapy (HDR-BT). Methods From November 2003 to December 2012, 283 patients with stage T3 prostate cancer received HDR-BT and external beam radiation therapy (EBRT) with long-term androgen deprivation therapy (ADT). Of these, 203 (72%) and 80 (28%) patients had stage T3a and T3b disease, respectively. The mean dose to 90% of the planning target volume was 7.5 Gy/fraction of HDR-BT. After five fractions, EBRT with 10 fractions of 3 Gy was administered. All patients first underwent ≥6 months of neoadjuvant ADT, and adjuvant ADT continued for 36 months. Median follow-up was 74 months from the start of radiotherapy. Results The 10-year biochemical recurrence (BCR) -free rate for stage T3a and T3b disease was 79% and 64%, respectively (P = 0.0083). The 10-year cancer-specific survival (CSS) rate for stage T3a and T3b was 96% and 91%, respectively (P = 0.0305). Although grade groups ≥4 were independent predictors for BCR in cT3a patients (P = 0.0270), they failed to significantly predict prostate cancer-specific mortality (PCSM) among cT3a patients. Among cT3b patients, grade group 5 was a significant predictor of both BCR (P = 0.0017) and PCSM (P = 0.0233). Among stage T3a patients, no significant difference existed in 10-year CSS between grade groups 5 and 4 (94% vs 97%, P = 0.3960). In contrast, grade group 5 had a significantly worse outcome in 10-year CSS than grade group 4 among stage T3b patients (74% vs 100%, P = 0.0350). Conclusions Stage T3a patients with grade groups 4/5 and stage T3b with grade group 4 had fairly low PCSM risk. Approximately one of four patients among stage T3b patients with grade group 5 showed PCSM after combined HDR-BT and EBRT with long-term ADT. Stage T3b patients with grade group 5 may have a greater risk for PCSM.

An important clinical question of great interest to clinicians is how to best sequence androgen receptor targeted agents (ARTAs) and chemotherapy for metastatic castration-resistant prostate cancer (mCRPC), but the answer is still unclear.To evaluate and compare the clinical outcomes of ARTA and docetaxel (DTX) as second-line treatment in the post first-line ARTA, we conducted a retrospective analysis of chemotherapy-naive mCRPC patients who had received sequential treatment with ARTA followed by another ARTA (ARTA-ARTA) or ARTA followed by DTX (ARTA-DTX).A total of 97 patients were treated with the ARTA-ARTA sequence and 42 with the ARTA-DTX sequence. A prostate-specific antigen (PSA) response to the second-line treatment was observed in 18.6% in the ARTA-ARTA and in 33.3% in the ARTA-DTX sequence, but the difference in PSA response was not statistically significant (P = .057). The median progression-free survival (PFS) was significantly different between ARTA and DTX in the second-line treatment (hazard ratio [HR], 0.38; 95% confidence interval [CI], 0.24-0.59; P .001). The favorable outcome in the ARTA-DTX sequence compared with the ARTA-ARTA sequence remained (HR, 0.51, 95% CI, 0.33-0.80; P = .004) in the combined PFS (first-line PFS + second-line PFS). However, no statistically significant difference in overall survival (OS) between the 2 groups was observed (HR, 0.60; 95% CI, 0.34-1.09; P = .095). In multivariate analysis, the ARTA-DTX sequence was identified as an independent prognostic factor for combined PFS, but not OS.ARTA-DTX might improve clinical outcomes in terms of second-line PFS and combined PFS, compared with the ARTA-ARTA sequence. However, this significance was not observed for OS.

Despite the absence of local prostate cancer recurrence, some patients develop distant metastases after prostate brachytherapy. We evaluate whether prostate brachytherapy procedures have a potential risk for hematogenous spillage of prostate cancer cells. Fifty-nine patients who were undergoing high-dose-rate (HDR) or low-dose-rate (LDR) brachytherapy participated in this prospective study. Thirty patients with high-risk or locally advanced cancer were treated with HDR brachytherapy after neoadjuvant androgen deprivation therapy (ADT). Twenty-nine patients with clinically localized cancer were treated with LDR brachytherapy without neoadjuvant ADT. Samples of peripheral blood were drawn in the operating room before insertion of needles (preoperative) and again immediately after the surgical manipulation (intraoperative). Blood samples of 7.5 mL were analyzed for circulating tumor cells (CTCs) using the CellSearch System. While no preoperative samples showed CTCs (0%), they were detected in intraoperative samples in 7 of the 59 patients (11.8%; preoperative vs. intraoperative, p = 0.012). Positive CTC status did not correlate with perioperative variables, including prostate-specific antigen (PSA) at diagnosis, use of neoadjuvant ADT, type of brachytherapy, Gleason score, and biopsy positive core rate. We detected CTCs from samples immediately after the surgical manipulation. Further study is needed to evaluate whether those CTCs actually can survive and proliferate at distant sites.

Objective: Abiraterone acetate has been approved in .70 countries for chemotherapy-naive metastatic castration-resistant prostate cancer patients. Efficacy and safety of abiraterone acetate (1000 mg/once daily) with prednisolone (5 mg/twice daily) in chemotherapy-naive Japanese patients with metastatic castration-resistant prostate cancer was evaluated. Methods: Men, � 20 years, with prostate-specific antigen levels of � 5 ng/ml and evidence of progression were enrolled in this Phase 2, multicenter, open-label study. Primary efficacy end- point was proportion of patients achieving a prostate-specific antigen decline of � 50% from baseline (prostate-specific antigen response) after 12 week of treatment. Secondary efficacy endpoints and safety were assessed. Results: A confirmed prostate-specific antigen response was observed in 29/48 (60.4%) patients by week 12; lower limit of two-sided 90% confidence interval was .35% (threshold re- sponse rate), demonstrating efficacy of abiraterone acetate. Secondary efficacy endpoints: prostate-specific antigen response rate during treatment period: 62.5%; objective radiographic response, partial response: 4/18 (22.2%) patients; complete response: none; stable disease: 11/18 (61.1%) patients; median percent change in prostate-specific antigen level from baseline at Week 12: 266.62%. Median prostate-specific antigen response duration and progression- free survival were not reached, and median radiographic progression-free survival was 253 days. Of 31/48 (64.6%) patients experienced adverse events of special interest; most common was hepatic function abnormality (37.5%, Grade 3: 10.4%). One Grade 3 hypertension was the only mineralocorticoid adverse event .Grade 1/2. Conclusions: Efficacy of abiraterone acetate plus prednisolone was demonstrated by decline in prostate-specific antigen levels with evidence of antitumor activity by radiography in Japanese patients with chemotherapy-naive metastatic castration-resistant prostate cancer. Abiraterone acetate plus prednisolone had an acceptable safety profile. Clinical trial registration no: NCT01756638.

Objective: In this Phase 2 multicenter study the efficacy and safety of oral abiraterone acetate (1000 mg/once daily) plus prednisolone (5 mg/twice daily) was evaluated in metastatic castration-resistant prostate cancer patients from Japan who had previously received docetaxelbased chemotherapy. Methods: Men (aged � 20 years) with metastatic castration-resistant prostate cancer (prostate-specific antigen levels: � 5 ng/ml), who had received 1 or 2 cytotoxic chemotherapies (with � 1 regimen being docetaxel) for prostate cancer, were enrolled in this open-label, single-arm study. Primary efficacy endpoint was proportion of patients achieving a � 50% prostate-specific antigen decline from baseline (prostate-specific antigen response rate) after 12-week treatment. Safety and pharmacokinetics were also assessed. Results: Confirmed prostate-specific antigen response rate by Week 12 was 28.3% (90% confidence interval: 17.6%; 41.1%) or 13 out of 46 (full analysis set) treated patients. However, total prostate-specific antigen response rate including confirmed and unconfirmed responses was 34.8% (90% confidence interval: 23.2%; 47.9%). Secondary efficacy endpoints and outcomes were: improvement in Eastern Cooperative Oncology Group performance status score by � 1 unit: 7/16 patients (43.8%); objective radiographic response: complete response, partial response and stable disease in 0, 1/22 (4.5%) and 9/22 (40.9%) patients, respectively; pain palliation response: 9/16 (56.3%) patients. The most common adverse events (.20% patients) were upper respiratory tract infection (13/47, 27.7% patients) and hepatic function abnormal (10/47, 21.3% patients, Grade 3: 8.5%). All mineralocorticoid-related toxicities were Grade 1/2. Conclusions: Abiraterone acetate plus prednisolone showed favorable efficacy in metastatic castration-resistant prostate cancer Japanese patients who had received chemotherapy. Abiraterone acetate plus prednisolone had an acceptable safety profile. Clinical trial registration no: NCT01795703.

Purpose: The purpose of this work was to report measured catheter displacement prior to the delivery of highdose-rate brachytherapy (HDR) in the treatment of prostate cancer. Material and methods: Data from 30 prostate cancer patients treated with HDR brachytherapy were analyzed retrospectively. Eighteen transperineal hollow catheters were inserted under transrectal ultrasound guidance. Gold marker seeds were also placed transperineally into the base and apex of the prostate gland. Five treatment fractions of 7.5 Gy each were administered over 3 days. The patient underwent CT scanning prior to each treatment fraction. Catheter displacement was measured from the pre-treatment CT dataset reconstructed at 1.25 mm slice thickness. Results: Most of catheters were displaced in the caudal direction. Variations of 18 catheters for each patient were small (standard deviations < 1 mm for all but one patient). Mean displacements relative to the apex marker were 6 ± 4 mm, 12 ± 6 mm, 12 ± 6 mm, 12 ± 6 mm, and 12 ± 6 mm from plan to 1 st , 2 nd , 3 rd , 4 th , and 5 th fractions, respectively. Conclusions: Our results indicate that catheter positions must be confirmed and if required, adjusted, prior to every treatment fraction for the precise treatment delivery of HDR brachytherapy, and to potentially reduce over-dosage to the bulbo-membranous urethra. J Contemp Brachytherapy 2014; 6, 2: 161–166 DOI: 10.5114/jcb.2014.43619

The purpose of this study was to report the outcomes of high-dose-rate (HDR) brachytherapy and hypofractionated external beam radiotherapy (EBRT) combined with long-term androgen deprivation therapy (ADT) for National Comprehensive Cancer Network (NCCN) criteria-defined high-risk (HR) and very high-risk (VHR) prostate cancer. Data from 178 HR (n = 96, 54%) and VHR (n = 82, 46%) prostate cancer patients who underwent (192)Ir-HDR brachytherapy and hypofractionated EBRT with long-term ADT between 2003 and 2008 were retrospectively analyzed. The mean dose to 90% of the planning target volume was 6.3 Gy/fraction of HDR brachytherapy. After five fractions of HDR treatment, EBRT with 10 fractions of 3 Gy was administered. All patients initially underwent ≥ 6 months of neoadjuvant ADT, and adjuvant ADT was continued for 36 months after EBRT. The median follow-up was 61 months (range, 25-94 months) from the start of radiotherapy. The 5-year biochemical non-evidence of disease, freedom from clinical failure and overall survival rates were 90.6% (HR, 97.8%; VHR, 81.9%), 95.2% (HR, 97.7%; VHR, 92.1%), and 96.9% (HR, 100%; VHR, 93.3%), respectively. The highest Radiation Therapy Oncology Group-defined late genitourinary toxicities were Grade 2 in 7.3% of patients and Grade 3 in 9.6%. The highest late gastrointestinal toxicities were Grade 2 in 2.8% of patients and Grade 3 in 0%. Although the 5-year outcome of this tri-modality approach seems favorable, further follow-up is necessary to validate clinical and survival advantages of this intensive approach compared with the standard EBRT approach.

Aims: Inflammatory myofibroblastic tumor (IMT) of the urinary bladder is a clinically and histologically uncommon benign tumor that can be easily mistaken for a malignant neoplasm. We sought to determine whether immunohistochemical staining would be evaluated IMT of the urinary bladder. We have also shown the literatures that imminohistochemical staining of IMT was investigated to distinguish malignant lesions using PubMed data base. Methods: Immunohistochemical staining, including anaplastic lymphoma kinase (ALK), p53, cytokeratin, vimentin, desmin, alpha-smooth muscle actin, myoglobin, smooth muscle myosin and S100, was carried out on serial sections from archival specimens of three patients who underwent transurethral resection and partial cystectomy. Results: Immunohistchemical staining in all patients was positive for ALK and weak positive for p53 protein. In the literatures, positive rates of ALK and p53 inthe IMT of the urinary bladder were 60.9% and 53.1%, respectively. Sarcoma and carcinosarcoma were shown in the pathological specimens with negative ALK and strongly positive p53 inthe same data base. Conclusions: Both ALK and p53 were potentially useful protein markers to distinguish between IMT and sarcoma. However, this study was small sample size. Further study was warranted an investigation of the availability of these proteins in IMT.

Background Both abiraterone acetate (AA) and enzalutamide are promising agents for patients with pre- and post-chemotherapy metastatic castration-resistant prostate cancer (mCRPC). Several retrospective analysis suggested clinical cross-resistance between these agents in patients previously treated with docetaxel. However, data on the antitumor activity of AA as a second androgen receptor-targeting new agent after the failure of enzalutamide in chemotherapy-naive mCRPC patients is unavailable. Methods Patients with chemotherapy-naïve mCRPC who were treated with AA after disease progression with enzalutamide, were retrospectively reviewed at five institutions. Primary outcome measure was the rate of any prostate-specific antigen (PSA) decline. Secondary outcome measures were progression-free survival (PFS) and overall survival (OS) with subsequent AA treatment. We also performed correlation analysis between previous PSA response, PFS duration to enzalutamide and subsequent PSA response, PFS duration to AA. Results A total of 14 patients were identified. Any PSA declines and PSA decline ≥50 % with AA treatment, were observed in 36 and 7 % of patients, respectively. Median PFS with initial enzalutamide was 5.0 months (95 % CI 3.7–6.4 months), and for subsequent AA treatment was 3.4 months (95 % CI 0.8–6.0 months). Median OS from initiation of AA was 9.1 months (95 % CI 5.6–12.5 months). No significant correlations were observed between these PSA responses (Pearson r = −0.67, p = 0.82) and PFS duration (Kendall tau r = 0.33, p = 0.87). Conclusions The PSA decline with subsequent AA treatment in chemotherapy-naive mCRPC patients after a failure of enzalutamide was modest, however, the PFS and OS with subsequent AA treatment were comparable to those of enzalutamide previously reported as a second androgen receptor-targeting new agent after AA failure. The PSA response and PFS duration to previous enzalutamide treatment did not predict those of subsequent AA treatment.

cancer and locally advanced prostate cancer patients. The objective of the current study was to examine the rate of adherence to these guidelines within a large-scale population-based data repository. We hypothesized near-perfect guideline adherence. METHODS: Between 2003 and 2009, in the Surveillance Epidemiology and End Results (SEER)-Medicare database, 14,180 patients were diagnosed with high-risk (T1-T2 with WHO histological grade 3), or locally advanced (T3-T4) prostatic adenocarcinoma. We assessed the annual rates of adherence to guidelines with respect to use of RT-ADT in the overall population and after stratification according to stage-grade groupings (T1-T2 G3 vs. T3-T4 any grade), age (66-69 vs. 70-74 vs. 75-79 vs. 80), Charlson comorbidity index-CCI (0 vs. 1 vs. 2) and pre-existing baseline cardiovascular (CV) risk. Linear regression model was used to test the slope of rates of combination treatment over time. Multivariate logistic regression analyses were performed to assess the predictors of RT-ADT use. RESULTS: RT-ADT rates, and guideline adherence, were 58.1 to 75.0%, with the highest rate (75.0%) in 2003, and the lowest (58.1%) in 2009. When stratified according to stage-grade groupings, age, CCI and pre-existing baseline CV risk, similar results were obtained. In multivariate analyses, more recent year of diagnosis (OR 0.90, p

Objective: To evaluate risk factors for Denosumab-induced hypocalcemia in prostate cancer patients with bone metastases. Methods: In this single-arm, open-label, prospective multicenter study, 48 prostate cancer patients with bone metastases received Denosumab (120 mg on day 1) and androgen-deprivation therapy. Serum calcium, albumin, alkaline phosphatase (ALP), and phosphate levels; chronic kidney disease stage; and serum prostate specific antigen and urine N-terminal telopeptide (u-NTx) levels were examined. Patients were divided into 2 groups on the basis of whether or not they developed hypocalcemia at 1 week or 1 month after Denosumab administration. Risk factors for hypocalcemia were determined by univariate and multivariate logistic regression analysis. Results: Nineteen patients (39.6%) demonstrated hypocalcemia at 1 week after Denosumab administration, and 16 (33.3%) were hypocalcemic at 1 month. Patients with hypocalcemia at 1 week had higher baseline serum ALP levels (1283.4 ± 1489.7 [mean ± SD] vs 467.3 ± 655.8, P=0.013) than patients without hypocalcemia. Patients with hypocalcemia at 1 month had higher baseline serum ALP (1455.5 ± 1694.1, P=0.002) and u-NTx levels (190.9 ± 63.9, P=0.013) and more bone metastases (extent of disease grade ≥ 3; 10 patients, 20.8%, P=0.006) at baseline than patients without hypocalcemia. Multivariate logistic regression analysis revealed that baseline u-NTx of >100 nmol bone collagen equivalents/mmol creatinine was a significant independent risk factor for hypocalcemia (odds ratio=12.41, 95% confidence interval=1.059-145.600, P=0.049). Conclusions: Baseline u-NTx level is an independent risk factor for Denosumab-induced hypocalcemia in prostate cancer patients with bone metastases.

Purpose The International Commission on Radiological Protection recommends removing the prostate before cremation if death occurs within 12 months after 125 I brachytherapy. However, the incidence of death within this time frame has not been robustly investigated in any country. The purpose this study was to investigate the incidence and cause of death and actions taken when death has occurred within 12 months after 125 I brachytherapy for prostate cancer in Japan. Methods and Materials Data were extracted from the Japan Radioisotope Association database to investigate the total number of implantation cases, number of early deaths after implantation, cause of death, and postmortem actions between September 2003 and the end of June 2010 in Japan. Early death was defined as occurring within 12 months after 125 I brachytherapy for prostate cancer. Results During the study period, 15,427 patients underwent 125 I brachytherapy and 43 (0.28%) died within 12 months after implantation. For 37 of the 43 patients (86%), the brachytherapy source was retrieved together with the prostate gland at autopsy; however, autopsy could not be performed in six (14%) of the deceased patients. The largest proportion of early deaths was because of cerebrovascular or cardiovascular disease (17/43, 40%), followed by malignant tumor (15/43, 35%), and respiratory disease or infection (7/43, 16%). Conclusions The incidence of early deaths within 12 months after 125 I brachytherapy in Japan was 0.28%. In almost all cases, the brachytherapy sources were removed in the intact prostate before the body was cremated and stored appropriately.

Approximately 80% of patients with prostate cancer will develop bone metastases, which often lead to bone pain and skeletal-related events. Sr-89 is an established alternative for the palliation of bone pain in prostate cancer. We aimed to assess the effect of Sr-89 radionuclide therapy on quality of life (QOL) in prostate cancer patients with painful bone metastases.Thirteen patients received a single intravenous injection of Sr-89 at a dose of 2.0 MBq/kg. All patients underwent QOL evaluation prior to Sr-89 treatment and 1, 2, and 3 months afterward using the Japanese version of the EORTC QLQ-BM22, EORTC QLQ-C30, a VAS, and face scale. We also evaluated PSA and ALP response and toxicity of the Sr-89 therapy.The pain characteristics subscale of the EORTC QLQ-BM22 was significantly reduced from 1 month onward compared with the baseline. The functional interference and psychosocial aspects subscales were significantly higher than baseline from 2 months onward. At 2 months, VAS indicated a significant reduction in pain as compared to the baseline. Sr-89 therapy caused a nonsignificant reduction in PSA and ALP levels. No patients had leukocyte toxicity, and one patient had grade 3 platelet toxicity.Sr-89 radionuclide therapy can provide not only reduced pain characteristics but also better psychosocial aspects and functional interference in patients with painful bone metastases of prostate cancer.

Recent advances in high-intensity focused ultrasound, which was developed in the 1940s as a viable thermal tissue ablation approach, have increased its popularity. High-intensity focused ultrasound is currently utilized the most in Europe and Japan, but has not yet been approved by the Food and Drug Administration, USA, for this indication. The purpose of the present report is to review the scientific foundation of high-intensity focused ultrasound technology and the clinical outcomes achieved with commercially available devices. Recently published articles were reviewed to evaluate the current status of high-intensity focused ultrasound as a primary or salvage treatment option for localized prostate cancer. Improvements in the clinical outcome as a result of technical, imaging and technological advancements are described herein. A wide range of treatment options for organ-confined prostate cancer is available. However, high-intensity focused ultrasound is an attractive choice for men willing to choose less invasive options, although establishing the efficacy of high-intensity focused ultrasound requires longer follow-up periods. Technological advances, together with cultural and economic factors, have caused a dramatic shift from traditional open, radical prostatectomy to minimally invasive techniques. High-intensity focused ultrasound is likely to play a significant role in the future of oncology practice.

Purpose To compare the efficacy of three α 1A /α 1D -adrenoceptor (AR) antagonists—naftopidil, tamsulosin, and silodosin—that have differing affinities for the α 1 -AR subtypes in treating urinary morbidities in Japanese men with 125 I prostate implantation (PI) for prostate cancer. Methods and Materials This single-institution prospective randomized controlled trial compared naftopidil, tamsulosin, and silodosin in patients undergoing PI. Patients were randomized and received either naftopidil, tamsulosin, or silodosin. Treatment began 1 day after PI and continued for 1 year. The primary efficacy variables were the changes in total International Prostate Symptom Score (IPSS) and postvoid residual urine (PVR). The secondary efficacy variables were changes in IPSS storage score and IPSS voiding score from baseline to set points during the study (1, 3, 6, and 12 months). Results Two hundred twelve patients were evaluated in this study between June 2006 and February 2009: 71, 70, and 71 patients in the naftopidil, tamsulosin, and silodosin groups, respectively. With respect to the primary efficacy variables, the mean changes in the total IPSS at 1 month after PI in the naftopidil, tamsulosin, and silodosin groups were +10.3, +8.9, and +7.5, respectively. There were significantly greater decreases with silodosin than naftopidil at 1 month in the total IPSS. The mean changes in the PVR at 6 months were +14.6, +23.7, and +5.7 mL in the naftopidil, tamsulosin, and silodosin groups, respectively; silodosin showed a significant improvement in the PVR at 6 months vs. tamsulosin. With respect to the secondary efficacy variables, the mean changes in the IPSS voiding score at 1 month in the naftopidil, tamsulosin, and silodosin groups were +6.5, +5.6, and +4.5, respectively; silodosin showed a significant improvement in the IPSS voiding score at 1 month vs. naftopidil. Conclusions Silodosin has a greater impact on improving PI-induced lower urinary tract symptoms than the other two agents.

Objective: To evaluate the efficacy and toxicity of a gemcitabine and paclitaxel regimen for patients with advanced urothelial carcinoma who had previously been treated with methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy, and to determine the prognostic factors for survival in second-line chemotherapy. Methods: From June 2005 to April 2010, 24 eligible patients who had previously been treated with methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy were enrolled in this study. Patients received paclitaxel 200 mg/m 2 on Day 1 and gemcitabine 1000 mg/m 2 on Days 1, 8 and 15. The gemcitabine and paclitaxel regimen was repeated every 3 weeks. Patients were evaluated every two cycles by imaging study. Results: Ten of 24 patients (42%) had major response to the gemcitabine and paclitaxel regimen, including 2 patients (8%) who had complete response. Median survival time and median progression-free survival were 12.4 and 6.1 months, respectively. Good performance status and major response to first-line methotrexate, vinblastine, doxorubicin and cisplatin treatment were significant predictors of overall survival and progression-free survival. Grade 3 or 4 neutropenia occurred in 16 patients (67%), but there were no severe infections. There were no treatment-related deaths. Conclusions: Gemcitabine and paclitaxel chemotherapy had favorable benefit and safety profiles, and the regimen is recommended as a potential second-line chemotherapy for advanced or metastatic urothelial carcinoma previously treated with methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy.

Introduction The mechanisms of radiation‐induced erectile dysfunction (ED) are unclear, as clinical studies are limited, and previous animal models were based on wide‐field irradiation, which does not model current radiotherapy (RT) techniques. Aims To perform functional and morphological analyses of erectile function (EF) utilizing image‐guided stereotactic prostate‐confined RT in a rat model. Methods Sixty young adult male rats aged 10–12 weeks old were divided into age‐matched sham and RT groups. A single 20‐Gy fraction to the prostate was delivered to RT animals. Penile bulb, shaft, and testes were excluded from treatment fields. Main Outcome Measures Bioassay and intracavernous pressure (ICP) measurements were conducted at 2, 4, and 9 weeks following RT. Perfusion analysis of the corpora cavernosa (CC) was conducted using Hoechst injected prior to sacrifice. Penile shaft and cavernous nerve (CN) were evaluated by immunohistochemistry. Plasma testosterone level was analyzed using a testosterone enzyme‐linked immunosorbent assay (ELISA) assay kit. Results Irradiated animals demonstrated statistically significant time‐dependent functional impairment of EF by bioassay and ICP measurement from 4 weeks. Neuronal nitric oxide synthase (NOS) expression was decreased in CN by 4 weeks. In CC, expression levels of anti‐alpha smooth muscle actin and endothelial NOS were significantly decreased at 9 weeks. In penile dorsal vessels, smooth muscle/collagen ratio was significantly decreased at 4 and 9 weeks. Additionally, Hoechst perfusion showed time‐dependent decrease in CC of RT animals, whereas CD31 expression was not affected. No toxicities were noted; testosterone levels were similar in both groups. Conclusion We demonstrated time‐dependent ED following image‐guided stereotactic RT. Our results imply that reduction of neuronal NOS expression in cavernous nerve could trigger consecutive reduction of smooth muscle content as well as blood perfusion in CC that resulted in corporal veno‐occlusive dysfunction. Present study could be a cornerstone to future research that may bring comprehensive scientific understanding of radiation‐induced ED. Kimura M, Yan H, Rabbani Z, Satoh T, Baba S, Yin F‐F, Polascik TJ, Donatucci CF, Vujaskovic Z, and Koontz BF. Radiation‐induced erectile dysfunction using prostate‐confined modern radiotherapy in a rat model. J Sex Med 2011;8:2215–2226.

Chemotherapy/Radiation therapy/Chemoradiotherapy/Bladder cancer/Urothelial carcinoma. The objectives of this study were to determine the tolerability of combined use of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) with exter nal beam radiation therapy (EBRT) and to access the efficacy in patients with locally advanced or metastatic bladder cancer. From December 2000 to November 2010, 30 eligible patients were enrolled in this study. After receiving one cycle of MVAC treatment, all patients received EBRT with a half dose of MVAC treatment followed by two more cycles of chemotherapy. A standard fractionation with daily dose of 1.8–2.0 Gy was used, with the total dose up to 60 Gy over 5–6 weeks. The four-field box technique was utilized for radiation fields. Thirteen patients (43%) had complete response and 11 (37%) had partial response, with an overall response rate of 80%. The median overall survival and progression-free survival was 25.5 months and 12.8 months, respectively. In the complete-response patients, median overall survival was 37.1 months. Grade 3 or 4 neutropenia occurred in 25 patients (83%), but there were no severe infections. One patient (3%) had hemorrhagic radiation cystitis. There were no treatment-related deaths. Combined use of MVAC treatment with EBRT is a favorable therapeutic option for patients with advanced or metastatic bladder carcinoma. Given the safety and benefit profile found in this study, appropriate case selection is warranted in the future.

Purpose To compare the results of intraoperative ultrasound (US)-based dosimetry with those of postimplant computed tomography (CT)-based dosimetry after 125I prostate brachytherapy. Methods and Materials Subjects comprised 160 patients who underwent prostate brachytherapy using 125I seed implants. Prescribed dose was set as 145 Gy to the periphery of the prostate. Implantation was performed using an intraoperative interactive technique. Postimplant dosimetry was performed on Days 1 and 30 after implantation using CT. Dosimetric results for the prostate, urethra, and rectum were compared among intraoperative US and CT on Day 1 (CT1) and Day 30 (CT30). Results Mean minimal dose received by 90% of prostate volume was 133.7%, 115.6%, and 125.8% of the prescribed dose on US, CT1, and CT30, respectively: This value temporarily decreased on Day 1 and increased on Day 30. Other parameters for the prostate and urethra showed similar trends. Conversely, mean rectal volume receiving 100% of the prescribed dose was 0.69, 0.46, and 1.02 mL on US, CT1, and CT30, respectively. Rectal parameters tended to be underestimated on US relative to CT30-based dosimetry. A positive linear relationship was identified between US and CT observations for every prostate parameter and the dose covering 30% of the urethra. Conclusions Our results demonstrate significant differences between dosimetric parameters obtained by US, CT1, and CT30. However, significant correlations also exist between US and CT, at least in prostate and urethral parameters. Clarification of the degrees of difference might make US planning more feasible.

In addition to open surgery, curative therapies for prostate cancer now include endoscopic surgery and radiation therapies. Because of the expansion and subdivision of treatment methods for prostate cancer, the medical fee point schedule in Japan was revised in fiscal year 2006. We examined changes in medical income and expenditure after this revision of the medical fee system.We studied income and expenditure, after institution of the new medical fee schedule, for the five types of therapies for prostate cancer performed at our hospital: two surgical therapies (radical retropubic prostatectomy and laparoscopic prostatectomy) and three radiation therapies (three-dimensional conformal radiation therapy, (192)Ir high-dose-rate brachytherapy, and (125)I low-dose-rate brachytherapy).Low-dose-rate brachytherapy was found to be associated with a profit of yen199 per patient. Laparoscopic prostatectomy, a highly advanced medical treatment that the fee revision changed from a partially insured to an insured procedure, yielded a profit of yen75,672 per patient. However, high-dose-rate brachytherapy was associated with a loss of yen654,016 per patient.Given the loss in hospital income per patient undergoing high-dose-rate brachytherapy, the medical fee point system for this procedure should be reassessed.

Purpose To evaluate the severity of genitourinary (GU) toxicity in high-dose-rate (HDR) brachytherapy combined with hypofractionated external beam radiotherapy (EBRT) for prostate cancer and to explore factors that might affect the severity of GU toxicity. Methods and Materials A total of 100 Japanese men with prostate cancer underwent 192 Ir HDR brachytherapy combined with hypofractionated EBRT. Mean (SD) dose to 90% of the planning target volume was 6.3 (0.7) Gy per fraction of HDR. After 5 fractions of HDR treatment, EBRT with 10 fractions of 3 Gy was administrated. The urethral volume receiving 1–15 Gy per fraction in HDR brachytherapy (V1–V15) and the dose to at least 5–100% of urethral volume in HDR brachytherapy (D5–D100) were compared between patients with Grade 3 toxicity and those with Grade 0–2 toxicity. Prostate volume, patient age, and International Prostate Symptom Score were also compared between the two groups. Results Of the 100 patients, 6 displayed Grade 3 acute GU toxicity, and 12 displayed Grade 3 late GU toxicity. Regarding acute GU toxicity, values of V1, V2, V3, and V4 were significantly higher in patients with Grade 3 toxicity than in those with Grade 0–2 toxicity. Regarding late GU toxicity, values of D70, D80, V12, and V13 were significantly higher in patients with Grade 3 toxicity than in those with Grade 0–2 toxicity. Conclusions The severity of GU toxicity in HDR brachytherapy combined with hypofractionated EBRT for prostate cancer was relatively high. The volume of prostatic urethra was associated with grade of acute GU toxicity, and urethral dose was associated with grade of late GU toxicity.

OBJECTIVE To examine the incidence, timing, and magnitude of the prostate-specific antigen (PSA) level ‘bounce’ after permanent prostate brachytherapy (BT) and correlate the PSA bounce with clinical and dosimetric factors in Japanese patients with prostate cancer. PATIENTS AND METHODS A multi-institutional pooled analysis was carried out in 388 consecutive patients with T1–T2N0M0 prostate cancer treated with 125I-seed implant BT with no hormonal therapy or external beam radiotherapy. All patients had ≥1 year of follow-up and at least three follow-up PSA level measurements. Three definitions of PSA bounce were used: definition A, a PSA level rise of 0.1 ng/mL; definition B, a PSA level rise of 0.4 ng/mL; and definition C, a PSA level rise of 35% over the previous value, followed by a subsequent fall. RESULTS The actuarial likelihood of having PSA bounce at 24 months was 50.8% for definition A, 23.5% for definition B, and 19.4% for definition C. The median time to develop PSA bounce was 12 months for definition A, 18 months for definition B, and 18 months for definition C. There was a PSA bounce magnitude of 2 ng/mL in 5.3% of patients, and 95.3% of PSA bounce occurred within 24 months after 125I-BT. Among the before and after 125I-BT factors, clinical stage, initial PSA level, and Gleason score did not predict for PSA bounce using any definition; only being younger predicted for PSA bounce on multivariate analysis (P

OBJECTIVES The lymphatic vessel endothelial hyaluronan receptor (LYVE-1) is a novel lymphatic vessel marker that is expressed on lymph vessel endothelial cells. The objective of this study was to determine the LYVE-1 expression patterns in normal urothelium and to compose the geometric topography of the lymphatic network. METHODS Immunohistochemical staining for LYVE-1 and von Willebrand factor was performed to assess the differences in the distribution of lymphatic vessels between the components in the urinary bladder. The sizes of the individual lymphatic vessels were categorized as small, medium, and large. To compare the lymphatic density (counts per square millimeter), the number of lymphatic vessels of the five random areas was counted in each specimen. RESULTS LYVE-1 expression and the lymphatic density of the muscularis propria were significantly greater than those of other layers, including the epithelium, lamina propria, perivesical fat, and serosa (P