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Purpose: Patients with biochemically recurrent prostate cancer (BRPC) after radical prostatectomy and a short PSA doubling time are at risk for distant metastases. Apalutamide, an androgen receptor antagonist, and abiraterone acetate plus prednisone (AAP) prolong survival in the metastatic setting. We evaluated whether intensification of androgen-deprivation therapy (ADT) improves outcomes in BRPC., Patients and Methods: PRESTO is a randomized phase III, open-label trial in patients with BRPC and PSA doubling time ≤9 months (ClinicalTrials.gov identifier: NCT03009981). Patients were randomly assigned 1:1:1 to receive a finite 52-week treatment course with ADT control, ADT + apalutamide, or ADT + apalutamide + AAP. The primary end point was PSA progression-free survival (PSA-PFS), defined as serum PSA >0.2 ng/mL after treatment completion., Results: Five hundred three patients were enrolled. The median PSA was 1.8 ng/mL (IQR, 1.0-3.6). At the first planned interim analysis, both experimental arms significantly prolonged PSA-PFS compared with the control arm (median, 24.9 months for ADT + apalutamide v 20.3 months for ADT; hazard ratio [HR], 0.52 [95% CI, 0.35 to 0.77]; P = .00047; median, 26.0 months for ADT + apalutamide + AAP v 20.0 months for ADT; HR, 0.48 [95% CI, 0.32 to 0.71]; P = .00008). Median time to testosterone recovery did not differ across treatment arms. The most common grade ≥3 adverse event was hypertension (7.5%, 7.4%, and 18% in ADT, ADT + apalutamide, and ADT + apalutamide + AAP arms, respectively)., Conclusion: Intensified AR blockade for a finite duration prolongs PSA-PFS with a manageable safety profile, without adversely affecting time to testosterone recovery. The addition of apalutamide to ADT should be considered in patients with high-risk BRPC.

Purpose: To evaluate late gastrointestinal (GI) and genitourinary (GU) toxicity of moderately hypofractionated intensity modulated proton therapy (IMPT) targeting the prostate and pelvic lymph nodes., Methods and Materials: A target accrual of 56 patients with high-risk or unfavorable intermediate risk prostate cancer were enrolled into a prospective study (ClinicalTrials.gov: NCT02874014) of moderately hypofractionated IMPT. IMPT with pencil beam scanning was used to deliver 6750 and 4500 cGy relative biological effectiveness in 25 daily fractions simultaneously to the prostate and pelvic lymph nodes, respectively. All received androgen deprivation therapy. Late GI and GU toxicity was prospectively assessed using Common Terminology Criteria for Adverse Events version 4.0, at baseline, weekly during radiation therapy, 3-month postradiation therapy, and then every 6 months. Actuarial rates of late GI and GU toxicity were estimated using Kaplan-Meier method., Results: Median age was 75.5 years. Fifty-four patients were available for late toxicity evaluation. Median follow-up was 43.9 months (range, 16-66). The actuarial rate of late grade ≥2 GI toxicity at both 2 and 3 years was 7.4% (95% confidence interval [CI], 0.2%-14.2%). The actuarial rate of late grade 3 GI toxicity at both 2 and 3 years was 1.9% (95% CI, 0%-5.4%). One patient experienced grade 3 GI toxicity with proctitis. The actuarial rate of late grade ≥2 GU toxicity was 20.5% (95% CI, 8.9%-30.6%) at 2 years, and 29.2 % (95% CI, 15.5%-40.7%) at 3 years. None had grade 3 GU toxicity. The presence of baseline GU symptoms was associated with a higher likelihood of experiencing late grade 2 GU toxicity., Conclusions: A moderately hypofractionated IMPT targeting the prostate and regional pelvic lymph nodes was generally well tolerated. Patients with pre-existing GU symptoms had a higher rate of late grade 2 GU toxicity. A phase 3 study is needed to assess any therapeutic gain of IMPT, in comparison with photon-based radiation therapy., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: The objective of this study was to report acute changes in patient-reported quality of life (PRQOL) using the 26-item Expanded Prostate Index Composite (EPIC-26) questionnaire in a prospective study using hypofractionated intensity-modulated proton beam therapy (H-IMPT) targeting the prostate and the pelvic lymph nodes for high-risk or unfavorable intermediate-risk prostate cancer., Methods: Fifty-five patients were enrolled. H-IMPT consisted of 45 GyE to the pelvic lymph nodes and 67.5 GyE to the prostate and seminal vesicles in 25 fractions. PRQOL was assessed with the urinary incontinence (UI), urinary irritative/obstructive symptoms (UO), and bowel function (BF) domains of EPIC-26 questionnaire. Mean changes in domain scores were analyzed from pretreatment to the end of treatment and 3 months posttreatment. A clinically meaningful change (or minimum important change) was defined as a score change > 50% of the baseline standard deviation., Results: The mean scores of UO, UI, and BF at baseline were 84.6, 91.1, and 95.3, respectively. At the end of treatment, there were statistically significant and clinically meaningful declines in UO and BF scores (-13.5 and -2.3, respectively), while the decline in UI score was statistically significant but not clinically meaningful (-13.7). A clinically meaningful decline in UO, UI, and BF scores occurred in 53.5%, 22.7%, and 73.2% of the patients, respectively. At 3 months posttreatment, all three mean scores showed an improvement, with fewer patients having a clinically meaningful decline in UO, UI, and BF scores (18.4%, 20.5%, and 45.0%, respectively). There was no significant reduction in the mean UO and UI scores compared to baseline, although the mean BF score remained lower than baseline and the difference was clinically meaningful., Conclusions: UO, UI, and BF scores of PRQOL declined at the end of H-IMPT. UO and UI scores showed improvement at 3 months posttreatment and were similar to the baseline scores. However, BF score remained lower at 3 months posttreatment with a clinically meaningful decline., (© 2022 Wiley Periodicals LLC.)

Purpose: Men with low serum testosterone at the time of prostate cancer diagnosis are frequently considered to have more aggressive disease. We examined treatment outcomes in men with clinically localized high-risk cancer to determine if baseline testosterone level identified men at higher risk for cancer progression after treatment., Materials and Methods: Alliance/CALGB 90203 randomized men with clinically localized high-risk prostate cancer to radical prostatectomy alone or neoadjuvant chemohormonal therapy and radical prostatectomy. Men with available baseline testosterone levels who had not received androgen deprivation prior to study enrollment were studied (656). Testosterone level was examined as a continuous variable, as quartiles, and separately in men with an absolute testosterone level above/below 150 ng/dl. Outcomes evaluated were overall survival and event-free survival with events defined by biochemical recurrence, secondary treatment, prostate cancer metastasis, and death., Results: We were unable to demonstrate a difference between baseline serum testosterone level measured as a continuous variable, as quartiles, or as a dichotomous variable (above/below 150 ng/dl) with the outcomes measured. This finding was observed in both arms of the study., Conclusions: Baseline serum testosterone level did not predict outcomes in men with clinically localized high-risk prostate cancer treated with radical prostatectomy alone or neoadjuvant chemohormonal therapy and radical prostatectomy.

Purpose: Radical prostatectomy (RP) alone is often inadequate in curing men with clinically localized, high-risk prostate cancer (PC). We hypothesized that chemohormonal therapy (CHT) with androgen-deprivation therapy plus docetaxel before RP would improve biochemical progression-free survival (BPFS) over RP alone., Patients and Methods: Men with clinically localized, high-risk PC were assigned to RP alone or neoadjuvant CHT with androgen deprivation plus docetaxel (75 mg/m 2 body surface area every 3 weeks for 6 cycles) and RP. The primary end point was 3-year BPFS. Biochemical failure was defined as a serum prostate-specific antigen level > 0.2 ng/mL that increased on 2 consecutive occasions that were at least 3 months apart. Secondary end points included 5-year BPFS, overall BPFS, local recurrence, metastasis-free survival (MFS), PC-specific mortality, and overall survival (OS)., Results: In total, 788 men were randomly assigned. Median follow-up time was 6.1 years. The overall rates of grade 3 and 4 adverse events during chemotherapy were 26% and 19%, respectively. No difference was seen in 3-year BPFS between neoadjuvant CHT plus RP and RP alone (0.89 v 0.84, respectively; 95% CI for the difference, -0.01 to 0.11; P = .11). Neoadjuvant CHT was associated with improved overall BPFS (hazard ratio [HR], 0.69; 95% CI, 0.48 to 0.99), improved MFS (HR, 0.70; 95% CI, 0.51 to 0.95), and improved OS (HR, 0.61; 95% CI, 0.40 to 0.94) compared with RP alone., Conclusion: The primary study end point, 3-year BPFS, was not met. Although some improvement was seen in secondary end points, any potential benefit must be weighed against toxicity. Our data do not support the routine use of neoadjuvant CHT and RP in patients with clinically localized, high-risk PC at this time., Competing Interests: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Background: To assess whether a prespecified statistical model based on the four kallikrein markers measured in blood-total, free, and intact prostate-specific antigen (PSA), together with human kallikrein-related peptidase 2 (hK2)-or any individual marker measured in pretreatment serum were associated with biochemical recurrence-free (BCR) or metastasis-free survival after radical prostatectomy (RP) in a subgroup of men with very high-risk disease., Methods: We identified 106 men treated at Mayo Clinic from 2004 to 2008 with pathological Gleason grade group 4 to 5 or seminal vesicle invasion at RP. Univariable and multivariable Cox models were used to test the association between standard predictors (Kattan nomogram and GPSM [Gleason, PSA, seminal vesicle and margin status] score), kallikrein panel, and individual kallikrein markers with the outcomes., Results: BCR and metastasis occurred in 67 and 30 patients, respectively. The median follow-up for patients who did not develop a BCR was 10.3 years (interquartile range = 8.2-11.8). In this high-risk group, neither Kattan risk, GPSM score, or the kallikrein panel model was associated with either outcome. However, after adjusting for Kattan risk and GPSM score, separately, preoperative intact PSA was associated with both outcomes while hK2 was associated with metastasis-free survival., Conclusions: Conventional risk prediction tools were poor discriminators for risk of adverse outcomes after RP (Kattan risk and GPSM risk) in patients with very high-risk disease. Further studies are needed to define the role of individual kallikrein marker forms in the blood to predict adverse prostate cancer outcomes after RP in this high-risk setting., (© 2019 Wiley Periodicals, Inc.)

Objective: To evaluate whether germline variations in genes involved in sex steroid biosynthesis and metabolic pathways predict time to treatment failure for patients with advanced prostate cancer undergoing androgen deprivation therapy (ADT), because there are few known clinical predictors of response., Patients and Methods: In a cohort of 304 patients with advanced prostate cancer undergoing ADT, we genotyped 746 single-nucleotide polymorphisms (SNPs) from 72 genes from germline DNA (680 tagSNPs from 58 genes and 66 candidate SNPs from 20 genes [6 genes common in both]). Association with the primary end point of time to ADT failure was assessed using proportional hazards regression models at the gene level (for genes with tagging SNPs) and at the SNP level. False discovery rates (FDRs) of 0.10 or less were considered noteworthy to account for multiple testing., Results: At the gene level, TRMT11 showed the strongest association with time to ADT failure (P<.001; FDR=0.008). Two of 4 TRMT11 tagSNPs were associated with time to ADT failure. Median time to ADT failure for rs1268121 (A>G) was 3.05 years for the AA, 4.27 years for the AG, and 6.22 years for the GG genotypes (P=.002), and for rs6900796 (G>A), it was 2.42 years for the GG, 3.52 years for the AG, and 4.18 years for the AA genotypes (P<.001). No other gene level or SNP level tests had an FDR of 0.10 or less., Conclusion: Genetic variation in TRMT11 was associated with time to ADT failure. Confirmation of these preliminary findings in an independent cohort is needed., (Copyright © 2012 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Purpose: 17-Allylamino-17-demethoxygeldanamycin (17-AAG) is a benzoquinone ansamycin antibiotic with antiproliferative activity in several mouse xenograft models, including prostate cancer models. A two-stage phase II study was conducted to assess the activity and toxicity profile of 17-AAG administered to patients with metastatic, hormone-refractory prostate cancer., Experimental Design: Patients with at least one prior systemic therapy and a rising prostate-specific antigen (PSA) were eligible. Patients received 17-AAG at a dose of 300 mg/m2 i.v. weekly for 3 of 4 weeks. The primary objective was to assess the PSA response. Secondary objectives were to determine overall survival, to assess toxicity, and to measure interleukin-6, interleukin-8, and maspin levels and quality of life., Results: Fifteen eligible patients were enrolled. The median age was 68 years and the median PSA was 261 ng/mL. Patients received 17-AAG for a median number of two cycles. Severe adverse events included grade 3 fatigue (four patients), grade 3 lymphopenia (two patients), and grade 3 back pain (two patients). The median PSA progression-free survival was 1.8 months (95% confidence interval, 1.3-3.4 months). The 6-month overall survival was 71% (95% confidence interval, 52-100%)., Conclusions: 17-AAG did not show any activity with regard to PSA response. Due to insufficient PSA response, enrollment was stopped at the end of first stage per study design. The most significant severe toxicity was grade 3 fatigue. Further evaluation of 17-AAG at a dose of 300 mg/m2 i.v. weekly as a single agent in patients with metastatic, hormone-refractory prostate cancer who received at least one prior systemic therapy is not warranted.

Purpose: Extraprostatic extension (EPE) of tumor conveys an adverse prognosis in early-stage prostate cancer. Previous studies reported on the linear and radial distance of EPE (EPEr) as measured from the prostate edge. In this study, the correlation of the EPEr from a large whole mount prostatectomy series was determined with respect to the needle biopsy and prostatectomy specimen findings., Methods and Materials: In a 24-month period, 404 patients underwent radical prostatectomy and the specimens were whole mounted. The preoperative records, biopsy findings, and EPEr from these specimens were evaluated., Results: The range of the EPEr distance was 0.0-5.7 mm. A three-category model was used that included 283 patients (70%) with no EPE, 59 (15%) with "near EPE" (range, 0.01-0.59 mm), and 62 (15%) with "far EPE" (>or=0.6 mm). Univariate analysis revealed that patient age and prostate volume did not correlate with EPEr, in contrast to all other factors evaluated. Multivariate analysis identified the preoperative serum prostate-specific antigen, the percentage of cancer in the biopsy cores, and clinical tumor stage as significant. However, the Gleason score was not associated with the EPEr. Greater discrimination was possible in estimating the probability of extension in the "near" category than in the "far" category., Conclusion: EPEr is associated with the preoperative prostate-specific antigen level, percentage of cancer in the biopsy cores, and clinical tumor stage. These data might be useful in planning local therapies for prostate cancer, but additional studies identifying factors associated with EPEr beyond 3-5 mm could have relevance regarding the appropriate radiotherapeutic management strategies.

Objectives: To assess the impact of clinical selection criteria on pathologic features among patients treated by radical retropubic prostatectomy and to evaluate the implications of broadening eligibility for permanent prostate brachytherapy monotherapy., Methods: A consecutive series of 423 patients with prostate cancer, who underwent diagnostic biopsy and subsequent radical retropubic prostatectomy, were selected for this study. Four subgroups were defined using the American Brachytherapy Society selection criteria, including prostate size limits (group 1), no prostate size limits (group 2A), a modified set of criteria (group 2B), and clinical Stage T1-T2 (group 3). The rates of extraprostatic extension, seminal vesicle invasion, and lymph node involvement were compared., Results: Adverse pathologic features at radical retropubic prostatectomy were noted in 8 (9.3%) of 86 patients in group 1, 11 (5.6%) of 195 patients in group 2A, 35 (12.0%) of 292 patients in group 2B, and 90 (21.8%) of 413 patients in group 3. The rates of extraprostatic extension, seminal vesicle invasion, and lymph node involvement appeared comparable among groups 1 (5.8%, 3.5%, and 0.0%, respectively), 2A (3.6%, 2.1%, and 0.0%, respectively), and 2B (6.9%, 3.8%, and 1.4%, respectively), but were greater in group 3 (9.7%, 7.8%, and 4.4%, respectively)., Conclusions: Judicious broadening of the clinical selection criteria may allow a greater number of patients to be eligible for permanent prostate brachytherapy monotherapy by including patients whose risk of having adverse pathologic features is comparable to that of patients currently deemed suitable for permanent prostate brachytherapy monotherapy. Prospective assessment of oncologic outcomes of such an approach is required.

Purpose: Limited duration neoadjuvant cytoreductive hormonal therapy (NHT) is used before the definitive radiotherapeutic management of prostate cancer to decrease target volume size and/or to decrease urinary obstructive symptoms. The purpose of this study is to examine the effect of NHT on prostate volume before permanent prostate brachytherapy (PPB) and on prostatic edema after PPB., Methods and Materials: Between May 1998 and February 2004, 408 patients underwent PPB at our institution and provided research authorization for the use of their records. Of these, 122 (30%) underwent NHT. Of the 122, 78 (64%) underwent transrectal ultrasound before the start of NHT. Patients undergoing PPB who received NHT were compared with a similar non-NHT group (N = 286). Detailed measurements of prostate volume were performed by transrectal ultrasound before and after NHT, if applicable. In addition, intraoperative preimplantation transrectal ultrasound and post-implantation transrectal ultrasound were also performed. Post-implantation computed tomography was per formed within 1 day of PPB., Results: The mean duration of NHT was 4.0 +/- 1.1 months (range, 1-8 months). The mean prostate volume before NHT was 63.3 +/- 22.8 cc (range, 19-138 cc), and after NHT (before PPB), it was 41.6 +/- 16.4 cc (18-98 cc). The median prostate volume decrease after NHT was 22.7 cc or 34.9%. There was no significant difference in the degree of postimplantation prostate edema, as measured by the postimplantation to preimplantation ratio (1.18 +/- 0.05 [range, 0.8-1.9]) for the NHT group and 1.21 +/- 0.03 (range, 0.8-1.9) for the non-NHT group (P = 0.5)., Conclusions: Prostate volume decreased by approximately one third after 4 months of NHT. NHT did not affect the degree of post-PPB prostatic edema.

Background: The efficacy of brachytherapy for patients with localized prostate carcinoma depends on adequate radiotherapeutic coverage of the primary tumor and its subclinical extraprostatic extensions. Predictive models based on pretherapy factors may be useful to estimate the likelihood for clinically relevant extraprostatic disease and may be incorporated into selection criteria for this procedure., Methods: Multivariate logistic regression model building was performed using pretherapy factors in 2905 surgically staged patients with localized prostate carcinoma to estimate the probability of seminal vesicle and/or lymph node involvement. Bootstrap methods were employed to assess the stability of the final model parameters and to determine the sensitivity and specificity of the final model., Results: Clinical tumor classification, biopsy Gleason score groupings, and serum prostate specific antigen (PSA) levels were associated with seminal vesicle and/or pelvic lymph node involvement. These factors were incorporated into a multivariate model that predicted for these adverse histopathologic features. Allowing for up to a 10% likelihood for seminal vesicle and/or pelvic lymph node involvement, patients with tumors classified as T1c-T2a, Gleason scores of 2-6, and PSA < or = 16 ng/mL; or with tumors classified as T1c-T2a, Gleason scores of 7-10, and PSA < or = 4 ng/mL; or with tumors classified as T2b-T2c, Gleason scores of 2-6, and PSA < or = 6 ng/mL would be potential candidates for brachytherapy alone., Conclusions: The predictive model presented may provide criteria whereby an adequately performed prostate brachytherapy procedure is expected to encompass the intraprostatic and adjacent extraprostatic disease. Prostate brachytherapy alone may be considered in these circumstances, whereas the addition of external beam radiotherapy may be reserved for patients with disease that is apt to extend beyond the brachytherapy target volume., (Copyright 2002 American Cancer Society.)