Active surveillance outcomes in prostate cancer patients: the use of transperineal template-guided mapping biopsy for patient selection.

PURPOSE: To evaluate active surveillance (AS) outcomes including overall survival (OS), freedom from distant metastases (FDM), freedom from therapeutic intervention (FTI), and quality of life (QOL) outcomes in prostate cancer patients using transperineal template-guided mapping biopsy (TTMB) for patient selection. METHODS: From April 2005-January 2016, 226 consecutive, prospectively evaluated prostate cancer patients underwent TTMB for either low-grade prostate cancer or persistently elevated prostate-specific antigen (PSA) and/or the presence of ASAP. Evaluated outcomes included OS, FDM, FTI and QOL including urinary, bowel, sexual function and depression. Repeat biopsy was based on PSA kinetics and/or abnormal digital rectal examination. RESULTS: Of the 226 patients, 212 (93.8%) were Gleason 3 + 3 and 14 (6.2%) were Gleason 3 + 4. The median follow-up was 5.0 years (range 0.8-13.0 years). The mean prostate volume was 61.3 cm3 with a mean of 59.5 TTMB cores/patient. At the time of AS enrollment, an average of 72.9 cores (TRUS + TTMB) had been obtained for each patient. At 8 years, OS, FTI and FDM were 92.5, 96.8 and 100%. Two hundred and twenty-two patients (98.2%) had a PSA doubling time of more than 3 years. No statistical changes in urinary function, bowel function or depression were noted. At 8 years, 73% of the patients maintained erectile function. CONCLUSION: Within the confines of the follow-up of this study, the use of TTMB for patient selection identifies a cohort of patients unlikely to develop biochemical or clinical progression and maintain a favorable quality of life.

Radical Prostatectomy, External Beam Radiotherapy, or External Beam Radiotherapy With Brachytherapy Boost and Disease Progression and Mortality in Patients With Gleason Score 9-10 Prostate Cancer.

Importance: The optimal treatment for Gleason score 9-10 prostate cancer is unknown. Objective: To compare clinical outcomes of patients with Gleason score 9-10 prostate cancer after definitive treatment. Design, Setting, and Participants: Retrospective cohort study in 12 tertiary centers (11 in the United States, 1 in Norway), with 1809 patients treated between 2000 and 2013. Exposures: Radical prostatectomy (RP), external beam radiotherapy (EBRT) with androgen deprivation therapy, or EBRT plus brachytherapy boost (EBRT+BT) with androgen deprivation therapy. Main Outcomes and Measures: The primary outcome was prostate cancer-specific mortality; distant metastasis-free survival and overall survival were secondary outcomes. Results: Of 1809 men, 639 underwent RP, 734 EBRT, and 436 EBRT+BT. Median ages were 61, 67.7, and 67.5 years; median follow-up was 4.2, 5.1, and 6.3 years, respectively. By 10 years, 91 RP, 186 EBRT, and 90 EBRT+BT patients had died. Adjusted 5-year prostate cancer-specific mortality rates were RP, 12% (95% CI, 8%-17%); EBRT, 13% (95% CI, 8%-19%); and EBRT+BT, 3% (95% CI, 1%-5%). EBRT+BT was associated with significantly lower prostate cancer-specific mortality than either RP or EBRT (cause-specific HRs of 0.38 [95% CI, 0.21-0.68] and 0.41 [95% CI, 0.24-0.71]). Adjusted 5-year incidence rates of distant metastasis were RP, 24% (95% CI, 19%-30%); EBRT, 24% (95% CI, 20%-28%); and EBRT+BT, 8% (95% CI, 5%-11%). EBRT+BT was associated with a significantly lower rate of distant metastasis (propensity-score-adjusted cause-specific HRs of 0.27 [95% CI, 0.17-0.43] for RP and 0.30 [95% CI, 0.19-0.47] for EBRT). Adjusted 7.5-year all-cause mortality rates were RP, 17% (95% CI, 11%-23%); EBRT, 18% (95% CI, 14%-24%); and EBRT+BT, 10% (95% CI, 7%-13%). Within the first 7.5 years of follow-up, EBRT+BT was associated with significantly lower all-cause mortality (cause-specific HRs of 0.66 [95% CI, 0.46-0.96] for RP and 0.61 [95% CI, 0.45-0.84] for EBRT). After the first 7.5 years, the corresponding HRs were 1.16 (95% CI, 0.70-1.92) and 0.87 (95% CI, 0.57-1.32). No significant differences in prostate cancer-specific mortality, distant metastasis, or all-cause mortality (≤7.5 and >7.5 years) were found between men treated with EBRT or RP (cause-specific HRs of 0.92 [95% CI, 0.67-1.26], 0.90 [95% CI, 0.70-1.14], 1.07 [95% CI, 0.80-1.44], and 1.34 [95% CI, 0.85-2.11]). Conclusions and Relevance: Among patients with Gleason score 9-10 prostate cancer, treatment with EBRT+BT with androgen deprivation therapy was associated with significantly better prostate cancer-specific mortality and longer time to distant metastasis compared with EBRT with androgen deprivation therapy or with RP.

Incidence, grade and distribution of prostate cancer following transperineal template-guided mapping biopsy in patients with atypical small acinar proliferation.

PURPOSE: To evaluate the role of transperineal template-guided mapping biopsy (TTMB) in patients with atypical small acinar proliferation (ASAP) diagnosed via transrectal ultrasound-guided needle biopsy (TRUS). METHODS: In total, 132 consecutive patients with TRUS-diagnosed ASAP underwent TTMB by means of an anatomic-based technique with sampling of 24 biopsy regions. For each of the 24 regions, 1-3 biopsy cores were obtained (depending on prostate size). No patient underwent pre-biopsy MRI imaging. The Gleason score, location of each positive biopsy core, the number of biopsy cores and percent involvement of each core were recorded. Anterior versus posterior cancer distribution was determined for both low- and high-grade (Gleason score ≥7) cancer. RESULTS: The mean patient age was 63.8 years with a mean PSA of 6.8 ng/mL. Of the 132 patients, 86 (65.2%) were diagnosed with prostate cancer. Of the entire cohort, 47 patients (54.7% of cancer patients and 35.6% of the entire cohort) were diagnosed with Gleason score ≥7. For both low- and high-grade cancers, the anterior gland and especially the anterior apex were the most common cancer locations. CONCLUSION: In patients with ASAP, TTMB diagnosed prostate cancer in 65.2% of patients and 35.6% of the entire cohort had high-grade prostate cancer. A predilection for anterior-based cancers, especially the anterior apex, was identified. Our study may serve as a baseline reference for MRI-guided biopsy regimens.

ACR appropriateness Criteria® Postradical prostatectomy irradiation in prostate cancer.

The purpose of this article is to present an updated set of American College of Radiology consensus guidelines formed from an expert panel on the appropriate use of radiation therapy in postprostatectomy prostate cancer. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. Recent and relevant literature reviewed by the panel led to establishment of criteria for appropriate use of radiation therapy in postprostatectomy prostate cancer. The discussion includes treatment technique, appropriate dose, field design, and the role of prostate-specific antigen (PSA). Ratings and commentary of the panel on multiple treatment parameters were used to reach consensus. Patients with high-risk pathologic features benefit from postprostatectomy radiation therapy.

The addition of low-dose-rate brachytherapy and androgen-deprivation therapy decreases biochemical failure and prostate cancer death compared with dose-escalated external-beam radiation therapy for high-risk prostate cancer.

BACKGROUND: The objective of this study was to determine whether the addition of low-dose-rate brachytherapy or androgen-deprivation therapy (ADT) improves clinical outcome in patients with high-risk prostate cancer (HiRPCa) who received dose-escalated radiotherapy (RT). METHODS: Between 1995 and 2010, 958 patients with HiRPCa were treated at Schiffler Cancer Center (n = 484) or at the University of Michigan (n = 474) by receiving either dose-escalated external-beam RT (EBRT) (n = 510; minimum prescription dose, 75 grays [Gy]; median dose, 78 Gy) or combined-modality RT (CMRT) consisting of (103) Pd implants (n = 369) or (125) I implants (n = 79) both with pelvic irradiation (median prescription dose, 45 Gy). The cumulative incidences of biochemical failure (BF) and prostate cancer-specific mortality (PCSM) were estimated by using the Kaplan-Meier method and Fine and Gray regression analysis. RESULTS: The median follow-up was 63.2 months (interquartile range, 35.4-99.0 months), and 250 patients were followed for >8 years. Compared with CMRT, patients who received EBRT had higher prostate-specific antigen levels, higher tumor classification, lower Gleason sum, and more frequent receipt of ADT for a longer duration. The 8-year incidence BF and PCSM among patients who received EBRT was 40% (standard error, 38%-44%) and 13% (standard error, 11%-15%) compared with 14% (standard error, 12%-16%; P < .0001) and 7% (standard error 6%-9%; P = .003) among patients who received CMRT. On multivariate analysis, the hazard ratios (HRs) for BF and PCSM were 0.35 (95% confidence interval [CI], 0.23-0.52; P < .0001) and 0.41 (95% CI, 0.23-0.75; P < .003), favoring CMRT. Increasing duration of ADT predicted decreased BF (P = .04) and PCSM (P = .001), which was greatest with long-term ADT (BF: HR, 0.33; P < .0001; 95% CI, 0.21-0.52; PCSM: HR, 0.30; P = .001; 95% CI, 0.15-0.6) even in the subgroup that received CMRT. CONCLUSIONS: In this retrospective comparison, both low-dose-rate brachytherapy boost and ADT were associated with decreased risks of BF and PCSM compared with EBRT.

Incidence and pathological features of prostate cancer detected on transperineal template guided mapping biopsy after negative transrectal ultrasound guided biopsy.

PURPOSE: We determined the incidence of cancer detection by transperineal template guided mapping biopsy of the prostate in patients with at least 1 previously negative transrectal ultrasound guided biopsy. MATERIALS AND METHODS: From January 2005 to January 2012 at least 1 negative transrectal ultrasound guided biopsy was done in 485 patients in our clinical database before proceeding with transperineal template guided mapping biopsy. No study patient had a previous prostate cancer diagnosis. The incidence of patients with 1, 2, or 3 or greater previous transrectal ultrasound guided biopsies was 55.3%, 25.9% and 18.8%, respectively. Transperineal template guided mapping biopsy was done in 74.8% of patients for increasing or occasionally persistently increased prostate specific antigen, in 19.4% for atypical small acinar proliferation and in 5.8% for high grade prostatic intraepithelial neoplasia. RESULTS: For the entire study population a median of 59 cores was submitted at transperineal template guided mapping biopsy. Cancer was ultimately detected in 226 patients (46.6%) using the transperineal template guided method, including 196 (86.7%) with clinically significant disease according to the Epstein criteria. The most common cancer detection site on transperineal template guided mapping biopsy was the anterior apex. CONCLUSIONS: Transperineal template guided mapping biopsy detected clinically significant prostate cancer in a substantial proportion of patients with negative transrectal ultrasound guided biopsy. This technique should be strongly considered in the context of increasing prostate specific antigen with failed confirmation of the tissue diagnosis.

Intrafraction displacement of prone versus supine prostate positioning monitored by real-time electromagnetic tracking.

Implanted radiofrequency transponders were used for real-time monitoring of the intrafraction prostate displacement between patients in the prone position and the same patients in the supine position. Thirteen patients had three transponders implanted transperineally and were treated prone with a custom-fitted thermoplastic immobilization device. After collecting data from the last fraction, patients were realigned in the supine position and the displacements of the transponders were monitored for 5-7 minutes. Fourier transforms were applied to the data from each patient to determine periodicity and its amplitude. To remove auto correlation from the stream of displacement data, the distribution of short-term and long-term velocity components were calculated from Poincaré plots of paired sequential vector displacements. The mean absolute displacement was significantly greater prone than supine in the superior-inferior (SI) plane (1.2 ± 0.6 mm vs. 0.6 ± 0.4 mm, p= 0.015), but not for the lateral or anterior-posterior (AP) planes. Displacements were least in the lateral direction. Fourier analyses showed the amplitude of respiratory oscillations was much greater for the SI and AP planes in the prone versus the supine position. Analysis of Poincaré plots confirmed greater short-term variance in the prone position, but no difference in the long-term variance. The centroid of the implanted transponders was offset from the treatment isocenter by > 5 mm for 1.9% of the time versus 0.8% of the time for supine. These results confirmed significantly greater net intrafraction prostate displacement of patients in the prone position than in the supine position, but most of the difference was due to respiration-induced motion that was most pronounced in the SI and AP directions. Because the respiratory motion remained within the action threshold and also within our 5 mm treatment planning margins, there is no compelling reason to choose one treatment position over the other.

External Beam Radiation Therapy With or Without Brachytherapy Boost in Men With Very-High-Risk Prostate Cancer: A Large Multicenter International Consortium Analysis.

PURPOSE: Very-high-risk (VHR) prostate cancer (PC) is an aggressive subgroup with high risk of distant disease progression. Systemic treatment intensification with abiraterone or docetaxel reduces PC-specific mortality (PCSM) and distant metastasis (DM) in men receiving external beam radiation therapy (EBRT) with androgen deprivation therapy (ADT). Whether prostate-directed treatment intensification with the addition of brachytherapy (BT) boost to EBRT with ADT improves outcomes in this group is unclear. METHODS AND MATERIALS: This cohort study from 16 centers across 4 countries included men with VHR PC treated with either dose-escalated EBRT with ≥24 months of ADT or EBRT + BT boost with ≥12 months of ADT. VHR was defined by National Comprehensive Cancer Network (NCCN) criteria (clinical T3b-4, primary Gleason pattern 5, or ≥2 NCCN high-risk features), and results were corroborated in a subgroup of men who met Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trials inclusion criteria (≥2 of the following: clinical T3-4, Gleason 8-10, or PSA ≥40 ng/mL). PCSM and DM between EBRT and EBRT + BT were compared using inverse probability of treatment weight-adjusted Fine-Gray competing risk regression. RESULTS: Among the entire cohort, 270 underwent EBRT and 101 EBRT + BT. After a median follow-up of 7.8 years, 6.7% and 5.9% of men died of PC and 16.3% and 9.9% had DM after EBRT and EBRT + BT, respectively. There was no significant difference in PCSM (sHR, 1.47 [95% CI, 0.57-3.75]; P = .42) or DM (sHR, 0.72, [95% CI, 0.30-1.71]; P = .45) between EBRT + BT and EBRT. Results were similar within the STAMPEDE-defined VHR subgroup (PCSM: sHR, 1.67 [95% CI, 0.48-5.81]; P = .42; DM: sHR, 0.56 [95% CI, 0.15-2.04]; P = .38). CONCLUSIONS: In this VHR PC cohort, no difference in clinically meaningful outcomes was observed between EBRT alone with ≥24 months of ADT compared with EBRT + BT with ≥12 months of ADT. Comparative analyses in men treated with intensified systemic therapy are warranted.

Erectile dysfunction is predictive of all-cause mortality in patients with prostate cancer treated with permanent interstitial brachytherapy.

OBJECTIVE: To evaluate the relationship between pre-treatment erectile function and all-cause mortality in patients with prostate cancer treated with brachytherapy. PATIENTS AND METHODS: In all, 1279 consecutive patients with clinically localized prostate cancer and pre-implant erectile function assessed by the International Index of Erectile Function-6 (IIEF-6) underwent brachytherapy. Potency was defined as an IIEF-6 score of ≥13 without pharmacological or mechanical support. Patients were stratified into IIEF-6-score cohorts (≤12, 13-23 and 24-30). The median follow-up was 5.0 years. RESULTS: The 8-year overall survival (OS) of the study population was 85.1%. The 8-year OS for IIEF-6scores ≤12, 13-23 and 24-30 were 78.0%, 92.8% and 91.4%, respectively (P < 0.001). Cardiovascular events accounted for a significant portion of deaths in each IIEF-6 group. When combined with other risk factors for cardiovascular disease, an IIEF-6 score of ≤12 had an additive effect on all-cause mortality (IIEF-6 score of ≤12 and less than two comorbidities vs two or more comorbidities were 18.2% and 32.1%). CONCLUSIONS: A pre-implant IIEF-6score of ≤12 was associated with a higher incidence of all-cause mortality. Pre-treatment erectile dysfunction is a surrogate for underlying vascular pathology, probably explaining the lower OS in this subset of patients. Aggressive treatment of medical co-morbidity is warranted to impactOS.

ACR-ABS-ASTRO Practice Parameter for Transperineal Permanent Brachytherapy of Prostate Cancer.

AIM/OBJECTIVES/BACKGROUND: The American College of Radiology (ACR), American Brachytherapy Society (ABS), and American Society for Radiation Oncology (ASTRO) have jointly developed the following practice parameter for transperineal permanent brachytherapy of prostate cancer. Transperineal permanent brachytherapy of prostate cancer is the interstitial implantation of low-dose rate radioactive seeds into the prostate gland for the purpose of treating localized prostate cancer. METHODS: This practice parameter was developed according to the process described under the heading The Process for Developing ACR Practice Parameters and Technical Standards on the ACR website (https://www.acr.org/Clinical-Resources/Practice-Parameters-and-Technical-Standards) by the Committee on Practice Parameters-Radiation Oncology of the Commission on Radiation Oncology, in collaboration with ABS and ASTRO. RESULTS: This practice parameter provides a framework for the appropriate use of low-dose rate brachytherapy in the treatment of prostate cancer either as monotherapy or as part of a treatment regimen combined with external-beam radiation therapy. The practice parameter defines the qualifications and responsibilities of all involved radiation oncology personnel, including the radiation oncologist, medical physicist, dosimetrist, radiation therapist, and nursing staff. Patient selection criteria and the utilization of supplemental therapies such as external-beam radiation therapy and androgen deprivation therapy are discussed. The logistics of the implant procedure, postimplant dosimetry assessment, and best practices with regard to safety and quality control are presented. CONCLUSIONS: Adherence to established standards can help to ensure that permanent prostate brachytherapy is delivered in a safe and efficacious manner.

Interplay Between Duration of Androgen Deprivation Therapy and External Beam Radiotherapy With or Without a Brachytherapy Boost for Optimal Treatment of High-risk Prostate Cancer: A Patient-Level Data Analysis of 3 Cohorts.

IMPORTANCE: Radiotherapy combined with androgen deprivation therapy (ADT) is a standard of care for high-risk prostate cancer. However, the interplay between radiotherapy dose and the required minimum duration of ADT is uncertain. OBJECTIVE: To determine the specific ADT duration threshold that provides a distant metastasis-free survival (DMFS) benefit in patients with high-risk prostate cancer receiving external beam radiotherapy (EBRT) or EBRT with a brachytherapy boost (EBRT+BT). DESIGN, SETTINGS, AND PARTICIPANTS: This was a cohort study of 3 cohorts assembled from a multicenter retrospective study (2000-2013); a post hoc analysis of the Randomized Androgen Deprivation and Radiotherapy 03/04 (RADAR; 2003-2007) randomized clinical trial (RCT); and a cross-trial comparison of the RADAR vs the Deprivación Androgénica y Radio Terapía (Androgen Deprivation and Radiation Therapy; DART) 01/05 RCT (2005-2010). In all, the study analyzed 1827 patients treated with EBRT and 1108 patients treated with EBRT+BT from the retrospective cohort; 181 treated with EBRT and 203 with EBRT+BT from RADAR; and 91 patients treated with EBRT from DART. The study was conducted from October 15, 2020, to July 1, 2021, and the data analyses, from January 5 to June 15, 2021. EXPOSURES: High-dose EBRT or EBRT+BT for an ADT duration determined by patient-physician choice (retrospective) or by randomization (RCTs). MAIN OUTCOMES AND MEASURES: The primary outcome was DMFS; secondary outcome was overall survival (OS). Natural cubic spline analysis identified minimum thresholds (months). RESULTS: This cohort study of 3 studies totaling 3410 men (mean age [SD], 68 [62-74] years; race and ethnicity not collected) with high-risk prostate cancer found a significant interaction between the treatment type (EBRT vs EBRT+BT) and ADT duration (binned to <6, 6 to <18, and ≥18 months). Natural cubic spline analysis identified minimum duration thresholds of 26.3 months (95% CI, 25.4-36.0 months) for EBRT and 12 months (95% CI, 4.9-36.0 months) for EBRT+BT for optimal effect on DMFS. In RADAR, the prolongation of ADT for patients receiving only EBRT was not associated with significant improvements in DMFS (hazard ratio [HR], 1.01; 95% CI, 0.65-1.57); however, for patients receiving EBRT+BT, a longer duration was associated with improved DMFS (DMFS HR, 0.56; 95% CI, 0.36-0.87; P = .01). For patients receiving EBRT alone (DART), 28 months of ADT was associated with improved DMFS compared with 18 months (RADAR HR, 0.37; 95% CI, 0.17-0.80; P = .01). CONCLUSIONS AND RELEVANCE: These cohort study findings suggest that the optimal minimum ADT duration for treatment with high-dose EBRT alone is more than 18 months; and for EBRT+BT, it is 18 months or possibly less. Additional studies are needed to determine more precise minimum durations.

Prostate cancer death is unlikely in high-risk patients following quality permanent interstitial brachytherapy.

OBJECTIVE: To evaluate cause-specific survival (CSS), biochemical progression-free survival (bPFS) and overall survival (OS) in high-risk prostate cancer brachytherapy patients. PATIENTS AND METHODS: From April 1995 to June 2005, 284 patients with high-risk prostate cancer (Gleason score ≥ 8 or prostate-specific antigen > 20 ng/mL or clinical stage ≥ T2 c) underwent brachytherapy. Supplemental external beam radiation therapy was given to 257 (90.5%) patients and 179 (63.0%) received androgen deprivation therapy (ADT). Median follow up was 7.8 years. The median post-implant day 0 D90 was 118.9% of prescription dose. Patients with metastatic prostate cancer or castrate-resistant disease without obvious metastases who died of any cause were classified as dead from prostate cancer. Multiple parameters were evaluated for impact on survival. RESULTS: Twelve-year CSS, bPFS and OS were 94.2%, 89.0% and 69.7%. On multivariate analysis, bPFS was best predicted by percent positive biopsies and ADT. The analysis failed to identify any predictors for CSS, while OS was highly correlated with patient age, percent positive biopsies and diabetes. Fourteen percent of patients died from diseases of the heart, while 8%, 8% and 6% of patients died from non-prostate cancer, other causes and prostate cancer, respectively. When OS was stratified by patients with 0-3 vs ≥ 4 comorbidities, the 12-year OS was 73.0% and 52.7% (P = 0.036). CONCLUSIONS: High-quality brachytherapy results in favourable bPFS and CSS for high-risk patients. Death from diseases of the heart is more than twice as likely as death from prostate cancer. Strategies to improve cardiovascular health may positively impact OS.

Effect of the timing of hydrogel spacer placement on prostate and rectal dosimetry of low-dose-rate brachytherapy implants.

PURPOSE: To verify the dose sparing effect of hydrogel spacer (SpaceOAR™) on rectal dosimetry for prostate brachytherapy, and to determine whether prostate and rectal dosimetry was affected by the time gap between hydrogel spacer injection and brachytherapy dosimetry. MATERIAL AND METHODS: The 103Pd brachytherapy dosimetry of 174 consecutive intermediate- and high-risk patients injected with hydrogel was compared with a dosimetry of 174 contemporaneous patients without hydrogel injections. Of the SpaceOAR™ patients, 91 had hydrogel injected upon completion of brachytherapy implant, while the remaining 83 patients had hydrogel placed prior to external beam radiation therapy (EBRT), followed 2-10 weeks later by brachytherapy. Brachytherapy implants were either planned with the prostate undistorted by any hydrogel or planned with hydrogel in place. Dosimetry of the prostate and tissues at risk was determined from CT imaging on the day of brachytherapy implant. RESULTS: SpaceOAR™ significantly reduced mean and maximum rectal doses as well as rectal wall V50, but there was a statistically significant reduction of planning target volume (PTV) D90 to 121.1% of the prescribed dose in hydrogel patients compared to 123.3% in the non-hydrogel patients. Rectal dosimetry was similar between patients injected with hydrogel after brachytherapy and those with spacer injected prior to EBRT. However, patients who had hydrogel placed prior to EBRT had statistically significantly higher dosimetry indices of PTV and urethra relative to those with spacer placed at the completion of brachytherapy. CONCLUSIONS: There was a significant rectal dose sparing in the cohort with hydrogel spacer compared to a reference group without spacer injection. The rectal dose sparing effect was similar in the sub-group of patients injected with hydrogel prior to EBRT and the sub-group injected with hydrogel at the conclusion of brachytherapy.

The Impact of Body Mass Index on Freedom From Therapeutic Intervention and Quality of Life in Active Surveillance Prostate Cancer Patients.

OBJECTIVE: The objective of this study was to evaluate the impact of body mass index (BMI) on overall survival, freedom from distant metastases, rates of therapeutic intervention (TI), and quality of life (QOL) in active surveillance (AS) prostate cancer patients. MATERIALS AND METHODS: Three hundred forty consecutive, prospectively evaluated AS patients underwent a staging transperineal template-guided mapping biopsy before AS enrollment and were stratified by BMI (<25, 25 to 29.9, 30 to 34.9, and >35 kg/m2). Evaluated outcomes included overall survival, freedom from distant metastases, TI, QOL to include urinary, bowel, sexual function and depression and serial postvoid residual urine measurements. The relationship between BMI and anterior prostate cancer distribution was evaluated. Repeat biopsy was based on prostate specific antigen kinetics, abnormal digital rectal examination and patient preference. RESULTS: Of the 340 patients, 323 (95%) were Gleason 3+3 and 17 patients (5.0%) were Gleason 3+4. The median follow-up was 5.2 years (range: 1 to 14 y). At 10 years, TI was instituted in 4.7%, 2.2%, 9.5%, and 25.0% of patients in BMI cohorts <25, 25 to 29.9, 30 to 34.9, and ≥35 (P=0.075). No patient has developed distant metastases. The median time to TI was 4.86 years. In multivariate analysis, TI was most closely predicted by prostate specific antigen density (P=0.071). At 8 years, no statistical differences in urinary function, bowel function, depression or postvoid residual were noted. However, a trend for erectile dysfunction was identified (P=0.106). CONCLUSION: At 10 years, BMI did not statistically predict for TI, geographic distribution of prostate cancer or QOL parameters.

The impact of age on prostate cancer progression and quality of life in active surveillance patients.

Objectives: To evaluate the impact of age on overall survival (OS), freedom from distant metastasis (FDM), rates of therapeutic intervention (TI), and quality of life (QOL) in active surveillance (AS) prostate cancer patients. Materials and methods: Three hundred and five consecutive, prospectively evaluated AS patients who underwent a staging transperineal template-guided mapping biopsy (TTMB) prior to enrollment on AS were evaluated and stratified by age. Evaluated outcomes included OS, FDM, TI, and QOL to include urinary, bowel, sexual function, and depression. Post void residual (PVR) urine measurements were also followed. Repeat biopsy was based on PSA kinetics, abnormal digital rectal examination or patient preference. Results: Of the 305 patients, 290 (95.1%) were Gleason 3 + 3 and 15 patients (4.9%) were Gleason 3 + 4. The median follow-up was 5.5 years (range 1-14 years). At 10 years, TI was 0%, 1.0%, and 11.4% for patients ≤59, 60-69, and ≥70 years of age (P < .001). No patient has developed distant metastasis. The median time to TI was 4.71 years. No statistical differences in urinary function, bowel function, or depression were noted. Potency preservation was dependent on patient age. Conclusion: Within the confines of the follow-up of our series, younger patients were less likely to proceed to therapeutic intervention. In addition, patient age did not adversely impact QOL outcomes.

Low dose rate brachytherapy for primary treatment of localized prostate cancer: A systemic review and executive summary of an evidence-based consensus statement.

PURPOSE: The purpose of this guideline is to present evidence-based consensus recommendations for low dose rate (LDR) permanent seed brachytherapy for the primary treatment of prostate cancer. METHODS AND MATERIALS: The American Brachytherapy Society convened a task force for addressing key questions concerning ultrasound-based LDR prostate brachytherapy for the primary treatment of prostate cancer. A comprehensive literature search was conducted to identify prospective and multi-institutional retrospective studies involving LDR brachytherapy as monotherapy or boost in combination with external beam radiation therapy with or without adjuvant androgen deprivation therapy. Outcomes included disease control, toxicity, and quality of life. RESULTS: LDR prostate brachytherapy monotherapy is an appropriate treatment option for low risk and favorable intermediate risk disease. LDR brachytherapy boost in combination with external beam radiation therapy is appropriate for unfavorable intermediate risk and high-risk disease. Androgen deprivation therapy is recommended in unfavorable intermediate risk and high-risk disease. Acceptable radionuclides for LDR brachytherapy include iodine-125, palladium-103, and cesium-131. Although brachytherapy monotherapy is associated with increased urinary obstructive and irritative symptoms that peak within the first 3 months after treatment, the median time toward symptom resolution is approximately 1 year for iodine-125 and 6 months for palladium-103. Such symptoms can be mitigated with short-term use of alpha blockers. Combination therapy is associated with worse urinary, bowel, and sexual symptoms than monotherapy. A prostate specific antigen <= 0.2 ng/mL at 4 years after LDR brachytherapy may be considered a biochemical definition of cure. CONCLUSIONS: LDR brachytherapy is a convenient, effective, and well-tolerated treatment for prostate cancer.

Performance of a Prostate-Specific Membrane Antigen Positron Emission Tomography/Computed Tomography-Derived Risk-Stratification Tool for High-risk and Very High-risk Prostate Cancer.

Importance: Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) can detect low-volume, nonlocalized (ie, regional or metastatic) prostate cancer that was occult on conventional imaging. However, the long-term clinical implications of PSMA PET/CT upstaging remain unclear. Objectives: To evaluate the prognostic significance of a nomogram that models an individual's risk of nonlocalized upstaging on PSMA PET/CT and to compare its performance with existing risk-stratification tools. Design, Setting, and Participants: This cohort study included patients diagnosed with high-risk or very high-risk prostate cancer (ie, prostate-specific antigen [PSA] level >20 ng/mL, Gleason score 8-10, and/or clinical stage T3-T4, without evidence of nodal or metastatic disease by conventional workup) from April 1995 to August 2018. This multinational study was conducted at 15 centers. Data were analyzed from December 2020 to March 2021. Exposures: Curative-intent radical prostatectomy (RP), external beam radiotherapy (EBRT), or EBRT plus brachytherapy (BT), with or without androgen deprivation therapy. Main Outcomes and Measures: PSMA upstage probability was calculated from a nomogram using the biopsy Gleason score, percentage positive systematic biopsy cores, clinical T category, and PSA level. Biochemical recurrence (BCR), distant metastasis (DM), prostate cancer-specific mortality (PCSM), and overall survival (OS) were analyzed using Fine-Gray and Cox regressions. Model performance was quantified with the concordance (C) index. Results: Of 5275 patients, the median (IQR) age was 66 (60-72) years; 2883 (55%) were treated with RP, 1669 (32%) with EBRT, and 723 (14%) with EBRT plus BT; median (IQR) PSA level was 10.5 (5.9-23.2) ng/mL; 3987 (76%) had Gleason grade 8 to 10 disease; and 750 (14%) had stage T3 to T4 disease. Median (IQR) follow-up was 5.1 (3.1-7.9) years; 1221 (23%) were followed up for at least 8 years. Overall, 1895 (36%) had BCR, 851 (16%) developed DM, and 242 (5%) died of prostate cancer. PSMA upstage probability was significantly prognostic of all clinical end points, with 8-year C indices of 0.63 (95% CI, 0.61-0.65) for BCR, 0.69 (95% CI, 0.66-0.71) for DM, 0.71 (95% CI, 0.67-0.75) for PCSM, and 0.60 (95% CI, 0.57-0.62) for PCSM (P < .001). The PSMA nomogram outperformed existing risk-stratification tools, except for similar performance to Staging Collaboration for Cancer of the Prostate (STAR-CAP) for PCSM (eg, DM: PSMA, 0.69 [95% CI, 0.66-0.71] vs STAR-CAP, 0.65 [95% CI, 0.62-0.68]; P < .001; Memorial Sloan Kettering Cancer Center nomogram, 0.57 [95% CI, 0.54-0.60]; P < .001; Cancer of the Prostate Risk Assessment groups, 0.53 [95% CI, 0.51-0.56]; P < .001). Results were validated in secondary cohorts from the Surveillance, Epidemiology, and End Results database and the National Cancer Database. Conclusions and Relevance: These findings suggest that PSMA upstage probability is associated with long-term, clinically meaningful end points. Furthermore, PSMA upstaging had superior risk discrimination compared with existing tools. Formerly occult, PSMA PET/CT-detectable nonlocalized disease may be the main driver of outcomes in high-risk patients.

Comparison of Multimodal Therapies and Outcomes Among Patients With High-Risk Prostate Cancer With Adverse Clinicopathologic Features.

Importance: The optimal management strategy for high-risk prostate cancer and additional adverse clinicopathologic features remains unknown. Objective: To compare clinical outcomes among patients with high-risk prostate cancer after definitive treatment. Design, Setting, and Participants: This retrospective cohort study included patients with high-risk prostate cancer (as defined by the National Comprehensive Cancer Network [NCCN]) and at least 1 adverse clinicopathologic feature (defined as any primary Gleason pattern 5 on biopsy, clinical T3b-4 disease, ≥50% cores with biopsy results positive for prostate cancer, or NCCN ≥2 high-risk features) treated between 2000 and 2014 at 16 tertiary centers. Data were analyzed in November 2020. Exposures: Radical prostatectomy (RP), external beam radiotherapy (EBRT) with androgen deprivation therapy (ADT), or EBRT plus brachytherapy boost (BT) with ADT. Guideline-concordant multimodal treatment was defined as RP with appropriate use of multimodal therapy (optimal RP), EBRT with at least 2 years of ADT (optimal EBRT), or EBRT with BT with at least 1 year ADT (optimal EBRT with BT). Main Outcomes and Measures: The primary outcome was prostate cancer-specific mortality; distant metastasis was a secondary outcome. Differences were evaluated using inverse probability of treatment weight-adjusted Fine-Gray competing risk regression models. Results: A total of 6004 men (median [interquartile range] age, 66.4 [60.9-71.8] years) with high-risk prostate cancer were analyzed, including 3175 patients (52.9%) who underwent RP, 1830 patients (30.5%) who underwent EBRT alone, and 999 patients (16.6%) who underwent EBRT with BT. Compared with RP, treatment with EBRT with BT (subdistribution hazard ratio [sHR] 0.78, [95% CI, 0.63-0.97]; P = .03) or with EBRT alone (sHR, 0.70 [95% CI, 0.53-0.92]; P = .01) was associated with significantly improved prostate cancer-specific mortality; there was no difference in prostate cancer-specific mortality between EBRT with BT and EBRT alone (sHR, 0.89 [95% CI, 0.67-1.18]; P = .43). No significant differences in prostate cancer-specific mortality were found across treatment cohorts among 2940 patients who received guideline-concordant multimodality treatment (eg, optimal EBRT alone vs optimal RP: sHR, 0.76 [95% CI, 0.52-1.09]; P = .14). However, treatment with EBRT alone or EBRT with BT was consistently associated with lower rates of distant metastasis compared with treatment with RP (eg, EBRT vs RP: sHR, 0.50 [95% CI, 0.44-0.58]; P < .001). Conclusions and Relevance: These findings suggest that among patients with high-risk prostate cancer and additional unfavorable clinicopathologic features receiving guideline-concordant multimodal therapy, prostate cancer-specific mortality outcomes were equivalent among those treated with RP, EBRT, and EBRT with BT, although distant metastasis outcomes were more favorable among patients treated with EBRT and EBRT with BT. Optimal multimodality treatment is critical for improving outcomes in patients with high-risk prostate cancer.

Patterns of Clinical Progression in Radiorecurrent High-risk Prostate Cancer.

The natural history of radiorecurrent high-risk prostate cancer (HRPCa) is not well-described. To better understand its clinical course, we evaluated rates of distant metastases (DM) and prostate cancer-specific mortality (PCSM) in a cohort of 978 men with radiorecurrent HRPCa who previously received either external beam radiation therapy (EBRT, n = 654, 67%) or EBRT + brachytherapy (EBRT + BT, n = 324, 33%) across 15 institutions from 1997 to 2015. In men who did not die, median follow-up after treatment was 8.9 yr and median follow-up after biochemical recurrence (BCR) was 3.7 yr. Local and systemic therapy salvage, respectively, were delivered to 21 and 390 men after EBRT, and eight and 103 men after EBRT + BT. Overall, 435 men developed DM, and 248 were detected within 1 yr of BCR. Measured from time of recurrence, 5-yr DM rates were 50% and 34% after EBRT and EBRT + BT, respectively. Measured from BCR, 5-yr PCSM rates were 27% and 29%, respectively. Interval to BCR was independently associated with DM (p < 0.001) and PCSM (p < 0.001). These data suggest that radiorecurrent HRPCa has an aggressive natural history and that DM is clinically evident early after BCR. These findings underscore the importance of further investigations into upfront risk assessment and prompt systemic evaluation upon recurrence in HRPCa. PATIENT SUMMARY: High-risk prostate cancer that recurs after radiation therapy is an aggressive disease entity and spreads to other parts of the body (metastases). Some 60% of metastases occur within 1 yr. Approximately 30% of these patients die from their prostate cancer.

Relationship between prostate cancer mortality and number of unfavourable risk factors in men treated with definitive brachytherapy.

OBJECTIVE: To explore whether the number of unfavourable pretreatment risk factors predicts cause-specific mortality in men treated with prostate brachytherapy. PATIENTS AND METHODS: Between April 1995 and March 2006, 739 patients were treated who had at least one of the following adverse risk factors: pretreatment prostate-specific antigen (PSA) level of >10 ng/mL, a Gleason score of > or =7, clinical stage > or =T2b, or a PSA velocity (PSAV) of >2 ng/mL/year. Supplemental external beam radiotherapy (EBRT) was delivered to 464 (62.8%) men and 301 (40.7%) received androgen deprivation therapy (ADT). Of men with more than two risk factors, 87% received EBRT and 62% received ADT. RESULTS: The biochemical progression-free survival (bPFS), cause-specific survival (CSS) and overall survival for all patients were 95.0%, 97.9% and 70.0% at 12 years. Men with three or four risk factors had a prostate cancer-specific mortality (PCSM) at 12 years of 5.3%, vs 1.7% for men with one or two risk factors (P= 0.006). When 'percentage of positive biopsy cores >50%' replaced PSAV as a risk factor, men with two or more risk factors had a PCSM of 8.9%, vs 1.0% for men with one or two risk factors (P= 0.001). There was no difference in all-cause mortality between the groups in either analysis. CONCLUSION: Multimodal brachytherapy results in high rates of bPFS and CSS, even for men with several unfavourable risk factors. Men with two or more unfavourable risk factors had a slightly greater risk of PCSM and no difference in all-cause mortality. The presence of three or four unfavourable intermediate-risk factors does not appear to clearly identify a group that requires further treatment intensification, although the percentage of positive cores might be more predictive than PSAV.