Aims: There is a lack of early predictive measures of outcome for patients with intermediate-risk prostate cancer (PCa) treated with stereotactic body radio-therapy (SBRT). The aim of the present study was to explore 4-year prostate-specific antigen response rate (4yPSARR) as an early predictive measure. Materials and methods: Individual patient data from six institutions for patients with intermediate-risk PCa treated with SBRT between 2006 and 2016 with a 4-year (42-54 months) PSA available were analysed. Cumulative incidences of biochemical failure and metastasis were calculated using Nelson-Aalen estimates and overall survival was calculated using the Kaplan-Meier method. Biochemical failure-free survival was analysed according to 4yPSARR, with groups dichotomised based on PSA <0.4 ng/ml or >0.4 ng/ml and compared using the Log-rank test. A multivariable competing risk analysis was carried out to predict for biochemical failure and the development of metastases. Results: Six hundred and thirty-seven patients were included, including 424 (67%) with favourable and 213 (33%) with unfavourable intermediate-risk disease. The median follow-up was 6.2 years (interquartile range 4.9-7.9). The cumulative incidence of biochemical failure and metastasis was 7 and 0.6%, respectively; overall survival at 6 years was 97%. The cumulative incidence of biochemical failure at 6 years if 4yPSARR <0.4 ng/ml was 1.7% compared with 27% if 4yPSARR >0.4 ng/ml (P < 0.0001). On multivariable competing risk analysis, 4yPSARR was a statistically significant predictor of biochemical failure-free survival (subdistribution hazard ratio 15.3, 95% confidence interval 7.5-31.3, P < 0.001) and metastasis-free survival (subdistribution hazard ratio 31.2, 95% confidence interval 3.1-311.6, P = 0.003). Conclusion: 4yPSARR is an encouraging early predictor of outcome in patients with intermediate-risk PCa treated with SBRT. Validation in prospective trials is warranted. (c) 2021 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Aims: Intermediate-risk prostate cancer is heterogenous. The absolute percentage of biopsied tissue positive for Gleason pattern 4 disease (APP4) is a possible prognostic measure. Here we sought to determine the impact of APP4 in a prospective multi-institutional pooled analysis of men with intermediate-risk prostate cancer treated with stereotactic body radiotherapy (SBRT).Materials and methods: Patients with intermediate-risk prostate cancer treated with SBRT (40 Gy in five fractions or 26 Gy in two fractions) with or without androgen deprivation therapy treated on prospective clinical trials were included. Pathology reports were queried to obtain APP4, calculated as the percentage of Gleason pattern 4 disease within the tumour(s) multiplied by the percentage of total biopsied tissue positive for disease divided by 100. The optimal APP4 cut-off points for biochemical failure and distant metastasis were calculated and used as a stratification in the cumulative incidence of biochemical failure and distant metastasis. Multivariable competing risk models were developed.Results: In tota, 227 patients were included. The median follow-up was 56.5 months. The optimal APP4 cut-off points were 5% for biochemical failure and 20% for distant metastasis. At 4 years, the cumulative incidence of biochemical failure was 23.6% and 2.3% for APP4 > 5% and ? 5%, respectively (P < 0.0001). The cumulative incidence of distant metastasis was 12.5% for APP4 > 20% and 1% for APP4 ? 20% (P 1/4 0.02). APP4 sub-stratified favourable intermediate-risk prostate cancer and unfavourable intermediate-risk prostate cancer into groups at similarly low and similarly high risk of biochemical failure and distant metastasis. On multivariable competing risk analysis, APP4 > 5% (P 1/4 0.0004) was significantly associated with biochemical failure, but APP4 (log) was not for distant metastasis (P 1/4 0.08).Conclusion: APP4 may be an easily accessible promising prognostic measure for patients with intermediate-risk prostate cancer treated with SBRT. Incorpo-ration of APP4 into prospective trials will help to determine its value.(c) 2022 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

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 Deprivacion Androgenica y Radio Terapia (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.

Background and purpose: The optimal dose for prostate stereotactic body radiotherapy (SBRT) is still unknown. This study evaluated the dose-response relationships for prostate-specific antigen (PSA) decay and biochemical recurrence (BCR) among 4 SBRT dose regimens. Materials and methods: In 1908 men with low-risk (50.0%), favorable intermediate-risk (30.9%), and unfavorable intermediate-risk (19.1%) prostate cancer treated with prostate SBRT across 8 institutions from 2003 to 2018, we examined 4 regimens (35 Gy/5 fractions [35/5, n = 265, 13.4%], 36.25 Gy/5 fractions [36.25/5, n = 711, 37.3%], 40 Gy/5 fractions [40/5, n = 684, 35.8%], and 38 Gy/4 fractions [38/4, n = 257, 13.5%]). Between dose groups, we compared PSA decay slope, nadir PSA (nPSA), achievement of nPSA <= 0.2 and <= 0.5 ng/mL, and BCR-free survival (BCRFS). Results: Median follow-up was 72.3 months. Median nPSA was 0.01 ng/mL for 38/4, and 0.17-0.20 ng/mL for 5-fraction regimens (p < 0.0001). The 38/4 cohort demonstrated the steepest PSA decay slope and greater odds of nPSA <= 0.2 ng/mL (both p < 0.0001 vs. all other regimens). BCR occurred in 6.25%, 6.75%, 3.95%, and 8.95% of men treated with 35/5, 36.25/5, 40/5, and 38/4, respectively (p = 0.12), with the highest BCRFS after 40/5 (vs. 35/5 hazard ratio [HR] 0.49, p = 0.026; vs. 36.25/5 HR 0.42, p = 0.0005; vs. 38/4 HR 0.55, p = 0.037) including the entirety of follow-up, but not for 5-year BCRFS (>= 93% for all regimens, p >= 0.21). Conclusion: Dose-escalation was associated with greater prostate ablation and PSA decay. Dose-escalation to 40/5, but not beyond, was associated with improved BCRFS. Biochemical control remains excellent, and prospective studies will provide clarity on the benefit of dose-escalation. (C) 2020 Elsevier B.V. All rights reserved.

Background While multiple randomized trials have evaluated the benefit of radiation therapy (RT) dose escalation and the use and prolongation of androgen deprivation therapy (ADT) in the treatment of prostate cancer, few studies have evaluated the relative benefit of either form of treatment intensification with each other. Many trials have included treatment strategies that incorporate either high or low dose RT, or short-term or long-term ADT (STADT or LTADT), in one or more trial arms. We sought to compare different forms of treatment intensification of RT in the context of localized prostate cancer. Methods Using preferred reporting items for systemic reviews and meta-analyses (PRISMA) guidelines, we collected over 40 phases III clinical trials comparing different forms of RT for localized prostate cancer. We performed a meta-regression of 40 individual trials with 21,429 total patients to allow a comparison of the rates and cumulative proportions of 5-year overall survival (OS), prostate cancer-specific mortality (PCSM), and distant metastasis (DM) for each treatment arm of every trial. Results Dose-escalation either in the absence or presence of STADT failed to significantly improve any 5-year outcome. In contrast, adding LTADT to low dose RT significantly improved 5-year PCSM (Odds ratio [OR] 0.34, 95% confidence interval [CI] 0.22–0.54, p < 0.001) and DM (OR 0.35, 95% CI 0.20–0.63. p < 0.001) over low dose RT alone. Adding STADT also significantly improved 5-year PCSM over low dose RT alone (OR 0.55, 95% CI 0.41–0.75, p < 0.001). Conclusion While limited by between-study heterogeneity and a lack of individual patient data, this meta-analysis suggests that adding ADT, versus increasing RT dose alone, offers a more consistent improvement in clinical endpoints.

Key Points Question Is previously occult, nonlocalized (regional or metastatic) disease detected on prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) associated with clinically significant outcomes in patients with high-risk and very high-risk prostate cancer? Findings In this cohort study of 5275 patients, a nomogram estimative of an individual’s risk of nonlocalized disease on PSMA PET/CT was significantly associated with long-term outcomes, including distant metastasis and prostate cancer–specific mortality. The nomogram performed favorably compared with other risk-stratification tools. Meaning These findings suggest that previously occult disease may be associated with outcomes in this patient population.

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.

A substantial proportion of patients with BCR after SBRT for localized PCa ultimately develop DM, particularly those with higher iPSA and shorter time to BCR. The association with SBRT dose is likely reflective of the use of higher doses in more modern cohorts with higher-risk disease, while the association with GG likely reflects the more aggressive biology of these tumors at presentation. Further research into patterns of failure after SBRT is needed, especially in the context of more sensitive nuclear imaging. Early predictors of treatment failure are needed to facilitate timely treatment intensification.

Prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/ computed tomography (CT) is an emerging imaging modality with greater sensi-tivity and specificity over conventional imaging for prostate cancer (PCa) staging. Using data from two prospective trials (NCT03368547 and NCT04050215), we explored predictors of overall upstaging (nodal and metastatic) by PSMA PET/CT among patients with cN0M0 National Comprehensive Cancer Network high-risk PCa on conventional imaging (n = 213). Overall, 21.1%, 8.9%, and 23.9% of patients experienced nodal, metastatic, and overall upstaging, respectively, without histo-logic confirmation. On multivariable analysis, Gleason grade group (GG) and percent positive core (PPC) on systematic biopsy significantly predict overall upstaging (odds ratio [OR] 2.15, 95% confidence interval [CI] 1.33-3.45; p = 0.002; and OR 1.03, 95% CI 1.01-1.04; p < 0.001). Overall upstaging was signifi- cantly more frequent among men with GG 5 disease (33.0% vs. 17.6%; p = 0.0097) and PPC >= 50% (33.0% vs 15.0%; p = 0.0020). We constructed a nomogram that predicts overall upstaging using initial prostate-specific antigen, PPC, GG, and cT stage, with coefficients estimated from a standard logistic regression model (using maximum likelihood estimation). It is internally validated with a tenfold cross-validated area under the receiver operating characteristic curve estimated at 0.74 (95% CI 0.67-0.82). In our cohort, 90% of patients who had a nomogram-estimated risk below the cutoff of 22% for overall upstaging could have been spared PSMA PET/CT as our model correctly predicted no upstaging. In other words, the predictive model only missed 10% of patients who would otherwise have benefitted from PSMA PET/CT. Patient summary: We analyzed predictors of overall upstaging (lymph node or/ and metastasis) by prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) from conventional imaging in men with high-risk prostate cancer undergoing initial staging deemed free of disease in the lymph nodes and distant metastasis by conventional imaging techniques. We found that the pathologic grade and disease burden in a prostate biopsy are associated with upstaging. We also developed a tool that predicts the probability of upstaging according to an individual patient's characteristics. Our study may help in defining patient groups who are most likely to benefit from the addition of a PSMA PET/CT scan. (c) 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.

You have accessJournal of UrologyProstate Cancer: Localized: Radiation Therapy (PD08)1 Sep 2021PD08-09 META-ANALYSIS OF RADIATION THERAPY AND ANDROGEN DEPRIVATION THERAPY IN LOCALIZED PROSTATE CANCER Tommy Jiang, Daniela Markovic, Jay Patel, Jesus Juarez, Martin Ma, David Shabsovich, Nicholas Zaorsky, Nicholas Nickols, Robert Reiter, David Elashoff, Matthew Rettig, Daniel Spratt, and Amar Kishan Tommy JiangTommy Jiang More articles by this author , Daniela MarkovicDaniela Markovic More articles by this author , Jay PatelJay Patel More articles by this author , Jesus JuarezJesus Juarez More articles by this author , Martin MaMartin Ma More articles by this author , David ShabsovichDavid Shabsovich More articles by this author , Nicholas ZaorskyNicholas Zaorsky More articles by this author , Nicholas NickolsNicholas Nickols More articles by this author , Robert ReiterRobert Reiter More articles by this author , David ElashoffDavid Elashoff More articles by this author , Matthew RettigMatthew Rettig More articles by this author , Daniel SprattDaniel Spratt More articles by this author , and Amar KishanAmar Kishan More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000001976.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Dose escalation of radiation therapy (RT) and the addition or prolongation of androgen deprivation therapy (ADT) have been independently shown to improve long-term outcomes in randomized trials for localized prostate cancer (PCa). We sought to explore the relative benefits of RT dose intensification and concomitant ADT compared to each other as well as to the historical standard of low dose RT. METHODS: PubMed was searched for Phase III randomized, controlled trials using RT for localized PCa following PRISMA guidelines. Selected trial arms were categorized as low or high dose as well as with or without ADT (categorized as short or long-term). 74 Gy was used as the threshold for “high dose” and 8 months of ADT therapy was the threshold for long-term ADT (LTADT). Outcomes included 5-year overall survival (OS), 5-year prostate cancer specific mortality (PCSM), and 5-year incidence of distant metastases (DM). Pairwise comparisons between treatments were performed using random effects meta regression models with a Bonferroni correction, where the null hypothesis was rejected for p <0.006 with respect to OS and PCSM (9 pairwise comparisons for each) and p <0.008 with respect to DM (6 pairwise comparisons). RESULTS: Forty trials recruiting a total of 21,429 patients met our inclusion criteria. Comparisons of each treatment type are shown in Table 1. Of note, when using low dose RT as the reference, low Dose RT + LTADT showed statistical improvement in PCSM (OR: 0.34 [0.22-0.54]), and DM (OR: 0.35 [0.20-0.63]). Dose escalation alone showed no statistical improvement in any reported outcome compared to low dose RT alone. When compared together, low Dose RT + LTADT was associated with improved 5-yr PCSM (OR: 0.40 [0.25-0.64]) when compared to high Dose RT alone. Improvement in OS and DM did not reach statistical significance. Overall, there was no statistical improvement in 5-year OS comparing any of the treatment modalities. CONCLUSIONS: The results of this meta-analysis suggest the benefit of adding any ADT (STADT or LTADT) to low dose RT alone outweighs the benefits of solely intensifying radiation dose. Dose escalation alone did not demonstrate any significant improvement in OS, PCSM, or DM and appeared to be associated with worse outcomes when compared to low dose RT + LTADT. Source of Funding: N/A © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e117-e117 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Tommy Jiang More articles by this author Daniela Markovic More articles by this author Jay Patel More articles by this author Jesus Juarez More articles by this author Martin Ma More articles by this author David Shabsovich More articles by this author Nicholas Zaorsky More articles by this author Nicholas Nickols More articles by this author Robert Reiter More articles by this author David Elashoff More articles by this author Matthew Rettig More articles by this author Daniel Spratt More articles by this author Amar Kishan More articles by this author Expand All Advertisement Loading ...

Context: The use, common findings, and impact of modern molecular positron emission tomography (PET)/computed tomography (CT) imaging prior to salvage radiation therapy (RT) in men with biochemical recurrence after radical prostatectomy (RP) have not been evaluated comprehensively. Objective: We performed a scoping systematic review of the literature assessing detection rates, detection patterns, changes in management, as well as changes in patient outcome resulting from molecular PET/CT imaging using three molecular tracers: F-18-fluciclovine, Ga-8 prostate-specific membrane antigen (PSMA)-11, and F-18-DCFPyL. Evidence acquisition: A computerized bibliographic search of the Medline/PubMed database was carried out from inception to October 1, 2020. We included published reports and abstracts evaluating the utility of (1)Fluciclovine, Ga-68-PSMA-11, and F-18-DCFPyL PET in the detection of recurrent disease in the post-RP, pre-salvage RT setting. Outcomes of interest were extracted and tabulated, and existing evidence was synthesized qualitatively. Evidence synthesis: A total of 45 studies were included in our qualitative synthesis. Detection rates were high across most studies, and there was often a clear relationship between prostate-specific antigen (PSA) level and positive imaging findings. Though limited randomized data are available, there appears to be increased sensitivity with the use of PSMA ligands compared with fluciclovine at low PSA values. Most studies have shown that only one-third to one-half of patients with detected lesions have lesions in the prostatic fossa alone. Management changes occur in nearly 50% of patients undergoing molecular imaging, and biochemical response in patients who undergo molecular PET-based RT planning appears to be statistically superior to the response in patients who undergo conventional imaging-based RT planning alone. High biochemical responses from molecular PET-based salvage RT, ranging from 45% to 94%, did not appear to come at the expense of increased genitourinary or gastrointestinal toxicity. The presence or absence of avid lesions appears to be a strong prognostic factor. Conclusions: Molecular PET/CT imaging in the post-RP, pre-salvage RT setting often triggers management changes that result from detecting lesions in locations not typically included in consensus-driven postoperative RT fields. Ongoing trials will assess the benefit of PSMA PET in guiding salvage RT following RP and determine its impact on long-term outcomes. Patient summary: We reviewed and reported detection rates, detection patterns, and changes in management resulting from molecular positron emission tomography/computed tomography imaging in men with biochemically recurrent prostate cancer following radical prostatectomy. Prior to the receipt of salvage radiation therapy, molecular tracers targeting prostate-specific membrane antigen appear to be especially sensitive at identifying the place where prostate cancer has come back after surgery, which can help radiation oncologists better target the recurrent disease and potentially improve the rates of cure from prostate cancer in this setting. Future studies will determine whether these imaging tools will change cure

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.

Metastasis-free survival (MFS), a composite of Distant Metastasis (DM) incidence and Overall Survival (OS), is a validated surrogate clinical endpoint for patients with prostate cancer. However, improvements in OS and DM can be a result of competing factors such as changes in upfront staging, treatment of metastatic disease, or a reflection of improved medical care over time. The purpose of this meta-analysis is to monitor how OS and DM rates may be changing over time, using patients on randomized trials as the focus of the study. We performed a meta-analysis on radiotherapy (RT) randomized trials between 1985 and 2005; comparing OS, Prostate Cancer-Specific Mortality (PCSM), and DM. Outcomes were divided among 4 treatments: RT alone, RT with Short-Term Androgen Deprivation Therapy (RT+STADT), RT with Long-Term ADT (RT+LTADT), and high dose RT. Forest plots were generated for each treatment and outcome using a random effect statistical model. Multivariable meta-regression evaluated the association between outcomes vs year of study (midpoint of enrollment period), median age, and percent of patients with high risk disease. In total, 52 studies were included in this analysis (15 evaluating RT alone, 21 evaluating RT+STADT, 7 evaluating RT+LTADT, and 9 evaluating high dose RT). Year of study was significantly associated with improved 5-year OS in for RT alone, RT+STADT, and RT+LTADT on univariate analysis (p<0.05 for all). It was also associated with improved PCSM and DM outcomes in patients receiving RT alone and RT+STADT (p<0.01), and improved PCSM in patients getting high dose RT (p<0.05). However, the association with OS and treatment strategy only remained significant after adjustment for median age and percentage of patients with high-risk disease in patients receiving RT+LTADT. In this group, year of study was associated with increased OS (log OR = 0.059, p = 0.012). Year of study (log OR = -0.069, p = 0.016) and younger age (log OR = -0.348, p < 0.001) were negatively associated with PCSM (p<0.01) We identified a significant increase in OS and decrease in PCSM over time in patients receiving RT+LTADT for localized prostate cancer, while DM did not change. These data suggest that improvement of overall medical care as well as improved treatment of metastatic disease have concrete effects on OS and PCSM. These data are important for patients and physicians alike. Additionally, given that OS may be a primary driver of MFS, these findings may have implications for the powering of clinical trials.

Conventional imaging for initial staging of prostate cancer (PCa) lacks sensitivity and underestimates disease burden. Prostate-specific membrane antigen PET/CT (PSMA PET) is an emerging imaging modality shown to have improved sensitivity over conventional imaging in the setting of biochemical recurrence. We sought to evaluate the impact of 68Ga-PSMA PET on initial staging of patients with high risk PCa, as well as clinicopathologic features that might predict for upstaging, by analyzing patients who prospectively underwent PSMA PET on a clinical trial. This was a post hoc analysis of 249 eligible patients with NCCN high/very high risk PCa who underwent a staging PSMA PET (12/2016 to 1/2020) on a prospective trial. Patients with known non-regional lymph node or distant metastasis on prior imaging, or initiation of androgen deprivation therapy more than 3 months before PSMA PET were excluded. Chi square analysis was used to evaluate the association of clinicopathologic features (Gleason grade group [GG], initial PSA [iPSA], T stage, percent positive cores [PPC]≥50%) with upstaging. Overall, 22.9% patients were upstaged by PSMA PET; 18.9% of patients with iN0 disease by CT or MRI were found to have N1 disease by PSMA PET, and 10.6% of patients who had M0 disease by CT or bone scan had M1 disease by PSMA PET. New M1a disease was found in 7.4% and M1b/M1c disease was found in 5.3% of patients. PSMA PET detected ECE, SVI or invasion of surrounding structures in 8.1% patients deemed T2 on prior MRI imaging. PPC≥50% was significantly associated with regional and any nodal upstage (23.9% vs. 12.1%, p = 0.0227 and 22.6% vs. 3.7%, p = 0.0261, respectively), and any upstage in general (29.3% vs. 14.6%, p = 0.0102). Patients with GG 5 or ≥50% PPC were more likely to have regional nodal upstage (23.4% vs. 6.3%, p = 0.0031) and any upstage in general (28.2% vs. 9.4%, p = 0.0024), while GG 5 together with ≥50% PPC was predictive of M stage upstage (23.3% vs. 4.7%, p = 0.0063). cT and iPSA were not associated with upstaging. PSMA PET/CT has a significant impact on initial staging of high risk PCa patients. This impact appears to be most marked in patients with GG 5 or PPC≥50%.

OBJECTIVES:We present the case of a 56-year-old male with myelodysplastic syndrome (MDS) whose bone marrow immunophenotype showed lower positivity for CD45 and positivity for CD34; 8.66% of this population also expressed partial positives for MPO, CD16, CD117, CD36, CD33, and CD71, as well as positives for CD13, HLA-DR, and CD11b. No alterations in the pattern of maturation were seen in CD13 vs CD16 and CD13 vs CD11b. An analysis of a population of mature lymphocytes revealed CD45 high CD3+ in 87.5% of cells, CD45 high CD19+ in 7.6% of cells, and 4.9% NK cells. These results are consistent with a myelodysplastic syndrome with an excess of blasts type 1. Chromosome analysis of the bone marrow revealed an abnormal karyotype with a t(1;6)(p12;p11.1) as well as deletion 5q and a ring 11 in 12 of the 20 metaphase cells examined. The t(1;6)(p12;p11.1) has not been reported in association with any particular hematological malignancy and provides further insight into the range of cytogenetic abnormalities in MDS.

OBJECTIVES:Chronic lymphocytic leukemia (CLL) is among the most common forms of leukemia diagnosed in the United States. It is associated with a variety of clinically significant genetic abnormalities, including cytogenetic abnormalities that are assessed routinely. Herein, we present a case of CLL for which molecular cytogenetic analysis revealed concomitant deletion of TP53 (17p13.1) in 87% of cells analyzed and amplification (3-20 signals) of C-MYC (8q24.1) in 47% of cells analyzed. Although rearrangements involving C-MYC are common in CLL, amplification is a rarer phenomenon that has not been investigated as thoroughly and may be overlooked during routine analysis. We review this case in the context of available literature on the plethora of genetic abnormalities involving C-MYC in CLL and their relevance to the pathogenesis of the disease. All in all, this case highlights the role of comprehensive, multidisciplinary genetic testing in the management of CLL.

OBJECTIVES:Myelodysplastic syndromes present with a range of cytogenetic abnormalities that are used to guide diagnosis and management of the disease. Herein, we present the case of a 72-year-old female patient who presented with pancytopenia. Peripheral blood showed Hb 9.0 g/dl, neutrophils less than 1800/mm3, and platelets less than 100,000/mm3. Bone marrow showed erythroid hyperplasia, megaloblastic changes, dyserythropoiesis, multinuclearity, nuclear bridges, nuclear budding, atypical mitoses, and ring sideroblasts. Also, CD34 and CD117 as well as myeloperoxidase positive populations were present. On this basis, a diagnosis of myelodysplastic syndrome was rendered. Chromosome studies showed an abnormal female karyotype with an isochromosome 17q as well as deletion 20q in 17 of the 20 metaphase cells examined. The remaining three cells were cytogenetically normal. Molecular cytogenetic studies using a TP53-specific probe showed only one TP53 signal in 87% of the nuclei examined. An i(17q) as a sole cytogenetic aberration is rare among both MDS and myeloid malignancies in general, but is functionally similar to aberrations of 17p that lead to loss of TP53. This case provides further insight into the spectrum of cytogenetic abnormalities present in MDS.

OBJECTIVES:Transient myeloproliferative disorder (TMD), now more commonly known as transient abnormal myelopoiesis (TAM), is a condition closely associated with Down syndrome. Ninety-five percent of Down syndrome cases occur as a result of chromosomal nondisjunction and are rarely due to mosaicism or translocation. TMD is found exclusively in neonates and is most commonly characterized by trisomy 21, somatic GATA1 mutation, and the increased presence of megakaryoblasts. TMD often does not manifest clinically, but patients may show hepatomegaly, splenomegaly and other symptoms. While TMD is almost always present with trisomy 21, there are not many other cytogenetic abnormalities associated with TMD, with a few rare cases such as monosomy 7 and trisomy 8. Recent studies have suggested liver hematopoietic progenitor cells as the candidate for TMD origin. Furthermore, GATA1 mutations associated with TMD are found to encode for a stop codon in the N-terminal activation region of gene sequences. It has been shown that those mutations can cause overproliferation of megakaryocytes, which can cooperate with Down syndrome cells, which have trisomy 21, in the progression of TMD into acute megakaryoblastic leukemia (AMKL). Since GATA1 mutations are present in all cases of myeloid leukemia of Down Syndrome, monitoring GATA1 in patients with trisomy 21 may assist with earlier diagnosis of TMD. Another likely cause of TMD is the amplification of the RUNX1 transcription factor gene located on chromosome 21. It has been shown that RUNX1 is associated with leukemias of myeloid lineage. While most cases of TMD will spontaneously resolve, some will evolve into acute myeloid leukemia (AML). In this review, we will discuss the cytogenetic, molecular genetics and clinical aspects of TMD.

Background and purpose: Stereotactic body radiation therapy (SBRT), low dose rate brachytherapy (LDR-BT) and high dose rate brachytherapy (HDR-BT) are ablative-intent radiotherapy options for prostate cancer (PCa). These vary considerably in dose delivery, which may impact post-treatment prostate-specific antigen (PSA) patterns and biochemical control. We compared PSA kinetics between SBRT, HDR-BT, and LDR-BT, and assessed their relationships to biochemical recurrence-free survival (BCRFS). Methods and materials: Retrospective PSA data were analyzed for 3502 men with low-risk (n = 2223; 63.5%), favorable intermediate-risk (n = 869; 24.8%), and unfavorable intermediate-risk (n = 410; 11.7%) PCa treated with SBRT (n = 1716; 49.0%), HDR-BT (n = 512; 14.6%), or LDR-BT (n = 1274; 36.4%) without upfront androgen deprivation therapy at 10 institutions from 1990 to 2017. We compared nadir PSA (nPSA), time to nPSA, achievement of nPSA <0.2 ng/mL and <0.5 ng/mL, rates of nPSA <0.4 ng/mL at 4 years, and BCRFS. Results: Median follow-up was 72 months. Median nPSA and nPSA <0.2 ng/mL were stratified by risk group (interaction p < 0.001). Median nPSA and time to nPSA were 0.2 ng/mL at 44 months after SBRT, 0.1-0.2 ng/mL at 37 months after HDR-BT, and 0.01-0.2 ng/mL at 51 months after LDR-BT (mean log nPSA p < 0.009 for LDR-BT vs. SBRT or HDR-BT for low/favorable intermediate-risk). There were no differences in nPSA 0.4 ng/mL at 4 years (p 0.51). BCRFS was similar for all three modalities (p > 0.27). Continued PSA decay beyond 4 years was predictive of durable biochemical control. Conclusion: LDR-BT led to lower nPSAs with longer continued decay compared to SBRT and HDR-BT, but no differences in BCRFS. (C) 2020 Elsevier B.V. All rights reserved.