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The field of radionuclide therapy (RNT) for prostate cancer (PC) is growing rapidly, with recent Food and Drug Administration approval of the first 177Lu-PSMA ligand. We aimed to develop the first patient-reported outcome (PRO) measure for PC patients receiving RNT. Methods: We identified relevant symptoms and toxicities by reviewing published trials and interviews with PC patients receiving RNT (n = 29), caregivers (n = 14), and clinicians (n = 11). Second, we selected items for measure inclusion. Third, we refined the item list with input from experts in RNTs and PROs. Fourth, we finalized the Functional Assessment of Cancer Therapy-Radionuclide Therapy (FACT-RNT) with patient input. Results: This multistep process yielded a brief 15-item measure deemed by key stakeholders to be relevant and useful in the context of RNT for PC. Conclusion: The FACT-RNT is a new standardized tool to monitor relevant symptoms and toxicities among PC patients in RNT trials and real-world settings.

PurposeGermline testing (GT) is a central feature of prostate cancer (PCA) treatment, management, and hereditary cancer assessment. Critical needs include optimized multigene testing strategies that incorporate evolving genetic data, consistency in GT indications and management, and alternate genetic evaluation models that address the rising demand for genetic services.MethodsA multidisciplinary consensus conference that included experts, stakeholders, and national organization leaders was convened in response to current practice challenges and to develop a genetic implementation framework. Evidence review informed questions using the modified Delphi model. The final framework included criteria with strong (> 75%) agreement (Recommend) or moderate (50% to 74%) agreement (Consider).ResultsLarge germline panels and somatic testing were recommended for metastatic PCA. Reflex testing-initial testing of priority genes followed by expanded testing-was suggested for multiple scenarios. Metastatic disease or family history suggestive of hereditary PCA was recommended for GT. Additional family history and pathologic criteria garnered moderate consensus. Priority genes to test for metastatic disease treatment included BRCA2, BRCA1, and mismatch repair genes, with broader testing, such as ATM, for clinical trial eligibility. BRCA2 was recommended for active surveillance discussions. Screening starting at age 40 years or 10 years before the youngest PCA diagnosis in a family was recommended for BRCA2 carriers, with consideration in HOXB13, BRCA1, ATM, and mismatch repair carriers. Collaborative (point-of-care) evaluation models between health care and genetic providers was endorsed to address the genetic counseling shortage. The genetic evaluation framework included optimal pretest informed consent, post-test discussion, cascade testing, and technology-based approaches.ConclusionThis multidisciplinary, consensus-driven PCA genetic implementation framework provides novel guidance to clinicians and patients tailored to the precision era. Multiple research, education, and policy needs remain of importance.

BackgroundThe NRG/RTOG 9413 study showed that whole pelvic radiotherapy (WPRT) plus neoadjuvant hormonal therapy (NHT) improved progression-free survival in patients with intermediate-risk or high-risk localised prostate cancer compared with prostate only radiotherapy (PORT) plus NHT, WPRT plus adjuvant hormonal therapy (AHT), and PORT plus AHT. We provide a long-term update after 10 years of follow-up of the primary endpoint (progression-free survival) and report on the late toxicities of treatment.MethodsThe trial was designed as a 2 × 2 factorial study with hormonal sequencing as one stratification factor and radiation field as the other factor and tested whether NHT improved progression-free survival versus AHT, and NHT plus WPRT versus NHT plus PORT. Eligible patients had histologically confirmed, clinically localised adenocarcinoma of the prostate, an estimated risk of lymph node involvement of more than 15% and a Karnofsky performance status of more than 70, with no age limitations. Patients were randomly assigned (1:1:1:1) by permuted block randomisation to receive either NHT 2 months before and during WPRT followed by a prostate boost to 70 Gy (NHT plus WPRT group), NHT 2 months before and during PORT to 70 Gy (NHT plus PORT group), WPRT followed by 4 months of AHT (WPRT plus AHT group), or PORT followed by 4 months of AHT (PORT plus AHT group). Hormonal therapy was combined androgen suppression, consisting of goserelin acetate 3·6 mg once a month subcutaneously or leuprolide acetate 7·5 mg once a month intramuscularly, and flutamide 250 mg twice a day orally for 4 months. Randomisation was stratified by T stage, Gleason Score, and prostate-specific antigen concentration. NHT was given 2 months before radiotherapy and was continued until radiotherapy completion; AHT was given at the completion of radiotherapy for 4 months. The primary endpoint progression-free survival was analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00769548. The trial has been terminated to additional follow-up collection and this is the final analysis for this trial.FindingsBetween April 1, 1995, and June 1, 1999, 1322 patients were enrolled from 53 centres and randomly assigned to the four treatment groups. With a median follow-up of 8·8 years (IQR 5·07-13·84) for all patients and 14·8 years (7·18-17·4) for living patients (n=346), progression-free survival across all timepoints continued to differ significantly across the four treatment groups (p=0·002). The 10-year estimates of progression-free survival were 28·4% (95% CI 23·3-33·6) in the NHT plus WPRT group, 23·5% (18·7-28·3) in the NHT plus PORT group, 19·4% (14·9-24·0) in the WPRT plus AHT group, and 30·2% (25·0-35·4) in the PORT plus AHT group. Bladder toxicity was the most common grade 3 or worse late toxicity, affecting 18 (6%) of 316 patients in the NHT plus WPRT group, 17 (5%) of 313 in the NHT plus PORT group, 22 (7%) of 317 in the WPRT plus AHT group, and 14 (4%) of 315 in the PORT plus AHT group. Late grade 3 or worse gastrointestinal adverse events occurred in 22 (7%) of 316 patients in the NHT plus WPRT group, five (2%) of 313 in the NHT plus PORT group, ten (3%) of 317 in the WPRT plus AHT group, and seven (2%) of 315 in the PORT plus AHT group.InterpretationIn this cohort of patients with intermediate-risk and high-risk localised prostate cancer, NHT plus WPRT improved progression-free survival compared with NHT plus PORT and WPRT plus AHT at long-term follow-up albeit increased risk of grade 3 or worse intestinal toxicity. Interactions between radiotherapy and hormonal therapy suggests that WPRT should be avoided without NHT.FundingNational Cancer Institute.

Purpose: Currently, no genomic signature exists to distinguish men most likely to progress on adjuvant androgen deprivation therapy (ADT) after radical prostatectomy for high-risk prostate cancer. Here we develop and validate a gene expression signature to predict response to postoperative ADT.Experimental Design: A training set consisting of 284 radical prostatectomy patients was established after 1:1 propensity score matching metastasis between adjuvant-ADT (a-ADT)-treated and no ADT-treated groups. An ADT Response Signature (ADT-RS) was identified from neuroendocrine and AR signaling-related genes. Two independent cohorts were used to form three separate data sets for validation (set I, n = 232; set II, n = 435; set III, n = 612). The primary endpoint of the analysis was postoperative metastasis.Results: Increases in ADT-RS score were associated with a reduction in risk of metastasis only in a-ADT patients. On multivariable analysis, ADT-RS by ADT treatment interaction term remained associated with metastasis in both validation sets (set I: HR = 0.18, Pinteraction = 0.009; set II: HR = 0.25, Pinteraction = 0.019). In a matched validation set III, patients with Low ADT-RS scores had similar 10-year metastasis rates in the a-ADT and no-ADT groups (30.1% vs. 31.0%, P = 0.989). Among High ADT-RS patients, 10-year metastasis rates were significantly lower for a-ADT versus no-ADT patients (9.4% vs. 29.2%, P = 0.021). The marginal ADT-RS by ADT interaction remained significant in the matched dataset (Pinteraction = 0.035).Conclusions: Patients with High ADT-RS benefited from a-ADT. In combination with prognostic risk factors, use of ADT-RS may thus allow for identification of ADT-responsive tumors that may benefit most from early androgen blockade after radical prostatectomy. We discovered a gene signature that when present in primary prostate tumors may be useful to predict patients who may respond to early ADT after surgery. Clin Cancer Res; 24(16); 3908-16. ©2018 AACR.

Purpose It is clinically challenging to integrate genomic-classifier results that report a numeric risk of recurrence into treatment recommendations for localized prostate cancer, which are founded in the framework of risk groups. We aimed to develop a novel clinical-genomic risk grouping system that can readily be incorporated into treatment guidelines for localized prostate cancer. Materials and Methods Two multicenter cohorts (n = 991) were used for training and validation of the clinical-genomic risk groups, and two additional cohorts (n = 5,937) were used for reclassification analyses. Competing risks analysis was used to estimate the risk of distant metastasis. Time-dependent c-indices were constructed to compare clinicopathologic risk models with the clinical-genomic risk groups. Results With a median follow-up of 8 years for patients in the training cohort, 10-year distant metastasis rates for National Comprehensive Cancer Network (NCCN) low, favorable-intermediate, unfavorable-intermediate, and high-risk were 7.3%, 9.2%, 38.0%, and 39.5%, respectively. In contrast, the three-tier clinical-genomic risk groups had 10-year distant metastasis rates of 3.5%, 29.4%, and 54.6%, for low-, intermediate-, and high-risk, respectively, which were consistent in the validation cohort (0%, 25.9%, and 55.2%, respectively). C-indices for the clinical-genomic risk grouping system (0.84; 95% CI, 0.61 to 0.93) were improved over NCCN (0.73; 95% CI, 0.60 to 0.86) and Cancer of the Prostate Risk Assessment (0.74; 95% CI, 0.65 to 0.84), and 30% of patients using NCCN low/intermediate/high would be reclassified by the new three-tier system and 67% of patients would be reclassified from NCCN six-tier (very-low- to very-high-risk) by the new six-tier system. Conclusion A commercially available genomic classifier in combination with standard clinicopathologic variables can generate a simple-to-use clinical-genomic risk grouping that more accurately identifies patients at low, intermediate, and high risk for metastasis and can be easily incorporated into current guidelines to better risk-stratify patients.

Purpose Guidelines are limited for genetic testing for prostate cancer (PCA). The goal of this conference was to develop an expert consensus-driven working framework for comprehensive genetic evaluation of inherited PCA in the multigene testing era addressing genetic counseling, testing, and genetically informed management. Methods An expert consensus conference was convened including key stakeholders to address genetic counseling and testing, PCA screening, and management informed by evidence review. Results Consensus was strong that patients should engage in shared decision making for genetic testing. There was strong consensus to test HOXB13 for suspected hereditary PCA, BRCA1/2 for suspected hereditary breast and ovarian cancer, and DNA mismatch repair genes for suspected Lynch syndrome. There was strong consensus to factor BRCA2 mutations into PCA screening discussions. BRCA2 achieved moderate consensus for factoring into early-stage management discussion, with stronger consensus in high-risk/advanced and metastatic setting. Agreement was moderate to test all men with metastatic castration-resistant PCA, regardless of family history, with stronger agreement to test BRCA1/2 and moderate agreement to test ATM to inform prognosis and targeted therapy. Conclusion To our knowledge, this is the first comprehensive, multidisciplinary consensus statement to address a genetic evaluation framework for inherited PCA in the multigene testing era. Future research should focus on developing a working definition of familial PCA for clinical genetic testing, expanding understanding of genetic contribution to aggressive PCA, exploring clinical use of genetic testing for PCA management, genetic testing of African American males, and addressing the value framework of genetic evaluation and testing men at risk for PCA-a clinically heterogeneous disease.

Management of men with prostate cancer is fraught with uncertainty as physicians and patients balance efficacy with potential toxicity and diminished quality of life. Utilization of genomics as a prognostic biomarker has improved the informed decision-making process by enabling more rationale treatment choices. Recently investigations have begun to determine whether genomic information from tumor transcriptome data can be used to impact clinical decision-making beyond prognosis. Here we discuss the potential of genomics to alter management of a patient who presented with high-risk prostate adenocarcinoma. We suggest that this information help selecting patients for advanced imaging, chemotherapies, or clinical trial.

IntroductionThe purpose of the study was to determine whether racial differences exist in the pattern of local disease progression among men treated with radical prostatectomy (RP) for localized prostate cancer (PCa), which is currently unknown. In this study we evaluated the pattern of adverse pathologic features in an identical cohort of African-American (AA) and Caucasian (CS) men with PCa.Patients and methodsThe overall cohort consisted of 1104 men (224 AA, and 880 CS) who underwent RP between 1990 and 2012. We compared preoperative factors and pathologic outcomes after RP across race groups. Multivariate analysis was used to identify factors predictive of adverse pathologic outcomes. The effect of race on adverse pathologic outcomes and biochemical control rate (BCR) was evaluated using multivariate regression model and Kaplan-Meier analysis.ResultsThe 10-year BCR was 59% versus 82% in AA and CS men, respectively (P = .003). There was no significant difference in extraprostatic spread (P = .14), positive surgical margin (P = .81), lymph node involvement (P = .71), or adverse pathologic features (P = .16) across race groups. However, among patients with ≥ 1 adverse pathologic features, AA men had higher rate of seminal vesicle invasion (SVI) compared with CS men (51% vs. 30%; P = .01). After adjusting for known predictors of adverse pathologic features AA race remained a predictor of SVI.ConclusionAA men have an increased risk of SVI after RP, particularly among men with Gleason ≤ 6 disease. This might represent racial differences in the biology of PCa disease progression, which contribute to poorer outcomes in AA men.

PurposeTo explore whether disparities in outcomes exist between African American (AA) and Caucasian (CS) men with low-grade prostate cancer and similar cancer of the prostate risk assessment-postsurgery (CAPRA-S) features following prostatectomy (RP).MethodsThe overall cohort consisted of 1,265 men (234 AA and 1,031 CS) who met the National comprehensive cancer network criteria for low- to intermediate-risk prostate cancer and underwent RP between 1990 and 2012. We first evaluated whether clinical factors were associated with adverse pathologic outcomes and freedom from biochemical failure (FFbF) using the entire cohort. Next, we studied a subset of 705 men (112 AA and 593 CS) who had pathologic Gleason score≤6 (low-grade disease). Using this cohort, we determined whether race affected FFbF in men with RP-proven low-grade disease and similar CAPRA-S scores.ResultsWith a median follow-up time of 27 months, the overall 7-year FFbF rate was 86% vs. 79% in CS and AA men, respectively (P = 0.035). There was no significant difference in one or more adverse pathologic features between CS vs. AA men (27% vs. 31%; P = 0.35) or CAPRA-S score (P = 0.28). In the subset analysis of patients with low-grade disease, AA race was associated with worse FFbF outcomes (P = 0.002). Furthermore, AA race was a significant predictor of FFbF in men with low-grade disease (hazard ratio = 2.01, 95% CI: 1.08-3.72; P = 0.029).ConclusionsAA race is a predictor of worse FFbF outcomes in men with low-grade disease after RP. These results suggest that a subset of AA men with low-grade disease may benefit from more aggressive treatment.

BackgroundImproved clinical predictors for disease progression are needed for localised prostate cancer, since only a subset of patients develop recurrent or refractory disease after first-line treatment. Therefore, we undertook an unbiased analysis to identify RNA biomarkers associated with metastatic progression after prostatectomy.MethodsProstate cancer samples from patients treated with radical prostatectomy at three academic institutions were analysed for gene expression by a high-density Affymetrix GeneChip platform, encompassing more than 1 million genomic loci. In a discovery cohort, all protein-coding genes and known long non-coding RNAs were ranked by fold change in expression between tumours that subsequently metastasised versus those that did not. The top ranked gene was then validated for its prognostic value for metastatic progression in three additional independent cohorts. 95% of the gene expression assays were done in a Clinical Laboratory Improvements Amendments certified laboratory facility. All genes were assessed for their ability to predict metastatic progression by receiver-operating-curve area-under-the-curve analyses. Multivariate analyses were done for the primary endpoint of metastatic progression, with variables including Gleason score, preoperative prostate-specific antigen concentration, seminal vesicle invasion, surgical margin status, extracapsular extension, lymph node invasion, and expression of the highest ranked gene.Findings1008 patients were included in the study: 545 in the discovery cohort and 463 in the validation cohorts. The long non-coding RNA SChLAP1 was identified as the highest-ranked overexpressed gene in cancers with metastatic progression. Validation in three independent cohorts confirmed the prognostic value of SChLAP1 for metastatic progression. On multivariate modelling, SChLAP1 expression (high vs low) independently predicted metastasis within 10 years (odds ratio [OR] 2·45, 95% CI 1·70-3·53; p

This study aimed to explore the effects of a decision support intervention (DSI) and shared decision making (SDM) on knowledge, perceptions about treatment, and treatment choice among men diagnosed with localized low-risk prostate cancer (PCa). At a multidisciplinary clinic visit, 30 consenting men with localized low-risk PCa completed a baseline survey, had a nurse-mediated online DS session to clarify preference for active surveillance (AS) or active treatment (AT), and met with clinicians for SDM. Participants also completed a follow-up survey at 30 days. We assessed change in treatment knowledge, decisional conflict, and perceptions and identified predictors of AS. At follow-up, participants exhibited increased knowledge (p < 0.001), decreased decisional conflict (p < 0.001), and more favorable perceptions of AS (p = 0.001). Furthermore, 25 of the 30 participants (83 %) initiated AS. Increased family and clinician support predicted this choice (p < 0.001). DSI/SDM prepared patients to make an informed decision. Perceived support of the decision facilitated patient choice of AS. [ABSTRACT FROM AUTHOR]

Background: We describe a randomized, non-blinded Phase II interventional study to assess the safety and efficacy of stereotactic ablative radiotherapy (SABR) for hormone-sensitive oligometastatic prostate adenocarcinoma, and to describe the biology of the oligometastatic state using immunologic, cellular, molecular, and functional imaging correlates. 54 men with oligometastatic prostate adenocarcinoma will be accrued. The primary clinical endpoint will be progression at 6 months from randomization with the hypothesis that SABR to all metastases will forestall progression by disrupting the metastatic process. Secondary clinical endpoints will include local control at 6 months post-SABR, toxicity and quality of life, and androgen deprivation therapy (ADT)-free survival (ADT-FS). Further fundamental analysis of the oligometastatic state with be achieved through correlation with investigational 18F-DCFPyL PET/CT imaging and measurement of circulating tumor cells, circulating tumor DNA, and circulating T-cell receptor repertoires, facilitating an unprecedented opportunity to characterize, in isolation, the effects of SABR on the dynamics of and immunologic response to oligometastatic disease.Methods/design: Patients will be randomized 2:1 to SABR or observation with minimization to balance assignment by primary intervention, prior hormonal therapy, and PSA doubling time. Progression after 6 months will be compared using Fisher's exact test. Hazard ratios and Kaplan-Meier estimates of progression free survival (PFS), ADT free survival (ADT-FS), time to locoregional progression (TTLP) and time to distant progression (TTDP) will be calculated based on an intention-to-treat. Local control will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Withdrawal from the study prior to 6 months will be counted as progression. Adverse events will be summarized by type and grade. Quality of life pre- and post- SABR will be measured by Brief Pain Inventory.Discussion: The ORIOLE trial is the first randomized, non-blinded Phase II interventional study in the North America evaluating the safety and efficacy of SABR in oligometastatic hormone-sensitive prostate cancer. Leading-edge laboratory and imaging correlates will provide unique insight into the effects of SABR on the oligometastatic state.Trial Registrations: ClinicalTrials.gov Identifier: NCT02680587. URL of Registry: https://clinicaltrials.gov/show/NCT02680587 Date of Registration: 02/08/2016. Date of First Participant Enrollment: 05/23/2016. [ABSTRACT FROM AUTHOR]

Purpose: Multigene panels are commercially available for the evaluation of prostate cancer (PCA) predisposition, which necessitates tailored genetic counseling (GC) for men. Here we describe emerging results of Genetic Evaluation of Men, prospective multigene testing study in PCA to inform personalized genetic counseling, with emerging implications for referrals, cancer screening, and precision therapy. Patients and Methods: Eligibility criteria for men affected by or at high risk for PCA encompass age, race, family history (FH), and PCA stage/grade. Detailed demographic, clinical, and FH data were obtained from participants and medical records. Multigene testing was conducted after GC. Mutation rates were summarized by eligibility criteria and compared across FH data. The 95% CI of mutation prevalence was constructed by using Poisson distribution. Results: Of 200 men enrolled, 62.5% had PCA. Eleven (5.5%; 95% CI, 3.0% to 9.9%) had mutations; 63.6% of mutations were in DNA repair genes. FH of breast cancer was significantly associated with mutation status (P =.004), and FH that met criteria for hereditary breast and ovarian cancer syndrome was significantly associated with PCA (odds ratio, 2.33; 95% CI, 1.05 to 5.18). Variants of uncertain significance were reported in 70 men (35.0%). Among mutation carriers, 45.5% had personal/FH concordant with the gene. A tailored GC model was developed based on emerging findings. Conclusion: Multigene testing for PCA identifies mutations mostly in DNA repair genes, with implications for precision therapy. The study highlights the importance of comprehensive genetic evaluation for PCA beyond metastatic disease, including early-stage disease with strong FH. Detailed FH is important for referrals of men for genetic evaluation. The results inform precision GC and cancer screening for men and their male and female blood relatives. [ABSTRACT FROM AUTHOR]

High-dose rate brachytherapy (HDR-BT) monotherapy and robotic arm (i.e., CyberKnife) stereotactic body radiation therapy (SBRT) are emerging technologies that have become popular treatment options for prostate cancer. Proponents of both HDR-BT monotherapy and robotic arm SBRT claim that these modalities are as efficacious as intensity-modulated radiation therapy in treating prostate cancer. Moreover, proponents of robotic arm SBRT believe it is more effective than HDR-BT monotherapy because SBRT is non-invasive, touting it as 'virtual HDR-BT.' We perform a comparative effective analysis of the two technologies. The tumor control rates and toxicities of HDR-BT monotherapy and robotic arm SBRT are promising. However, at present, it would be inappropriate to state that HDR-BT monotherapy and robotic arm SBRT are as efficacious or effective as other treatment modalities for prostate cancer, which have stronger foundations of evidence. Studies reporting on these technologies have relatively short follow-up time, few patients and are largely retrospective. [ABSTRACT FROM AUTHOR]

Background: Currently there is controversy surrounding the optimal way to treat patients with prostate cancer in the post-prostatectomy setting. Adjuvant therapies carry possible benefits of improved curative results, but there is uncertainty in which patients should receive adjuvant therapy. There are concerns about giving toxicity to a whole population for the benefit of only a subset. We hypothesized that making post-prostatectomy treatment decisions using genomics-based risk prediction estimates would improve cancer and quality of life outcomes. Methods: We developed a state-transition model to simulate outcomes over a 10 year horizon for a cohort of post-prostatectomy patients. Outcomes included cancer progression rates at 5 and 10 years, overall survival, and quality-adjusted survival with reductions for treatment, side effects, and cancer stage. We compared outcomes using population-level versus individual-level risk of cancer progression, and for genomics-based care versus usual care treatment recommendations. Results: Cancer progression outcomes, expected life-years (LYs), and expected quality-adjusted life-years (QALYs) were significantly different when individual genomics-based cancer progression risk estimates were used in place of population-level risk estimates. Use of the genomic classifier to guide treatment decisions provided small, but statistically significant, improvements in model outcomes. We observed an additional 0.03 LYs and 0.07 QALYs, a 12% relative increase in the 5-year recurrence-free survival probability, and a 4% relative reduction in the 5-year probability of metastatic disease or death. Conclusions: The use of genomics-based risk prediction to guide treatment decisions may improve outcomes for prostate cancer patients. This study offers a framework for individualized decision analysis, and can be extended to incorporate a wide range of personal attributes to enable delivery of patient-centered tools for informed decision-making. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the influence of timing of salvage and adjuvant radiation therapy on outcomes after prostatectomy for prostate cancer. Methods: Using the Surveillance, Epidemiology, and End Results-Medicare linked database, we identified prostate cancer patients diagnosed during 1995–2007 who had one or more adverse pathological features after prostatectomy. The final cohort of 6,137 eligible patients included men who received prostatectomy alone (n = 4,509) or with adjuvant (n = 894) or salvage (n = 734) radiation therapy. Primary outcomes were genitourinary, gastrointestinal, and erectile dysfunction events and survival after treatment(s). Results: Radiation therapy after prostatectomy was associated with higher rates of gastrointestinal and genitourinary events, but not erectile dysfunction. In adjusted models, earlier treatment with adjuvant radiation therapy was not associated with increased rates of genitourinary or erectile dysfunction events compared to delayed salvage radiation therapy. Early adjuvant radiation therapy was associated with lower rates of gastrointestinal events that salvage radiation therapy, with hazard ratios of 0.80 (95% CI, 0.67–0.95) for procedure-defined and 0.70 (95% CI, 0.59, 0.83) for diagnosis-defined events. There was no significant difference between ART and non-ART groups (SRT or RP alone) for overall survival (HR = 1.13 95% CI = (0.96, 1.34) p = 0.148). Conclusions: Radiation therapy after prostatectomy is associated with increased rates of gastrointestinal and genitourinary events. However, earlier radiation therapy is not associated with higher rates of gastrointestinal, genitourinary or sexual events. These findings oppose the conventional belief that delaying radiation therapy reduces the risk of radiation-related complications. [ABSTRACT FROM AUTHOR]

Abstract: Studies of dose-escalated external beam radiation therapy (EBRT) and low dose rate brachytherapy (LDR-BT) have shown excellent rates of tumor control and cancer specific survival. Moreover, LDR-BT combined with EBRT (i.e. “LDR-BT boost”) is hypothesized to improve local control. While phase II trials with LDR-BT boost have produced mature data of outcomes and toxicities, high dose rate (HDR)-BT has been growing in popularity as an alternative boost therapy. Boost from HDR-BT has theoretical advantages over LDR-BT, including improved cancer cell death and better dose distribution from customization of catheter dwell times, locations, and inverse dose optimization. Freedom from biochemical failure rates at five years for low-, intermediate-, high-risk, and locally advanced patients have generally been 85–100%, 80–98%, 59–96%, and 34–85%, respectively. Late Radiation Therapy Oncology Group grade 3–4 toxicities have also been encouraging with <6% of patients experiencing any toxicity. Limitations of current HDR-BT boost studies include reports of only single-institution experiences, and unrefined reports of toxicity or patient quality of life. Comparative effectiveness research will help guide clinicians in selecting the most appropriate treatment option for individual patients based on risk-stratification, expected outcomes, toxicities, quality of life, and cost. [Copyright &y& Elsevier]

Intensity-modulated radiation therapy ( IMRT) is frequently utilized after prostatectomy without strong evidence for an improvement in outcomes compared to conformal radiation therapy ( RT). We analyzed a large group of patients treated with RT after radical prostatectomy ( RP) to compare complications after IMRT and CRT. The Surveillance, Epidemiology and End Results ( SEER)-Medicare database was queried to identify male Medicare beneficiaries aged 66 years or older who underwent prostatectomy with 1+ adverse pathologic features and received postprostatectomy RT between 1995 and 2007. Chi-square test was used to compare baseline characteristics between the treatment groups. First complication events, based upon administrative procedure or diagnosis codes occurring >1 year after start of RT, were compared for IMRT versus CRT groups. Propensity score adjustment was performed to adjust for potential confounders. Multivariable Cox proportional hazards models of time to first complication were performed. A total of 1686 patients were identified who received RT after RP ( IMRT = 634, CRT = 1052). Patients treated with IMRT were more likely to be diagnosed after 2004 ( P < 0.001), have minimally invasive prostatectomy ( P < 0.001) and have positive margins ( P = 0.019). IMRT use increased over time. After propensity score adjustment, IMRT was associated with lower rate of gastrointestinal ( GI) complications, and higher rate of genitourinary-incontinence complications, compared to CRT. The observed outcomes after IMRT must be considered when determining the optimal approach for postprostatectomy RT and warrant additional study. [ABSTRACT FROM AUTHOR]

Low-dose rate brachytherapy (LDR-BT), involving implantation of radioactive seeds into the prostate, is an established monotherapy for most low-risk and select intermediate- and high-risk prostate cancer patients. High-dose rate brachytherapy (HDR-BT) is an advanced technology theorized to be more advantageous than LDR-BT from a radiobiological and radiophysics perspective, to the patient himself, and in terms of resource allocation. Studies of HDR-BT monotherapy have encouraging results in terms of biochemical control, patient survival, treatment toxicity and erectile preservation. However, there are still certain limitations that preclude recommending HDR-BT monotherapy for prostate cancer outside the setting of a clinical trial. HDR-BT monotherapy should be considered experimental at present. [ABSTRACT FROM AUTHOR]

Abstract: Prostate cancer is the second most prevalent solid tumor diagnosed in men in the United States and Western Europe. Conventionally fractionated external beam radiation therapy (1.8–2.0Gy/fraction) is an established treatment modality for men in all disease risk groups. Emerging evidence from experimental and clinical studies suggests that the α/β ratio for prostate cancer may be as low as 1.5Gy, which has prompted investigators around the world to explore moderately hypofractionated radiation therapy (2.1–3.5Gy/fraction). We review the impetus behind moderate hypofractionation and the current clinical evidence supporting moderate hypofractionated radiation therapy for prostate cancer. Although hypofractionated radiation therapy has many theoretical advantages, there is no clear evidence from prospective, randomized, controlled trials showing that hypofractionated schedules have improved outcomes or lower toxicity than conventionally fractionated regimens. Currently, hypofractionated schedules should only be used in the context of clinical trials. High dose rate brachytherapy and stereotactic body radiation therapy (fraction size 3.5Gy and greater) are alternative approaches to hypofractionation, but are beyond the scope of this report. [Copyright &y& Elsevier]

External beam radiation therapy (EBRT) combined with brachytherapy (BT) is an attractive treatment option for select patients with clinically localized prostate cancer. Either low- or high-dose rate BT may be combined with EBRT ('LDR-BT boost,' 'HDR-BT boost,' respectively). HDR-BT boost has potential theoretical benefits over LDR-BT boost or external beam radiation therapy monotherapy in terms of radiobiology, radiophysics and patient convenience. Based on prospective studies in this review, freedom from biochemical failure (FFBF) rates at 5 years for low-, intermediate- and high-risk patients have generally been 85-100%, 68-97%, 63-85%, respectively; late Radiotherapy and Oncology Group Grades 3 and 4 genitourinary and gastrointestinal toxicities are seen in <8% of patients. HDR-BT boost is now a relatively well-established treatment modality for certain intermediate-risk and high-risk prostate cancer patients, though limitations exist in drawing conclusions from the currently published studies. [ABSTRACT FROM AUTHOR]

Purpose: Controversy exists whether the prostate-specific antigen (PSA) bounce phenomenon following definitive radiation for prostate cancer has prognostic significance. Here, we perform a meta-analysis to determine the association between PSA bounce and biochemical control after brachytherapy alone. Material and methods: We reviewed Medline, EMBASE, and CENTRAL citations through February 2012. Studies that recorded biochemical failure rates in bouncers and non-bouncers were included. Hazard ratios describing the impact of bounce on biochemical failure were extracted directly from the studies or calculated from survival curves. Pooled estimates were obtained using the inverse variance method. A random effects model was used in cases of significant effect heterogeneity (p < 0.10 using Q test). Results: The final analysis included 3011 patients over 6 studies treated with brachytherapy. Meta-analysis revealed that patients experiencing PSA bounce after brachytherapy, conferred a decreased risk of biochemical failure (random effects model HR = 0.42, 95% CI: 0.30-0.59; p < 0.001). Conclusions: Our meta-analysis determined that PSA bounce predicts for improved biochemical control following brachytherapy. To our knowledge, this is the first study describing this effect. [ABSTRACT FROM AUTHOR]

Background: Angiogenesis is a key element in solid-tumor growth, invasion, and metastasis. VEGF is among the most potent angiogenic factor thus far detected. The aim of the present study is to explore the potential of VEGF (also known as VEGF-A) as a prognostic and predictive biomarker among men with locally advanced prostate cancer. Methods: The analysis was performed using patients enrolled on RTOG 8610, a phase III randomized control trial of radiation therapy alone (Arm 1) versus short-term neoadjuvant and concurrent androgen deprivation and radiation therapy (Arm 2) in men with locally advanced prostate carcinoma. Tissue samples were obtained from the RTOG tissue repository. Hematoxylin and eosin slides were reviewed, and paraffin blocks were immunohistochemically stained for VEGF expression and graded by Intensity score (0-3). Cox or Fine and Gray's proportional hazards models were used. Results: Sufficient pathologic material was available from 103 (23%) of the 456 analyzable patients enrolled in the RTOG 8610 study. There were no statistically significant differences in the pre-treatment characteristics between the patient groups with and without VEGF intensity data. Median follow-up for all surviving patients with VEGF intensity data is 12.2 years. Univariate and multivariate analyses demonstrated no statistically significant correlation between the intensity of VEGF expression and overall survival, distant metastasis, local progression, disease-free survival, or biochemical failure. VEGF expression was also not statistically significantly associated with any of the endpoints when analyzed by treatment arm. Conclusions: This study revealed no statistically significant prognostic or predictive value of VEGF expression for locally advanced prostate cancer. This analysis is among one of the largest sample bases with long-term follow-up in a well-characterized patient population. There is an urgent need to establish multidisciplinary initiatives for coordinating further research in the area of human prostate cancer biomarkers. [ABSTRACT FROM AUTHOR]

Abstract: Prostate cancer is the second most prevalent solid tumor diagnosed in men in the United States and Western Europe. Stereotactic body radiation therapy (SBRT) is touted as a superior type of external beam radiation therapy (EBRT) for the treatment of various tumors. SBRT developed from the theory that high doses of radiation from brachytherapy implant seeds could be recapitulated from advanced technology of radiation treatment planning and delivery. Moreover, SBRT has been theorized to be advantageous compared to other RT techniques because it has a treatment course shorter than that of conventionally fractionated EBRT (a single session, five days per week, for about two weeks vs. eight weeks), is non-invasive, is more effective at killing tumor cells, and is less likely to cause damage to normal tissue. In areas of the US and Europe where there is limited access to RT centers, SBRT is frequently being used to treat prostate cancer, even though long-term data about its efficacy and safety are not well established. We review the impetus behind SBRT and the current clinical evidence supporting its use for prostate cancer, thus providing oncologists and primary care physicians with an understanding of the continually evolving field of prostate radiation therapy. Studies of SBRT provide encouraging results of biochemical control and late toxicity. However, they are limited by a number of factors, including short follow-up, exclusion of intermediate- and high-risk patients, and relatively small number of patients treated. Currently, SBRT regimens should only be used in the context of clinical trials. [Copyright &y& Elsevier]

Purpose: A new technique called 'curvilinear approach' for prostate seed implantation has been proposed. The purpose of this study is to evaluate the dosimetric benefit of curvilinear distribution of seeds for low-dose-rate (LDR) prostate brachytherapy. Methods: Twenty LDR prostate brachytherapy cases planned intraoperatively with VariSeed planning system and I-125 seeds were randomly selected as reference rectilinear cases. All the cases were replanned by using curved-needle approach keeping the same individual source strength and the volume receiving 100% of prescribed dose 145 Gy (V100). Parameters such as number of needles, seeds, and the dose coverage of the prostate (D90, V150, V200), urethra (D30, D10) and rectum (D5, V100) were compared for the rectilinear and the curvilinear methods. Statistical significance was assessed using two-tailed student's t-test. Results: Reduction of the required number of needles and seeds in curvilinear method were 30.5% (p < 0.001) and 11.8% (p < 0.49), respectively. Dose to the urethra was reduced significantly; D30 reduced by 10.1% (p < 0.01) and D10 reduced by 9.9% (p < 0.02). Reduction in rectum dose D5 was 18.5% (p < 0.03) and V100 was also reduced from 0.93 cc in rectilinear to 0.21 cc in curvilinear (p < 0.001). Also the V150 and V200 coverage of prostate reduced by 18.8% (p < 0.01) and 33.9% (p < 0.001), respectively. Conclusions: Significant improvement in the relevant dosimetric parameters was observed in curvilinear needle approach. Prostate dose homogeneity (V150, V200) improved while urethral dose was reduced, which might potentially result in better treatment outcome. Reduction in rectal dose could potentially reduce rectal toxicity and complications. Reduction in number of needles would minimize edema and thereby could improve postimplant urinary incontinence. This study indicates that the curvilinear implantation approach is dosimetrically superior to conventional rectilinear implantation technique. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: For prostate cancer that is thought to be locally recurrent after prostatectomy, the optimal timing, dose and techniques for salvage radiotherapy (SRT) have not been established. Here we perform a systematic review of published reports including regression meta-analysis and radiobiologic modelling to identify predictors of biochemical disease control and late toxicity. Methods: We performed a review of published series reporting treatment outcomes following SRT. Studies with at least 30 patients, median PSA before SRT of less than 2.0ng/mL, and median follow-up of greater than 36months were identified. Univariate and multivariate analyses were performed to test Gleason Score, SRT dose, SRT timing, pre-SRT PSA, whole pelvic irradiation and androgen deprivation therapy as predictors of 5-year biochemical progression-free survival (bPFS) and severe (grade⩾3) late GI and GU toxicity. bPFS and toxicity data were fit to tumour control probability and normal tissue complication probability models, respectively. Results: Twenty-five articles met the inclusion criteria for this analysis. Five-year bPFS ranged from 25% to 70%. Severe late GI toxicity rates were 0% to 9%, and severe late GU toxicity rates were 1–11%. On multivariate analysis, bPFS increased with SRT dose by 2.5%perGy and decreased with pre-SRT PSA by 18.3%perng/mL (p <0.001). Late GI and GU toxicity increased with SRT dose by 1.2%perGy (p =0.012) and 0.7%perGy (p =0.010), respectively. Radiobiological models demonstrate the interaction between pre-SRT PSA, SRT dose and bPFS. For example, an increase in pre-SRT PSA from 0.4 to 1.0ng/mL increases the SRT dose required to achieve a 50% bPFS rate from 60 to 70Gy. This could increase the rate of severe late toxicity by approximately 10%. Conclusion: Biochemical control rates following SRT increase with SRT dose and decrease with pre-SRT PSA. Severe late GI and GU toxicity rates also increase with SRT dose. Radiobiological models suggest that the therapeutic ratio of SRT may be improved by initiating treatment at low PSA levels. [Copyright &y& Elsevier]

Ionizing radiation (IR) is used frequently in the management of multiple tumor types, including both organ-confined and locally advanced prostate cancer (PCa). Enhancing tumor radiosensitivity could both reduce the amount of radiation required for definitive treatment and improve clinical outcome. Androgen suppression therapy improves clinical outcomes when combined with radiation therapy but is associated with significant acute and chronic toxicities; hence, there is a clear need for alternative means to increase the therapeutic window of radiotherapy. Herein, it is demonstrated that the mammalian target of rapamycin (mTOR) inhibitors rapamycin (sirolimus) and temsirolimus limit both hormone therapy (HT)-sensitive and castration-resistant PCa (CRPC) cell proliferation as single agents and have a profound radiosensitization effect when used in combination with IR. Importantly, the observed radiosensitization was influenced by the treatment schedule, in which adjuvant administration of mTOR inhibitors was most effective in limiting PCa cell population doubling. This schedule-dependent influence on in vitro treatment outcome was determined to be the result of relative effects on the cell cycle kinetics. Finally, adjuvant administration of either mTOR inhibitor tested after IR significantly decreased clonogenic cell survival of both HT-sensitive and CRPC cells compared with IR alone. Taken together, these data demonstrate that inhibition of mTOR confers a radiosensitization phenotype that is dependent on relative cell cycle kinetics and provide a foundation for clinical assessment. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: Radiation therapy (RT) is delivered as adjuvant and salvage therapy after radical prostatectomy for prostate cancer. Interest in dose escalation in this setting may necessitate more advanced RT techniques, such as intensity modulation. This study was designed to compare intensity-modulated radiation therapy (IMRT) versus 3-dimensional conformal radiation therapy (3DCRT) planning. Methods: Twenty patients were identified who received post--radical prostatectomy RT with 4-field, 3DCRT plans to 68.4 Gy. Contours were revised to comply with the European Organization for Research and Treatment of Cancer consensus guidelines. The IMRT plans with 5 versus 9 coplanar fields were compared for 10 patients. Then the 9-field IMRT plans were compared to 3DCRT in all 20 patients. Differences in dose-volume histogram values were evaluated using 2-tailed paired t tests. Cone beam computed tomographic images were analyzed to evaluate rectum doses in the treatment position during the RT course. The IMRT plans to 72.0 Gy were compared to 3DCRT to 68.4 Gy to be able to consider potential use in dose escalation. Results: The 9-field IMRT plans (vs 3DCRT) improved bladder mean dose and volume receiving 65 Gy or more (V65), as well as rectum mean dose (31.6 Gy vs 36.1 Gy; P < .001), volume receiving 75% or more of the prescription dose (24.4% vs 31.0%; P < .001), and V65 (10.5% vs 20.0%; P < .001). Advantages of IMRT were at the cost of small increases in maximum point doses delivered to the bladder and rectum. Cone beam computed tomographic images (n = 132) were analyzed for 8 patients; rectum mean dose and V65 were also improved by IMRT on these scans. IMRT allowed increasing dose to 72.0 Gy with similar bladder and rectum mean doses, V65, and V40 compared to 3DCRT to a total dose of 68.4 Gy. Conclusions: The IMRT improves dosimetric parameters for the rectum and bladder, which may allow dose escalation after radical prostatectomy. Future studies should determine whether these advantages translate into improved clinical outcomes for prostate cancer patients. [Copyright &y& Elsevier]

Background: Pelvic irradiation for a malignant tumor may cause osteonecrosis of the acetabulum. The purpose of this study was to evaluate the outcome of uncemented total hip arthroplasty in patients with a history of pelvic irradiation for the treatment of prostate cancer. Methods: We performed a retrospective review of the clinical records and radiographs of fifty-eight patients (sixty-six hips) who had had radiation therapy for prostate cancer and had subsequently undergone an elective primary uncemented total hip arthroplasty at our institution. The mean age of the patients at the time of the index operation was seventy-four years. The mean duration of follow-up was 4.8 years (range, two to 7.5 years). Results: At the time of the final follow-up, fifty-one patients (fifty-eight hips) who were still living and had been followed for a minimum of two years had a well-ingrown and functioning replacement. The mean Harris hip score had significantly improved from 47 points preoperatively to 90 points at the time of the final follow-up (p < 0.05). The mean scores on the physical and mental health measures of the Short Form-36 had also improved significantly from 45.1 and 65.3 points, respectively, before the operation to 73.4 and 83.7 points postoperatively (p < 0.05 for both). There was no aseptic loosening of either component in any of the hips. Two hips had revision of the femoral component; one was revised because of a periprosthetic fracture of the femur and the other because of subsidence of the femoral component. Conclusions: Uncemented total hip arthroplasty can be a successful option for the treatment of coxarthrosis in patients with a history of pelvic irradiation for prostate cancer. Osseointegration of uncemented components does not seem to be compromised in these patients in the short term. [ABSTRACT FROM AUTHOR]

: PurposeThe use of a posterior dose margin in 125I prostate brachytherapy is controversial. The posterior margin is often eliminated to lower the risk of late rectal morbidity (Radiation Therapy Oncology Group protocols 9805 and P-0019), but this may compromise the posterior prostate dose coverage. The purpose of this work is to determine whether it is necessary to eliminate the posterior margin to achieve an acceptably low risk of Grade 2 (bleeding/ulceration) late rectal morbidity.: Methods and materialsThe present work is an extension of a previous study in which we reported the probability of Grade 2 late rectal morbidity (bleeding/ulceration) as a function of the maximum rectal dose. Here, we define the relationship between the maximum rectal dose and the width of the posterior dose margin. From this relationship, and the probability of late morbidity determined earlier, we assessed the probability of late rectal morbidity as a function of the width of the posterior dose margin. The present work was based on the preplans of 15 permanent 125I prostate seed implants having volumes ranging from 19 to 78 cm3. All used peripheral loading with 125I sources in the range 0.35–0.45 mCi. The maximum rectal dose was taken to be the isodose line coincident with the posterior edge of the prostate. The maximum rectal dose and the corresponding margin width were determined from the isodose distribution. The sensitivity of the relationship between the maximum rectal dose and the margin width to the prostate volume, the seed density, and the distance of the most posterior seeds from the posterior edge of the prostate was investigated.: ResultsThe maximum rectal dose is directly proportional to the margin width. This relationship is relatively insensitive to the prostate volume and the seed density, but is sensitive to the location of the posterior seeds relative to the posterior edge of the gland. Moving the seeds from 5 mm to 3 mm from the edge typically increased the maximum rectal dose by 17%. With the posterior seeds 3 mm from the edge, the maximum rectal doses that corresponded to 1 mm, 2 mm, 3 mm, 4 mm, and 5 mm margins were 187 ± 6 Gy, 222 ± 8 Gy, 257 ± 11 Gy, 292 ± 14 Gy, and 327 ± 17 Gy, respectively. The corresponding probabilities that a patient will experience late rectal morbidity are ≤1%, ≤2%, ≤3%, ≤5%, and ≤7%, respectively.: ConclusionsOur results indicate that a 2–3-mm posterior dose margin can be used in prostate brachytherapy with a relatively low (2–3%) risk of Grade 2 (bleeding/ulceration) late rectal morbidity, provided the sources in the posterior row are implanted at least 3 mm from the edge of the prostate. A practical guideline is to keep the maximum rectal dose below 150% of the target dose. [Copyright &y& Elsevier]

Purpose: To determine the effect of edema on the dosimetric parameters V100 (percentage of prostate volume that received a dose equal to or greater than the prescribed dose) and D90 (minimal dose delivered to 90% of prostate volume) in 125I prostate brachytherapy and to determine whether the edema can be used to predict implant quality on the day of the implant (Day 0).Methods and Materials: Fifty consecutive patients treated with 125I implants who had two postimplant CT scans were selected for this study. The mean interval between the studies was 46 ± 23 days. The implants were preplanned to deliver 150 Gy to the prostate plus a 3–5-mm symmetric dose margin using peripherally loaded 0.4–0.6-mCi (NIST-99) 125I seeds. A dose-volume histogram was compiled for each postimplant CT scan. The V100 and D90 from the first and second CT scans were compared to determine the effect of edema on these parameters. A multivariate regression analysis was performed to define the linear relationships for predicting the V100 or D90 at 30–60 days after implant from the magnitude of the edema and the values of V100 and D90 on Day 0.Results: V100 and D90 increased by 5% ± 6% and 15% ± 17%, respectively, during the interval between the first and second postimplant CT scans. The mean edema was 1.53 ± 0.20. The increases in V100 and D90 were found to be proportional to the edema and the values of V100 and D90 on Day 0. The increase in V100 was also found to depend on the width of the preplan dose margin. Linear relationships were derived that predict the V100 and D90 at 30–60 days after implant with a standard error of ±4% and ±24 Gy, respectively.Conclusion: V100 and D90 increased by 5% ± 6% and 15% ± 17%, respectively, during the first 30–60 days after implant. The results of a multivariate linear regression analysis showed that the increases in V100 and D90 were proportional to both the magnitude of the edema and the values of these parameters on Day 0. The relationships derived by linear regression analysis predict V100 and D90 at 30–60 days after implant to within ±4% and ±24 Gy, respectively. However, predicting the 30–60-day V100 and D90 on Day 0 is a poor substitute for obtaining a 30–60-day CT scan, because the uncertainty in the predicted values is greater by a factor of ≥2. Nevertheless, on average, the predicted values should provide a more reliable estimate of the actual V100 and D90 than the Day 0 values that ignore the effect of edema altogether. The increase in V100 was also found to depend on the width of the preplan dose margin; therefore, our results for V100 are only valid for implants planned with a 3–5-mm margin. [Copyright &y& Elsevier]

Background: Measuring patient-reported outcomes (PROs) requires an individual's perspective on their symptoms, functional status, and quality of life. Digital health enables remote electronic PRO (ePRO) assessments as a clinical decision support tool to facilitate meaningful provider interactions and personalized treatment.Objective: This study explored the feasibility and acceptability of collecting ePROs using validated health-related quality of life (HRQoL) questionnaires for prostate cancer.Methods: Using Apple ResearchKit software, the Strength Through Insight app was created with content from validated HRQoL tools 26-item Expanded Prostate Cancer Index Composite (EPIC) or EPIC for Clinical Practice and 8-item Functional Assessment of Cancer Therapy Advanced Prostate Symptom Index. In a single-arm pilot study with patients receiving prostate cancer treatment at Thomas Jefferson University Hospital and affiliates, participants were recruited, and instructed to download Strength Through Insight and complete ePROs once a week over 12 weeks. A mixed methods approach, including qualitative pre- and poststudy interviews, was used to evaluate the feasibility and acceptability of Strength Through Insight for the collection and care management of cancer treatment.Results: Thirty patients consented to the study; 1 patient failed to complete any of the questionnaires and was left out of the analysis of the intervention. Moreover, 86% (25/29) reached satisfactory questionnaire completion (defined as completion of 60% of weekly questions over 12 weeks). The lower bound of the exact one-sided 95% CI was 71%, exceeding the 70% feasibility threshold. Most participants self-identified with having a high digital literacy level (defined as the ability to use, understand, evaluate, and analyze information from multiple formats from a variety of digital sources), and only a few participants identified with having a low digital literacy level (defined as only having the ability to gather information on the Web). Interviews were thematically analyzed to reveal the following: (1) value of emotional support and wellness in cancer treatment, (2) rise of social patient advocacy in online patient communities and networks, (3) patient concerns over privacy, and (4) desire for personalized engagement tools.Conclusions: Strength Through Insight was demonstrated as a feasible and acceptable method of data collection for ePROs. A high compliance rate confirmed the app as a reliable tool for patients with localized and advanced prostate cancer. Nearly all participants reported that using the smartphone app is easier than or equivalent to the traditional paper-and-pen approach, providing evidence of acceptability and support for the use of remote PRO monitoring. This study expands on current research involving the value of digital health, as a social and behavioral science, augmented with technology, can begin to contribute to population health management, as it shapes psychographic segmentation by demographic, socioeconomic, health condition, or behavioral factors to group patients by their distinct personalities and motivations, which influence their choices.Trial Registration: ClinicalTrials.gov NC03197948; http://clinicaltrials.gov/ct2/show/NC03197948. [ABSTRACT FROM AUTHOR]

Decipher is a genomic classifier (GC) prospectively validated postprostatectomy. We validated the performance of the GC in pretreatment biopsy samples within the context of 3 randomized phase 3 high-risk definitive radiation therapy trials. A prespecified analysis plan (NRG-GU-TS006) was approved to obtain formalin-fixed paraffin-embedded tissue from biopsy specimens from the NRG biobank from patients enrolled in the NRG/Radiation Therapy Oncology Group (RTOG) 9202, 9413, and 9902 phase 3 randomized trials. After central review, the highest-grade tumors were profiled on clinical-grade whole-transcriptome arrays and GC scores were obtained. The primary objective was to validate the independent prognostic ability for the GC for distant metastases (DM), and secondary for prostate cancer–specific mortality (PCSM) and overall survival (OS) with Cox univariable and multivariable analyses. GC scores were obtained on 385 samples, of which 265 passed microarray quality control (69%) and had a median follow-up of 11 years (interquartile range, 9-13). In the pooled cohort, on univariable analysis, the GC was shown to be a prognostic factor for DM (per 0.1 unit; subdistribution hazard ratio [sHR], 1.29; 95% confidence interval [CI], 1.18-1.41; P <.001), PCSM (sHR, 1.28; 95% CI, 1.16-1.41; P <.001), and OS (hazard ratio [HR], 1.16; 95% CI, 1.08-1.22; P <.001). On multivariable analyses, the GC (per 0.1 unit) was independently associated with DM (sHR, 1.22; 95% CI, 1.09-1.36), PCSM (sHR, 1.23; 95% CI, 1.09-1.39), and OS (HR, 1.12; 95% CI, 1.05-1.20) after adjusting for age, Prostate Specific Antigen, Gleason score, cT stage, trial, and randomized treatment arm. GC had similar prognostic ability in patients receiving short-term or long-term androgen-deprivation therapy, but the absolute improvement in outcome varied by GC risk. This is the first validation of a gene expression biomarker on pretreatment prostate cancer biopsy samples from prospective randomized trials and demonstrates an independent association of GC score with DM, PCSM, and OS. High-risk prostate cancer is a heterogeneous disease state, and GC can improve risk stratification to help personalize shared decision making. [ABSTRACT FROM AUTHOR]

The article presents the recently published researches that help illuminate complexity in prostate cancer. One study focuses on the process of decision making and communication in early prostate cancer. Another study looks at the association of neoadjuvant hormonal treatment and suggests that it may adversely influence the biology of the cancer cells. Two papers look at hormone refractory prostate cancer and one attempts to improve current treatments in advanced disease.

Abstract: Purpose: To demonstrate how a suboptimal 125I prostate implant can be salvaged by reimplantation. Methods and materials: A 125I implant was preplanned to deliver 150 Gy to the prostate of a patient with early stage prostate cancer. A CT scan at 35 days postimplant indicated that V100 and D90 were 46% and 49 Gy, respectively. The cause was a systematic source placement error that left the base significantly underdosed. A reimplantation of the underdosed region was planned by superimposing a template grid onto the 35-day postimplant CT scan images and digitizing them into the treatment planning computer as if they were TRUS images. The reimplantation was carried out under fluoroscopy guidance so that the initial implant was visible. Results: The reimplantation increased V100 and D90 to 98% and 201 Gy, respectively. The misplaced seeds resulted in a high dose to the apical region and urethra, which was further increased by the reimplantation. The patient experienced increased urinary morbidity, which was relieved by medication. Conclusion: It is feasible to salvage a suboptimal prostate seed implant by reimplanting the underdosed regions under fluoroscopy guidance based on a plan generated from the postimplant CT scan. [Copyright &y& Elsevier]

: PurposeTo determine whether potential extraprostatic extension (EPE) of prostate adenocarcinoma is covered by the prescribed dose when permanent 125I implants are planned with a 5-mm treatment margin.: Methods and materialsThe postimplant dosimetry of 60 consecutive 125I prostate implants was analyzed to determine whether there was a residual 3-mm margin, adequate for treatment of potential EPE. The implants were peripherally loaded and planned with a nominal 5-mm symmetric dose margin. Extraprostatic seeds were not used at midgland, although extraprostatic seeds were placed at the base and apex. The radial distance between the edge of the prostate and the prescription isodose line (145 Gy) was measured at the left lateral, left posterolateral, posterior, right posterolateral, and right lateral positions at the base, midgland, and apex in both the preplan and postimplant dosimetry.: ResultsThe mean postimplant margin at the base (4±2 mm) was significantly less (p<0.01) than planned (6±2 mm) by 2 mm. The planned and postimplant margins at the midgland (5±1 mm and 5±2 mm) and apex (7±2 mm and 7±3 mm) were indistinguishable (p = 0.31 and p = 0.69, respectively). At the base, 69% of the measurements were &ges;3 mm compared with 89% and 91% at the midgland and apex, respectively. Overall, 83% of the margin measurements were &ges;3 mm. The prostate postimplant V100 and D90 were 96±4% and 193±27 Gy, respectively.: ConclusionsA 5-mm planning dose margin can potentially treat most EPE. However, the postimplant margin, like other dosimetric parameters, is sensitive to source placement errors and the percentage of EPE treated depends upon how well the plan is executed. Because implant quality is operator dependent, we would not recommend brachytherapy alone for patients with a high risk of EPE. [Copyright &y& Elsevier]

High dose-rate (HDR) brachytherapy is commonly administered as a boost to external beam radiation therapy (EBRT). Our purpose was to compare toxicity with increasingly hypofractionated EBRT in combination with a single 15 Gy HDR boost for men with intermediate-risk prostate cancer. Forty-two men were enrolled on this phase IB clinical trial to one of three EBRT dose cohorts: 10 fractions, seven fractions, or five fractions. Patients were followed prospectively for safety, efficacy, and health-related quality of life (Expanded Prostate Index Composite). Efficacy was assessed biochemically using the Phoenix definition. With a median follow up of 36 months, the biochemical disease-free survival was 95.5%. One man developed metastatic disease at 5 years. There was no significant minimally important difference in EPIC PRO for either urinary, bowel, or sexual domains. There was one acute Grade 3 GI and GU toxicity, but no late Grade 3 GU or GI toxicities. Fifteen gray HDR brachytherapy followed by a five fraction SBRT approach results in high disease control rates and low toxicity similar to previously reported HDR protocols with significant improvement in patient convenience and resource savings. While mature results with longer follow up are awaited, this treatment approach may be considered a safe and effective option for men with intermediate-risk disease. [ABSTRACT FROM AUTHOR]

Purpose: Cabazitaxel has been demonstrated to improve the overall survival for men with metastatic castrate-resistant prostate cancer. The purpose of this study was to determine the maximum tolerated dose for concurrent cabazitaxel with androgen deprivation and intensity modulated radiation therapy in men with high-risk prostate cancer.Methods and Materials: Twenty men were enrolled in this institutuional review board-approved phase I clinical trial using a 3 + 3 design. Patients were followed prospectively for safety, efficacy, and health-related quality of life (Expanded Prostate Index Composite). Efficacy was assessed biochemically using the Phoenix definition.Results: With a median follow-up time of 56 months, the maximum tolerated dose of concurrent cabazitaxel was 6 mg/m2. The 5-year biochemical disease-free survival was 73%, despite 75% of patients having very high risk prostate cancer per the National Comprehensive Cancer Network guidelines. Four patients were unable to complete chemotherapy owing to dose-limiting toxicities (eg, rectal bleeding, diarrhea, and elevated transaminase). There was no significant minimally important difference in Expanded Prostate Index Composite patient-reported outcomes for either the urinary or bowel domains; however, there was a significant decrease in the sexual domain.Conclusions: This is the first clinical trial of prostate cancer to report on the combination of cabazitaxel and radiation therapy. The maximum tolerated dose of concurrent cabazitaxel with radiation and androgen deprivation therapy was determined to be 6 mg/m2. Despite the aggressive nature of the disease, robust biochemical control was observed. [ABSTRACT FROM AUTHOR]

Survivorship care for patients with prostate cancer requires careful consideration of unique disease-specific factors, including the prolonged natural disease history, the potential for competing health risks, and the consequences of long-term androgen deprivation therapy. However, current prostate cancer survivorship research is unfortunately limited by the lack of a robust supportive evidence base, variability in the definitions and measurement of survivorship outcomes, and a heavy reliance on expert opinion. As a result, the conduct of quality prostate cancer survivorship research is of increasing importance for patients, medical providers, and other key stakeholders. This manuscript harmonizes a path forward for improving prostate cancer survivorship by defining prostate cancer survivorship and survivorship research, as well as by highlighting key research priorities and cooperative mechanisms for survivorship studies within prostate cancer, with a particular focus on men with advanced disease. [ABSTRACT FROM AUTHOR]

Background Prostate cancer patients who have a detectable prostate-specific antigen (PSA) postprostatectomy may harbor pre-existing metastatic disease. To our knowledge, none of the commercially available genomic biomarkers have been investigated in such men. Objective To evaluate if a 22-gene genomic classifier can independently predict development of metastasis in men with PSA persistence postoperatively. Design, setting, and participants A multi-institutional study of 477 men who underwent radical prostatectomy (RP) between 1990 and 2015 from three academic centers. Patients were categorized as detectable PSA ( n = 150) or undetectable ( n = 327) based on post-RP PSA nadir ≥0.1 ng/ml. Outcome measurements and statisitical analysis Cumulative incidence curves for metastasis were constructed using Fine-Gray competing risks analysis. Penalized Cox univariable and multivariable (MVA) proportional hazards models were performed to evaluate the association of the genomic classifier with metastasis. Results and limitations The median follow-up for censored patients was 57 mo. The median time from RP to first postoperative PSA was 1.4 mo. Detectable PSA patients were more likely to have higher adverse pathologic features compared with undetectable PSA patients. On MVA, only genomic high-risk (hazard ratio [HR]: 5.95, 95% confidence interval [CI]: 2.02–19.41, p = 0.001), detectable PSA (HR: 4.26, 95% CI: 1.16–21.8, p = 0.03), and lymph node invasion (HR: 12.2, 95% CI: 2.46–70.7, p = 0.003) remained prognostic factors for metastasis. Among detectable PSA patients, the 5-yr metastasis rate was 0.90% for genomic low/intermediate and 18% for genomic high risk ( p < 0.001). Genomic high risk remained independently prognostic on MVA (HR: 5.61, 95% CI: 1.48–22.7, p = 0.01) among detectable PSA patients. C-index for Cancer of the Prostate Risk Assessment Postsurgical score, Gandaglia nomogram, and the genomic classifier plus either Cancer of the Prostate Risk Assessment Postsurgical score or Gandaglia were 0.69, 0.68, and 0.82 or 0.81, respectively. Sample size was a limitation. Conclusions Despite patients with a detectable PSA harboring significantly higher rates of aggressive clinicopathologic features, Decipher independently predicts for metastasis. Prospective validation of these findings is warranted and will be collected as part of the ongoing randomized trial NRG GU-002. Patient summary Decipher independently predicted metastasis for patients with detectable prostate-specific antigen after prostatectomy. [ABSTRACT FROM AUTHOR]

Background Despite salvage radiation therapy (SRT) for recurrent prostate cancer (PCa) after radical prostatectomy (RP), some patients still progress to metastases. Identifying these men would allow them to undergo systemic therapy including testing novel therapies to reduce metastases risk. Objective To test whether the genomic classifier (GC) predicts development of metastatic disease. Design, setting, and participants Retrospective multi-center and multi-ethnic cohort study from two academic centers and one Veterans Affairs Medical Center in the United States involving 170 men receiving SRT for recurrent PCa post-RP. Outcome measurements and statistical analysis Time from SRT to development of metastatic disease tested using Cox regression, survival c-index, and decision curve analysis. Performance of GC was compared to the Cancer of the Prostate Risk Assessment Score and Briganti risk models based on these metrics. Results and limitations With a median 5.7 yr follow-up after SRT, 20 patients (12%) developed metastases. On multivariable analysis, for each 0.1 unit increase in GC (scaled from 0 to 1), the hazard ratio for metastasis was 1.58 (95% confidence interval 1.16–2.17; p = 0.002). Adjusting for androgen deprivation therapy did not materially change the results. The c-index for GC was 0.85 (95% confidence interval 0.73–0.88) versus 0.63–0.65 for published clinico-pathologic risk models. The 5-yr cumulative incidence of metastasis post-SRT in patients with low, intermediate, and high GC scores was 2.7%, 8.4%, and 33.1%, respectively ( p < 0.001). Conclusions While validation in larger, prospectively collected cohorts is required, these data suggest GC is a strong predictor of metastases among men receiving SRT for recurrent PCa post-RP, accurately identifying men who are excellent candidates for systemic therapy due to their very high-risk of metastases. Patient summary Genomic classifier and two clinico-pathologic risk models were evaluated on their ability to predict metastases among men receiving salvage radiation therapy for recurrent prostate cancer. Genomic classifier was able to identify candidates for further therapies due to their very high-risk of metastases. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) subtypes based on ETS gene expression have been described. Recent studies suggest there are racial differences in tumor location, with PCa located anteriorly more often among African-American (AA) compared to Caucasian-American (CA) men. In this retrospective analysis of a multi-institutional cohort treated by radical prostatectomy (179 CA, 121 AA), we evaluated associations among molecular subtype, race, anatomic tumor location, and androgen receptor (AR) signaling. Subtype (m-ERG + , m-ETS + , m-SPINK1 + , or triple-negative) was determined using distribution-based outlier analysis. AR signaling was investigated using gene expression profiling of canonical AR targets. m-ERG + was more common in CA than AA men (47% vs 22%, p < 0.001). AA men were more likely to be m-SPINK1 + (13% vs 7%; p = 0.069) and triple-negative (50% vs 37%; p = 0.043). Racial differences in molecular subtypes did not persist when tumors were analyzed by location, suggesting a biologically important relationship between tumor location and subtype. Accordingly, anterior tumor location was associated with higher Decipher scores and lower global AR signaling. Patient summary This study demonstrates associations among patient race, prostate cancer molecular subtypes, and tumor location. Location-specific differences in androgen regulation may further underlie these relationships. [ABSTRACT FROM AUTHOR]

Background Prostate cancer (PCa) molecular subtypes have been defined by essentially mutually exclusive events, including ETS gene fusions (most commonly involving ERG ) and SPINK1 overexpression. Clinical assessment may aid in disease stratification, complementing available prognostic tests. Objective To determine the analytical validity and clinicopatholgic associations of microarray-based molecular subtyping. Design, setting, and participants We analyzed Affymetrix GeneChip expression profiles for 1577 patients from eight radical prostatectomy cohorts, including 1351 cases assessed using the Decipher prognostic assay (GenomeDx Biosciences, San Diego, CA, USA) performed in a laboratory with Clinical Laboratory Improvements Amendment certification. A microarray-based (m-) random forest ERG classification model was trained and validated. Outlier expression analysis was used to predict other mutually exclusive non- ERG ETS gene rearrangements (ETS + ) or SPINK1 overexpression (SPINK1 + ). Outcome measurements Associations with clinical features and outcomes by multivariate logistic regression analysis and receiver operating curves. Results and limitations The m-ERG classifier showed 95% accuracy in an independent validation subset (155 samples). Across cohorts, 45% of PCas were classified as m-ERG + , 9% as m-ETS + , 8% as m-SPINK1 + , and 38% as triple negative (m-ERG − /m-ETS − /m-SPINK1 − ). Gene expression profiling supports three underlying molecularly defined groups: m-ERG + , m-ETS + , and m-SPINK1 + /triple negative. On multivariate analysis, m-ERG + tumors were associated with lower preoperative serum prostate-specific antigen and Gleason scores, but greater extraprostatic extension ( p < 0.001). m-ETS + tumors were associated with seminal vesicle invasion ( p = 0.01), while m-SPINK1 + /triple negative tumors had higher Gleason scores and were more frequent in Black/African American patients ( p < 0.001). Clinical outcomes were not significantly different among subtypes. Conclusions A clinically available prognostic test (Decipher) can also assess PCa molecular subtypes, obviating the need for additional testing. Clinicopathologic differences were found among subtypes based on global expression patterns. Patient summary Molecular subtyping of prostate cancer can be achieved using extra data generated from a clinical-grade, genome-wide expression-profiling prognostic assay (Decipher). Transcriptomic and clinical analysis support three distinct molecular subtypes: (1) m-ERG + , (2) m-ETS + , and (3) m-SPINK1 + /triple negative (m-ERG − /m-ETS − /m-SPINK1 − ). Incorporation of subtyping into a clinically available assay may facilitate additional applications beyond routine prognosis. [ABSTRACT FROM AUTHOR]

Purpose To determine if increasing the biologically equivalent dose (BED) via various radiation fractionation regimens is correlated with clinical outcomes or toxicities for prostate cancer. Methods and materials We performed a meta-analysis that included 12,756 prostate cancer patients from 55 studies published from 2003 to 2013 who were treated with non-dose-escalated conventionally fractionated external beam radiation therapy (non-DE-CFRT), DE-CFRT, hypofractionated RT, and high dose rate brachytherapy (HDR-BT; either mono or boost) with ⩾5-year actuarial follow-up. BEDs were calculated based on the following formula: ( nd [1 + d /( α / β )]), where n is the number of fractions, and d is dose per fraction; assuming an α / β of 1.5 for prostate cancer and 3.0 for late toxicities. Mixed effects meta-regression models were used to estimate weighted linear relationships between BED and the observed percentages of patients experiencing late toxicities or 5-year freedom from biochemical failure (FFBF). Results Increases in 10 Gy increments in BED (at α / β of 1.5) from 140 to 200 Gy were associated with 5-unit improvements in percent FFBF. Dose escalation of BED above 200 Gy was not correlated with FFBF. Increasing BED (at α / β of 3.0) from 98 to 133 Gy was associated with increased gastrointestinal toxicity. Dose escalation above 133 Gy was not correlated with toxicity. Conclusions An increase in the BED to 200 Gy (at α / β of 1.5) was associated with increased disease control. Doses above 200 Gy did not result in additional clinical benefit. [ABSTRACT FROM AUTHOR]

Purpose: Prostate volume greater than 50 cc is traditionally a relative contraindication to prostate seed implantation (PSI), but there is little consensus regarding prostate size and clinical outcomes. We report biochemical control and toxicity after low-dose-rate PSI and compare outcomes according to the prostate size. Methods and Materials: A total of 429 men who underwent low-dose-rate PSI between 1998 and 2009 were evaluated. Median followup was 38.7 months. Patients were classified by prostate volume into small, medium, and large subgroups. Differences were analyzed using the Mann-Whitney and Pearson's χ² tests for continuous and categorical variables, respectively. Cox proportional hazards regression models were used to evaluate effect of prostate size on outcomes. Results: Patient pretreatment factors were balanced between groups except for age (p = 0.001). The 10-year actuarial freedom from biochemical failure for all patients treated with PSI was 96.3% with no statistically significant difference between large vs. small/medium prostate size (90% vs. 96.6%, p = 0.47). In a multivariate analysis, plan type (hazard ratio [HR] = 0.25, p = 0.03), dose to 90% of the gland (D90: HR = 0.98, p = 0.02), volume receiving 200 Gy (V200: HR = 0.98, p = 0.026), and biologic effective dose (HR = 0.99, p = 0.045), but not prostate size (HR = 2.27, p = 0.17) were significantly associated with freedom from biochemical failure. Prostate size was not significantly associated with time to maximum American Urologic Association score. Conclusion: In men with large prostates, the PSI provides biochemical control and temporal changes in genitourinary toxicity that are comparable with men having smaller glands. Accurate dose optimization and delivery of PSI provides the best clinical outcomes regardless of gland size. [ABSTRACT FROM AUTHOR]

Purpose/objective: Risk-stratification for post-prostatectomy radiotherapy (PORT) using conventional clinicopathologic indexes leads to substantial over- and under-treatment. Better patient selection could spare unnecessary toxicities and improve outcomes. We investigated the prognostic utility of unfavorable subpathologies intraductal carcinoma and cribriform architecture (IDC/CA), and a 22-gene Decipher genomic classifier (GC) in prostate cancer (PCa) patients receiving PORT.Material/methods: A cohort of 302 men who received PORT at 2 academic institutions was pooled. PORT was predominately delivered as salvage (62% of cases); 20% received HT+PORT. Specimens were centrally reviewed for IDC/CA presence. In 104 cases, GC scores were determined. Endpoints were biochemical relapse-free (bRFR) and metastasis-free (mFR) rates.Results: After a median follow-up of 6.49-years, 135 (45%) and 40 (13%) men experienced biochemical relapse and metastasis, respectively. IDC/CA were identified in 160 (53%) of cases. Men harboring IDC/CA experienced inferior bRFR (HR 2.6, 95%CI 1.8-3.2, P<0.001) and mFR (HR 3.1, 95%CI 1.5-6.4, P = 0.0014). Patients with GC scores, 22 (21%) were stratified low-, 30 (29%) intermediate-, and 52 (50%) high-risk. GC low-risk was associated with superior bRFR (HR 0.25, 95%CI 0.1-0.5, P<0.001) and mFR (HR 0.15, 95%CI 0.03-0.8, P = 0.025). On multivariable analyses, IDC/CA and GC independently predicted for bRFR, corresponding to improved discrimination (C-index = 0.737 (95%CI 0.662-0.813)).Conclusions: IDC/CA subpathologies and GC predict for biochemical relapse and metastasis beyond conventional clinicopathologic indexes in the PORT setting. Patients harboring IDC/CA are at higher risk of relapse after maximal local therapies, thus warranting consideration for treatment intensification strategies. Conversely, for men with absence of IDC/CA and low GC scores, de-intensification strategies could be explored. [ABSTRACT FROM AUTHOR]