bluuebunny/crossref_metadata_2025 huggingface dataset:
Inclusion of corrected calcium and creatinine levels in a novel nomogram for prediction of pathologically localized prostate cancer.
Authors: Eminaga Okyaz , Alhamad Omran , Engelmann Udo , Wille Sebastian , Heidenreich Axel
Published: February 2017

140

Background: The role of routine parameters in the prediction of organ-confined Prostate Cancer (oPCa) remains unclear. Methods: We conducted a retrospective study of 246 patients with PCa diagnosed on biopsy, who underwent radical prostatectomy with extended lymph node dissection. None of these patients received a neoadjuvant therapy. Gleason score (xGLS), percent of positive cores involved by PCa (pCores), results of transrectal evaluation (TRUS, DRE), prostate volume (PVol), albumin-corrected Calcium (Ca), Hemoglobin (Hb), Creatinine (Crea), PSA, and age at RPE were considered. Postoperative variables including Gleason score (pGLS), TNM stages were evaluated. These patients were divided according to disease advancement into pathologically localized (pT2) and advanced PCa (pT3/4 or pN1). A L2 penalized regression model including all preoperative parameters was evaluated to design a nomogram for oPCa prediction. Furthermore, the internal validation of the nomogram was performed using bootstrapping and cross-validations. The precision and accuracy of the novel nomogram were evaluated by using AUC, F-Score, Brier-Score and the classification accuracy (CA). Results: The lowest probability for pathologically localized PCa was found in patients having the following features: PSA > 20 ng/ml, detection of PCa in all cores, high Ca [1.21 fold over upper normal limit (ULN)] and Crea levels (2.27 fold over ULN), xGls > 7 and normal PVol. A nomogram for oPCa was developed including the following parameter: Crea, Ca, PSA, xGls, PVol, TRUS, pCores. The sensitivity and the specificity of the nomogram for prediction of pathologically localized PCa were 92.2% and 35.9%, respectively. AUC of 0.811, CA of 80.1%, F-Score 0.879, a precision of 84.0%. and Brier-Score of 0.2599 were calculated. The predicted probability of the novel nomogram was associated with higher accuracy for prediction of oPCa compared to those of Partin table and Kattan nomogram. Conclusions: Serum creatinine and corrected calcium are indpendent predictors of oPCa. The novel nomogram can predict oPCa with high precision and accuracy. However, an external validation of the novel nomogram is needed.
Intermediate-risk prostate cancer treated with external beam radiotherapy (EBRT): A risk group with heterogeneous behavior.
Authors: Pérez de la Puente Constanza , Losco Federico , Chacon Carolina , Sade Juan Pablo , Giornelli Gonzalo H. , Chacon Matias , Chacon Reinaldo D.
Published: February 2017

145

Background: In men with intermediate-risk prostate cancer (IR-PC) treated with low dose EBRT, the addition of androgen deprivation therapy (ADT) prolongs overall survival. Zumsteg proposes a subdivision for de IR-PC group: favorable or unfavorable. Purpose: retrospective evaluation of EBRT efficacy according to IR-PC subgroups (favorable or unfavorable). Methods: From the institutional radiotherapy department database, from 2000 to 2011, 95 men with IR-PC were identified and subdivided as follows: Favorable Risk (FR) – Gleason 3+4 or less and positive prostate biopsies (ppb) not exceeding 50% and only one intermediate-risk factor excluding 4+3; Unfavorable risk (UR) – Gleason 4+3 or at least 2 intermediate-risk factors or at least one intermediate risk factor and ppb >50%. Results: 95 patients were included in the analysis, mean FUP 6.2 years. 32.6% (31) had >50% ppb, 14.7% (14) had Gleason 4+3, 38.9% (37) had 2 intermediate-risk factors. 42.1% (40) were FR and 57.9% (55) were UR. Median EBRT dose: 79.8Gy. Only 25% of FR patients received some hormonal therapy treatment. There were no differences in time to Prostatic Specific Androgen (PSA) nadir (FR 12 vs UR 13 months; p= .50), biochemical relapse free survival (RFS) (FR 60 vs US 58 months; p= .80), or doubling time PSA (FR 12 vs UR 11 months; p= .19). Biochemical relapse (BR) and local relapse (LR) rates were lower for FR (BR: FR 27.5 vs UR 38.2%, p= .17; LR: FR 5 vs UR 14.5%, p= .40). Local RFS (FR 13.6 vs UR 9.6 years; p= .11) and distant RFS (FR 13.1 vs UR 12.4 years; p= .65) were longer for FR patients. Conclusions: Short course ADT is the standard treatment in IR-PC patients when EBRT is indicated, especially if they have UR features. In our study IR-PC group had heterogeneous outcomes and, in spite the study limitations, FR patients had a trend for better prognosis even with a very low use of ADT. If Favorable IR-PC patients may avoid ADT morbidity should be answered by a randomized trial.
Single institution, retrospective comparison of toxicity and outcome for static 5-field IMRT versus VMAT in the delivery of prostate and pelvic nodal irradiation in high-risk prostate cancer.
Authors: Turner Philip Geoffrey , Jain Suneil , Corey Gemma , Mitchell Darren M. , Tumelty Karen , Irvine Denise , Harney Jacqueline A. , Houghton Fionnuala , McAleese Jonathan , Shum Lin , Stewart David P. , O'Sullivan Joe M.
Published: February 2017

147

Background: There is emerging evidence for the role of pelvic nodal irradiation in high-risk prostate cancer. We have assessed the toxicity rates and outcomes with 2 different radiotherapy techniques. Methods: The baseline disease metrics, toxicity and outcome data for men treated at our institution with prostate and pelvic nodal irradiation during a 2 year period were retrospectively collected. The radiotherapy technique, either 5-field IMRT or VMAT was recorded along with a single dose-level to indicate normal tissue exposure (V50 to bowel and rectum, that is the percentage of total organ receiving ≥ 50Gy). Results: 67 men with a median age of 64 years were identified; 83.6% were Gleason ≥ 8, 82.1% were ≥ T3a, 50.7% were N1, 4.5% were M1a/M1b. All had neoadjuvant and concurrent hormone therapy. All received 74Gy to prostate; 70.1% received 60Gy to pelvic nodes, 28.4% received 55Gy to pelvic nodes (1 patient received 56Gy). 55.2% were treated with static IMRT and 44.8% with VMAT with no significant difference in nodal dose received by static vs VMAT groups. Median follow up was 25 months. Analysis found V50 rectum was significantly lower in those treated with VMAT compared to static IMRT (48.5% vs 54.76% p = 0.001). Acute bowel toxicity rates (RTOG grade) were 80.6% grade < 2, 19.4% grade 2, nil > grade 2. Late bowel toxicity rates (RTOG grade) were 88% grade < 2, 12% grade 2, nil > grade 2. There was no significant difference in rates of acute or late bowel toxicity in groups treated with static IMRT vs VMAT. 13 patients (19.4%) underwent lower GI endoscopy during follow up, 9 had radiation proctitis. There was no significant difference in rates of endoscopy or proctitis for VMAT vs IMRT groups. 11.9% of patients developed biochemical failure during follow up. Rates of biochemical failure were not significantly different in groups separated by dose to pelvic nodes or radiotherapy technique. Conclusions: In a single institution, retrospective analysis, prostate and pelvic nodal irradiation is associated with acceptable rates of toxicity. Treatment with VMAT is associated with a significantly lower V50 rectum than that delivered by static IMRT.
MRI-US fusion targeted biopsy results in patients without history of prostate biopsy.
Authors: Nawaf Cayce , Rosoff James , Weinreb Jeffrey , Lu Amanda , Levi Angelique , Humphrey Peter , Schulam Peter , Sprenkle Preston
Published: February 2017

150

Background: Results from 12-core template mapping biopsy (Mbx) and concurrent MRI-US fusion targeted biopsy (Tbx) were compared in 118 men without prior biopsy. Methods: Between 12/2012 and 06/2015, 374 men with an indication for prostate biopsy presented to our institution and underwent pre-biopsy mpMRI followed by 12-core standard trans-rectal mapping biopsy (Mbx) and MRI-Ultrasound fusion targeted biopsy (Tbx) of lesions identified on mpMRI. The combination of Mbx and Tbx, when both occurred, constitutes a fusion biopsy (Fbx). Men who underwent both Mbx with or without Tbx using the Artemis/Pro-Fuse system with no previous biopsy were included. Patients without a lesion on MRI underwent Mbx only. Maximum Gleason scores (GS) was assigned on a per patient basis with Mbx GS available for all patients in the cohort and Tbx GS available only for patients with a lesion visible on MP-MRI. Clinically significant (CS) was defined as GS ≥3+4. GS per patient was compared by chi-square and McNemar’s test. Results: 118 men met inclusion criteria (mean age=64.9, mean PSA=11.5). Prostate cancer was detected in 64 (54%) Fbx cases. Cancer detection rates for Mbx and Tbx were 54% and 57%, respectively. In patients where Fbx identified CS cancer, Tbx was more likely to have identified the cancer than Mbx (96% vs 72%; p < 0.001). Fewer GS 6 cancers were detected by Tbx (n=7) than by Mbx (n=25), and Tbx alone would have prevented the detection of 21 (18%) cases of GS 6 disease. Conversely, more GS≥ 7 (50% of men) was detected on Tbx than on Mbx (33% of men). In total, there were 16 patients (13.5%) that were missed or understaged by Tbx, but only 4 of these patients (3%) were GS≥ 7. In contrast, there were 19 (16%) patients that were missed or understaged by Mbx, but 17 (14%) of these 19 patients harbored GS≥ 7 disease. Conclusions: In biopsy-naive men who are suspected to have prostate cancer, Tbx provides improved detection of CS prostate cancer compared with Mbx while decreasing the detection of low-grade disease. Tbx alone in biopsy-naive men should be considered if missing 3% of CS disease is acceptable. [Table: see text]
Diagnostic capability of multiparametric MRI in patients with transrectal prostate biopsy.
Authors: Altamirano Jaime Antonio , Pinto Ivan Federico , Vilches Roberto Mauricio , Diaz Jorge Gonzalo , Sandoval Camilo , Vidal Alvaro Daniel , Canals Mauricio , Roman Cristobal , Rojas Alejandro , Quiroz Maria Jesus , Vega Andres
Published: February 2017

155

Background: The prostatic multiparametric MRI (mpMRI) is the combination of anatomical imaging and functional sequences. Nowadays this technique is still being researched due to its positive published results. The objective of this study is to show our experience in the application of the mpMRI in patients, prior to the TRUS-guided biopsy, and the sensitivity and specificity of its measured parameters and their combination. Methods: Prospective cohort. MpMRI was indicated to patients prior to the TRUS-Guided biopsy. Diffusion, PIRADS, DCE and T2 parameters were observed on the MRIs, and the presence of cancer and Gleason score on the biopsy. Logistic regression test was performed with a 95% confidence interval. We assigned different values, depending of the importance of each factor, applying binominal regression. Results: We registered 73 patients with mpMRI prior to the TRUS-Guided Biopsy, and their results. The cancer detection rate was 60.27% (44 patients). The T2 signal had a sensibility of 81.82% and a specificity of 27.59%, ROC curve 0.54 (CI 0.44 – 0.64). The diffusion has a sensibility of 30% and a specificity of 85.19% with a ROC curve of 0.58 (CI 0.48-0.68). The DCE has a sensibility and specificity of 77.78% and 35.29% respectively, ROC curve of 0.57 (CI 0.42-0.71). By combining the T2, diffusion and DCE parameters, having 2 or more altered values, we obtained a sensibility of 84.62% with a 41.18% specificity, curve of 0.68 (CI 0.54-0.81). The sensitivity and specificity with a PIRADS score ≥ 3 was of 68.42 and 36.36% with a ROC curve of 0.56 (CI 0.36-0.76). With a PIRADS ≥ 4 the sensitivity and specificity was 57.89% and 54.55% respectively. The calculated measured score was assigned as 7 points for altered T2, 8 points for altered diffusion and 5 points for altered DCE. With a total value ≥ 12 the sensitivity of the score was 84.62% with a 41.18% sensitivity, ROC curve 0.68 (CI 0.54-0.81). Conclusions: The use of isolated mpMRI parameters have low performance, whereas this is greatly increased when used combined. The assigned weight of each parameter is a factor to consider and review on the existing scores.
Diagnostic capability of prostate multiparametric magnetic resonance in prediction of cancer and histological grade.
Authors: Altamirano Jaime Antonio , Pinto Ivan Federico , Quiroz Maria Jesus , Diaz Jorge Gonzalo , Canals Mauricio , Vilches Roberto Mauricio , Sandoval Camilo , Vidal Alvaro Daniel , Rojas Alejandro , Roman Cristobal
Published: February 2017

161

Background: The prostatic multiparametric MRI (mpMRI) can enhance the performance of the prostate core biopsy to detect cancer. The objective of this study is to assess the capability of MpMRI to identify high- and intermediate-risk prostate cancer. Methods: Prospective cohort. MpMRI was performed to patients with TRUS-guided biopsy indication prior to the biopsy. Diffusion, PIRADS, DCE and T2 parameters were observed on the MRI, and the presence of cancer and Gleason score on the biopsy. The results were divided between no cancer, and presence of cancer Gleason 6 or higher. Logistic regression test was performed with a 95% confidence interval. We assigned different values, depending on the importance of each factor, applying binominal regression. Ordinal regression was then performed and Odds ratio calculated. Results: Seventy three patients met the described criteria. Cancer detection rate was 60.27% (44 patients). Seventeen of these patients were Gleason score six. The calculated score, gave 7 points for altered T2, 8 points for altered diffusion and 5 points for altered DCE. With a score of 12 points or more, the calculated sensibility was 84,62% and the specificity was 41.18%. The estimated OR was 1.15 [IC 1-1.38]. We calculated that having one altered parameter, had a probability between 0.17 and 0.25 of having intermediate and high-risk cancer. With more than one altered parameter, the probability was 0.37. One or more altered parameters gives a probability of having Gleason 6 score of 0.20 to 0.25. Conclusions: The MpMRI is a useful tool because it has high correlation with the histological grade, and it´s an excellent test for predicting high- and intermediate-risk prostate cancer when two or more parameters are altered. Based on this findings we strongly suggest TRUS-guided biopsy with an altered MpMRI.
Sipuleucel-T (sip-T)–induced proliferative CD8+ T-cell responses to immunizing and secondary antigens.
Authors: Antonarakis Emmanuel S. , Quinn David I. , Kibel Adam S. , Petrylak Daniel Peter , Chang Nancy N. , Cummings Crystal , Chinn Jason , Pufnock Jeff , Sheikh Nadeem Anwar , Drake Charles G.
Published: February 2017

165

Background: Sip-T is an FDA-approved autologous immunotherapy for patients (pts) with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). Sip-T is manufactured from peripheral blood mononuclear cells cultured with PA2024, a fusion antigen of prostatic acid phosphatase (PAP) conjugated to granulocyte macrophage-colony stimulating factor (GM-CSF). In sip-T–treated pts, T cell and antibody responses to PA2024 or PAP as well as antibody responses to secondary antigens (i.e., antigen spread) correlate with improved overall survival. To explore the biology of this relationship, we further characterized the T cell subpopulations involved in the cellular immune responses to sip-T. Methods: In vitro proliferative CD8+ (cytotoxic T lymphocyte) and CD4+ (T helper) T cell responses to PA2024 and PAP as well as to secondary antigens (PSA, LGALS3, and KRAS) were evaluated using flow cytometry on pt samples from two sip-T–containing clinical trials (STAND [NCT01431391] and STRIDE [NCT01981122]). Results: PA2024-specific CD8+ and CD4+ responses were observed beginning 2 weeks after the first sip-T infusion through week 26 in most evaluable pts. CD8+ and CD4+ responses to PAP were also observed, although the magnitude of this response (to a self-antigen) was smaller when compared with PA2024 responses. Most pts with CD8+ responses to PA2024 also had a CD4+ response, which occurred more frequently than CD8+ responses. Both CD8+ and CD4+ responses to secondary antigens were amplified after sip-T, and these CD8+ proliferative responses to secondary antigens were greater in magnitude compared with CD4+ responses. Conclusions: Here,we report the first evidence of antigen-specific CD8+ responses in pts receiving sip-T, indicating CD8+ T cell involvement in sip-T–mediated immune responses that occur in concert with the expected CD4+ T cell responses to soluble antigens (i.e., PA2024). These CD8+ responses were durable, lasting up to 26 weeks post–sip-T treatment. Importantly, responses to secondary antigens and in particular, CD8+ responses, were also amplified after sip-T treatment, suggesting that antigen spread could be resulting from sip-T–mediated tumor cell lysis. Clinical trial information: NCT01431391 and NCT01981122.
Sensitivity analyses for progression-free survival (PFS) and radiographic PFS (rPFS) from the phase II STRIVE trial comparing enzalutamide (ENZA) with bicalutamide (BIC) in men with castration-resistant prostate cancer (CRPC).
Authors: Penson David F. , Armstrong Andrew J. , Concepcion Raoul S. , Wu Kenneth , Wang Fong , Krivoshik Andrew P. , Phung De , Higano Celestia S.
Published: February 2017

169

Background: STRIVE was arandomized, double-blind, phase 2 trial comparing ENZA vs BIC in nonmetastatic (M0) or metastatic (M1) CRPC. In this study, ENZA significantly reduced the risk of prostate cancer progression or death compared with BIC in patients with M0 or M1 CRPC. Methods: 396 men with M0 (n = 139) or M1 (n = 257) CRPC were randomized to ENZA 160 mg/day or BIC 50 mg/day. The primary endpoint of PFS was defined as the time from randomization to radiographic progression, PSA progression, or death from any cause, whichever occurred first. rPFS was defined as the time from randomization to death or the first objective evidence of radiographic disease progression in soft-tissue disease per RECIST v1.1 or in bone per PCWG2 guidelines. Sensitivity analyses were prespecified to assess the impact of alternative definitions for PFS in all patients and were performed post hoc for the key secondary endpoint of rPFS in patients with M1 disease only (table). Results: Consistent with the primary analyses of PFS and rPFS, the results from all sensitivity analyses favored ENZA over BIC (table). Conclusions: PFS and rPFS sensitivity analyses in STRIVE demonstrated a consistent and robust treatment benefit with ENZA compared with BIC by any variation of the original definition of PFS. Clinical trial information: NCT01664923. [Table: see text]
The RADICAL-PC trial.
Authors: Pinthus Jehonathan H , Klotz Laurence , Lukka Himanshu , Duivenvoorden Wilhelmina CM , Pettit Shirley , Pohl Kayla , Siemens D. Robert , Fradet Vincent , Mourtzakis Marina , Kavsac Peter , Devereaux PJ , Leong Darryl
Published: February 2017

178

Background: Cardiovascular disease (CVD) occurs frequently in men with prostate cancer (PC), but the reasons are unclear. Specifically, the role of androgen deprivation therapy (ADT) in promoting CVD remains uncertain. There is a lack of evidence to inform preventive strategies against CVD in this high risk group. It is unknown if the evidence to support CVD preventive strategies in the general population can be validly extrapolated to men with PC. Methods: RADICAL-PC combines two prospective studies, one of which is embedded in the other. The Role of Androgen Deprivation Therapy in Cardiovascular Disease – A Longitudinal Prostate Cancer Study (RADICAL PC1) is a prospective cohort study of men within one year of their first diagnosis of PC, or who are within one month of commencing ADT for the first time. Its goal is to identify factors associated with the development of CVD among men with PC, with a particular focus on ADT. The Randomized Intervention for Cardiovascular and Lifestyle Risk Factors in Prostate Cancer Patients (RADICAL PC2) is a randomized, controlled trial embedded in RADICAL PC1. RADICAL PC2 will test a systematic approach to modifying CV and lifestyle risk factors. The intervention group will receive: 1) Standardized advice on healthy diet and exercise; 2) Low-dose antiplatelet agent; 3) Low- to moderate-dose statin; and 4) ACE-I for baseline systolic blood pressure ≥ 130mmHg. Results: The study has been recently funded by Movember clinical trial program of Prostate Cancer Canada, and is launched across Canada. The primary outcome is the occurrence of the composite of cardiovascular death, myocardial infarction, stroke, heart failure, or arterial revascularization. For RADICAL-PC1, 6000 participants will have 90% power to detect a hazard ratio 0.86 for a given exposure. For RADICAL-PC2, 4116 participants randomized, with 434 primary outcome events will have 85% power to detect a hazard ratio of 0.75 in the intervention group. Conclusions: RADICAL PC will be one of the largest prospective studies of CVD – the main competing risk – in men with PC. It will clarify the determinants of CVD in these men, the role of ADT in CVD, and will simultaneously test an intervention to lower the CVD risk in this high-risk population.
Androgen-deprivation therapy plus docetaxel-based chemotherapy in metastatic hormone-sensitive prostate cancer. A meta-analysis of randomized clinical trials.
Authors: Ramos-Esquivel Allan , Baptista Joao M. , Corrales-Rodriguez Luis , GonzÃƒÂ°lez Ileana , Juarez Villegal Melissa , Zeledon Zenen , FernÃƒÂ°ndez Cristina
Published: February 2017

188

Background: Androgen-deprivation therapy (ADT) is the standard of treatment for patients with newly diagnosed metastatic prostatic cancer. Nevertheless, recent trials have suggested a role for chemotherapy in these patients. We performed a systematic review and meta-analysis to assess the efficacy and safety of docetaxel-based chemotherapy in combination with ADT for patients with hormone-sensitive metastatic prostate cancer. Methods: Randomized clinical trials (RCT) were identified after systematic searching of electronic databases (MEDLINE, OVID and The Cochrane Central Register of Controlled Trials), as well as ASCO conference proceedings from 2010 to 2015. We included only RCT comparing ADT versus the combination of ADT plus docetaxel-based chemotherapy in patients with newly diagnosed metastatic prostate cancer. A random-effect model was used to determine the pooled hazard ratio (HR) for the efficacy outcomes: overall survival (OS) and clinical progression-free survival (PFS), according to the inverse-variance method. Heterogeneity was measured using the Q and I2statistics. Results: Three RCT (n = 2 262), were included in our meta-analysis (E3805, GETUG-AFU 15 and the M1 subgroup from STAMPEDE Trial). Docetaxel-based chemotherapy plus ADT was associated with improved OS (HR: 0.74; 95% CI: 0.60-0.90; p = 0.003). The heterogeneity of these trials was moderate (Tau2: 0.02; I2: 51%; p = 0.13). Clinical PFS was also significantly better in patients receiving docetaxel-based chemotherapy (HR: 0.67; 95% CI 0.55-0.82; p = 0.0001), with moderate between-study heterogeneity detected (Tau2: 0.01; I2: 42%; p = 0.19). Different subset of patients in these trials can explain the aforementioned heterogeneity. Regarding adverse drug reactions grade 3 or higher, neutropenia was reported in a range from 36% in the GETUG-AFU 15 Trial to 12% in the STAMPEDE trial and febrile neutropenia was reported from 6.1% in the E3805 Trial to 12% in the STAMPEDE Trial. Conclusions: The addition of docetaxel-based chemotherapy to ADT improves OS and clinical PFS. New trials are needed to determine which patients benefit the most from this intervention.
Stereotactic body radiation therapy for low-, intermediate- and high-risk prostate cancer: Disease control and quality of life at 9 years.
Authors: Katz Alan J. , Kang Josephine
Published: February 2017

20

Background: Stereotactic body radiation therapy (SBRT) takes advantage of the prostate’s low α/β ratio to deliver a large radiation dose in a few fractions. This prospective study expands upon prior studies to further evaluate SBRT efficacy and QOL for a large patient population that includes low-, intermediate- and high-risk patients with prostate cancer. Methods: 515 patients with organ-confined prostate cancer (471 T1c and 44 T2a, all N0M0) received robotic SBRT. The median age was 69 years and the median PSA was 6.48 ng/ml. By NCCN criteria, 324 patients were low-risk, 139 were intermediate-risk, and 52 were high-risk. Androgen deprivation therapy was administered to 70 patients for up to one year. 158 patients with Gleason scores < 4+3 received 35 Gy delivered in 5 daily fractions. The remaining patients, from all risk groups, received a total dose of 36.25 Gy in 5 daily fractions. The proximal seminal vesicles were treated except in low-risk cases. Biochemical failure was assessed using the Phoenix criterion and QOL was assessed with EPIC scoring. Results: At a median follow-up of 84 months, 74 patients died (72 from unrelated causes). The median PSA at 78 months was 0.11 ng/ml. The actuarial 9 year freedom from biochemical failure was 95%, 89%, and 66% for the low-, intermediate- and high-risk groups (p = 0.01). For patients with Gleason scores < 4+3, there was no difference in terms of median nadir or biochemical control between doses of 35 and 36.25 Gy. Late RTOG toxicity was mild with 4% grade 2 rectal, 9.5% grade 2 urinary, and 1.9% grade 3 urinary. Late grade 2-3 urinary toxicity was 6.9% for 35 Gy vs. 13.2% for 36.25 Gy (p = 0.01). Mean EPIC urinary and bowel QOL declined at 1 month post-treatment and returned to baseline by 2 years where it remains. EPIC sexual QOL declined by 29% at 78 months. Conclusions: SBRT alone produces excellent biochemical control rates at up to 9 years with mild toxicity and minimal impact on quality of life. These long-term results appear superior to standard IMRT with lower cost and are strikingly similar to HDR therapy. These results also strongly suggest that 35 Gy is as effective as 36.25 Gy for patients with Gleason < 4+3, with less urinary toxicity.
Comorbidity and the risk of all-cause and prostate cancer–specific mortality in men with unfavorable risk prostate cancer undergoing high dose radiation therapy alone.
Authors: Huynh Mai Anh , Chen Ming-Hui , Wu Jing , Braccioforte Michelle H. , Moran Brian Joseph , D'Amico Anthony V.
Published: February 2017

207

Background: An association between shortened survival and 6 months of androgen deprivation therapy (ADT) use has been observed in men with moderate to severe comorbidity undergoing external beam radiation therapy (RT) for unfavorable-risk prostate cancer (PC). Whether these men would benefit from treatment with high dose RT alone remains unknown and was explored. Methods: Between October 1997 and May 2013, 7533 men with T1-3NxM0 PC were treated with brachytherapy with or without neoadjuvant RT at the Chicago Prostate Cancer Center. We used competing risks and Cox regression multivariable analyses to evaluate whether the risk of PC-specific and all-cause mortality (PCSM, ACM) were increased in men with unfavorable-intermediate or high risk as compared to favorable-intermediate or low risk PC undergoing brachytherapy adjusting for number of comorbidities (diabetes mellitus, myocardial infarction, congestive heart failure), age at and year of brachytherapy, use of supplemental RT, and an RT treatment propensity score. Results: Of 7533 men treated with curative intent 5737 (76.2%), 1470 (19.5%) and 326 (4.3%) had no, 1, or 2 or more comorbidities respectively. After a median follow up of 7.7 years 958 men died, 81 (8.5%) and 877 (91.5%) of PC and other causes respectively. In the no comorbidity subgroup the risk of PCSM (Adjusted hazard ratio (AHR): 2.39; [95% Confidence interval (CI): 1.32 to 4.31]; p = 0.004) and ACM (AHR: 1.25; [95% CI:1.05 to 1.50]; p= 0.013) were significantly increased in men with unfavorable-intermediate or high-risk PC as compared to favorable-intermediate or low risk PC; however, this was not the case in men with 1 or at least 2 comorbidities as shown in the table. Conclusions: Withholding ADT in men with unfavorable-intermediate or high-risk PC and at least 1 significant comorbidity did not appear to increase the risk of PCSM or shorten survival. [Table: see text]
Analysis of Surveillance, Epidemiology, and End Results Program (SEER) PSA coding error using primary data.
Authors: Schultheiss Timothy E. , Hall Matthew David , Farino Ginamarie , Wong Jeffrey Y.C.
Published: February 2017

21

Background: SEER did not report PSA values for the 2014 submission because of inaccurate coding. This inaccuracy was a result of a confusing data entry guideline where PSA is coded in a 3-digit field with an implied decimal between digits 2 and 3. Our study uses original registry data to assess the magnitude and implications of these coding errors. Methods: The National Oncology Data Alliance is a database of more than 150 Commission-on-Cancer compliant tumor registries that use proprietary cancer registry software sold by Elekta AB (Stockholm, Sweden) and contains the same data sent to state tumor registries and SEER. De-identified data from all newly diagnosed prostate cancer cases from 2005-2013 were extracted (n = 89,379). PSA data were acquired from both the Collaborative Staging (CS) Site Specific Factor 1 (SSF1) for prostate cancer and from de-identified text fields. SSF1 contained the error prone datum that was transferred to SEER. The PSA data contained in the text fields, which are used to record lab results, etc. verbatim, were taken to be definitive. PSA values from both SSF1 and text fields were complete in 63,051 patients. AJCC Stage was determined using the clinical T stage field and the SSF fields that code for Gleason score. We calculated the error rates and their directions for PSA stratification into three levels (0 to < 10, 10 to < 20, and ≥ 20) and for the AJCC stage. Results: The measured error rate in PSA values in SSF1 caused by erroneous decimal placement was 9.0%. The resulting error rate in PSA stratification was 7.5%, with the SSF1 PSA value giving a higher PSA category in 4.8% of cases and lower in 2.7%. The consequent error rate in AJCC staging was 2.8% overall, with the PSA error resulting in a higher stage group in 1.9% and lower in 0.9%. Conclusions: Many factors can contribute to the overall error rate in PSA values in SEER data, but we are addressing only the errors associated with the implied decimal. The consequences of this error are modest despite a 9% error rate. However, SSF1 for prostate cancer is not the only confusing SSF introduced by the CS system. The current cancer registry database design is derived from outdated technology and needs restructuring to be a more effective surveillance and research tool.
Sequential administration of new agents (NAs) after docetaxel (DOC) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts): Impact of disease control (DC) duration in second line on the subsequent line outcomes.
Authors: Maines Francesca , De Giorgi Ugo , Facchini Gaetano , Fratino Lucia , Gasparro Donatello , Alesini Daniele , Basso Umberto , Tucci Marcello , Ortega Cinzia , Scagliarini Sarah , Verderame Francesco , Barni Sandro , D'Angelo Alessandro , Vicario Giovanni , Donini Maddalena , Carrozza Francesco , Sava Teodoro , Sirotova Zuzana , Santini Daniele , Caffo Orazio
Published: February 2017

210

Background: Abiraterone acetate (AA), cabazitaxel (CABA), and enzalutamide (ENZ) are NAs which demonstrated their efficacy in mCRPC pts who have previously treated with DOC. Unfortunately all pts develop a resistance to these drugs and eventually show a progression of disease. Since the androgen receptor machinery remains the ultimate target of NAs in mCRPC post-DOC, some mechanisms of resistance could be common to all NAs. To date, NAs are sequentially administered in the hope of obtaining a cumulative survival benefit. To date it is unknown if the DC duration influence the outcomes of the subsequent treatments. The present study was aimed to retrospectively assess this issue in a large series of mCRPC pts. Methods: We recorded the clinical outcomes of all treatments received after DOC. For the study purpose, we categorized the pts according to the duration of DC (absence of progression) during NA-based second line: DC ≤ 3 mos (primary resistance – PRe); DC from 3.1 to 11.9 mos (intermediate sensitivity – IS); DC ≥ 12 mos (long term disease control – LTDC). Results: A consecutive series of 291 mCRPC pts, median age 71 yrs (46-91), with bone (88%), nodal (53%) or visceral (18%) mets, was collected. All pts received a NA-based as second line after DOC: 160 (55%) received AA, 99 (33%) CABA and 32 (11%) ENZ. PRe was observed in 56 pts (23 AA – 25 CABA – 8 ENZ), IS in 178 (101 AA – 58 CABA – 19 ENZ), LTDC in 57 (36 AA – 16 CABA – 5 ENZ). The third-line clinical outcomes are detailed in the table. Conclusions: From this data, it appears that DC duration may be a prognostic factor, as a probable result of pts/disease selection. In fact, pts progressing more than 12 mos from the start of NA-based second line appear to have more probabilities to live longer, compared to pts progressing earlier, when they receive another NA-based third line therapy. [Table: see text]
Impact of single agent daily prednisone on survival and toxicities in post-docetaxel men with metastatic castration-resistant prostate cancer (mCRPC): An analysis of 2 phase III trials.
Authors: Sonpavde Guru , Pond Gregory Russell , Templeton Arnoud J. , Kwon Eugene D. , De Bono Johann S.
Published: February 2017

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Background: Daily oral prednisone (P) has been employed for the therapy of mCRPC, alone or in combination regimens. Despite palliative benefits and PSA responses, the overall clinical impact of P is unknown and it may foster resistance mechanisms. We performed a pooled analysis of control arms of randomized trials which either did or did not administer single agent P to evaluate its impact on overall survival (OS) and toxicities. Methods: Individual patient data from control arms ofrandomized trials of post-docetaxel men receiving placebo or P + placebo were eligible for analysis. Patient demographics, survival, and toxicity data were collected. The impact of P on OS and toxicities was investigated in Cox regression models adjusted for known clinical and laboratory prognostic factors. Statistical significance was defined as a p-value < 0.05 and all tests were two-sided. Results: The control arms of 2 randomized phase III trials were available totaling 794 men: the COU-AA-301 trial (n = 394) administered P plus placebo and the CA184-043 trial (n = 400) administered placebo alone. P plus placebo was not significantly associated with OS compared to placebo alone in a multivariable analysis (HR = 0.89 [95% CI 0.72-1.10], p = 0.27). Other factors associated with poor OS were Eastern Cooperative Oncology group (ECOG)-performance status (PS) ≥ 1, Gleason Score ≥ 8, liver metastasis, high PSA, hypoalbuminemia, and elevated LDH.In contrast, CTCAE grade ≥ 3 therapy-related toxicities were significantly increased with P plus placebo compared to placebo alone (HR = 1.48 (1.03-2.13), p = 0.034) in a multivariable analysis. Other baseline factors significantly associated with a higher risk of grade ≥ 3 toxicities were ECOG-PS ≥ 1, hypoalbuminemia and elevated LDH. Conclusions: P plus placebo compared with placebo alone for post-docetaxel men with mCRPC was not associated with extension of OS, but was associated with higher grade ≥ 3 toxicities. With the exception of the use of P in combination with abiraterone, P alone or in combination regimens should be questioned given its unclear palliative benefits and association with increased toxicities.
Trends in utilization of novel oral therapeutic agents for men with metastatic castrate-resistant prostate cancer within the United States Veteran’s Affairs Health System.
Authors: Henry Elizabeth , Silva Abigail , Tarlov Elizabeth , Gaynor Ellen R.
Published: February 2017

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Background: Therapeutic options for men with metastatic castrate resistant prostate cancer (mCRPC) have expanded significantly over the past 5 years with several new agents demonstrating improved survival, including two oral agents. Abiraterone acetate (AA), a CYP-17 androgen synthesis inhibitor, obtained initial FDA approval in 2011 for post-docetaxel (D) use, and gained expanded approval in 2012 for pre-D use. Enzalutamide (ENZ), an androgen receptor signaling inhibitor, also gained FDA approval in 2012 (post-D) and indication was expanded in 2014 (pre-D). Due to the relatively recent approvals of these agents, there is limited data on rates of uptake and prescribing patterns for patients (pts) with mCRPC. Methods: For this observational study, Veterans Affairs (VA) healthcare system data (including hospitalizations, outpatient visits, and pharmacy) were used to identify male veterans who received treatment for mCRPC between fiscal years 2008 and 2014. Descriptive statistics were used to classify treatment patterns. Results: During the time period, 75,199 pts with prostate cancer were medically or surgically castrated. Of those, 43,805 were treated with anti-androgens and 7,890 went on to receive advanced lines of therapy associated with mCRPC. The median age at the time of mCRPC treatment was 73y. Between 2008-2010 (pre-AA) and 2011-2014 (post-AA), the proportion of mCRPC pts treated with ketoconazole or D dropped from 95% to 59% (p < 0.0001). Conversely, the proportion of pts who received AA or ENZ increased from 19% to 68% (p < 0.0001). Among the 3,763 pts treated with AA or ENZ between 2011 and 2014, the proportion treated with first-line D decreased, while the proportion treated with first-line AA increased (p < 0.00001). Conclusions: The FDA approval of AA and ENZ has had a significant impact on treatment patterns for men with mCRPC within VA, with decreased use of ketoconazole and delayed use of chemotherapy. Further information regarding patient and disease characteristics is needed. The rapid uptake of these novel agents has significant implications for disease-related outcomes as well as anticipated pharmacy costs within the VA.
The expression profiles of miRNAs in the progression of prostate cancer from high-grade prostatic intraepithelial neoplasia to metastatic diseases.
Authors: Eminaga Okyaz , Fries Jochen , Woetzel Fabian , Neiss Susanne , Warnecke-Eberz Ute , Heitmann Michaela , Heidenreich Axel
Published: February 2017

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Background: The epigenetic regulation by miRNA plays an important role in tumor progression of prostate cancer (PCa). Methods: The expression data of 1054 miRNAs from TCGA were applied to identify relevant miRNAs associated with tumor progression (i.e. miR-210, miR-375, miR-378, miR-345, miR-143 miR-183 and miR-98). miRNA were isolated by miRNeasy FFPE kit (Qiagen, Hilden, Germany) from paraffin-embedded tissues of prostate specimens with PCa, HGPIN and normal tissues. Early-stage PCa was defined as PCa with pT2 tumor stage, Gleason score < = 7a (3+4) and PSA level < 10 ng/ml. PCa with pT3/4 or Gleason > 7a was defined as advanced PCa. PCa with pN1 were considered as metastatic diseases. Additionally, 3 cases with castration-resistant prostate cancer (CRPC) were considered. Quantitative miRNA expression data were acquired and analyzed using a real-time TaqMan-based PCR. ANOVA analyses were performed to evaluate the expression of miRNAs between HGPIN, Normal and PCa tissues. The small nuclear U6 RNA was used as an endogenous control Results: ANOVA analysis revealed a significant variation in expression of all miRNAs among groups. The expression level of miR-183 and miR-375 increased with the tumor progression. miR-143, miR-375-3p were inversely correlated with the tumor progression. miR-210 and miR-183 were significantly overexpressed in metastatic diseases compared to non-metastatic diseases (FDR < 0.01), whereas the expression level of miR-378-3p was lower in metastatic diseases than in organ-confined PCa. The expression of miR-98 was lower in PCa compared to normal tissues. In silico analysis, the down-regulation of miR-98 and miR-345-5p seems to activate the HIF-1 signaling pathway initiating the up-regulation of miR-210 that interact with genes related to cell cycle, RNA transcription, homologous recombination and non-homologous end-joining. Conclusions: Our data reveal epigenetic regulations of miRNA, which are associated with transition from normal tissues to HGIPN, from HGPIN to early-stage PCa, and early-stage PCa to advanced PCa. Advanced PCa represents the first stage of metastatic diseases.
Correlation of a novel whole blood RT-PCR assay measuring AR-V7 expression with outcomes in metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone acetate (ABI).
Authors: Todenhöfer Tilman , Azad Arun , Stewart Craig , Gao Jian , Eigl Bernhard J. , Black Peter C. , Joshua Anthony M. , Chi Kim N.
Published: February 2017

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Background: Expression of androgen receptor splice variant 7 (AR-V7) in circulating tumor cells (CTCs) has been associated with resistance to ABI and enzalutamide (ENZ) (Antonarakis et al. N Engl J Med 2014). We have developed a RT-PCR assay that is neither time sensitive nor requires CTC enrichment for detection of prostate cancer (PCa)-associated transcripts in whole blood. Using this assay, our aim was to correlate AR-V7 expression with outcomes on ABI. Methods: 2.5 ml whole blood was collected into PAXgene RNA tubes from mCRPC patients (pts) commencing ABI. RT-PCR was performed for the following genes: AR-V7, FOXA1, GRHL2, HOXB13, KLK2, KLK3 and TMPRSS2:ERG. For each gene, the highest CT value among 20 normal controls was set as the threshold for a positive (+) test. Clinical endpoints were PSA50 response rate (RR) (PSA decline ≥ 50% confirmed ≥ 3 weeks later), PSA30 RR, time to PSA (PCWG2 criteria) or clinical progression (change in anti-cancer therapy or decline in ECOG performance status (PS) ≥ 2 levels due to PCa), and overall survival (OS). Results: Whole blood samples were obtained from 37 pts. Median age was 70. 59% received prior docetaxel. All pts were ABI and ENZ naïve. PSA50 RR was 37% and PSA30 RR was 48%. Median progression-free survival (PFS) was 3.8 months (mos) and median OS was 21.0 mos. 11% (4/37) of pts were AR-V7+. AR-V7+ pts were more likely to have high ALP (P= 0.04; Χ2), high LDH (P= 0.07) and ECOG PS ≥ 2 (P= 0.052). Pts with an AR-V7+ test had lower PSA50 RR (0% vs. 42%, P= 0.10; Χ2) and PSA30 RR (0% vs. 52%, P= 0.051) together with shorter median PFS (0.7 mos vs. 4.0 mos, P< 0.001; log-rank) and median OS (5.5 mos vs. 22.1 mos, P< 0.001). Other factors linked with worse OS were high ALP (P= 0.02), liver metastases (P= 0.03), ≤ 36 mos on primary hormone therapy (P= 0.04), HOXB13+ (P= 0.03) and KLK2+ (P< 0.001). Conclusions: RT-PCR detection of AR-V7 transcripts in whole blood was associated with a 0% PSA RR and significantly inferior PFS and OS in pts treated with ABI. These results reinforce the potential utility of AR-V7 as a prognostic and predictive biomarker for mCRPC. Validation of the assay in larger datasets is ongoing.
Race, inflammation, and prostate cancer: A comparison of African Americans and Caucasians.
Authors: Ernst Emma M. , Ledet Elisa M. , Feibus Allison H. , Silberstein Jonathan L. , Sartor Oliver
Published: February 2017

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Background: African-Americans (AA) have the highest rate of prostate cancer (PCa) incidence and mortality. Studies have shown higher rates of chronic prostate inflammation in AAs compared to Caucasians (CA). In order to better understand racial disparity in PCa and chronic inflammation (CI), this study examined the effects of race and CI on clinical parameters among PCa patients. Methods: This retrospective study sample consisted of 61 AA and 52 CA PCa patients who underwent radical prostatectomies (RP) at Tulane Hospital between 2013 and 2015. Clinical data was extracted from biopsy and RP pathology reports. The study examined the relationship between CI, race, percent of positive cores, extra-prostatic extension, PSA, PSA density, urinary PCA3 and TMPRSS2, and prostate size (g). Pearson’s chi-square, Fisher’s exact, and Kruskal-Wallis tests were used to analyze categorical, non-continuous data; ANOVA tests were used to analyze continuous data. Differences between biopsy and surgical/pathologic Gleason scores and clinical/pathological stages were also assessed. Results: 94 patients (52 AAs and 42 CAs) had CI to some degree and 19 did not (9 AAs and 10 CAs). There was no difference in rate of CI between AA and CA patients (P = 0.526). Among all patients sampled, AAs had higher percentages of positive cores (P = 0.005), PCA3 copy levels (P =0.004), and PCA3 scores (P <0.001), lower TMPRSS2 scores (P =0.039), and were more likely to have “high” or “intermediate” NCCN risk strata (P =0.010). Among patients with CI, AAs were more likely than CAs to have extra-prostatic extension (P =0.026) and less likely to have undergone a prior prostate biopsy (P =0.043). Patients without CI were more likely than patients with CI to have positive tumor margins (P =0.035) and SV invasion (P =0.013). There were no significant relationships between race and CI, and changes in either total Gleason score or stage from biopsy to RP. Conclusions: This study showed that AAs and patients without CI had more advanced forms of PCa (possibly due to PSA detection biases). Findings did not reveal any significant link between race and CI. Larger studies are needed to confirm these results and better understand the relationship between race, CI, and PCa.
Patient stem cell (SC)-derived prostate cancer (PC) organoids (Org) to recreate clonal heterogeneity of PC foci and measure therapeutic response potential.
Authors: Ferrari Anna C. , DiPaola Robert S. , Bertino Joseph R. , Kim Isaac Yi , Stein Mark N. , Sabaawy Hatem E. , Bartucci Monica
Published: February 2017

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Background: In spite of significant outcome gains in recurrent and de novo metastatic PC, resistance inevitably develops to androgen deprivation (ADT) and chemotherapy. Resistance is supported by clonal heterogeneity due to complex genomic and epigenetic alterations within PC foci in the primary and metastases (mets) and by the enrichment of residual tumor foci with PC SCs that survive therapy. PCSCs maintain self-renewal capacity, adapt over time to different microenvironments and retain tumor propagating activity leading to castration resistant (CR) PC progression. To study these processes, we generated patient SC-derived PC Org from primary and mets specimens. Methods: We isolated cells from normal epithelium and PC foci of 4 histopathologically mapped radical prostatectomy specimens and 2 CRPC mets. We developed a 3D culture system utilizing single tumor initiating cells expressing CD29hi/CD49bhi/CD44hiand co-cultured with epithelial/mesenchymal growth factors. Org growth peaked at 2 weeks, and Org could be passaged up to 6 months without significant deviation from early passages. We evaluated Org morphology, molecular markers and biologic response (proliferation, viability and secondary Org-forming potential) in response to ADT, docetaxel (Doc), abiraterone (Abi), enzalutamide (E), BEZ325,and a BMI-1 inhibitor. Results: The Org, ~6 per region, mirror original foci in morphology (well-organized glandular structure with central E-Cad+ cells of variable nuclear-cytoplasmic ratios, AR and PSA expression, peripheral Vimentin+cells, surrounding basement membrane) and in molecular alterations (TMRSS2-Ets fusions/Erg-overexpression, PTEN loss, RB, CHD1, BMI-1, AR-Vs). ADT decreased growth and Org forming potential. ADT plus Doc, Abi or E further reduced viability and Org-forming potential; ADT plus BEZ325 only reduced viability. The BMI-1 inhibitor selectively blocked self-renewal and restored Doc growth inhibition of a Doc-resistant CRPC-derived Org. Conclusions: We established a personalized SC-derived PC Org system to study in real time the potential efficacy of therapeutic alternatives, as well as mechanisms of resistance.