bluuebunny/crossref_metadata_2025 huggingface dataset:
Prostate-specific membrane antigen (PSMA) PET-CT imaging in the investigation and management of biochemical recurrence in prostate cancer.
Authors: Keane Fergus , Ged Yasser , Greally Megan , Maher Michael A. , O'Malley Kieran , McCaffrey John
Published: February 2018

208

Background: It is estimated that within ten years of primary treatment for prostate cancer up to 40% of patients post radical prostatectomy, and up to 50% of patients post radiotherapy will develop disease recurrence. While monitoring of PSA levels is informative of biochemical recurrence, it may precede radiologically detectable recurrence by months to years, and cannot differentiate local/regional recurrence from systemic disease. This represents a management dilemma for treating physicians. The incorporation of PET probes targeting prostate-specific membrane antigen (PSMA) for prostate cancer shows promise for improving the management of patients with prostate cancer, when used alongside existing imaging techniques, like CT, MRI and bone scans. Methods: Retrospective review of all patients referred from our institution for PSMA imaging was carried out. Baseline clinical features were determined and we analyzed impact of PSMA imaging on management outcomes and survival data. Results: 33 patients referred for 68Ga-PSMA-PET imaging were identified. Median age at diagnosis was 65 years (51 -75). The indication for referral in all patients was biochemical recurrence in the absence of radiological evidence of disease by CT imaging and bone scan. Median PSA at time of referral for PSMA scan was 7.3ug/L (1.4ug/L to 87.7ug/L). 100% of patients (n = 33) were upstaged following PSMA imaging, and 30% (n = 10) had more than one site of metastatic disease identified. Most common sites of metastasis were lymph node and bone. Median number of sites of metastatic disease identified by PSMA imaging was one. These results led to a change in management for 96% patients (n = 32). All patients at the time of this review are alive with a median follow up of 13 months, and median progression-free survival of 11 months. Conclusions: PSMA PET-CT directly led to an alteration in the treatment of the majority of patients in this study. This real world data reflects the growing role of PSMA imaging in influencing clinical decisions for prostate cancer patients with biochemical recurrence. Prospective data from randomized studies are awaited to further validate the role of PSMA PET-CT in this patient cohort.
68-Ga-PSMA-PET in lymph node staging in PSA recurrent prostate cancer-does the primary influence the result?
Authors: Pfister David , Kohl Tobias , Porres-Knoblauch Daniel , Haidl Friederike , Heidenreich Axel
Published: February 2018

210

Background: Prostate cancer is the most common cancer in western countries. 68Ga PSMA-PET is the most accurate tool to detect lymph node metastases even at low PSA values. Salvage lymph node dissection prolongs biochemical recurrent free survival, whereas salvage radical prostatectomy has the potential to achieve long term tumor control at least in node negative disease. We compared the diagnostic value of 68Ga-PSMA PET in patients with biochemical recurrence after radical prostatectomy an salvage radiotherapy (Group1) and in patients with local recurrence after radiotherapy (Group2) to evaluate the influence of the primary. Methods: We retrospectively reviewed 57 and 31 patients in Group I and II respectively. In Group I a salvage lymph node dissection was performed on the side of the positive PSMA-staining. In Group II an extended pelvic lymph node dissection was performed in addiction to a salvage radical prostatectomy. Sensitivity, Specificity, posisive and negative predictive value as well as accuracy of PSMA-PET was calculated per lesion. Results: A total of 649 (2-32) and 515 (3-29) lymph nodes had been dissected. In 39 (68%) and 11(35,5%) at least one positive lymph node could be found. Mean diameter of the metastases was 0,81 (0,1-2,6)cm and 0,8(0,1-2) cm respectively. Sensitivity, Specificity, pos and neg. predicitve value as well as accuracy in Group I and two are 85, 96, 77, 98, 94,6 and 40, 100, 100, 98, 97,6%. Conclusions: In salvage surgeries in PCA good diagnostic tools to identify lymph node metastases are mandatory. With the primary in situ there is a significant reduced sensitivity of only 40% to identify positive nodes. The specific role of the primary tumor is not yet known.
Value of bone scan index for predicting overall survival among patients treated with radium-223 for bone metastatic castration-resistant prostate cancer.
Authors: Yoneyama Shuko , Miyoshi Yasuhide , Tsutsumi Sohgo , Kawahara Takashi , Hattori Yusuke , Yokomizo Yumiko , Hayashi Narihiko , Yao Masahiro , Uemura Hiroji
Published: February 2018

216

Background: The objective of this study was to evaluate the bone scan index (BSI) as a prognostic biomarker for overall survival (OS) among patients treated with radium-223 (Ra-223) for bone metastatic castration-resistant prostate cancer (mCRPC). Methods: We retrospectively identified 42 men who had been treated with Ra-223 for bone metastatic CRPC between 2012 and 2017 and investigated correlations between the baseline clinical factors of age, time to CRPC, previous use of docetaxel, PSA, Gleason score, alkaline phosphatase (ALP), and BSI and OS by multivariate analysis using the Cox proportional hazard model. We also analyzed the correlations between OS and absolute BSI value or BSI change from baseline after 12 weeks of treatment. Continuous variables were classified as dichotomous. Results: The median age, PSA, and time to CRPC were 75.5 years, 42.8 ng/mL, and 11.2 months, respectively. The median observation period was 11.7 months. Twenty-five (59.5 %) of the 42 patients had completed six cycles of Ra-223 treatment. Twenty-two patients (52.4 %) had died, including 20 (47.6 %) of cancer, by the time of analysis. The median OS in the entire cohort was 20.7 months. Multivariate analysis also showed that only BSI (≥1.5 vs. < 1.5, HR 3.72, 95% CI 1.17–11.79, p = 0.026) was significantly correlated with OS. The BSI had decreased in 16 (51.6%) of the 31 patients who had undergone bone scans after 12 weeks of treatment . Multivariate analysis showed that absolute BSI value after 12 weeks treatment was significantly correlated with OS (BSI (≥2.0 vs. < 2.0%, HR 13.07, 95% CI 2.61–65.53, p = 0.002). No correlation was found between BSI change from baseline after 12 weeks and OS. Conclusions: According to multivariate analysis, both baseline BSI and PSA were significant prognostic factors for OS among men treated with Ra-223. Absolute BSI value after 12 weeks of Ra-223 treatment was also found to be an independent prognostic factor for OS.
Neuropsychiatric adverse events of enzalutamide and abiraterone acetate: Meta-analysis of randomized clinical trials with real world reporting patterns from EudraVigilance.
Authors: Moreno Perez Maria Paola , Sanchez Iznaola Miguel , Garcia Angela , Muñoz del Toro Jacobo , Casariego Joaquin , Robinson Paul , Parra Rafael
Published: February 2018

217

Background: Androgen deprivation is associated with cognitive decline and mood changes. Abiraterone acetate plus prednisone (AAP) and enzalutamide (ENZ) are oral hormonal agents for the treatment of metastatic castration resistant prostate cancer (mCPRC); both target the androgen signaling pathway. Meta-analysis for individual neuropsychiatric adverse effects (NAEs) associated with these drugs has not been available in the literature. Methods: Following the methodology presented by Ruiz et al. a further meta-analysis was performed to estimate the pooled Relative Risk (RR) of NAEs for AAP and ENZ. A complementary analysis of the EudraVigilance database was performed to explore the consistency of the real world adverse drug reactions (ADR) reporting pattern with the meta-analysis. Results: The meta-analysis results indicate that patients treated with ENZ had a statistically significant higher risk of restless leg syndrome (RLS), anxiety, headache and insomnia vs control. Both AAP and ENZ showed significant increased risk for falls vs control. The Proportional Reporting Ratio (PRR) of ADRs reported in Eudra is higher with ENZ than with AAP for all the variables analyzed. Conclusions: NAEs studied are more prevalent with ENZ vs placebo than AAP vs prednisone plus placebo. Reporting trend in Eudra is consistent with this results. [Table: see text]
Multiparametric MRI-based intraprostatic tumor volume delineation in localized prostate cancer.
Authors: Lee Joon Kyu , Liu Chang , Elshaikh Mohamed A. , Wen Ning
Published: February 2018

22

Background: Multiparametric MR imaging (mpMRI) has shown promising results in the diagnosis and localization of prostate cancer. Furthermore, mpMRI may play an important role in identifying a suitable target volume for intraprostatic radiotherapy boost. We sought to investigate the level of correlation between dominant tumor foci contoured on various mpMRI sequences. Methods: mpMRI data from 18 patients with MR-guided biopsy-proven prostate cancer were obtained from the SPIE-AAPM-NCI Prostate MR Classification Challenge. Each case consisted of T2-weighted, apparent diffusion coefficient (ADC), and ktrans images computed from dynamic contrast-enhanced sequences. All image sets were rigidly co-registered, and the dominant tumor foci were identified and contoured for each MRI sequence. Hausdorff distance (HD), mean distance to agreement (MDA), and Dice and Jaccard coefficients were calculated between the contours for each pair of MRI sequences (i.e., T2 vs. ADC, T2 vs. ktrans, and ADC vs. ktrans). The Pearson correlation coefficient (PCC) was also obtained for Dice and Jaccard between these image pairs. Results: The dominant tumor foci were located in the peripheral zone, transition zone, and anterior fibromuscular stroma in 5 (28%), 7 (39%), and 6 (33%) patients, respectively. Mean tumor volumes in the T2-weighted, ADC, and ktrans sequences were 2.71 +/- 2.74 mL, 2.71 +/- 2.67 mL, and 2.21 +/- 1.86 mL, respectively. Mean HD and MDA were lowest (4.34 +/- 1.52 mm and 1.00 +/- 0.52 mm) and Dice and Jaccard coefficients highest (0.74 +/- 0.12 and 0.60 +/- 0.15) for T2 vs. ADC. The PCC for Dice was 0.15 between T2 vs. ADC and T2 vs. ktrans, 0.37 between T2 vs. ADC and ADC vs. ktrans, and 0.62 between T2 vs. ktrans and ADC vs. ktrans, and similar values were obtained for Jaccard (0.12, 0.32, and 0.67, respectively). Four patients were excluded in the PCC calculation as no vascular permeability was visible in the ktrans maps. Conclusions: This analysis suggests that T2-weighted and ADC sequences have high correlation in identifying a suitable intraprostatic radiotherapy boost volume for localized prostate cancer. Furthermore, ktrans maps may provide additional information for tumor volume delineation.
Correlation of primary biopsy mutational landscape to pre-docetaxel LDH for prediction of docetaxel therapeutic response.
Authors: Hiew Kenneth , Hart Claire Alexandre , Ali Adnan , Lau Maurice , Ramani Vijay A.C. , Sangar Vijay , Maddineni Satish , Elliott Tony , Clarke Noel , Brown Mick D.
Published: February 2018

220

Background: There is a lack of biomarkers to predict docetaxel response. Here we assess the potential of pre-treatment LDH, associated to the mutational background of the primary biopsy taken prior to 1st line therapy with ADT, to predict docetaxel response in the castrate resistant setting. Methods: Clinical and associated primary biopsy targeted next-generation sequencing data from matched training (n = 150) and test (n = 120) sets of retrospective progressive mCRPC patients (diagnosed 1996-2006) treated with docetaxel therapy were analyzed. LDH thresholds were determined and validated on the training and test sets respectively. Clinico-pathological associations with LDH were assessed using student t-test, Wilcoxon test and Chi-square test and predictive value of LDH determined by linear regression analysis for PSA and radiologic response. Time to event outcomes (PFS & OS) was evaluated by Kaplan-Meier. Meta-analysis of LDH association with DNA repair genes in the MSKCC and SU2C/PCF was conducted using cBioPortal Results: Using pre-docetaxel serum LDH of ≥450U/L as a prognostic threshold (AUC:0.75 (SD 0.054, 95% CI, 0.650–0.864, P < 0.001)) patients with LDH ≥450U/L were poorer PSA responders, with shorter PFS (213 vs 372 days, HR 1.876 (95% CI, 1.289-2.730)) and OS (362 vs 563 days, HR 1.630 (95% CI, 1.127-2.357)). LDH was also an independent surrogate marker for prediction of poor radiologic response and survival following docetaxel chemotherapy (P = 0.043). Genomic analysis showed that patients with LDH ≥450U/L (9/14 (64.3%)) have a higher tumour mutational burden (TMB) at the point of primary pre-ADT biopsy (mean, 46.2 vs 6.2 mutations/MB; p = 0.129) and that they were more likely to have DNA repair gene mutation(s) (BRCA1/2, ATM, CHEK2 and Fanconi’s anemia gene). Meta-analysis of the large MSKCC and the SU2C-PCF patient genomic databases confirmed the positive correlation between the LDH gene LDHA and PARP1 gene (r = 0.667, p < 0.01) expression and expression of other DNA repair genes. Conclusions: High pre-treatment serum LDH coupled with mutations in the DNA repair pathway in primary pre-ADT biopsy correlates with poor docetaxel response and overall survival in the castrate resistant state.
The importance of non-regional lymph nodes in assigning risk in primary metastatic prostate cancer.
Authors: Clarke Noel , Ali Adnan , Mistry Hitesh , Hoyle Alex
Published: February 2018

227

Background: Patients diagnosed with non-regional lymph nodes (NRLN) in isolation exhibit a more prolonged clinical course than those with bone or visceral metastases in trial data, but evaluation of survival data in general populations is sparse and their presence doesn’t feature in risk estimations based on tumour volume. Methods: The evaluation and prognostic relevance of NRLN metastasis presenting synchronously with osseous or non-ossesous metastasis in hormone-naive prostate cancer was evaluated using the Surveillance, Epidemiology and End-results (SEER) database. Patients with stage M1a-c PCa diagnosed between 2004 and 2009 were identified and included within the analysis. Kaplan Meier was used to estimate overall (OS) and cancer specific survival (CSS) rates in relation to metastatic distribution. Multivariate cox-regression models were used to identify predictors of OS and CSS. Results: Of 4869 metastatic PCa patients identified, osseous metastasis was the most common finding (65.1%); followed by non-osseous (17.5%), osseous + NRLN (7.8%), NRLN (4.9%), non-osseous + osseous (±NRLN) (2.9%) and non-osseous + NRLN (1.8%). Median follow-up was 93 mo. Median OS and CSS were 28 and 34 mo respectively. Patients with osseous + NRLN metastasis had a significantly worse median OS (30 mo vs 25 mo, p = 0.001) and CSS (37 mo vs 29 mo, p < 0.001) compared to osseous only metastasis. On multivariate cox regression, osseous + NRLN metastasis was an independent predictor of OS and CSS when compared to osseous only metastasis (both p-values < 0.01). Conclusions: NRLN metastasis in the presence of osseous metastasis represents a poor prognostic feature when compared to osseous metastasis alone. The current therapeutic stratification of “low vs high volume” disease does not account for this phenomenon and patients requiring aggressive therapy may not receive maximal therapeutic benefit as a consequence.
Comparison of enzalutamide and bicalutamide in patients with non-metastatic castration-resistant prostate cancer: Number needed to treat to achieve one additional patient free of clinical progression events.
Authors: Karsh Lawrence Ivan , Penson David F. , Concepcion Raoul , Flanders Scott , Brown Bruce A. , Yang Hongbo , Ramaswamy Krishnan , Schultz Neil M.
Published: February 2018

228

Background: Androgen receptor inhibitors enzalutamide (ENZA) and bicalutamide (BIC) are used to treat metastatic castration-resistant prostate cancer (mCRPC). The Phase 2 STRIVE trial included 35% non-metastatic (m0) and 65% metastatic CRPC patients (pts); ENZA reduced the risk of progression or death among pts, with an adverse event profile consistent with previous trials. The objective of this analysis was to compare ENZA with BIC using the number needed to treat (NNT) to achieve one additional pt with m0CRPC, with either a progression-free survival (PFS) event, radiographic PFS (rPFS), or free of prostate-specific antigen (PSA) progression at 1 year and 2 years. Methods: The 1- and 2-year event rates of PFS, rPFS, and progression-free PSA among pts treated with ENZA and BIC were obtained from the STRIVE trial report. The NNT was calculated as the reciprocal of the absolute risk reduction between ENZA and BIC at each time point. This represents the number of pts that need to be treated with ENZA, compared with BIC, to obtain one additional pt free of a clinical progression event. PFS was defined as the time from randomization to investigator-assessed radiographic (bone or soft tissue) progression, PSA progression, or death. The 95% confidence interval (CI) of the NNT was derived based on the 95% CI of the event rate difference. Results: The NNT to achieve one additional pt with PFS at 1 year, comparing ENZA with BIC, was 2.2 (95% CI 1.7, 3.4), suggesting that treating three pts with ENZA instead of BIC would result in one additional pt free of progression or death at the end of 1 year. The NNT to achieve one additional pt with PFS at 2 years was also 2.2 (95% CI 1.5, 3.7). For rPFS, the NNTs comparing ENZA with BIC were 4.7 (95% CI 2.8, 14.6) and 3.0 (95% CI 2.0, 6.1) at 1 and 2 years, respectively. For progression-free PSA, the NNTs were 2.0 (95% CI 1.5, 2.8) and 2.0 (95% CI 1.4, 3.3) at 1 and 2 years, respectively. Conclusions: This analysis supports the superior clinical benefit of ENZA versus BIC in men with m0CRPC. Pts treated with ENZA showed low NNT values across all clinical outcomes and time points. Clinical trial information: NCT01664923.
Treatment duration and utilization patterns in metastatic castration-resistant prostate cancer patients receiving enzalutamide or abiraterone acetate.
Authors: Kassabian Vahan , Flanders Scott , Wilson Samuel , Brown Bruce A. , Song Yan , Yang Hongbo , Lechpammer Stanislav , Schultz Neil M.
Published: February 2018

229

Background: Enzalutamide (ENZA) and abiraterone acetate (ABI) are approved hormonal therapies for men with metastatic castration-resistant prostate cancer (mCRPC). This study assessed real-world treatment duration and utilization patterns in patients receiving ENZA or ABI. Methods: Adult mCRPC patients initiating ENZA or ABI before or after cytotoxic chemotherapy were identified from the Truven MarketScan® claims database (2012–2015). The index date was the first initiation of ENZA or ABI; continuous insurance enrollment for ≥6 months prior to and ≥3 months after the index date was required. Treatment discontinuation was defined as a prescription gap of ≥45 days. Median treatment duration was estimated using Kaplan–Meier method. Treatment switching was defined as starting a new mCRPC-related therapy within 30 days before to 45 days after the discontinuation date. Analyses were separately conducted for chemo-naïve and chemo-experienced patients. Results: The study included 3230 chemo-naive (ENZA 920; ABI 2310) and 692 chemo-experienced patients (ENZA 262; ABI 430). Among chemo-naive patients, ENZA cohort was older (mean age 74.5 vs 73.5; p = 0.013), with a higher proportion of comorbidities vs ABI cohort. Treatment duration was longer for ENZA cohort than ABI cohort (log-rank p = 0.008; median = ENZA 10.7 vs ABI 8.8 months). Within 1 year of initiation, 55.7% of ENZA and 60.8% of ABI cohort discontinued treatment and 22.5% and 34.7%, respectively, switched to other mCRPC therapies. Results were consistent among subgroups with specific comorbidities. Treatment duration was shorter among chemo-experienced patients than chemo-naïve; the difference between ENZA vs ABI among chemo-experienced patients was not statistically significant (log-rank p = 0.255; median = ENZA 7.5 vs ABI 7.1 months). Conclusions: Despite a more complex profile at baseline, chemo-naive mCRPC patients in the ENZA cohort had a longer treatment duration and lower proportion of switching to other prostate-cancer-directed therapies vs the ABI cohort. The difference of treatment duration between the two cohorts was not statistically significant for chemo-experienced patients.
Androgen deprivation therapy and overall survival for Gleason 8 versus Gleason 9-10 prostate cancer.
Authors: Yang David Dewei , Mahal Brandon Arvin Virgil , Muralidhar Vinayak , Martin Neil E. , Orio Peter F. , Mouw Kent William , King Martin T. , Choueiri Toni K. , Trinh Quoc-Dien , Hoffman Karen E. , Spratt Daniel Eidelberg , Feng Felix Y , Nguyen Paul L.
Published: February 2018

23

Background: While the addition of androgen deprivation therapy (ADT) to external beam radiotherapy is known to improve overall survival in Gleason 8-10 prostate cancer, it has been hypothesized that Gleason 9-10 disease, which is less differentiated than Gleason 8 disease, may be less sensitive to ADT. To investigate this idea, we examined the association between ADT and overall survival for Gleason 8 versus Gleason 9-10 prostate cancer. Methods: We identified 20,139 men in the National Cancer Database diagnosed with localized or locally advanced, Gleason 8-10 prostate cancer from 2004 through 2011 who received external beam radiotherapy. Patients with clinical evidence of nodal or metastatic disease were excluded. Cox proportional hazards regression was used to examine the association between ADT and overall survival. Results: Median follow-up was 4.0 years. 78.2% (9,509) of the 12,160 men with Gleason 8 disease and 86.6% (6,908) of the 7,979 men with Gleason 9-10 disease received ADT. On multivariable analysis, ADT was associated with a significant improvement in overall survival for Gleason 8 patients (adjusted hazard ratio 0.79, 95% confidence interval 0.71-0.88, P< 0.001) but not Gleason 9-10 patients (adjusted hazard ratio 0.96, 95% confidence interval 0.83-1.10, P= 0.532), with a significant interaction ( Pinteraction= 0.020). When considering Gleason 9-10 patients separately as Gleason 9 and Gleason 10, a higher Gleason score correlated with an increased adjusted hazard ratio for the association between ADT and overall survival ( Pinteraction= 0.012). Conclusions: In contrast to the significant survival advantage of ADT for Gleason 8 disease, our results strongly suggest that Gleason 9-10 disease may be less sensitive to ADT and that a higher Gleason score predicts lesser sensitivity. Consideration should be given to treatment intensification for Gleason 9-10 patients through enrollment in clinical trials or potentially adding novel antiandrogens or docetaxel, which have shown efficacy in both castration-resistant and castration-sensitive settings.
Health care resource utilization and costs in metastatic castration-resistant prostate cancer patients treated with enzalutamide or abiraterone acetate.
Authors: Kassabian Vahan , Flanders Scott , Wilson Samuel , Brown Bruce A. , Song Yan , Yang Hongbo , Lechpammer Stanislav , Schultz Neil M.
Published: February 2018

232

Background: Cost of care is an important component of valuation of novel treatments in oncology. Enzalutamide (ENZA) and abiraterone acetate (ABI) are approved hormonal agents for the treatment of metastatic castration-resistant prostate cancer (mCRPC). This study compared healthcare resource utilization (HRU) and costs for patients treated with ENZA or ABI in the U.S. Methods: Adult mCRPC patients initiating ENZA or ABI before and or after cytotoxic chemotherapy were identified from the Truven MarketScan claims database (2012–2015). The first claim of ENZA or ABI was defined as the index date; continuous enrollment ≥6 months before and ≥3 months after the index date was required. HRU and costs were estimated during the post-index period for both cohorts. Generalized linear models compared HRU and costs between the cohorts and were adjusted for baseline demographic and clinical covariates. Analyses were separately conducted for chemo-naïve and chemo-experienced patients. Results: The study included 3230 chemo-naive patients (ENZA 920; ABI 2310) and 692 chemo-experienced patients (ENZA 262; ABI 430). Among chemo-naive patients, ENZA cohort was older (mean age: 74.5 vs 73.5; p=0.013), with a higher proportion of baseline comorbidities vs ABI cohort. During the post-index period, ENZA cohort had fewer all-cause inpatient admissions (IPA) [adjusted incidence rate ratio (IRR) 0.87; p=0.033], all-cause outpatient visits (OPV) [adjusted IRR 0.94; p=0.004], and PC-related OPV (adjusted IRR 0.92; p<0.001) vs the ABI cohort. Within 3 months of the index date, ENZA cohort was less likely to have an all-cause IPA (adjusted odds ratio [OR] 0.75; p=0.029). In addition, ENZA cohort had lower PC-related IPA and emergency department (ED) costs vs ABI cohort. The differences of HRU and medical costs between the 2 cohorts were not statistically significant for chemo-experienced patients. Conclusions: Despite a higher comorbidity burden at baseline, chemo-naive mCRPC patients treated with ENZA incurred less HRU and lower PC-related IPA and ED costs vs ABI cohort. Differences between the 2 cohorts were not statistically significant for chemo-experienced patients.
Detection of prostate cancer lesions using Gallium-68 PSMA-11 PET in men with biochemical recurrence following radical prostatectomy.
Authors: Gadzinski Adam J. , Greene Kirsten L , Carroll Peter , Ryan Charles J. , Feng Felix Y , Hope Tom
Published: February 2018

236

Background: Conventional imaging techniques infrequently detect the site of prostate cancer disease in men with biochemical recurrence following radical prostatectomy (RP). We examine the use of Gallium-68 Prostate-Specific Membrane Antigen (PSMA) positron emission tomography (PET) to determine the site of disease recurrence in these men. Methods: We retrospectively reviewed men with persistently detectable prostate specific antigen (PSA) and those with formal biochemical recurrence (PSA ≥ 0.2 ng/mL) following RP who underwent PSMA PET scan under our institution's prospective trials (NCT02918357 & NCT02611882). We assessed the location of detected recurrences, and examined the distribution of recurrence location (prostate bed, pelvic lymph nodes (LN), and extra-pelvic disease) according to PSA at time of PET scan. Results: One hundred and fifty-eight men underwent PSMA PET after RP, 46% of men had previously undergone either adjuvant or salvage radiation therapy. Eleven men (7%) had the scan for persistently detectable PSA < 0.2 and 93% of men had biochemical recurrence. At time of RP, 66% of men had ≥pT3a disease, 40% had positive surgical margins, and 18% had positive lymph nodes. Gleason grade at RP was ≤3+3 in 5% of men, 3+4 in 27%, 4+3 in 32% and ≥4+4 in 36%. Overall, 77% of men had a lesion detectable on PSMA PET. Men with higher PSA at time of scan had a higher prevalence of lesions, with all men PSA > 6.0 having at least one lesion on PSMA PET (Table). Overall, we found extra-pelvic lesions in 44% of all men, and 58% of men with PSA ≥ 1.0. These are areas not typically covered by salvage radiation fields. Conclusions: PSMA PET detects lesions in a high proportion of men with biochemical recurrence following RP, with many lesions outside of the pelvis. This may facilitate more precise targeting of treatment areas for these patients. Clinical trial information: NCT02918357. Clinical trial information: NCT02611882. [Table: see text]
Impact of a geriatric oncology (GO) clinic on cancer treatment plans and supportive care for older adults with genitourinary (GU) cancer.
Authors: Alibhai Shabbir M.H. , Loucks Allison , Jin Rana , Puts Martine , Watt Sarah , Berger Arielle
Published: February 2018

238

Background: Older adults with cancer are complex due to multiple comorbidities, polypharmacy, and functional/cognitive impairments, leading to over-treatment and undertreatment. Studies examining the impact of geriatric assessment (GA) in older adults with various cancers found a median of 39% of treatment plans were revised after the GA ( Ann Oncol 2014; 25:307). Although these findings support the need for a GO clinic, whether such a clinic leads to changes in treatment in patients with GU malignancies is not clear. We examined the impact on the treatment plan of a GO assessment in GU patients, along with other enhancements to patient care for consecutive patients referred to the GO clinic in a tertiary care hospital. Methods: All referred older adults (age 65+) with a GU malignancy seen in the GO clinic at the Princess Margaret Cancer Centre, Toronto, Canada between July 2015 and June 2017 were included. Patients were seen by a geriatric oncologist and GO nurse and treatment recommendations were provided to the referring oncologist. Pre- and post-GO clinic treatment plans and enhancements to supportive care were recorded prospectively. Analyses were descriptive. Results: 98 patients (mean age 80) were seen in the GO clinic, of whom 35 were seen pre-treatment (25 prostate, 5 kidney, 5 bladder). 31 of 35 were referred for input on the treatment plan. The initial treatment plan included surgery (n = 6), radiation (n = 14), systemic therapy (n = 8), and hormonal therapy (n = 11). The final treatment plan was intensified in 1 patient, reduced in 6 patients, changed to best supportive care in 8 patients, and unchanged in 15 patients. Overall, GO resulted in a treatment modification in 52% of patients. Enhancements to care included comorbidity management (87%), educational support (94%), disease-related symptoms (39%), and peri-operative management (19%). Conclusions: The GO clinic results in modifications to the proposed treatment plan in over half of referred patients (predominantly a reduction in treatment intensity), and enhancements to care in the vast majority of patients. GO clinics have the potential to avoid overtreatment and improve care for older adults with GU malignancies.
Optimal timing of post-prostatectomy radiotherapy for prostate cancer with high-risk pathologic features: A multi-institutional analysis.
Authors: Hwang William L. , Tendulkar Rahul D. , Niemierko Andrzej , Agrawal Shree , Stephans Kevin L. , Spratt Daniel Eidelberg , Hearn Jason W.D. , Koontz Bridget F. , Lee W. Robert , Michalski Jeff M. , Pisansky Thomas Michael , Liauw Stanley L. , Abramowitz Matthew , Pollack Alan , Moghanaki Drew , Anscher Mitchell , Den Robert Benjamin , Zietman Anthony L. , Stephenson Andrew J. , Efstathiou Jason A
Published: February 2018

24

Background: The use of radical prostatectomy (RP) as initial treatment of high-risk/locally-advanced prostate cancer is increasing but patients (pts) with adverse pathologic features such as positive surgical margins or T3 disease have up to 70% recurrence risk. These high-risk pts may be managed with adjuvant radiotherapy (ART) or early salvage radiotherapy (ESRT). The optimal timing of post-operative radiotherapy is unclear. Methods: Individual data from 1566 consecutive pts with pT2N0M0/R1 or pT3N0M0/R0-1 disease who underwent post-prostatectomy ART or ESRT (1987-2013) at 10 academic centers were pooled. Post-irradiation freedom from biochemical failure (FFBF), freedom from distant metastases (FFDM), prostate-cancer specific survival (PCSS), and overall survival (OS) were compared using Kaplan-Meier and multivariate competing-risks regression (MVA) analyses. Propensity score (PS) matching was used to account for covariates potentially associated with treatment allocation. All outcomes were measured from the date of surgery to address lead time bias. Results: After PS-matching, median follow-up after surgery was 66 vs. 73 months for the ART and ESRT groups, respectively, and baseline characteristics were well-matched. ART was associated with higher FFBF (12-yr: 69% vs. 43%; log-rank P < 0.0001), FFDM (12-yr: 95% vs. 85%; log-rank P = 0.03), PCSS (12-yr: 99% vs. 94%; log-rank P = 0.048), and OS (12-yr: 91% vs. 79%; log-rank P = 0.01). ART, lower Gleason score, lower T-stage, nodal irradiation, and postoperative androgen deprivation therapy were favorable prognostic features on MVA for BF. Sensitivity analysis demonstrated that the decreased risk of BF associated with ART remained significant unless more than 56% of ART pts were cured by surgery alone. This threshold is greater than the estimated 12-yr FFBF of 46% after RP alone as determined by a contemporary nomogram. Conclusions: To the best of our knowledge, this represents the largest multi-institutional study to date comparing ART to ESRT. ART was associated with reduced biochemical recurrence, distant metastases, and death compared to ESRT for high-risk pts, pending prospective validation.
Prognostic and therapeutic significance of ribonucleotide reductase small subunit M2 in prostate cancer.
Authors: Mazzu Ying Zhang , Gerke Travis A. , Chakraborty Goutam , Armenia Joshua , Atiq Mohammad Omar , Komura Kazumasa , Yoshikawa Yuki , Lee Gwo-Shu Mary , Mucci Lorelei A. , Kantoff Philip W.
Published: February 2018

240

Background: DNA-repair defects are common in advanced prostate cancer (PC) and high-risk localized tumors. Besides deficiency of DNA repair, overexpression of DNA repair genes could also contribute to poorer outcomes for PC patients. The nucleotide metabolism enzyme ribonucleotide reductase (RNR) plays the key role in DNA synthesis and repair. RRM2, the rate-limiting RNR subunit, is frequently up-regulated in cancer, and its overexpression leads to chemoresistance. Although targeting RRM2 by siRNA and small molecules has been applied in clinical trials in multiple cancers, limited knowledge of RRM2 function in PC delays potential clinical application of RRM2 inhibition. Methods: We leveraged publically available PC clinical cohorts to examine RRM2 levels and clinical outcomes. siRNAs was applied to knockdown of RRM2 in multiple PC cell lines. Cell growth, cell cycle and apoptosis were analyzed to determine siRRM2 or RRM2 inhibitor (COH29)-induced phenotypes. RNA-seq and protein array were performed to identify downstream targets of RRM2. Immunohistochemistry staining was applied to determine prevalence of RRM2 protein expression in PC tissues microarrays (TMAs). Results: In PC cohorts, increased RRM2 expression was associated with a higher likelihood of metastasis, poorer disease-free survival, and increased risk of development of lethal disease (N = 1200, PHS/HPFS cohorts). In PC cells, Inhibition of RRM2 induced remarkable cell growth inhibition, cell cycle arrest (at S phase) and apoptosis. DNA damage was observed in siRRM2/COH29-treated PC cells with increased activation of DNA damage markers. GSEA analysis of the RNA-seq dataset revealed multiple biological processes were affected by inhibition of RRM2, such as cell cycle, apoptosis, and DNA damage response. Intriguingly, MYC oncogenic signaling is the major downstream targets of RRM2. Furthermore, inhibition of RRM2 can block multiple oncogenic signaling including mTOR/AKT, SFK, and STAT signaling by repressing the key phospho-kinases in PC cells. Among 121 cases on the PC TMAs, 20% showed strong RRM2 protein expression. Conclusions: RRM2 may serve as a prognostic biomarker and novel therapeutic target in PC.
Concurrent deletion of BRCA2 and RB1 and aggressive prostate cancer.
Authors: Chakraborty Goutam , Armenia Joshua , Mazzu Ying Zhang , Nanjangud Gouri , Chadalavada Kalyani , Atiq Mohammad Omar , Komura Kazumasa , Yoshikawa Yuki , Khan Nabeela , Du Shin-Yi , Lee Gwo-Shu Mary , Kantoff Philip W.
Published: February 2018

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Background: Pathogenic variants of BRCA2 have been observed in a substantial subset of men with metastatic castration resistance prostate cancer (mCRPC). Prostate cancer (PC) patients with germline mutations of BRCA2 experience more rapid progression of their localized PC to mCRPC. This stands in contrast to other cancers where BRCA2 alterations do not appear to be associated with a worse prognosis. We identified homozygous and hemizygous deletions of BRCA2 in a subset of primary PC, which had been previously unrecognized. BRCA2 deletion in PC more frequently co-exists with RB1 deletion rather than alone. BRCA2-RB1 co-deletion in primary PC (TCGA and Taylor cohort) is associated with a shorter disease free survival and increased genomic instability in patients, indicating that BRCA2-RB1 null tumors are likely very aggressive in nature. Methods: To determine the underlying molecular and genomic consequences of BRCA2- RB1 loss, we CRISPR/shRNA-out these genes from human PC cell lines and subjected them to various in vitro assays, RNA-seq and kinase arrays. We applied a 3-color FISH assay to identify the deletion of BRCA2 and RB1 in PC. Results: BRCA2-RB1 null LNCaP cells exhibit androgen independence as evidenced by relative resistance to enzalutamide, and increased growth in absence of androgen but show enhanced sensitivity towards PARPi or platinum. Moreover, the null cell induces an aggressive EMT like phenotype, which is associated with enhanced migration and invasion. RNA-seq and array results show significant activation of EMT related signaling pathways including an unexpected activation of WNK1 upon co-deletion of BRCA2-RB1. FISH assay revealed significant co-deletion of BRCA2-RB1 in ADT resistant aggressive PC tumor cells. More importantly these cells also show greater sensitivity towards PARPi or platinum. Conclusions: Our finding suggests that concurrent deletion of BRCA2-RB1 is most likely is a driver of therapy resistant aggressive PC rather than the consequence of exposure to therapy. We propose that screening for BRCA2-RB1 deletion early could be implemented to identify those at highest risk of aggressive PC and provide an opportunity for early intervention and alternative treatments.
Abiraterone acetate (AA) or docetaxel (D) in metastatic castration-sensitive prostate cancer (mCSPC): A systematic review and network meta-analysis of randomized clinical trials (RCTs).
Authors: Riaz Irbaz Bin , Almutairi Abdulaali , Ali Zeeshan , Alhifany Abdullah , Bhattacharjee Sandipan , Abraham Ivo , Kohli Manish
Published: February 2018

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Background: AA and D have been shown in separate trials to increase overall survival in patients with mCSPC compared to Androgen Derivation Therapy (ADT). In the absence of head to head clinical trials and to provide clinical guidance, we performed an indirect comparison of AA and D using network meta-analysis. Methods: We performed a search of MEDLINE, EMBASE, Cochrane Library, and Cochrane Central Register of Controlled Trials to identify relevant clinical trials. Collected data included hazard ratio and confidence interval (CI) for Overall Survival (OS) and number of adverse events in each study arm. Risk for bias was assessed using the Cochrane Collaboration’s tool. Bayesian network meta-analysis was conducted using WinBUGS 1.4.3 software (MRC Biostatistics Unit, Cambridge, UK) to perform an indirect comparison of D and AA. Results: Five clinical trials were included in this analysis. Two trials (LATITUDE, STAMPEDE) compared AA to ADT and three trials (CHAARTED,STAMPEDE, GETUG-AFU 15 study) compared D to ADT. Results from both fixed effect and random effect network meta-analyses for the primary outcome (OS) revealed no statistical significance between AA and D (HR 0.81,95%CI 0.65-1.01; HR 0.81, 95%CI 0.40-1.82) respectively. Comparatively, abiraterone had statistically significant fewer events of anemia (OR 0.14,95%CI 0.08-0.23), neutropenia (OR 0.06,95%CI 0.03-0.12), peripheral edema (OR 0.21,95%CI 0.09-0.44), dyspnea (OR 0.22,95%CI 0.08-0.51), nausea (OR 0.09,95%CI 0.02-0.24), diarrhea (OR 0.06,95%CI 0.02-0.15), constipation (OR 0.25,95%CI 0.11-0.53), and fatigue (OR 0.12,95%CI 0.07-0.20). AA had statistically significant more events of hot flashes (OR 3.85, 95% CI2.33-6.25). For other adverse events, both drugs were statistically similar. Conclusions: There is no difference in OS using AA for longer periods in CSPC than a regimen of a limited number of cycles of D. There are significant differences in side effect profile of these drugs. Further analyses are needed to determine cost effectiveness of AA vs D under consideration of comparative efficacy and safety.
Radical prostatectomy in metastatic castration-resistant prostate cancer: Feasibility, safety, and quality of life outcomes.
Authors: Reichard Chad A. , Gregg Justin , Achim Mary F. , Aparicio Ana , Pisters Louis L. , Ward John Francis , Davis John W. , Chapin Brian Francis
Published: February 2018

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Background: Ongoing studies are evaluating the role of definitive treatment of the primary tumor in men with de novo metastatic prostate cancer. If proven beneficial, the optimal timing of the intervention will need to be considered. Little is known regarding the safety and quality of life outcomes of RP in metastatic castration resistant PCa (mCRPC). Methods: 14 pts undergoing RP on clinical trials and in the setting of mCRPC from 2008-2016 were analyzed. Intra-op and post-op complications were assigned Clavien-Dindo grade. Post-op expanded prostate cancer index composite (EPIC) urinary domains quality of life (QOL) outcomes were reviewed. Results: Patient characteristics were summarized (Table). 5 (36%) pts received platinum based chemo prior to RP. 4 pts had a decrease in PSA post RP (range: 0.2-57.3 ng/ml); 7 pts had an increase in PSA post RP (range: 0.1-24.5 ng/ml); and 3 pts’ PSA was unchanged. Positive surgical margin rate was 57%. 3 of 6 cN0 pts were pN1. 1 of 8 cN1 pts were pN0. 12/14 pts underwent extended lymphadenectomy with a median 3 (IQR 0-4) positive LNs out of 17 (IQR 11-25) LNs removed. Median op time was 239 min (IQR 186-304). Median EBL was 200cc (IQR 150-225). 8 pts had bilateral non-nerve sparing. Median pre-op and <3month post-op EPIC urinary function QOL scores were 84 (IQR 70-95) and 78 (IQR 62-810) respectively. 30-day mortality was 0% and 12/14 pts were alive at 1 year post RP. There were no intra-op complications. There was one Clavien Grade III complication (pelvic abscess), with remaining 5 complications either Grade I or II. Conclusions: In this select cohort of pts with mCRPC, RP was feasible with limited complications. Differences in pre-op and post-op urinary QOL scores were not clinically significant. Given the retrospective nature of the review and the heterogeneity of this heavily pre-treated population, clinical benefit cannot be ascribed to the intervention. Thus, we caution against RP in mCRPC outside of well-designed clinical trials other than for palliation. [Table: see text]
Multi-parametric MRI guided dose escalated radiotherapy for treatment of localized prostate cancer (PCa): Initial toxicity results of a prospective phase II trial.
Authors: Blumenfeld Philip , Chowdhary Mudit , Deane Leslie A. , Pfanzelter Nick , Shors Stephanie , Braun Ryan , White Greg M , Coogan Christopher , Hoeksema Jerome , Khare Narenda , Vourganti Srinivas , Turian Julius , Kuzel Timothy , Wang Dian
Published: February 2018

25

Background: Multi-parametric MRI (mpMRI) of PCa uses advanced sequences to detect aggressive, high grade and bulky lesions. Given known advantages of hypofractionated radiotherapy (RT) to treat PCa (low a/b ratio), we conducted a phase II trial to escalate a high dose to mpMRI lesion(s) via Image-Guided (IG)-RT/Volumetric Arc Therapy (VMAT)/Stereotactic Body Radiotherapy (SBRT) technology. We present the acute toxicity results of this novel approach. Methods: 22 pts with mpMRI lesion(s) were prospectively treated to a course of IGRT/VMAT to the prostate & seminal vesicle +/- pelvic lymph nodes (PLN) to a dose of 45 Gy in 25 fractions followed by SBRT boost, 18 Gy in 3 fraction to the prostate with a simultaneous integrated boost 21 Gy in 3 fractions (EQD2 = 85.2 Gy using a/b 3 or 93.4 Gy using a/b 1.5) to the mpMRI prostatic lesion(s). Placement of 3 polymer based fiducial markers visible in both CT and MRI for image co-registration and treatment guidance was performed. Genitourinary (GU) and gastrointestinal (GI) adverse events (AE) were scored using CTCAE v4. DSMC approved reporting of acute AE results prior to completion of trial accrual as an interim safety assessment prior to final trial accrual. Results: Median age was 66.5 years (range: 57-80). All patients had PI-RADS grade 3-5 mpMRI lesion(s); 41.0%, 45.4% and 13.6% having 1, 2 and 3 lesions respectively. Ten (45%) pts had Gleason Score (GS) 8-10 and 12 had GS 7 disease. Median PSA was 8.97 (range: 4.0-77.9). Eleven (50%), 10 (46%), and 1 (5%) pts had stage T1, T2, and T3 tumor, respectively. Nine pts received treatment to the PLN and 15 received androgen deprivation therapy. All patients completed the protocol treatment without reporting acute GI or GU AEs grade ≥3 during treatment or at follow up. Grade 2 GI (diarrhea) and GU toxicity (frequency) was seen in 2 (9%) and 9 (41%) pts, respectively, during treatment. Of the 16 pts (71%) with least 3 months follow-up all grade 2 GI and 55.5% GU toxicities had resolved. Conclusions: Early results of this prospective Phase II study suggest that high-dose RT for localized PCa via mpMRI-guided RT/VMAT and SBRT boost is tolerable with a favorable acute toxicity profile.
Whole blood AR-V7 and AR-V9 mRNA expression and treatment response in metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Kwan Edmond Michael , To Sarah , Fettke Heidi , Mant Andrew Michael , Docanto Maria , Martelotto Luciano , Bukczynska Patricia , Ng Nicole , Graham Lisa-Jane , Parente Phillip , Pezaro Carmel Jo , Mahon Kate Lynette , Horvath Lisa , Todenhöfer Tilman , Azad Arun
Published: February 2018

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Background: Androgen receptor splice variant (AR-V) expression has previously been regarded as a negative predictive biomarker for response to abiraterone and enzalutamide in mCRPC patients. However, recent data questions this association. We designed a whole blood assay to detect AR-V7 and AR-V9, the two most abundantly expressed AR-Vs, and correlated expression with clinical outcomes in patients commencing abiraterone or enzalutamide. Methods: We developed a quantitative real-time polymerase chain reaction assay to detect AR-V7 and AR-V9 from whole blood collected in PAXgene tubes. The assay was applied to samples prospectively collected from 37 mCRPC patients prior to commencing abiraterone or enzalutamide, and at treatment cessation. Patients positive for either AR-V7 or AR-V9 were defined as AR-V-positive, and AR-V-negative if neither variant was detected. AR-V expression was correlated with PSA response rate (chi-square test) and PSA progression-free survival (PSA-PFS) (log-rank test). Assay sensitivity was determined by serially diluting RNA from VCaP prostate cancer cells (known to express AR-V7) to establish a lower limit of detection. Results: The median follow-up was 7.29 months (IQR 4.21-10.55); 9 of 37 patients (24%) were AR-V-positive. We observed similar response rates in AR-V-positive (6/9) and AR-V-negative (18/28) patients (66% vs. 64%, p = 0.896). PSA-PFS did not differ significantly between groups (9.2 months vs. not reached, p = 0.355). Two patients converted from AR-V-negative to AR-V-positive (PSA-PFS 3.35 and 0.60 months respectively), and one patient remained AR-V-positive at baseline and end-of-treatment sampling. The lower limit of detection for AR-V7 was 0.1%, and AR-V7/V9 was not detected in any of the 13 normal male controls. Conclusions: We developed a sensitive and specific whole blood assay for AR-V7 and AR-V9 detection in patients with mCRPC. Neither PSA response rates nor PSA-PFS differed significantly between AR-V-positive and AR-V-negative patients. These data support recent literature questioning the role of AR-V expression as a negative predictive biomarker in mCRPC patients receiving abiraterone or enzalutamide.