bluuebunny/crossref_metadata_2025 huggingface dataset:
Objective response of the dual CYP17-Lyase (L) inhibitor / androgen receptor (AR) antagonist, VT-464, in patients with CRPC.
Authors: Nordquist Luke T. , Shore Neal D. , De Bono Johann S. , Gupta Shilpa , Berry William R. , Gillessen Silke , Liu Glenn , Vogelzang Nicholas J. , Efstathiou Eleni , Fleming Mark T. , George Daniel J. , Araujo John C. , Zhang Jingsong , Kurman Michael R , Eisner Joel Robert , Moore William R.
Published: February 2017

273

Background: VT-464 is an oral, CYP17-L inhibitor and non-clinically an antagonist of the AR and its variants associated with clinical resistance to enzalutamide (ENZ) and abiraterone (AA). The safety, tolerability and initial pharmacodynamic effects (tumor responses, PSA and testosterone (T) decreases) of VT-464 given without steroid supplementation either bid with food or QD at night with dinner were evaluated in the Phase (Ph) 1/2 studies INO-VT-464-CL-001 (NCT02012920) and INO-VT-464-CL-004 (NCT02361086), respectively. Patients were either treatment-naïve (TN), or had failed AA or ENZ or AA/ENZ/chemotherapy (at least 2 out of the three). Preliminary objective response results from both studies are presented herein. Methods: Target lesions were assessed at baseline and during therapy using CT or MRI. Target lesion responses were categorized as a complete response (CR), partial response (PR), progressive disease (PD), or stable disease (SD) using RECIST 1.1. Patients with ≥ 1 target lesion and ≥ 1 post-baseline scan following VT-464 BID (INO-VT-464-CL-001) or QD (INO-VT-464-CL-004) were included in the analysis. Results are reported through a data cutoff of 01 Sep 2015. Results: Combined, 23 patients (8 TN, 4 AA, 7 ENZ, 4 AA/ENZ/chemotherapy) from both Ph 1/2 studies had ≥ 1 target lesion and ≥ 1 post-baseline scan. Of 15 patients included who were treated BID (Study 001), 1 had PD, 12 had SD and 2 had a PR. Of 8 patients who were treated QD (Study 004), 2 had PD, 5 had SD and 1 had a PR. No patient had a CR in either study. For the 3 patients with PRs one patient had a prior response to ENZ but failed taxane-based chemotherapy, another was de novo resistant to ENZ, while the third was TN. For the 3 PRs, one was confirmed with a repeat scan 8-weeks later and the others have repeat scans pending. Conclusions: Potent and selective CYP17-L inhibition, PSA reductions, and objective tumor responses in TN and ENZ-failure patients have been observed with oral VT-464 administered bid (de Bono et al, GU ASCO 2015) or QD (Shore et al, GU ASCO 2016). Preliminary results demonstrate that the QD regimes are as efficacious as BID regimens. All Ph 2 CRPC studies now utilize a 750 mg QD regimen. Clinical trial information: NCT02012920 and NCT02361086.
PSA levels after dexamethasone withdrawal (DW) in castration resistant prostate cancer (CRPC).
Authors: Zafeiriou Zafeiris , Bianchini Diletta , Rescigno Pasquale , Kolinsky Michael , Mateo Joaquin , Lorente David , Perez Lopez Raquel , Jayaram Anurhada , Mehra Niven , Sumanasuriya Semini , Recine Federica , Sideris Spyridon , Sharp Adam , Wong Sophia , Tunariu Nina , Attard Gerhardt , De Bono Johann S.
Published: February 2017

278

Background: PSA decline (PSAD) in CRPC after withdrawal of antiandrogens and steroid related drugs is well established. DW responses have been anecdotal and not well characterized. In this study we investigated the frequency and magnitude of PSA changes after DW. Methods: We retrospectively identified patients treated in the Royal Marsden for CRPC with D monotherapy. Patients were considered evaluable if they had between DW and their next treatment or radiotherapy an interval of at least 7 days, no other intervention and at least one PSA reading. Patients who received radiotherapy during treatment with D or received D for palliation of symptoms were excluded. The number of patients showing PSAD was recorded together with its percentage change from baseline. Chi-square test was used to compare response rates between different groups and 95% confidence intervals (CI) for the description of frequencies. PSA progression (PSAP) was defined according to Prostate Cancer Working Group 2 criteria. Results: 200 patients were identified who had received D of which 50 were evaluable. During D treatment PSA responses were not available for 5 patients, while 16 (35%, 95%CI [20%-50%]) had a ≥ 50% PSAD which was confirmed a month later with a second reading. For the responders, the median duration of PSA response from initiation of treatment to PSAP was 293 days (range: 219 to 1063). After DW, PSAD was observed in 12 patients (24%, 95% CI [12%,36%]). PSAD ≥ 25%, ≥ 30% and ≥ 50% was observed in 6, 3 and 2 patients respectively (12%, 6% and 4%) and in only one could the ≥ 30% PSAD be confirmed with a second reading a month later. In 5 cases of ≥ 25% PSAD, next treatment was initiated despite a dropping PSA, after 8 to 43 days. In one case only was PSAP reached during DW with a response duration of 53 days from DW to PSAP. The frequency of ≥ 25% PSAW responses was not significantly different between patients with and without prior response to dexamethasone: 6% and 17% respectively, Chi-square test p = 0.29. One patient reported improvement of his urinary symptoms after DW. Conclusions: DW responses are observed in a minority of patients. This phenomenon merits further prospective characterization and needs to be considered in the design of clinical trials.
A phase I/IIa trial of prostate specific membrane antigen (PSMA) positron emission tomography (PET) imaging with 89Zr-Df-IAB2M in metastatic prostate cancer (PCa).
Authors: Morris Michael J. , Martinez Danny Francisco , Durack Jeremy C. , Slovin Susan F. , Danila Daniel Costin , O' Donoghue Joseph A. , Parada Nicole Andrea , Lyashchenko Serge K. , Carrasquillo Jorge A. , Ruan Shutian , Lewis Jason Stuart , Keppler Jennifer , Wu Anna M. , Reuter Victor E. , Weber Wolfgang , Scher Howard I. , Larson Steven M. , Pandit-Taskar Neeta
Published: February 2017

287

Background: There is a pressing need for improved imaging biomarkers to identify disease distribution and response in both localized and advanced prostate cancer patients. PSMA-directed imaging is undergoing analytic and clinical validation for these contexts of use. IAB2M is an anti-PSMA recombinant minibody (Mb) derived from huJ591. We have previously reported on 28 pts imaged with IAB2M(Pandit-Taskar et al, SNM 2015). Here we report the lesion targeting and uptake (SUV) of the Mb and correlation with pathology of biopsied lesions on the full complement of the 38 pts examined in this trial. Methods: 38 pts with progressive metastatic PCa received escalating amounts of the Mb (16 pts at 10mg, 16 pts at 20mg, 6 pts at 50mg) in a phase I/IIa trial. All pts underwent standard imaging (SI) using CT, bone scintigraphy (BS), FDG PET, followed by imaging with 5 mCi of IAB2M. Whole body PET/CT scans were performed and evaluated for lesion targeting and SUVmax. Biopsy (bx) locations were selected by a consensus panel prioritized on the basis of: IAB2M & FDG positivity, IAB2M & FDG mismatch, and CT or BS positivity & any PET mismatch. Results: A total of 556 lesions (410 bone, 146 soft tissue) in 38 pts were detected by SI or IAB2M. In bone, IAB2M detected 344 lesions (83.9%), CT 209 (51%), BS 211 (51.5%), and FDG 109 (26.6%). For soft tissue, IAB2M detected 119 (81.5%), CT 83 (56.8%), and FDG 79 (54.1%). The SUV for bone lesions ranged from 2.1-60.4 for 10mg Mb, 1.7- 33 in 20mg Mb, and 2.3-17.5 in 50mg Mb. For soft tissue lesions, SUV range was 3.1-45.4, 2.1-20, and 1.9-13.8 respectively. 28 bxs (13 bone, 15 soft tissue) were obtained from 27 pts; 27 bxs were evaluable (1 was non-diagnostic). 20/27 (74.1%) bxs were pos for PCa; 20/24 (83.3%) IAB2M pos lesions were path pos and 3/3 (100%) IAB2M neg lesions were neg on path. All imaging and path correlated (true pos + true neg) in 23/27 (85.2%) bxs. Conclusions: PET imaging with IAB2M has demonstrated higher lesion detection when compared with SI. IAB2M’s high concordance with path suggests pos findings represent bx confirmed PCa. Further studies to examine biochemically recurrent prostate cancer are planned. Clinical trial information: NCT01923727.
Feasibility of salvage focal nodal SBRT or protracted elective nodal irradiation in 18F fluoro-choline PET based nodal failures from prostate cancer.
Authors: Lepinoy Alexis , Martin Etienne , Quivrin Magali , Gauthier Mélanie , Maingon Philippe , Brunotte Francois , Cochet Alexandre , Crehange Gilles
Published: February 2017

290

Background: 1) To establish the feasibility of salvage nodal radiotherapy in patients with 18F Fluoro-choline (FCH) PET+ nodal recurrence only from a prostate cancer. 2) To compare salvage focal FCH PET+ stereotactic radiation therapy (sf-SRT) with salvage elective nodal irradiation with a protracted FCH PET+ nodal boost (seni-PRT) . Methods: Between 2009 and 2014, 42 patients out of 102 patients with FCH PET for a rising PSA after RP or radiotherapy had positive lymph nodes only. Twenty nine patients had sf-SRT and 13 patients had seni-PRT in a curative intent. Acute and late genito urinary (GU) and gastro intestinal (GI) toxicities were assessed with CTCAE v4. Failure was defined as a rising PSA higher than the maximal pre-therapeutic PSA value followed by 2 consecutive rises or a nodal or distant metastatic failure or the initiation of any salvage therapy. Results: Seventy-six nodes were diagnosed with FCH PET/CT with a median PSA value of 2.8 [0.3 -29.2] at time of failure. Mean number of nodes was higher in the seni-PRT group than in the sf-SRT group (2.8 vs 1.6). The median prophylactic dose of WPRT and/or LA was 48.0 Gy [36.0-54.0] and the median dose delivered to involved FCH PET+ nodes was 66.0 Gy [46.0-70.0] with a median dose per fraction of 2.0 [1.8-2.2]. In the sf-SRT group, the median dose to the involved nodes was 36 Gy [18-45] with a median dose per fraction of 7.5 Gy [6-15]. After a median follow-up of 19.1 months [2.9-74.1], no difference was observed for GI or GU toxicities between the 2 groups (p = 0.26 and p = 0.19). One grade 4 GI and GU toxicity occurred in 1 patient in the seni-PRT group. The median freedom from failure (FFF) time was 14.8 months for sf-SRT and 37.6 months for seni-PRT with 2-year FFF rates of 47.8 % and 72.7 %, respectively. Conclusions: FCH PET+ node-targeted salvage radiotherapy is feasible with very low rates of toxicity. Freedom from failure was significantly improved with protracted elective nodal irradiation, suggesting that nodal disease diagnosed on FCH PET may not be an oligometastatic disease. Dose escalated seni-PRT is currently being investigated in a French phase II trial (Oligopelvis- GETUG P07).
Optimal sequencing of enzalutamide and abiraterone in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Maughan Benjamin Louis , Suzman Daniel L. , Nadal Rosa Maria , Bassi Sunakshi , Antonarakis Emmanuel S.
Published: February 2017

308

Background: Both enzalutamide and abiraterone are approved for the treatment of mCRPC, each demonstrating improved overall survival (OS) versus placebo. However, it is unclear what the optimal sequencing of these two therapies should be to maximize clinical outcomes and survival. Here, we compare clinical outcomes among patients with mCRPC who received enzalutamide first followed immediately by abiraterone (enza-to-abi) or the opposite sequence (abi-to-enza). Methods: A retrospective review of consecutive mCRPC patients treated at Johns Hopkins with enza-to-abi or abi-to-enza was conducted. The combined PFS (PFS = PFS1 + PFS2) was the primary endpoint, measured from the start of the first therapy (i.e. enza or abi) until disease progression on the subsequent therapy (i.e.abi or enza). The OS from the start of the first therapy until death was the secondary endpoint. Cox proportional hazards multivariable regression analysis was performed to determine whether one sequence was better than the other after adjusting for baseline characteristics. Results: 71 patients were identified: 58 received abi-to-enza and 13 received enza-to-abi. Comparisons of baseline characteristics between groups identified differences in PSA levels (P = 0.007), hemoglobin (P < 0.001), and presence of visceral disease (P = 0.035). The abi-to-enza group had a longer combined PFS than the enza-to-abi group: median 16.3 vs 12.5 mo (HR 0.53, P = 0.04). There was also a numeric improvement in OS in the abi-to-enza group compared to the enza-to-abi group: median 29.0 vs 21.0 mo (HR 0.51, P < 0.10). In multivariable analyses incorporating PSA level, hemoglobin, visceral disease and prior docetaxel use, both combined PFS (HR 2.59, P = 0.03) and OS (HR 4.59, P < 0.01) demonstrated improved outcomes with the abi-to-enza sequence. Conclusions: This hypothesis-generating study potentially suggests superior PFS and OS in men with mCRPC receiving abiraterone then enzalutamide (compared to enzalutamide then abiraterone), although this could be due to baseline imbalances or the small sample size of this study. Prospective validation of this concept is ongoing (NCT02125357).
Pre-treatment nomogram to predict potency after treatment for localized prostate cancer.
Authors: Zabell Joseph , Sanda Martin G. , Litwin Mark S. , Suarez Jose Francisco , Regan Meredith M. , Saigal Christopher , Kwan Lorna , Gao Tianming , Rabah Danny , Klein Eric A. , Kattan Michael W. , Stephenson Andrew J.
Published: February 2017

32

Background: Radical prostatectomy (RP), external beam radiotherapy (EBRT), and brachytherapy are commonly utilized treatments for localized prostate cancer and may negatively impact sexual function to varying degrees. Patient-, disease-, and treatment-specific factors may all impact post-treatment sexual function. We aimed to evaluate predictors of post-treatment impotency, and develop a prognostic nomogram using prospective, patient-reported data from multiple validated health-related quality-of-life (HRQOL) instruments. Methods: Between 1999 and 2011, patient-reported data regarding treatment-related effects on erectile function were obtained from 2668 patients enrolled in one of four prospective longitudinal HRQOL protocols from the United States and Spain. Patients were treated with RP (n=1,294), EBRT (n=630), or brachytherapy (n=744). Although different HRQOL instruments were used in each protocol, questions pertaining to quality and frequency of erections were identical across the different instruments. Patient responses were obtained at baseline and 2 years after treatment. The endpoint of the model was impotency at 2 years post-treatment. Logistic regression analysis was used to model clinical information and outcome data. Internal validation was performed using bootstrapping. Results: 1,306 patients were potent at baseline and had 24-month follow-up. Differences in baseline patient characteristics such as patient age, ethnicity, and disease severity existed between the treatment groups. The impotency rate at 2 years was 62%, 53%, and 41% for patients treated by RP, EBRT, and brachytherapy, respectively. In multivariable analysis, age, PSA, modality of treatment, frequency of preoperative erections, diabetes, and hypertension were associated with post-treatment impotency (all p<0.05). A nomogram based on the predictive parameters had a concordance index of 0.726 and predictions were well-calibrated with observed outcome. Conclusions: A validated nomogram that predicts 2-year risk of impotency after treatment of localized prostate cancer has been developed and is anticipated to be useful for patient counseling regarding treatment options.
Gaps in treatment amongst metastatic castration resistant prostate cancer (mCRPC) patients taking abiraterone acetate or enzalutamide.
Authors: Behl Ajay , Ellis Lorie , Pilon Dominic , Xiao Yongling , Lefebvre Patrick , Dawson Nancy Ann
Published: February 2017

334

Background:Abiraterone acetate (ABI) and enzalutamide (ENZ) are novel oral therapies offering survival benefit to metastatic castration-resistant prostate cancer (mCRPC) patients. The efficacy of cancer treatments rely on patient consistency and adherence to recommended dosage regimens. Factors such as drug-drug interactions and intolerance or toxicities can result in patients or their providers reducing the drug dosage. This study aims to describe treatment discontinuation patterns observed for ABI and ENZ. Methods: The Truven Health MarketScan Research Databases were used to conduct a retrospective analysis of mCRPC patients initiated on ABI or ENZ (index date) between 10/01/2012 to 12/31/2014 with ≥6 months of continuous eligibility prior to index date and a PC diagnosis during the period of continuous eligibility. Patients were observed until loss to follow-up, or end of data availability. Kaplan-Meier (KM) survival curves were used to compare the rates of having a refill gap (i.e., ≥14 days, ≥30 days, or ≥60 days) in patients initiated on ABI or ENZ. Results: The table below summarizes the KM probabilities of having a refill gap among patients initiated on ABI or ENZ. Conclusions: Significantly higher rates of refill gaps ≥30 days and ≥ 60 days were observed for patients initiating ENZ as compared to ABI after 6 months of observation in this initial analysis. Additional research is needed to understand the reasons for gaps in treatment in patients treated with mCRPC therapies. [Table: see text]
Serum parathyroid hormone and calcium changes in metastatic castration resistant prostate cancer patients receiving enzalutamide in post-docetaxel setting.
Authors: Gernone Angela , Pappagallo Maria Nicla , Silvestris Francesco ,   Franco Silvestris
Published: February 2017

349

Background: Among novel hormonal therapeutic targets for post docetaxel mCRPC, Enzalutamide is an oral androgen-receptor blocker disrupting the androgen-receptor nuclear translocation that significantly increases the OS. In this study we evaluated the potential association of both PTH and Ca levels change in pts with mCRPC after the first Enzalutamide administration. Methods: Between 01 and 05/2015, 20 mCRPC pts relapsed after 2-3 prior lines of therapy (docetaxel, cabazitaxel, abiraterone) have been treated with Enzalutamide that was orally administered at 160 mg/day as continuous dosing. Patient characteristics included: median age 67 years (range 50-84), median baseline PSA 120 ng/ml (range 6-1200), median ECOG P S: 1 (range 0-2), Gleason score ≥ 7. In addition 80% of pts had ≥ 2 metastatic sites. Pretreatment baseline and follow up data including measurement of serum Ca and PTH levels (6.5-36.8 pg/ml), ALP, PSA and QoL parameters were evaluated through all lines of therapy. Pts with bone metastasis received zoledronic acid or denosumab with Ca and vitamin D supplementation. Results: In 18/20 pts with bone disease progression we recorded increased PTH levels and, contrarily, decreased Ca levels after 1 month of Enzalutamide despite vit. D and Ca supplementation. PTH levels remained unchanged after 3 months. In 2/20 pts without bone disease progression PTH ranged normal. All pts reported PSA response ≥ 50%, with improved QoL and are still on treatment since Enzalutamide is well tolerated. We did not find PTH change in bone mCRPC pts treated with prior therapy. Conclusions: Our study showed that increase in PTH levels and reduction in Ca levels and increase in PTH levels after 1 month of Enzalutamide treatment is associated with a dramatic reduction of PSA level. These data support a relationship between PTH and Ca changes in pts treated with Enzalutamide and, thus, their changes level may be adopted in clinical practice as surrogate to reflect the drug activity. No studies have evaluated the variations in serum PTH levels following Enzalutamide treatment and whether these early changes relate to the clinical outcome.
Metabolomics analysis of non-muscle invasive and muscle-invasive bladder cancer.
Authors: Sahu Divya , Lotan Yair , Wittman Bryan , Neri Bruce , Hansel Donna E.
Published: February 2017

362

Background: Bladder cancer accounts for greater than 70,000 new cancer cases in the United States annually and an annual global incidence of more than 400,000 patients. Despite its high incidence, therapeutic options are limited both in early and late stage cancers and there is need for alternative, rational therapies in this population. Methods: We extensively analyzed benign urothelium, high-grade non-muscle invasive bladder cancer and advanced, muscle-invasive bladder cancer using global metabolomics profiling, coupled with publicly available data on transcriptomics of key enzymes, to determine pathways that may be suitable for future therapeutics development. Results: Categorical pathways globally dysregulated in cancer relative to benign urothelium included glucose, TCA cycle, lipid, amino acid and nucleotide pathways. Bladder cancers demonstrated Warburg metabolism, with elevated glucose utilization to drive glycolysis and sorbitol pathway intermediates. Elevated late TCA cycle intermediates, coupled with higher levels of amino acids and dipeptides, suggest the possibility of anaplerotic activity in bladder cancer as a mechanism to sustain energy production. Medium and long chain fatty acids were produced at the expense of dicarboxylic fatty acids. Muscle-invasive bladder cancers showed enhanced use of COX and LOX metabolomics pathways and a possible role for inflammation in regulating NAD+ synthesis in muscle-invasive bladder cancer. Transcriptomic profiling validated that the majority of metabolomics pathway alterations corresponded to gene expression changes of enzymes responsible for metabolite production. Conclusions: This study identifies multiple parallel metabolomics changes unique to non-muscle invasive and muscle-invasive bladder cancer that can be used to justify testing novel therapeutics targeting metabolomics pathways in bladder cancer.
COXEN prediction of antineoplastic drug sensitivity in bladder cancer patients.
Authors: Kothari Shalin , Gustafson Daniel , Killian Keith , Costello James , Edelman Daniel C. , Walling Jennifer , Meltzer Paul S. , Theodorescu Dan , Apolo Andrea B.
Published: February 2017

365

Background: COXEN (Co-eXpression ExtrapolatioN) uses molecular profiles as a “rosetta stone” for translating drug sensitivities of one set of cancers into predictions for another completely independent set of cell lines or human tumors. The ability of COXEN to predict drug effectiveness in pts using tumor samples from in vitro assays is unique. Methods: We tested the predictive value of COXEN for standard chemotherapies in a cohort of bladder cancer pts. Total RNA was extracted from formalin fixed paraffin embedded (FFPE) tissue and converted to cDNA, amplified with Ovation FFPE WTA, and hybridized to a GeneChip Human Genome U133 Plus 2.0 array. Using gene expression data from 278 independent bladder tumors, COXEN scores were generated using bioinformatics models originally built using the NCI-60 cell line panel and a model building algorithm (MiPP). Gene expression data was processed to score 76 FDA approved antineoplastic drugs. Results: A total of 24 samples were tested (15 tumors with 1 sample and 9 tumors with 2 biological replicas (2 samples from the same tumor)) from 15 pts who received chemotherapy (median age 64 (41-74); 73% male; with muscle invasive bladder cancer (MIBC) (12/15, 80%) or metastatic bladder cancer (mBC) (3/15, 20%)). Response to therapy was confirmed by pathologic response in MIBC pts and radiologic response in mBC pts. Chemotherapies evaluated included: methotrexate/vinblastine/doxorubicin/cisplatin; gemcitabine/cisplatin; gemcitabine/carboplatin; and cisplatin/etoposide. COXEN accurately predicted antineoplastic drug sensitivity in 11/15 (73%) pts (75% MIBC and 67% mBC), of which 7/11 pts had 2 biological samples. However, only 3/7 (43%) biological replicas confirmed COXEN prediction. COXEN accurately predicted drug sensitivity in 9/10 (90%) pts with response and 2/5 (40%) pts with resistance to therapy. Conclusions: COXEN did well in predicting antineoplastic drug response for the majority of bladder cancer pts in this cohort. However, predictions from 2 samples within the same tumor were not always consistent, likely due to the expected tumor heterogeneity found in bladder cancer tumors. A prospective clinical trial in patients with mBC using COXEN to select next best therapy is in development.
Effects of interruptions of radiotherapy on outcomes of patients with prostate cancer.
Authors: Dong Yanqun , Li Tianyu , Churilla Thomas M. , Viterbo Rosalia , Sobczak Mark L. , Smaldone Marc C. , Chen David Y. T. , Uzzo Robert G. , Hallman Mark , Horwitz Eric M.
Published: February 2017

37

Background: To evaluate if interruptions of radiotherapy have any effect on outcomes for men with localized prostate cancer (PCa) treated with definitive external beam radiation therapy (EBRT). Methods: We included men with localized PCa treated with definitive 3DCRT or IMRT of escalated dose (≥74 Gy in daily fraction of 2 Gy, or 70.2 Gy in daily fraction of 2.7 Gy) between 1989 and 2013. Men receiving androgen deprivation therapy, or follow up <1 year were excluded. The nontreatment day ratio (NTDR) was defined as the number of nontreatment days divided by the total elapsed days of therapy, to account for the difference in total RT dose and planned RT duration. NTDR was analyzed for each NCCN risk group. Results: A total of 1,796 men including 861 low risk, 821 intermediate risk, and 114 high risk were included, with median follow up of 53.5 m (range 12 to 185.8 m). The median NTDR was 31% (range 23.1%-71.2%), translating to approximately 2 breaks (each break represents a missed treatment that would be made up in the end) for an 8-week RT with 5 treatments per week. The 75th percentile of NTDR was 33.3%, translating to approximately 4 breaks, which was used as the cutoff to compare the outcomes with NTDR ≥33.3% vs <33.3%. There were no significant differences in freedom from biochemical failure (FFBF), distant metastasis (DM), cancer-specific survival(CSS), or overall survival (OS) for men with NTDR ≥33.3% compared to NTDR<33.3% for each risk group (Table). Multivariable analyses including NTDR, age, race, Gleason score, T stage, and PSA were performed using the PHREG procedure. NTDR ≥33.3% was not significantly associated with increased hazard ratio for outcomes in each risk group compared to NTDR <33.3%. Conclusions: Interruptions of RT do not cause significant difference in outcomes in each risk group for men with localized PCa treated with definitive EBRT of escalated dose. [Table: see text]
A randomized trial comparing two different retention periods of intravesical pirarubicin instillation for intermediate risk non-muscule invasive bladder cancer (NMIBC) after transurethral resection.
Authors: Kasejima Yutaka , Takahashi Wataru , Kawano Yoshiaki , Yamaguchi Takahiro , Tanoue Ken-ichiro , Sakakida Hiroshi , Yatsuda Junji , Murakami Youji , Sugiyama Yutaka , Eto Masatoshi
Published: February 2017

384

Background: Anthracyclines are recommended reagents for one immediate intravesical instillation after transurethral resection (TUR) and additional adjuvant instillation in intermediate risk NMIBC to reduce the risk of recurrence. Several studies have showed that Pirarubicin (THP), an anthracycline analogue, can rapidly penetrate tumor tissue after intravesical instillation. Therefore long instillation time (e.g. 120 min) may not be required for its prophylactic effect against recurrence without compromising its efficacy. Methods: This randomised, prospective, open-label trial intended to enroll 160 pts with primary NMIBC with intermediate risk based on EORTC criteria. Pts who seemed likely to be at intermediate risk were provisionally registered and then randomised into two groups with different intravesical THP retention times before TUR, (a) 30 min versus (b) 120 min. The registration was finally confirmed by pathology results of TUR. All registered pts received initial THP instillation within 24 hr after TUR and then intended to continue weekly repetitive THP instillation for a total of 9 treatments. Follow-up period is 4 years. Primary endpoint is change from baseline in quality of life measurements (e.g. OABSS and I-PSS), which were evaluated prior to each THP intravesical instillation. Secondary endpoint is recurrence-free survival. Results: 126 pts were enrolled for provisional registration. After excluding pts due to the result of pathology by TUR, 29 pts were assigned to group (a), and 26 pts to group (b). Although not statistically significant, there is a trend that group (a) is less prone to increase in OABSS after 3rd instillation compared to group (b). Log-rank test shows that there is no significant difference in recurrence-free survival between the groups during follow-up period (HR = 2.161, 95% C.I.: 0.4317-10.82, p= 0.3484). Conclusions: Shortening intravesical instillation period to 30 min has little effect on reducing the adverse effect of THP. However, it does not compromise the prophylactic effect on recurrence in intermediate risk NMIBC pts. Clinical trial information: UMIN000006861.
Outcomes of advanced urothelial carcinoma following discontinuation of programmed death (PD)-1 or PD-ligand (L)-1 inhibitors.
Authors: Sonpavde Guru , Pond Gregory Russell , Mullane Stephanie A. , Ramirez Ana Arlene , Vogelzang Nicholas J. , Necchi Andrea , Powles Thomas , Bellmunt Joaquim
Published: February 2017

385

Background: The outcomes and therapy of advanced urothelial carcinoma (UC) patients (pts) following discontinuation of PD-1/PD-L1 inhibitors are unclear. We performed a retrospective analysis to examine the frequency of systemic therapy administered following PD-1/PD-L-1 inhibitors and outcomes in these pts. Methods: Data were collected from institutions for pts with advanced UC following prior PD-1/PD-L1 inhibitors as salvage therapy. Baseline demographics and therapy administered following prior check-point inhibitors was captured. Univariable Cox regression analyses examined clinical factors potentially associated with overall survival (OS) following check-point inhibitors. Results: Data from 62 pts were available from 4 institutions with capture of therapy and outcomes following checkpoint inhibitor immunotherapy. The median age was 65.5 years and 51 (82.3%) were male. The median duration of PD-1/PD-L1 inhibitors available from 55 pts was 64 days (range 7-669). Of these pts, 22 (35.5%) received post-PD1/PD-L1 pathway inhibitor therapy with a variety of chemotherapy (n = 16), chemobiologic combination (n = 1), biologic agents (n = 4) and immunotherapy (n = 1). The median time from last PD1/PD-L1 pathway inhibitor therapy to subsequent therapy was 58 days (range 14-242). The median OS of all pts following completion of PD-1/PD-L1 inhibitors was 149 days (95% CI: 75-359). Among pts who received some post-PD1/PD-L1 pathway inhibitor therapy, median OS was 182 days (95% CI: 121-372), and the median time to progression was 124 days (95% CI: 61-273) when examining from start of post-PD1/PD-L1 therapy. Among these 22 pts, the only significant baseline prognostic factor associated with OS was performance status. Conclusions: In this dataset, 35.5% of pts with advanced UC received subsequent systemic therapy following salvage therapy with PD1/PD-L1 inhibitors. Outcomes with subsequent therapy appear similar to historically observed outcomes in pts who had not received prior PD1/PD-L1 inhibitors. Further study of pts post-PD1/PD-L1 inhibitor therapy is warranted to identify factors associated with outcomes and potentially synergistic sequences.
Development of a PSA tracking system for patients wtih prostate cancer following definitive radiotherapy to enhance rural health.
Authors: Chang Michael G. , DeSotto Kristine , Taibi Paul , Troeschel Sandra
Published: February 2017

39

Background: Patients with prostate cancer (PC) may benefit from early intervention when they experience relapse/recur. About 50% of our PC patients are rural and experience barriers to care due to distance, cost, and convenience. We sought to create a PSA tracking system with the Veterans Administration’s (VA) Electronic Medical Record (EMR) that would provide a remote way to monitor disease progression after definitive radiotherapy (XRT) by annual PSA testing alone. Methods: Using VA’s EMR, we developed a query tool to identify all patients ever treated at our center with XRT for prostate cancer who were alive, had not been seen in our clinic in more than a year, did not have metastatic disease, and had a rising PSA of at least 0.5 ng/ml above nadir, or who had no PSA drawn within 15 months. Results: Among roughly 50,000 unique patients in the McGuire VAMC EMR, we found 1,858 patients treated with XRT for PC more than 5 years ago between 1997 and 2015. Of these 1,190 were still alive and 455 had not been seen by our clinic in 400 days or more. Of these 455 patients, 159 patients had not had a PSA drawn within 15 months and/or their most recent PSA was more than 0.5 ng/ml above nadir, triggering a chart review followed by either a phone call, repeat testing, in person follow up visit, or removal from follow up monitoring if clinically indicated. 296 patients were receiving appropriate care outside of our clinic and had no sign of significant rise in PSA. An analysis by the VA showed annual savings of $60,360 per year in fuel costs by avoiding unnecessary visits. Conclusions: The VA’s robust EMR and a new query tool can identify patients with prostate cancer who are lost to follow up or who needed intervention from among thousands of patients in the EMR, improving quality while reducing cost and unnecessary time and travel for rural and all patients. More importantly, our tool could be modified to improve survival for all VA patients with prostate cancer by creating a VA-wide PSA failure detection system. The system would alert providers to any patient who may benefit from early salvage radiotherapy or hormonal therapy before their disease progresses beyond the therapeutic window of benefit.
Definitive radiotherapy in the management of node-positive bladder cancer: A National Cancer Data Base (NCDB) analysis.
Authors: Stokes William Allen , Rusthoven Chad G , Yeh Norman , Kavanagh Brian D.
Published: February 2017

394

Background: The survival impact of definitive radiotherapy (RT) in lymph node positive (N+) non-metastatic (M0) bladder cancer is unclear, as reflected in the National Comprehensive Cancer Network (NCCN) guideline recommendation for chemotherapy (CT) with or without RT in this population. We conducted the present analysis of the NCDB to determine whether RT at a definitive dose would be associated with improved overall survival (OS) in patients with N+ bladder cancer. Methods: NCDB was queried for subjects diagnosed from 1998-2012 with cN1-3 M0 cancer of the urinary bladder who did not undergo cystectomy. Definitive RT included external beam radiotherapy to the pelvis or bladder regions to a cumulative dose of ≥ 54Gy (per NCCN guideline for gross nodal disease). Cox regression was used to assess the association of definitive RT with overall survival while controlling for patient-related, tumor-related, and treatment-related factors. Results: 3,298 N+ subjects not undergoing cystectomy were identified, of whom 840 (25.5%) received any RT and 392 (11.9%) received ≥ 54Gy. In the entire cohort, multivariate analysis adjusting for age, year, sex, race, location, income, comorbidity, histology, grade, T-stage, N-stage, and receipt of chemotherapy demonstrated an OS benefit (HR for death 0.69; 95%CI 0.59-0.82; p < 0.01) with cumulative RT dose ≥ 54Gy. On subgroup analysis, this OS benefit persisted both among the 1905 patients (331 receiving ≥ 54Gy) undergoing CT (HR 0.66; 95%CI 0.46-0.95; p = 0.02) and among the 1393 patients (61 receiving ≥ 54Gy) not undergoing CT (HR 0.67; 95%CI 0.55-0.82; p < 0.01). Conclusions: In the largest analysis to date of definitive radiotherapy for N+ bladder cancer, receipt of a definitive RT dose was associated with improved OS, irrespective of receipt of CT. Intermediate oncologic endpoints including locoregional control and disease-free survival were unavailable for analysis. With a minority of N+ subjects receiving any radiotherapy, this intervention appears to be underutilized among these patients.
Long-term outcomes after bladder-preserving combined-modality therapy for patients with muscle-invasive bladder cancer.
Authors: Giacalone Nicholas J , Clayman Rebecca Helen , Shipley William U. , Niemierko Andrzej , Heney Niall M. , Michaelson M Dror , McGovern Francis J. , Kaufman Donald S. , Zietman Anthony L. , Efstathiou Jason A.
Published: February 2017

398

Background: Transurethral resection of bladder tumor (TURBT), chemotherapy (CT), and radiation therapy (RT) is an established treatment paradigm for muscle-invasive bladder cancer (MIBC). Herein we report long-term outcomes for MIBC patients treated with combined-modality therapy (CMT). Methods: We analyzed 465 patients with MIBC (cT2-T4a) treated on successive protocols at a single center between 1986 and 2012. Patients underwent TURBT followed by concurrent cisplatin-based chemoradiation (CRT). A subset of patients received neoadjuvant CT. Repeat cystoscopy was performed after 40 Gy. Patients with a complete response (CR) received consolidation CRT to 64-65 Gy, while those with less than a CR or invasive recurrence were recommended to undergo salvage RC. Overall survival (OS) and disease-specific survival (DSS) were evaluated using Kaplan-Meier method and Cox proportional hazards regression. Results: Median follow-up was 4.8 years for all patients and 7.5 years for surviving patients. CR to induction CRT was achieved in 76% patients; 84% of patients with a complete TURBT achieved a CR vs. 59% with an incomplete TURBT, p< 0.001. When evaluated in four-year intervals, the CR rate improved from 64% in 1986-1990 to 96% in 2010-2012. Salvage RC was performed in 125 patients (27%), 55 for less than CR and 70 for superficial or invasive recurrence. Among patients with a CR, the 10-year actuarial rates for non-invasive, invasive, pelvic, and distant failure were 32%, 16%, 14%, and 29%, respectively. Median OS was 6.4 years. Five- and 10-year OS rates were 57% and 39% (T2 = 66%, 46%; T3-T4a = 41%, 26%), respectively. Five- and 10-year DSS rates were 66% and 59% (T2 = 75%, 66%; T3-T4a = 50%, 45%), respectively. In multivariate analyses, T2 disease (vs. T3-4; HR 0.55, 95%CI 0.40-0.76) and CR to induction therapy (HR 0.40, 95%CI 0.28-0.55) were significant predictors for improved OS. Age was not associated with DSS (HR 1.01, 95%CI 0.99-1.03). Conclusions: These data support the high rates of CR and bladder preservation in patients receiving CMT, and demonstrate long-term DSS similar to modern cystectomy series. CMT should be considered as an alternative treatment strategy for selected patients with MIBC.
Validation of a genomic classifier for prediction of metastasis following postoperative salvage radiation therapy.
Authors: Den Robert Benjamin , Choeurng Voleak , Howard Lauren , de Hoedt Amanda , Du Plessis Marguerite , Yousefi Kasra , Lam Lucia L.C. , Buerki Christine , Trabulsi Edouard John , Dicker Adam , Davicioni Elai , Karnes Jeffrey , Freedland Stephen J.
Published: February 2017

4

Background: Management of patients with a postoperative rising prostate-specific antigen (PSA) level is complex. Additional local treatment such as salvage radiation therapy (SRT) may be sufficient for many patients but some may require concurrent systemic therapy in order to delay or prevent metastatic disease. As PSA recurrence on its own is a poor surrogate for metastatic disease we hypothesized that the Decipher genomic classifier (GC), a validated predictor of metastasis may be able to better distinguish those patients where additional therapy is beneficial from those where SRT on its own is likely sufficient. Methods: Genomic classifier (GC) scores were calculated from 170 prostate cancer patients, who received SRT at the Veteran Affairs Medical Center Durham, Thomas Jefferson University and Mayo Clinic, between 1990 and 2010. SRT was defined as administration of RT with Pre-RT PSA levels > 0.2 ng/ml. GC and CAPRA-S scores were compared using survival c-index, competing-risks and Cox regression analysis for the prediction of metastasis. Results: Survival c-index for predicting metastasis 5 years post SRT was 0.85 (95% CI: 0.73-0.88) for GC and 0.63 (95% CI: 0.49-0.77) for CAPRA-S. The cumulative incidence of metastasis at 5 years post-SRT was 2.7%, 8.4%, and 33.1% for low, average, and high GC scores (p < 0.001) and 16.9%, 2.3% and 17.2% for low, average and high CAPRA-S scores (p = 0.113). In univariable analysis only GC, extraprostatic extension, path GS and Pre-RT PSA were significant predictors of metastasis. In multivariable analyses with clinical risk factors or the CAPRA-S risk model, GC was the only independent predictor of metastasis with a HR of 1.63 (1.22-2.18, p < 0.001) for a 10% unit increase in risk score. Conclusions: In patients treated with postoperative SRT for PSA recurrence, GC is a powerful predictor of metastasis. Patients with low Decipher have excellent prognosis with SRT and may avoid concurrent hormonal therapy. Patients with high Decipher risk are at highest risk for metastatic disease and SRT failure and may benefit from intensified systemic therapy.
A dual stable isotope method by LC-MS/MS to define patterns of androgen metabolism in localized versus advanced prostate cancer.
Authors: Dai Charles , Chung Yoon-Mi , Klein Eric A. , Sharifi Nima
Published: February 2017

40

Background: Prior work has shown that androstenedione (AD) rather than testosterone (T) is the preferred substrate of 5α-reductase for dihydrotestosterone (DHT) synthesis in castration-resistant prostate cancer. However, patterns of metabolism in hormone-naive prostate cancer are still poorly defined. Previously, we reported on the utility of dual radioisotope labeling of steroid precursors to characterize androgen metabolism in localized prostate tissue. We now describe an alternative approach via stable isotope labeling and analysis by liquid chromatography-tandem mass spectrometry (LC-MS/MS), which has unique advantages over the former method. Methods: LNCaP cell lines and prostate tissue from patients undergoing radical prostatectomy for localized cancer were incubated in serum-free media, spiked with 13C-labeled AD and 2H-labeled T. Media was collected at 7, 24, and 48 hours of incubation. Steroids were extracted, separated, and then analyzed by way of LC-MS/MS to identify labeled metabolites of AD and T. Results: Incubation of labeled AD and T resulted in conversion over time to both 13C-labeled and 2H-labeled downstream metabolites, 5α-dione and DHT. Although both precursors contributed to 5α-dione and DHT formation, the steroid of origin could be determined on the basis of differential labeling. In ex-vivo tissue incubations, unlabeled 5α-dione was also observed, which was distinguishable from its stable isotopic form and most likely represents endogenous steroid. Conclusions: Both cell lines and tissue appear to metabolize labeled AD and T, and formation of DHT occurs through both precursors. Furthermore, the presence of endogenous 5α-dione suggests that alternative pathways of DHT synthesis, which bypass T, may be naturally accessible in the hormone-naïve setting. We propose a robust ex-vivo technique to readily track simultaneous pathways of DHT synthesis in prostate cancer. Future work will focus on defining metabolic phenotypes of localized prostate cancer and specific patterns of flux under different hormonal and pharmacologic conditions.
Evaluation of early response to neoadjuvant chemotherapy in muscle-invasive bladder cancer using dynamic contrast-enhanced MRI and diffusion weighted MRI: MARBLE study.
Authors: Pearson Rachel Anne , Thelwall Pete E , Snell Jim , McKenna Jill , Pieniazek Piotr , Fitzgerald Emily Louise , Heer Rakesh , McMenemin Rhona Margaret , Pedley Ian D. , Azzabi Ashraf S. , Newell Herbie , Maxwell Ross J. , Plummer Elizabeth R. , Frew John A.
Published: February 2017

403

Background: Functional imaging techniques which evaluate early treatment responses may identify non-responders who would benefit from a switch in therapy. This is a prospective feasibility study of serial diffusion-weighted (DW) and dynamic contrast-enhanced (DCE) MRI scanning in patients undergoing neoadjuvant chemotherapy for muscle-invasive bladder cancer. Methods: Scans were performed before and during chemotherapy (10-17 days after the first and second cycles). A repeatability DW-MRI scan was acquired on the first visit. Regions-of-interest (ROI) encompassing the entire tumour were defined. Analysis of MRI parameters was undertaken and related to findings from the routine restaging CT scan performed after 3 cycles of chemotherapy. Results: 10/16 patients were male, median age 59 years, 14/16 had T3/4 disease, and 5/16 were node positive. 10/16 have completed 3 or 4 cycles of chemotherapy to date and attended for the restaging CT scan. Radiological response was identified in all cases. In the DW-MRI analysis there was no significant difference in mean tumour ADC or tumour volume between baseline and repeatability scans (mean ADC 1.19 and 1.2 respectively, n=16). Visual assessment showed a fall in contrast agent uptake within the primary bladder tumour after treatment. Conclusions: The scanning protocols enabled visualisation of the bladder tumours and derivation of kinetic parameters. DW-MRI measurements were comparable between baseline and repeat scan, suggesting that a change in ADC was more likely to be attributable to treatment response or disease progression than measurement error or inherent variation. Statistically significant rises in mean ADC and decreases in tumour volume were observed early in the treatment pathway. No patients progressed on treatment in this study. Larger studies of DCE and DW-MRI as surrogate response imaging biomarkers in bladder cancer are recommended. Clinical trial information: Study ID 14489. [Table: see text]
Mitomycin-C induction and maintenance topical therapy for upper tract urothelial carcinoma
Authors: Wagenheim Gavin Neal , Papadopolous John , Navai Neema , Davis John W. , Karam Jose A. , Kamat Ashish M. , Wood Christopher G. , Dinney Colin P. N. , Matin Surena F.
Published: February 2017

411

Background: Reported recurrence rates following endoscopic treatment of upper tract urothelial carcinoma (UTUC) are high, from 30% to 70%. Adjuvant BCG topical therapy results are inferior to what is seen in adjuvant treatment of bladder cancer. This is likely due to difficulty in definitive delivery to the upper tract and the absence of a reservoir for dwell times. There is limited reported use of adjuvant mitomycin-c (MMC) for UTUC, and to our knowledge no reported experience of topical delivery using the SWOG maintenance regimen. We hypothesized that a chemotherapeutic agent may be effective topical therapy of the upper tract, particularly when given using SWOG recommendations. We report efficacy, safety, and tolerability of this approach. Methods: We reviewed charts of patients undergoing primary endoscopic biopsy/resection and ablation of an UTUC, recording clinical, pathologic, laboratory, and follow up information. Patients were offered induction and maintenance topical therapy after endoscopic control. MMC was given as initial adjuvant topical agent for 6 weeks induction and 3 weeks maintenance for up to 2 years per SWOG protocol. Delivery was either via percutaneous nephrostomy or ureteral catheter, per patient preference. Results: 28 patients were identified, 21 (75%) low grade and 7 (25%) high grade. Delivery of MMC was via percutaneous nephrostomy in 29% and ureteral catheter in 71%. 46% were treated on an imperative basis, 46% elective, and 7% palliative. No patients discontinued therapy due to intolerance, and 61% received maintenance. Only 11% of patients undergoing induction and 6% maintenance incurred complications. With a mean follow up of 22 months (range 1−79), recurrence-free, progression-free, and nephroureterectomy-free survival in all patients, low-grade patients, and high-grade patients was 68%, 67%, and 71%; 89%, 90%, and 86%; and 89%, 90%, and 86%, respectively. Conclusions: In patients with complete endoscopic control, upper tract topical instillation of MMC induction and maintenance via percutaneous nephrostomy or ureteral catheter is a well−tolerated, feasible, and perhaps beneficial treatment of low-grade and possibly high-grade tumors.