bluuebunny/crossref_metadata_2025 huggingface dataset:
BC2001 long-term outcomes: A phase III randomized trial of chemoradiotherapy versus radiotherapy (RT) alone and standard RT versus reduced high-dose volume RT in muscle-invasive bladder cancer.
Authors: Hall Emma , Hussain Syed A. , Porta Nuria , Crundwell Malcolm , Jenkins Peter , Rawlings Christine Lisa , Tremlett Jean , Friend Charlotte , Stubbs Clive , Lewis Rebecca , James Nicholas D. , Huddart Robert Anthony ,   on behalf of the BC2001 Investigators
Published: March 2017

280

Background: BC2001 showed that adding chemotherapy (5FU+MMC) to radiotherapy significantly improved rates of muscle invasive bladder cancer (MIBC) locoregional control (LRC) [James 2012] but that reduced high dose volume RT rather than standard RT did not significantly reduce late side effects [Huddart 2013]. Here we present an update of the time to event outcomes after a median 10 years follow up. Methods: Under the 2x2 partial factorial design, 458 pts were randomised to RT (178) or cRT (182) (CT comparison) and/or to stRT (108) or RHDVRT (111) (RT comparison). Primary endpoint was LRC, secondary endpoints included overall survival (OS), bladder-cancer specific survival (BCSS), metastasis free survival (MFS) and salvage cystectomy rates. Results: Median follow up was 118 months (95%CI: 112-122). LRC and invasive LRC (ILRC) were improved with cRT (Table 1). Though no statistically significant differences between groups were found in OS, cRT exhibited a trend towards improvement in BCSS, significant when adjusted by known prognostic factors. Similar trend was found for MFS. Salvage cystectomy rate was lower for cRT (2-year rate, cRT:11% vs RT:17%, p=0.03). No differences between stRT and RHDVRT were found for any trial endpoint. Conclusions: With extended follow-up, an improvement in LRC and a reduced salvage cystectomy rate is confirmed with cRT. After adjustment for known prognostic factors this results in an improvement in BCSS. This updated data supports the use of cRT with 5FU/MMC and confirms this should be a standard of care for this patient population. Clinical trial information: ISRCTN68324339. [Table: see text]
Health-related quality of life (HRQoL) in the KEYNOTE-045 study of pembrolizumab versus investigator-choice chemotherapy for previously treated advanced urothelial cancer.
Authors: Vaughn David J. , Bellmunt Joaquim , De Wit Ronald , Fradet Yves , Lee Jae-Lyun , Fong Lawrence , Vogelzang Nicholas J. , Climent Miguel Angel , Petrylak Daniel Peter , Choueiri Toni K. , Necchi Andrea , Gerritsen Winald R. , Gurney Howard , Quinn David I. , Culine Stephane , Sternberg Cora N. , Mai Yabing , Li Haojie , Perini Rodolfo F. , Bajorin Dean F.
Published: March 2017

282

Background: In KEYNOTE-045 (NCT02256436) (N = 542), pembro 200 mg Q3W significantly improved OS over investigator’s choice of paclitaxel, docetaxel, or vinflunine as second-line therapy for advanced UC following platinum-based chemo (HR 0.73; P = 0.0022). Fewer treatment-related AEs were reported with pembro. We present results of the prespecified HRQoL analysis of KEYNOTE-045. Methods: The EORTC QLQ-C30 HRQoL instrument was administered electronically at cycles 1–4, then every 2 cycles for up to 1 y and 30 d after discontinuation. The key HRQoL end points were 1) change from baseline to wk 15 and 2) time to deterioration (TTD) (defined as ≥ 10-point decrease from baseline) in the QLQ-C30 global health status/QoL score. HRQoL was assessed in patients (pts) who received ≥ 1 dose of assigned study treatment and completed ≥ 1 HRQoL instrument (N = 520). Score change from baseline was compared using a constrained longitudinal data analysis model. TTD was compared using a stratified log-rank test and Cox proportional hazards model. Results: Baseline global health status/QoL scores were similar between arms. HRQoL compliance at wk 15 was 88% for both arms. From baseline to wk 15, scores were stable for pembro (n = 266) (least squares [LS] mean +0.75 [95% CI –2.34 to +3.83]) but worsened for chemo (n = 254) (LS mean –8.30 [95% CI –11.76 to –4.83]); the difference in LS means between arms was 9.05 (95% CI 4.61-13.48; nominal 2-sided P < 0.001). At wk 15, pts without PD had improved scores with pembro but worsened scores with chemo (LS mean +5.97 vs –4.31), while pts with PD had less worsening with pembro (LS mean –3.54 vs –13.95). TTD was prolonged with pembro (HR 0.70; 95% CI 0.55-0.90; nominal 1-sided P = 0.002; median 3.5 mo vs 2.2 mo). Rates of improvement (defined as ≥ 10-point increase from baseline) at wk 15 were 31.2% with pembro and 22.0% with chemo; rates of deterioration were 28.9% and 40.6%, respectively. Conclusions: Pembro was associated with substantially better HRQoL for a longer duration than investigator-choice chemo in pts with previously treated advanced UC. Along with superior OS, these data support pembro as a new standard-of-care in this population. Clinical trial information: NCT02256436.
Results of a randomised phase II study of hypofractionated bladder radiotherapy (RT) with or without image guided adaptive planning (HYBRID - CRUK/12/055).
Authors: Huddart Robert Anthony , Henry Ann , Khoo Vincent , Staffurth John , Syndikus Isabel , Hansen Vibeke , McNair Helen , Hafeez Shaista , Lewis Rebecca , Parsons Emma , Baker Angela , Vassallo - Bonner Catalina , Moinuddin Syed Ali , Mossop Helen , Birtle Alison J. , Horan Gail , Rimmer Yvonne L. , Venkitaraman Ramachandran , Mitra Anita , Hall Emma ,   On behalf of all HYBRID PIs
Published: March 2017

283

Background: Muscle invasive bladder cancer (MIBC) incidence increases with age, with many patients (pts) unfit for radical therapy. We aimed to demonstrate feasibility of delivery & acceptable rates of hypofractionated RT toxicity using image guided adaptive techniques for these pts in a multicentre trial. Methods: Pts with T2-T4aN0M0 MIBC had 36 Gray (Gy) in 6 fractions (fr) over 6 weeks & were randomised (1:1) to standard (SP) or adaptive planning (AP). For AP 3 RT plans (small, medium, large) were generated with preRT cone beam (CB) CT used to select best fitting ‘plan of the day’ at each fr. A QA programme aided standardised CBCT image interpretation. The SP group had RT with 1 plan. The aim was to exclude ≥30% grade ≥3 (≥G3) acute (to 3 months (m)) non-genitourinary (GU) toxicity for AP in pts with no MIBC death by 3m (p0=0.7 p1=0.9 α=0.05 β=0.2). Secondary endpoints included 36Gy/6fr acute toxicity in pts who had ≥1 RT fr & proportion of AP fr using small/large plan. Adverse events (AEs) were assessed (CTCAE v4) weekly on RT, 4 weeks & 3m post RT. Blind independent review assessed relatedness of non-GU AEs to RT. Results: Between Apr 2014 & Aug 2016 65 pts were randomised (SP (n=32) AP (n=33)) from 12 UK sites. Median age was 85yrs; 68% male; 92% transitional cell MIBC; 99% grade 3; 25% clinical stage T3 & 6% T4. 58 pts are evaluable to date, ≥G3 acute non-GU adverse reactions (AR) were reported in 2/30 (7%; 90% CI: 1%–20%) AP (G3 hyperkalemia & hyponatremia; G3 diarrhea & dehydration) & 3/28 (11%; 90% CI: 3% –25%) SP pts (G3 fatigue; G3 hyperkalemia, weight loss & anorexia; G3 diarrhoea). 24/65 (37%; 90% CI: 27%-48%) pts who had ≥1 RT fr had ≥G3 acute AEs including G4 hyponatremia (2 AP pts), G5 pneumonia (1 SP, 1 AP), G5 sepsis (1 AP) & G5 renal failure (1 SP) (all G4/5 unrelated to RT). 7/65 pts received <6 fr RT due to toxicity. In the 33 AP pts 40/182 fr (22%) used a small plan & 29/182 (16%) large (adaption rate=38%; 95% CI: 31%-45%). Conclusions: Though overall ≥G3 AE rate was significant, 36Gy/6fr with AP is feasible, met predefined toxicity criteria (<30% ≥G3 acute non-GU ARs) & with >25% fr adapted has potential for benefit. Comparative randomised studies are needed to quantify benefits of AP over SP. Clinical trial information: 18815596.
Pembrolizumab as first-line therapy in cisplatin-ineligible advanced urothelial cancer: Results from the total KEYNOTE-052 study population.
Authors: Balar Arjun Vasant , Castellano Daniel E. , O'Donnell Peter H. , Grivas Petros , Vuky Jacqueline , Powles Thomas , Plimack Elizabeth R. , Hahn Noah M. , De Wit Ronald , Pang Lei , Savage Mary , Perini Rodolfo F. , Keefe Stephen Michael , Bajorin Dean F. , Bellmunt Joaquim
Published: March 2017

284

Background: Treatment options are limited for patients (pts) with advanced urothelial cancer (UC) ineligible to receive cisplatin-based chemotherapy. Interim results from the first 100 pts enrolled in the phase 2, open-label KEYNOTE-052 (ClinicalTrials.gov, NCT02335424) study suggested first-line pembrolizumab (pembro) had antitumor activity and acceptable safety in this pt population. Results from the fully enrolled study are presented. Methods: Key eligibility criteria included age ≥ 18 y, advanced UC of the renal pelvis, ureter, bladder, or urethra, cisplatin ineligibility (ECOG PS 2, creatinine clearance ≥ 30 to < 60 mL/min, grade ≥ 2 neuropathy or hearing loss, NYHA Class 3 heart failure), no prior systemic chemotherapy for advanced UC, measurable disease per RECIST v1.1, ECOG PS 0-2, and provision of a tumor sample for biomarker analyses. Pembro 200 mg was administered every 3 wk. Imaging was performed at wk 9, then every 6 wk for the first year, and every 12 wk thereafter. The primary end point was confirmed overall response rate (ORR; RECIST v1.1, independent review). Efficacy data are presented for pts with ≥ 4 mo follow-up, and safety data are presented for all pts. Results: In total, 370 pts were enrolled; median age was 74 y (range, 34-94 y); 42% had an ECOG PS 2. Reasons for cisplatin ineligibility included ECOG PS 2 (32%), renal dysfunction (49%), and both ECOG PS 2 and renal dysfunction (10%). ORR (95% CI) was 27% (22%-32%) among pts with ≥ 4 mo follow-up (n = 307); 6% of pts achieved a complete response. Among the ≥ 4 mo follow-up group, median (range) time to response was 2.0 (1.6-4.8) mo; median (range) duration of response was not reached (1+ to 14+ mo). 78% of responders had a response for ≥ 6 mo (KM estimate). PFS and OS rates at 6 mo were 31% and 67%, respectively (KM estimate). Any grade and grade ≥ 3 drug-related AEs occurred in 229 (62%) and 58 (16%) pts. 19 (5%) pts discontinued treatment because of a drug-related AE. Conclusions: Results from the fully enrolled KEYNOTE-052 study confirm that pembro elicits clinically meaningful and durable responses in cisplatin-ineligible pts with UC, including elderly pts and those with poor performance status. Clinical trial information: NCT02335424.
Updated efficacy and tolerability of durvalumab in locally advanced or metastatic urothelial carcinoma.
Authors: Powles Thomas , O'Donnell Peter H. , Massard Christophe , Arkenau Hendrik-Tobias , Friedlander Terence W. , Hoimes Chris , Lee Jae-Lyun , Ong Michael , Sridhar Srikala S. , Vogelzang Nicholas J. , Fishman Mayer N. , Zhang Jingsong , Srinivas Sandy , Parikh Jigar , Antal Joyce , Jin Xiaoping , Gupta Ashok Kumar , Hahn Noah M.
Published: March 2017

286

Background: Anti-PD-L1 immunotherapy has shown promising clinical activity in urothelial carcinoma (UC). We report on a planned update of efficacy and follow-up in patients (pts) receiving durvalumab for the treatment of locally advanced or metastatic UC. Methods: Pts received durvalumab 10 mg/kg Q2W up to 12 months (mo), unacceptable toxicity or confirmed progressive disease. Tumor PD-L1 expression was assessed using the validated Ventana SP263 assay (PD-L1 high = TC ≥ 25% or IC ≥ 25%). Primary endpoints were confirmed ORR by RECIST v1.1 with blinded independent central review (BICR) and safety. Duration of response (DoR) and overall survival (OS) were key secondary endpoints. Results: As of July 24, 2016 (data cutoff [DCO]), the primary efficacy population included 103 pts who were followed for at least 13 weeks (median duration of follow up 7.3 mo); 37% had ≥ 2 prior regimens; 97% had prior platinum treatment; 95% had visceral metastases; and 49% had liver metastases at baseline. As of the DCO, 21 pts (20.4%) had a confirmed response per BICR (including 5 pts [4.9%] with a complete response) and an additional 3 pts had an unconfirmed response. Responses were seen in both PD-L1 high and PD-L1 low/negative subgroups (Table). Responses occurred early (median time to response 1.4 mo) and were durable. Median DoR has not been reached. Of the 21 confirmed responders, 18 pts had an ongoing response, 16 pts had DoR ≥ 6 mo and 7 pts had DoR ≥ 9 mo. Treatment-related Grade 3/4 AE rates were low (5.2%; as treated population, n = 191); Grade 3/4 immune-mediated AEs (imAEs) occurred in 3 pts, and 1 pt discontinued treatment due to an imAE of acute kidney injury. Conclusions: Durvalumab administered at 10 mg/kg Q2W showed clinical activity and an excellent safety profile in pts with locally advanced or metastatic UC. Clinical trial information: NCT01693562. [Table: see text]
Association of treatment facility case volume with survival in patients undergoing radiotherapy/chemoradiotherapy for muscle-invasive bladder cancer: An analysis of the National Cancer Database.
Authors: Bajaj Amishi , Block Alec , Martin Brendan , Korpics Mark , Hentz Courtney , Blackwell Robert H , Gaynor Ellen R. , Henry Elizabeth , Gupta Gopal Nand , Harkenrider Matthew M. , Solanki Abhishek Ashok
Published: March 2017

295

Background: Excellent outcomes with bladder-preserving trimodality therapy have been demonstrated at centers with expertise and high-volume. Some argue that these results may not be replicated at other centers with lower case volumes. We analyzed the National Cancer Database to determine if treatment at a high-volume facility is associated with improved overall survival (OS) for patients undergoing radiotherapy (RT) or chemoradiotherapy (CRT) for non-metastatic muscle-invasive bladder cancer (MIBC). Methods: Patients with cT2-4 N0-3 M0 transitional cell MIBC treated with RT or CRT were selected. The case volume variable was derived by calculating a count of patient records by each facility using the entire database of 439,188 patients. Multivariate analysis (MVA) was performed using the Cox proportional hazards model, which was used to assess the association of case volume with OS while controlling for clinicodemographic and treatment factors associated with OS on univariate analysis, including clustering of patients within their treatment facility type. Results: 872 patients treated with radiotherapy from 2008-2012 at 452 unique facilities were identified. 502 (58%) patients received RT, and 370 (42%) patients received CRT. The median case volume at each unique facility was 376 cases with an interquartile range of 235 – 579 cases. In the entire radiotherapy cohort, MVA controlling for patient case load, age, sex, education, T Stage, N Stage, cumulative radiotherapy dose, Charlson-Deyo comorbidity score, and geographic location, demonstrated that treatment at a facility with a higher case volume was associated with improved OS. For every 250 patient increase in facility case volume, the hazard of death at any given time for patients receiving radiotherapy decreased by 7% (HR = 0.93, 95% CI: 0.87 – 0.98, p = .01). Conclusions: To the authors’ knowledge, this is the first analysis demonstrating an association between treatment facility case volume and OS in the treatment of MIBC patients with RT or CRT. Consideration should be given to referring patients to high volume facilities for treatment of MIBC.
Outcome of BC2001 patients (CRUK/01/004) who received neoadjuvant chemotherapy prior to randomization to chemo-radiotherapy (cRT) versus radiotherapy (RT).
Authors: Hussain Syed A. , Hall Emma , Porta Nuria , Crundwell Malcolm , Jenkins Peter , Rawlings Christine Lisa , Tremlett Jean , Hendron Carey , Lewis Rebecca , Huddart Robert Anthony , James Nicholas D. ,   on behalf of the BC2001 Investigators
Published: March 2017

298

Background: Neoadjuvant chemotherapy is considered standard of care for patients with muscle invasive bladder cancer (MIBC). Gemcitabine plus cisplatin or carboplatin (GC) has been adopted as a standard neoadjuvant regimen for MIBC. BC2001 showed that adding chemotherapy (5FU+MMC) to radiotherapy (55Gy/20f or 64Gy/32f) significantly improved rates of muscle invasive bladder cancer (MIBC) locoregional control (LRC) [James 2012]. We report outcome of patients (pts) receiving neoadjuvant chemotherapy prior to starting BC2001 trial treatment (cRT or RT alone). Methods: Between August 2001 and April 2008, 360 pts were randomised to RT (178) or cRT (182); 117 (32.5%) received neoadjuvant chemotherapy (61 RT, 56 cRT). Primary endpoint was LRC, secondary endpoints included toxicity, overall survival (OS) and metastasis free survival (MFS). Cox models adjusted by known prognostic factors were used to estimate randomised treatment effect in this subgroup of pts. Toxicities were compared by Chi squared tests. Results: Median age of the 117 pts was 66 (interquartile range: 60-73) years, 86% were male, 73% had baseline 0 WHO performance status. 81% had T2 and 87% G3 tumours. Neoadjuvant treatment received was GC (73.5%), MVAC (13.6%), CMV (11.1%) or other (<2%). 92.3% cRT and 91.8% RT pts completed radiotherapy as planned. Grade 3 or above adverse events during treatment occurred in 27.4% pts (32.2% cRT vs 22.9 RT, p-value(p)=0.27), and in 9.5% during follow-up (13.4% cRT vs 5.3% RT, p=0.21). There was a trend for improved LRC in the cRT group (hazard ratio HR=0.64, 95CI% 0.33-1.23, p=0.18), while no differences in OS (HR=0.95, 95CI% 0.57-1.57, p=0.83) or MFS (HR=0.93, 95CI% 0.52-1.65, p=0.80) were observed. Median OS was 46.7 months ,cRT: 50.4 months vs RT: 46.7 months. MFS: Median: 68.5 months, cRT: 118.5 months vs RT: 54.2 months. Conclusions: The benefit in improved LRC of synchronous chemotherapy with 5FU/MMC was also found in the subgroup of BC2001 pts receiving neoadjuvant chemotherapy, with no significant increase in late toxicity. Neoadjuvant chemotherapy did not compromise the delivery of radical curative treatment with RT or cRT. Clinical trial information: ISRCTN68324339.
Luminal and basal subtyping of prostate cancer.
Authors: Feng Felix Yi-Chung , Zhao Shuang , Chang Seiwon Laura , Erho Nicholas , Lehrer Jonathan , Alshalalfa Mohammed , Cooperberg Matthew R. , Kim Won , Ryan Charles J. , Den Robert B. , Freedland Stephen J. , Posadas Edwin M. , Klein Eric A. , Davicioni Elai , Ross Ashley , Schaeffer Edward M. , Nguyen Paul L. , Carroll Peter , Karnes Jeffrey , Spratt Daniel Eidelberg
Published: March 2017

3

Background: There is a clear need to develop a clinically relevant molecular subtyping approach for prostate cancer. We hypothesized that prostate cancer can be subtyped based on luminal versus basal lineage. Methods: We applied the PAM50 classifier, which is used clinically to identify luminal and basal cancers in breast cancer, to subtype a total of 3,782 prostate cancer samples using a high-density microarray platform run in a CLIA-certified laboratory. We examined the associations of these subtypes and clinical outcomes. Results: We demonstrate that PAM50 segregates prostate cancer into three reproducible subtypes in both retrospective cohorts and on prospective validation: luminal A (33.3%-34.3%), luminal B (28.5%-32.6%), and basal (34.1%-37.1%). Luminal B prostate cancers exhibited the worst clinical prognoses, followed by basal and luminal A subtypes (10-year biochemical recurrence-free survival: 29/39/41%; distant metastasis-free survival: 53/73/73%; prostate cancer-specific survival: 78/86/89%; overall survival: 69/80/82% respectively) on both univariable and multivariable analyses accounting for standard clinicopathologic prognostic factors. Known luminal lineage markers, such as NKX3.1 and KRT18, and the basal lineage CD49f signature, were enriched in luminal- and basal-like cancers respectively, demonstrating the connection between these subtypes and established prostate cancer biology. While both luminal-like subtypes were associated with increased AR expression and signaling, only luminal B prostate cancers were significantly associated with post-operative response to androgen deprivation therapy (ADT) in a subset analysis matching patients based on clinicopathologic variables (interaction p = 0.006, luminal B 10-year metastasis: 33% (treated) vs. 55% (untreated), non-luminal B: 37% (treated) vs. 21% (untreated)). Conclusions: These findings contribute novel insight into the biology of prostate cancer, and provide translatable clinical tools for personalizing post-operative ADT for patients with prostate cancer. Similar to breast cancer, these findings suggest that luminal/basal subtyping may be useful in treatment selection in prostate cancer.
A hypoxia transcriptomic signature to predict benefit from hypoxia-modifying treatment for muscle-invasive bladder cancer patients.
Authors: Choudhury Ananya , Yang Lingjian , Irlam Joely J , Williamson Amanda , Denley Helen , Hoskin Peter , West Catharine
Published: March 2017

301

Background: Hypoxia modification improves overall survival (OS) in muscle invasive bladder cancer (MIBC) patients treated with radical radiotherapy. There is evidence that hypoxic tumours benefit most from hypoxia modification. The study aimed to identify or derive a hypoxia gene signature that predicts benefit from hypoxia-modifying treatment in MIBC. Methods: Bladder cancer transcriptomic data were available from public datasets and generated for 152 tumour samples from the BCON phase III trial of radiotherapy (RT) alone or RT with carbogen and nicotinamide (CON) using Affymetrix Human 1.0 Exon ST arrays. Published hypoxia signatures were tested. A novel signature was then derived by identifying candidate hypoxia genes from the literature and evaluating their bladder cancer specificity in the publically available datasets. A gene co-expression network was built and hub genes identified to generate a signature. Results: None of the published hypoxia signatures were prognostic in public datasets or predicted benefit from hypoxia modification in the BCON patients. A novel 24-gene signature was derived and its prognostic significance was validated in 7 surgical cohorts. The signature was then independently validated in BCON patients. Patients categorised as high- versus low-hypoxia by the signature had a poor local progression free survival (LPFS) following radiotherapy alone (HR 2.37, 95% CI 1.26-4.47, P= 0.0076). The signature also predicted benefit from CON with high-hypoxia patients receiving CON having a better LPFS than those receiving radiotherapy alone (HR 0.47, 95% CI 0.26-0.86, P= 0.0147). Prognostic and predictive significance remained after adjusting for clinicopathological variables (including gender, necrosis, age, stage and carcinoma in situ). Conclusions: A 24-gene hypoxia signature has strong, independent prognostic and predictive value with the potential for stratifying patients with MIBC for treatment with hypoxia-modification strategies.
An oral methionine aminopeptidase II inhibitor for high-risk non-muscle invasive bladder cancer relapsed after intravesical therapies: Update of a phase II trial.
Authors: Ye Dingwei , Yao Xudong , Wang Gongxian , Pu Jinxian , Yao Xin , Zhou Fangjian , Qi Jun , Ye Zhangqun , Xie Liping , Chen Jimin , Xie Keji , Zhao Xiaokun , Xu Zhihui , Guo Hongqian , Yang Yong , Cao Dalong , Yang Bin , Zhang Cheng , Lu Yong , Du Jun
Published: March 2017

303

Background: In 2016, we reported the preliminary results of APL-1202, an oral MetAP2 inhibitor, in the first 18 patients enrolled in the phase II trial. The purpose of the present study is to update the results of efficacy, safety, pharmacokinetics at steady state and translational studies in 41 patients. Methods: This is an open-label, single-arm phase II trial conducted in 15 hospitals in China. High-risk in recurrence is defined according to EORTC recurrence score and probability tables in EAU 2012 Guidelines on NMIBC. The primary end point is the recurrence-free survival rate at 1 year. Plasma and urine samples at steady state were collected for pharmacokinetic studies, and separate plasma samples were collected for translational studies. Results: From May 2014, a total of 41 patients have been enrolled in this study, including 39 relapsed after intravesical chemotherapies only (chemo-failed subgroup), and 2 after both chemo and BCG treatments (BCG-failed subgroup). All of patients had TaT1 papillary tumors, and 3 with concurrent carcinoma in situ . APL-1202 did not cause any drug-related SAEs. By the time of this abstract submission, the 1-year recurrence-free rate is 54.3% (37.2-73.2%, 95% Confidence Interval) with a median recurrence-free survival of 14.7 months. APL-1202’s plasma exposure at steady state appears to increase proportionally to the increase of doses. Conclusions: APL-1202 is safe and well tolerated at a daily dose up to 750mg, TID, for 12 weeks followed by 3 months on-and-off in patients with recurred high-risk NMIBC. According to the EAU 2012 Guidelines on NMIBC, naïve high-risk NMIBC patients treated by intravesical chemotherapies have a 1-year recurrence-free rate of 39% (33-45%, 95% CI) with a median recurrence-free survival of 9 months. Our results support the concept that oral MetAP2 inhibitor APL-1202 as a second-line therapy has the potential to achieve at least similar efficacy with the first-line intravesical chemotherapies, and warrant a randomized trial alone or in combination with other therapies in NMIBC patients. Clinical trial information: CTR20131716.
18F-FDG-PET/CT imaging to assess response to treatment with cabozantinib at 4 weeks versus 8 weeks of therapy in patients (pts) with metastatic urothelial carcinoma (mUC).
Authors: Davarpanah Nicole N. , Lindenberg Liza , Paul Dereck W , Steinberg Seth M. , Francis Deneise C , Berniger Marilise Anne , Weaver Juanita , McKinney Yolanda , Parnes Howard L. , Choyke Peter L. , Apolo Andrea B.
Published: March 2017

317

Background: This study investigates whether changes in 18F-FDG-PET/CT correlate with response to cabozantinib at an early time point (4 wks) versus the conventional time point of restaging (8 wks) in pts with mUC, using Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST). Methods: 68 pts with mUC in a single arm phase II clinical trial of cabozantinib underwent FDG-PET/CT scans at baseline, 4 and 8 wks. Up to 5 lesions with the highest Standard Uptake Value (SUV) were designated as target lesions. Response was determined using 2 versions of PERCIST (1 lesion vs top 5 lesions with highest FDG uptake) for FDG-PET/CT at 4 and 8 wks. PERCIST response classifications were compared to RECIST v1.1 at 8 wks. Results: 54 pts had evaluable disease. The single lesion 4 wk response by PERCIST showed 40% partial metabolic response (PMR), 33% stable metabolic disease (SMD), and 27% progressive metabolic disease (PMD). The single lesion 8 wk response by PERCIST showed 31% PMR, 31% SMD, and 38% PMD. The single lesion analysis coincided with multiple lesion PERCIST analysis in 86% of pts at 4 wks and 89% at 8 wks. The 4 wk PET/CT was predictive of the 8 wk PET/CT in 75% of single lesion and 76% of multiple lesion analyses. In lesion-based analysis, the 4 wk PET/CT was predictive of the 8 wk PET/CT in 74% of bone, 89% of lung, 77% of lymph node, 74% of soft tissue, and 58% of liver lesions. Only 42% of the 8 wk PERCIST and RECIST classifications coincided. At 8 wks, 40% showed response in FDG PET-CT restaging vs 7% complete/partial response by RECIST. Conclusions: The 4 wk PET/CT scan predicts the therapy response at the 8 wk PET/CT scan however the 4 wk scan overestimates the 8 wk response. The single lesion analysis by PERCIST correlates with the multiple lesion analysis and may have more clinical utility. In the lesion-based analysis, the 4 wk PET/CT scan is predictive of the 8 wk PET/CT for bone, lung, lymph node and soft tissue but not for liver lesions. Response classifications by PERCIST are not in agreement with response classifications by RECIST. Although the methods may be complementary, they are not interchangeable. Further studies are required to validate these findings. Clinical trial information: NCT01688999.
Cross-sectional evaluation of long-term bowel issues after radical cystectomy.
Authors: Hupe Marie C , Vahlensieck Winfried , Hennig Martin Jp , Ozimek Tomasz , Struck Julian , Tezval Hossein , Merseburger Axel Stuart , Kuczyk Markus A , Kramer Mario W
Published: March 2017

318

Background: We had previously shown that a significant number of patients after radical cystectomy (RC) suffer from changes in bowel habits and defecation. Reports addressing long-term bowel disorders following RC are rare. This cross sectional study evaluates long-term bowel issues in a large cohort with the help of an issue-tailored questionnaire. Methods: For this purpose a questionnaire assessing changes in bowel function and its impact on daily life was developed and distributed among members of the German bladder cancer self-help group. A total of 431 patients after RC were evaluated. Symptoms such as diarrhea, constipation, urge to defecate, sensation of incomplete defecation, flatulence, and impact on quality of life (QoL) were assessed. Results: A total of 324 patients were followed ≥1 year, 43% patients of those reported current bowel disorders, 40% life restriction and 60% dissatisfaction. Most frequent bowel symptoms were flatulence (49%), followed by diarrhea (30%) and the sensation of incomplete defecation (23%). The highest prevalence rate of diarrhea is reported in year 3 after surgery: <3 months after surgery 14%, 3-11 months 21%, 12-23 months 18%, 24-35 months 44%, 36-59 months 36%, ≥60 months 27% (p<0.01). Also flatulence is a long-term bowel symptom with a prevalence of 50% ≥1 year vs 37% <1 year after surgery (p=0.0334), while the prevalence of other bowel symptoms did not change over time. After 12 months, diarrhea significantly correlated with flatulence, uncontrolled stool loss, urge to defecate, younger age at time of surgery, and the size of bowel segment for urinary diversion (all p<0.01). Patients suffering from diarrhea report a higher defecation frequency, a lower QoL, a higher dissatisfaction level, a lower energy level (all p<0.01), and a lower health state (p=0.0488). Conclusions: Diarrhea is a prominent long-term bowel symptom after RC. A better understanding of long-term bowel symptoms might lead to optimized surgical procedures, post-operative medication and patient education.
Can index lesion tumor volume on T2 weighted MRI predict biochemical recurrence following radical prostatectomy?
Authors: Sugano Dordaneh , Sidana Abhinav , Calio Brian P. , Gaur Sonia , Maruf Mahir , Jain Amit L , Merino Maria J , Choyke Peter L. , Turkbey Baris , Wood Bradford J. , Pinto Peter A.
Published: March 2017

32

Background: Several studies have demonstrated an association in prostate cancer patients between the tumor volume of the index lesion calculated from whole mount pathology after radical prostatectomy and biochemical recurrence (BCR). We aimed to evaluate whether the index lesion tumor volume (ILTV) measured on MRI would have similar predictive ability. Methods: Clinical and pathologic data from a prospectively maintained, single-institution database was analyzed for 501 patients who underwent RARP (without prior therapy) between 2007 and 2016. Patients were excluded if they were found to have metastatic disease on pathology or if postoperative PSA ≥ 0.2ng/ml after RARP. ILTV was calculated from T2W MRI by multiplying length by width by depth by 0.52. Tumor volume was stratified into two categories based on the cutoff of 2cm3. BCR was defined as 2 PSA values ≥ 0.2 ng/ml, 1 PSA value ≥ 0.4 ng/ml, or receipt of radiation therapy/hormonal therapy after RARP. Cox proportional hazard regression was used to assess associations of clinical, imaging, and histopathological variables with BCR. Results: The median age of our cohort was 60 years (IQR 10) and median PSA was 6.20 ng/ml (IQR 6). Of the 493 patients who met our inclusion criteria, 55 (11.2%) experienced BCR. Patients with ILTV > 2cc had a higher incidence of BCR compared to those with ILTV < 2cc (18.0% vs 8.8%, p = 0.008). On univariate analysis, age (HR 0.96, p = 0.026), PSA (HR 1.04, p < 0.001), black race (HR 1.816, p = 0.047), Gleason 8-10 on biopsy (HR 3.725, p < 0.001), and ILTV (HR 2.496, p = 0.002) were significant for prediction of BCR. Although age (HR 0.955, p = 0.021), PSA (HR 1.029, p = 0.013), and Gleason 8-10 on biopsy (HR3.367, p < 0.001) were found to be independent predictors of BCR, tumor volume was not found to be an independent predictor (HR 0.960, p = 0.642). Conclusions: Although ILTV alone was predictive of BCR, ILTV was not found to be an independent predictor of BCR, indicating that at this time, MRI cannot yet measure ILTV with enough accuracy to predict oncologic outcomes. As imaging technology improves, ILVT may provide additional prognostic information.
A genome-wide query of somatic copy number alterations to predict lymph node metastases and survival in patients with muscle-invasive bladder cancer.
Authors: Lindquist Karla , Sanford Thomas , Friedlander Terence W. , Paris Pamela , Porten Sima P.
Published: March 2017

325

Background: Patients with muscle-invasive bladder cancer (MIBC) have a poor prognosis if the cancer has metastasized to surrounding lymph nodes (LN). Adding tumor-based genomic tests that improve prediction of LN status and prognosis over clinical variables alone would be useful to clinicians in making treatment decisions, potentially improving outcomes for these patients. Methods: We performed a genome-wide query of copy number alterations (CNAs) in MIBC tumors from 237 patients in The Cancer Genome Atlas who had radical cystectomy and lymphadenectomy ( ≥ 10 nodes) without neoadjuvant treatment. We independently analyzed pathology reports and copy number data to confirm LN status and gene-level CNAs. Using elastic net and logistic regression models, we sought to identify a set of genes with CNAs that predict LN status. We also tested for association between CNAs and survival. Results: We identified 26 genes with CNAs that predicted LN status. Those located on chr3p25 and chr11p11 had gains associated with LN positivity after adjusting for age, gender, race, pathological tumor stage, histology, and number of nodes examined (p = 0.03). CNAs at these loci were also associated with one-year survival in the cohort overall (p < 0.01), as well as in LN-positive patients after adjusting for node stage, LN density, and extracapsular extension (p < 0.01). Conclusions: We have identified a small set of genes with CNAs in MIBC tumors that robustly predict LN status and one-year survival. A simple copy number-based test based on these genes could potentially improve preoperative LN status determination and help inform adjuvant treatment decisions to improve outcomes in MIBC patients.
Prostate cancer in 671 hypogonadal men with and without long-term testosterone treatment: Results from a controlled registry study.
Authors: Haider Ahmad , Haider Karim Sultan
Published: March 2017

33

Background: Despite persisting concerns, there is no evidence that TTh in men with hypogonadism increases PCa incidence or severity. Rather, a Canadian group recently found that long-term TTh decreased the risk of PCa diagnosis (Wallis et al., Lancet Diab Endocrinol 2016; 4:498). We assessed incidence and severity of PCa in hypogonadal men on long-term TTh (T-group) in comparison to an untreated hypogonadal control group (CTRL). Methods: 375 men (age range: 33-70) with testosterone ≤ 350 ng/dL and symptoms received testosterone undecanoate 1000 mg every 3 months for up to 10 years. 296 hypogonadal men (57-74) opted against TTh. Median follow-up: 7 years. Prostate volume (PV), PSA, weight and C-reactive protein (CRP) were measured and digital rectal examination/transrectal ultrasound performed before treatment initiation and then regularly every 3-6 months. Biopsies were performed when indicated according to EAU guidelines. Results: In the T-group, PV increased slightly but significantly by 2.41 mL (p < 0.0001), PSA by 0.22 (NS). In CTRL, PV decreased slightly but significantly by -1.20 mL (p < 0.005), PSA by -0.38 (p < 0.0001). Weight dropped by 18.23% in the T-group and increased by 1.78% in CTRL, CRP decreased significantly in the T-group and remained unchanged in CTRL. In the T-group, 8 men (2.1%) were diagnosed with PCa. In CTRL, 12 (4.1%) were diagnosed with PCa. The incidence per 10,000 years was 32 in the T-group and 64 in CTRL. The mean baseline age of PCa patients was 65 years in both groups. Prostatectomy was performed in all men. In the T-group, all patients had a Gleason score ≤ 6 and a predominant Gleason score of 3. Tumor grade was G2 in all 8 (100%), tumor stage T2a in 6 (75%) and T2b in 2 (25%) patients. In CTRL, Gleason score was > 6 in all 12 patients. Three men had a predominant Gleason score of 3, 8 had 4, and 1 had 5. Tumor grade was G2 in 5 (41.7%) and G3 in 7 (58.3%) patients, tumor stage T2b in 1 (8.3%), T2c in 1 (8.3%), T3b in 4 (33.3%) and T3c in 6 (50%) patients. Conclusions: TTh in hypogonadal men regularly monitored may decrease incidence of PCa compared to hypogonadal CTRL. PCa was less severe in the T-group. Weight loss and reduced inflammation by TTh may have contributed to our findings.
Avelumab in patients with metastatic urothelial carcinoma: Pooled results from two cohorts of the phase 1b JAVELIN Solid Tumor trial.
Authors: Patel Manish R. , Ellerton John Allan , Infante Jeffrey R. , Agrawal Manish , Gordon Michael S. , Aljumaliy Raid , Britten Carolyn D. , Dirix Luc , Lee Keun-Wook , Taylor Matthew H. , Schöffski Patrick , Wang Ding , Ravaud Alain , Gelb Arnold , Xiong Junyuan , Rosen Galit , Apolo Andrea B.
Published: March 2017

330

Background: Avelumab is a fully human anti‒PD-L1 IgG1 antibody with promising efficacy and safety in patients (pts) with metastatic urothelial carcinoma (mUC). To further characterize the clinical activity of avelumab in mUC, we report a planned interim pooled analysis of 2 cohorts from a large phase 1b trial (NCT01772004). Methods: Pts with mUC progressed after platinum-based therapy or cisplatin-ineligible, and unselected for tumor PD-L1 expression, received avelumab 10 mg/kg (1 h IV) Q2W. Response was assessed every 6 wks by independent review per RECIST v1.1. Endpoints included objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety (NCI CTCAE v4.0), and tumor PD-L1 expression (clone 73-10). Results: As of Mar 19, 2016, 241 pts received avelumab for a median of 8 wks (range 2-80); median follow-up was 7.3 mos (range 0-18.2). Primary tumor sites were upper tract (renal pelvis/ureter [23.7%]) and lower tract (bladder/urethra [76.3%]). 95.4% of pts had progressed on prior platinum therapy, and 63.4% had received ≥ 2 prior lines for advanced disease (range 0-6). In 153 pts with ≥ 6 mos follow-up, confirmed ORR was 17.6% (95% CI 12.0-24.6) with 9 complete responses and 18 partial responses; 24/27 (88.9%) were ongoing. Median DOR was not reached, and the 24-wk DOR rate was 92.0% (95% CI 71.6, 97.9). 36 pts had stable disease as best response (disease control rate 41.2%). Median PFS was 6.4 wks (95% CI 6.1-11.4), and median OS was 7.0 mos (95% CI 5.6-11.1). Based on a ≥ 5% PD-L1 staining cutoff in evaluable pts with PD-L1+ (n = 56) and PD-L1– (n = 75) tumors, ORR was 25.0% (95% CI 14.4-38.4) vs 14.7% (95% CI 7.6-24.7; p = 0.178). Treatment-related adverse events (TRAE) of any grade occurring in ≥ 10% of pts were infusion-related reaction (22.8%) and fatigue (12.0%). 7.5% had a grade ≥ 3 TRAE; fatigue (1.2%)/asthenia (0.8%) occurred in > 1 pt. 28 pts (11.6%) had an immune-related TRAE (grade ≥ 3 in 2.5%). There was 1 treatment-related death (pneumonitis). Conclusions: Avelumab is well tolerated and shows promising clinical activity, including durable responses, in pts with mUC, regardless of tumor PD-L1 expression status. Follow-up is ongoing. Clinical trial information: NCT01772004.
A multicohort phase I study of ramucirumab (R) plus pembrolizumab (P): Interim safety and clinical activity in patients with urothelial carcinoma.
Authors: Petrylak Daniel Peter , Arkenau Hendrik-Tobias , Perez-Gracia Jose Luis , Krebs Matthew , Santana-Davila Rafael , Yang Jing , Rege Jessicca , Mi Gu , Ferry David , Herbst Roy S.
Published: March 2017

349

Background: Hallmarks of tumor growth include immunosuppression and angiogenesis. This is the first study to combine R (anti-VEGFR2) with P (anti-PD-1) to simultaneously target both processes in the urothelial tumor microenvironment. Methods: This ongoing, multi-cohort, phase 1a/b trial (NCT02443324) enrolled patients (pts) with histologically confirmed transitional cell carcinoma of the urothelium (bladder, urethra, or renal pelvis) with prior progression on platinum-based systemic therapy, measurable disease, ECOG PS 0-1, and baseline tumor tissue. Eligible pts received R at 10 mg/kg on Day 1 given with P 200 mg on Day 1 q3W. PD-L1 was classified as positive (≥1%) or negative using the DAKO PD-L1 22C3 IHC pharmDx assay. Tumor response was assessed every 6 wks (RECIST v1.1). The primary objective was to assess safety and tolerability of adding R to P and preliminary efficacy will be assessed as a secondary objective. Results: As of 23-June-2016, 24 pts have been treated. The median age was 63 years, 58% were male, 50% had ECOG PS 0, 50% were PD-L1 positive and 67% received study treatment as third or subsequent regimen. Median duration of treatment was 2.14 mo and 2.37 mo for R and P, respectively. All grades treatment-related AEs (TRAE) occurred in 13 (54%) pts; TRAEs occurring in ≥10% of pts were fatigue (21%), nausea (17%), pyrexia (13%), elevated alanine aminotransferase (13%) and elevated aspartate aminotransferase (13%). Three (13%) pts had grade 3 TRAEs (hypertension, colitis, pulmonary embolism; n=1 each). No treatment-related grade 4 or 5 events occurred. Preliminary efficacy data showed two (8%) PD-L1 positive pts had confirmed partial response, 10 (42%) pts had stable disease, and 10 (42%) had progressive disease as their best response. Two (8%) pts were not evaluable for response at the time of analysis. Median duration of response has not been reached (>2.92 mo). Median PFS was 1.87 mo (95% CI, 1.28 to 3.38). Five (21%) pts remain on treatment. Conclusions: R plus P generated no new safety signals and demonstrated antitumor activity in pts with previously treated advanced urothelial carcinoma. Clinical trial information: NCT02443324.
Assessment of blood and tissue myeloid derived suppressor cells (MDSC), clinicopathologic factors, and treatment response in urothelial carcinoma (UC) patients (pts) undergoing surgery.
Authors: Ornstein Moshe Chaim , Diaz-Montero C. Marcela , Rayman Patricia A. , Elson Paul , Haywood Samuel , Kim Jin Sub , Pavicic Paul G , Finke James , Rini Brian I. , Stephenson Andrew J. , Lamenza Marcelo , Dann Priscilla , Brey Nicole DiBiase , Devonshire Sarah , Ko Jennifer S , Fergany Amr Farouk , Ernstoff Marc S. , Hoimes Christopher J. , Garcia Jorge A. , Grivas Petros
Published: March 2017

362

Background: MDSC are heterogeneous immunosuppressive cells with potential predictive/prognostic role in cancer. The association between MDSC, clinicopathologic factors and pathologic response in pts with UC merits evaluation. Methods: Peripheral blood and/or tissue was collected from 120 pts. MDSC were measured in fresh unfractionated whole blood (WB), in peripheral blood mononuclear cells (PBMC) and fresh tumor tissue. MDSCs were identified by flow cytometry in WB and defined as LinloCD33+/HLADR- ((T)otal MDSC). MDSC subsets were defined as LinloCD33+/HLADR- and (G)ranulocytic (CD15+CD14-), (M)onocytic (CD15-CD14+), (I)mmature (CD15-CD14-, CD11b+ ). MDSC populations were presented as % of live nucleated blood cells and as absolute numbers from WB. Spearman correlations (r) and Wilcoxon rank sum test were used to assess correlations between MDSC populations, clinicopathologic factors and pT0N0%. Results: Of 120 pts, 82 were non-metastatic: 58 had only blood, 23 had blood & tissue, 1 had only tissue available for analysis. Of these 82 non-metastatic pts, 70 were men, median age 68; 81 pts had primary UC histology, 1 small cell cancer, 24 had mixed UC histology; 24 had prior intravesical therapy, 34 had neoadjuvant therapy (79% cisplatin-based, 21% unknown), 4 pts had post-op recurrence. At cystectomy: 15/82 pT0, 22/82 pT3/4; 37/82 CIS; 8/78 pN+. Significant associations were seen between MDSC blood levels and mixed histology, CIS, pN+, and lower pT0N0% (Table). Tumor M-MDSCs were associated with pN+ (p=0.05). There was significant correlation between tumor and WB % M-MDSC (r=0.55, p=0.007), and tumor and WB % G-MDSC (r=0.46, p=0.03). Conclusions: Blood MDSC levels correlate with several clinicopathologic factors and may predict pathological complete response (pT0N0). Assessment of association between MDSC levels, outcome and immunotherapy response is ongoing including in metastatic pts. [Table: see text]
Association of perioperative venous thromboembolism with long-term oncologic outcomes following radical cystectomy.
Authors: Zaid Harras B. , Tollefson Matthew K. , Frank Igor , Parker William P. , Thompson Robert Houston , Tarrell Robert F. , Thapa Prabin , Cheville John C. , Boorjian Stephen A.
Published: March 2017

364

Background: Venous thromboembolism (VTE) has been reported to occur in 2-5% of patients undergoing radical cystectomy (RC). While VTE is an important cause of perioperative morbidity, the association of these events with long-term cancer prognosis has not been established. Herein, we evaluated the association of perioperative VTE with patients’ risk of subsequent disease recurrence and mortality. Methods: We reviewed 2889 patients undergoing RC between 1980−2009 at the Mayo Clinic to identify patients diagnosed with a VTE within 90 days of RC. These cases were then matched in a 1:2 fashion to control patients undergoing RC who did not develop VTE. Matching was performed on the basis of age, BMI, receipt of neoadjuvant chemotherapy, and pathologic T and N stages. Recurrence-free (RFS), cancer-specific (CSS), and overall survival (OS) were estimated utilizing the Kaplan-Meier method and compared with the log-rank test. Results: A total of 132 patients with a VTE within 90 days of RC were identified, accounting for 4.6% of all patients analyzed. These cases were matched to 257 controls per criteria noted above, and were overall well-matched. Of the 389 patients in this study, median follow-up after RC was 9.2 years, during which time 152 (39%) patients experienced recurrence and 306 (78%) died, including 157 (40%) who died of bladder cancer. We found no significant difference in 5-year RFS (59% versus 61%; p = 0.75); CSS (57% versus 64%; p = 0.13); or OS (45% versus 50%; p = 0.15) between patients with versus without perioperative VTE, respectively. Conclusions: We found that VTE within 90 days of RC did not significantly impact long-term cancer outcomes. While these events represent an important cause of perioperative morbidity, no interaction with oncologic control was noted, and patients may be counseled accordingly.