bluuebunny/crossref_metadata_2025_split 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.