bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II trial of gemcitabine, carboplatin, and bevacizumab in chemotherapy-naive patients (Pts) with advanced/metastatic urothelial carcinoma (UC).
Authors: Balar A. V. , Milowsky M. I. , Apolo A. B. , Ostrovnaya I. , Iasonos A. , Trout A. , Regazzi A. M. , Garcia-Grossman I. R. , Gallagher D. J. , Bajorin D. F. 
Published: February 2017

248 Background: Effective treatment for pts with advanced UC unfit to receive cisplatin-based therapy remains an unmet need. A recent phase III study showed limited benefit of gemcitabine-carboplatin (GC) alone (median OS 9.3 months) (DeSantis ASCO 2010). We recently identified the VEGF-axis as a viable pathway for UC treatment (JCO 2010;Mar 10). We propose that bevacizumab, a monoclonal antibody against VEGFR, may be safely added to GC and improve time to progression (TTP) in pts with advanced UC. Methods: Primary endpoints (N=47 planned enrollment) were median TTP, to test an improvement of 50% over a 4.8 months median TTP seen with GC alone (Urology 2004;64:479), and safety. Secondary endpoints were response rate (RR) and overall survival (OS). Pts first received a single dose of bevacizumab 10 mg/kg. 2 weeks later they received 6 cycles of gemcitabine 1,000 mg/m2 on day(D) 1 and D 8, and both carboplatin AUC 4.5 and bevacizumab 15 mg/kg on D1 every 21 days. Pts who achieved at least stable disease were eligible to receive maintenance bevacizumab at 15 mg/kg q21 days for 18 additional doses. Restaging evaluations were performed after every 3 cycles of therapy. Results: 51 pts (37 M, 14 F; median age 67 (Range 42-83)) were enrolled from 6/06 to 6/10. Primary tumor sites include bladder (31), renal pelvis (17) and ureter (2). 38 pts (74.5%) had visceral disease including lung (22), liver (13), bone (9) and adrenal (2). 13 pts had LN only disease. 46 of 51 pts were evaluable for response rate (RR) and TTP, 51 for toxicity. RR by RECIST was 46% (21 pts; PR 18, CR 3). 12 achieved stable disease; 1 too early to assess. Responses by MSKCC Risk Scores of 0, 1 and 2 were seen in 8/11(73%), 10/29 (35%), and 3/6 (50%) pts, respectively. 39% of pts had grade 3/4 toxicity, notably vascular thromboembolic events (VTE) in 18%. Conclusions: Bevacizumab can be safely added to GC in the treatment of advanced UC. The 16% VTE rate is similar to the 17% rate seen at MSKCC with GC alone. (JCO 2009;27:15s). Addition of bevacizumab does not improve the RR seen with GC alone in phase II and III studies (Bellmunt Eur J Cancer 2001; DeSantis ASCO 2010). Analysis of bevacizumab's impact on TTP and OS is ongoing and will be updated. [Table: see text]
Patterns of utilization of urine-based markers in non-muscle-invasive bladder cancer: Results from the BCAN/SUO/AUA/LUGPA electronic survey.
Authors: Smith A. , Nielsen M. E. , Ferguson J. , Manvar A. , Pruthi R. , Wallen E. , Lotan Y. 
Published: February 2017

261 Background: In addition to cytologic evaluation, there are currently four urine-based tests approved by the FDA for bladder cancer detection. At this point, the Guidelines panels from the AUA and EAU do not make specific recommendations about the ideal role of these tests. Furthermore, there is a paucity of data on current patterns of care in this area of practice. Methods: An electronic survey was developed by the Bladder Cancer Advocacy Network (BCAN) to elicit self-reported practices of the use of cytology and urine-based markers in the settings of general use, surveillance, and assessment of response after intravesical therapy for patients with NMIBC. The survey was circulated to urologists via the AUA, SUO and LUGPA distribution lists. 512 respondents completed the survey. Results: Among all respondents, 93% report sending cytology routinely (25% via barbotage) in general use. In contrast, 37% report using NMP22 in this setting, 54% report using FISH, and 32% (45% of SUO respondents vs. 31% of AUA respondents, p=0.04) responded that there is “no role for urine-based markers in this setting.” Similar proportions were reported in the specific settings of routine surveillance and post-BCG assessment. When presented with the vignette of a positive marker test and negative cytology and cystoscopy, 36% chose to proceed to the OR for biopsy, 37% chose to repeat cystoscopy and cytology in 3 months, 21% chose “no role for markers in this setting” and 13% chose “other.” Conclusions: In the absence of more specific guidance, the results of this survey suggest considerable variation in the use and interpretation of urine-based markers in NMIBC. FISH is the marker reported to be used most commonly in multiple settings, however 31-45% of respondents report “no role” for any of the tests in their practice. Greater than one out of three respondents reported taking patients for biopsy under anesthesia in the setting of an isolated positive marker. These preliminary data underscore the need for prospective studies to validate the optimal role of urine-based markers in the setting of NMIBC. No significant financial relationships to disclose.
Sunitinib in BCG-refractory non-muscle-invasive transitional cell carcinoma of the bladder.
Authors: Garcia J. A. , Stephenson A. J. , Ireland J. , Finke J. , Elson P. , Schaaf L. , Gong M. C. , Campbell S. , Dreicer R. 
Published: February 2017

262 Background: Treatment options for pts with BCG-refractory NMITCC are limited and there is no established role for systemic chemotherapy in this setting. While cystectomy remains the gold standard, the vast majority of pts are unable or unwilling to have surgery. Sunitinib is an oral tyrosine kinase inhibitor of VEGFR-2, PDGFR, KIT and FLT3 with demonstrated antitumor activity in advanced TCC. To determine the clinical and biologic effects of sunitinib in BCG-refractory NMITCC pts a prospective phase II study was conducted. Methods: Pts with biopsy proven BCG- refractory NMITCC received three 28-day cycles of continuous sunitinib (37.5 mg PO). Subsequently, pts underwent cystoscopic evaluation. If no tumor was found, pts continued with standard cystoscopic surveillance. A single stage design was employed to test the hypothesis of a 25% improvement in the 12-month CR rate over the 20% CR historically observed in this setting. Overall response rate (ORR), disease-free recurrence (DFR) and safety were recorded. Exploratory endpoints included treatment effect on CTCs, type-1 response and immunosuppressive Treg cells. Results: To date 17 of a planned 31 pts are enrolled. Median age is 72 years (range, 54-82); 94% of pts were ECOG 0; 6 pts had received additional intravesical therapy other than BCG. Fourteen pts have already completed 3 cycles of treatment and 13 pts had at least once cystoscopic assessment. Among these, 8 pts (62%) were NED in their first cystoscopic evaluation. Most common treatment-related toxicity observed in both studies included fatigue, HTN, stomatitis, PPE, diarrhea and thrombocytopenia. Treatment with sunitinib also resulted in a sustained increase (compared to pre-treatment) in CD3+ and CD4+ IFN-g producing T-cells (p < 0.07). In addition there was a significant decrease in CD33+ MDSC following 2 and 3 cycles of therapy (p < 0.04). There was also a significant decrease in T regulatory cells following 2 cycles of therapy (p = 0.04); however it was not maintained during cycle 3 (p = 0.36). Conclusions: Sunitinib has modest clinical activity in pts with BCG-refractory NMITCC. Early immune studies also denote the ability of sunitinib to restore the balance of type-1 and type-2 immune response in bladder cancer. [Table: see text]
Reported patterns of utilization of intravesical therapy in non-muscle-invasive bladder cancer: Results from the BCAN/SUO/AUA/LUGPA electronic survey.
Authors: Smith A. , Nielsen M. E. , Manvar A. , Ferguson J. , Pruthi R. , Wallen E. , Lotan Y. 
Published: February 2017

267 Background: Guidelines recommend intravesical chemotherapy and immunotherapy in the management of non-muscle-invasive bladder cancer (NMIBC) to reduce the risks of recurrence and potentially progression. Nevertheless, recent claims-based analyses have suggested exceedingly low rates of utilization of some of these therapies in practice. In general, there is a paucity of data to inform our understanding of current patterns of care. Methods: An electronic survey was developed by the Bladder Cancer Advocacy Network (BCAN) to elicit self-reported practices of utilization of intravesical chemo- and immuno-therapy for patients with NMIBC. The survey was circulated to urologists via the AUA, SUO and LUGPA distribution lists. 512 respondents completed the survey. Results: Overall, 63% of respondents reported routine administration of perioperative mitomycin-c (MMC) after TURBT [80% of SUO respondents vs. 55% of AUA/LUGPA respondents (p<0.001)]. Whereas 5% of respondents reported routine induction therapy with all new low-grade (LG) diagnoses, 99% reported routinely doing so in new high-grade (HG) cases; most commonly with single- agent BCG (94%; vs. 9% BCG/IFN and 5% MMC). Reported induction therapy was higher in the setting of high-volume (77%) or frequently recurrent LG (44%) disease. 89% reported routinely using maintenance therapy for HG, vs. 29% for LG. Reduced strength BCG was most commonly endorsed only in the settings of poor tolerance of full strength (84%) or maintenance (11%), with only 3% endorsing routine use. Routine post-BCG biopsy, even with normal cystoscopy, was endorsed by 28% of respondents, and 64% of respondents used urine-based markers to assess response to intravesical therapy. Conclusions: Urologists report grade-specific patterns of utilization of intravesical therapy for NMIBC, at rates higher than suggested in some claims-based analyses. Variation exists in post-treatment followup practices. Further study is needed to rectify these self-reported patterns of care with results from claims-based analyses. No significant financial relationships to disclose.
The neoadjuvant management of bladder cancer in Canada: A survey of genitourinary medical oncologists.
Authors: Hsu T. , North S. , Eigl B. J. , Chi K. N. , Canil C. M. , Wood L. , Lau A. , Panzarella T. , Sridhar S. S. 
Published: February 2017

285 Background: The uptake of neoadjuvant chemotherapy (NC) for the treatment of stage II/III bladder cancer remains variable despite evidence supporting its use. The aim of this study is to better understand the use of NC in Canada to facilitate standardization of practice and develop a platform for clinical trials. Methods: The survey was initially tested on a subset of medical oncologists. It was then e-mailed to 30 medical oncologists across Canada who primarily treat bladder cancer. Results: In total, 25 (83%) surveys were completed. Respondents were 92% academic based, 100% full time, and 52% in practice for >10 years. The majority of referrals for all stages came from urologists with 4 respondents (16%) seeing 5-10 cases/yr, 10 (40%) seeing 11-15/yr, 5 (20%) seeing 16- 20/yr and 6 (24%) seeing >20/yr. Of these 8 reported having only 1-2 referrals for NC; 7 had 3-4 NC referrals; 7 had 5-6 NC referrals; and 2 reported seeing >6 referrals/year. Patients referred for NC tended to be younger (50-65); Performance Status (PS) 0/1; T-stage T3a/T3b; or nodal status N1/N2. 96% indicated they do offer NC to selected patients as both standard of care and to downsize tumors. Key factors cited for not offering NC were: Age >85, PS 3/4; T-stage T2a or T4a; Nodal status: N3; GFR <40ml/min. Main baseline staging modalities included CT chest/abdomen/pelvis, bone scan and cystoscopy. Gemcitabine/cisplatin was most commonly used with 20% using high-dose MVAC. Six (27%) reported doing midway staging with CT abdomen/pelvis and cystoscopy; 36% report staging after completion of chemo. Average time from last chemotherapy to cystectomy was 4-6 wks, with no patients being offered adjuvant chemotherapy postoperatively. Conclusions: The majority of GU MO in Canada would offer NC. Stage, PS, renal function, and comorbidities were the biggest determinants of offering NC, while age played a lesser role. The number of overall referrals for NC, however, remains relatively low. We plan to survey urologists in Canada to determine if differences in attitudes about NC or barriers to referrals account for the low number of referrals. No significant financial relationships to disclose.
Sequential FDG-PET/CT as a surrogate marker of response to sunitinib in metastatic clear cell renal cancer.
Authors: Powles T. , Chowdhury S. , Avril N. , Bomanji J. , Shamash J. , Sarwar N. , Rockall A. , Sahdev A. , Nathan P. D. , Kayani I. 
Published: February 2017

301 Background: The purpose of this study was to investigate sequential FDG PET-CT as a correlative marker in metastatic clear cell renal cancer (mRCC) patients treated with first line sunitinib. Three sequential scans were performed to determine the importance of the timing of scans. Methods: Forty-four untreated mRCC patients with MSKCC intermediate risk and poor risk disease were enrolled into a prospective study. FDG PET-CT scans were performed before (n=44), after 4 weeks (n=43) and 16 weeks (n=40) of sunitinib given at standard doses as the translational aspect of this trial ( NCT01024205 ). The primary endpoint was to determine whether 18F-FDG PET-CT response (defined as a 20% reduction in SUVmax) correlated with survival. Results: Forty-three (98%) patients had FDG PET-CT avid lesions at diagnosis (median SUVmax 6.8 range: <2.5–18.4). In multivariate analysis a high SUVmax and increased number of PET positive lesions correlated with worse overall survival (OS) (HR: 3.30 (95%CI: 1.36–8.45) and 3.67 (95%CI: 1.43–9.39) respectively[p<0.05]). After 4 weeks of sunitinib, metabolic responses occurred in 24 (57%) patients at 4 weeks, but this did not correlate with progression-free survival [PFS] (HR for responders= 0.87 [95%CI: 0.40–1.99]) or OS (HR for responders= 0.80 [95%CI: 0.34–1.85]) (p>0.05 for both). After 16 weeks of treatment, FDG PET-CT demonstrated disease progression in 28% (n=12) patients. At this time point, the FDG PET-CT correlated with both OS and PFS (HR 5.96 [95%CI: 2.43–19.02] and HR 12.13 [95%CI: 3.72–46.45] respectively). Conclusions: Baseline FDG PET prior to sunitinib yields prognostically significant data. FDG PET response at 16 weeks predicts outcome, which is not the case at 4 weeks. This subsets of patients with a poor prognosis at 16 weeks could be investigated within the context of a randomized clinical trial. [Table: see text]
Hand–foot syndrome (HFS) as a potential biomarker of efficacy in patients (pts) with metastatic renal cell carcinoma (mRCC) treated with sunitinib (SU).
Authors: Michaelson M. D. , Cohen D. P. , Li S. , Motzer R. J. , Escudier B. , Barrios C. H. , Burnett P. E. , Puzanov I. 
Published: February 2017

320 Background: HFS and related skin toxicities are common side effects of tyrosine kinase inhibitors such as SU, a multitargeted inhibitor of VEGF and PDGF receptors plus other receptor tyrosine kinases. In a randomized phase III trial of treatment-naïve mRCC pts, SU showed superior progression-free survival (PFS) and objective response rate (ORR) over interferon-alfa, with a median PFS of 11 mo and median overall survival (OS) of 26.4 mo, establishing SU as a reference standard of care (Motzer et al, 2009). In this retrospective analysis, correlations between SU-associated HFS and efficacy endpoints were investigated in mRCC pts from 5 clinical trials in the first- and second-line treatment settings. Methods: Analyses included pooled data from 770 pts who received single-agent SU as 50 mg/d on a 4-week-on/2-week-off schedule (n=544; 71%) or 37.5 mg continuous once-daily dosing (n=226; 29%). Median PFS and OS were estimated by Kaplan–Meier methods and compared between pts with vs without HFS using a log-rank test. ORR was compared by Pearson's chi-square test. Tumor response was assessed by investigators and adverse events were recorded regularly. Multivariate and time-dependent covariate analyses were performed. Results: Of 770 pts, 179 (23%) developed any-grade HFS, compared with 591 (77%) who did not. Most instances of HFS (63%) initially occurred during the first 3 treatment cycles. Pts who developed HFS had significantly better ORR (55.6% vs. 32.7%), PFS (14.3 vs. 8.3 mo), and OS (38.3 vs. 18.9 mo) than pts who did not develop HFS (p<0.0001). In a multivariate analysis, SU-associated HFS remained a significant independent predictor of both PFS and OS (and of OS by time-dependent covariate analysis). Conclusions: In mRCC pts, SU-associated HFS was significantly and independently associated with improved clinical outcomes. Overall, pts who did not develop HFS still had substantial benefit from SU. However, the presence of HFS identified a subset of pts that manifested highly favorable efficacy results with SU. These findings suggest that development of HFS may serve as a predictive biomarker of SU efficacy, although prospective validation is warranted. [Table: see text]
Phase II trial of bevacizumab monotherapy in nonmetastatic castrate-resistant prostate cancer (CRPC).
Authors: Ogita S. , Tejwani S. , Heilbrun L. K. , Fontana J. A. , Heath E. I. , Freeman S. , Smith D. W. , Baranowski K. , Vaishampayan U. N. 
Published: February 2017

33 Background: To this day, no therapy has proven efficacy in the clinical management of PSA relapse non-metastatic CRPC. Investigating novel therapeutic agents that will induce a PSA response, and delay progression to overt metastases is of paramount importance. Methods: A single arm multi-center phase II clinical trial is being conducted. Inclusion criteria are PSA only progression despite androgen deprivation therapy, defined as three rising PSA levels with a measurement interval of at least 2 weeks, and minimum PSA level ≥ 1 ng/mL. Patients with radiologic evidence of bone metastases were excluded. Bevacizumab single agent was administered at 10 mg/kg every 14 days. PSA was evaluated at least every 6 weeks and bevacizumab was continued until PSA progression or new metastasis. Results: 15 patients (see Table ) have been enrolled on this ongoing trial. Toxicities observed were grade 4 pulmonary embolism, grade 3 hypertension, and grade 3 proteinuria in one patient each, but no treatment related mortality. Median treatment duration was 12.6 weeks (range 11–33.1 wks). 12 patients are evaluable for PSA response. Four patients had PSA decline of 14, 20.9, 24, and 45% respectively. Median PSA doubling time during bevacizumab increased to 5.93 months (range 0.81–27.09 months) from pretherapy median of 4.08 months, a 45% improvement. Five patients have progressed to develop bone metastases at median of 7.7 months (range 2.8–18.2) after protocol registration. Conclusions: Bevacizumab was well tolerated, and impacted PSA kinetics in non-metastatic CRPC. Further investigations are warranted. Supported in part by Genentech Inc. (clinicaltrials.gov NCT00478413 ). [Table: see text] [Table: see text]
Predictors and outcomes for late recurrence of renal cell carcinoma.
Authors: Kim S. P. , Weight C. J. , Leibovich B. C. , Thompson R. H. , Lohse C. M. , Boorjian S. A. 
Published: February 2017

348 Background: While the initial natural history after surgical resection for localized renal cell carcinoma (RCC) has been well-characterized, recurrence patterns for patients who experience late recurrence of disease continue to be defined. Here, we evaluated the clinical characteristics and survival of patients who experienced disease recurrence > 5 years following nephrectomy. Methods: We identified 1,454 patients who were treated with radical nephrectomy (RN) or nephron-sparing surgery (NSS) for unilateral, sporadic pT1-4NxM0 RCC between 1970-2000 and who had remained free of disease for 5 years after surgery. Late (> 5 years) recurrence was then recorded and was classified as renal (ipsilateral/contralateral kidney) recurrence and distant (all other sites) recurrence. The incidence of late recurrence was estimated using the Kaplan Meier method, and clinicopathological variables subsequent disease relapse were analyzed using Cox proportional hazard regression models. Results: Median follow-up after nephrectomy in the cohort here was 13.9 years (range 5.1-38.9). In total, 63 patients experience a late recurrence in the ipsilateral/contralateral kidney, at a median of 9.3 years (range 5.1-25.3) after surgery. 172 (11.8%) patients developed late distant metastases, at a median of 9.6 years (range: 5.1-26.6). Estimated recurrence-free survival at 10 and 15 years following nephrectomy was 97.3% and 95.2% for renal recurrence and 93.1% and 85.9% for distant recurrence, respectively. Increased tumor size (HR 1.1; p<0.001) was associated with a higher rate of late renal recurrence, while increased tumor size (HR 1.1; p=0.018), clear cell or collecting duct histology (HR 3.7; p<0.001), and tumor stage pT1b (HR 2.8; p<0.001), pT2a (HR 4.5; p<0.001), pT2b (HR 3.4; p=0.007), and pT3/4 (HR 5.1; p<0.001) were predictive of the development of late distant metastasis. Conclusions: Patients undergoing surgery for localized RCC remain at life-long risk of disease recurrence. Approximately 5% experience renal recurrence and 15% demonstrate distant relapse, during the ensuing 10 years. Continued investigation to identify potential site-specific predictors of late recurrence is necessary to guide postoperative surveillance regimens. No significant financial relationships to disclose.
C-met as a therapeutic target using ARQ 197 in renal cell carcinoma.
Authors: Gibney G. , Conrad P. , Aziz S. A. , Camp R. L. , Schwartz B. E. , Chen C. , Kelly W. K. , Kluger H. M. 
Published: February 2017

360 Background: c-Met is a receptor tyrosine kinase involved in normal cellular growth and vascular development. It has also been identified as a proto-oncogene. Activating c-Met mutations and indirect c-Met activation via von Hippel-Lindau gene silencing have been demonstrated in renal cell carcinoma (RCC) for papillary and clear cell histologic subtypes, respectively. We studied c-Met expression in a large cohort of RCC tumors and investigated in vitro activity of the new selective c-Met inhibitor, ARQ 197. Methods: Tissue microarrays were performed to analyze c-Met protein expression in situ in 317 RCC tumor specimens using Automated Quantitative Analysis (AQUA). Western blots were performed for c-Met, phospho-c-Met and downstream pathway markers in 6 RCC cell lines (A498, ACHN, Caki-1, Caki-2, 769P, and 786-O). In vitro activity of ARQ 197 was studied by cell viability and clonogenic assays, and by changes in c-Met and down-stream mediators. Results: c-Met expression is higher in RCC than adjacent normal renal tissue (p < 0.0001) and is expressed in all subtypes of RCC, including clear cell carcinoma; expression is highest in papillary and sarcomatoid subtypes. Greater c-Met expression correlates with higher tumor grade (p = 0.0019) and clinical stage (p = 0.0208), and is an independent predictor of poor overall survival (Multivariate Cox LR 5.7, p = 0.017). c-Met expression correlates to decreased survival in the clear cell subset as well. c-Met protein is activated (phosphorylated) in all 6 RCC cells. ARQ 197 inhibits cell growth in RCC cell lines at nanomolar concentrations (IC50 350-680 nM) and inhibits colony formation at 500 nM. ARQ 197 decreases phosphorylation of c-Met in time- and dose-dependent patterns with dose-dependent decreases in phospho-ERK. Conclusions: c-Met expression is an independent predictor of survival in RCC, including clear cell subtype, suggesting that it is a potential therapeutic target worthy of further investigation. ARQ 197 effectively inhibits proliferation of clear cell carcinoma cell lines. Further preclinical studies are planned to determine mechanism of cellular arrest and apoptosis and markers of drug sensitivity and resistance. [Table: see text]