bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of the novel anti-androgen ARN-509 on response and seizure in castration-resistant prostate cancer models.
Authors: Hager J. H. , Smith N. D. , Bischoff E. , Jung M. E. , Sawyers C. L. , Heyman R. A. , Rix P. J. 
Published: February 2017

28 Background: ARN-509 is a second-generation anti-androgen discovered in a screen to identify full androgen receptor (AR) antagonists in the context of AR over-expressing prostate cancer cells, a model for castration resistant prostate cancer (CRPC). It has been reported that other second-generation anti-androgens, MDV3100 and BMS-641988, can induce seizures at high dose in pre-clinical species and man and that this is mediated through antagonism of the CNS-based GABAA receptor. To define the clinical potential of ARN-509, we carried out a comprehensive assessment of its in vitro and in vivo activity in validated models of CRPC and assessed its seizure inducing potential. Methods: ARN-509 and MDV3100 were profiled in a series of assays to monitor both on- and off-target activity. Comparative in vivo efficacy in the LNCaP/AR mouse xenograft model of CRPC and pharmacokinetics were determined. Seizure inducing potential was assessed in an acute pentylenetetrazol (PTZ) infusion model. Results: In vivo, in the LNCaP/AR model of CRPC, an ARN-509 dose of 10 mg/kg/day exhibited tumors regressions equivalent in frequency and magnitude to a 30 mg/kg/day dose of MDV3100. Tumor re-growth following once daily dosing (30 mg/kg) for 28 days revealed that ARN-509 treated tumors exhibited a more durable response than MDV3100 treated tumors as evidenced by a significantly longer time to re-growth. At doses that yielded equivalent degree of tumor regression, the steady state plasma and brain levels were significantly lower for ARN-509 (10 mg/kg) than MDV3100 (30 mg/kg). ARN-509 and MDV3100 exhibit similar binding affinity to the GABAA receptor; IC50 3.0 and 2.7 mM, respectively. In vivo seizure potential of ARN-509 and MDV3100 was assessed in an acute PTZ infusion model in mice. MDV3100 was found to produce a dose dependant lowering of seizure threshold, while ARN-509 had no effect at any dose tested. Conclusions: ARN-509 is a second-generation anti-androgen with significant efficacy and an appropriate safety profile that supports its clinical development in both CRPC and earlier stages of prostate cancer. ARN-509 is currently in a phase I/II study in CRPC patients. [Table: see text]
Ability of urovysion FISH analysis to select patients with low- or intermediate-risk non-muscle-invasive bladder cancer (LI-NMIBC) for decreased surveillance.
Authors: Rosevear H. M. , Lightfoot A. J. , O'Donnell M. A. 
Published: February 2017

283 Background: Recurrent LI-NMIBC is difficult to detect cytologically, requiring frequent cystoscopies. Urovysion's (Abbot Laboratories, Downers Grove, IL) fluorescent in situ hybridization assay (FISH) detects genetic changes associated with LI-NMIBC and may be useful in identifying patients for extended screening intervals. Methods: Charts of 54 consecutive patients with LI-NMIBC who underwent cystoscopy, cytology, and FISH analysis every 3 months for the first year after resection since 2004 were retrospectively identified and reviewed. We analyzed the number of tumors or high-grade cytologies that would have been missed if surveillance cystoscopy, cytology, and FISH analysis had not been done between 3 and 12 months post-resection for patients with a normal cystoscopy, cytology, and FISH analysis at 3 months after initial resection and compared those results to patients with normal cystoscopy, cytology, and abnormal FISH analysis. Results: Mean age of the 54 patients was 67 (range 25–89) and 41 were males. Thirty-nine patients had normal cystoscopy, cytology, and FISH analysis at 3-months follow-up. If no further surveillance was done until 1 year post-resection, 2 low-grade tumors (3 and 7 mm at 7 months post-resection) and 2 incidents of high-grade cytology would have been missed (4 of 39, 10%). Fifteen patients had normal cystoscopy and cytology but abnormal FISH analysis results at 3 months. If no further surveillance had been done until 1 year after resection, 6 tumors (6 of 15, 40%) (5, 8, 3, 3, 9, 2 mm at 5, 6, 6, 7, 9, 10 months post-resection) and no high-grade cytology would have been missed. Overall, statistically fewer patients with normal compared to abnormal FISH analysis at first follow-up developed tumors before 1 year (4 of 39 vs. 6 of 15, p=0.033). Conclusions: FISH analysis can be used to significantly increase our ability to select patients suitable for extended screening intervals. It may be prudent to include FISH analysis at the first post-resection follow-up before selecting patients with LI-NMIBC for an extended screening interval. [Table: see text]
Everolimus in metastatic renal cell carcinoma (mRCC): Subgroup analysis of patients (pts) with one versus two prior vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) therapies enrolled in the phase III RECORD-1 study.
Authors: Figlin R. A. , Calvo E. , Motzer R. J. , Hutson T. E. , Oudard S. , Porta C. , Grunwald V. , Ravaud A. , Kpamegan E. 
Published: February 2017

304 Background: The mammalian target of rapamycin (mTOR) inhibitor everolimus is the only medication to have shown efficacy in a randomized, controlled, phase III clinical trial (RECORD-1) in pts with mRCC after progression on VEGFR-TKIs. Everolimus more than doubled progression-free survival (PFS) vs. placebo (4.9 vs 1.9 months) and reduced the risk of disease progression by 67%. This analysis evaluated the effect of everolimus on survival in pts who had received 1 vs 2 prior VEGFR-TKIs. Methods: Pts with mRCC who progressed on sunitinib (SU) and/or sorafenib (SOR) were randomized (2:1) to receive everolimus 10 mg/day (n = 277) or placebo (n = 139) plus best supportive care in the double- blind, phase III RECORD-1 study (ClinicalTrials.gov: NCT00410124 ). Results: Before enrollment, the majority of pts received only 1 VEGFR- TKI (317 pts, 74%), with 317 pts receiving either SU or SOR (everolimus = 211; placebo = 106) and 99 pts receiving both SU and SOR (everolimus = 66; placebo = 33). Median PFS was 5.42 mo (95% confidence interval [CI]: 4.30, 5.82) in pts receiving everolimus who had received 1 prior VEGFR-TKI and 1.87 mo (95% CI: 1.84, 2.14) in those receiving placebo (hazard ratio [HR]: 0.31; 95% CI: 0.23, 0.42; p < .001). Median PFS was 3.78 mo (95% CI: 3.25, 5.13) for the everolimus group in pts who received 2 prior VEGFR-TKIs, versus 1.87 mo (95% CI: 1.77, 3.06) for the placebo group (HR: 0.37; 95% CI: 0.22, 0.63; p < 0.001). Conclusions: Pts in all stratified subgroups derived significant clinical benefit from everolimus treatment, including pts previously treated with either 1 or 2 VEGFR-TKIs. However, there was a trend toward a longer PFS in pts treated with 1 prior VEGFR-TKI compared with 2 VEGFR-TKIs. [Table: see text]
Phase I/II trial of concurrent sunitinib (SU) and image-guided radiotherapy (IGRT) followed by maintenance systemic therapy for patients with oligometastases.
Authors: Kao J. , Cesaretti J. A. , Sung M. W. , Stock R. , Galsky M. D. , Packer S. , Chen S. 
Published: February 2017

306 Background: Preclinical data suggest that SU enhances the efficacy of radiotherapy. We tested the combination of SU and hypofractionated IGRT in a cohort of patients with historically incurable distant metastases. Methods: Eligible patients had 1 to 5 sites of metastatic solid tumors measuring ≤ 6 cm. The most common tumor types treated were head and neck, liver, lung, kidney, and prostate cancers. Patients were treated with concurrent SU (25 to 50 qd d 1–28) and IGRT (40 to 50 Gy in 10 fractions d 8–19). Following IGRT, patients could either receive maintenance SU (50 mg daily, 4 weeks on/2 weeks off starting on d 43) or alternate forms of systemic therapy. Most patients were treated with the recommended phase II dose of SU 37.5 mg and IGRT 50 Gy. Maintenance SU was used in 40% of patients. Results: Between 2/07 and 6/08, 43 patients with 81 metastatic lesions were enrolled with a median follow up for surviving patients was 20.1 months (range, 5–37 months). The incidence of acute grade ≥ 3 toxicities was 33%, most commonly myelosuppression, bleeding and abnormal liver function tests. The 2-year estimates for local control and distant control were 74% and 43%, respectively. The 2-year estimates for progression- free survival and overall survival were 39% and 46%, respectively. To date, 15 (35%) patients were alive without evidence of disease, 6 (14%) were alive with distant metastases, 13 (30%) were dead from distant metastases, 1 (2%) was dead from local progression, 6 (14%) were dead from comorbid illness, and 2 (5%) were dead from treatment-related toxicities. Predictors of improved progression-free survival were genitourinary primary tumor (HR 0.18; p=0.04), IGRT dose > 40 Gy (HR 0.21; p=0.005), number of metastases (HR 2.22; p=0.006) and maintenance SU (HR 0.31; p=0.06). Flow cytometry demonstrates a significant reduction in immune suppressive myeloid derived suppressor cells and T regulatory cells in SU treated patients. Conclusions: Concurrent SU and IGRT achieves durable local and distant control in a significant subset of patients with oligometastases, particularly patients with genitourinary primary tumors with ≤ 2 distant metastases. [Table: see text]
Phase III, randomized, placebo-controlled study of everolimus in patients with metastatic renal cell carcinoma (mRCC): Subgroup analysis of patients intolerant of prior vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy.
Authors: Hutson T. E. , Bracarda S. , Escudier B. , Porta C. , Figlin R. A. , Calvo E. , Grunwald V. , Ravaud A. , Kpamegan E. , Motzer R. J. 
Published: February 2017

312 Background: In the RECORD-1 phase III study, the mammalian target of rapamycin (mTOR) inhibitor everolimus (ClinicalTrials.gov: NCT00410124 ) prolonged progression-free survival (PFS) versus placebo (median PFS 4.9 vs 1.9 months) in patients with mRCC whose disease progressed during or within 6 months of VEGFr-TKI (sunitinib and/or sorafenib) therapy. In this retrospective analysis, we evaluated the effect of everolimus on PFS in the subgroup of patients who discontinued prior VEGFr-TKI therapy because of adverse events. Methods: In the randomized, double-blind RECORD-1 trial, patients with mRCC who had prior VEGFr-TKI therapy were randomized (2:1) to receive everolimus 10 mg/day (n = 277) or placebo (n = 139) plus best supportive care. Results: Patients who were intolerant of prior VEGFr-TKI therapy included 50 patients (sunitinib = 26; sorafenib = 24) in the everolimus group and 13 patients (sunitinib = 5; sorafenib = 8) in the placebo group. The median PFS in the sunitinib group was 5.13 mo (95% confidence interval [CI]: 3.71, not available [NA]) in patients receiving everolimus vs 2.81 mo (95% CI: 1.87, 3.71) in those receiving placebo (HR: 0.28; 95% CI: 0.07, 1.18; p = 0.033). In the sorafenib subgroup, median PFS was 5.59 mo (95% CI: 3.78, NA) versus 1.91 mo (95% CI: 1.68, 3.48), respectively (HR: 0.29; 95% CI: 0.09, 0.91; p = 0.012). Conclusions: Everolimus prolonged PFS in a subgroup of patients with mRCC who were intolerant of prior VEGFr-TKI therapy. These results suggest that mTOR inhibition with everolimus was active in patients with mRCC who were intolerant of a previous VEGFr-TKI. [Table: see text]
A randomized, double-blind phase III study (VEG105192) of pazopanib (paz) versus placebo (pbo) in patients with advanced/metastatic renal cell carcinoma (mRCC): Updated safety results.
Authors: Sternberg C. N. , Hawkins R. E. , Szczylik C. , Davis I. D. , Wagstaff J. , McCann L. , Chen M. , Rubin S. D. 
Published: February 2017

313 Background: This study evaluated the efficacy and safety of paz in 435 pts with mRCC. The primary endpoint of PFS with paz vs pbo was met with a median PFS of 9.2 vs. 4.2 mo (HR 0.46; p<0.0001) respectively. Final OS was 22.9 mos in paz arm vs. 20.5 mos in pbo (HR 0.91; p=0.224); however, OS was confounded by extensive crossover of pbo pts to paz and other therapies. Two independent analyses to adjust for crossover, IPCW (Inverse Probability of Censoring Weighted) and RPSFT (Rank Preserving Structural Failure Time) suggest an OS benefit with paz;HR 0.504; p=0.002 by IPCW and HR 0.43; p=0.172 by RPFST. At the final OS analysis, pts on the paz arm had a 30% increase or in absolute terms 70 yrs (303.7 yrs from 233.5 yrs) in cumulative exposure since analysis 2 yrs ago (Sternberg; JCO 2010). Updated safety data is reported. Methods: Pts with clear cell mRCC and measurable disease with no prior treatment or 1 prior cytokine-based trt were randomized (2:1) to paz 800 mg QD or pbo and treated until progression (PD), death, or unacceptable toxicity. Upon PD, pts on the pbo arm could receive paz through a parallel open-label study. Results: Median exposure duration was nearly doubled in the paz arm vs. pbo (7.4 mo vs. 3.8 mo). In the paz arm, 32% of subjects remained on treatment > than 12 mos, 15% for > 24 mos and 8% for > 36 mos. The mean daily dose of paz was 679 mg. ALT elevations >3xULN occurred in 54 pts; upon interruption of paz, or with continuation (adaptation), 85% of pts had documented recovery, 9% no recovery data and 6% not recovered. Further details regarding these and less frequent class effect AEs such as hand-foot syndrome (6%), myocardial dysfunction (<1%) will be reported. Conclusions: This safety update reflects a 30% increase in the cumulative exposure to paz since the previous clinical cutoff. There are no significant changes to the type, frequency or severity of AEs and no differences in grade 3, 4, or 5 AEs. No new safety signals have been detected. [Table: see text] [Table: see text]
Efficacy of targeted drug therapy for metastatic renal cell carcinoma in the elderly patient population.
Authors: Khambati H. , Choueiri T. K. , Kollmannsberger C. K. , North S. , Bjarnason G. A. , Vaishampayan U. N. , Wood L. , MacKenzie M. J. , Rini B. I. , Heng D. Y. ,   International mRCC Database Consortium
Published: February 2017

318 Background: Targeted therapy has become the mainstay of treatment for metastatic renal cell carcinoma (mRCC). The efficacy of this therapy on the older population is poorly understood. Methods: Data from patients with mRCC treated with first-line anti-VEGF therapy were collected through the International mRCC Database Consortium from 14 centers. Results: One thousand three hundred eighty-one patients were treated with targeted therapy as their first-line treatment. Of those, 144 (10%) were seventy-five years or older (median=78 years, range=75–89). Four percent of these individuals were favorable risk, 69% intermediate risk, and 27% poor risk as per Heng et al. JCO 2009 prognostic factors. There was no statistical difference in these prognostic groups between the older (≥75) and younger populations (<75) (p=0.1779). The initial treatment for those ≥ 75 years was with sunitinib (n=98), sorafenib (n=35), bevacizumab (n=7), and AZD2171 (n=4). The older population had fewer nephrectomies (71% vs. 80%, p=0.0133) and fewer brain metastases (3% vs. 9%, p=0.0128). Only 23% of older patients went on to receive second line therapy in comparison to 39% of the younger population (p<0.0001). The overall response rate, median treatment duration and overall survival for the older vs. younger group were 18% vs. 25% (p=0.0975), 5.5 months vs. 7.5 months (p=0.1388), and 16.8 months vs. 19.7 months (p=0.3321), respectively. When adjusted for known poor prognostic factors, age over 75 years was not found to be associated with poorer overall survival (HR 1.002, 95%CI 0.781–1.285) or shorter treatment duration (HR 1.018, 95%CI 0.827–1.252). Conclusions: Overall response rates, treatment duration, and overall survival rates are not different between the older and younger populations and age is not a prognostic factor. Thus, the decision to treat with targeted therapy should not depend on age alone. [Table: see text]
Brain metastases in patients treated with targeted therapy for metastatic renal cell carcinoma (mRCC).
Authors: Alharbi H. , Choueiri T. K. , Kollmannsberger C. K. , North S. , MacKenzie M. J. , Knox J. J. , Rini B. I. , Heng D. Y. 
Published: February 2017

326 Background: Patients with brain metastases from advanced RCC treated in the targeted therapy era are not well characterized. Methods: Data from patients with mRCC treated with targeted therapy were collected through the International mRCC Database Consortium from 6 centers. Results: One hundred six out of 705 (15%) patients with mRCC had brain metastases. Forty-seven patients had brain metastases at the start of first-line anti-VEGF therapy and the rest developed metastases during follow-up. Of the patients with brain metastases, 6%, 68%, and 26% were in the favorable, intermediate and poor prognosis groups, respectively, per the Heng et al JCO 2009 criteria. Ninety percent had cerebral metastases, 17% had cerebellar metastases, 40% had a Karnofsky performance status (KPS) <80%, and 81% had symptoms of brain metastases. The median largest size and number of brain metastases was 1.8 cm (range 0.2–6.6) and 1 (range 1–20), respectively. Patients were treated with first-line sunitinib (n=77), sorafenib (n=23), bevacizumab (n=5), and temsirolimus (n=1). Local disease treatment included whole brain radiotherapy (81%), stereotactic radiosurgery (25%), and neurosurgery (25%). The brain metastases of 59 patients were evaluable and based on the local treatment and/or targeted therapy achieved 7 (12%) complete responses, 23 (39%) partial responses, 14 (24%) patients with stable disease, and 15 (25%) patients with progressive disease in the brain metastases. Patients with more than 4 brain metastases vs. those with no more than 4 have an overall survival time from diagnosis of brain metastasis of 3.9 vs. 15.4 months (p=0.0051). Previous nephrectomy, sarcomatoid, and non-clear cell histology are not associated with development of brain metastases. On multivariable analysis, KPS<80% (p=0.0139), diagnosis to treatment with targeted therapy <1 year (p=0.0012), and higher number of brain metastases (p=0.0311) were associated with worse survival from diagnosis of brain metastases. Conclusions: In patients with brain metastases from RCC, KPS at start of therapy, diagnosis to treatment time and number of brain metastases may be prognostic factors for overall survival. [Table: see text]
Use of early primary tumor response to predict overall survival in patients with metastatic RCC undergoing treatment with sunitinib.
Authors: Abel E. , Culp S. H. , Tannir N. M. , Matin S. F. , Tamboli P. , Wood C. G. 
Published: February 2017

329 Background: In metastatic renal cell carcinoma (mRCC) patients treated with sunitinib and the primary tumor in situ, there is minimal predictive data available to help guide clinicians during treatment with targeted therapy. In prior studies, early primary tumor response (PTR) was associated with improved overall PTR, but the effect on overall survival (OS) is unknown. The purpose of our study was to evaluate whether early PTR was associated with improved OS in mRCC patients undergoing treatment with sunitinib. Methods: We reviewed our institutional database to identify patients with mRCC treated with sunitinib with primary tumor in situ. Clinical and pathological data were collected for each patient. Sequential abdominal CT or MRI scans were reviewed to evaluate PTR. Early PTR was defined as ≥ 10% decrease in tumor diameter within the first 90 days of treatment. Univariable and multivariable stepwise Cox proportional hazards regression analysis were performed to identify predictors of OS in these patients. Results: 75 consecutive patients were identified between 2005 and 2009 with a median follow-up of 15 months. 24 patients exhibited an early PTR; median maximum response 23.1% (range: −53.4, −10.2) and decrease in primary tumor diameter at a median of 90.5 days. Early PTR was associated with a decreased risk of death on multivariate analysis (HR: 0.18; 95% CI 0.05, 0.62, p<0.01). In addition, median OS was improved in patients with an early PTR (30.2 vs. 12.7 months). Independent predictors of decreased survival on multivariate analysis included local symptoms, multiple bone metastases, clinical evidence of venous thrombus, LDH > upper limit of normal, and >2 visceral metastatic sites. Conclusions: Early PTR ≥ 10% is associated with improved survival, better response in metastatic sites, and better overall PTR in patients with mRCC. Future studies should consider this variable when evaluating sunitinib in mRCC treatment. [Table: see text]
Long-term survival of patients with metastatic renal cell carcinoma (mRCC) treated with targeted therapy (TT) without cytoreductive nephrectomy (CN).
Authors: Richey S. L. , Culp S. H. , Jonasch E. , Corn P. G. , Pagliaro L. C. , Tamboli P. , Patel K. , Matin S. F. , Tannir N. M. 
Published: February 2017

346 Background: We recently reported on 188 patients (pts) with mRCC treated with TT without CN [Richey et al, J Clin Oncol 28:15s, 2010 (suppl; abstr 4613); Annals of Oncology- in press]. We report here outcome data on pts who survived > 24 months (mos). Methods: We retrospectively reviewed records of patients with mRCC who received TT without CN and survived longer than 24 mos from treatment initiation. Pts did not undergo CN due to medical comorbidity, unresectable primary tumor, heavy disease burden, or patient preference. Kaplan-Meier methods were used to estimate median overall survival (OS). Long-term complications related to therapy were evaluated. Results: 22 pts were identified meeting the inclusion criteria. Median follow-up was 30.4 mos (range, 24.1- 68.7), with median OS time of 34.1 mos (95% CI: 30.2, 37.2). Median time on therapy (TOT) was 25.3 mos (IQR: 13.7, 28.5). Six pts (27.3%) were alive at the time of analysis, with median TOT of 26.9 mos (range: 13.7, 62.5) (IQR: 24.6, 33.4). Eastern Cooperative Oncology Group performance status was 0 or 1 in 86% of pts. Ten (45%) and 12 (55%) pts had intermediate- and poor-risk disease by Heng et al criteria (JCO 2009), respectively. Patients received the following types of TT: sunitinib 14 (63.6%), sorafenib 13 (59.1%), temsirolimus 5 (22.7%), bevacizumab 5 (22.7%), pazopanib 3 (13.6%), everolimus 4 (18.2%), erlotinib 3 (13.6%), investigational targeted agent 1 (4.6%). Four (18.2%), 5 (22.7%), and 13 (59.1%) pts received 1, 2, or ≥ 3 different therapies, respectively. During treatment with TT, 6 pts (27.3%) developed hypertension, 6 pts (27.3%) developed hypothyroidism, 2 pts (9.1%) developed congestive heart failure, 1 pt (4.6%) developed stroke. No pts developed bleeding or myocardial infarction. By radiographic assessment of best primary tumor response, 4 (18.2%) pts had a partial response (≥30% decrease), 10 (45.5%) exhibited a decrease <30%, and 6 (27.3%) had stable or increased size of the primary tumor. Conclusions: These data highlight the potential for long-term survival of patients with mRCC treated with TT without CN, and underscore the challenges in managing therapy-related long-term adverse events. No significant financial relationships to disclose.