bluuebunny/crossref_metadata_2025_split huggingface dataset:
Real-world clinical outcomes of pazopanib immediately following immunotherapy discontinuation for the treatment of advanced renal cell carcinoma.
Authors: Cao Xiting , Tang Derek , Ratto Barbara Elizabeth , Poole Austin , Ravichandran Shoba , Jin Lixian , Gao Wei , Swallow Elyse , Vogelzang Nicholas J. 
Published: March 2019

573 Background: In the first-line setting (1L), pazopanib (PAZ) is recommended by NCCN for treatment of advanced renal cell carcinoma (aRCC). In 2018, immuno-oncology (IO) therapy became commonly used 1L treatment option for aRCC. This study reports real-world clinical outcomes of PAZ following IO therapy among aRCC patients (pts) in an evolving treatment landscape. Methods: This retrospective chart review study used medical record data collected by medical oncologists. Included pts were those ≥ 18 at initiation of IO therapy who initiated 2L+ PAZ for clear cell aRCC before November 2017, and had complete medical records from the diagnosis of aRCC to discontinuation of PAZ, death, or the chart extraction date (May 2018), whichever occurred first. Primary outcome was PAZ duration of therapy (DOT). Secondary outcomes were progression-free survival (PFS) and overall survival (OS) since PAZ initiation, reasons for PAZ discontinuation, and adverse events (AEs). Time-to-event outcomes were analyzed by Kaplan-Meier method. Results: 258 eligible pts initiated the IO therapies before PAZ as follows: nivolumab (NIVO) (68%), NIVO+ipilimumab (IPI) (14%), pembrolizumab (12%), and IPI (3%). Ninety-seven (38%), 56 (22%), and 92 (36%) pts were grouped as favorable, intermediate, or poor risk by Heng criteria, respectively. Overall, the median PAZ DOT was 13.4 months (Ms) (95% confidence interval [CI] 10.1-16.0). When stratified by lines of therapy, pts who received PAZ as 2L (n=182) or 3L+ (n=76) had DOT of 13.4 Ms (95% CI 11.1-NR) and 9.6 Ms (95% CI 6.2-NR), respectively. The PFS and OS outcomes are shown in the Table. One hundred-nine (42%) pts reported an AE. The most frequently (>10%) reported AEs were fatigue (29%), diarrhea (14%), decreased appetite (14%), and hypertension (13%). Conclusions: In this real-world study, 2+L PAZ following prior IO therapy was well-tolerated, effective, and non-cross-resistant with IO therapy for aRCC pts. [Table: see text]
First-line (1L) immuno-oncology (IO) combination therapies in metastatic renal cell carcinoma (mRCC): Preliminary results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).
Authors: Dudani Shaan , Graham Jeffrey , Wells Connor , Pal Sumanta K. , Dizman Nazli , Donskov Frede , Bjarnason Georg A. , Hansen Aaron Richard , Iafolla Marco Adelmo James , Vaishampayan Ulka N. , Porta Camillo , Beuselinck Benoit , Yan Flora , Wood Lori , Liow Elizabeth Chien Hern , Kollmannsberger Christian K. , Yuasa Takeshi , Zhang Chiyuan A , Choueiri Toni K. , Heng Daniel Yick Chin 
Published: March 2019

584 Background: In mRCC, ipilimumab and nivolumab (ipi-nivo) is a 1L treatment option. Recent data have also shown efficacy of 1L PD(L)1-VEGF (PV) inhibitor combinations. The efficacy of these two strategies has not been compared. Methods: Using the IMDC dataset, patients (pts) treated with any 1L PV combination were compared to those treated with ipi-nivo. Multivariable Cox regression analysis was performed to control for imbalances in IMDC risk factors. Results: 164 pts received 1L IO combination therapy: 104 treated with PV combinations and 60 with ipi-nivo. Baseline characteristics and IMDC risk factors were comparable between groups (Table). When comparing PV combinations vs ipi-nivo, 1L response rates (RR) were 30% vs 39% (p = 0.29), time to treatment failure (TTF) was 13.2 (95% CI 8.3-16.1) vs 8.5 months (95% CI 5.7-14.0, p = 0.31), and median overall survival (OS) was not reached (NR) (95% CI 19.7-NR) vs NR (95% CI 27.6-NR, p = 0.39). When adjusted for IMDC risk factors, the hazard ratio (HR) for TTF was 0.77 (95% CI 0.44-1.35, p = 0.36) and the HR for death was 0.94 (95% CI 0.33-2.71, p = 0.91). Similar results were seen when restricting the cohort to IMDC intermediate/poor risk pts only. In pts receiving subsequent VEGF TKI monotherapy, second-line (2L) RR (13% vs 45%, p = 0.07) and TTF (5.5 vs 5.4 months, p = 0.80) for PV combinations (n = 15) vs ipi-nivo (n = 20) were not significantly different. Conclusions: There does not appear to be a superior 1L IO combination strategy in mRCC, as PV combinations and ipi-nivo have comparable RR, TTF and OS. Although there is a trend towards differences in RR, there does not appear to be a significant difference in TTF for patients receiving 2L VEGF TKI therapy. [Table: see text]
Angiogenic factor and cytokine analysis among patients with renal cell carcinoma treated with adjuvant VEGFR TKIs.
Authors: Xu Wenxin , Puligandla Maneka , Haas Naomi B. , Flaherty Keith , Uzzo Robert , Dutcher Janice P. , DiPaola Robert S. , Bhatt Rupal Satish 
Published: March 2019

586 Background: VEGFR TKIs are important therapeutic agents in RCC, but their adjuvant use remains limited. Investigating the effects of these medications on circulating angiogenic factors and cytokines in the adjuvant setting can elucidate whether changes in cytokine levels result from drug-host or drug-tumor interactions, and may reveal biomarkers to guide patient selection for adjuvant treatment. Methods: In the ECOG-ACRIN 2805 (ASSURE) trial, patients with resected RCC were randomized to sunitinib, sorafenib, or placebo. Plasma was collected at start of treatment and 4 or 6 weeks after treatment initiation. All paired samples available by July 2010 were analyzed, corresponding to 413 patients. We analyzed VEGF, PlGF, sFlt1, KDR/sVEGFR-2, Ang2, bFGF, HGF, IFNg, IL8, CXCL9, CXCL10, and CXCL11. Mixed effects models were used to test for changes from baseline. Cox models were used to assess associations between disease-free survival (DFS) and angiogenic factor and cytokine levels. Results: VEGF and PlGF increased after 4 weeks on either treatment (p < 0.0001 for both), and at 6 weeks VEGF and PIGF levels returned to baseline for patients on sunitinib (corresponding to the 2 week break in the sunitinib schedule) but not sorafenib. Levels of sFLT-1 decreased after 4 weeks on suntinib and after 6 weeks on sorafenib (p < 0.0001). sVEGFR2 decreased after both 4 and 6 weeks of treatment on both sunitinib and sorafenib (p < 0.0001). Patients on placebo had no significant changes in circulating angiogenic factor or cytokine levels. CXCL-10 levels increased after 4 weeks on both sunitinib and sorafenib but not on placebo, and remained elevated at 6 weeks on sunitinib. Higher baseline CXCL-10 was associated with worse DFS (HR 1.41 per log increase in CXCL-10, Holm adjusted p-value 0.003, 95% CI 1.18-1.70). This remained significant after adjustment for T-stage, Fuhrman grade, and ECOG PS. Conclusions: Among patients treated with VEGFR TKIs in the adjuvant setting for RCC, drug-host interactions mediate changes in cytokines and angiogenic factors. Elevated CXCL-10 prior to treatment was associated with higher recurrence risk. Studies to understand the functional consequences of these changes are underway.
Eficacy and safety of first-line TKI in elderly with metastatic renal cancer.
Authors: Leite Luciana de Moura , Rinck Jose A. , Dettino Aldo A. , Zequi Stenio Cassio , Da Costa Alexandre Andre B. A. , Garcia Daniel , Formiga Maria Nirvana 
Published: March 2019

588 Background: Data on 1st line treatment with tyrosine kinase inhibitors (TKI) in elderly patients(pts) with metastatic renal cell carcinoma (mRCC) is controversial, and there is rationale for inferior outcomes due to multiple comorbidities and polypharmacy. We aimed to compare the efficacy and safety between the elderly (E) and non-elderly (NE) in 1st line therapy, and to explore factors influencing survival and toxicity. Methods: We retrospectively reviewed all medical records of mRCC pts treated with 1st line TKI at our institution (2007 – 2018). Categorial variables were compared by Fisher’s exact test and continuous, Mann–Whitney. Survival was estimated by Kaplan-Maier method, prognostic factors adjusted by Cox regression model. Results: From 171 eligible pts, 64 (37.4%) had ≥ 65years old, with median age of 70.5 for E and 56 for NE. In both groups most were male, had clear cell histology, good/intermediate IMDC risk, prior nephrectomy and > 1 metastatic (mets) site. Sites of mets were evenly distributed. E pts had more diabetes (35.9 vs16.8%, p.009) , hypertension (67.2 vs 46.7%, p.01), cardiovascular disease (15.6 vs 6.5%, p.06), moderate/severe renal dysfunction (62.5 vs 28.8%, p < 0001), high Charlson Comorbidities Index (CCI≥3, 48.4% vs 20.8%, p < .0001), polypharmacy (34.4 vs15.9%, p.008), worst ECOG (≥2, 28.2 vs 12.3%, p.01), and a trend to worst nutrition (weight loss 35.9 vs 22.5%, p.07). Sunitinib was used for 60.9 vs 79.4%, Pazopanib 35.9 vs 18.7%, Sorafenib 3.1 vs 1.9%, comparing E and NE pts. Median overall survival (OS) and progression free survival (PFS) was 23.7 vs 25.6m (p.8) and 9.3 vs 10.9m (p.7), respectively. After adjusting for prognostic factors, age continues not to influence OS (HR 1.17, IC95 0.77-1.78, p.45). Grade (G) 3/4 toxicity was seen in 59.4 vs 53.3%, dose reduction in 54.7 vs 53.3% and suspension due to toxicity 25 vs 13.3% for E and NE, respectively. In the E, none of the comorbidities, CCI or polypharmacy impaired OS or toxicity, but pts using sunitinibe had greater G3/4 toxicity than with pazopanib (71.8 vs 39.1%, p.02). Conclusions: Elderly had similar outcomes to NE pts, despite greater comorbidities and polypharmacy, hence efficacious therapies shouldn’t avoided. Pazopanib seems to be safer in this subgroup.
Expectations of cure among patients with advanced genitourinary cancer treated with immunotherapy.
Authors: Bergerot Cristiane Decat , Bergerot Paulo Gustavo , Philip Errol James , Hsu Joann , Dizman Nazli , Vaishampayan Ulka N. , Dorff Tanya B. , Pal Sumanta K. 
Published: March 2019

591 Background: Over the past 15 years, considerable progress has been made in systemic therapy options for genitourinary (GU) cancers. In diseases such as metastatic renal cell carcinoma (RCC) and urothelial cancer (UC), immunotherapeutic strategies such as programmed death-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibition have elicited durable responses, albeit in a minority of patients. We examined expectations for clinical outcome with immunotherapy among patients with advanced GU cancers. Methods: A survey study was conducted in patients with advanced GU cancers initiating PD-1/PD-L1 inhibitors from October 2017 to September 2018. Patients were screened prior to initiation of immunotherapy for their expectation of cure (divided into 4 quartiles), symptoms of anxiety and depression (PROMIS-A and PROMIS-D), and quality of life (QOL; FACT-G). For purposes of the survey, cure was equated to a durable complete response. Differences in frequency of anxiety, depression and QOL were compared amongst subsets of patients divided by expectation of cure. Results: Among 60 patients, median age was 67, 72% were male and 81% were married. Types of cancer included RCC (69%), UC (19%) and prostate cancer (12%). The majority were in the 1st or 2nd line of therapy (40% and 31%, respectively). Despite extensive counseling from GU medical oncologists, 23% of patients thought that cure was “very likely”, defined as in the range of 76-100%. Approximately 70% of patients estimated cure in the range of 0-25%, in line with clinical counseling. These patients had higher rates of anxiety (P = 0.01), depression (P = 0.002) and poorer QOL (P = 0.003) compared to patients who felt cure was very likely. Conclusions: A considerable proportion of patients with advanced GU malignancies harbor unrealistic expectations around the potential benefit of immunotherapy. Although a first instinct may be to remedy these expectations, it is important to bear in mind that these patients had better emotional well-being and QOL. We will validate these findings and assess these parameters longitudinally in an upcoming SWOG trial for patients with mRCC receiving upfront immunotherapy.
The significance of insulin receptor expression to predict the resistance to VEGFR-TKIs and induce PD-L1 expression in advanced clear cell renal cell carcinoma.
Authors: Takahashi Masayuki , Daizumoto Kei , Fukawa Tomoya , Fukuhara Yayoi , Ozaki Keisuke , Tsuda Megumi , Kusuhara Yoshito , Mori Hidehisa , Yamamoto Yasuyo , Yamaguchi Kunihisa , Fukumori Tomoharu , Kanayama Hiroomi 
Published: March 2019

592 Background: Previously we have identified the prognostic gene set of ccRCC patients, where insulin receptor (INSR) expression was decreased in the patients with poor outcome (Proc Natl Acad Sci U S A., 2001). We examined the clinical significance of decreased INSR expression and sought to elucidate the underlying mechanisms. Methods: The INSR expression was immunohistochemically examined in the nephrectomy specimens of RCC patients (n = 33) who then received axitinib. We established patient derived Xenograft model (PDX) of ccRCC and examined the INSR expression in the axitinib resistant PDX tumors by Western blotting. As the INSR is expressed in the vascular endothelial cells, we co-cultured the RCC cell lines with the human renal glomerular endothelial cells (HGEC) treated with si-RNA of INSR (si-INSR) and the microarray experiment was conducted. Results: In RCC patients with axitinib, those with low INSR expression had poor outcome (median PFS 19.5 vs 2.3 months, p < 0.001; median OS 34.2 vs 5.6 months, p = 0.001). The INSR expression was the significantly independent predictor of PFS (p = 0.006). In the axitinib-resistant PDX tumors, the expression of INSR was decreased. In the co-culture experiments, the microarray experiments revealed that the decreased INSR expression in the HGECs may be involved with the important signaling pathway including interferon response in Caki-1 cells. Interferon- β was highly expressed in HGECs with si-INSR. The decreased INSR expression and the increased interferon-β expression in HGEC were confirmed when axitinib was administered. The Caki-1 cells that was co-cultured with HGECs treated with si-INSR demonstrated high expression of PD-L1. The PD-L1 expression was increased in a concentration-dependent manner of recombinant interferon-β and increased phosphorylation of STAT1 and STAT3 were observed. Conclusions: In conclusion, the decreased INSR expression could be a biomarker to predict the resistance to VEGFR-TKIs. The decreased INSR expression was correlated with the increased interferon-β expression in HGECs, which leads to the induction of PD-L1 through increased phosphorylation of STAT1 and STAT3.
Disparities in survival outcomes in African Americans in renal cell carcinoma: Impact of oncological versus nononcological factors.
Authors: Meagher Margaret Frances , Bradshaw Aaron , Anyakora David , Patil Dattatraya H , Saito Kazutaka , Cotta Brittney , Yasuda Yosuke , Eldefrawy Ahmed , Ryan Stephen , Nasseri Ryan , Alksne Juliana , Wan Fang , Fujii Yasuhisa , Master Viraj A. , Derweesh Ithaar 
Published: March 2019

595 Background: African-Americans have increased incidences of renal cortical tumor subtypes of lower oncological potential in the setting of lower risk disease when compared to other ethno-racial groups. However, survival outcomes are similar. We investigated the impact of African-American race on overall survival, oncological outcomes, functional outcomes, and non-cancer mortality. Methods: Multi-institutional retrospective analysis of patients who underwent partial or radical nephrectomy between 1998-2018. Primary outcome was overall survival (OS). Secondary outcomes included non-cancer mortality (NCM), recurrence free survival (RFS), and estimated glomerular filtration rate (eGFR) decline. Multivariable logistic regression (MVA) were used to elucidate predictive factors for OS, NCM, and RFS, and eGFR <45 and <30 ml/min/1.73m2. Results: 3,088 patients were divided into African American (AA, n=353) and Non-African American (NAA, n=2735) sub-groups. No difference was noted between groups with respect to mean tumor size (p=0.211) or metastases presence (p=0.846). African-American race was an independent risk factor for functional decline to eGFR<45 (OR 4.43, p<0.001) and eGFR<30 (OR 5.15, p<0.001). MVA for worsened NCM demonstrated African-American race (OR=1.72, p=0.042), increasing age (OR=1.03, p=0.001), radical nephrectomy (OR=2.98, p<0.001), and increasing tumor size (OR=1.26, p<0.001) to be independent risk factors. MVA for worsened OS included increasing age (OR=1.04, p<0.001), tumor size (OR=1.182, p<0.001), clear cell histology (OR=1.62, p<0.001), high tumor grade (OR=2.12, p<0.001), and post-operative eGFR <45 (OR=2.12, p<0.001). MVA for worsening RFS demonstrated high tumor grade (OR=2.38, p<0.001) and increasing clinical tumor size (OR=1.152, p<0.001) to be independent factors. Conclusions: African Americans undergoing renal surgery for RCC appear to have similar OS and RFS, but poorer NCM than non-African American patients. The cause of these disparities is multi-faceted and likely associated with functional decline. Nephron-sparing management should be considered in African-Americans presenting with renal cortical tumors.
Development and validation of a novel scoring index (C-reactive protein, age, race, and tumor size) to predict renal functional decline post partial nephrectomy.
Authors: Meagher Margaret Frances , Patil Dattatraya H , Saito Kazutaka , Cotta Brittney , Yasuda Yosuke , Bradshaw Aaron , Eldefrawy Ahmed , Ryan Stephen , Nasseri Ryan , Anyakora David , Alksne Juliana , Wan Fang , Fujii Yasuhisa , Master Viraj A. , Derweesh Ithaar 
Published: March 2019

597 Background: Functional decline is a sequelae of extirpative renal surgery with potential for significant morbidity. We utilized pre-operative patient demographics, C-reactive protein, and tumor size to design and validate a novel scoring index to predict functional decline post partial nephrectomy. Methods: A multi-institutional dataset was utilized for analysis of patients with pre-operative estimated glomerular filtration rate (eGFR) > 60mL/min/1.73m2 by CKD-EPI equation. Multivariable analysis (MVA) was carried out for potential variables associated with development of post-operative chronic kidney disease (CKD) stage IIIB at last follow-up (eGFR < 45 mL/min/1.73m2). Significant variables were included in the predictive model and assigned an index score based on odds ratio. Receiver-operating-characteristic (ROC) analysis was employed to evaluate predictive validity, and bootstrapping technique was utilized to validate the model. Results: 924 patients were analyzed. 826 patients had post-operative eGFR > 45, while 111 patients had eGFR. Factors on MVA independently associated with increased risk of development of eGFR < 45 included age 65+ (OR = 2.6, p < 0.001), African-American race (OR = 2.3, p = 0.006), C-reactive protein level > 0.5mg/dL (OR = 5.3, p < 0.001), and tumor size > 4 cm (OR = 1.458, p = 0.189). For CART (C-reactive protein, Age, Race, Tumor size) score, the following values were assigned: age ( < 65 = 1, age > 65 = 3), race (non-African-American = 1, African-American = 2), tumor size ( < 4 = 1, > 4cm = 2), and CRP ( < 0.5mg/dL = 1, > 0.5mg/dL = 4). Analysis demonstrated 2.6% (12/469) of patients with a low (4-6) score had de novo eGFR < 45 postoperatively, while 35% (41/117) of patients with a high (10-11) score had de novo eGFR < 45. ROC analysis revealed AUC of 0.778, and ROC bootstrapping validation of 95 randomly selected patients revealed an AUC of 0.808. Conclusions: CART score represents a novel composite score that significantly predicts development of eGFR < 45 after surgery. This scoring system may assist in patient counseling and clinical decision making, as well as an impetus to improve outcomes in at-risk patient subgroups.
A phase I pilot study of preoperative radiotherapy for prostate cancer: Long-term toxicity and oncologic outcomes.
Authors: Sanmamed Noelia , Glicksman Rachel , Thoms John , Zlotta Alexandre , Finelli Antonio , Van Der Kwast Theodorus , Sweet Joan , Jewett Michael , Klotz Laurence , Rosewall Tara , Fleshner Neil Eric , Bristow Robert G. , Warde Padraig , Berlin Alejandro 
Published: March 2019

60 Background: Pre-operative radiotherapy (PreORT) improves local control in various cancer types, and has become an established oncologic treatment strategy. During 2001-2004, we conducted a phase I pilot study assessing the role of short-course PreORT for men with unfavourable intermediate- and high-risk localized prostate cancer (PCa). We present long-term follow-up toxicity and oncologic outcomes. Methods: Eligible patients had histologically proven PCa, cT1-T2N0M0, PSA > 15-35 ng/ml with any Gleason score, or PSA 10-15 ng/ml with Gleason score ≥7. Patients received 25 Gy in five consecutive daily fractions to the prostate, followed by radical prostatectomy (RadP) within 14 days after RT completion. Primary outcomes were intra-operative morbidity, and late genitourinary (GU) and gastrointestinal (GI) toxicities. Acute toxicity was assessed during radiotherapy treatment on daily basis using RTOG grade scoring scale. Patients were assessed post-RadP clinically and with PSA at 1 and 6 months, and every 6 months. Intra- and Post-RadP toxicity was documented prospectively and scored as per Common Terminology Criteria for Adverse Events v4.0. Biochemical failure (BF) was determined based on two consecutive post-RadP PSA > 0.2 ng/ml. Results: Fifteen patients were enrolled; 14 patients completed PreORT followed by RadP, which also included bilateral lymph node dissections in 13 cases. Median follow-up was 12.2 years (range 6.7-16.3 years). Late GU toxicity was common, with 2 patients (14.3%) experiencing G2 toxicity, and 6 patients (42.8%) G3 toxicity. There were no G4-5 late GU toxicity. Late GI toxicity was infrequent, with only 1 patient (7.1%) experiencing transient G2 proctitis. At last follow-up, 8 (57.1%) and 6 (42.8%) patients experienced BF and metastatic disease recurrence, respectively. Conclusions: The use of PreORT in men with high-risk PCa is associated with unexpected high-rates of late GU toxicity. Future studies examining the role of RT pre-RadP must cautiously select RT technique and dose schedule. Importantly, long-term follow-up data is essential to fully determine the therapeutic index of PreORT in the management of localized PCa. Clinical trial information: NCT00252447.