bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sunitinib versus sorafenib as first-line therapy followed by sorefenib and sunitinib for patients with metastatic renal cell carcinoma (RCC) with clear cell histology: A multicenter randomized trial, CROSS-J-RCC.
Authors: Tomita Yoshihiko , Naito Sei , Sassa Naoto , Takahashi Atsushi , Kondo Tsunenori , Koie Takuya , Obara Wataru , Kobayashi Yasuyuki , Teishima Jun , Takahashi Masayuki , Matsuyama Hideyasu , Ueda Takeshi , Yamaguchi Kenya , Kishida Takeshi , Shiroki Ryoichi , Saika Takashi , Shinohara Nobuo , Oya Mototsugu , Kanayama Hiroomi 
Published: March 2017

469 Background: SWITCH, a prospective, randomized sequential trial to evaluate SU/SO versus SO/SU, revealed no difference in first-line or total PFS or OS, but no direct comparison was obtained between 1st line sunitinib (SU) and sorafenib (SO) for clear cell (CC) metastatic renal cell carcinoma (mRCC). Methods: Treatment-naïve patients with CC mRCC, ECOG PS 0/1 and MSKCC favorable or intermediate risk were randomized to receive open-label SU/SO or SO/SU at the standard dosage and schedule. The primary endpoint was 1st line PFS, and secondary endpoints were total PFS and OS. The calculated sample size was 59 per group, with α = 0.05, β = 0.10, and a censoring rate of 15%. Results: Of 124 patients enrolled in this study from February 2010 to July 2012 from 39 institutions, 120 could be evaluated (SU/SO, 57 and SO/SU, 63). Baseline patients' characteristics in the SU/SO and SO/SU groups were as follows: favorable risk, 21% and 22%; and presence ofnephrectomy, 88% and 89%, respectively. First-line mPFS was 8.7 and 7.0 months in the SU/SO and SO/SU groups, respectively (HR, 0.67; 95% CI, 0.42–1.08; p= 0.095). There was no statistically significant difference in total (T)-PFS, 27.8 M, and 22.6 m (HR 0.73, CI 0.428-1.246; p=0.247), or OS 38.4 m and 30.9 m (HR 0.934, CI 0.588-1.485; p=0.773). Subgroup analyses showed that T-PFS was NR and 27.8 m (p=0.021) in the favorable risk, and 38.4 m and 16.1 m (p=0.009) in with less than 5 metastatic sites, 6.5 m and 13.6 m (p=0.025) without nephrectomy in the SU/SO and SO/SU groups, respectively. The most common adverse events (AEs) in case of first-line SU or SO (all grade, all cause) were hand–foot syndrome (71% vs. 86%), hypothyroidism (70% vs. 33%), fatigue (57% vs. 40%), hypertension (55% vs. 44%), and diarrhea (23% vs. 38%). AEs were generally lower during second-line therapy. Conclusions: There was no significant difference in first-line PFS, T-PFS, and OS between the two sequential treatments. Although fewer patients received second-line treatment in the SU/SO group, OS in this group was numerically longer than that in the SO/SU group. Clinical trial information: 01481870.
Toxicity, quality of life outcomes, and dosimetric impact in phase III trial of hypofractionated or standard fractionated proton therapy for low-risk prostate cancer patients: PCG GU 002.
Authors: Schmidt Matthew Q. , Vargas Carlos E. , Hartsell William F. , Dunn Megan , Keole Sameer R. , Doh Lucius , Chang John Han-Chih , Sinesi Christopher , Larson Gary L. 
Published: March 2017

48 Background: The purpose of this study is to identify differences in toxicity, quality of life (QOL), and dosimetric endpoints among patients with low-risk prostate adenocarcinoma treated with either standard fractionation or hypofractionation proton-beam therapy. Methods: We analyzed the results of the first 75 patients treated in our phase III trial comparing 38Gy relative biological effectiveness (RBE) in 5 fractions (fx) (n = 46) vs. 79.2Gy (RBE) in 44 fx. (n = 29). All patients had low-risk prostate cancer and were treated with proton radiation using fiducial markers and daily image guidance. We evaluated American Urological Association (AUA) Symptom Index, adverse events (AEs), and Expanded Prostate Index Composite (EPIC) domains at pretreatment and 3, 6, 12, 18, 24, 36 and 48 months. Doses to the prostate were selected based on similar long term effects to normal tissue based on an α/β = 3.5 for an EQD2 of 76Gy. Results: The median follow-up was 36 months for both groups; 23 (30%) patients reached a follow-up of 48 months. We observed a small difference in AUA score (3.2 vs. 8.6, p = 0.002) at 1-year favoring the 79.2Gy arm. AUA scores were not statistically different at 18 months and after. Similarly, EPIC Urinary symptoms favored the 79.2Gy arm at 1 year (92.3 vs. 84.5, p = 0.009) and 18 months (92.3 vs. 85.3, p = 0.03); bother scores were not significantly different at any other time points. G2 or higher GU toxicity was similar between arms (p = 0.8). No differences in EPIC Bowel symptoms, EPIC Sexual symptoms, or bowel G2 or higher toxicities were seen. One death was observed in the 38Gy arm due to an unrelated case of multiple myeloma. The bladder V80 (79.2Gy arm, p = 0.04) and V39 (38Gy arm, p = 0.05) were predictive for G2 or higher GU AE. There was no association observed between rectal dose and G2 or higher rectal toxicity. Conclusions: Patients treated in the hypofractionated and standard arms tolerated treatment well. A small and temporary difference in the GU domain was seen favoring the standard arm. As predicted long term effects on the GU domain and bowel were similar for both arms, suggesting that the α/β is similar to 3.5 for long term effects. Clinical trial information: 01230866.
Effect of nivolumab on tumor growth rate (TGR) in metastatic renal cell carcinoma (mRCC).
Authors: Mazza Camille , Arfi-Rouche Julia , Koscielny Serge , Caramella Caroline , Lahmar Jihene , Escudier Bernard J. , Albiges Laurence 
Published: March 2017

481 Background: Response assessment under immune checkpoint inhibitors is a challenge that RECIST criteria may not adequately reflect. TGR takes into account the pretreatment kinetics and allows dynamic assessments. How TGR varies under nivolumab remains unknown. We aim at describing the pattern of TGR changes during nivolumab treatment. Methods: We performed a central radiological review of all consecutive patients treated with nivolumab at Gustave Roussy within the GETUG-AFU 26 NIVOREN (EudraCT 2015-004117). Tumor response was assessed at week 8 and every 8-12 weeks subsequently using RECIST 1.1. TGR was computed for the pre nivolumab treatment (TGR pre) and at first (TGR N1) and second assessment (TGR N2) under nivolumab. Results: A total of 45 patients treated with nivolumab between Feb and Jul 2016 were reviewed. Median age at nivolumab start was 60 years-old, 74 % were male. Median number of prior lines of systemic therapies was 2. Median follow-up from nivolumab start was 6 months. TGR pre and TGR N1 were available in 39 patients. Overall, mean decrease in TGR N1 compared to TGR pre was 26%. Among 39 evaluable patients, 23 (59%) patients had a decrease in TGR N1 compared with TGR pre; while an increase was described in 16 (41%) patients. Only one patient out of 39 (2.5%) had a major increase of more than 50% in TGR N1 compared with TGR pre, and could be defined as a hyper-progressor. Consecutive TGR N1 and TGR N2 were available in 24 patients. There was a high correlation between TGR N1 and TGR N2 (r=0.7), suggesting that first evaluation of tumor kinetics adequately reflects subsequent response to nivolumab. However, 4/24 patients (17%) had an initial increase in TGR N1 with subsequent decrease in TGR N2, defining potentially the pseudo-progressors. Conversely, 6/24 patients (25%) had an initial decrease in TGR N1 before a rebound in TGR N2 suggesting a prompt acquired resistance to nivolumab. Conclusions: We report the first TGR assessment of mRCC patients under nivolumab. Overall, 59 % of patients had a decrease in TGR under nivolumab compared to pre nivolumab. TGR in patients with mRCC might provide early information about tumor response to nivolumab. Analysis extended to the entire study population and correlation with PFS and OS will be reported.
Clinical activity of PD1/PDL1 inhibitors in metastatic non-clear cell renal cell carcinoma (nccRCC).
Authors: Moreira Raphael Brandao , McKay Rana R. , Xie Wanling , Heng Daniel Yick Chin , de Velasco Guillermo , Castellano Daniel E. , Fay Andre Poisl , Schutz Fabio Augusto Barros , Wells Connor , Hsu JoAnn , Pal Sumanta K. , Lee Jae-Lyun , Motzer Robert J. , Feldman Darren R. , Choueiri Toni K. 
Published: March 2017

482 Background: PD1/PDL1 inhibitors have shown significant activity in the treatment of patients (pts) with metastatic clear cell renal cell carcinoma (ccRCC), but their activity in nccRCC is poorly characterized. Methods: We conducted a retrospective multicenter study of pts with metastatic nccRCC treated with PD1/PDL1 inhibitors. Baseline clinical parameters, overall response rate (ORR) by RECIST, time-to-treatment failure (TTF), and overall survival (OS) were summarized. Results: We identified 40 pts across 8 academic institutions. Fourteen (35%) had papillary histology, 10 (25%) chromophobe, 3 (8%) translocation, and 7 (18%) unclassified. Six (16%) had ccRCC with a sarcomatoid component > 30%. 20% had International Metastatic RCC Database Consortium (IMDC) favorable-risk disease, 60% intermediate, and 20% poor-risk. Ten (25%) were treatment-naïve and the majority received PD1/PDL1 monotherapy (n=30, 75%), while the remaining received a combination of PD1/PDL1 with anti-VEGF(R) or anti-CTLA4 therapy. ORR for the total cohort was 18% and 10% for PD1/PDL1 monotherapy pts (Table). With a median follow-up of 5.6 months, the overall median TTF was 4.7 months (2.9-15.9) and six-month OS was 81% (60-91%). Conclusions: PD1/PDL1 blockade resulted in some activity in pts with various nccRCC histologies. In the absence of available clinical trials, this data may support the use of PD1/PDL1 blocking agents in pts with nccRCC. [Table: see text]
Tumor genomic analysis for 128 renal cell carcinoma (RCC) patients receiving first-line everolimus: Correlation between outcome and mutations status in MTOR, TSC1, and TSC2.
Authors: Voss Martin Henner , Chen David , Marker Mahtab , Xu Jianing , Patel Parul , Han Xia , Hsieh James , Motzer Robert J. 
Published: March 2017

484 Background: MTOR inhibitors are standard agents in the management of advanced RCC. Case series have suggested somatic mutations in MTOR, TSC1, and TSC2 may sensitize tumors to everolimus (EVE) [Voss et al., CCR 2014; Kwiatkowski et al., CCR 2016]. We sought to test this hypothesis through next generation sequencing (NGS) of tumors from a large cohort of patients (pts) treated with everolimus (EVE) on the randomized RECORD3 trial of first-line EVE vs. sunitinib. Methods: Somatic mutations were investigated using a custom exon-targeted NGS platform with deep sequence coverage. This analysis focused on mutations in TSC1, TSC2, PTEN, PIK3CA, and MTOR. Association between genotypes and progression free survival (PFS) was assessed by Cox PH models and log-rank tests. Mutations in other pathways and non-genetic covariates were investigated. Functional investigation of individual mutations in MTOR, TSC1, and TSC2 were undertaken. Results: 238 pts received 1st line EVE with median PFS of 7.85 mo (95% CI 5.6-8.2). Tumor sampleswere analyzed for 128 pts. Median depth of coverage was ~540X. There was no correlation between PFS and mutation status of mTOR, TSC1, or TSC2 (15 pts [12%]; HR 0.99 [95% CI 0.47-2.07]; p=0.4697); the objective response rate (ORR) in this group was 0%. Individual PFS for all 15 pts clustered outside the 95% CI for the population of 128 everolimus-treated pts (8 pts PFS<2.8mo; 7pts PFS>8.3mo). 3 of 8 pts with PFS<2.8mo had >1 mutation in MTOR, TSC1, or TSC2, while none among the 7 pts with PFS >8.3mo. When including pts with mutations in PTEN, PIK3Ca, MTOR, or TSC1 (30pts [23%]), we found no association between mutation status and PFS (HR 1.02 [95% CI 0.61-1.71]; p=0.3025). Functional investigations suggest varying biologic effects of individual mutations. Conclusions: "One-dimensional" mutation status for core components of the MTOR signaling pathway did not correlate with PFS in this dataset. Grouping based on more detailed characterization incorporating copy number status and functional annotation may provide better insights and should be considered for future biomarker development. Clinical trial information: NCT00903175.
Fourth-line targeted therapy in metastatic renal cell carcinoma (mRCC): Results from the International mRCC Database Consortium (IMDC).
Authors: Stukalin Igor , Wells Connor , Fraccon Anna Paola , Pasini Felice , Porta Camillo , Moreira Raphael Brandao , Srinivas Sandy , Bowman I. Alex , Brugarolas James , Lee Jae-Lyun , Donskov Frede , Beuselinck Benoit , Bamias Aristotelis , Rini Brian I. , Sim Hao-Wen , Agarwal Neeraj , Rha Sun Young , Kanesvaran Ravindran , Choueiri Toni K. , Heng Daniel Yick Chin 
Published: March 2017

498 Background: Fourthline targeted therapy efficacy in mRCC is not well characterized and is not reimbursed in many jurisdictions worldwide. Methods: The IMDC consists of consecutive patient series from 35 international cancer centers. It was queried for mRCC patients who received fourth line targeted therapy. Kaplan Meier estimates were used for time to treatment failure (TTF) and overall survival (OS). Results: 594 out of 7498 (8%) mRCC patients initially treated with first line targeted therapy eventually received fourth line therapy from a class of approved agents. Baseline characteristics are displayed in Table 1. The most common fourth line therapies were everolimus 17%, sorafenib 15%, axitinib 13%, pazopanib 13%, sunitinib 13%, nivolumab 7%. IMDC prognostic group distributions (Heng et al JCO 2009) and their associated survivals (both determined from fourth line therapy initiation) were 5% favorable risk (OS 23.1 (14.7-not reached)), 66% intermediate risk (OS 13.8 (11.4-17.5)), and 29% poor risk (OS 7.8 (4.93-12.2)) (OS p<0.0001). Overall response rate for fourth-line therapy was 12.5% and 41.5% had stable disease in those patients that were evaluable (n=407). Median TTF on fourth line therapy was 4.40 months (95% CI 3.98-5.06) and median OS from fourth line therapy initiation was 12.8 months (95% CI 11.4-14.4). Conclusions: Fourth line targeted therapy has demonstrated activity, is uncommon, and should be offered to clinically eligible patients. Further studies are required to determine appropriate sequencing. IMDC criteria appear to stratify favorable/intermediate/poor risk patients well in the fourth line setting. [Table: see text]
Litmus test or destination systemic therapy? Trends in referral for surgery after initial systemic therapy in metastatic kidney cancer.
Authors: Macleod Liam Connor , Dash Atreya , Schade George , Tykodi Scott S. , Gore John L. 
Published: March 2017

502 Background: With nine new targeted and immunotherapeutic agents for metastatic kidney cancer (mRCC) since 2005, there is no randomized data supporting sequencing cytoreductive nephrectomy (CN) and newer systemic therapies (ST). Increased disease control with ST engenders concern that CN may shorten life or delay therapy. Thus, in all the best prognostic candidates, initial ST as a “litmus” test may be advocated prior to CN. We evaluated use of CN after initial ST, hypothesizing receipt of deferred CN to be associated with increased survival time, markers of increased performance status, less rapid disease, and socioeconomic status. Methods: The National Cancer Database was screened for adult patients with biopsy-proven mRCC treated with initial systemic therapy between 2006-2013. Covariates included demographic, oncologic, hospital-level, and geographic variables. Unadjusted and multivariable logistic regression was performed, identifying factors associated with CN after initial ST. Results: Of 14,651 patients treated with initial ST for mRCC, 709 (4.8%, median OS 19 months, IQR 9-35) underwent delayed CN compared with 13,942 (95.2%, median OS 5 months, IQR 2-13) treated with ST alone. On multivariable analysis, survival ≥3 months was highly associated with receipt of CN (OR 10.6, 95% CI 5.5, 20.5). However, of 9,796 surviving ≥3 months, only 689 (7%) underwent CN. Factors associated with lower odds of CN included older age, greater comorbidity, higher clinical stage (T and N), and unfavorable metastatic sites (i.e., brain, bone, liver) with all p<0.001. Educational attainment was associated with receipt of CN, but hospital characteristics and travel burden were not. Conclusions: Effectiveness of CN in the modern mRCC era is uncertain. Initial ST is typically for those with poor prognosis. Yet, after an initial litmus test, re-evaluation of risk rarely leads to CN. Socioeconomic factors may affect CN decision-making, a potential disparity that merits further investigation.
Categorization of gene expression subtypes in clear cell renal cell carcinoma with sarcomatoid features.
Authors: Joshi Shreyas , Peri Suraj , Ross Eric A. , Uzzo Robert G. , Kutikov Alexander , Geynisman Daniel M. 
Published: March 2017

519 Background: Presence of sarcomatoid features in Renal Cell Carcinoma (sRCC) tumors signals aggressive clinical behavior and poor prognosis compared to Clear Cell Renal Cell Carcinoma (ccRCC). However, the underlying gene expression patterns of sRCC are poorly understood. We sought to categorize ccRCC and sRCC gene expression subtypes and compare survival outcomes, as well as evaluate whether sRCC gene expression patterns are similar to non-renal sarcomas. Methods: We identified 511 ccRCC cases, of which 36 had a sarcomatoid component from The Cancer Genome Atlas. Enrichment analysis was used to measure associations between gene expression signatures for soft tissue sarcomas and expression profiles of sRCC and ccRCC cases measured by RNA-Seq. The resulting scores were used to identify distinct patient groups using K-means clustering. Overall survival (OS) was evaluated by Kaplan-Meier, log rank, and Cox regression methods. Results: Our analysis identified 4 distinct clusters that differ in enrichment for soft-tissue sarcoma gene expression profiles. The clusters showed significantly different OS distributions (p-value<0.001 log rank). Most sRCC cases (69%) segregated into a single cluster with the worst prognosis. Among ccRCC cases, 57% of patients with higher levels of sarcoma signature enrichment were associated with a shorter OS, which is independent of tumor stage. 5-year/median OS survival estimates for ccRCC cases in the 4 clusters, by increasing levels of sarcoma profile enrichment, were 83%/NR, 75%/NR, 67%/90.9 mo, and 49%/56.7 mo. We also validated existence of these clusters in another sRCC cohort (Sircar 2015). Conclusions: We identified strong associations between sarcoma expression signatures and gene expression profiles of sRCC. We also found that 57% of morphologically non-sRCC cases demonstrate enrichment for sarcoma expression signatures, and these patients have worse OS than their non-sarcoma enriched ccRCC counterparts. The presence of sarcoma expression signatures has not been previously evaluated in RCC. These signatures portend poor survival and may be clinically actionable, as they describe unique subtypes of RCC that may not correspond to histologic characterization.
Beyond classical risk adjustment: Socioeconomic status and hospital performance in urologic oncology.
Authors: Odisho Anobel Y. , Gore John L. , Etzioni Ruth Douglas 
Published: March 2017

526 Background: Safety-net hospitals care for more patients of lower socioeconomic status (SES) than non-safety-net hospitals and may be disproportionately punished under readmission risk adjustment models that do not incorporate (SES). We developed a readmission risk adjustment framework incorporating SES to assess impact of SES on safety-net hospital rankings for patients undergoing major surgery for urologic malignancies. Methods: Quasi-experimental design using California Office of Statewide Health Planning and Development data from 2007-2011. Subjects included all patients undergoing radical cystectomy for bladder cancer (n = 3,771), partial nephrectomy (n = 5,556), and radical nephrectomy (n = 13,136) for kidney cancer. Unadjusted hospital rankings and predicted rankings under a base model, which simulated the Medicare Hospital Readmissions Reduction Program model, were compared with predicted rankings under models incorporating socioeconomic status. Socioeconomic status was derived from a multifactorial neighborhood score at the ZIP code level calculated from US Census data. The main outcome measures were hospital rankings based on 30-day all-cause readmission rate and differences between model predicted rankings. Results: For all procedures, the addition of socioeconomic status, geographic, and hospital factors changed the overall hospital rankings significantly compared with the base model (p < 0.01), with the exception of socioeconomic status in radical cystectomy (p = 0.07) and socioeconomic status and rural factors in partial nephrectomy (p = 0.12). For radical nephrectomy and partial nephrectomy, the addition of socioeconomic status and hospital factors significantly improved the mean ranking of safety-net hospitals and improved the ratio of observed relative to expected rankings (p < 0.01). For radical cystectomy there was no significant change in rankings with the addition of socioeconomic status, rural status, or hospital factors. Conclusions: Adding socioeconomic status to existing Medicare readmission risk adjustment models leads to significant changes in hospital rankings, with a differential impact on safety-net hospitals.
Clinical outcomes and late toxicity of hypofractionated intensity-modulated radiotherapy for high-risk prostate cancer.
Authors: Wang Michael , Pearcey Robert , Pervez Nadeem , Yee Don , Mihai Alina , Patel Samir , Amanie John , Parliament Matthew , Murtha Albert , Ghosh Sunita , Mackenzie Marc , Field Colin , Usmani Nawaid 
Published: March 2017

56 Background: Since prostate cancer has intrinsic high radiation-fraction sensitivity, hypofractionated radiotherapy (HFRT) could offer treatment advantages. However, dose-escalated HFRT may increase risks of late genitourinary (GU) and gastrointestinal (GI) toxicity. Intensity-modulated radiotherapy (IMRT) can potentially deliver dose-escalated HFRT without increasing late toxicities. This study’s acute toxicity data was previously published. We now present five-year efficacy results and late toxicity data for prostate cancer patients treated with HFRT using IMRT. Methods: From 2005-2012, our Phase II prospective study enrolled one hundred patients with either high risk disease (one or more of: Stage ≥ T3, Gleason ≥ 8, or PSA ≥ 20 ng/mL) or high tier intermediate risk disease (Gleason 7 and PSA ≥ 15 ng/mL). All patients received HFRT using IMRT in 25 daily fractions. Sixty patients received 68 Gy to the prostate and proximal seminal vesicles, with simultaneous integrated boost (SIB) of 45 Gy to pelvic lymph nodes and distal seminal vesicles. Forty patients received 68 Gy to the prostate, and a SIB of 50 Gy to pelvic lymph nodes and seminal vesicles. Adjuvant hormonal therapy was given for two to three years. Biochemical failure was determined by the Phoenix definition. Late toxicity scores were recorded every 6 months after completing RT. Results: Median age of patients was 67 years. 33% had Stage ≥ T3, 52% had Gleason ≥ 8, and 44% had PSA ≥ 20 ng/mL. After a median follow-up of 5.4 years, median PSA at last follow-up was 0.10 ng/mL. Five-year biochemical control rate (BCR) was 91.8%, five-year progression-free survival (PFS) was 92.8%, and five-year overall survival (OS) was 88.7%. Five-year cumulative incidence of Grade ≥ 3 GU and GI toxicity were 13.0% and 16.7% respectively. At the five-year efficacy endpoint, ongoing Grade ≥ 3 GU and GI toxicity were 1.9% and 0% respectively. Conclusions: Dose-escalated HFRT using IMRT results in favourable five-year BCR, PFS, and OS for patients with localized high-risk prostate cancer, and is well-tolerated with acceptable late GU and GI toxicity. These findings support ongoing Phase III trials that are assessing the clinical use of IMRT-based HFRT. Clinical trial information: NCT00126802.