bluuebunny/crossref_metadata_2025 huggingface dataset:
VinCaP: A phase II trial of vinflunine chemotherapy in locally-advanced and metastatic carcinoma of the penis (CRUK/12/021).
Authors: Pickering Lisa M. , Tovey Holly , Elliott Tony , Burnett Stephanie M. , Bahl Amit , Kirkbride Peter , Mitra Anita , Thomson Alastair H , Vasudev Naveen , Slade Rachel , Tregellas Lucy , Morgan Bruno , Hassall Alison , Hall Emma , Nicholson Steve
Published: February 2018

547

Background: Platinum-based combination chemotherapy regimens are used in the treatment of carcinoma of the penis, but toxicity limits their value for patients with metastatic disease. This trial aims to define both the toxicity and the rate of disease control for the non-platinum cytotoxic agent Vinflunine. Methods: A phase II single-arm trial was designed to demonstrate a clinical benefit rate of at least 40% and to exclude a rate of less than 15% (p0 = 0.15, p1 = 0.40, α = 0.05, β = 0.80, Fleming-A’hern exact design). 22 evaluable patients were required. Key eligibility criteria included measurable, histologically-proven squamous cell carcinoma of the penis staged as M1; or M0, Tx, N3; or M0, Tx, N2 and deemed inoperable by multidisciplinary team; or M0, T4 any N. Patients were required to have ECOG performance status of 0, 1 or 2 and adequate hepatic and renal function. Treatment comprised four 21-day cycles of vinflunine (320mg/m2) with RECIST v1.1 restaging following cycle 4 (response primary endpoint). Patients deemed to be benefitting from treatment were permitted to continue vinflunine at the discretion of the treating clinician until progression or unacceptable toxicity. Results: 25 patients were recruited from 8 UK centres between June 2014 and May 2017. Median age was 68 years; 19 patients had metastatic (M1) disease. All patients have completed trial treatment and primary endpoint assessment. Data cleaning for the primary analysis is currently in progress, with the snapshot for the primary analysis due in October 2017 and primary analysis to be presented to the trial oversight committees in November 2017. Conclusions: It is hoped that single-agent vinflunine will be associated with a favourable toxicity profile combined with meaningful clinical responses. The results will be available for presentation at the meeting. Clinical trial information: NCT02057913.
Current practice patterns surrounding fertility concerns in stage I seminoma patients: Survey of United States radiation oncologists.
Authors: Post Carl M , Jain Aditya , Degnin Catherine , Chen Yiyi , Craycraft Michael Ellis , Hung Arthur , Jaboin Jerry Jeff , Thomas Charles R. , Mitin Timur
Published: February 2018

553

Background: Patients with testicular seminoma may face fertility issues because of their underlying disease as well as treatments they undergo. The current patterns of practice among US radiation oncologists aimed at assessing and preserving fertility in patients with Stage I seminoma are unknown. Methods: We surveyed practicing US radiation oncologists via an IRB-approved online questionnaire. Respondents’ characteristics, and perceived patient infertility rates were analyzed for association with treatment recommendations. Results: We received 353 responses, of whom one quarter (23%) consider themselves experts. A vast majority (84%) recommend observation as a default strategy. 52% routinely advise fertility assessment for patients prior to observation or chemotherapy, and 74% routinely do so prior to adjuvant RT. Nearly two-fifths believe that 10% and 30% of patients are infertile following orchiectomy. Thirty-seven and 22% believe infertility rates following para-aortic RT to be 30 and 50%, respectively. 80% routinely use clamshell scrotal shielding. Responders with higher perceived infertility rates are more likely to recommend fertility assessment/sperm banking (Fisher’s exact p<0.0001). Responders who routinely advised fertility assessment were more likely to use clamshell shielding (Cochran-Armitage trend test p = 0.0007). Clamshell use was positively correlated with higher perceived infertility rates following para-aortic RT (Spearman’s correlation coefficient = 0.006). Conclusions: Despite a clear knowledge of fertility issues in men diagnosed with seminoma, there is no universal adoption of fertility assessment among US radiation oncologists.
High-dose chemotherapy (HDC) and stem-cell rescue as salvage treatment for germ cell testicular tumors in second- and third-line, and outside clinical trials.
Authors: Ronchi Fernanda Carneiro , Araujo Daniel Vilarim , Urvanegia Ana Claudia Machado , Rinck José Augusto
Published: February 2018

557

Background: Germ-cells testicular tumors are the most common cancer in young males, usually curable in early stages. Therefore, only 25% of relapsed patients are long-term survivors. Previous non-randomized studies showed promising results with HDC, however, the only randomized trial did not support this approach. Here we report our experience in a Brazilian academic center Methods: We conducted a retrospective review of all consecutive patients treated with salvage HDC followed by Stem-Cell transplantation at our service (1996 – 2016). Survival curves were estimated by Kaplan-Maier method. Prognostic factors were determined by Cox regression model. Results: We found 36 eligible patients. The cohort median follow-up was 56 months (m). At 2 years 50.4% of the patients were alive, and 46.7% were disease-free. The median overall survival (OS) was not-reached and the median progression-free survival (PFS) was 21.8 m. The overall response-rate was 61.2% (22% had complete response and 39% had partial response). All patients who achieved complete response were alive at the last follow-up, and only one had progressive disease. Out of the patients who achieved partial response, one third were rescued with surgery (46% teratoma, 23% fibrosis, and 31% residual disease). Approximately 80% were alive in 2 years vs 20% not operated. Complete response (vs. others) and HDC as second line treatment (vs. 3rd and 4th) were good prognostic factors, (HR N/A; p 0,03, HR 0.19; CI: 0.04-0.88, p = 0.01 respectively). In 2 years, the OS in patients treated in 2nd line was approximately 80%, 50% for 3rd line, and 0% of those treated in 4th line. 89% of the patients experienced grade 3 toxicity, and 25% grade 4. The most common were neutropenic fever (69%), mucositis (36%) and diarrhea (25%). There were 3 deaths related to the treatment. Conclusions: Patients with complete response have sustained long-term survival, and represent the subgroup with evident benefit of the treatment. Surgery, when feasible, can rescue 80% of the patients with partial response. According to our data, we do not recommend this modality of treatment in 4th line.
Safety and efficacy of axitinib (axi) in combination with pembrolizumab (pembro) in patients (pts) with advanced renal cell cancer (aRCC).
Authors: Atkins Michael B. , Plimack Elizabeth R. , Puzanov Igor , Fishman Mayer N. , McDermott David F. , Cho Daniel C. , Vaishampayan Ulka N. , George Saby , Olencki Thomas , Tarazi Jamal Christo , Rosbrook Brad , Fernandez Kathrine C. , Lechuga Mariajose , Choueiri Toni K.
Published: February 2018

579

Background: Prior studies combining programmed death-1 (PD-1) checkpoint inhibitors with tyrosine kinase inhibitors of the vascular endothelial growth factor (VEGF) pathway have been characterized by excess toxicity precluding further development. We hypothesized that a combination of axi, a more selective VEGF-pathway inhibitor, with pembro (anti-PD-1) would be well tolerated and yield antitumour activity in treatment-naïve pts with aRCC. Methods: This ongoing open-label phase Ib study of axi/pembro comprised a dose-finding phase to determine the maximum tolerated dose and dose expansion phase. Axi 5 mg was administered orally twice daily with pembro 2 mg/kg administered intravenously every 3 weeks. Tumors were assessed, using RECIST v1.1, at baseline, week 12, and every 6 weeks thereafter. The primary endpoint was dose-limiting toxicity (DLT) during the first 2 cycles (6 weeks), with secondary endpoints evaluating safety, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: Between 23 Sept 2014 and 13 Oct 2015, 52 treatment-naïve pts with aRCC were enrolled. No unexpected toxicities were observed. Three DLTs were reported among the 11 pts treated in the dose-finding phase: transient ischemic attack (n = 1) and < 75% of planned axi dosage administered due to treatment-related toxicity (n = 2). At cutoff date (March 30, 2017), 25 pts were receiving study treatment. Most common (≥10%) grade ≥3 all-causality AEs included hypertension (23%), diarrhoea (10%) and fatigue (10%). Most common ( > 10%) potentially immune-related AEs included diarrhoea (29%), increased alanine aminotransferase (17%), or aspartate aminotransferase (13%), hypothyroidism (13%), and fatigue (12%). ORR was 73.1% (95% confidence intervals [CIs], 59.0–84.4). Median (95% CI) PFS was 20.9 (15.4–not evaluable) months. OS data were not mature at minimum follow-up period of 17.6 months, with 6 treatment-unrelated deaths reported. Conclusions: The combination axi/pembro is tolerable and exhibits promising antitumour activity in treatment-naïve pts with aRCC. A randomized phase 3 trial comparing the combination to sunitinib monotherapy is underway. Clinical trial information: NCT02133742.
Effect of crizotinib on disease control in patient with advanced papillary renal cell carcinoma type 1 with MET mutations or amplification: Final results of EORTC 90101 CREATE.
Authors: Schoffski Patrick , Wozniak Agnieszka , Escudier Bernard , Rutkowski Piotr , Anthoney Alan , Bauer Sebastian , Sufliarsky Jozef , Van Herpen Carla M.L.- , Lindner Lars , Grünwald Viktor , Zakotnik Branko , Lerut Evelyne , Debiec-Rychter Maria , Marreaud Sandrine , Lia Michela , Raveloarivahy Tiana , Collette Sandra , Albiges Laurence
Published: February 2018

580

Background: Papillary renal cell carcinoma type 1(PRCC1) is associated with MET alterations. Our phase II trial assessed the efficacy and safety of crizotinib in patients (pts) with advanced/metastatic PRCC1 with/without MET mutations( MET+, MET-). Methods: Eligible pts with reference pathology-confirmed PRCC1 received oral crizotinib 250mg twice-daily. Pts were attributed to MET+/ MET- sub-cohorts by sequencing of MET exons 16-19 in tumour tissue. Primary endpoint was objective response rate (ORR). If at least 2 of the first 12 eligible/evaluable MET+ pts achieved a confirmed partial (PR) or complete response (RECIST 1.1), a maximum of 35 pts were enrolled. Other endpoints included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS) and rate (PFSR), overall survival (OS) and safety. Results: 23 of 41 pts consenting were eligible, treated and evaluable. In 4 MET+ pts, 2 achieved a PR and 1 had stable disease (SD) (ORR 50%; 95% CI: 6.8-93.7%), DOR was 666 and 1138 days, 1-year PFSR was 75.0% (12.8-96.1%), 1-year OS: 75.0% (12.8-96.1%). Among 16 MET- pts, 1 achieved a PR lasting 302+ days and 11 had SD (ORR: 6.3%; 0.2-30.2%), 1-year PFSR: 27.3% (8.5-50.4%), 1-year OS: 71.8% (41.1-88.4%). Among 3 pts with unknown MET status ( MET?) due to technical failure, 1 achieved a PR lasting 211+ days and 1 had SD (ORR 33.3%, 0.8%-90.6%), 1-year PFSR: 66.7% (5.4-94.5%), 1-year OS: 100%. MET amplification was found post hoc in 1 MET+ (PR, DOR: 1138 days) and 1 MET- case (SD). Common treatment-related AEs were oedema (47.8%), fatigue (47.8%), nausea (39.1%), diarrhoea (39.1%), and blurred vision (34.8%). Conclusions: Crizotinib is active and well tolerated in advanced, metastatic PRCC1, achieving objective responses and long-lasting disease control in pts with MET mutations or amplification. Sporadic, durable responses are also seen in MET-/ MET? cases, suggesting the presence of other alterations of MET or alternative pathways. Clinical trial information: NCT01524926.
Homologous repair deficiency in VHL-mutated clear cell renal cell carcinoma.
Authors: Pilie Patrick Glen , Zhou Lijun , Peterson Christine B , Peng Yang , Peng Guang , Jonasch Eric
Published: February 2018

585

Background: Clear cell renal cell carcinoma (ccRCC) displays genomic instability across all tumor stages, indicative of increased replicative stress and defects in DNA damage response (DDR) pathways including homologous repair (HR); however ccRCC does not display mutations in canonical DDR genes and advanced ccRCC is not traditionally sensitive to DNA damaging agents. We hypothesized that biallelic VHL loss is sufficient to cause HR deficiency (HRD) and that early stage ccRCC is more likely to display HRD than late stage disease. Methods: We performed whole-exome (WES) sequencing of 15 small ccRCC tumors to assess for mutational burden, mutational signature, and cancer-related driver gene mutations. We performed in silico genomic, transcriptomic, and proteomic analysis of tumors in KIRC TCGA to assess for HRD. Finally, we assessed HR efficiency as a product of biallelic VHL loss in engineered cell line models. Results: 15/15 early stage ccRCC had VHL mutations, approximately 100 additional mutations per tumor, but no common mutations found in KIRC TCGA. In silico analysis showed 67% of KIRC TCGA displayed HRD gene signature, and was significantly higher in stage I disease (p = 2.21e-08). Patients with VHL-mutated tumors are more commonly HRD than HR intact (HRI) (p = 0.03), with frameshift/nonsense variants in VHL more likely to result in HRD than missense variants (p = 0.02). Multivariate analysis showed HRD predicted for better overall survival compared to HRI (p < 0.0001). Proteomic analysis of KIRC TCGA revealed HRI samples had significantly higher protein expression of Rad51 and RAPTOR when compared to HRD samples. Lastly, etoposide-treated MEF Vhl-/- cell lines displayed reduced HR efficiency when compared to Vhl intact controls. Conclusions: Biallelic loss of VHL is sufficient to cause HRD. HRD gene signature predicts for significantly better OS in ccRCC patients, and early stage ccRCC is more likely to be HRD. mTOR/PI3K signaling pathway proteins are differentially expressed in HRI patient samples from TCGA compared to HRD, suggesting a possible role for these oncogenes driving a HRI phenotype. Treatment strategies combining PARP inhibitors with PI3K/mTOR inhibitors should be tested in advanced VHL-mutated ccRCC.
Japan multicenter prospective study: FDG PET/CT in the assessment of advanced renal cell carcinoma treated with sorafenib.
Authors: Nakaigawa Noboru , Tateishi Ukihide , Kato Takuma , Kaneta Tomohiro , Kondo Keiichi , Sugimoto Mikio , Yao Masahiro , Inoue Tomio , Kakehi Yoshiyuki , Kubota Yoshinobu
Published: February 2018

605

Background: We previously reported that the early assessment by FDG-PET/CT of patients with advanced renal cell carcinoma (aRCC) treated with tyrosine kinase inhibitors (TKIs) predicted the disease course. In this study, we investigated prospectively the relationship of the clinical outcome of patients with aRCC treated with sorafenib and radiological parameters obtained with FDG-PET/CT at baseline and 4 weeks (4W). Methods: The patients with TKI-naïve aRCC planning to be treated by sorafenib were enrolled and assessed by FDG-PET/CT at baseline and at 4W. The relationship between radiological parameters, (1) max SUVmax at baseline, (2) change in max SUVmax at 4week, and (3) response criteria defined by Ueno D et al. ( The prognosis of aRCC which max SUVmax decreased more or 20% at 4W demonstrated good prognosis. BMC Cancer 2012) and progression-free survival (PFS) and overall survival (OS) was exploratory evaluated. This study is multicenter-study using PET/CT systems which quality is ensured by previous phantom study. Results: Total 34 patients were enrolled. The median PFS were 9.7 months and mean OS were 35.8 months (survival curve did not reach 0.5). The median of max SUVmax (the highest standardized uptake value in each patients) at baseline was 5.1. The median PFS of patients with baseline max SUVmax ≤ 5.1 showed longer PFS and OS compared that with max SUVmax > 5.1 (median PFS 11.9months vs. 9.2 month P= 0.0354, median OS --- vs. 15.3 months P= 0.027 ). The median change ratio in max SUVmax at 4W was -9.5%. The change ratio did not affect the PFS and OS, analyzing the total patients. When the patients with max SUVmax > 4.0 at baseline were focused, the PFS of patients which max SUVmax decreased more or 20% at 4W demonstrated tendency to be longer than that of other patients (median PFS 15.6 months vs 9.2 months, P= 0.0727) Conclusions: In this study, we demonstrated that the pretreatment max SUVmax predicted the PFS and OS of aRCC treated by sorafenib, but change of max SUV max at 4W did not. The change ratio could have potency as a predict marker for the PFS in the cases with high max SUVmax at baseline. It was speculated that the accurate assessment of change ratio in the cases with low max SUVmax at baseline was difficult. Clinical trial information: 000009812.
Using aorta lesion attenuation difference (ALAD) on preoperative contrast-enhanced CT scan to differentiate between malignant and benign renal tumors.
Authors: Grajo Joseph , Terry Russell , Ruoss Justin , Pavlinec Jonathan , Noennig Blake , Bozorgmehri Shahab , Blute Mike , Crispen Paul , Su Li-Ming
Published: February 2018

606

Background: To evaluate the ability of Aorta−Lesion−Attenuation−Difference (ALAD) to differentiate malignant renal tumors from renal oncocytomas. Methods: A retrospective review of preoperative CT scans and surgical pathology from robotic assisted partial nephrectomy specimens obtained by a single surgeon was performed. ALAD was calculated by measuring the difference in Hounsfield units (HU) between the aorta and the lesion of interest on the same image slice in the nephrographic phase on preoperative CT scan. The discriminative ability of ALAD to differentiate malignant pathology from oncocytoma was evaluated by sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under curve (AUC) using ROC analysis. Results: A total of 218 preoperative CT scans and corresponding pathology reports were reviewed. Pathology review revealed 22 oncocytomas (10.1%), 11 chromophobe RCC (5%), 37 papillary RCC (17%), and 148 clear cell RCC (67.9%). ALAD was able to differentiate malignant pathology from oncocytoma using a HU threshold of 24 with a sensitivity of 84%, specificity of 86%, PPV of 98%, and NPV of 33%. The AUC for malignant pathology versus oncocytoma was 0.86 (95% CI 0.77−0.96). Subgroup analysis showed that ALAD was able to differentiate chromophobe RCC from oncocytoma using a HU threshold of 24 with a sensitivity of 100%, specificity of 86%, PPV of 75%, and a NPV of 100%. The AUC for chromophobe RCC versus oncocytoma was 0.98 (95% CI 0.91−1.00). Conclusions: ALAD measurements based upon preoperative CT scans provide good discrimination between malignant renal tumors and oncocytomas, potentially decreasing the need for biopsy in certain patients. ALAD also discriminates well between chromophobe RCC and oncocytoma, which may aid in the management of patients with indeterminate diagnoses of oncocytic neoplasm on biopsy. Further validation of ALAD will be necessary prior to routine use in clinical practice.
Development of a conversation aid tool for patients with localized renal cell carcinoma at high risk of recurrence.
Authors: Stewart Grant , Bargo Danielle , Kilgariff Sarah , Trennery Claire , Bennett Bryan , Battle Dena , Casper Jochen , Staehler Michael D.
Published: February 2018

608

Background: Approximately 15% of nephrectomised patients who are diagnosed with loco-regional renal cell carcinoma (RCC) are considered to be at high risk of recurrence according to the postoperative UCLA Integrated Staging System (UISS) and 60% of these patients are expected to recur within five years of diagnosis. This study aimed to develop a conversation aid tool to improve knowledge about RCC for post-nephrectomy RCC patients who are at high-risk of recurrence. Specifically, to enable patients to make an informed decision about whether to proceed/not proceed with adjuvant therapy, should adjuvant therapy become standard-of-care in the future. Methods: A review of existing evidence relating to the development of conversation aid tools and previously developed tools was undertaken. Following the review, a focus group with a steering committee (RCC patients, caregivers and a clinician), and semi-structured interviews were conducted with clinicians to identify information currently provided as standard of care. Additional interviews were conducted with post-nephrectomy patients, to identify information patients would prefer to have been given post-nephrectomy. Results: The evidence review of 10 articles provided a framework for the development of a tool to enable better patient/clinician communication. Clinicians described a typical post-nephrectomy consultation and highlighted key topics of discussion, which included recovery, risk of relapse and ongoing care. The research highlighted that patients are expected to absorb a significant amount of information during consultations in order to take an active role in their care. Findings from the focus group and clinician/patient interviews led to the development of a conversation aid tool providing patients with key questions to ask their clinicians to increase knowledge of RCC post-nephrectomy and also the information they may require when considering adjuvant therapy, including: prognosis, risk of relapse, and the risk/benefit profile of available treatment options. Conclusions: The conversation aid tool may be useful for patients to improve knowledge of RCC and help make informed decisions about their future treatment and care.
Impact of comorbidities on functional recovery from partial nephrectomy.
Authors: Isharwal Sudhir , Ye Wenda , Wang Alice Y. , Abraham Joseph , Zabell Joseph , Dong Wen , Wu Jitao , Suk-Ouichai Chalairat , Caraballo Elvis , Gao Tianming , Campbell Steven C.
Published: February 2018

612

Background: Preservation of parenchymal mass and ischemia type/duration can influence functional recovery after partial nephrectomy (PN). Some have hypothesized that relevant comorbidities may also impact functional recovery, but this has not been adequately investigated. Methods: 405 patients with PN at our center (2007-2015) had necessary data to determine function/parenchymal mass preserved within the ipsilateral kidney. All comorbidities potentially associated with renal functional status were reviewed. Multivariable linear regression assessed factors associated with functional recovery, defined as percent ipsilateral GFR preserved. Results: Median tumor size and R.E.N.A.L. score were 3.5cm and 8, respectively. Overall, 264 (65%) patients had warm ischemia and 141cold ischemia (median durations = 21/27 minutes, respectively). The median ipsilateral GFR preserved was 79%. Age, comorbidity index, hypertension, and proteinuria all associated with preoperative GFR (all p < 0.01). Parenchymal mass preserved and ischemia characteristics significantly associated with functional recovery (all p < 0.001). On univariable analysis of comorbidities, only hypertension associated significantly with functional recovery. However, on multivariate analysis, none of the analyzed comorbidities associated with functional recovery. Conclusions: Recovery of function after PN depends primarily on parenchymal mass preservation and ischemia characteristics, while comorbidities failed to associate with functional outcomes. Comorbidities can impact function leading into surgery and may influence long-term functional stability, yet our data suggest that they do not influence short-term recovery after PN. [Table: see text]
Real world outcomes of nivolumab and cabozantinib in metastatic renal cell carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).
Authors: Stukalin Igor , Wells J Connor , Graham Jeffrey , Yuasa Takeshi , Beuselinck Benoit , Kollmannsberger Christian K. , Ernst D. Scott , Agarwal Neeraj , Le Tri , Donskov Frede , Hansen Aaron Richard , Bjarnason Georg A. , Srinivas Sandy , Wood Lori , Alva Ajjai Shivaram , Kanesvaran Ravindran , Fu Simon Yuen Fai , Davis Ian D. , Choueiri Toni K. , Heng Daniel Yick Chin
Published: February 2018

615

Background: The immuno-oncology (IO) checkpoint inhibitor nivolumab and the tyrosine kinase inhibitor (TKI) cabozantinib have both been shown in phase III clinical trials to be effective in metastatic renal cell carcinoma (mRCC) after progression on first-line therapy. We sought to explore the real-world efficacy of these therapies in second-line mRCC. Methods: Using the IMDC database, a retrospective analysis was performed on mRCC patients treated with second-line nivolumab or cabozantinib. Baseline characteristics and IMDC risk factors were collected. Overall survival (OS), time to treatment failure (TTF), and response rates were determined for each therapy. Multivariable Cox regression analysis was performed to determine survival differences. Results: 225 patients were treated with nivolumab and 53 with cabozantinib. There was no significant difference in OS identified, with a mOS for nivolumab of 22.1 months (95% CI 17.18 – NR) and 23.7 months (95% CI 15.52 vs. NR) for cabozantinib, p = 0.6053. The TTF was also similar, with 6.90 months (95% CI 4.60 – 9.20) for nivolumab versus 7.39 months (95% CI 5.52 – 12.85) for cabozantinib, p = 0.1983. The adjusted hazard ratio (HR) for nivolumab vs. cabozantinib was 1.297 (95% CI – 0.728 – 2.312), p = 0.3775. Conclusions: Nivolumab and cabozantinib appear to have similar efficacy in terms of OS and TTF in this real-world patient population, thus both novel agents are reasonable therapeutic options for patients progressing after initial first-line therapy. [Table: see text]
Evaluation of predictive biomarkers for nivolumab in metastatic clear cell renal cell carcinoma (mccRCC) using RECIST and immune-related (IR) RECIST.
Authors: Pignon Jean-Christophe , Jegede Opeyemi , Horak Christine , Wind-Rotolo Megan , Catalano Paul J. , Grosha Jonian , Flaifel Abdallah , Novak Jesse , Mahoney Kathleen Margaret , Freeman Gordon J. , Sharpe Arlene , Wu Catherine J. , Hodi F. Stephen , Motzer Robert J. , Choueiri Toni K. , Atkins Michael B. , McDermott David F. , Signoretti Sabina
Published: February 2018

619

Background: Development of predictive biomarkers would help select patients more likely to respond to nivolumab (nivo) in mccRCC. Here we evaluated biomarkers for nivo using endpoints based on either RECIST 1.1 (ORR and PFS) or irRECIST (irORR and irPFS), which were proposed to more accurately predict benefit of immunotherapy. Methods: We retrospectively analyzed tumor tissues from the Checkmate 010 trial (PMID: 25452452). PD-L1 expression on tumor cells (TC) was studied by IHC. Percentages of CD8+ tumor infiltrating cells (TIC) expressing the immune checkpoints PD1, TIM3 and LAG3 (either alone or in various combination) were determined by immunofluorescence (IF) and their predictive value assessed by the presence of a dose response relationship (DRR) with PFS or irPFS. The candidate biomarkers were then correlated with clinical outcomes using optimized cutoffs. Results: As previously shown, TC PD-L1 expression was not associated with PFS or ORR. In contrast, pts with TC PD-L1 ≥1% had longer median irPFS and higher irORR (Table). None of the TIC phenotypes determined by IF displayed a DRR with PFS. Conversely, we found that % of CD8+ TIC that are PD1+TIM3-LAG3- (% CD8+ PD1+TIM3-LAG3- TIC) was correlated with irPFS (HR = 0.58, p = 0.007). At the optimized cutoff (36%), pts with high % CD8+ PD1+TIM3-LAG3- TIC had longer median irPFS and higher irORR (Table). Notably, combination of TC PD-L1 expression with % CD8+ PD1+TIM3-LAG3- TIC identified 3 groups of pts for which irPFS and irORR were significantly different (Table). Conclusions: Our results suggest that, in mccRCC, tumor-immune biomarkers for nivo response show improved association with clinical endpoints defined by irRECIST relative to RECIST. The increased predictive value of TC PD-L1 combined with immune checkpoints expression on CD8+ TIC seen in this cohort requires independent validation. [Table: see text]
Hypofractionated external beam radiation therapy in combination with HDR boost for localized prostate cancer: Quality of life outcomes.
Authors: Morgan Tiffany , Press Robert H. , Cutrell Patrick , Zhang Chao , Chen Zhengjia , Rahnema Sara , Sanda Martin George , Pattaras John , Patel Pretesh R , Jani Ashesh B. , Rossi Peter John
Published: February 2018

62

Background: There is limited data to support the use of hypofractionated external beam radiation (HypoF) in combination with high dose rate brachytherapy (HDR). We report our quality of life (QOL) outcomes when treating intermediate (IR) and high risk (HR) prostate cancer patients with external beam radiation (EBRT) plus HDR. Methods: The charts of 54 patients with localized adenocarcinoma of the prostate treated with standard fractionation (SF) or HypoF EBRT plus HDR boost at a single institution between 2012 and 2015 were reviewed. All patients completed the American Urological Association Symptom Score (AUASS) and Expanded Prostate Index for Prostate Cancer – Clinical Practice (EPIC-CP) quality of life assessments prior to treatment and completed at least one follow-up survey. Linear mixed models were performed to test whether there was any significant change over time for each outcome and to detect whether there was any significant difference in each outcome between the different treatments. Results: Thirty-eight patients were treated with SF and 16 with HypoF. Median age at treatment was 68 years (range 55-82 years). Median follow-up for the cohort was 22.2 months (range 1.57-50.60 months). A majority of patients had clinical T1c disease (n = 35), Gleason score of 7 (n = 35), and a PSA < 10 (n = 39). Thirty-one patients had NCCN IR, and 23 had HR disease. There was no significant difference in AUA score (p = 0.98), incontinence and urinary irritation/obstruction scores (p = 0.81 and p = 0.62, respectively), and rectal toxicity (p = 0.97) between the two dosing groups over time, or at any discrete time point. Likewise, sexual function, vitality score, and QOL scores were not significantly different between the dose groups over time (p = 0.59, p = 0.37, and p = 0.71, respectively). All QOL categories, except sexual function, trended toward baseline with increasing time from intervention. Conclusions: Our study suggests HypoF EBRT can be delivered in combination with HDR for patients with IR and HR adenocarcinoma of the prostate without increasing toxicity compared to SF with an HDR boost. This has important implications in terms of patient convenience and resource utilization.
Application of Canadian hereditary renal cell carcinoma risk criteria to a population database.
Authors: Kushnir Igal , Kirk Leah , Mallick Ranjeeta , Kim Raymond , Graham Gail E , Breau Rodney H. , Lattouf Jean-Baptiste , Violette Philippe , Pautler Stephen E. , Care Melanie , Kapoor Anil , Jewett Michael A.S. , Wood Lori , Tanguay Simon , Heng Daniel Yick Chin , Basappa Naveen S. , So Alan I. , Pouliot Frederic , Reaume M. Neil
Published: February 2018

621

Background: Canadian criteria for identifying patients (pts) and families at risk for hereditary renal cell carcinoma (RCC) were published in 2013. They included characteristics for pts with RCC (age ≤ 45 years, bilateral or multifocal tumours, associated medical conditions and non-clear cell histologies with unusual features) and for any pts who have a family history of specific clinical or genetic diagnoses associated with renal neoplasms. The clinical impact of these criteria on genetic testing had yet to be evaluated. Methods: The Canadian hereditary RCC risk criteria were applied to pts from 16 centres in the Canadian Kidney Cancer Information System prospective database. The primary endpoint was the proportion of pts who met at least one criterion. Secondary endpoints included the number of pts with more than one criterion and the number of pts receiving genetic testing (with or without at risk criteria). Results: From January 2011 to May 2017, 8097 pts were entered in the database. 2827 (35%) met at least one criterion for genetic testing. The majority (83%) met just 1 criterion, while 16% met 2 criteria. The criterion of non-clear cell histology with unusual features contributed the largest proportion of at risk pts (59%), followed by age ≤ 45 years (29%), then first or second degree relative with renal tumour (16%). 69 pts underwent genetic testing, with 59 being classified at risk ( < 3% of at risk). Details about the genetic testing results will be presented. Conclusions: The application of the Canadian hereditary RCC risk criteria to a population database resulted in 35% of pts being identified at risk for hereditary RCC. However, the true incidence of hereditary RCC in this population is unknown as most pts did not undergo genetic testing, and thus the sensitivity or specificity of the criteria cannot be determined. The low proportion of at risk pts that underwent genetic testing was disappointing and highlights that there may be gaps in reporting, knowledge and/or barriers in access to genetic testing. The results have helped determine the proportion of at risk pts in Canada, what criteria are most common, and importantly, have established a foundation and benchmark to improve upon.
Incorporation of PBRM1, BAP1, TP53 mutation status into the Memorial Sloan Kettering Cancer Center (MSKCC) risk model: A genomically annotated tool to improve stratification of patients (pts) with advanced renal cell carcinoma (RCC).
Authors: Voss Martin Henner , Cheng Yuan , Marker Mahtab , Kuo Fengshen , Choueiri Toni K. , Hsieh James J , Reising Albert , Motzer Robert J. , Hakimi A. Ari
Published: February 2018

639

Background: The MSKCC risk model, an established prognostic tool fo r metastatic RCC, integrates clinical + laboratory data, but is ignorant to tumor genomics. Mutations in BAP1, PBRM1, TP53, cumulatively found in over 50% of pts, have prognostic value in RCC. We sought to study the use of integrating mutation status into the MSKCC model using two large clinical trial datasets. Methods: Pts had received first line sunitinib or pazopanib on the phase III COMPARZ (training set, n = 357) or the phase II RECORD3 trial (validation set, n = 130). Genes were evaluated by next generation sequencing using archival tissue. Association of mutation status and overall survival (OS) was tested by multivariate Cox regression analysis (MVA) in the training set. An annotated model was constructed combining the original clinical variables and mutation status for the 3 genes. We compared risk group assignment and concordance index (c-index) for the original vs. new model in training and validation set. Results: Mutation status for each gene: BAP1, TP53 and PBRM1 independently correlated with OS on MVA (p≤0.0035). Comparing the original (clinical only) to the annotated (clinical + genomics) model, risk categories changed in 139 pts (39%). The C-index was improved with integration of genomic information (0.595 original model - > 0.628 new model). The independent validation cohort confirmed improvement of c-index for predicting OS with integration of genomic data (c-index 0.622 original model - > 0.641 new model). Conclusions: Mutation status for BAP1, PBRM1, and TP53 has prognostic value in pts with advanced RCC. The annotated risk model alters risk status in over 1/3 of pts and improves accuracy of estimating outcomes in patients receiving first-line therapy. Clinical trial information: NCT00720941. [Table: see text]
CD73 expression in primary and metastatic renal cell carcinoma (RCC).
Authors: Tripathi Abhishek , Johnston Sarah E , Zhao Yan D , Hassan Oudai , Thompson Linda F , Lalani Aly-Khan A. , Wei Xiao X. , Giannakis Marios , Signoretti Sabina , Choueiri Toni K. , Harshman Lauren Christine
Published: February 2018

643

Background: Agents targeting the PD-1 pathway have improved outcomes in RCC. CD73 may be an additional mechanism which tumors can exploit for immune evasion. It is regulated by hypoxia inducible factor (HIF) and converts AMP to adenosine. The resulting increase in extracellular adenosine can inhibit T-cell effector function. We evaluated CD73 expression in primary and metastatic tumor samples in patients with RCC. Methods: A commercial TMA (US Biomax) consisting of 31 primary clear cell RCC samples (2 with sarcomatoid features) with 8 matched and 1 unmatched metastases was used to assess CD73 expression. A genitourinary pathologist (OH) confirmed pathology and grade. Immunohistochemistry (IHC) was performed using a monoclonal anti-CD73 antibody (Cell Signaling; D7F9A). A combined score (CS: % of cells positive x intensity) was employed to quantify CD73 expression. Expression levels between matched primary and metastatic tissue was compared using Wilcoxon signed-rank test. Correlation of CD73 expression (CS > 0) in primary tumor with baseline clinical and pathologic characteristics was assessed using Kruskal-Wallis and Fisher's exact tests. Overall survival (OS) was estimated using the Kaplan-Meier method. Comparison between CD73 expression groups used log rank test. Results: CD73 expression was seen in 19% (n = 6) of primary and 66.7% (n = 6) of metastatic samples. Among matched primary and metastatic samples (n = 8 each), median CS was 25 (Q1-Q3:0-105) in metastatic samples while none of the corresponding primary samples demonstrated CD73 expression (median CS = 0, p = 0.062). CD73 expression in primary tumor samples did not correlate with baseline clinical or pathologic features. Five-year OS was 50% in patients who expressed CD73 in primary tumors compared to 84% in those who did not (p = 0.26). Conclusions: We observed a numerical increase in CD73 expression in metastatic tissue compared to primary RCC samples and worse 5 year OS. The small number of samples has limited statistical significance. Further studies are needed to examine the impact of CD73 expression on outcomes in RCC patients treated with currently approved checkpoint inhibitors and the investigational CD73 antagonists that are in early phases of development.
Efficacy of treatment beyond third-line (3L) in metastatic clear-cell renal cell carcinoma (mccRCC).
Authors: Guida Annalisa , Le Teuff Gwénaël , Silva Carolina Alveosta , Colomba Blameble Emeline , Salviat Flore , Baciarello Giulia , Derosa Lisa , Loriot Yohann , Fizazi Karim , Di Palma Mario , Massard Christophe , Escudier Bernard , Albiges Laurence
Published: February 2018

647

Background: During the last decade, 10 agents have been approved for the treatment of patients (pts) with mccRCC, and guidelines have been developed up to 3L. The aim of the study is to describe the potential benefit of therapies beyond 3L in clinical practice Methods: Retrospective data analysis was performed using IGRECC (Institut Gustave Roussy REnal Cell Carcinoma) database to describe clinical features and outcomes beyond 3L in mccRCC. Kaplan Meier estimation was applied for progression free survival (PFS) and overall survival (OS) Results: Between 2005 and 2016, 825 (80%) pts had mccRCC and were treated with targeted therapies, of which 517 (63%) had 2L, 271 (33%) had 3L, 145 (18%) had 4L and 75 (9%) had 5L of therapy. Baseline characteristics and treatments are displayed in Table 1. With a median follow-up of 29 months (mo) (min: 20 max: 51), for patients receiving 4L, the median PFS is 5 mo (95%CI 4 – 6) and the median OS is 15.5 mo (95%CI 12 – 21). Pts with International Metastatic Renal Cell Cancer Database Consortium (IMDC) score favourable (18%), intermediate (59%), and poor risk (23%) at 4L initiation had a median OS of 24 mo (95%CI 11 – NR), 16 mo (95%CI 12.6 – 24), and 8 mo (95%CI 6 – 15), respectively (p < 0.0036). Partial response (PR) and stable disease (SD) were achieved in 13% and 56% of 122 evaluable pts. With a median follow-up of 16 mo (min: 13 max: 37) in 5L, the median PFS is 4.5 mo (95%CI 3 – 6) and the median OS is 19.5 mo (95%CI 11 - 28). Pts with a poor IMDC score risk at 5L initiation (33%) had a median OS of 7 mo (95%CI 3 – 10) (p < 0.0001). PR and SD were achieved in 16% and 52% of 55 evaluable pts in 5L Conclusions: The approved agents remain active as 4L or 5L options for mccRCC in pts who can reach this situation. Interestingly, both PFS and OS appear to be very similar in 4L and 5L as compared to 3L. Therefore, we believe that selected pts may derive benefit from these treatments beyond the barriers of regulatory or reimbursement approval [Table: see text]
Gut microbiome composition and response to sunitinib in metastatic renal cell carcinoma (mRCC).
Authors: Gong Jun , Dizman Nazli , Poroyko Valeriy , Won Haejung , Bergerot Cristiane Decat , Bergerot Paulo Gustavo , Maia Manuel C. , Hsu Joann , Frankel Paul Henry , Jones Jeremy , Salgia Ravi , Pal Sumanta K.
Published: February 2018

657

Background: Recent evidence supports a link between stool microbiome composition and immunotherapy response. However, it is unclear how the microbiome may influence clinical outcome in mRCC where vascular endothelial growth factor-targeted therapies remains a standard of care. Methods: Five consecutive stool samples were collected at baseline and at weeks 2, 3, 4 and 12 of treatment with sunitinib in patients (pts) with mRCC. In responders (R: complete/partial response and stable disease) and non-responders (P: primary progression), gut microbiota composition was assessed through extraction of microbial DNA where 16s RNA gene tags (v4) were generated by PCR amplification and sequenced using MiSeq (Illumina). Sequence reads were processed by Mothur software, assembled in Operational Taxonomic Units (OTUs), taxonomically annotated to the genus level, and used to construct Bray-Curtis dissimilarity matrix. The similarity of samples was visualized by principle coordinate (PCo) analysis and further confirmed by k-means clustering and ANOSIM tests. Differentially abundant taxa were determined by METASTATS. Results: Stool bacteriomic profiling identified 25,304 OTUs attributable to 165 genera from 8 phyla in 4 of 6 pts evaluable for response. PCo analysis revealed clear separation of R and P (accounting for 28.9 % of dataset variation) where subsequent k-means clustering confirmed the difference of microbiota in 2 clusters that perfectly align with R and P groups. The significance of this separation was confirmed by ANOSIM analysis (p = 0.005). Analysis of microbiota composition in P and R groups revealed 14 differentially abundant taxonomic units at the genus level. Of those at ≥1% abundance, Bacteroides, Barnesiella and Phascolarctobacterium were elevated in R, while Bifidobacterium and Dorea were elevated in P (p < 0.01 for all). Of those at < 1% abundance, Lactococcus, Sporobacter, Acidaminococcus, Actinomyces, and Asaccharobacter were elevated in P (p < 0.01 for all). Conclusions: Although limited by sample size, we report the first in-human study to suggest a link between microbiota and response to sunitinib as we identified a significant discrepancy in stool bacteriomic distribution between P and R.
Impact of intravenous acetaminophen on outcomes following radical nephrectomy.
Authors: Zlatev Dimitar V. , Friedlander David F. , Tinay Ilker , Wang Ye , Pucheril Daniel , Chung Benjamin I. , Chang Steven Lee
Published: February 2018

663

Background: Intravenous acetaminophen (IVA) was approved for use in the United States (US) for moderate to severe pain in 2010. The role of postoperative IVA following radical nephrectomy (RN) is of particular interest given the potential nephrotoxic and bleeding risks associated with other non-opioid alternatives such as parenteral non-steroidal anti-inflammatory drugs. However, given the relatively high cost of IVA versus other pain medications, the benefit of IVA in the postoperative period is unclear. We sought to determine if the use of postoperative IVA is associated with improved outcomes following RN. Methods: Using the Premier Hospital Database (Premier, Inc., Charlotte, NC), we retrospectively identified patients who underwent RN for a diagnosis of kidney cancer or renal mass in the US between 2011 and 2015. To limit confounding, only elective procedures and those with no complications (Clavien Classification of Surgical Complications score of 0) were included for analysis. Analysis was furthermore limited to patients of surgeons who either uniformly used or never used postoperative IVA. Chargemaster data for each patient was reviewed to determine use of IVA and narcotic pain medications postoperatively. Multivariable logistic regression was used to assess the relationship between postoperative IVA and the odds of a prolonged length of stay (LOS, top quartile). Multivariable quantile regression was used to determine the association of postoperative IVA with the use of narcotic pain medications (measured by morphine equivalents) and direct index hospitalization costs. Results: Among our cohort of 9,809 patients undergoing RN, 1,147 (11.7%) received postoperative IVA. The use of postoperative IVA was associated with a 64% decreased odds of prolonged LOS (OR 0.36, 95% CI: 0.19 to 0.69, p < 0.05). There was no significant impact of postoperative IVA on the use of narcotic pain medications or direct costs during the index hospitalization ($12,567 vs. $12,533, p > 0.05). Conclusions: The use of IVA following RN is associated with a reduced length of stay, no change in use of narcotic pain medications, and no increase in hospitalization costs.
Defining individual recurrence risk following surgery for high risk non-metastatic renal cell carcinoma.
Authors: Abel Edwin J , Raman Jay D. , Shapiro Daniel D , Chan Wilson , Allen Glenn O. , Patil Dattatraya , Master Viraj A.
Published: February 2018

664

Background: Current models to estimate renal cell carcinoma (RCC) recurrence risk following surgery are derived from populations containing primarily low-risk patients. The objective of this study was to evaluate risk factors for recurrence among high risk non-metastatic RCC patients following attempted curative surgery. Methods: Data from 3 independent centers was analyzed for consecutive ≥ pT3a RCC patients without evidence of lymph node or distant metastases who were treated surgically from 2000-2016. Univariate and multivariate Cox proportional hazard models were used to evaluate associations of common clinical and pathological variables with recurrence risk. A risk model was constructed using independent predictors and recurrence risk was evaluated using Kaplan-Meier analysis. Results: Of 771 patients, 190 (24.6%) had RCC recurrence following attempted curative surgery at median 10.2 months (IQR 4.4-20.7). Median overall follow-up interval was 21.4 months (IQR 6.6-53.5). After multivariate Cox proportional hazard analysis, significant associations with RCC recurrence were not identified with: age, gender, race, systemic symptoms, local symptoms, pT stage, perinephric fat invasion, tumor thrombus, sinus fat invasion, serum hemoglobin, or serum albumin. Independent predictors included grade 4 HR 3.27 (95% CI 2.17, 4.92); tumor diameter > 7cm HR 1.70 (95% CI 1.18, 2.45), tumor necrosis HR 1.47 (95% CI 1.06, 2.02), and sarcomatoid/ rhabdoid features HR 1.86 (95% CI 1.12, 3.09) An unweighted risk model was created by assigning one point for each independent predictor. Estimated 3-year recurrence risk was 14%, 25%, 40%, 49%, and 69% for patients with 0,1,2,3 and 4 risk factors (p < 0.001) respectively. Conclusions: Independent predictors of recurrence for high risk non-metastatic RCC include: tumor diameter, necrosis, nuclear grade 4, and sarcomatoid/ rhabdoid features. This model may be used to estimate individual risk in RCC adjuvant therapy clinical trials.