bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase I trial of muscadine grape skin in men with biochemically recurrent prostate cancer.
Authors: Paller Channing Judith , Rudek Michelle A. , Antonarakis Emmanuel S. , Eisenberger Mario A. , Hammers Hans J. , Zhou Xian Chong , Dowling Donna , King Serina , Hudock Susan , Denmeade Samuel R. , Wagner William D. , Rosner Gary L. , Hudson Tamaro , Carducci Michael Anthony
Published: February 2017

263

Background: New therapies are being explored as an alternative to observation in men with biochemically recurrent prostate cancer (BRPC). Muscadine Grape Skin (MPX) is comprised of ellagic acid, quercetin, and resveratrol and demonstrates preclinical activity against prostate cancer cells in vitro. Here we summarize data from a phase I dose finding trial. Methods: This phase I study assigned non-metastatic BRPC patients to increasing doses of MPX (Muscadine Naturals) in cohorts of two patients, with six patients at the highest dose, using a modified continual reassessment method. Dose selection is based on preclinical data showing the equivalent of 500 to 4,000 mg of MPX to be safe in mouse models. Our primary end point was to determine the recommended phase II dosing. We calculated changes in prostate-specific antigen (PSA) doubling time (PSADT) from at least three measurements prior to trial initiation and PSA measurements on study. Results: The cohort (n=14, 71% white, 29% black) had a median follow-up of 14.7 (6.9 to 20.7) months, median age 61, median Gleason seven, and median PSA of 5.1 ng/mL (0.2 to 153.4). Four patients had possibly related gastrointestinal symptoms, including grade 1 flatulence, grade 1 soft stools, and grade 1 burping. No other related adverse events were reported and one patient reported improvement of chronic constipation. Two of 14 patients came off study for metastatic disease. Median within-patient PSADT increased from 9.4 to 12.3 months with a PSADT difference of 3.9 months. Conclusions: These data suggest that 4,000 mg of MPX is safe, and exploratory review of change in PSADT suggests there is enough data to proceed to a phase II trial. Both low dose (500 mg) and high dose (4,000 mg) MPX are being further investigated in a multicenter, placebo-controlled, dose evaluating phase II trial. Clinical trial information: NCT01317199.
Expression of prostate-specific membrane antigen (PSMA) on circulating tumor cells (CTCs) in castration-resistant prostate cancer.
Authors: Lee Florence , Yu Angela , Anderson Amanda , Marrinucci Dena , Magargal Wells W. , DiPippo Vincent A. , Olson William C.
Published: February 2017

266

Background: Prostate-specific membrane antigen (PSMA) is expressed ubiquitously in prostate adenocarcinoma, and the intensity of expression increases with disease aggressiveness. Exploiting PSMA for therapy could potentially be aided by a minimally invasive means for measuring PSMA on tumor cells. Here we describe the development and characteristics of a novel assay for quantitating PSMA on canonical and non-canonical circulating tumor cells (CTCs). Methods: The PSMA CTC test was developed using LNCaP (high PSMA), 22Rv1 (low PSMA) and PC3 (no PSMA) cells spiked into normal blood. Nucleated blood cells were plated onto glass slides and subjected to immunofluorescent staining followed by CTC identification using the Pyxis Scanning Platform at Epic Sciences. The four-color assay evaluated PSMA expression on individual CTCs, identified as cells which are cytokeratin+, CD45-, and with an intact DAPI nucleus. Multiple antibody clones and assay conditions were evaluated, and the final PSMA CTC test has high specificity and sensitivity. Acceptance criteria included signal intensities in LNCaP versus PC3, subcellular localization of PSMA, and potential interference by a PSMA-targeted therapy. Clinical feasibility of the optimized assay was assessed on samples from CRPC patients. Results: The average PSMA signal intensity for LNCaP was 20-fold higher than that for PC3 and 10-fold higher than the minimum cutoff. PSMA displayed a predominantly membrane-localized pattern of staining that was distinct from cytokeratin. Assay performance was unaffected by the presence of PSMA ADC, a PSMA-targeted antibody-drug conjugate that is in phase II clinical testing. In feasibility tests on patient samples, the assay demonstrated utility in detecting and quantitating PSMA on individual and clustered CTCs as well as on apoptotic, cytokeratin-negative, and small cytokeratin-positive CTC candidates. Conclusions: PSMA expression was successfully detected and quantitated on diverse types of circulating cells present in the blood of patients with CRPC. Assay performance was unaffected by the presence of a PSMA-targeted therapeutic agent. PSMA CTC data are being collected in the ongoing phase II study of PSMA ADC for comparison with treatment outcomes.
Standardizing patient-centered outcomes measurement in prostate cancer: An international, cross-disciplinary effort.
Authors: Martin Neil E. , Massey Laura , Stowell Caleb , Graefen Markus , Huland Hartwig ,   ICHOM Prostate Cancer Working Group
Published: February 2017

271

Background: The prospective collection of standardized, patient-centered outcomes for men with prostate cancer will allow intra- and inter-institutional comparisons, patient education, self-assessment and dissemination of best practices. We lack recommended standardized sets of such outcomes. Methods: Through the International Consortium for Health Outcomes Measurement, a working group of urologists, radiation oncologists, registry representatives and patient advocates convened to develop a recommended minimum set of measures which institutions would collect on all prostate patients. Using a modified Delphi method over a series of in-person meetings and conference calls, a final set of recommendations was developed. Results: Approximately 30 experts in prostate cancer care from North America, Europe, Australia, and the Middle East participated in the process, representing academic centers, registries and patients. We defined the scope of this initial effort as outcomes related to the management of localized prostate cancer. The group recommended cross-disciplinary measures applicable to a variety of treatment approaches from surveillance to radiation and prostatectomy. Standards were identified for disease control definitions as well as baseline patient and disease-specific risk stratification factors. Domains of patient reported outcomes to be tracked in follow up were identified including urinary incontinence, urinary irritation, bowel irritation, sexual function, and symptoms related to hormonal therapy. Finally, specific tools to assess these domains and gaps in our current tools were identified. The final recommended set will be presented. Conclusions: Standardized outcome reporting is a necessary component in the movement towards high-value health care. Patient-centered outcomes related to toxicity and disease control can be identified and systemized by a multidisciplinary group of experts. The result of this project is an initial step in what will be an iterative process with the goal of improving the care of all men with prostate cancer. An international pilot project has been proposed based on implementing the final set of recommendations.
Phase II study of neoadjuvant sorafenib plus cisplatin and gemcitabine (S-CG) for patients with muscle-invasive transitional cell carcinoma of the bladder (MIBC): Results at the end of first stage (NCT01222676).
Authors: Necchi Andrea , Giannatempo Patrizia , Mariani Luigi , Fina Emanuela , Nicolai Nicola , Pennati Marzia , Zaffaroni Nadia , Farè Elena , Piva Luigi , Biasoni Davide , Catanzaro Mario , Torelli Tullio , Stagni Silvia , Maffezzini Massimo , Colecchia Maurizio , Paolini Biagio , Cappelletti Vera , Daidone Maria Grazia , Gianni Alessandro M. , Salvioni Roberto
Published: February 2017

305

Background: The small, yet significant, survival advantage with neoadjuvant chemotherapy in MIBC needs to be improved. A rationale exists for inhibiting the RAF/MEK/ERK pathway and investigating S-CG combination in an ongoing open-label, single-group, phase II trial. Methods: Patients (pts) with T2-4N0 MIBC received 4 cycles of cisplatin 70 mg/m2 on day 1 and gemcitabine 1000 mg/m2 on day 1 and 8, every 3 weeks. Sorafenib 400 mg q12h was administered daily from day 1 to cystectomy. An optimal 2-stage Simon’s design is applied. 6 pathologic complete responses (pT0, primary endpoint) should be observed in the first stage before moving to full enrollment of 45 cases. Residual carcinoma in situ with no evidence of invasive tumor was considered as pT0. Intention-to-treat analysis was applied. Biomarker and circulating tumor cell (CTC) analysis is ongoing. Results: 23 pts were enrolled from 04/11 to 07/13. Thus far, 21 completed the treatment and are evaluable. Median age was 61yrs (IQR: 54-66). 11 had T2, 9 T3, and one a T4 disease. 6 pts had hydronephrosis at presentation. 19 pts underwent radical cystectomy. Eight pts (38.1%, 95% CI: 18.1-61.6%) had a pT0 and 2 pts a pT<2. G3-4 side effects consisted of hematologic toxicity in 8 pts (38%), hand-foot syndrome (HFS) in 3 pts, hypertension and asthenia in 2 pts each. 9 pts (42.8%) needed a temporary interruption of sorafenib, 6 a dose reduction, and 2 suspended the drug. After a median follow up of 12.6 months, 3 pts (14.3%) had a recurrence or progression and died, the remaining are disease-free. Median increase from baseline to day 8 of second cycle was observed for VEGF levels (85.8 to 119.5 pg/mL). All pts had a stepwise reduction of CTC count/5mL blood by ScreenCell (median baseline of 8 [0-40] to 2[0-6]). 3 pT0 pts starting with cT3b disease had a decrease from baseline 21, 10, and 40 cells to ≤3 cells. Increase in circulating EpCAM±Muc-1 levels by CTC was seen in accordance with disease progression (PD). Conclusions: Sorafenib seems to enhance the efficacy of CG in this setting. If confirmed, research should delineate the mechanisms behind clinical benefit and characterize PD. Clinical trial information: NCT01222676.
Impact of prior platinum agent and site of primary in patients with advanced urothelial carcinoma (UC) receiving salvage therapy.
Authors: Sonpavde Guru , Bellmunt Joaquim , Rosenberg Jonathan E. , Bajorin Dean F. , Regazzi Ashley Marie , Choueiri Toni K. , Qu Angela Q. , Niegisch Guenter , Albers Peter , Necchi Andrea , di Lorenzo Giuseppe , Fougeray Ronan , Wong Yu-Ning , Sridhar Srikala S. , Ko Yoo-Joung , Milowsky Matthew I. , Galsky Matt D. , Pond Gregory Russell
Published: February 2017

336

Background: The prognostic impact of prior platinum agent (cisplatin vs. carboplatin) and site of primary (bladder vs. other) in the context of salvage therapy for advanced UC is unknown. Methods: We pooled 10 prospective phase II trials of ≥ second-line therapy for advanced UC with data recorded for prior platinum agent and site of primary in addition to major prognostic factors: TFPC (time from prior chemotherapy), Hb (hemoglobin), PS (performance status), and LM (liver metastasis) status. Cox proportional hazards regression was used to evaluate the association of prior platinum agent and site of primary with overall survival (OS) and progression-free survival (PFS). Trial was included as a stratification factor throughout. Kaplan-Meier method was used to estimate PFS and OS. Results: Of 731 patients overall, 559 had received one prior chemotherapy regimen, 663 were evaluable for prior platinum regimen and 512 for site of primary. The overall median PFS and OS were 2.7 and 6.8 months, respectively. The trials evaluated vinflunine (N=151), docetaxel +/- vandetanib (N=148), paclitaxel-gemcitabine (N=98), sunitinib (N=77), volasertib (N=50), nab-paclitaxel (N=48), everolimus (N=45), pazopanib (N=43), cetuximab +/-paclitaxel (N=39) and paclitaxel-cyclophosphamide (N=32). Prior platinum was cisplatin in 501 (75.6%) and carboplatin in the rest. Prior carboplatin was associated with worse OS on univariate analysis (HR 1.23 [1.00-1.52], P=0.048) but not significantly associated with either OS or PFS on multivariate analysis. Bladder was the site of primary in 388 (75.8%). The site of primary was not significantly associated with PFS and OS in either univariate or multivariate analyses. Conclusions: Neither prior platinum agent (cisplatin vs. carboplatin) nor site of primary (bladder vs. other) were independently associated with OS or PFS in patients receiving salvage therapy for advanced UC. Trials of salvage therapy may continue to utilize the previously recognized prognostic factors, and could allow patients with all sites of primary disease and regardless of the prior platinum agent. These data need external validation.
Denosumab for the prevention of symptomatic skeletal events in patients with castration-resistant advanced prostate cancer: A comparison with skeletal-related events.
Authors: Smith Matthew R. , Coleman Robert E. , Klotz Laurence , Pittman Kenneth B. , Milecki Piotr , Wei Rachel , Balakumaran Arun , Fizazi Karim
Published: February 2017

35

Background: In a randomized controlled trial of men with castration-resistant prostate cancer (CRPC) and bone metastases, denosumab was superior to zoledronic acid (ZA) for reducing skeletal-related events (SRE, defined as pathological fracture, surgery or radiation to bone [including the use of radioisotopes], or spinal cord compression) (Fizazi, et al. Lancet 2011;377:813-822.). Recently, the composite endpoint of symptomatic skeletal event (SSE, defined as symptomatic fracture, surgery or radiation to bone, or spinal cord compression) was introduced as an alternative term/clinical trial endpoint to describe skeletal morbidity. Methods: Men with CRPC, ≥ 1 bone metastasis, and no prior IV bisphosphonate use received either SC denosumab 120 mg or IV ZA 4 mg (adjusted for creatinine clearance) in a blinded fashion every 4 weeks. Oral calcium and vitamin D supplements were recommended. SSEs included pathologic fractures considered symptomatic by the investigator, spinal cord compression and surgery and radiation to bone. Results: As previously reported, fewer men who received denosumab than ZA had confirmed first SREs, and experienced multiple SREs (Table). Similarly, fewer patients in the denosumab group than the ZA group had confirmed first SSE and multiple SSEs. The median (95% CI) estimate of time to first SSE (superiority analysis) for denosumab was not reached (28.8 mo, not estimable), and for ZA it was 24.2 (20.7, 30.2) mo (HR = 0.78 (0.66, 0.93) P = 0.01). Conclusions: Denosumab reduced the risk of skeletal events in men with CRPC regardless of endpoint definition as SRE or SSE. The risk of developing SSEs was reduced by up to 22% when comparing denosumab with ZA. Clinical trial information: NCT00321620. [Table: see text]
Sorafenib monotherapy in patients with inoperable/recurrent germ cell tumors (GCT) refractory to chemotherapy: Phase II study.
Authors: Skoneczna Iwona Anna , Natorska Urszula , Tacikowska Malgorzata , Kraszewska Ewa , Kotowicz Beata , Fuksiewicz Malgorzata , Rogowski Wojciech W , Federowicz Irena , Poniatowska Grazyna , Chaladaj-Kujawska Agnieszka , Michalski Wojciech
Published: February 2017

367

Background: The phase II trial was conducted in the population of incurable patients with refractory or relapsed GCT to evaluate the activity of sorafenib, an oral multitarget inhibitor of Raf kinase and the tyrosine kinases VEGFR-2 and PDGFR-alpha. Methods: Patients with progressive metastatic GCT received sorafenib monotherapy continuosly 400mg bid until progression of disease or unacceptable toxicity. Serum tumor markers (STM) were assessed every 4 weeks and imaging was performed every 12 weeks. Responses were assessed using RECIST; STM normalization was required for complete responses and partial responses required at least STM stabilization. STM-only declines were recorded as stable disease. Descriptive analysis of efficacy and tolerance was conducted. Results: 18 male patients with nonseminoma were included between 9/2008 and 6.2010. Pts received median 3 (range 3-4) prior chemotherapy treatments, 2 had received prior high-dose therapy. Median age was 35 (range 26-48), primary site was testicular in 16 and in 2 cases retroperitoneal. All patients had STM elevation before treatment. Median treatment duration was 83 days (31, 617), 12/18 patients were treated more than 2 cycles, 8 pts experienced some degree of STM decline with prolonged SD lasted more than 350 days in 3 pts. No partial or complete responses were observed. Drug related adverse events (AEs) were mainly grade 1 and 2; 55% of patients experienced diarrhea, 44% rash, 55% HFSR, 33% hypertension, 28% fatigue. Some G3 toxicity occurred: diarrhea in one pts, hypertension in one patient, HFSR in 2/18. 31% and 22% of pts required dose interruption and reduction respectively due to AEs. Conclusions: Sorafenib monotherapy was well tolerated but did not demonstrated significant activity in patients with highly refractory GCT, although there were some prolonged SD observed. Clinical trial information: NCT00772694.
Survival analyses of adjuvant or neoadjuvant combination of a taxane plus cisplatin and 5-fluorouracil (T-PF) in patients with bulky nodal metastases from squamous cell carcinoma of the penis (PSCC): Results of a single high-volume center.
Authors: Giannatempo Patrizia , Paganoni Anna , Sangalli Laura , Colecchia Maurizio , Piva Luigi , Catanzaro Mario , Torelli Tullio , Farè Elena , Raggi Daniele , Biasoni Davide , Stagni Silvia , Pizzocaro Giorgio , Salvioni Roberto , Nicolai Nicola
Published: February 2017

377

Background: Bulky nodal metastases (N2-N3) of PSCC represent a negative prognostic factor, yet efficacy of multimodal treatment is not defined. For these patients (pts) we explore T-PF combination in adjuvant and neo-adjuvant setting. Methods: Paclitaxel (120 mg/m2, d1) or docetaxel (75 mg/m2 d1) plus cisplatin (75-100 mg/m2 d1) and 5-fluorouracil (5FU, 750-1000 mg/m2 96h d1) were scheduled prior to or following radical inguino-pelvic dissections in N2-3 M0 pts, according to protocol indications. Primary endpoints were overall (OS) and progression-free survival (PFS); safety and response-rate represented secondary endpoints. Association of survival with treatment setting and pre-specified covariates was explored. Results: From 6/2004 to 10/2012, 47 consecutive pts received neoadjuvant (N=28) or adjuvant (N=19) T-PF. 18 (38.3%) were disease-free after a median follow-up (FU) of 22 mos (IQR 17-42). Durable remissions were more frequently observed in adjuvant (52.6%; median FU: 42 mos) than in neoadjuvant group (28.6%; median FU: 17 mos). Distribution of OS and PFS were statistically in favour of adjuvant T-PF (p=0.01 at Wilcoxon test; p=0.008 at t test). However, Kaplan-Meyer curves did not show significant differences. A model including therapy setting, N category, laterality, pelvic extent and p53 status showed that only adjuvant administration was associated with improved OS (p=0.008), while adjuvant therapy (p=0.002), pelvic extent (p=0.029) and laterality (p=0.086) were associated with PFS. In neoadjuvant group we recorded 43% responses (complete [CR] and partial) and 4 (14%) pathologic CR. Surgery was possible in 18 (64.3%) pts, independently of response. Neither OS nor PFS were associated with response. Tolerability was mild to moderate. Conclusions: Adjuvant chemotherapy was the most important favourable predictor of OS and PFS. Adjuvant T-PF results are among the best available ones. Neoadjuvant T-PF compares with other recent schedules in terms of activity and efficacy. Surgery remains the mainstay treatment for resectable nodal metastases from PSCC.
Utilization of adjuvant therapy in Medicaid and uninsured seminoma patients: Results from the National Cancer Database.
Authors: Paly Jonathan J. , Lin Chun Chieh , Gray Phillip John , Jemal Ahmedin , Efstathiou Jason Alexander
Published: February 2017

388

Background: Seminoma is the most common testicular cancer, and cancer specific survival approaches 100% if diagnosed and treated early. Following orchiectomy, several adjuvant therapy options exist for patients with stage 1A/B and 2A/B disease. As the Affordable Care Act’s (ACA) individual insurance mandate and expansion of Medicaid coverage will begin in 2014, we sought to understand whether differences exist in receipt of adjuvant therapy between uninsured and Medicaid patients in order to predict possible treatment patterns after the ACA takes effect. Methods: Uninsured and Medicaid patients diagnosed with seminoma from 1998-2010 in the National Cancer Data Base were identified. Multivariate logistic regressions were used to assess the relationship between uninsured status vs. Medicaid and receipt of adjuvant therapy. Results: Of 41,745 seminoma patients, 5,895 (14%) patients were on Medicaid or uninsured. Compared to Medicaid patients, uninsured patients were more likely to be younger (<29 years old), Hispanic, live in the South, treated in community hospitals, reside in areas with higher education levels, and present with stage IA/B disease (66.5% vs 59.4%, p < 0.01). After controlling for sociodemographic and clinical characteristics, uninsured stage IA/B patients had a 16% decreased likelihood of receiving adjuvant radiation or chemotherapy than Medicaid patients (p<0.05). In addition, stage 1A/B patients who were Hispanic, aged 50 or more, diagnosed in 2006-2010, treated in low-volume-case facilities or had tumor size < 4cm were less likely to receive adjuvant therapy. No treatment differences by insurance were seen in stage IIA/B patients. Conclusions: Our analysis suggests a modest association between the decision to seek optional adjuvant therapy and uninsured vs. Medicaid status in patients with stage IA/B seminoma. Given that national recommendations support surveillance, it will be increasingly important to counsel newly insured patients on the benefits of post-orchiectomy surveillance for early stage disease. In addition, no difference in management was identified for CS 2A/B patients suggesting that required therapy was not modified or avoided in the uninsured.
Identification of quality improvement opportunities in kidney cancer surgery through a regional hospital-based urologic quality collaborative.
Authors: Gore John L. , Porter Michael P , Lin Daniel W. , Harper Jonathan D. , Schmidt Zeila , Flum David R ,   SCOAP-CERTAIN Collaborative
Published: February 2017

413

Background: Patient selection for radical (RN) and partial nephrectomy (PN) for suspicion of kidney cancer may depend more on provider factors than patient characteristics. Observational data suggests that patients with small renal tumors have better overall survival when managed with PN rather than RN. We prospectively evaluated perioperative processes of care for patients undergoing kidney cancer surgery at Washington State hospitals participating in a surgical collaborative to identify quality improvement opportunities in kidney cancer care. Methods: We developed a chart abstraction tool that captures potential quality concerns in kidney cancer surgical care. The abstraction tool was implemented at nine regional hospitals with data consolidated for review quarterly. A sampling of PN and RN cases was abstracted. Hospital-specific feedback reports were blinded to hospital identity; data were analyzed as aggregate rates and hospital-specific rates using descriptive statistics. Presented results were not risk-adjusted. Results: We identified 75 patients undergoing RN or PN at 9 area hospitals from 2011-2013. Staging evaluations were uncommon (preoperative chest x-ray and chest CT in 41% and 20%, respectively). 13% percent of patients had a preoperative renal mass biopsy. For renal tumors ≤ 4 cm, 16/32 (50%) underwent PN. Hospital-specific utilization of PN for small renal masses exhibited variation: in 2 hospitals, 100% of tumors ≤ 4 cm were treated with PN, while 1 hospital performed RN in all cases, and the remaining hospitals ranged from 33%-67% utilization of PN. PN was less common for tumors 4-7 cm in size (4/26 cases [15%]). Venous thromboembolic events occurred in 4% of kidney cancer surgeries. Conclusions: We identified substantial variation in selection of surgical technique and postoperative outcomes following PN and RN for kidney cancer. Patients with small renal masses appear to have variable access to PN, which could impact their long-term health outcomes. Better understanding of provider knowledge and attitudes toward management of small renal masses could inform quality improvement initiatives to address the variations in care identified.
Correlation of PDL1 tumor expression and treatment outcomes in patients with renal cell carcinoma (RCC) receiving tyrosine kinase inhibitors: COMPARZ study analysis.
Authors: Choueiri Toni K. , Figueroa David J , Liu Yuan , Gagnon Robert C. , Deen Keith C. , Carpenter Christopher , Bartlett-Pandite Arundathy N. , De Souza Paul , Powles Tom , Motzer Robert John
Published: February 2017

416

Background: The interaction of PDL1 (B7H1) with its receptor PD-1 on activated T cells contributes to suppression of antitumor immune responses. Tumor PDL1 expression has been associated with poor outcomes in RCC but has not been investigated as a biomarker of response in RCC patients receiving standard vascular endothelial growth factor (VEGF)-targeted therapy. Methods: Formalin-fixed paraffin-embedded tumor samples were collected at baseline from consenting patients enrolled in COMPARZ—a phase lll clinical trial comparing pazopanib and sunitinib as first-line interventions for metastatic RCC (Motzer et al, NEJM 2013). PDL1 expression was evaluated using the anti-PDL1 mouseIgG1 (clone 5H1; Thompson) on the Leica automated immunohistochemistry platform. Additional dual PDL1/CD68 staining was performed on tumor associated macrophages (TAMs). Tumor PDL1 expression was quantified by an H-score (HS). PDL1+ TAMs were assessed semiquantitatively. In addition, intra-tumor CD8+ T cells were quantified morphometrically. The association between PDL1 HS, CD8+T cell counts, and survival was investigated using Kaplan-Meier analysis. Results: HS data were available from 453 of 1110 patients. 64% of patients had negative (HS = 0) PDL1 expression (HS range 0-290), but PDL1 expression was associated with tumours containing higher numbers of infiltrating macrophages. Peripheral CD8+ T cells in the invasive margin surrounding the tumor were also observed. Patients with HS >50 (n = 61, 13%) had significantly shorter overall survival (OS) in both pazopanib (19.7 vs 31.6 mo) and sunitinib (15.3 vs 27.7 mo) arms. In both arms, patients with HS >50 with intratumoral CD8+T cell counts >300 had the shortest OS. Results were similar for progression-free survival and persisted on multivariate analysis. Conclusions: This is the largest report to show that tumors’PDL1 expression and CD8+ T cell counts are associated with treatment outcome in metastatic RCC patients. Increased PDL1, or increased PDL1 plus tumor CD8+ T cell counts, were associated with shorter OS. These findings may have major implications for future trial designs that involve PD-1 inhibitors.
Survival outcomes associated with different sunitinib dosing regimens in metastatic renal cell carcinoma.
Authors: Cheng Winnie , Kletas Victoria , De Lemos Mario Law , Man Sally , Kollmannsberger Christian K.
Published: February 2017

417

Background: Standard dosing regimen of sunitinib for metastatic renal cell carcinoma (mRCC) consists of 4 weeks treatment followed by 2-weeks rest (intermittent dosing, ID). Alternative regimens have been suggested, including continuous daily dosing (continuous dosing, CD) and non-conventional dosing (non-conventional dosing: e.g. 2 weeks on / 1-week off, ND) to provide more individualized therapy with less toxicities. It is unclear whether non-standard sunitinib dosing affects survival outcomes. Methods: mRCC patients treated with sunitinib between July 1, 2007 and July 1, 2011 were identified from the British Columbia Cancer Agency (BCCA) pharmacy database, a publicly funded cancer care organization. Medical records and dispensing data were reviewed retrospectively to categorize sunitinib dosing as ID, CD or ND. Primary outcome was to compare overall survival (OS) associated with varying regimens, with secondary outcomes of progression free survival (PFS) and incidence of treatment discontinuation due to adverse effects (AE). Results: A total of 180 patients were identified. Heng prognostic risk criteria were assessable in 162 patients. Of these, 34 (21%), 80 (49%) and 48 (30%) had low-, intermediate- and high-risk disease. Most patients received ID (120, 67%), followed by CD (32,18%) and ND (28,16%). Compared to ID, CD was associated with similar OS (median 9 vs. 13 months, HR 0.67, 95% CI 0.43-1.06, p=0.088) while ND was associated with significantly longer OS (median 9 vs. 23 months, HR 0.55, 95% CI 0.34-0.90, p=0.016). PFS was significantly better for CD (median 4 vs. 9 months, HR 0.61, 95% CI 0.40-0.94, p=0.025) and ND (median 4 vs. 10 months, HR 0.61, 95% CI 0.39-0.95, p=0.03) when compared to ID. Similar to prior sunitinib trials, a significant proportion of patients (20%) discontinued sunitinib therapy due to AE. Conclusions: In comparison to the standard ID regimen, dosing sunitinib with alternative regimens appears to be associated with improved OS and PFS in patients with mRCC. Presently, a prospective Canadian trial is underway investigating the efficacy and safety of individualized sunitinib dosing regimens.
Response to systemic therapy in non-clear cell renal cell carcinomas: A systematic review and meta-analysis.
Authors: Vera-Badillo Francisco Emilio , Templeton Arnoud , Ocana Alberto , deGouveia Paulo , Aneja Priya , Knox Jennifer J. , Tannock Ian , Duran Ignacio , Escudier Bernard J. , Amir Eitan
Published: February 2017

425

Background: Clinical data supporting the efficacy of systemic therapy in non-clear cell renal cell carcinoma (non-ccRCC) are limited and based on retrospective analyses, expanded access programs and single arm phase II trials. Therefore the optimal treatment for this subgroup remains uncertain. Methods: A systematic review of electronic databases was conducted to identify publications evaluating the outcomes of patients with non-ccRCC (excluding those with sarcomatoid tumors) treated with different systemic approaches (immunotherapy, chemotherapy, targeted agents, small molecules). The primary endpoint was response rate and secondary endpoints were median progression free (PFS) and overall survival (OS). Where possible, data were pooled in a meta-analysis using the Mantel-Haenszel random-effect modeling. For studies comprising of unselected patients, outcomes of those with non-ccRCC were compared with clear cell renal cell carcinoma (ccRCC). Results: Forty-nine studies comprising 7,799 patients were included: 471 patients were enrolled on studies conducted exclusively in non-ccRCC and 7,328 patients on studies of unselected renal cell carcinoma. Among these, 903 (12%) had non-ccRCC and 6,425 (88%) had ccRCC. For non-ccRCC, overall response rate, median PFS and median OS were 9%, 7.9 and 13.4 months, respectively. By comparison, the overall response rate for ccRCC was 15% (Risk Ratio for response [RR] 0.67, 95% CI 0.52-0.86, p=0.002). This association was independent of type of treatment administered. Among the different novel agents (bevacizumab, lenalidomide, linefanib, sorafenib, sunitinib, pazopanib, everolimus and temsirolimus), sunitinib was significantly less efficacious in non-ccRCC than ccRCC (RR 0.56, 95% CI 0.42-0.72), but there was no significant difference in response rates for sorafenib (RR 0.64, 95% CI 0.31-1.35) or other agents (RR 1.10, 95% CI 0.50-2.44), However, confidence intervals were wide. Results of further analyses will be presented at the meeting. Conclusions: Patients with non-ccRCC have lower response rates than those with ccRCC, but the absolute difference between them is modest. Further study of targeted therapy in non-ccRCC is warranted.
Circulating biomarkers and outcomes in a single-arm phase II trial of first-line sunitinib alternating with everolimus for advanced renal cell carcinoma (aRCC): EVERSUN ANZUP trial 0901.
Authors: Yip Sonia , Pavlakis Nick , Harvie Rozelle , Martin Andrew , Jovanovic Lidija , Hudson Amanda , Thompson Jennifer F. , Nelson Colleen , Long Anne , Steer Christopher , Harrison Michelle L. , Kannourakis George , Goldstein David , Kichenadasse Ganessan , Lowenthal Raymond M. , Stockler Martin R. , Davis Ian D. ,   ANZUP Cancer Trials Group
Published: February 2017

428

Background: We sought biomarkers at baseline associated with clinically important outcomes in this trial of alternating sunitinib and everolimus. Methods: Baseline blood was tested for circulating tumor cells (CTCs) using CellSearch CTC system (Veridex). Baseline serum was tested for protein biomarkers: bFGF, CAIX; e-selectin; HIF1; IL8; NGAL; PDGF; PLGF; vCAM; VEGF-A, C and D; VEGFR1-3; by multiplex immunoassays (Bio-Plex system BioRad) or ELISA (R&D Systems DuoSets). Biomarker levels were dichotomised according to median or limit of detectability. Outcomes were progression free, overall survival (PFS, OS), objective tumour response (OTR) and toxicity (cycle 1 grade 3-5 AEs). Regression models were used for hazard ratios (HR), odds ratios (OR), p-values (p) in univariable analysis, adjusted for established prognostic factors in multivariable analysis. Results: Patient (n=55) characteristics were mean age 61 yrs: male 71%; MSKCC good risk 16%, intermediate risk 84%. There were 47 progression events and 30 deaths after a median follow-up of 20 mos. CTCs were detected in 5/31 (16%). Univariable analysis showed associations between OTR and low levels of bFGF (6 v 0, p 0.009); shorter OS and high levels of both NGAL (HR 2.5, p 0.02) and IL8 (HR 2.3, p 0.04); toxicity with detectable levels of CAIX (OR 4.7, p 0.03); none was associated with PFS. Adjusting for MSKCC prognostic score, age, gender and presence of liver or bone metastases: shorter PFS was associated with high bFGF (HR 2.0, p 0.03), low vCAM1 (HR 0.50, p 0.04), undetectable HIF1 (HR 0.33, p 0.01), shorter OS was associated with high NGAL (HR 2.5, p 0.03) and undetectable HIF1 (HR 0.35, p 0.04). Toxicity was associated with detectable CAIX (OR 5.8, p 0.04). None were statistically significant after adjusting for multi-comparisons. Conclusions: This exploratory study did not find strong statistical evidence for the prognostic value of these circulating baseline biomarkers. Prognostic value of changes from baseline during therapy remains an important area of study. EVERSUN is an ANZUP Cancer Trials Group Ltd trial coordinated by NHMRC Clinical Trials Centre (ACTRN12609000643279).
Integrated analysis of metastatic disease in clear cell renal cell carcinoma: A collaborative TCGA analysis.
Authors: Hakimi A. Ari , Jacobsen Anders , Mano Roy , Gonen Mithat , Voss Martin Henner , Reuter Victor E. , Rathmell Kimryn , Maranchie Jodi Kathleen , Appleman Leonard Joseph , Tamboli Pheroze , Signoretti Sabina , Choueiri Toni K. , Russo Paul , Motzer Robert John , Hsieh James ,   Clinical TCGA ccRCC Consortium
Published: February 2017

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Background: We sought to identify molecular and genetic features that were associated with metastatic disease at presentation in a cohort of patients derived from the Cancer Genome Atlas (TCGA) ccRCC dataset though our collaborative Clinical TCGA (cTCGA) consortium. Methods: Three hundred forty two patients comprising the cTCGA dataset were further evaluated for additional clinical information including the presence and timing of metastatic disease. Patients with clinical stage I or II disease were excluded. Clinical, molecular and genetic data were obtained and evaluated for their association with metastatic disease at presentation. Using somatic mutations (Exome-seq), DNA copy number (aCGH), mRNA expression (RNA-seq), and miRNA expression (miRNA-seq) data, we inferred molecular and genetic features associated with metastasis. We used random forest and elastic-net statistical learning methods to infer sparse feature combinations associated with metastatic disease at presentation. Results: The study cohort consisted of 147 patients, 81 (55%) of which had metastatic disease at presentation. Median follow was 26 months (Interquartile Range 10, 60) from the time of RCC diagnosis No significant difference in patient gender and age as well as tumor necrosis was found between patients with or without metastatic disease. However, patients with metastatic disease had larger tumors (median diameter 9.2cm vs. 6.8cm, p<0.001), and a higher percent of Fuhrman nuclear grade 3 or 4 disease (85% vs. 71%, p=0.04). Using both statistical learning methods we found that lower expression levels of GARNL3, C1orf172, NEK6 and SLC12A7 and higher expression levels of CEBPD, PITX2 and COMMD5 were associated with metastatic disease at presentation. Conclusions: When evaluating for various clinical, molecular and genetic features, alterations in specific gene expression are associated with metastatic disease in ccRCC patients. External validation in additional data sets is currently underway and further functional studies are required to better understand the therapeutic potential of these genes.
ADAPT: An ongoing international phase III randomized trial of autologous dendritic cell immunotherapy (AGS-003) plus standard treatment in advanced renal cell carcinoma (RCC).
Authors: Figlin Robert A. , Wood Christopher G. ,   ADAPT Study Group
Published: February 2017

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Background: AGS-003 is an autologous immunotherapy designed to induce an immune response to a patient’s own tumor. Sunitinib is a receptor tyrosine kinase inhibitor that has emerged as the standard of care in treatment-naïve RCC patients. The antitumor activity of sunitinib, together with its ability to reverse the immune suppression seen in RCC patients provided the rationale to combine sunitinib treatment with AGS-003 immunotherapy. In a single arm phase 2 study, AGS-003 in combination with sunitinib was safe and yielded a median overall survival (OS) of over 30 months in synchronous mRCC patients with one (DxTx<1yr) or more RCC risk factors. Methods: The study is seeking to enroll adults with synchronous mRCC with a time from diagnosis to treatment of < 1yr (DxTx<1yr) who are good candidates for surgery and standard targeted therapy (initiating with, but not limited to sunitinib), clear cell histology, 1-4 Heng RCC risk factors, KPS ≥ 70%, life expectancy of at least 6 months and adequate end organ function. Exclusion criteria include prior systemic RCC treatment, brain metastases, or requirement for chronic immunosuppressive therapy. While therapy initiates with sunitinib for all subjects, changes to other TKIs or mTOR inhibitors is permitted for early progression or toxicity. Results: Currently 94 sites have been initiated with more than 120 patients consented for tumor collection and 35 randomized to treatment as of September 2013. To date, nearly 50% of patients consented for tumor collection have been excluded from participation in the treatment phase of the ADAPT study due to non-clear cell histology, cardiac history, thromboembolic disorders and other criteria making them unsuitable candidates to initiate standard TKI therapy. Conclusions: Patients with newly diagnosed, synchronous mRCC present with poor prognosis and other features which may prohibit the safe or effective initiation and administration of TKIs. Exclusion criteria have recently been amended to optimize enrollment. Further details regarding study progress, baseline patient characteristics, eligibility disposition and updated figures will be presented. Clinical trial information: NCT01582672.
Outcomes of patients (pts) with metastatic non-clear-cell renal cell carcinoma (nccRCC) treated with pazopanib.
Authors: Matrana Marc Ryan , Baiomy Ali , Elsayes Khaled M. , Shetty Aditya , Teegavarapu Purnima Sravanti , Xiao Lianchun , Jonasch Eric , Tannir Nizar M.
Published: February 2017

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Background: Pazopanib prolongs progression-free survival (PFS) in treatment-naive and cytokine-refractory metastatic clear-cell RCC. Outcomes and safety data with pazopanib in metastatic nccRCC are limited. Methods: We retrospectively reviewed records of metastatic nccRCC pts who received pazopanib in the frontline and salvage settings (11/2009-11/2011). Response was assessed by a blinded radiologist (RECIST v1.1). PFS and overall survival (OS) were estimated by Kaplan-Meier methods. Log rank tests and univariate Cox models were used to evaluate the associations of OS and PFS with pt characteristics. Results: 29 pts were identified (frontline, 9; salvage after PD with other targeted therapies, 20). Seven (24%) had papillary, 4 (14%) chromophobe, 5 (17%) unclassified, and 13 (45%) other subtypes. PFS, OS, and objective response rates (ORR) are shown in the table. Improved OS was associated with prior nephrectomy in frontline pts, and in salvage pts with younger age, non-white race, absence of bone metastases, normal platelet count, higher albumin level, KPS>80, and MSKCC good-risk disease. There were no significant associations between frontline pt characteristics and PFS, but improved PFS was associated with normal platelet count, KPS>80, lower LDH, and higher albumin level in the salvage setting. Common adverse events (AEs): fatigue (31%), elevated transaminases (24%), diarrhea (21%), nausea/vomiting (17%), anorexia (17%), hypothyroidism (7%), and hypertension exacerbation (7%); 83% of AEs were grade 1/2. Six (21%) discontinued therapy due to AEs. There were no treatment-related deaths. Conclusions: Pazopanib demonstrated efficacy in pts with metastatic nccRCC. Toxicity was mild/moderate and manageable. [Table: see text]
Neutrophil to lymphocyte ratio (NLR) and its effect on the prognostic value of the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model for patients treated with targeted therapy (TT).
Authors: Templeton Arnoud J. , Heng Daniel Yick Chin , Choueiri Toni K. , McDermott David F. , Fay André P , Srinivas Sandy , Harshman Lauren Christine , Beuselinck Benoit , Smoragiewicz Martin , Kim Jenny J. , Knox Jennifer J.
Published: February 2017

470

Background: The neutrophil to lymphocyte ratio (NLR) is a marker of host inflammation and appears to have prognostic value in many solid tumors. We have found in a pilot RCC study that a NLR > 2.5 was predictive of a lower likelihood of response to TT on a multivariable analysis. Here we aim to explore the added value of the NLR to improve the prognostic value of the established IMDC criteria (Heng et al JCO 2009). Methods: We included patients from 7 consortium sites where NLR data was available for patients treated with TT and compared NLR cutoff <= 2.5 vs. >2.5 (i.e. low vs. high NLR) and adjusted using proportional hazards regression for the known poor prognostic criteria (listed in Table). Results: Data from 859 patients were included. NLR values were: Mean 4.98, Median 3.51, Mode 2.5, 95%CI 1.42 – 14.0. Using Cutoff <=2.5 vs. >2.5 Median overall survival (OS) is 30.4 months (95%CI 24.9-37.0, n= 237) vs. 15.7 months (95%CI 13.0-17.2, n=622); log-rank p value <0.0001. If we adjust for all six IMDC poor prognosis criteria in a proportional hazards regression model: HR of death for high NLR is 1.506 (1.177-1.928) p=0.0011, demonstrating NLR is still an independent predictor of poor OS even after using IMDC criteria. Conclusions: The NLR is a simple clinical value and is independently associated with poor overall survival even after adjustment for IMDC factors, including neutrophilia. The updated data set will be presented. [Table: see text]
Preclinical activity of the heat shock protein 90 inhibitor ganetespib in clear cell renal cell carcinoma.
Authors: Parasramka Mansi , Proia David A. , Joseph Richard Wayne
Published: February 2017

478

Background: Resistance invariably develops in all patients with metastatic ccRCC treated with mTOR inhibitors. Previously we demonstrated that dual inhibition of Hsp90 and the mTOR pathway in lung cancer models leads to synergistic reductions in tumor growth. Herein, we tested the efficacy of ganetespib as a single agent and in combination with mTOR inhibition using in vitro and in vivoccRCC models. Methods: For the in vitro work we utilized the following seven ccRCC cell lines: Caki-1, Caki-2, A-498, A-704, 769-P, 786-O, ACHN. For the in vivo work we used A498 xenografts. In vitro, we determined the single agent EC50 of everolimus and ganetespib at 72 hours by assessing percent viability of A498 cells compared to vehicle using the MTS assay. We then performed combinations of ganetespib and everolimus at EC20, EC30, and EC50 in A498 cells. Translating these studies in vivo, we compared the combinatorial activity of ganetespib and temsirolimus to monotherapy in mice bearing A498 tumor xenografts. Results: As a single agent, all ccRCC cell lines tested were sensitive to ganetespib at nanomolar concentration (EC50 15 – 75 nm) and to everolimus at micromolar concentrations (EC50 4 – 54 mm). In vitro, the combination of ganetespib and everolimus also decreased cell viability in an additive fashion. In vivo, ganetespib and temsirolimus demonstrated comparable single agent activity at sub-MTD doses (T/C = 63 and 60, respectively). Combining ganetespib with temsirolimus improved tumor growth suppression by ~30% (T/C = 43). Conclusions: Given the broad in vitro sensitivity of ccRCC cell lines to single agent ganetespib as well as the in vivo activity of the combination of ganetespib and temsirolimus, we believe ganetespib warrants further study in ccRCC. Updated results will be presented at the conference including the in vivo activity of the combination of ganetespib and antivascular endothelial growth factor agents.
Circulating tumor cell kinetics in mRCC patients treated with sunitinib.
Authors: Mittal Kriti , Williams Anthony , Rawal Siddarth , Alva Venur Vyshak , Lu Bo , Torres-Munoz Jorge , Borden Ernest C. , Ao Zheng , OMalley Martin , Wood Laura S. , Zheng Siyang , Datar Ram H , Tai Yu-Chong , Cote Richard J. , Rini Brian I.
Published: February 2017

481

Background: Detection of circulating tumor cells (CTCs) in renal cell carcinoma (RCC) is limited by inconsistent expression of epithelial cell adhesion molecule. We have previously detected CTCs using microfilter devices that exploit size differences between larger epithelial tumor and smaller non-tumor blood cells. Methods: Treatment naive pts with clear cell metastatic RCC (mRCC) were enrolled on a prospective phase II trial of intermittent sunitinib. Peripheral blood samples were collected at baseline, day 28 of cycles 1, 2, 4, and after the 8-week off-treatment period. Peripheral blood was diluted 1:1 with PBS and 1% formalin. Cells were captured with microfilters, stained with pan cytokeratin (CK) and CD45, conjugated with Alexa Fluor (AF) 594 and AF 488. Microfilters were cover-slipped with a DAPI containing medium for nuclear visualization. CTCs were identified as large CK+/CD45- events. Results: Pt characteristics (n=17) included 13 male/4 female; median age 65 years; median performance status KPS 90%; 100% prior nephrectomy. By Heng criteria, 4 pts were favorable, 12 intermediate and 1 poor risk. Site of metastases included lungs (59%), bone (41%) and lymph nodes (35%). Baseline CTCs (35 total samples collected) were detectable in at least one sample in 9 patients (53%), with a median CTC count of 6 (range, 1-31/ml); overall median CTC count was 1 CTC/ml including undetectable patients at baseline. Intrapatient variability was observed with the maximum intrapatient range of 4 to 58 CTCs/ml. After cycle 1 of sunitinib, median CTCs increased to 23 cells/ml (range, 0-94). Median CTCs after cycle 2 was 2 cells/ml (range, 0-322) and cycle 4 was 4.5 cells/ml (range, 0-500). After the 8 week off-treatment period, a median of 3.5 CTCs/ml (range, 0-242) were detected. In 6 patients with undetectable CTCs at baseline, CTCs were detected during the first 2 cycles of treatment, and in 4 of these patients, they declined or became undetectable by the last sampling period. Conclusions: A high rate of CTC detection is demonstrated using micro-filters in mRCC. CTC levels tend to increase during the first few weeks of treatment with sunitinib, and then decline with continued sunitinib and after sunitinib is held.