bluuebunny/crossref_metadata_2025 huggingface dataset:
The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model as a prognostic tool in metastatic renal cell carcinoma (mRCC) patients previously treated with first-line targeted therapy (TT).
Authors: Ko Jenny J. , Xie Wanling , Heng Daniel Yick Chin , Kroeger Nils , Lee Jae-Lyun , Rini Brian I. , Knox Jennifer J. , Bjarnason Georg A. , Harshman Lauren Christine , Pal Sumanta Kumar , Yuasa Takeshi , Smoragiewicz Martin , Donskov Frede , Bamias Aristotelis , Wood Lori , Ernst D. Scott , Agarwal Neeraj , Vaishampayan Ulka N. , Rha Sun Young , Choueiri Toni K.
Published: February 2017

398

Background: Prior prognostic models for 2nd-line systemic therapy have not been studied in the setting of contemporary sequential targeted therapy (TT). We sought to validate the IMDC prognostic model in patients with mRCC receiving next-line TT after progression on 1st-line TT. Methods: Patients who received 2nd-line TT after progressing on 1st-line TT for mRCC at 19 centres were analyzed. For the patients who had immunotherapy (22%) prior to their 1st TT, we examined their second TT (ie 3rd-line therapy). The endpoint was median overall survival (OS) since the initiation of 2nd-line therapy. Additionally, we compared the IMDC model with the 3-factor-MSKCC model (Motzer et al JCO 2004) used for previously-treated patients. Results: 1,021 patients treated with a second TT were included. Median time on 2nd-line TT was 3.9 months (range 0-76+). 871 (85%) of patients had stopped 2nd-line TT by the time of analysis. Median OS since 2nd-line TT was 12.5 months (95% CI: 11.3-14.3 months), with 369 (36.1%) of patients remaining alive. 5 out of 6 pre-defined factors in IMDC model (anemia, thrombocytosis, neutrophilia, KPS <80%, and <1 year from diagnosis to treatment) measured at the time of 2nd-line TT were independent predictors of poorer OS (HR between 1.39 and 1.58, p<0.05). Hypercalcemia was not statistically significant in multivariable analysis (p=0.3008) likely due to the low incidence of hypercalcemia (9%). The concordance index using all 6 prognostic factors was 0.70, and was 0.66 with the 3-factor-MSKCC model. When patients were divided into 3 risk categories using IMDC criteria, median OS was 35.8 months (95% CI 28.3-47.8) in the favorable risk group (n=76), 16.6 months (95% CI 14.9-17.9) in the intermediate risk group (n=529), and 5.4 months (95% CI 4.7-6.8) in the poor risk group (n=261). Conclusions: The IMDC prognostic model has been validated in and can be applied to patients previously treated with TT, in addition to previously validated populations in 1st-line TT and non-clear cell setting.
Results of a feasibility study of I-124 girentuximab in metastatic clear cell renal cell carcinoma (m ccRCC).
Authors: Keefe Stephen Michael , Rosen Mark Alan , Robinson Janelle , McGibney Karen , Marshall Amy , Mamtani Ronac , Vaughn David J. , O'Dwyer Peter J. , Haas Naomi B. , Pryma Daniel A.
Published: February 2017

406

Background: Carbonic anhydrase IX (CAIX), a transmembrane glycoprotein with an intracellular enzymatic domain, is overexpressed in ccRCC as a result of VHL loss. Chimeric antibody girentuximab is a monoclonal antibody that binds an extracellular epitope of CAIX. Iodine radiolabeled (I-124) girentuximab can be used as a PET radiotracer and has been shown to identify ccRCC primary tumors with high sensitivity and specificity. This study was designed to test the feasibility of using I-124 girentuximab PET/CT in the m ccRCC setting and to produce preliminary data regarding the operating characteristics of these scans in m ccRCC. Methods: Patients (pts) with ccRCC refractory to standard antiangiogenic therapy were treated with brivanib (Bristol-Myers Squibb, Co.), a tyrosine kinase inhibitor of VEGFR2 and FGFR. Baseline I-124 girentuximab scans were obtained. For 1 pt, a second scan was performed after 8 weeks. Clinical outcome was measured radiographically by RECIST 1.0 and standard cross-sectional imaging. Results: 5 pts had 6 I-124 girentuximab PET/CT scans. No adverse events occurred. 17 RECIST target lesions were identified at baseline. PET showed heterogeneous expression of CAIX in all scans: overall, 9 of 17 (53%) metastatic target lesions expressed CAIX. Progressive disease occurred in 5/6 pts within 4 months on treatment, and progression occurred in all 8 of the CAIX non-avid lesions (100%) in these pts. One pt achieved a RECIST partial response (PR) with treatment – the pt for whom paired studies were obtained. For this pt, a PET PR was observed 2 cycles earlier than with conventional imaging. Conclusions: I-124 girentuximab PET/CT was safe and feasible in m ccRCC. We found that metastases were detected. More importantly, for pts with ccRCC refractory to conventional antiangiogenic therapies, CAIX expression was heterogeneous, and progression occurred in CAIX non-avid lesions. Taken together, these data suggest that CAIX expression identified with this functional imaging modality represents a biological prerequisite for continued antiangiogenic therapeutic activity, and the heterogeneous CAIX expression observed helps to explain why brivanib was not useful in this setting. Clinical trial information: NCT01253668.
Interim results of a phase 1b/2a study evaluating the nano pharmaceutical CRLX101 with bevacizumab (bev) in the treatment of patients (pts) with refractory metastatic renal cell carcinoma (mRCC).
Authors: Keefe Stephen Michael , Heitjan Daniel , Hennessey Meliessa , Robinson Janelle , Mykulowicz Kristine , Marshall Amy , Gunnarsson Orvar , Mamtani Ronac , Vaughn David J. , Hoffman-Censits Jean H. , Nathanson Katherine L. , Lal Priti , Pryma Daniel A. , Eliasof Scott , Garmey Edward Graeme , Cohen Roger B. , Haas Naomi B.
Published: February 2017

412

Background: VHL is inactivated in most clear cell RCC (ccRCC) tumors giving rise to the HIF hypoxia response program and tumor angiogenesis. Antiangiogenic therapies are active in ccRCC, but resistance develops in all pts. Dual inhibition strategies may be needed to overcome resistance. CRLX101, a novel nano pharmaceutical formulation of camptothecin, has been shown in pre-clinical models to target HIF. We combined CRLX101 with bev in the treatment of pts with refractory mRCC in order to determine the safety and the recommended phase 2 dose (RP2D) of the combination, and to determine the therapeutic activity of treatment. Methods: Pts with mRCC refractory to conventional antiangiogenic therapies (all subtypes) were treated every 2 weeks with bev 10 mg/kg and escalating doses of CRLX101 (12 mg/m2, 15 mg/m2) in a standard 3+3 design with an expansion at the RP2D. Pts were treated until progression, death, or prohibitive toxicity. Adverse events were classified using CTCAE v 4.0. Radiographic results were assessed by RECIST v1.1. Results: 10 pts were enrolled on study – 6 clear cell, 2 papillary, 2 chromophobe. Median prior number of therapies was 2. No dose limiting toxicities were observed. CRLX101 at its single-agent RP2D (15 mg/m2) was safely combined with standard bev. 2 episodes of grade 3 non-infectious cystitis and 1 episode of grade 3 hypertension were observed. All other toxicities were grade 1 or 2. The median progression free survival (PFS) was 7.6 months which exceeded our pre-specified threshold of 16 weeks and has triggered 2nd stage accrual. 3 of 9 evaluable pts (33%) achieved a confirmed partial response (PR) including 1 patient with papillary mRCC; 4 pts (44%) displayed stable disease, and 2 had progressive disease as their best overall response. Conclusions: Our results demonstrate that CRLX101 can be safely combined with bev in pts with refractory mRCC. The RP2D is 15 mg/m2 q2w of CRLX101 with standard bev. Preliminary outcomes to date suggest that clinical benefit, manifest as prolonged PFS, is conferred to pts with all histologic subtypes of mRCC. Clinical trial information: NCT01625936.
The likelihood of death from prostate cancer in men with favorable or unfavorable intermediate-risk disease.
Authors: Keane Florence K. , Chen Ming-Hui , Zhang Danjie , Loffredo Marian J. , Kantoff Philip W. , Renshaw Andrew A. , D'Amico Anthony Victor
Published: February 2017

42

Background: Recently men with intermediate-risk prostate cancer (PC) were classified into favorable and unfavorable categories but whether the risk of PC-specific mortality (PCSM) amongst men with high-risk PC is higher compared to men with unfavorable intermediate-risk PC is unknown. Methods: In a prospective randomized trial conducted between 1995 and 2001, 206 men with intermediate or high-risk PC were randomized to 70 Gy with or without six months of androgen suppression therapy (AST). The subgroup of 197 patients with available information on percent positive biopsies formed the study cohort. Fine and Gray’s regression was used to assess whether men with high-risk PC had a significantly higher risk of PCSM compared to men with unfavorable intermediate-risk PC, adjusting for age, treatment, and comorbidity category. Results: After a median follow-up of 14.3 years there were 127 deaths (64.5%), of which 22 (17.3%) were from PC. There were no PC deaths in the favorable intermediate-risk group. There was no significant increase in the risk of PCSM in men with high-risk compared to unfavorable intermediate-risk PC (Adjusted Hazard Ratio: 1.59; 95% Confidence Interval: 0.66 to 3.83; P= 0.30) after adjusting for age, randomized treatment arm and comorbidity. Conclusions: Given no significant difference in the risk of PCSM in unfavorable intermediate compared with high-risk PC, these patients may merit treatment with RT and long-term AST. The lack of PC deaths in the favorable intermediate-risk group suggests that adding AST may not reduce the risk of PCSM in these patients. [Table: see text]
Differences in terms of progression-free survival (PFS) and overall survival (OS) in patients treated with first-line sorafenib, sunitinib, and pazopanib for late relapsing (>5 years) renal cell carcinoma.
Authors: Santoni Matteo , Porta Camillo , Procopio Giuseppe , Cerbone Linda , Basso Umberto , De Giorgi Ugo , Rizzo Mimma , Ortega Cinzia , Massari Francesco , Iacovelli Roberto , di Lorenzo Giuseppe , Milella Michele , Sabbatini Roberto , Atzori Francesco , De Vivo Rocco , Berardi Rossana , Santini Daniele , Cascinu Stefano
Published: February 2017

421

Background: Aim of this retrospective study was to investigate the clinico-pathological features and the outcome of patients (pts) with late relapsing renal cell carcinoma (LateR-RCC) treated with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) as first line therapy. Methods: Data were collected from 19 Italian centers involved in the treatment of metastatic RCC. Late relapse was defined as >5 yr after initial radical nephrectomy. MSKCC prognostic categories were assessed before starting first-line treatment with VEGFR-TKI. Overall survival (OS) and progression free-survival (PFS) were estimated with the Kaplan-Meyer method with 95% CI and curves were compared with log-rank test. A Cox-regression model was applied to the data with a univariate and multivariate approach. Variables included in the univariate analysis were gender, age, time from surgery, MSKCC risk-group and targeted therapy employed at first line. Results: A total of 2,490 pts were screened and 269 pts (11%) were identified as LateR-RCC and treated with first-line VEGFR-TKI. Median age was 66 yr (range 29-87). Median time to recurrence was 7.9 yr. MSKCC prognostic category was good in 63% of pts, intermediate in 31% and poor in 6%. First-line therapy consisted of sunitinib in 190 pts (71%), sorafenib in 58 pts (21%) and pazopanib in 21 pts (8%). The median PFS was 20.0 months (95% CI 17.0−25.1) for sunitinib and 14.1 months for both sorafenib (95% CI 11.0−29.0) and pazopanib (95% CI 11.2−NR). At multivariate analysis, only MSKCC prognostic group was an independent prognostic factor for OS (HR: 2.07; 95% CI, 1.52–2.82 p < 0.001) and PFS (HR 2.54; 95% CI, 1.93−3.36 p < 0.001), whereas first line TKI was not significantly associated with OS (HR: 0.94; 95% CI, 0.38–1.82 p = 0.895) and PFS (HR 0.77; 95% CI, 0.43−1.99 p= 0.547). Conclusions: No significant differences were found in terms of OS and PFS in pts with LateR-RCC treated with first-line sorafenib, sunitinib or pazopanib. Our data may be considered in the long-term management of these patients.
A single-arm, phase II, multicenter trial of sunitinib maleate (SU) in locally advanced or metastatic pheochromocytoma/paraganglioma (PC/PG): Interim results.
Authors: Leibowitz-Amit Raya , Joshua Anthony Michael , Ezzat Shereen , Bourdeau Isabelle , Olney Harold , Oosting Sjoukje , Ruether Joseph D. , Chin Soo , Palmieri Cristina , Seah Jo-An , Assa Sylvia L , Krzyzanowska Monika , Knox Jennifer J.
Published: February 2017

431

Background: Metastatic PC/PG is rare and may be sporadic or have a genetic basis. Treatment remains challenging in the absence of well-controlled randomized trials. Case reports suggest clinical activity of SU in this setting. We aim to prospectively evaluate radiological and biochemical response to SU, and assess its toxicity profile in PC/PG. Methods: This is an ongoing single-arm, phase II, multicenter, investigator-initiated clinical trial, enrolling patients (pts) with metastatic or unresectable locally advanced malignant PG or PC with ECOG PS 0-2, no previous treatment with tyrosine kinase inhibitors, and evidence of radiological progression or disease-related symptoms. All pts receive 50mg SU daily at standard dosing, following blood pressure stabilization, and are assessed for radiological and biochemical response (with urine metanephrines, catecholamines or serum chromogranin A) q12 weeks until disease progression, unacceptable toxicity or pts withdrawal. Futility was defined as no documented responses within the first 14 patients and would have led to trial cessation. Results: Since May 2009, 14 pts enrolled in 3 academic hospitals (Canada and the Netherlands). Interim results of 10 pts are presented (pts characteristics are tabulated). Two pts had symptoms related to hormonal-excess and both had clinical improvement on SU. All 10 pts had biochemical evidence of hormonal excess, of which 5 had biochemical response (50%). Best radiological responses achieved were partial response (3/10 pts; 30%, 1 unconfirmed), stable disease > 3 months (6/10; 60%) and progressive disease (1/10; 10%). Adverse events were consistent with known side-effects of SU. Seven pts had toxicity-related dose reductions, contributing to treatment cessation in two. Conclusions: This trial surpassed the pre-specified futility stopping rule with the current documented responses on SU and with durable patient benefit seen. Updated data will be presented and discussed. Clinical trial information: NCT00843037. [Table: see text]
Phase I trial of sunitinib (S) and temsirolimus (T) in metastatic renal cell carcinoma (mRCC).
Authors: Campbell Matthew T. , Millikan Randall E. , Altinmakas Emre , Xiao Lianchun , Tannir Nizar M.
Published: February 2017

433

Background: Anti-VEGF agents and mTOR inhibitors are mainstay therapies in mRCC. Pre-clinical data suggests synergistic anti-tumor effect when combining these 2 classes. A previous phase I trial using sunitinib (S) 25 mg/d 4 wks on, 2 wks off, and temsirolimus (T) 15 mg/wk was stopped after 2 of the first 3 pts developed dose limiting toxicity (DLT). Methods: Pts with any subtype mRCC (PS 0-1) were eligible. Each cycle consisted of daily S for 14 days on, 7 days off, and weekly T. The continuous reassessment method (CRM) was used. The primary objective was to find the maximum tolerated doses (MTD) of S and T. The total planned accrual was 60 pts. Results: Accrual was stopped after 20 pts received study drugs. Median age was 63.5 years; 13 pts received prior targeted therapy, 7 pts were treatment naïve; median number of prior treatments 1 (range 0-6). Treatment cohorts (#pts, S, T, dose in mg): 2 (S12.5,T6), 1 (S25,T12.5), 1 (S12.5,T8), 8 (S12.5alt25,T9), 2 (S25,T6), 2 (S25alt37.5,T6), 2 (S37.5,T6), 2 (S37.5,T8). Dose reduction was required in 6 of 20 pts; the most common DLT was mucositis in 3 of 20 pts, followed by thrombocytopenia in 2 of 20 pts. The mean number of cycles for all pts was 6.6±5.36, with mean time on study 159±120 days. One pt experienced DLT in cycle 1 and received no study related imaging, 1 had a partial response, 16 pts had stable disease, and 2 pts had progressive disease (PD) as best response. A total of 21 grade 3/4 adverse events (AEs) attributed to drug occurred in 11 of 20 pts. Reasons for study discontinuation were PD in 12 pts, toxicity in 6 pts, and pt preference in 2 pts. There were no treatment related deaths. Conclusions: The MTD of S and T using the CRM were not reached due to premature trial closure. However, we believe S 37.5 mg/d, 2 wks on, 1 wk off, and T 8-10 mg weekly may well be close to MTD. Clinical trial information: NCT01122615.
Contemporary outcomes of pT3 renal cell carcinoma: A Canadian multi-institutional experience.
Authors: Nayak Jasmir , Gardiner Clare , Liu Zhihui , Tanguay Simon , Kapoor Anil , Finelli Antonio , Rendon Ricardo A. , Black Peter C. , Klotz Laurence , Moore Ronald Brian , Kawakami Jun , Breau Rodney H. , Drachenberg Darrel E
Published: February 2017

434

Background: A large, multi-institutional analysis was undertaken to examine the pathological and oncological outcomes for patients with pT3 renal cell carcinoma (RCC) treated surgically. Materials and Methods: Institutional databases on patients surgically treated for RCC were obtained from 14 centers across 6 Canadian provinces forming the Canadian Kidney Cancer Information System (CKCis) database. Data were collected on 2204 patients and included patient characteristics, peri-operative information, pathological and oncological outcomes. Results: Of the 2,204 patients, 498 (22.6%) patients had pT3 disease according to the 2009 TNM staging system. Mean pathological tumor size was 8.6 cm. 443 (89.0%) patients underwent a radical nephrectomy (RN) and 55 (11.0%) underwent a partial nephrectomy (PN). Of those treated with RN, 247 (55.8%) were open, 159 (35.9%) laparoscopic and 1 (0.2%) robotic. In the PN group, 37 (67.3%), 14 (25.5%) and 4 (7.3%) patients were treated open, laparoscopic and robotically, respectively. Average operative time was 184 mins, with an average blood loss of 650 cc. Of the pT3 lesions, 365 (73.3%) were pT3a, 97 (19.5%) pT3b and 12 (2.4%) pT3c. 109 (22%) patients had a metastatic diagnosis before or at the time of nephrectomy. Of the remaining 389 patients, 68.9% remained free of disease after a median follow-up of 1.3 years. Common sites of metastatic disease included lung, lymph nodes and bone (77%, 35%, and 25%, respectively). Clear cell RCC was the predominant histopathology (74%). There were no peri-operative (<30 days) mortalities. Complications were found in 14.1% of patients. Systemic therapy was initiated in 132 (26.5%) of patients, most commonly with Sunitinib in 106 (80%) patients. Conclusions: Locally advanced, pT3 renal cell carcinoma is an aggressive disease that is associated with high rates of metastatic disease. Despite this, a significant portion remained disease free at the time of our follow-up.
Circulating microRNAs associated with docetaxel-resistant castration resistant prostate cancer.
Authors: Horvath Lisa , Lin Hui-Ming , Castillo Lesley , Mahon Kate Lynette , Chiam Karen , Lee Brian Yong , Nguyen Quoc , Qu Wenjia , Boyer Michael J. , Stockler Martin R. , Pavlakis Nick , Marx Gavin M. , Hiriyanna Gowda Girish Mallesara , Gurney Howard , Clark Susan J. , Swarbrick Alex , Daly Roger J.
Published: February 2017

44

Background: Despite a range of new treatments, docetaxel (DTX) remains the first-line chemotherapy for castration-resistant prostate cancer (CRPC). However, only 50% of patients respond to docetaxel at the cost of potentially significant toxicity. Therefore, there is a need for new biomarkers to identify early response to therapy. This study aims to determine if circulating microRNAs are associated with DTX chemotherapy outcome in CRPC. Methods: Global microRNA profiling was performed on DTX-resistant and sensitive cell lines to identify candidate circulating microRNA biomarkers. Custom Taqman Array MicroRNA cards measured the levels of 46 candidate microRNAs in plasma/serum from 97 CRPC patients, collected pre- and three weeks post-cycle one of DTX. Responses were defined by the PCWG1 serum prostate-specific antigen (PSA) response criteria; partial response (PR), stable disease (SD), progressive disease (PD). Multiple T-test, Mann-Whitney U, Kaplan-Meier, Receiver Operating Characteristic (ROC), and Cox regression analyses were used to assess the associations between microRNA levels and clinical outcomes. Results: Eighteen microRNAs were associated with PSA response or overall survival (p<0.05). DTX non-responders (PD+SD) and patients with shorter survival had high pre-DTX levels of miR-200 family members (miR-200a, miR-200b, miR-200c, miR-429; p<0.05), or decreased/unchanged post-DTX levels of miR-17 family members (miR-19b, miR-20a, miR-20b; p<0.05). The combined levels of miR-20a, miR-146a, miR-200b, miR-200c, miR-222, and miR-301b predicted PSA response (ROC AUC 0.74, 95% CI 0.64-0.84). Pre-DTX miR-200a levels (HR 3.0, 95%CI 1.6-5.8; p=0.001) and post-DTX change in miR-20a (HR 3.4, 95%CI 1.8-6.3; p=0.0002) were independent predictors of overall survival when modeled with hemoglobin levels (HR 2.6, 95%CI 1.4-5.1; p=0.02), PSA response (HR 2.1, 95%CI 1.1-3.9; p=0.03), and visceral metastases (HR 2.0, 95%CI 1.1-3.5; p=0.03). Conclusions: Circulating microRNAs are potential early predictors of DTX chemotherapy outcome and may be useful in stratifying patients in future clinical trials. These microRNAs may also be involved in DTX resistance and represent potential therapeutic targets.
Cell cycle progression score to predict metastatic progression of clear cell renal cell carcinoma after resection.
Authors: Askeland Eric J. , Chehval Vincent A. , Askeland Ryan W. , Sangale Zaina , Gangnang Fosso Placede , Xu Nafei , Rajamani Saradha , Stone Steven , Brown James A.
Published: February 2017

442

Background: Clear cell renal cell carcinoma (ccRCC) is primarily treated surgically when organ confined, but requires close follow-up to evaluate for recurrence. Expression levels of cell cycle progression (CCP) genes have prognostic value in certain cancers. We evaluated the prognostic value of the CCP expression in surgically resected ccRCC. Methods: Medical records were retrospectively reviewed. Patients with metastasis or lymph node involvement at surgery were excluded. Cases developed metastasis within 5 years of resection; controls were followed for at least 4.5 years without recurrence. Specimens were re-reviewed by a single pathologist. Tumor FFPE slides were macrodissected and RNA extracted. CCP score, sex, age, T stage, Fuhrman Nuclear grade (FNG), tumor size, smoking status, lymphovascular invasion (LVI), and time to metastasis were available for analysis. Univariate and multivariate analyses were used to evaluate association with metastatic progression. Subsequently, the tumor transcriptome was interrogated for other informative biomarkers using next-generation sequencing (NGS). Funding was by Myriad Genetics. Results: Twenty-six cases and 38 controls were evaluated. Median time to metastasis was 1.68 years (IQR 1.06-3.69) for the case group. Median follow-up was 6.69 years for controls. Univariate analysis revealed that LVI (OR 4.64, p=0.005), FNG (OR 4.16, p=0.0099) and CCP score (OR 2.65, p=0.0091) were significantly associated with progression to metastasis. In multivariate analysis, age (p=0.026), tumor size (p=0.022) and CCP score (p=0.026) were statistically significant. A step-wise multivariate model including age, CCP, tumor size and LVI had an AUC of 0.84, which decreased to 0.78 if CCP score was excluded. CCP scores calculated by qPCR and NGS were correlated (rho = 0.91). However, no other genes showed a significant association with metastasis or TNM stage (after correcting for multiple testing) in univariate analysis or after adjusting for CCP score. Conclusions: The cell cycle progression score predicts metastatic progression after resection of ccRCC and appears to add significant prognostic information to standard clinical and pathological variables.
A pilot study of supraphysiologic testosterone (T) and oral etoposide (E) in men with castrate-resistant prostate cancer (CRPC).
Authors: Schweizer Michael Thomas , Antonarakis Emmanuel S. , Wang Hao , Spitz Avery N. , Cao Haiyi , Pacheco Alberto , Eisenberger Mario A. , Carducci Michael Anthony , Denmeade Samuel R.
Published: February 2017

45

Background: Prostate cancer (PC) cells become resistant to chronic castration via an adaptive increase in androgen receptor (AR) expression, a liability that can be exploited therapeutically. Mechanistically, supraphysiologic androgens can induce PC cell death through topoisomerase 2 (topo2) mediated double-strand DNA breaks and disruption of DNA relicensing due to persistence of AR at origins of replication during the cell cycle. Methods: We evaluated parenteral T in combination with the topo2 inhibitor E in men with CRPC and low metastatic burden (≤5 bone and <10 soft tissue metastases). To rapidly cycle from supraphysiologic (>1500 ng/dL) to near castrate T levels, men received intramuscular T cypionate 400 mg on day (D) 1 and oral E 100 mg D 1-14 of a 28 D cycle. After 3 cycles, men with declining PSA could continue T alone every 28 D. The primary endpoint was PSA response, defined as a PSA below baseline, after cycle 3. Secondary endpoints included objective response rates and safety. Results: Sixteen men enrolled of which 14 completed 3 cycles of T+E and were evaluable for response. 7/14 went on the T-only expansion stage. After 3 cycles, 6/14 men had a PSA response. 7 (50%) had a PSA response at any timepoint [4 (29%) had PSA declines ≥50%] (table). In men with RECIST-evaluable disease, 2 had progressive and 3 had stable disease (SD), 4 had partial (PR) and 1 had a complete response (CR). Median response duration was 248 D (range, 80 to 359 D). Post T, 10/12 men had a PSA decline to subsequent androgen ablative therapies. Most adverse events (AEs) were ≤grade 2 and considered effects of E. One man died from neutropenic sepsis before completing the 1st cycle. AEs possibly related to T included lower extremity edema (n=1), priapism (n=1) and asymptomatic pulmonary embolism (n=2). No one developed new pain on T. Conclusions: T with or without E demonstrated preliminary efficacy in patients with CRPC as manifested by PSA and objective responses. This regimen is generally safe. Cyclic T-based therapies warrant further study. Clinical trial information: NCT01084759. [Table: see text]
Validation of the CAIX score as a prognostic biomarker for lymphatic spread and cancer-specific survival.
Authors: Chamie Karim , Said Jonathan W. , Belldegrun Arie S. , Pantuck Allan J.
Published: February 2017

454

Background: We recently developed a novel CAIX density scoring system that was found to be a significant prognostic biomarker in a cohort of patients with high-risk clear cell renal cell carcinoma (ccRCC). We sought to validate the association of CAIX score with lymphatic spread and survival in a cohort of patients with ccRCC. Methods: We reviewed the clinical and pathologic records of 418 patients who underwent radical nephrectomy at UCLA between 1985 and 1999. Clinical features included age, gender, race/ethnicity, and ECOG performance status. Pathologic features included TNM stage, nuclear grade, UCLA Integrated Staging System (UISS), and CAIX staining. CAIX score was stratified into low (0–99), intermediate (100–199), and high (200–300). We examined the association between the CAIX score, disease severity, and survival using logistic and Cox regression analyses, respectively. Results: Mean CAIX score was 237.4 (SD 98.3). Approximately 26% of patients with low CAIX scores had lymphatic involvement, compared with 28% of those with intermediate scores, and 8% with high scores, p<0.01. On multivariate analysis, patients with high CAIX scores had a significantly lower risk of lymphatic involvement (OR 0.19, p<0.01). When compared with those with low CAIX scores, patients with high CAIX scores were significantly less likely to recur (HR 0.53, p=0.02) or die (HR 0.41, p<0.01). Patients with intermediate scores were no less likely to recur HR 0.93, p=0.85) or die of their disease (HR 0.69, p=0.34). Lastly, patients with high-risk non-metastatic ccRCC were less likely to recur (HR 0.04, p<0.01). Conclusions: The CAIX score can help identify the majority of patients presenting with lymphatic spread and serves as a statistically significant prognostic biomarker for recurrence-free and disease-free survival after nephrectomy. We recommend that utility CAIX score be quantified for all patients with high-risk disease.
Trends in cytoreductive nephrectomy in the eras of immuno and targeted therapy.
Authors: Minnillo Brian J. , Zhu Hui , Maurice Matthew J. , Abouassaly Robert
Published: February 2017

472

Background: Since the publication of randomized studies demonstrating a survival advantage in patients with metastatic renal cell carcinoma (mRCC) treated with immunotherapy, cytoreductive nephrectomy (CN) has played an integral role in the management of these patients. Our objective is to describe the use of CN in the eras of immuno and targeted therapy for mRCC. Methods: Using the National Cancer Data Base (NCDB), a joint project of the Commission on Cancer of the American College of Surgeons and the American Cancer Society, we identified patients with histologically confirmed mRCC. We examined patient, provider and disease factors associated with CN. We also assessed short-term surgical outcomes of CN. A multivariable logistic regression was used to evaluate factors associated with CN. Results: From 1998 to 2011, 30.1%(17,714) of the 58,810 patients with mRCC underwent CN (Table). Over this timeframe, there was a gradual increase in the proportion undergoing surgery (17.3% to 35.7%). In those who underwent CN, the mean length-of-stay (LOS) was 6.1 days. The 30-day readmission rate and 30-day mortality were 5.6% and 3.8%, respectively. On multivariate analysis, patients who were treated at an academic facility (OR 1.94, 95% CI 1.79-2.11, p <.0001) were more likely to be treated with CN. After adjusting for covariates, patients of African American race (OR 0.52, 95% CI 0.48-0.56, p <.0001), a tumor size of >14cm (OR 0.57, 95%CI 0.52-0.62, p<.0001), or a Charlson/Deyo score of ≥ 2 (OR 0.62, 95% CI 0.57-0.68, p < .0001) were less likely to be treated surgically. Conclusions: Cytoreductive nephrectomy for mRCC appears to be steadily increasing over time, particularly in academic medical centers, even after adjusting for potential confounders. Despite this population’s advanced disease, LOS, 30-day readmission rate and 30-day mortality are relatively low. Our results suggest that CN utilization remains high in the era of targeted therapy. [Table: see text]
Bilateral multifocal papillary type I renal cell carcinoma: Clinical characteristics and association with chronic renal insufficiency.
Authors: Su Daniel , Okoro Chinonyerem , George Arvin , Linehan W. Marston , Metwalli Adam R.
Published: February 2017

482

Background: Patients with bilateral multifocal (BMF) RCC are at risk for multiple surgeries, progressive loss of renal tissue and chronic renal insufficiency. Although BMF papillary type I RCC is commonly associated with Hereditary Papillary Renal Cell Carcinoma (HPRC), with mutation of the MET proto-oncogene, sporadic (non-familial) BMF Pap1 RCC is far more common. Here we describe the histologic and clinical phenotype as well as clinical management of a population of patients with BMF RCC that has papillary type I histology that is distinct from the HPRC population. Methods: From 2000 to 2013, patients who were evaluated at the National Cancer Institute and were diagnosed with BMF on cross sectional imaging were included. Patients who tested negative for MET proto-oncogene mutation, who have a pathologic diagnosis of papillary type I were included. Phenotypic manifestations and clinical management were analyzed. Results: 61 patients with an average age of 54.3 years were identified. A disproportionate number (22, 36%) of these patients were of African American descent. Fifty seven (93%) were male. Two patients were found to have had metastatic disease on presentation (3%); 17 patients underwent unilateral radical nephrectomy for renal mass (28%) even though the average largest tumor diameter was only 2.9 cm. 12 patients (19%) underwent partial nephrectomy. The average preoperative serum creatinine was 1.48 mg/dl and average eGFR 62.2 ml/min, there was no difference between in eGFR in African American patients and Caucasian patients (62.09 ml/min and 63 ml/min). This population had an average of 2 tumors per side, many patients also had numerous cysts on both kidneys. Conclusions: BMF papillary type I RCC represents a novel entity which disproportionally affects African Americans. These patients often present with renal insufficiency and are at significant risk for further renal deterioration. As a small percentage of these patients with BMF papillary type I will present with metastatic disease, active surveillance until the largest renal tumor reaches 3 cm is recommended.
Association between rigors and overall survival (OS) in metastatic renal cell carcinoma (mRCC) patients treated with high-dose interleukin-2 (HD IL-2).
Authors: Batten Julia Anne , Samlowski Wolfram E. , Parikh Kinjal , Sendilnathan Arun , Crispin Hilda , Van Atta Joan , Sageser Daniel , Grossmann Kenneth F. , Wang Junfeng , Tantravahi Srinivas Kiran , Stenehjem David D. , Agarwal Neeraj
Published: February 2017

487

Background: HD IL-2 is associated with an objective response rate of 16-20% with durability of response in select mRCC patients. HD IL-2 is also associated with significant toxicity including vascular leak syndrome and inflammatory side effects. Few predictive markers can identify patients likely to respond to HD IL-2. Methods: Patients treated with HD IL-2 at the University of Utah Huntsman Cancer Institute from 2000 to 2012 with clear cell mRCC were evaluated. Grade of toxicities during HD IL-2 treatment were collected based on provider documentation in the electronic health record. Rates of adverse events (AEs) and overall survival stratified grade 3 AEs were evaluated by Kaplan-Meier survival estimates and Cox proportional hazards models. All AEs were graded per common terminology criteria version 4. Grade 3 rigors were defined as severe rigors requiring opioids. Results: A total of 85 patients were included with a median age of 56 years (range 32-76 years) and 79% (n = 67) were male. Patients belonged to the following MSKCC risk categories: 11 (13%) good, 70 (82%) intermediate, and 4 (5%) poor risk. The mean total dose received was 1097 MIU (range: 160 – 3048 MIU). The prevalence of grade 3 AEs is presented in the table. Median survival of patients with ≥grade 3 rigors after HD IL-2 administration was 1501 days vs 533 days for those without (p = 0.0005, HR 2.54). Presence of rigors was also associated with a significant improvement in progression free survival, time to next treatment and response rates. No other AEs predicted response to HD IL-2. Conclusions: Presence of grade 3 rigors predicts improved survival during HD IL-2 therapy. Notably, grade 3 fever was rarely observed because of our institutional protocol of routinely using scheduled antipyretics to diminish fevers. [Table: see text]
A phase I, open label, dose escalation and cohort expansion study to evaluate the safety and immune response to autologous dendritic cells (DC) transduced with AdGMCA9 (DC-AdGMCAIX) in patients with mRCC.
Authors: Kabbinavar Fairooz F. , Zomorodian Nazy , Belldegrun Arie S. , Wong Steven G. , Bot Adrian , Chodon Thinle , Comin-Anduix Begonya , Nguyen Phuong , Khan Faraz , Rettig Matthew , Pantuck Allan J.
Published: February 2017

490

Background: Carbonic anhydrase IX (CAIX) is an attractive target for the development of a RCC specific vaccine. We developed a fusion gene construct, GM-CSF + CAIX, transduced by a replication deficient adenovirus into autologous dendritic cells (DC) that are injected in patients with mRCC. This is a ph1 study of cancer vaccine against CAIX gene expressed on RCC tumors. Methods: A recombinant adenovirus encoding the GMCSF-CAIX fusion gene (AdGMCAIX) was produced per GMP in collaboration with the NCI RAID program. The final product is produced in an in-house GMP cell processing facility using DCs cultured ex vivo from patients’ PBMC's and engineered with AdGMCAIX prior to intradermal injection. The transduced DCs are expected to stimulate an antigen specific immune response against CAIX expressing RCC, leading to a potential anti-tumor effect. Dose escalation in 3 dose cohorts (5 X 106, 15 X 106, and 50 X 106 cells/administration) follows the std 3+3 ph1 design with an expansion cohort. DC-AdGMCAIX is given intradermally Q 2 weeks X 3 doses. The primary aim is safety of DC-AdGMCAIX injections. Secondary aims are to evaluate immune responses & the antitumor effects per RECIST 1.1. Pts with clear cell mRCC with ECOG 0-1 & measurable disease & adequate organ function were enrolled. Results: Six pts with clear cell mRCC are enrolled. Four pts received all 3 planned vaccine doses and the fifth pt only the 1st dose. No SAE’s were seen to date. One pt had chills that lasted several minutes and transient Gr1 leucopenia. One pt has worsening of pre-existing proteinuria, though unclear if related to the vaccine. One pt has PD & the other two have SD on D85 scans. Tumor bx shows intra-tumoral infiltration by T cells. Conclusions: These early data show that autologous DC transduced by Ad-GMCAIX vector can be safely given to mRCC patients without any acute SAE’s noted at the doses tested so far. The study will complete its 3rd cohort & expansion cohort enrollment. This data support the further development of Ad-GMCAIX vaccine strategies either alone or in combination with approved therapies. Funding: Supported by NCI RAID Initiative NSC 740833 and Kite Pharma.
Perioperative outcomes following surgical resection of renal cell carcinoma with upper level IVC thrombus: A contemporary multicenter experience.
Authors: Abel Edwin Jason , Thompson R. Houston , Margulis Vitaly , Heckman Jennifer E. , Merrill Megan M. , Darwish Oussama M. , Krabbe Laura-Maria , Boorjian Stephen A. , Leibovich Bradley C. , Wood Christopher G.
Published: February 2017

498

Background: Surgery for RCC patients with IVC thrombus above the hepatic veins is complex and associated with an increased risk of perioperative morbidity and mortality. However, minimal data exist that describe contemporary perioperative outcomes at major referral centers or the prognostic factors associated with adverse surgical outcomes. The objective of this study is to determine the preoperative predictors of major complications and 90 day mortality after surgery in RCC patients with IVC thrombus above the hepatic veins. Methods: Records were reviewed of all RCC patients with IVC tumor thrombus above hepatic veins who had surgery from 1/2000 to 12/2012 at Mayo Clinic, MD Anderson, UT Southwestern and the University of Wisconsin. Major complications were recorded were defined as 3A or greater according to the Clavien- Dindo system within 90 days of surgery. Univariate and multivariate (MV) analyses were used to evaluate associations of preoperative clinical, pathological or laboratory variables with risk of major complications or 90-day mortality. Results: A total of 162 patients were identified for study (thrombus level 3,4 in 69 and 93 patients, respectively, according to Neves classification). Cardiopulmonary bypass was used in 60/162 (37.5%), while 40 (24.7%) patients underwent pre-operative angioembolization. Major complications were reported in 55 (34.0%) patients, with the most common being respiratory (12.4%), hematologic (9.2%) and cardiac (8.6%). On MV analysis, preoperative systemic symptoms and level 4 thrombus were independently associated with an increased risk of major complications. Mortality was reported in 17 (10.5%) patients within 90 days after surgery. On MV analysis, ECOG performance status and low serum albumin were independently associated with increased risk of 90 day mortality. Conclusions: Contemporary perioperative mortality and major complication rates for RCC patients with upper level thrombus are 10 and 34%, respectively. ECOG PS >1 and low serum albumin are associated with an increased risk of perioperative mortality, and should be considered when selecting patients for neoadjuvant systemic therapy trials.
Temporal trends and factors associated with receipt of systemic therapy among patients undergoing cytoreductive nephrectomy.
Authors: Smaldone Marc C. , Handorf Elizabeth , Kim Simon , Thompson Robert Houston , Costello Brian Addis , Corcoran Anthony , Wong Yu-Ning , Uzzo Robert G. , Leibovich Bradley C. , Kutikov Alexander , Boorjian Stephen A.
Published: February 2017

503

Background: We evaluated temporal patterns in the utilization of systemic therapy among patients undergoing cytoreductive nephrectomy (CN) for metastatic Renal Cell Carcinoma (mRCC) from a large national cancer registry and assessed patient characteristics associated with receipt of systemic treatment. Methods: We reviewed the National Cancer Database to identify patients with stage IV RCC who underwent CN between 1998-2010. Systemic therapy was defined as any treatment with immunotherapy and/or chemotherapy (including targeted agents). We evaluated the association between clinicopathologic features and receipt of systemic therapy using multivariable logistic regression with generalized estimating equations, and assessed the interaction of treatment with time, stratified as immunotherapy (1998-2004) versus targeted-therapy (2005-2010) eras. Results: Of 22,409 patients with mRCC undergoing CN, 8,830 (39%) received systemic therapy. Receipt of systemic therapy increased from 32% in 1998 to 49% in 2010 (p<0.001), largely due to increased utilization of chemotherapy (13.9% vs. 46.7%; p<0.001). Following adjustment, increasing patient age (51-60 years: OR 0.82 [CI 0.73-0.92]; 61-70 years: OR 0.67 [CI 0.59-0.76]; ≥71 years: OR 0.36 [CI 0.31-0.43]), as well as coverage with Medicaid (OR 0.61 [CI 0.5-0.74]), Medicare (OR 0.70 [CI 0.62-0.79]), or no insurance (OR 0.75 [CI 0.63-0.91]) were associated with decreased utilization of systemic therapy. Although use of systemic therapy in the elderly (≥71 years) and in patients with Medicare/Medicaid remained lower throughout the study period, each of these cohorts was significantly more likely to receive systemic treatment in the targeted versus immunotherapy era (all p values <0.05). Conclusions: Utilization of systemic therapy among patients undergoing CN has increased over time, coinciding with the introduction of targeted therapies. Nevertheless, still less than half of such patients receive systemic treatment. While the etiology for lack of treatment is likely multifactorial, the potential health policy implications of continued disparities in care warrant further investigation.
Temporal changes in the survival of metastatic renal cell cancer patients and the impact of targeted agents: Single center experience.
Authors: Erman Mustafa , Arik Zafer , Kilickap Saadettin , Bilen Cenk Yucel , Yazici Sertac , Akdogan Bulent , Ozen Haluk
Published: February 2017

519

Background: Though targeted agents have dramatically changed the outcome of metastatic renal cell cancer (mRCC) patients, it has not been possible to show any survival advantage, probably due to substantial cross-over in randomized trials. The change in survival times following the introduction of targeted agents may yield indirect evidence of an improvement in overall survival (OS). Methods: First targeted agents were available in Turkey in 2007. Data from the hospital charts of adult mRCC patients treated between January 2003 and December 2012 were included. Demographic and clinical findings along with patient, tumor, and treatment-related prognostic factors and their correlation with progression-free survival (PFS), and OS were analyzed. Results: One hundred and seventy six patients had metastatic disease. Of these, 107 patients received at least one dose of interferon-α and 74 patients received at least one targeted therapy. Median follow-up was 19.1 months (range 1-97 months) and median OS was 24.6 months (95% CI, 20.4-28.9). Median OS of patients who received any targeted therapy was significantly better than those who did not (29.1 mths [95% CI, 21.4-36.8] vs 19.4 mths [95% CI, 14.2-24.6]; p=0.036). The study period of 2003-2012 was subdivided into 4 consecutive groups. Although not statistically significant, a trend toward better survival was observed with advancing years and increasing targeted therapy use (p=0.09). For example, median OS of patients diagnosed in 2006 and 2007 was 14.1 months (95% CI, 10.4-17.8) while median OS of those diagnosed in 2010 or later was 30.8 months (95% CI, 18.3-43.3). Patients in intermediate and poor Memorial Sloan-Kettering Cancer Center risk groups benefited more from targeted therapies (p=0.001). Conclusions: Patients who received any targeted therapy lived longer than those who did not. Trend toward better survival was associated with advancing years and increasing targeted therapy use. The introduction of targeted agents appear to benefit mRCC patients in terms of OS as well.
High preoperative monocyte-lymphocyte ratio (MLR) as a prognostic factor in nonmetastatic clear cell renal cell carcinoma.
Authors: Hutterer Georg C. , Stoeckigt Caroline , Stojakovic Tatjana , Martin Hernandez Jessica M. , Eberhard Katharina , Mannweiler Sebastian , Gerger Armin , Pummer Karl , Pichler Martin , Zigeuner Richard
Published: February 2017

534

Background: The ratio of peripheral blood absolute monocyte count to absolute lymphocyte count (MLR) has been proposed as a negative impact for patient’s survival in haematological cancers. However, findings about MLR’s potential prognostic significance in non-metastatic renal cell carcinoma (RCC) patients have not been reported yet. Methods: We retrospectively evaluated the prognostic significance of the MLR in a cohort comprising of 678 consecutive non-metastatic clear cell RCC patients, operated between 2000 and 2010 with curative radical or partial nephrectomy at a single tertiary academic centre. Pre-treatment MLR was calculated one day before surgical intervention. Patients were categorised using an MLR cut-off of 0.35. Cancer-specific- (CSS), metastasis-free- (MFS), as well as overall survival (OS) were assessed using the Kaplan-Meier method. To evaluate the independent prognostic significance of the MLR, multivariate Cox regression models were applied for all three endpoints. Additionally, the influence of the MLR on the predictive accuracy of the Leibovich prognosis score was determined by Harrell’s concordance index (c-index) and decision curve analysis (DCA). Results: An increased MLR was statistically significantly associated with poor outcomes for all three endpoints in univariable analyses (all p≤0.006). Multivariable analyses identified an increased MLR as an independent prognostic factor for patients’ CSS [HR=2.33, 95%CI=1.10-4.94, p=0.027], but not for MFS [HR=1.59, 95%CI=0.94-2.69, p=0.087], nor for OS [HR=1.37, 95%CI=0.93-2.03, p=0.112]. The estimated c-index was 0.83 using the Leibovich prognosis score and 0.86 when MLR was added. Conclusions: Regarding RCC patients’ CSS, an increased MLR represented an independent prognostic factor. Adding the MLR to well-established prognostic models such as the Leibovich prognosis score might improve their predictive ability.