bluuebunny/crossref_metadata_2025 huggingface dataset:
Gemcitabine-cisplatin (GC) plus radical cystectomy-pelvic lymph node dissection (RC-PLND) for patients (pts) with muscle-invasive bladder cancer (MIBC): Assessing impacts of neoadjuvant chemotherapy (NAC) and the PLND.
Authors: Tully Christopher Michael , Bochner Bernard H. , Dalbagni Guido , Zabor Emily C. , Herr Harry W. , Donat S. Machele , Ostrovnaya Irina , Regazzi Ashley Marie , Kim Philip H. , Sfakianos John P. , Rosenberg Jonathan E. , Bajorin Dean F.
Published: February 2017

355

Background: NAC and RC-PLND improves survival in MIBC and GC is a standard NAC option. However, little is known about GC efficacy endpoints and the individual contribution of NAC and surgery. Methods: Pts with clinical T2-T4aN0M0 MIBC treated from 1/2000 to 10/2012 with a planned 4 cycles of GC plus RC-PLND within 90 days (D) of NAC were evaluated retrospectively for the number (#) of cycles, dose delivered, D from end of NAC to RC-PLND, margin status, LN status and # of LN identified. Post-NAC pathologic endpoints included complete response (pT0), residual Non-MIBC disease (pTa/Tis/T1;N0) and ≥MIBC disease (≥pT2N0). Associations with overall survival (OS) and disease-free survival were analyzed using Cox regression; non-linear associations with # of resected LN used linear and quadratic terms. Results: 154 pts met inclusion criteria. 5-year (yr) OS was 61% (95% CI 53-71%). Post-NAC pT0 was achieved in 21% (32/154) and Non-MIBC in 25% (39/154 - pTa (2), pTis (25), pT1 (12)). Post-NAC pT0 and Non-MIBC had similar 5-yr OS (85% and 89%, respectively) and combined (<pT2) pts differed significantly from pts with ≥pT2, (87% (95% CI 78, 98%) and 38% (95% CI 27, 53%), respectively; p<0.001). Median D from NAC to RC-PLND was 34 and median # of resected LN was 19. On univariate analysis, # of cycles (4 vs <4), GC dose intensity and total dose, clinical stage (cT2 vs cT3/cT4), # of resected LN, positive (+) LN and + margins were significant for OS. In multivariate analysis, post-NAC pathology ≥pT2 (HR 6.7; 95% CI 2.6-17.4; p<0.001), + LN (HR 3.21; 95% CI 1.6-6.4; p=0.001) and + margins (HR 3.2; 95% CI 1.4-7.5; p=0.007) were significant for increased risk of death. Using a model with these 3 predictors to estimate the benefit of PLND, the hazard ratio decreased with each LN resected until 25 and then plateaued beyond 25 (p=0.016). Conclusions: NAC with GC has excellent drug delivery, permits rapid RC-PLND and achieves meaningful pathologic responses. Survival is similar with <pT2N0 and pT0N0 post NAC pathology. Pts with post NAC ≥pT2, + margins, and + LN do poorly. Increasing LN yield on PLND contributes to OS.
Development of a new outcome-prediction model for patients with urothelial carcinoma of the bladder prior to cystectomy.
Authors: Kramer Mario W. , von Klot Christoph A. J. , Heinisch Annika , Wegener Gerd , Abbas Mahmoud , Peters Inga , Tezval Hossein , Herrmann Thomas R. W. , Kuczyk Markus A. , Merseburger Axel S.
Published: February 2017

360

Background: Prognostic models for patients undergoing cystectomy are spares and mostly rely on histopathological parameters. The present study investigated clinical prognostic indicators that are available prior to cystectomy for developing a risk stratification model. Methods: Charts were reviewed from 279 bladder cancer patients that were treated with radical cystectomy and bilateral lymphadenectomy. Of those 194 were eligible for study entry due to availability of necessary data. None of the patients had neoadjuvant therapy. Various preoperative parameters were analyzed and optimum cut-off points were identified using ROC curves. A risk stratification model was developed based on multivariate analysis. Analyzed factors included serum-creatinine, hemoglobin, white blood cells, C - reactive protein (CRP), age, gender, and body mass index. Results: In multivariate analysis, preoperative serum-creatinine (>93 umol/l), white blood cells (>10.2 tsd/ul), CRP (>3 mg/l) and BMI (<18,5 kg/m2 or ≥30 kg/m2) were independent predictor of poor cancer-specific survival (CSS). A new scoring model was developed, consisting of those four parameters. The stratification model showed significant differences based on Kaplan-Meier analysis for the whole cohort as well as for subgroup analysis (pT2-4, Nx, M0) (p<0.001). CSS after 36 (60) months for low, intermediate and high risk group was 82.6% (76.2%), 37.7% (30.9%) and 22.2% (16.7%), respectively (p<0.0001). Conclusions: Our scoring model based on preoperative clinical parameters can discriminate bladder cancer patients prior to cystectomy in respect of CSS. This might help physicians to recommend treatment options such as neoadjuvant therapy. The scoring model needs external validation considering prospective study design and discriminating patients who received neoadjuvant chemotherapy.
Palonostron with aprepitant plus dexamethasone to prevent chemotherapy-induced nausea and vomiting (CINV) during gemcitabine/cisplatin (GC) in urothelial cancer (UC) patients: A multi-institutional retrospective study in Japan.
Authors: Kitamura Hiroshi , Takahashi Atsushi , Hotta Hiroshi , Kato Ryuichi , Kunishima Yasuharu , Takei Fumiyasu , Horita Hiroki , Masumori Naoya ,   Sapporo Medical University Urologic Oncology Consortium
Published: February 2017

362

Background: GC combination chemotherapy of is a standard regimen for advanced UC. Although this is a highly emetogenic chemotherapy, there has been no study concerning antiemetic prophylaxis for CINV during GC. The aims of this study were to evaluate CINV during GC and to compare the antiemetic efficacy of the triple combination of palonosetron, aprepitant and dexamethasone with that of our old regimen using first-generation 5-HT3 receptor antagonists and dexamethasone. Methods: We conducted a retrospective multi-institutional review of the medical records of 122 patients who received GC for advanced urothelial cancer between February 2005 and January 2012. Uncontrolled CINV events were identified through records of nausea and vomiting, additional infusion, rescue medications, and/or records of food intake. Nausea, vomiting, and anorexia were classified using the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Results: A total of 75 and 47 patients were treated with first-generation 5-HT3 receptor antagonists (ondansetron or granisetron) plus dexamethasone (group 1) and palonosetron with dexamethasone plus aprepitant (group 2), respectively. There was no significant difference in age, sex, or the dose of cisplatin between the 2 groups. Patients in group 2 had significantly higher CR (defined as no emetic episodes and no rescue medication use) rates than those in group 1 during the overall phase in the first cycle (85.7% versus 65.3%, p=0.012) and all cycles (78.7% versus 50.7%, p=0.0019) of GC. Patients in group 2 were more likely to achieve more favorable CINV control, e.g., a lower grade of nausea, vomiting, or anorexia, lower incidence of rescue therapy required, and shorter time to become CINV-free, than patients in group 1. Conclusions: This study shows that palonosetron in combination with aprepitant and dexamethasone is more effective to prevent chemotherapy-induced nausea and vomiting in UC patients treated with GC than first-generation 5-HT3 receptor antagonists plus dexamethasone.
Patterns of relapse in poor-prognosis germ cell tumors in the GETUG 13 trial: Implications for assessment of brain progression.
Authors: Loriot Yohann , Pagliaro Lance C. , Flechon Aude , Mardiak Jozef , Geoffrois Lionnel , Kerbrat Pierre , Chevreau Christine , Delva Remy , Rolland Frederic , Theodore Christine , Bui Binh , Gravis Gwenaelle , Eymard Jean-Christophe , Malhaire Jean-pierre , Linassier Claude , Habibian Muriel , Logothetis Christopher , Culine Stephane , Laplanche Agnes , Fizazi Karim
Published: February 2017

365

Background: GETUG 13 investigated personalized chemotherapy based on tumor marker decline in patients with poor-prognosis GCT and demonstrated that a dose-dense regimen improves progression-free survival in patients with an unfavorable decline (Fizazi K, ASCO 2013). We investigated the pattern of relapse for patients included in GETUG 13. Methods: We conducted an analysis of relapse events in patients from GETUG 13 and an unfavorable decline of tumor markers (n=203). Baseline procedures before inclusion in the trial comprised a thoraco-abdomino-pelvic CT scan and an MRI of the brain: 22 patients (10%) had evidence of brain metastases at presentation. Results: With a median follow-up of 4.1 years (0.3 ; 8.8 years) when the analysis was performed, a progression event was observed in 94/203 patients (46%). First event consisted in a marker progression only in 41 patients (43%), a radiographic progression only in 29 patients (31%), a mix progression on both markers and imaging in 11 patients (12%), and death in 13 patients (14%). In patients with radiographic progression only, brain was the predominant site (n=16/29, 55%). Among all patients who experienced a radiographic progression (as first and subsequent progression event, n=58), brain only was the site of progression in 26 patients (45%): 12/30 (40%) in patients treated with BEP and 14/28 (50%) in those treated with dose-dense chemotherapy. Conclusions: Brain metastases develop often, early, and frequently as the only site of relapse in the course of poor-prognosis GCT. This raises the question of early detection and treatment of brain metastases in these patients, for example by integrating a systematic brain MRI after 2-3 months of chemotherapy.
Thromboembolic events (TE) in men treated with bleomycine-etoposide-cisplatin (BEP): A monocentric review over one year.
Authors: Boyle Helen Jane , Lavergne Emilie , Bonnin Nathalie , Rosay Herve , Flechon Aude
Published: February 2017

375

Background: BEP chemotherapy (CT) is the standard regimen for patients (pts) with metastatic germ cell tumours (MGCT). Over the past years, it seemed that more pts developed TE. Methods: Files of all male pts treated with BEP CT for a MGCT, at the Centre Léon Bérard in 2012, were reviewed. The incidence of thrombosis was assessed and then, the study population was described by comparing affected pts with the others using the non parametric Wilcoxon test for the quantitative data and Fisher exact test for the qualitative one. Results: Finally, 45 men received BEP for MGCT at our institution in 2012. Median age at CT initiation was 33.6 years (range: 16.9-43.6). All pts but 1 had a testicular primary, 1 had a mediastinal primary. Ten had seminomas (22%) and 35 a non-seminomatous tumour (78%). According to the IGCCCG classification, 28 pts were classified as good prognosis (62%), 12 as intermediate prognosis (27%) and 5 as poor prognosis (11%). Seven pts received CT on a port-a-cath (16%), 13 pts on a brachial PICC line (29%) and 25 on a central venous cathether (CVC) inserted in the jugular (55%). Fifteen pts (33%) developed venous thrombosis: 4 of them had a pulmonary embolism. The TE was symptomatic for 9 pts and was discovered on a routine CT-scan for the other 6 pts. TE was related to tumoral compression for 4 pts (27%, 3 TE diagnosed before CT) and to the venous catheter for 8 pts (53%). For the 3 other pts no “obvious” cause was found. Median time from catheter insertion to thrombosis was 35 days (range: -32-80 days). TE occurred in 29% of pts with a porthacath, 31% of pts with a PICC line and 36% of pts with a CVC. No significant relationship was observed between thrombosis occurrence and age, IGCCCG prognostic group, type of venous catheter, presence of metastasis and lymph nodes status. Among the 27 pts (60%) who underwent post-CT surgery, 41% were on curative anticoagulant therapy (low molecular weight heparin). Conclusions: Incidence of TE is higher in this small study than those reported in other series. The reason for this is unclear and needs more investigations. Prospective evaluation of prophylactic use of anticoagulants and/or of new practices concerning catheters, as removing it on day 6, to avoid TE may be explored.
Relationship between abiraterone exposure, prostate-specific antigen (PSA) kinetics, and overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) .
Authors: Xu Steven , Ryan Charles J. , Stuyckens Kim , Smith Matthew R. , Saad Fred , Griffin Thomas W. , Park Youn Choi , Yu Margaret K. , Vermeulen An , Poggesi Italo , Nandy Partha
Published: February 2017

39

Background: Abiraterone, the active metabolite of abiraterone acetate (AA), is an effective androgen biosynthesis inhibitor for patients with metastatic castration-resistant prostate cancer (mCRPC). We conducted a sequential exposure-biomarker-survival modeling analysis to explore the relationship between prostate-specific antigen (PSA) kinetics and overall survival (OS) and to establish the exposure response for PSA kinetics and OS in chemotherapy-naïve and -pretreated patients with mCRPC following AA administration. Methods: The exposure-PSA-survival modeling framework was based on two phase III studies, COU-AA-301 (chemotherapy-pretreated, N = 1184) and COU-AA-302 (chemotherapy-naïve, N = 1081), and included a mixed-effects tumor growth inhibition (TGI) model to describe PSA dynamics in response to AA and a Cox proportional hazards survival model to evaluate the relationship between relative risk of death and PSA dynamic end points. Results: The TGI model best described the longitudinal PSA dynamics following AA treatment. Abiraterone exposure significantly increased PSA decay rate (maximum effect of 2.72, p < 0.0001). The estimated concentration for 50% of the maximum effect (EC50) was 4.75 ng/mL. The abiraterone effect on PSA kinetics was similar in chemotherapy-naïve and -pretreated subjects, and approximately 90% of subjects had a steady-state concentration greater than the EC50. All model-predicted PSA metrics were strongly associated with OS in both populations; model-based post-treatment PSA doubling time showed the strongest association (hazard ratios approximately 0.9 in both populations). Simulations showed that the modeling framework could accurately predict the survival outcome for both studies. Conclusions: The analysis revealed a similar effect of abiraterone on PSA kinetics and association between PSA kinetics and OS in chemotherapy-naïve and -pretreated subjects, providing additional evidence for surrogacy of PSA kinetics and the use of PSA end points to indicate clinical benefit of abiraterone in subjects with mCRPC regardless of prior chemotherapy. Furthermore, the study confirmed that the recommended 1,000 mg/d dose of AA leads to adequate clinical exposure above the effective level. Clinical trial information: NCT00638690, NCT00887198.
Lymphopenia as an independent predictor of worse survival in papillary renal cell carcinoma.
Authors: Mehrazin Reza , Uzzo Robert G. , Kutikov Alexander , Tomaszewski Jeffrey J. , Ginzburg Serge , Ruth Karen J. , Al-Saleem Essel , Chen David Y. T. , Viterbo Rosalia , Greenberg Richard E. , Smaldone Marc C. , Al-Saleem Tahseen I.
Published: February 2017

397

Background: Lymphopenia signifies inflammatory response and is an index of poor systemic immunity which can be associated with poor survival outcomes. The aim of this study was to evaluate the prognostic relevance of preoperative absolute lymphocyte count (ALC) in patients with papillary renal cell carcinoma (RCC). Methods: We retrospectively analyzed our institutional, prospectively maintained, renal cancer database and identified patients with pathologic diagnosis of papillary RCC after partial or radical nephrectomy. Patients with preoperative ALC value within 3 months prior to surgery were eligible for the study. ALC of 1,300 cells/µl was used as the cutoff value (our lowest laboratory reference value). We evaluated the correlation between ALC and age, gender, Charlson comorbidity index (CCI), pathologic T stage, nuclear grade, and overall TNM stage. Differences in overall survival (OS) by ALC status were assessed using the log−rank test. Cox proportional hazards modeling was used for multivariable analyses. Results: We identified 314 out of 2,732 patients with a pathologic diagnosis of papillary RCC after partial or radical nephrectomy from 1997 to 2013. Those undergoing multiple surgical procedures (multifocal or bilateral disease) or missing preoperative ALC were excluded from the study. A total 205 patients met inclusion criteria with a median follow up of 37.3 months. As a continuous variable, low absolute lymphocyte count was associated with higher pT stage (p=0.038), TNM stage (p=0.029) and older age (p=0.022). Lymphopenia below 1,300 cells/µl was also associated with pT stage (p=0.008) and TNM stage (p=0.018). On multivariable analysis, independent of stage, older age,and CCI, lymphopenia was associated with inferior overall survival (HR 2.1 [CI 1.1−4.03], p=0.037). Conclusions: In our series of patients with papillary renal cell carcinoma, lymphopenia was associated with lower overall survival independent of stage, age,and charlson comorbidity index. ALC significantly increases the accuracy of already established prognostic factors and can be helpful for patient counseling and design of clinical trials.
Cardiovascular events associated with androgen deprivation therapy in patients with prostate cancer: A systematic review and meta-analysis.
Authors: Carneiro Arie , Sasse Andre Deeke , Wagner Andrew , Toneto Bruno , Serpa Neto Ary , Chang Peter , Lima-Pompeo Antonio Carlos , Machado Marcos Tobias
Published: February 2017

40

Background: A recently published meta-analysis of randomized clinical trials (RCT) showed that androgen deprivation therapy (ADT) did not significantly increase cardiovascular mortality in prostate cancer patients. However, cardiovascular morbidity, which can impact quality of life, was not evaluated. Objectives: To evaluate the risk of cardiovascular morbidity and mortality associated with long-term ADT in patients with prostate cancer. Methods: We conducted a literaturesearch from 1960 and June 2012. We selected RCT and large cohort studies that evaluated first-line endocrine therapy, ADT greater than 6 months, and follow up greater than 1 year. Results: Thirteen studies (137,658 patients) were included. Of four cohort studies, 126,898 patients were included and 10,760 patients were part of nine RCTs. Analysis of the RCTs showed no differences in development of acute myocardial infarction (AMI) (OR 1.23; 95% CI: 0.92 – 1.64; I2: 0%) or stroke (OR 1.02; 95% CI: 0.71 – 1.46; I2: 0%) among patients receiving ADT or not. The analysis of three randomized studies that reported other nonfatal cardiovascular events demonstrated a significant increase in such events in the group receiving ADT (OR 1.55; 95% CI: 1.09 – 2.20; I2: 0%). When large cohort studies were included in the analysis, an increased risk of AMI among men who had ADT was found ( OR 2.01, 95% CI:1.90 – 2.13; I2: 91.3%). Conclusions: ADT in prostate cancer patients for at least 6 months is not associated with cardiovascular mortality, acute myocardial infarct and stroke. However, patients receiving ADT had a significant increase in nonfatal cardiovascular events.
Professional practice gaps and barriers to optimal care of renal cell carcinoma (RCC) among oncologists in the United States.
Authors: Rini Brian I. , Bowser Andrew , Lazure Patrice , Goldin Luba , Peloquin Sophie , Hayes Sean , Mortimer Jim A. , Peterson Eric D , Hutson Thomas E.
Published: February 2017

404

Background: New therapies for advanced RCC have improved patient outcomes while increasing the complexity of care. We sought to quantify practice gaps and barriers to optimal care among oncologists treating patients with RCC at academic and/or community centers in the United States. Methods: In total, 248 oncologists were recruited for a 2-phase (qualitative/quantitative) study. Eligible participants who had fully completed either one of the 2 phases were included in the analyses (n = 169). In the first phase, participants (n = 27) completed a brief online case-based survey and a 45-minute telephone interview on the attitudinal, contextual, and behavioral factors that influenced diagnosis and treatment. Selected interviews were transcribed and analyzed through thematic analysis. In the second phase, participants (n = 142) completed an online survey including case vignettes. Respondents’ answers were compared with optimal answers based on National Comprehensive Cancer Network kidney cancer guidelines (version 1.2013) and evidence-based opinions of 2 RCC experts. Results: Forty-six percent of participants correctly identified all predictors of short survival/poor risk in RCC. Regarding treatment options for a poor-risk patient, 37.5% chose temsirolimus and 11% sunitinib, both felt to be reasonable options. In a scenario focused on dose and treatment modification in a patient with treatment-related hypertension, 34% selected a nonoptimal management option. In a scenario focused on the importance of recognizing clinical symptoms as a component of treatment decision making, 40% of respondents were in agreement with expert- and evidence-supported treatment approach. Detailed results of this analysis will be presented. Conclusions: This study revealed clinically relevant practice performance gaps that affect delivery of care and patient health outcomes. Not recognizing predictors of poor risk or the importance of evaluating clinical symptoms can result in missed opportunities to change treatment strategy, leading to suboptimal outcomes. These results will support design of educational programs and performance improvement interventions.
c-Met abnormatities in patients with genitourinary (GU) malignancies and outcomes with c-MET inhibitors.
Authors: Fontes Jardim Denis Leonardo , Gagliato Debora De Melo , Falchook Gerald Steven , Wheler Jennifer J. , Zinner Ralph , Janku Filip , Subbiah Vivek , Piha-Paul Sarina Anne , Fu Siqing , Tannir Nizar M. , Corn Paul Gettys , Tang Chad , Hess Kenneth R. , Roy-Chowdhuri Sinchita , Kurzrock Razelle , Meric-Bernstam Funda , Hong David S.
Published: February 2017

407

Background: c-MET is a tyrosine kinase receptor involved in cancer growth, migration, development of metastasis and angiogenesis. Deregulation of this gene has been associated with poor prognosis and resistance to treatment in prostate, bladder and renal cell cancer (RCC). Methods: Patients with GU malignancies referred to the phase I clinic were evaluated for the presence of c-MET mutation and amplification. Their outcomes on protocols containing c-METinhibitors were also analyzed. Results: c-MET amplification was detected in 7 out of 97 (7.2%) patients (4/27 renal, 1/18 urothelial and 2/12 adrenocortical carcinoma), while c-MET mutation/variant in 3 out of 53 (5.7%) patients (2/20 renal and 1/15 prostate cancer). No demographic characteristics were associated with either c-MET abnormalities, but patients tested positive for either mutation or amplification had a higher number of metastatic sites (median number of sites of 4 versus 3 for wild type patients). Median overall survival from phase I consult was 4.4 and 10.6 months for patients with and without a c-MET alteration, respectively. Twenty-nine (25%) patients were treated under a protocol containing a c-MET inhibitor. Overall 6 (21%) patients had a partial response (all prostate and RCC) and 10 (34%) had stable disease as best response. Median time to tumor progression was 2.3 months (0.4-19.7) for all treated patients. No responses were detected in patients with a c-MET genetic abnormality or treated with a specific c-MET inhibitor as a single agent. Conclusions: c-MET mutation and amplification are present in different GU malignancies conferring a worse prognosis for patients referred to the phase I program. We observed activity of c-MET inhibitors for patients without c-MET genetic abnormalities and when c-MET inhibition was combined with other targets/drugs.
Open-label, phase II raptor study of everolimus (EVE) for papillary mRCC: Efficacy in type 1 and type 2 histology.
Authors: Escudier Bernard J. , Bracarda Sergio , Maroto Rey José Pablo , Szczylik Cezary , Nathan Paul D. , Negrier Sylvie , Cattaneo Agnese , Weiss Claudia , Porta Camillo , Gruenwald Viktor
Published: February 2017

410

Background: Prospectively collected data evaluating therapy for papillary mRCC are limited. RAPTOR (NCT00688753) evaluated the efficacy and safety of EVE as first-line therapy for papillary mRCC. Methods: Eligible pts had histologically confirmed type 1 or 2 papillary mRCC, ECOG PS ≤1, and no previous systemic therapy for mRCC. Central histology review was mandatory. EVE 10 mg/d was given until disease progression or intolerable toxicity. The primary end point was the PFS rate at 6 months assessed per RECIST 1.0 (central review) in the first 44 pts of the per-protocol population (PPFF; lack of centrally confirmed papillary histology was a protocol violation). Secondary end points included PFS, OS, and safety. Sensitivity (per protocol [PP] and ITT populations), supportive (local review), and subgroup (type 1 and 2 histology) analyses were performed. Results: 92 pts enrolled (median age, 60 y; 78% men). Among pts with papillary RCC per local review (99%), 58% had type 2 and 16% had type 1 (25% missing). Central review confirmed papillary histology in 76% of pts, 59% with type 2 and 33% with type 1 (9% missing). Reasons for discrepancies will be presented. Efficacy results are shown (Table). In the safety population (n=92), the most common grade ≥3 AEs were asthenia (11%), anemia (5%), and fatigue (5%). Conclusions: The RAPTOR study showed that EVE was well tolerated by and provided clinical benefit to pts with both type 1 and type 2 papillary mRCC, although both PFS and OS were longer in type 1. These results support further evaluation of EVE for pts with papillary mRCC. Clinical trial information: NCT00688753. [Table: see text]
Safety and efficacy of addition of VEGFR and EGFR-family small-molecule tyrosine kinase inhibitors to cytotoxic chemotherapy in solid cancers: A meta-analysis.
Authors: Funakoshi Tomohiro , Latif Asma , Galsky Matt D.
Published: February 2017

415

Background: The approach of combining cytotoxic chemotherapy with small molecule tyrosine kinase inhibitors (TKIs) has been explored in a large number of randomized trials, in a diverse range of tumor. We performed a systematic review and meta-analysis to evaluate the safety and efficacy of this therapeutic approach. Methods: PubMed and the ASCO databases were searched up to March 2013. Eligible studies included randomized trials in which the FDA approved TKI in combination with chemotherapy was compared with chemotherapy alone in patients with any type of solid cancer. The endpoints included safety [fatal adverse events (FAEs), treatment discontinuation, any severe (grade 3 or 4) adverse events (AEs), and individual severe AEs] and efficacy [progression-free survival (PFS), and overall survival (OS)]. The pooled relative risk (RR) or hazard ratio (HR), with corresponding 95% confidence intervals (CI) were calculated. Results: A total of 16,011 patients from 43 trials were included. Among the 43 trials, ten met their primary efficacy endpoints. Among the 21 phase III trials, two led to Food and Drug Administration approval for the combination. Compared with chemotherapy alone, the addition of a TKI significantly increased the risk of FAEs (RR, 1.63; 95% CI, 1.32-2.01), treatment discontinuation (RR, 1.80; 95% CI, 1.58-2.06), and any severe AE (RR, 1.25; 95% CI, 1.16-1.36). Compared with chemotherapy alone, the addition of a TKI was associated with a significant improvement in PFS (HR, 0.82; 95% CI, 0.76-0.89), but not OS (HR, 0.99; 95% CI, 0.95-1.03). Chemotherapy plus TKI was also associated with a significant higher risk of seven of the 11 evaluated individual AEs: neutropenia (RR, 1.18; P =.004), thrombocytopenia (RR, 1.70; P <.001), febrile neutropenia (RR, 1.48; P <.001), hypertension (RR, 3.01; P <.001), skin toxicities (RR, 6.38; P <.001), diarrhea (RR, 2.57; P =.002) and fatigue (RR, 1.35; P <.001). Conclusions: The addition of a VEGFR or EGFR-family TKI to chemotherapy in solid cancers increases the risk of severe toxicities and treatment discontinuations. These findings might explain the general lack of a survival benefit with these regimens.
PD-L1 expression in non-clear cell renal cell carcinoma.
Authors: Fay André P , Callea Marcella , Gray Kathryn P. , Ho Thai Huu , Song Jiaxi , Carvo Ingrid , Lampron Megan E. , Stanton Melissa L. , McDermott David F. , Atkins Michael B. , Freeman Gordon J , Hirsch Michelle S. , Signoretti Sabina , Choueiri Toni K.
Published: February 2017

424

Background: Programmed death-1 (PD-1) receptor negatively regulates T cell-mediated responses.PD-1 ligand (PD-L1) is aberrantly expressed in clear cell renal cell carcinoma (ccRCC) and is associated with worse prognosis. Levels of PD-L1 expressions in non-ccRCC and its association with clinicopathological features and survival are unknown. Methods: Formalin-fixed paraffin-embedded (FFPE) specimens were obtained from 97 patients with chromophobe (CHR), papillary (PAP), translocation Xp11.2 (TrL) RCC and oncoytoma (ONC) and were included in the analysis. PD-L1 expression was evaluated by immunohistochemistry using a mouse monoclonal anti-PD-L1 antibody (405.9A11). The assay was validated using FFPE cell line controls known to be positive or negative for PD-L1 expression by flow cytometry. PD-L1 tumor positivity (PD-L1+) was defined as ≥5% tumor cell membrane staining. For PD-L1 expression in immune cells, a combined score based on the intensity of infiltrate and percentage of positive cells was used. Baseline characteristics including stage/grade, and survival data were collected. Comparisons between PD-L1 expression and clinicopathological features were evaluated using chisq or wilcoxon rank sum tests. Cox model tests for association of PD-L1 expression with OS in univariate and multivariable analysis. Results: Among 97 patients, 12 (12.4%) were considered PD-L1+ in tumor cells: 2/36 (5%) of CHR RCC, 5/50 (10%) of PAP RCC, 3/7 (43%) of TrL RCC, and 2/4 (50%) of ONC. PD-L1 positivity in tumor cells was significantly associated with higher stage (p=0.026) and grade (p=0.046), as well as lower OS on univariate (p=0.02) but not multivariate analysis (p=0.29). On the other hand, PD-L1 positivity by immune cells was observed in 50 (51.5%) patients: 13/36 (36%) of CHR RCC, 30/50 (60%) of PAP RCC, 6/7 (86%) of TrL RCC, and 1/4 (25%) of ONC. PD-L1 positivity in immune cells did not correlate with stage (p=0.7), grade (p=0.1) or OS (p=0.8). Conclusions: PD-L1 expression is variable in non-ccRCC and depends on histology and tumor vs. immune cells scoring. Only PD-L1 positivity in tumors cells was associated with aggressive features. Patients with non-ccRCC should not be automatically excluded from trials of agents that target the PD-1/PD-L1 pathway.
Impact of angiotensin system inhibitors (ASI) on outcomes in patients (pts) with metastatic renal cell carcinoma (mRCC): Results from a pooled clinical trials database.
Authors: McKay Rana R. , Rodriguez Gustavo Enrique , Lin Xun , Simantov Ronit , Choueiri Toni K.
Published: February 2017

437

Background: Increasing evidence suggests that angiotensin II modulates angiogenesis and tumorigenesis. In this study, we utilized a clinical trials database to evaluate the role of ASIs (angiotensin-converting enzyme inhibitors and angiotension-receptor blockers) on survival outcomes in pts with mRCC. Methods: We conducted an analysis of pts with mRCC treated from 2003-2013 on phase III (NCT00083889, NCT00065468, NCT00678392, NCT00474786, NCT00631371, NCT00920816) and II clinical trials (NCT00054886, NCT00077974, NCT00267748, NCT00338884, NCT00137423, NCT00835978). We evaluated pts treated with ASIs at baseline or within the first 30 days of study. Statistical analyses were performed using Cox regression and the Kaplan-Meier method. Results: We identified 4,736 pts treated with sunitinib (n=1,059), sorafenib (n=772), axitinib (n=896), temsirolimus (TEM) (n=457), TEM + interferon-alfa (IFN-α) (n=208), bevacizumab (BEV) + TEM (n=393), BEV + IFN-α (n=391), or IFN-α (n=560). Most pts were < 65 years of age (69%), male (71%), with clear-cell histology (89%) and prior nephrectomy (70%). With regard to International mRCC Database Consortium risk groups, 14%, 42%, and 24% had favorable, intermediate, and poor-risk disease, respectively. 1383 (29%) pts received treatment with an ASI. Baseline hypertension was present in 84% of ASI users and 33% of ASI non-users. ASI use was associated with improved progression-free survival (PFS) and overall survival (OS) when compared to pts who did not receive an ASI (Table). This association was retained in multivariable analysis adjusted for age, gender, presence of bone metastases, and risk groups. Conclusions: This is the largest retrospective study to date evaluating the role of ASIs on outcomes in cancer pts. In this analysis, we demonstrate that concomitant use of ASIs may improve survival outcomes in pts with mRCC treated in the era of targeted therapy. [Table: see text]
Association between clinical response and toxicities with drug exposure in an alternative dosing regimen of sunitinib.
Authors: Kanesvaran Ravindran , Teo Yi Ling , Chue Xiu Ping , Chau Noan-Minh , Tan Min-Han , Wee Hwee Lin , Ho Han Kiat , Chan Alexandre
Published: February 2017

439

Background: An alternative dosing (AD) regimen of 37.5mg daily in repeated 4-weeks on, 2-weeks off cycle has been proposed to ameliorate frequent dose modifications due to toxicities as observed with the approved dosing regimen of sunitinib for metastatic renal cell carcinoma (mRCC). This study aims to determine the effect of drug exposure (sunitinib and active metabolite, SU12662) on clinical response and toxicities in patients receiving this AD regimen. Methods: All mRCC patients initiating AD sunitinib were invited to participate in this study. In week 4 of each cycle, toxicities were assessed and plasma steady-state levels (Cmax) were quantified using high-performance liquid chromatography. Clinical response was assessed after 2 treatment cycles; and was used with drug exposure and toxicities data for dose adjustments. Results: 36 patients with a mean age of 59.1 ± 10.1 years were recruited. Majority were males (81%) and Chinese (86%). Among the 24 and 16 analyzable cases for cycle 1 and 2, median total Cmax were 0.088 and 0.094 µg/ml respectively. Sixteen patients completed 2 treatment cycles; 7 (44%) partial response, 5 (31%) stable disease and 4 (25%) progressive disease. A dose increment to 50mg daily was performed for a patient with disease progression. Common grade 2 and above toxicities were hypertension, hand foot syndrome (HFS) and mucositis. Higher drug exposures were observed among patients who achieved clinical response and among those who experienced at least grade 2 toxicities. Conclusions: Drug exposure could likely be associated with clinical response and toxicities in this AD regimen. [Table: see text]
Heterogeneity of intermediate prognosis patients (pts) with metastatic renal cell cancer (mRCC) treated with sunitinib.
Authors: Sella Avishay , Michaelson M. Dror , Matczak Ewa M. , Simantov Ronit , Lechuga Mariajose , Lin Xun , Figlin Robert A.
Published: February 2017

446

Background: The Memorial Sloan Kettering Cancer Center risk model (MSKCC) stratifies pts with mRCC into 3 prognostic groups based on 5 risk factors. The Intermediate Prognosis (INTMP) risk group is characterized by the presence of 1 or 2 factors, equivalent to 15 possible distinct entities. This heterogeneity suggests that the efficacy of tyrosine kinase inhibitors may be less predictable in the INTMP than in the other groups. Methods: We identified 548 patients with INTMP mRCC from a pooled analysis of patients treated with sunitinib in 6 prospective phase II and III clinical trials. Statistical analysis was performed using Cox regression and Kaplan-Meier methods and Pearson chi-square tests. Results: Most INTMP pts were male (69%), with clear cell carcinoma (93%), good ECOG performance status (PS) (60.5% PS 0; 38% PS 1; 1.5% PS 2) and median age 60. There were 325 pts (56%) with 1risk factor, and the most common were <1 year from diagnosis (38%); low hemoglobin (Hg) (29%), or both (16%). Objective response rate (RR) was 35.4%, progression free survival (PFS) was 8.4 months (m) and overall survival (OS) was 20.5 m. The 325 (59.3%) pts with one risk factor fared better than the 223 (40.7%) patients with two: PFS 10.7 vs 6.5 m, HR 0.684(95% CI 0.563-0.832, p<0.001); OS 26.3 vs 14.1 m, HR 0.522 (95% CI 0.420-0.648, p<0.001). RR was similar (38.5% vs 30.9%, p=0.071). Sunitinib was more effective in pts with PS 0: PFS 9.7 vs 7.8 m, HR 0.797 (95% CI 0.654-0.972, p=0.0242); OS 24.7 vs 14.0 m, HR 0.529 (95% CI 0.426-0.657, p<0.001), RR 38.9% vs 30.1%, (p=0.036). The most common grade 3/4 adverse events (AE) were fatigue (17%), hypertension (10%), hand foot skin reaction (9%), and nausea (4%). Overall, 17% of patients discontinued due to AE, and the overall pattern of AEs did not vary among the subgroups. Conclusions: MSKCC INTMP is a heterogeneous group comprised mostly of pts with low Hg and/or < 1 year from diagnosis. PFS and OS are superior in pts with 1 vs. 2 risk factors, and PS is also an important factor in the INTMP group. Sunitinib is active and well-tolerated in INTMP pts. Clinical trial information: NCT00077974, NCT00083889, NCT00137423, NCT00267748, NCT00338884, NCT00054886.
Discrimination between Von Hippel-Lindau gene and hypoxia-regulated alterations in the metabolism and protein expression in renal cell carcinoma using ome-based strategies.
Authors: Seliger Barbara , Leisz Sandra , Schulz Kristin , Erb Susanne , Wang Ena , Marincola Francesco , Stehle Franziska
Published: February 2017

447

Background: The objective of this project is to dissect the von Hippel-Lindau- and hypoxia-regulated alterations in human renal cell carcinoma to define both novel prognostic markers as well as therapeutic targets. Methods: For this, the VHL-negative RCC cell line 786-O next to recently established gain of function VHL transfectants thereof were used as a model system and subsequently cultured under normoxic or hypoxic conditions. Whereas direct effects on the altered energy metabolism were determined by lactate, pyruvate and pH measurements. the resulting effects at the gene/protein expression profiles were determined by comparative cDNA micro array analysis/ 2DE-based proteome analyses, respectively. Some of the differentially expressed genes/proteins were verified by qPCR and/or Western blot analysis in a panel of RCC cell lines. Results: By employing the VHL-/VHL+RCC model system VHL-dependent, HIF-dependent as well as VHL/HIF-independent alterations in the gene and protein expression pattern were found. Some of the differentially expressed genes/proteins were either associated with the loss of VHL function, the hypoxic conditions or both. The genes/proteins defined as differentially expressed under these conditions are mainly involved in the cellular metabolism and predominantly localized in the cytoplasm or mitochondrion. The verification of the differentially expressed genes/proteins by qPCR and Western blot analysis revealed a heterogeneous expression in RCC cells and lesions. One such gene/protein is represented by the glutamine gamma glutamyl transferase (TGM2). Its expression was associated with the loss of VHL and induction of hypoxia. Furthermore, TGM2 might be an important marker for both VHL-independent and/or hypoxia-induced responses. Conclusions: The data demonstrate that VHL functionality and/or hypoxia induce distinct effects on the metabolic switch of RCC.
Sterotactic body radiosurgery for primary small renal tumors: A retrospective analysis.
Authors: Kaplan Irving D. , Wagner Andrew , Mahadevan Anand , Dagoglu Rabia N
Published: February 2017

475

Background: Small renal tumors are being diagnosed with increased frequency with the increasing use of axial imaging. Partial or total nephrectomy is the "gold standard" for management. Often patients are not candidates or refuse surgery. Stereotactic Radiotherapy (SBRT) is used to treat brain metastases from RCC. This study is aimed to evaluate the efficacy and toxicity of SBRT in the treatment of renal tumor. Methods: From June 2009 to December 2012, 21 patients with 22 lesions treated with 48Gy in 3 fractions were retrospectively evaluated. 21 patients had RCC and 1 had lymphoma. All patients had tracking during respiration. The Cyberknife system was used. All patients were with ondansetron and /or prochlorperazine to prevent nausea. Follow-up abdominal CT scans or MRI’s were used to evaluate efficacy. Blood Creatinine and urea values were used to track renal function. Clinical records were also evaluated for hypertension. Results: The median Follow up was 21 months (3-48 months). The median age was 82 (56-95). 4 patients had baseline chronic renal failure and 13 patients had baseline hypertension. 12 lesions (54.5%) were left sided and 10 lesions (45.5%) were right sided. 9 lesions (42.9%) were located at upper pole, 6 (28.5%) at lower pole, 5 (23.8%) at middle pole and 1 (4.8%) at renal pelvis. Median maximal tumor size was 3.8cm (1.9-7.7) and median treatment volume was 46cc (7.7-237cc). Five patients developed acute grade 1 fatigue and one patient developed pain which was attributed to inflammation and resolved. One patient developed worsening renal function and 1 patient developed hypertension. There were two local failures at 13 and 21 months. Two patients underwent surgery because one had progressive disease and one as a result of patient choice. 1y and 2y overall survival were both 95%. 1 y and 2 y local control rates were 92 and 84% respectively. Conclusions: This is the largest experience to report on the use of SBRT to treat small renal tumors. SBRT with a dose of 48Gy in 3 fractions of 16 Gy for small renal tumors seems to be an effective and a safe treatment with minimal acute toxicities. In addition tumors in locations not amenable to ablation (renal pelvis) can be safely treated with SBRT.
Results from a phase 2 trial of bortezomib (B) and sorafenib (S) in unresectable or metastatic renal cell cancer.
Authors: Lauer Richard C. , Rabinowitz Ian , Novak Terry , Edelman Martin J.
Published: February 2017

495

Background: B is a small molecule proteasome inhibitor that affects multiple signaling pathways. S is an orally active multikinase inhibitor with known activity in renal cell cancer. In vitro data has shown that S and B interact synergistically in a number of neoplastic cell lines to cause apoptosis. A phase 1 trial of S and B demonstrated no unexpected toxicities. We now report the results of this phase 2 efficacy trial. Methods: Eligibility included cytologically confirmed clear cell cancer with no prior chemotherapy, PS 0-1, Cr < 1.5 mg/dl, normal LFTs. Regimen: S 200 mg PO BID and B 1mg/m2 IV days 1,4,8, & 11 every 21 days. Patients were treated until disease progression or unacceptable toxicity. The primary objective of the study was to achieve a PFS of 70 weeks. Results: Seventeen patients were enrolled between April of 2011 and January of 2013. Median age was 62y (range 44-75). Four of 17 patients had known brain metastasis on entry to the trial. Median number of cycles = 4 (range 1-45+). Response: CR/PR/SD/PD =0/1/12/4 (RR: 6%, 95% CI = 0%, 29%) Median progression free survival was 13.7 weeks; median overall survival was 110 weeks Toxicity: See table. Only 1 pts. treatment was stopped due to an AE of pancreatitis. There were no toxic deaths. The study was halted for futility. Conclusions: 1.The combination of S and B was well tolerated. 2. The RR of 6% and PFS of 13.7 weeks is not superior to S as a single agent. 3. The combination of SB is not recommended for further development. Clinical trial information: NCT 01100242.
Epidemiology and outcome of sarcomatoid renal cell cancer compared to clear cell renal cancer: A Surveillance, Epidemiology, and End Results (SEER) database review.
Authors: Kanaan Mohammed Nawaf , Singh Parminder , Ahmann Frederick R. , Agarwal Amit Balkrishna
Published: February 2017

504

Background: Sarcomatoid renal cell carcinoma (SRCCa) is a rare type of RCCa. Few case series in literature indicated its dismal prognosis. We studied the epidemiology and survival outcome of SRCCa compared to clear RCCa (CRCCa) by reviewing the SEER database. Methods: SEER database (8.1.2) was reviewed for patients (pts) with histologically confirmed SRCCa and CRCCa between 2004 -2007. Variables included were: age, race, gender, laterality, surgery of primary RCCa and AJCC stage. Primary outcome was 3 year Disease Specific Survival (DSS). Data was analyzed using Chi square, Kaplan Meier and Cox proportional hazard model. Results: A total of 7,653 pts with CRCCa and 540 with SRCCa were included between 2004 and 2007. Mean age in SRCCa was 61 compared to 62 yrs in CRCCa. White to black race ratio was 7.5:1 in both types. Left primary was 54% in SRCCa and 51% in CRCCa. Male to female ratio was 1.9:1 in SRCCa and 1.7:1 in CRCCa (Table). The main stage at presentation was stage IV (63%) in SRCCa and stage I (53%) in CRCCa. Surgery rate was higher in SRCCa in stage II and IV, same between two groups in stage II and higher in CRCCa in stage I. When we analyzed the effect of RCCa type on DSS for each stage separately, SRCCa had worse 3-year DSS in stage I, II, III and IV independent of age, sex, race, gender and surgery. The Hazard Ratio was 4.97 for stage I, 11.37 for stage II, 3.91 for stage III and 1.58 for stage IV (p <0.001). Conclusions: SRCCa have no statistical significant difference in age, race, gender and laterality compared to CRCCa. When compared stage to stage, SRCCa have worse outcome than RCCa even after adjusting for potential confounders including age, race, gender and surgery. The effect appears to be less prominent in higher stages than in lower stages of the disease. [Table: see text]