bluuebunny/crossref_metadata_2025_split huggingface dataset:
Updated results of a prospective noninterventional study of everolimus after use of 1 VEGFR-TKI.
Authors: Bergmann Lothar , Goebell Peter J. , Kube Ulrich , Kindler Manfred , Herrmann Edwin , Janssen Jan , Schmitz Joerg , Weikert Steffen , Kloss Susanne , Steiner Gabriel , Jakob Andreas , Staehler Michael D. , Steiner Thomas , Overkamp Friedrich , Guderian Gernot , Doehn Christian 
Published: March 2020

e15044 Background: Everolimus (EVE, Afinitor) is approved for the treatment of metastatic renal cell cancer (mRCC) after failure of VEGF-targeted therapy. The option to treat mRCC with six approved targeted agents has sparked debate on proper sequencing of these agents. However, data beyond clinical trials is limited. Here, we report prospective non-interventional data on EVE in routine use after failure of the 1st VEGFR-TKI. Methods: A prospective, single arm non-interventional study for patients with mRCC enrolled 383 patients in Germany between 08/2009 and 01/2012 to determine effectiveness defined as time between first EVE intake until disease progression due to any cause (TTP) and treatment duration. A first interim analysis was previously conducted and presented (Bergmann et al., J Clin Oncol 29: 2011 [suppl; abstr 4552]). Here we present a second interim analysis which was carried out 10 months after the first to corroborate the previous results. Results: 196 pts were included at 79 sites between 08/2009 and 07/2011 and had been followed for a median of 4.5 months at the time of analysis. The safety population (pts with information on EVE treatment) and efficacy population (pts who fulfilled all criteria per observational plan) consisted of 195 pts and 165 pts, respectively. At the cut-off date for the interim analysis, 136 pts (69%) had discontinued the study. Median treatment duration was 7.3 months (95% CI: 4.7 mo; 10.9 mo) and median time to progression (TTP) was 7.0 months (95% CI: 5.1 mo; 9.0 mo) for the efficacy population. A total of 600 AEs were reported in 70% of pts of the safety population including 148 SAEs in 67 pts (34%). Subgroup analysis according to duration of prior VEGF-targeted treatment <6 months and ≥6 months revealed median TTPs of 6.8 months (95% CI: 4.4 mo; 13.4 mo) and 7.4 months (95% CI: 4.6 mo; 10.1 mo), respectively. Conclusions: This 2nd interim analysis of a non-interventional study on EVE in treatment of mRCC after prior failure of the 1st VEGFR-TKI confirms the longer TTP reported in the 1st interim analysis compared to the pivotal trial. The results also provide evidence that TTP under EVE does not necessarily correlate with time on prior treatment.
Brain metastases (BMs) from metastatic renal cell carcinoma (RCC) in patients (pts) treated with molecularly targeted agents (MTAs).
Authors: Ali Haris , Yan Jingsheng , Arriaga Yull Edwin , Xie Xian-Jin , Brugarolas James 
Published: March 2020

e15066 Background: Historically, the frequency of BMs from RCC is ~11%. Recent reports have suggested an improvement in the incidence of BMs with tyrosine kinase inhibitors (TKIs). What is not known is the impact of MTAs on the prevalence of BMs in metastatic RCC. Methods: We conducted a retrospective review of all pts with metastatic RCC treated with MTAs at a tertiary care center, UT Southwestern Harold C. Simmons Comprehensive Cancer Center, from 2006–2010. Statistical analyses were performed using the Cox proportional hazards model and the Kaplan-Meier method. Results: Fifty nine pts met inclusion criteria. 8 more pts presented with BMs and were not included in the incidence and survival analyses. Median age was 64.6 yrs. Per MSKCC criteria, 3 pts were in favorable (5%), 41 in intermediate (70%), and 15 in poor (25%) prognostic groups. Sites of metastases at presentation included lungs (65%), lymph nodes (40%), bones (30%), and liver (25.4%). Mean follow up time was 16 months, and at last follow up 24 pts were alive. The incidence of BMs was 11.9% (7/59) and the prevalence was 22% (15/67). Median overall survival was 1.97 yrs (95% CI, 1.04-3.89). Median survival for pts who developed BMs vs. without BMs was 1.21 yrs vs. 1.98 yrs (p=0.17). In multivariable analyses, only lack of nephrectomy was associated with increased risk of BMs, HR=9.819 (95 CI, 1.65-58.38; p=0.012). Conclusions: In our study, the incidence of BMs in RCC pts treated with MTAs was similar to what has been historically reported. In contrast, the prevalence of BMs was much higher at 22%. This is the first study to report the prevalence of BMs in patients with metastatic RCC treated with MTAs. As in other tumor types, the life-time risk of BMs appears to increase with the availability of highly-active MTAs.
Long-term progression-free survival (PFS) in patients under sunitinib treatment: A SOG_GU experience.
Authors: Afonso Francisco Javier , Calvo Ovidio Fernández , Esteban Emilio , Fernández Gabriel Elena , Vazquez-Estevez Sergio , Anido Urbano , Lázaro Quintela Martin , Santomé Lucía , Ramos Vazquez Manuel , Campos Balea Begoña , Leon Mateos Luis , Firvida Jose-luis , Aparicio Luis Anton 
Published: March 2020

e15067 Background:A multicenter retrospective analysis was performed in patients (pts) with metastatic RCC treated with sunitinib who achieved long-term PFS defined as ≥18 months. Methods: 46 pts (87% male) treated with sunitinib in first (74%) or subsequent lines were included. Median age was 59 years, most common histology was clear cell (93.5%), 89% had undergone prior nephrectomy, 28.3% were metastatic at diagnosis and 58.7% presented one site of metastasis, 28.3% two sites and 13% three or more and 12 (26%) had bone metastases. Good, medium, and poor prognosis (MKSCC) was presented in 30.4%, 67.4% and 2.2% of pts respectively. Median time from diagnosis to sunitinib treatment was 2.23 years and median duration of therapy was 27 months. At the time of analysis 37% were still receiving sunitinib. Reasons for discontinuation were progressive disease (83%), toxicity (10.3%) and death (3.4%). Results: Incidence of adverse events was as expected, with asthenia, hand food syndrome (HFS), hypertension, and mucositis as main toxicities. Efficacy results are described in the table. No significant differences in PFS with prior or nonprior history of hypertension, diabetes, or hyperlipidemia were observed. The emergence of drug-related toxicities, lack of bone metastasis, and being nonmetastatic at the time of diagnosis were independenly associated with a trend towards an improvement in PFS (p=NS)(see table). Conclusions: A comparison with a sunitinib-refractory population is planned and will provide additional information about prognostic biomarkers for long term response. [Table: see text]
Thymidine phosphorylase expression in metastatic kidney cancer as a potential predictor of outcome in patients treated with sunitinib.
Authors: Miscoria Manuela , Di Loreto Carla , Puglisi Fabio , Murray Paul Gerard , Deroma Laura , Atmadini Maizaton , Messahel Souad , Fasola Gianpiero , James Nicholas David , Porfiri Emilio 
Published: March 2020

e15091 Background: Aberrant tumour angiogenesis is a hallmark of Renal Cell Carcinoma (RCC). Sunitinib is a small molecule targeting angiogenesis licensed for advanced RCC (aRCC) treatment. Thymidine Phosphorylase (TP) is an enzyme involved in pyrimidine nucleotide metabolism with a role in angiogenesis upregulation in cancer. In RCC, TP expression is associated with poor prognosis. We studied TP immunohistochemical expression in RCC samples and its association with the outcomes in a cohort of aRCC patients treated with sunitinib. Methods: We identified 59 consecutive patients with aRCC treated with sunitinib at our Institution. Nuclear (N) and cytoplasm (C) scoring for TP, using the validated Tsuda scoring, was performed. TP expression and clinico-pathological variables were studied to assess their association with the outcome of S therapy. The log rank test has been used for the univariate analysis and the Cox regression for the multivariate analysis. Results: Thirty-four patients received sunitinib as first line treatment. Fifty patients (84%) had clear cell RCC, 7 (12%) showed sarcomatoid features. Forty-five patients (76%) achieved either an objective response or stable disease. At the time of the analysis 32 patients had died, 46 had progressed and 41 had stopped the treatment. After an average follow up of 21 months, median OS and PFS were 21.2, 12.8 months respectively. N TP staining was positive in 19 patients (32%) and C staining in 36 (61%) patients. A significant association was observed between the N and C expression (p=0.004). The univariate analysis identified an association between N TP expression and longer OS (29.8 vs 17.8 months; p=0.0463) even if the association was not significant in the multivariate analysis (HR=0.56; CI 0.19-1.6). No associations were noted with PFS. Conclusions: In our study TP was overexpressed in a significant percentage of kidney cancers. In patients treated with sunitinib, N TP expression was associated with better OS. The results of the multivariate analysis were probably affected by the limited sample size. Larger and prospective studies are necessary to define the role of TP in RCC.
Efficacy and safety of sunitinib (SU) in patients (pts) with metastatic renal cell carcinoma (mRCC) and lung metastases (mets) only at baseline.
Authors: Shinohara Nobuo , Akaza Hideyuki , Tomita Yoshihiko , Yuasa Takeshi , Fujimoto Hiroyuki , Niwakawa Masashi , Ozono Seiichiro , Mugiya Soichi , Miki Tsuneharu , Uemura Hirotsugu , Nonomura Norio , Takahashi Masayuki , Hasegawa Yoshihiro , Ueda Eiji , Shibata Atsushi , Kawai Norisuke , Naito Seiji 
Published: March 2020

e15098 Background: The lungs may be the sole site of mets in RCC.In this retrospective analysis, we analyzed the efficacy and safety of SU in mRCC pts from a global phase (ph) III study and a Japanese ph II study who had lung mets only at baseline. Methods: In the ph III study, treatment (Tx)-naïve mRCC pts were randomized 1:1 to SU 50 mg/d on a 4-weeks-on-2-weeks-off schedule (n=375) or interferon-a (IFN) 9 MU subcutaneously TIW (n=360). In the single-arm ph II study, Tx-naïve (n=25) and cytokine refractory (n=26) mRCC pts received the same SU Tx. In the ph III study, progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan–Meier method, with median values compared by log-rank test. In both studies, objective response rate (ORR) was calculated with a two-sided 95% CI. PFS, OS, ORR, and safety were analyzed at final data cutoff. Results: In the ph III study, 31 (8%) and 42 (11%) pts in the SU and IFN groups, respectively, had lung mets only, compared with 12 (24%) in the ph II study. Baseline characteristics in lung mets pts were similar to all pts. In lung mets pts from the ph III study, ORR was higher with SU than with IFN (58.1% [95% CI: 39.1–75.5] vs. 19.0% [95% CI: 8.6–34.1]; P<0.001); there was a trend for longer median PFS with SU (14.1 vs. 7.8 months; HR: 0.531 [95% CI: 0.278–1.015]; P=0.0513); and median OS was comparable in both Tx subgroups (HR: 0.739 [95% CI: 0.335–1.628]; P=0.4507), although, at 25% of events, median OS was 22.9 months with SU vs. 15.8 months with IFN. In lung mets pts from the ph II study, ORR was 75.0% (95% CI: 42.8–94.5); at the time of analysis, median PFS and OS had not been reached; 4 pts (33%) had died due to any cause and 8 (67%) were alive without disease progression. The most common grade ≥3 SU-related AEs were fatigue, hand-foot syndrome, and diarrhea (all 19%) in the ph III study, and decreased platelets (100%), white blood cells (92%), and neutrophils (92%) in the ph II study. Conclusions: In the ph III study, Tx-naïve mRCC pts with lung mets only had significantly higher ORR and a trend for improved PFS and OS with SU compared with IFN. In the Japanese ph II study, ORR with SU was 75% in lung mets pts. Thus, 1st-line use of SU in mRCC pts with lung mets should be encouraged.
Use of video endoscopic inguinal lymphadenectomy (VEIL) in patients with urogenital malignancies: An observational study.
Authors: S K Raghunath , Rawal Sudhir , Khanna Samir 
Published: March 2020

e15101 Background: Surgical morbidity especially skin related necrosis is seen in 50% of patients following open radical inguinal lymphadenectomy in patients with urogenital malignancies. Inguinal lymphadenectomy helps in local control of disease and survival but had significant associated morbidity. We evaluated the post operative morbidity associated with minimally invasive video endoscopic Inguinal Lymphadenectomy (VEIL). Methods: Twenty two patients with urogenital malignancies who underwent thirty nine VEIL surgeries were evaluated for postoperative outcomes and morbidity. None of the patients required conversion to open surgery. Results: The mean operative time was 125 min, drain retention was 5.4 days, mean duration of postoperative stay was 3 days and a mean of 10.5 nodes were removed. 4.5% (1/22) developed skin flap necrosis, 4.5% (1/22) developed post operative venous bleeding that was controlled with dressing, 18.1% (4/22) developed lymphocoele that was resolved within 1-3 weeks with aspirations. Persistent drain output >50ml/day was observed in 18.1 % (4/22) that was resolved by readjusting the drain. Histologically positive nodes were seen in 40.9% (9/22) of patients. Conclusions: These observations offer further support for using minimally invasive VEIL surgeries over open radical inguinal lymphadenectomy in patients with urogenital malignancies in reducing both surgical and skin related morbidity. Further randomized controlled studies are needed to validate these findings.
Effect of PEDF on survival and in vivo antitumor activities of low-dose chemotherapy in castration-refractory prostate cancer.
Authors: Gaines Natalie , Nelius Thomas , Gillen Jessica , Rinard Katherine , Lopez Jose , Hirsch Jennifer , Cobos Everardo , Reynolds C. Patrick , Filleur Stephanie 
Published: March 2020

e15103 Background: The development of metronomic/low-dose treatment with conventional chemotherapeutic drugs has recently shown promise in the treatment of castration-refractory prostate cancer (CPRC). Pigment Epithelium-Derived Factor (PEDF) is a natural angio-inhibitor which is downregulated in prostate cancer. Previously we demonstrated that overexpression of PEDF in human CRPC PC3 cells decreased tumor growth in vivo. In the present study, we further validate PEDF anti-tumor properties in highly metastatic CRPC LNCaP-derivative CL1 cells. We also hypothesized that PEDF may enhance the cytotoxic effects of low-dose docetaxel (Doc) and cyclophosphamide (CTX) chemotherapies in vivo. Methods: Human PC3 and CL1 cell lines were genetically modified to stably express fluorescent DsRed Express protein with PEDF. Resulting cells were characterized in vitro for PEDF expression by western blot and for proliferation by growth curves and clone formation in Matrigel. PEDF anti-tumor effects were assessed on established SC xenografts in mice treated with Doc (5mg/kg IP every 4 days, 1mg/kg IP daily for 10 days, 0.5mg/kg IP every other day), CTX (10-20mg/kg in drinking water) or placebo. Survival studies were performed by injecting CL1 cells that express PEDF or control into the left lobe of the dorsal prostate of anesthetized mice. Results: We showed that PEDF inhibits proliferation and induces differentiation of all CPRC cells tested in vitro. Similarly, PEDF expression decreases by 85% and 70% the development of SC PC3 and CL1 tumors, respectively. In the survival study, we found that PEDF expression prolongs significantly (p=0.01; 95% confidence interval) median survival of CL1 tumor-bearing mice (53±0.001 days versus 57±1). Most importantly, we demonstrated that PEDF enhances the cytotoxic effects of low-dose chemotherapy on established tumors (best Doc dose: 1mg/kg for PC3 and 5mg/kg for CL1; best CTX dose: 10mg/kg for PC3 and CL1). Conclusions: This data reinforces the significance of PEDF as a potential new target when treating advanced prostate cancer. It also emphasizes PEDF as a promising new agent to enhance the anti-tumor efficacy of low-dose Doc and CTX chemotherapies.
Analysis of time to castration-resistant prostate cancer (CRPC) after initiating primary androgen depletion therapy (PADT) of prostate cancer.
Authors: Akaza Hideyuki , Hinotsu Shiro ,   Japan Prostate Cancer Study Group (J-CaP)
Published: March 2020

e15106 Background: Recent clinical trials for developing new drugs for castration resistant prostate cancer (CRPC) have been done for the patients who are surgically or medically castrated, with castration level of testosterone. Although patients who received combined androgen blockade (CAB) with anti-androgen must have shown PSA progression after discontinuing the anti-androgen prior to study enrollment, such patients are analyzed together with patients with castration monotherapy. Methods: We analyzed the time to CRPC among the patients with primary androgen depletion therapy (PADT); LH-RH agonist or CAB (LH-RH agonist + anti-androgen) who have registered to the J-CaP study and were followed up for >10 years. Time to CRPC was defined as PSA progression or other disease progression. Patients were stratified into three risk groups using JCAPRA score (JCO 2009; 26: 4309). In addition to the time to CRPC, overall survival length (OS) after initiating PADT was analyzed. Results: Time to CRPC was significantly longer in the CAB group than monotherapy group in intermediate and high risk groups (Table). In addition, in the intermediate and high risk groups, OS was significantly longer for the patients with CAB (Log-rank test). Conclusions: The significant differences of the time to CRPC and OS will influence to the outcome of clinical trials of CRPC. It is important to take the type of ADT in to consideration when we analyze the results of clinical study of CRPC. [Table: see text]
A QTc study of cabazitaxel in patients with advanced solid tumors.
Authors: Wade James Lloyd , Dakhil Shaker R. , Baron Ari David , Rottey Sylvie , Millard Frederick E. , Daugaard Gedske , Machiels Jean-Pascal H. , Conkright William A. , Sharma Sunil , Soetekouw Patricia M.M.B. , Yachnin Jeffrey , Sengeløv Lisa , van Veldhuizen Peter , Agarwala Sanjiv S. , Nguyen TX Quyen , Chadjaa Mustapha , Maison-Blanche Pierre 
Published: March 2020

e15115 Background: Cabazitaxel (Cbz) improves overall survival in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) after docetaxel failure, compared with mitoxantrone (HR 0.70; 95% CI 0.59–0.83; p<0.0001). Following Cbz approval for the treatment of mCRPC, this study was undertaken to evaluate any effect of Cbz on the QTc interval. Methods: This prospective, multinational, open-label study (NCT01087021) enrolled pts with advanced solid tumors (without other therapeutic options). Cbz 25 mg/m² IV was administered on Day 1 Q3W. QTc and other ECG intervals were assessed on Day 1 of Cycle 1. Triplicate ECGs were obtained from 12-lead Holter recordings and concomitant serial blood samples were collected for pharmacokinetic (PK) analysis. The primary endpoint was change from baseline in the corrected QTc interval (according to the Fridericia formula [QTcF]). Results: A total of 96 pts were enrolled; 32 pts under the original protocol (6-h Holter) and 64 pts following protocol amendment 1, which extended ECG and PK monitoring (24-h Holter). Median age was 63 yrs (69.8% male), 30.5% and 57.9% of pts were ECOG PS 0 and 1 respectively; 33 pts (34.4%) had prostate cancer. Screening ECG was abnormal but not clinically significant in 39.6% of pts. The majority (n=65) of pts received ≥ 3 treatment cycles; safety and ECG parameters were evaluated in 95 and 94 pts, respectively. In the 24-h Holter group (n=63), the maximum least squares (LS) mean change from baseline in QTcF was 4.8 msec (90% CI 2.1–7.5), returning to baseline by 24 h. Similar results were observed in the overall population (n=94). At Cmax, Cbz concentration had no effect on QTcF change from baseline; the mean (CV%) Cmax (n=91) and AUC (n=92) were 276 ng/ml (63%) and 1245 ng.h/ml (82%). The LS mean change from baseline in heart rate increased up to 24 h but remained < 10 beats per minute. The most common grade 3/4 AEs were neutropenia (27.4%), febrile neutropenia (12.6%), fatigue (12.6%) and dehydration (5.3%). No grade 3/4 cardiac AEs were reported. Of the 6 deaths reported, 1 (infection) was study drug related. Conclusions: Cbz had no significant effect on QTc interval in pts with advanced tumors. The Cbz safety profile is consistent with previous findings and with other taxane-based therapies.
Taxane-based chemotherapy in senior adults with metastatic castration-resistant prostate cancer (mCRPC): A prospective international registry.
Authors: Droz Jean-Pierre , Efstathiou Eleni , Heidenreich Axel , Yildirim Asif , Cabrera Paula , Kim Choung-Soo , Horchani Ali , Rinck Jose A. , Ozen Haluk ,   for MATuRITY investigators
Published: March 2020

e15122 Background: Docetaxel every 3 weeks is the standard of care in mCRPC. Efficacy and toxicity of taxanes in older men (70+) is poorly documented. Their enrolment in randomized trials is limited by exclusion criteria. This prospective international registry evaluates taxane toxicity and efficacy in such men in real life. Methods: 333 men with mCRPC (median age 76) were evaluated. PS, grade 3-4 comorbidities (Cumulative Illness Scoring Rate-Geriatrics [CISR-G]), dependence (Activity Daily Living [ADL], Instrumental ADL [IADL]), nutritional status, primary therapy received and outcomes (overall survival (OS), progression-free survival (PFS), best clinical benefit [based on pain, analgesic consumption, PS], PSA response, toxicity) were collected. Follow-up under therapy was 6 months. Results: In all, 24.0% had PS ≥2, 13.5% grade 3-4 comorbidities, 21% were dependent in ≥1 IADL, 15.6% in ≥1 ADL and 12.8% had a weight loss ≥5% within the past 3 months. According to SIOG (International Society of Geriatric Oncology, BJU Int 2010; 106: 462-69) algorithm, 65.2% were fit, 13.5% vulnerable, 16.8% frail and 4.5% had terminal illness. Most patients (62.4%) had pain at enrolment. Primary therapy was a taxane in 58% (3-weekly, 84.4%; median, 5 months) and another therapy in 42%. Clinical characteristics of men treated by taxanes and other therapies were comparable. At 6 months, 91% were still alive with taxanes vs 81% with other therapies (HR [95% CI] 0.53 [0.30-0.93] p=0.027). Taxanes also significantly increased PFS (66% vs 50%, HR 0.55 [0.40-0.76], p<0.001), best clinical benefit (60% vs 36%, HR 2.05 [1.47-2.85], p<0.001) and PSA response ≥50% (52.5% vs 37.4%, p=0.018). Main grade 3-4 toxicities with taxanes were fatigue (17.1%), nausea/vomiting (14%), diarrhoea (8.8%), anaemia (7.8%), nail change (6.7%) and febrile neutropenia (2.6%). Conclusions: Taxanes appear the most effective first-line therapy in older men with mCRPC and show an acceptable and manageable toxicity. Further analyses will compare health status measured by SIOG algorithm to physician independent evaluation and identify the most pertinent geriatric predictors of health status.