bluuebunny/crossref_metadata_2025_split huggingface dataset:
Final results of the phase III, randomized, double-blind AVOREN trial of first-line bevacizumab (BEV) + interferon-α2a (IFN) in metastatic renal cell carcinoma (mRCC)
Authors: Escudier B. J. , Bellmunt J. , Negrier S. , Melichar B. , Bracarda S. , Ravaud A. , Golding S. , Jethwa S. ,   on behalf of the AVOREN Investigators
Published: August 2020

5020 Background: In the AVOREN trial, BEV (Avastin) + IFN significantly improved PFS and ORR compared with placebo + IFN in pts with mRCC [Escudier, Lancet. 2007]. The study was unblinded after interim analysis due to significant superiority of BEV + IFN and the DSMB recommended crossover of pts from placebo to BEV (n = 13). We report here the results of the final analysis. Methods: Eligible pts had predominantly clear-cell mRCC, prior nephrectomy, no prior systemic therapy for metastatic disease, KPS ≥70%, no CNS metastases and adequate organ function. Pts were randomised to IFN (9MIU tiw) + BEV (10 mg/kg q2w) or placebo until disease progression. Primary endpoint was OS, with pre-planned stratified and unstratified analyses according to regional regulatory requirements. Results: 649 pts were randomised to BEV + IFN (n = 327) or placebo + IFN (n = 322). An independent radiological review confirmed previous investigator assessments, showing PFS of 10.4 vs 5.5 months (HR 0.57) and a response rate of 31% vs 12% in the two arms, verifying the robustness of the investigator analysis. At the time of final OS analysis (444 events), median follow-up was 22.9 months in the BEV arm and 20.6 months in the placebo arm. Final median OS stratified for region and Motzer score was 23.3 months in the BEV + IFN arm and 21.3 months in the IFN + placebo arm (HR 0.86 [95% CI: 0.72–1.04], p = 0.1291). No new or unexpected AEs were observed. More pts in the IFN + placebo arm than the BEV + IFN arm received post-protocol therapy, including TKIs, mTOR inhibitors, cytokines and chemotherapy: 180 (55%) in the BEV + IFN arm and 202 (63%) in the IFN + placebo arm. Exploratory analysis showed that median OS in pts receiving second-line TKI therapy (BEV + IFN, n = 96; IFN + placebo, n = 81) was 38.6 months vs 33.2 months (HR = 0.77 [95% CI: 0.51–1.15], p = 0.1948). Further subgroup analyses will be presented. Conclusions: BEV + IFN is a first-line standard of care for pts with mRCC, improving PFS and ORR, with a trend toward improved OS, compared with IFN. The observed OS results may have been influenced by subsequent anti-neoplastic therapy, which was not prespecified in the protocol and represents an uncontrolled element of the OS analysis. [Table: see text]
Discovery of the methylation of the metastasis suppressor gene KiSS-1 in bladder cancer
Authors: Sanchez-Carbayo M. , Orenes E. , Gil M. , Piulats J. M. , Alvarez M. , Bellmunt J. , Palou J. , Cordon-Cardo C. , Ecke T. , Lopez-Beltran A. 
Published: August 2020

5023 Background: In an attempt to uncover the mechanisms by which the metastasis suppressor gene, KiSS1, is lost in bladder progression, we tested the hypothesis of epigenetic silencing. An enriched 5’-CpG islands was identified around the transcription start site of KiSS1, supporting its susceptibility to be epigenetically modified by hypermethylation. To the best of our knowledge, KiSS1 had not been reported to be epigenetically altered in bladder cancer or any other tumor type. In this report, the impact and clinical relevance of KiSS1 methylation along bladder cancer progression was evaluated using in vitro strategies as well as on tissue specimens. Methods: The methylation status of KiSS1 was analyzed by two polymerase chain reaction (PCR) analysis strategies of bisulfite-modified genomic DNA. First, by genomic sequencing of both strands of KiSS1 promoter and second, by methylated specific PCR (MS-PCR). The epigenetic silencing of KiSS1 by hypermethylation was tested in bladder cancer cells (n = 12) before and after azacytidine treatment. The methylation status of KiSS1 promoter was then evaluated by MS-PCR in a large series of 524 bladder tumors. KiSS1 transcript expression were analyzed by RTPCR on bladder tumors (n = 177) for which KiSS1 methylation was assessed by MS-PCR. Results: KiSS1 hypermethylation was frequent in the bladder cancer cells analyzed and associated with low gene expression by RT-PCR. KiSS-1 expression was increased in vitro by the demethylating agent azacytidine in methylated cells. KiSS1 was found to be frequently methylated in a large series of 524 bladder tumors (68.1%). KiSS1 methylation was significantly associated with tumor stage (p < 0.001) and tumor grade (p < 0.001). Interestingly, a significant association was found between transcript levels by quantitative RT-PCR in bladder tumors and increasing tumor stage (p < 0.001). Moreover, the presence of KiSS1 methylation was associated with low transcript expression (p < 0.001). Conclusions: KiSS1 was identified to be epigenetically modified in bladder cancer. The association of KiSS1 methylation with cancer progression suggests the utility of incorporating KiSS1 methylation assessment in the clinical management of patients affected by uroepithelial neoplasias. No significant financial relationships to disclose.
A risk-adapted study of cisplatin and etoposide, with or without ifosfamide, in patients with metastatic seminoma: Results of the GETUG S99 multicenter prospective study
Authors: Fizazi K. , Aubelle M. , Delva R. , Chevreau C. , Caty A. , Kerbrat P. , Rolland F. , Priou F. , Laplanche A. 
Published: August 2020

5031 Background: Cisplatin plus etoposide-based chemotherapy is the recommended treatment and results in a high cure rate in patients (pts) with metastatic seminoma (Eur Urol 2008, 53: 478–96). Whether pts with good-prognosis and intermediate-prognosis metastatic seminoma should be treated differently or not has not been defined. Methods: From December 1999 to September 2008, pts with pure seminoma, a normal serum alpha-feto protein value, and evidence of metastases were included in this prospective study. Pts with a good prognosis according to the IGGCCG classification were treated with 4 cycles of EP (cisplatin 20 mg/m2/day and etoposide 100 mg/m2/day x 5 days, every 3 weeks). Pts with an intermediate prognosis according to the IGCCCG or MRC classifications (extra-pulmonary visceral metastases or supra-diaphragmatic metastases plus serum LDH> 2 x N) (J Clin Oncol. 1997;15:594–603; Eur J Cancer. 1999;33:1347–1350) were treated with 4 cycles of VIP + G-CSF (cisplatin 20 mg/m2/day, ifosfamide 1.2 g/m2/day, and etoposide 75 mg/m2/day x 5 days, every 3 weeks + G-CSF). Toxicity was assessed using the NCI-CTC scale. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Results: 133 pts were included in this study. Median age was 36 years (20–66). The median follow-up is 3.6 years (0.4–9.1). 110 (83%) pts had good-prognosis metastatic seminoma and received EP. Grade 3–4 toxicity included mainly neutropenia (41%) and neutropenic fever (13%). The 3-year PFS rate in good-prognosis pts is 94% (87–97), and the OS rate is 99% (94–100). 23 (17%) pts had intermediate-prognosis disease and received VIP + G-CSF. Toxicity included grade 3–4 neutropenia (32%), neutropenic fever (18%), grade 3–4 thrombocytopenia (18%), and grade 3–4 anemia (19%). Platelet and erythrocyte transfusions were required in 32% and 36% of pts, respectively . The 3-year PFS rate is 86% (67–95), and the OS rate is 91% (72–97) in intermediate-prognosis pts. Overall, 92 pts (69%) had post-chemotherapy residual masses and 75 pts (56%) were managed with 18Flurorodeoxyglucose positron emission tomography. Conclusions: This risk-adapted chemotherapy yielded an excellent outcome with an OS rate of 97% in metastatic seminoma. No significant financial relationships to disclose.
Updated activity and safety results of a phase II randomized discontinuation trial (RDT) of AV-951, a potent and selective VEGFR1, 2, and 3 kinase inhibitor, in patients with renal cell carcinoma (RCC)
Authors: Bhargava P. , Esteves B. , Nosov D. A. , Lipatov O. N. , Lyulko A. A. , Anischenko A. A. , Chacko R. T. , Lee P. , Al-Adhami M. , Ryan J. 
Published: August 2020

5032 Background: AV-951 is a potent inhibitor of VEGFR-1, 2 & 3 kinases (IC50 0.21, 0.16 and 0.24 nM respectively), and inhibits cKit and PDGFR at 10-times higher concentrations (IC50 1.63 and 1.72 nM respectively). In a phase II RDT of AV-951 (1.5 mg/day; 3 wks on, 1 wk off) in RCC, preliminary ORR at wk 16 was 28% (ASCO GU. 2008; abstract #283). Methods: Pts with locally advanced or metastatic RCC (any histology) and no prior VEGF-targeted therapy received AV-951 for 16 wks, after which further treatment was assigned based on response. Pts with ≥ 25% tumor shrinkage continued treatment with AV-951, while pts with < 25% change from baseline were randomly assigned to receive AV-951 or placebo for 12 wks (double-blinded). The primary end points were (1) objective response rate (ORR) at 16 wks, (2) percentage of randomly assigned pts remaining progression free at 12 wks following randomization, (3) safety profile. Results: 272 pts were enrolled: 70% male, 93% white, median age 56 yrs. 53% pts were treatement naïve, 72% had undergone nephrectomy and 83% had RCC with clear cell component. With a median duration of treatment of 5 mo (range 0–12 mo), the investigator assessed ORR (CR+PR) is 27.2% (30% in clear cell RCC), SD 60.5% and Disease Control Rate (CR/PR + SD) 88%. 118 (43%) pts were randomized to AV-951 or placebo. The most common treatment-related AEs (all grades) were hypertension (HTN, 42%) and dysphonia (16%). Guidelines for management of HTN were provided to investigators, and 52% pts received anti-hypertensives. Minimal (all grades) diarrhea (9%), fatigue (8%), stomatitis (3%) and hand-foot syndrome (2%) were observed. Laboratory abnormalities (all grades) were notable for minimal neutropenia (8%) and elevations of AST (21%) and ALT (21%). AEs led to dose reduction in 4% and treatment discontinuation in 5.5% of pts. Conclusions: Interim results of this phase II study demonstrate that AV-951 is active in RCC. The AE profile of AV-951 is consistent with that of a selective VEGFR inhibitor, with minimal off-target toxicities. Updated results of ORR (including independent radiology assessment), safety, percentage of randomly assigned pts remaining progression free at 12 wks, and overall PFS will be presented. [Table: see text]
Phase I/II trial of CCI 779 and bevacizumab in advanced renal cell carcinoma (RCC): Safety and activity in RTKI refractory RCC patients
Authors: Merchan J. R. , Pitot H. C. , Qin R. , Liu G. , Fitch T. R. , Picus J. , Maples W. J. , Erlichman C. 
Published: August 2020

5039 Background: Combined mTOR and VEGF blockade is a potentially promising and rational strategy for the treatment of advanced RCC. We previously reported the phase I safety and efficacy results of CCI 779 (C) +bevacizumab (B) n RTKI naïve stage IV RCC patients (pts) (J Clin Oncol. 2007;25[18S Suppl]:5034). We now report the interim results of the phase 2 study of C+B in RTKI refractory RCC patients. Methods: Design: Open label, phase I/II study of C+B in advanced RCC pts. Patients with measurable stage IV RCC with a component of clear/conventional cell type, performance status 0–2 and good organ function were eligible. Up to two prior treatment regimens were allowed (at least one prior RTKI). Phase II dose was C = 25 mg IV weekly and B = 10 mg/kg every 2 weeks repeated in 4 week cycles. The primary objective of the phase II portion was to assess the proportion of patients who were progression-free 6 months after study entry. Secondary objectives were assessment of response rates and toxicity. Accrual goal = 40 pts. Results: Thirty-five pts have been enrolled into the phase 2 portion to date with 4 pts ineligible. Twenty-five pts are evaluable for response assessment and 29 pts are evaluable for toxicity. Baseline characteristics (N: 35): M/F: 28/7; Number of met. sites: 1/2/3+: 15/9/11; prior nephrectomy: 31; Number of prior therapies: 1 = 29; 2 = 2. Most common (>5%) Gr 3–4 AEs (N = 29) included fatigue (6), hypercholesterolemia (2), hypertriglyceridemia (2), anorexia (2), rash (2), and anemia (2). Responses were: PR/SD/PD = 4 (16%)/18 (72%)/3 (12%). Median number of cycles administered was 4. Six month progression free rates will mature by may 2009. Conclusions: C+B combination at the recommended phase 2 doses is feasible and well tolerated. Clinical benefit rates (PR/SD) in RTKI refractory RCC patients (88%) are encouraging. Data on 6 month progression-free rates are expected to mature in 4/09. Updated data on safety, response rates, and 6-month progression free rates will be presented on all evaluable patients. Correlative studies on available plasma, serum and tumor samples for angiogenic and molecular biomarkers are underway. Supported by N01-CM62205, R21 CA 119545–02, and Commonwealth Foundation. [Table: see text]
Choi response criteria for prediction of clinical outcome in patients with metastatic renal cell cancer treated with sunitinib
Authors: van der Veldt A. , Meijerink M. R. , van den Eertwegh A. J. , Haanen J. B. , Boven E. 
Published: August 2020

5044 Background: Sunitinib (SU) has been approved for the treatment of metastatic renal cell cancer (mRCC). Since SU can induce extensive necrosis, RECIST may be inappropriate for tumor response evaluation. We evaluated whether the new Choi criteria (J Clin Oncol. 2007;25:1753–1759) are of additional value to predict outcome in mRCC patients (pts) treated with SU. Methods: 56 mRCC pts treated with SU were included. Imaging data consisted of thoracic and abdominal helical CT scans at baseline, after a median of 2 months and were repeated during treatment. For Choi criteria the longest diameter was ≥15 mm. Density of these lesions was determined in Hounsfield units. According to Choi criteria partial response (PR) was defined as ≥10% decrease in size or ≥15% decrease in density, while progressive disease (PD) was defined as ≥10% increase in size without meeting PR criteria by density. Progression-free survival (PFS) and overall survival (OS) were calculated according to Kaplan-Meier. Log rank test was used to test the statistical difference between survival curves. Results: For RECIST and Choi criteria, respectively, 230 and 156 tumor lesions were eligible. At first evaluation, according to RECIST 7 pts had PR, 39 stable disease (SD), and 10 PD, while according to Choi criteria 33 pts had PR, 8 SD and 15 PD. The median tumor density decreased significantly (Wilcoxon Signed Ranks test, p ≤ 0.001). At first evaluation in patients with PR, Choi criteria had a significantly better predictive value for PFS and OS (p < 0.001 and p < 0.001, respectively) than RECIST (p = 0.384 and p = 0.392, respectively). When best response during treatment was analyzed according to RECIST, the predictive value of RECIST increased for both PFS and OS (p = 0.004 and p = 0.002, respectively). For clinical benefit (PR+SD), the predictive value of RECIST and Choi criteria for PFS and OS were comparable (both p < 0.001). Conclusions: Choi criteria can be easily applied on contrast-enhanced CT scans. RECIST and Choi criteria have similar predictive value for outcome in pts with clinical benefit. Choi criteria, however, are more useful to early define a large pt population with favourable clinical outcome. [Table: see text]
Phase II multicenter study of abiraterone acetate (AA) plus prednisone therapy in docetaxel-treated castration-resistant prostate cancer (CRPC) patients (pts): Impact of prior ketoconazole (keto)
Authors: Danila D. C. , de Bono J. , Ryan C. J. , Denmeade S. , Smith M. , Taplin M. , Bubley G. , Molina A. , Haqq C. , Scher H. I. 
Published: August 2020

5048 Background: AA is a potent blocker of CYP17, required for synthesis of testosterone in the testes, adrenals, and prostate tissue. Study objectives included confirming AA antitumor activity and safety in multicenter setting, describing changes in ECOG PS, and comparing keto-naïve pts to keto-exposed pts. Methods: The 58 pts had progressive, metastatic CRPC and had failed hormonal therapy and up to two cytotoxic regimens, including docetaxel. AA (1,000 mg QD) and prednisone (5mg BID) were administered daily, the registration trial regimen. 56/58 pts had available data. Results: Baseline demographics: median age - 69.0 (44–86) yrs; median PSA - 151.00 (10.0–3846.0) ng/mL; ECOG 0 (n = 23), 1 (n = 30), 2 (n = 2), missing (n = 1); median prior hormonal therapies were 4 and chemo 1; 24 pts had prior keto, 32 pts were keto-naïve and 2 pts had no data on keto exposure. 45% pts had total maximal PSA decline ≥50%. Total maximal PSA decline (≥30%, ≥50% and ≥90%) in prior keto vs. keto-naïve pts was observed respectively, in: 10 (42%) vs. 20 (63%) pts; 8 (33%) vs. 17 (53%); 1 (4%) vs. 10 (31%). From 32 pts with ECOG 1 or 2, 16 pts (50%, 95% CI 32–68) improved (PS 1 to 0 in 14 pts, PS 2 to 1 in 1 pt; PS 2 to 0 in 1 pt); 39 pts (64% of total 58 pts) maintained PS. Median time to PSA progression was 169 days (95% CI 82–200): keto-naïve-198 days, prior keto-99 days. The majority of AA-related adverse events (AEs) were grade 1–2. No AA-related grade 4 AE was noted. Conclusions: Abiraterone acetate was well-tolerated and produced anti-tumor activity in heavily pretreated pts, as evidenced by PSA declines and improved PS. Incidence of mineralocorticoid-related AEs (HTN or hypokalemia) was reduced with the addition of low-dose prednisone. The keto-naïve post-docetaxel CRPC population was selected for the ongoing phase III pivotal study to confirm these results. [Table: see text]
Use of PSA threshold to identify an increased 4-year risk of a prostate cancer diagnosis in U.S. men
Authors: Crawford E. D. , Moul J. 
Published: August 2020

5051 Background: Recent studies have shown that prostate specific antigen (PSA) values can be used to predict risk of developing prostate cancer (PCa) in the future. In the European Randomized Study of Screening for PCa (ERSPC) subjects with PSA of ≥1.5 ng/mL had a significantly greater risk of developing PCa after 4 years than subjects with PSA of <1.5 ng/mL (9.2% vs 1.5%, respectively; OR = 7.466; p < 0.001). This current analysis aimed to validate the ability of PSA of ≥1.5 ng/mL to predict the future risk of PCa in a US population of men within the Henry Ford Healthcare System (HFHS). Methods: This is a retrospective analysis of men enrolled in the Health Alliance Plan of the HFHS between 1997–2004 with at least 4 years of follow-up data. Men ≥40 years of age, with a baseline PSA value between 0–4.0 ng/mL, not receiving 5-alpha reductase inhibitors were included. Men were followed for 4 years after their first PSA value. The risk of 4-year PCa diagnosis was evaluated based on a 1.5 ng/mL PSA threshold, and was assessed by logistic regression, controlling for age and race. Results: A total of 21,502 patients were included in the analysis. At baseline, patients had a mean age of 55 years and a mean PSA of 1.0 ng/mL. Overall, 7.9% of patients with baseline PSA of 1.5–4 ng/mL were diagnosed with PCa after 4 years, compared to 0.5% of patients with a baseline PSA of <1.5 ng/mL. In a multivariate analysis (controlling for race and age), patients with a baseline PSA of 1.5–4 ng/mL were 12 times more likely to be diagnosed with PCa over 4 years than patients with baseline PSA of <1.5 ng/mL (OR = 12.4; 95% CI: 9.7–15.9; p < 0.0001). African Americans (n = 6,367) with baseline PSA 1.5–4 ng/mL vs baseline PSA<1.5 ng/mL had an even higher risk of being diagnosed with PCa over 4 years (OR = 17.0; 95% CI: 11.0–26.1; p < 0.0001). Conclusions: This analysis validates that men with PSA values 1.5 to 4 ng/mL are at a significantly increased risk for developing future prostate cancer compared to those with a PSA value below the 1.5 threshold. This threshold also confers increased 4-year risk in African American men. [Table: see text]
PCA3: A urine-based genetic assay for detection of prostate cancer in men with elevated PSA
Authors: Drewnowska K. , Crawford E. D. , Qian J. , Varvel S. , Wilk M. , Mason L. , Kaminetsky J. , Huisman T. K. , Bilowus M. , Freedman S. J. , Bostwick D. G. 
Published: August 2020

5054 Background: Currently, early detection of prostate cancer relies primarily on an abnormal digital rectal examination (DRE) and an elevated prostate-specific antigen (PSA) level leading to a prostate biopsy. However, because of low positive predictive values, up to 75% of men with elevated PSA and/or suspicious DRE have a negative biopsy. We investigated the value of a new molecular marker–PCA3 in predicting the likelihood of prostate cancer. Methods: We undertook a prospective, multi-practice, community-urologist-based, and IRB approved clinical trial to evaluate PCA3. Urine samples were obtained from 974 men with elevated serum PSA (> 2.5ng/ml) and/or abnormal digital rectal examination prior to routine minimum 10-core prostate biopsy following standard study protocol in 30 medical practices. Urine samples were processed within 48 hours of collection. PCA3 and PSA mRNA were isolated, amplified and quantified by magnetic target capture, transcription-mediated amplification, and chemiluminescent hybridization protection assay technologies. The PCA3 value was determined using the ratio of PCA3 mRNA copy number to the PSA mRNA copy number multiplied by 1,000. Results: In total, 380 of 974 patients (39%) were diagnosed with prostate cancer, with a mean Gleason score of 7 (range, 6–9) and 26% (range 1–100%) of the biopsy specimens involved by cancer. An additional 106 cases (11%) had only high-grade PIN and/or atypical small acinar proliferation suspicious for cancer (ASAP), and 488 cases (50%) were benign. The mean PCA3 value in men with prostate cancer was significantly higher than in those without cancer (48 vs. 26, p < 0.0001). PCA3 score was associated with the presence of cancer (p < 0.0001) and Gleason score (p = 0.0001), but was not associated cancer volume (p = 0.56). Using a cutoff value of 35, PCA3 had an odds ratio of 2.6 for predicting prostate cancer. PCA3 had a specificity of 77% and a sensitivity of 44% for the diagnosis of prostate cancer, while the specificity and sensitivity for serum PSA were 22% and 87%, respectively. Conclusions: We found that the PCA3 urine test significantly improved the specificity for the detection of prostate cancer compared to serum PSA. Further evaluation of this urinary marker in screening for prostate cancer appears indicated. No significant financial relationships to disclose.