bluuebunny/crossref_metadata_2025_split huggingface dataset:
Two cycles of carboplatin as adjuvant therapy in stage I seminoma: 8-year experience by the Hellenic Co-operative Oncology Group (HECOG).
Authors: Koutsoukos Konstantinos , Liontos Michael , Lykka Maria , Rigakos Georgios , Andreadou Anna , Efstathiou Eleni , Koutras Angelos , Papatsoris Athanasios , Chrisofos Michael , Stravodimos Kostas , Adamakis Ioanis , Alamanis Christos , Karavasilis Vasilios , Makatsoris Thomas , Galani Eleni P. , Klouvas George , Kosmidis Paris A. , Fountzilas George , Dimopoulos Meletios A. , Bamias Aristotelis 
Published: March 2020

4558 Background: Adjuvant chemotherapy is used in stage I testicular seminoma. We have reported a risk-adapted strategy of 2 cycles of cisplatin/etoposide (EP) in 64 patients with age < 34 and/or tumor diameter > 4cm) (Bamias et al, Urology 2007), resulting in no relapses over a median follow up of 5 years. Following the establishment of adjuvant carboplatin as a standard, we adopted this treatment for all patients with stage I seminoma. We report our 8-year experience and compare these results with our previous EP strategy. Methods: Patients with stage I seminoma, treated with 2 cycles of carboplatin AUC 6 and a minimum follow up of 1 year after chemotherapy were selected. All patients consented for the use of their medical information and the analysis was approved by the centers involved. Survival functions were presented using Kaplan-Meier curves. The log-rank test was used to test for survival differences across different categories. Results: 137 patients (Median age: 34; Age<34: 49%, tumor diameter>4cm: 42%; rete testis invasion: 24%), treated between 11/2003-12/2011 were selected. During a median follow up of 4 years, there were 5 relapses (5-y relapse rate [RR]: 97% [SE: 2%]): retroperitoneal lymph nodes (n=4) and isolated brain (n=1). All patients with relapse had tumor diameter > 4cm and/or age < 34. No relapse was associated with rete testis invasion. Patients with at least 1 of the above risk factors (n=94) had a significantly higher relapse rate compared with a similar population (n=64) treated with 2 cycles of adjuvant EP: 5-y RR was 95% (SE: 2%) vs.100% (SE 0%), (p=0.033). All relapsed patients were treated with BEP chemotherapy and are currently alive with no evidence of relapse. Neutropenia and nausea/vomiting were less frequent with carboplatin than with EP (11% vs. 36% and 15% vs. 65%). Conclusions: Our analysis confirms the association of age and tumor diameter with relapse in stage I seminoma treated with adjuvant carboplatin. Although adjuvant carboplatin in patients with age<34 and/or tumor diameter> 4 cm is associated with higher RR than EP, the prognosis of these patients is excellent with salvage chemotherapy and, therefore, the use of less toxic treatment is justified.
Genome-wide methylation profiling to identify potential epigenetic biomarkers associated with response to sunitinib in metastatic renal cell cancer (mRCC) patients (pts).
Authors: Kim Jenny J. , Labots Mariette , Marchionni Luigi , Begum Shahnaz , Meijer Gerrit A. , Verheul Henk M.W. , Carducci Michael Anthony , Hammers Hans J. , Allaf Mohammad , Netto George J. , Hoque Mohammad 
Published: March 2020

4566 Background: There exists a significant heterogeneity in the clinical response to sunitinib among pts treated for mRCC and, thus, a biomarker which would predict pts’ response up front would be an invaluable tool in the clinical management of these pts. In this regard, whole genome methylation array was performed between 2 extreme groups: sunitinib responders (RES) and non-responders (NRES) to identify differentially methylated genes between these subsets of pts. Methods: mRCC pts who received sunitinib therapy with available frozen nephrectomy tissues (stored at -80°C) and clinical data were identified. RES were identified as pts with progression free survival (PFS) of > or =11 months (mos) and NRES as those with PFS < or = 3 mos. After DNA extraction and quality assurance according to standard protocol, whole genome methylation array was performed using Infinium Humanmethylation450 BeadChip Kit - Illumina. Data normalization was achieved by subset-quantile within array normalization (PMID: 22703947). Differentially methylated regions were identified using logit transformed Beta values, using an F-test after shrinking variance via empirical Bayes (PMID: 21118553). Results: Total of 13 pts who received sunitinib therapy with available frozen nephrectomy tissues were identified. Of the 13, 5 pts qualified for each RES and NRES cohort as described in methods section. All pts in RES group had clear cell subtype. Two pts of the NRES group were of non-clear cell subtype. The QC plots showed that all arrays were successful. For RES vs. NRES, one genomic location, DENND2D, was significantly hypermethylated in the RES group with a false discovery rate (FDR) of <10%. DENND2D has been identified as a tumor suppressor-like gene in non-small cell lung cancer and melanoma cell lines in the recent past. Conclusions: In this study, DENND2D was significantly hypermethylated in sunitinib RES compared to NRES among mRCC pts. Data analysis with a less stringent FDR is also being pursued. Technical validation as well as clinical validation of DENND2D utilizing a larger pt cohort are ongoing.
Prognostic significance of bone metastases (BM) and bisphosphonate (BIS) therapy in patients with metastatic renal cell carcinoma (mRCC) treated with molecularly targeted agents (MTAs).
Authors: McKay Rana R. , Lin Xun , Perkins Julia Jane , Simantov Ronit , Choueiri Toni K. 
Published: March 2020

4572 Background: BM are frequently present in patients with mRCC. BM cause significant morbidity and are associated with high rates of skeletal related events (SREs). The purpose of this retrospective analysis was to assess the impact of BM and BIS use on outcomes including progression-free survival (PFS) and overall survival (OS) in patients with mRCC. Methods: We conducted a pooled analysis of patients with mRCC treated from 2003-2011 on phase III (NCT00083899, NCT00065468, NCT00678392) and phase II trials (NCT00054886, NCT00077974, NCT00083889, NCT00338884, NCT00137423). Statistical analyses were performed using Cox regression and the Kaplan-Meier method. Results: We identified 2,749 patients treated with sunitinib (n=1,059), sorafenib (n=335), axitinib (n=359), temsirolimus (TEM) (n=208), TEM + interferon-alfa (IFN) (n=208), or IFN (n=560). Most patients were male (71%), had baseline ECOG PS of 0 (47%) or 1 (51%), clear cell histology (91%), and prior nephrectomy (84%). 285 patients (10.4%) received treatment with BIS (zoledronic acid n=233, pamidronate n=57, unspecified n=1). No patients received denosumab. Of the 2,504 patients with data regarding site of metastasis at diagnosis, 31.9% (n=781) had BM. The rate of SREs in patients with BM compared to patients without BM was 6.4% versus 1.4% (p<0.0001). Presence of BM was associated with shorter PFS (5.1 vs. 6.7 months (mo), HR 1.195, 95% CI 1.076-1.328, p<0.0008) and OS (13.2 vs. 20.2 mo, HR 1.292, 95% CI 1.145-1.456, p<0.0001) when compared to those without BM. In patients with BM, the use of BIS was not associated with improved PFS (5.1 vs. 4.9 mo, HR 0.867, 95% CI 0.704-1.067, p=0.1785) or OS (13.3 vs. 13.1 mo, HR 0.904, 95% CI 0.722-1.132, p=0.3801) when compared to patients who did not receive BIS. In patients with BM stratified by type of first-line MTA (TKI, mTOR inhibitor, or IFN-based), use of BIS was not associated with improved PFS or OS. Conclusions: In this analysis, we confirm that the presence of BM is an adverse risk factor for shorter PFS and OS in patients with mRCC treated with MTAs. Treatment with BIS did not have a positive impact on survival in this cohort.
Association analysis of polymorphisms in genes related to sunitinib pharmacokinetics.
Authors: Diekstra Meta , Klümpen Heinz Josef , Lolkema Martijn P. J. K. , Yu Huixin , Kloth Jacqueline S.L. , Gelderblom Hans , van Schaik Ron H.N. , Gurney Howard , Swen Jesse J , Huitema Alwin D.R. , Steeghs Neeltje , Mathijssen Ron H.J. 
Published: March 2020

4580 Background: Sunitinib is approved as systemic therapy for mRCC, GIST and pNET. Interpatient variability in the pharmacokinetics (PK) of sunitinib is high, which may have serious consequences for efficacy and toxicity of the drug. The objective of this study was to evaluate whether polymorphisms in candidate genes involved in sunitinib metabolism are related to the PK of sunitinib and its active metabolite SU12662. Methods: In this multicenter study, steady state sunitinib plasma concentrations and genotypes were prospectively obtained from 115 patients. Single nucleotide polymorphisms (SNPs) and haplotypes in 8 genes encoding CYP1A1, CYP3A4, CYP3A5, ABCB1, ABCG2, NR1I2, NR1I3, and PORwere evaluated as covariates in a population pharmacokinetic model describing both sunitinib and SU12662 PK using NONMEM. First, candidate genotypes/haplotypes were individually tested for a potential association with sunitinib or SU12662 clearance. Next, potential significant SNPs (p<0.05) were simultaneously included in a multivariate model and tested by backward elimination with a significance threshold of p<0.0005. Results: Four out of 37 screened genotypes (from 14 different SNPs) were related to sunitinib clearance (CYP3A4*22 CC and CT, CYP3A5*3 GG, and ABCB1 (2677 TT)). CYP3A5*3 AG genotype was associated with clearance of SU12662. In the multivariate analysis, none of the SNPs reached the predefined significance threshold of p<0.0005. Nevertheless, CYP3A4*22T allele carriers showed a 22.5% decreased clearance of sunitinib (p<0.01). Conclusions: Our data suggest that individual SNPs or haplotypes in CYP1A1, CYP3A4, CYP3A5, ABCB1, ABCG2, NR1I2, NR1I3 and POR are not clearly associated with sunitinib or SU12662 clearance. Several (environmental) factors may also influence the PK of sunitinib. Interestingly, the recently identified CYP3A4*22 SNP potentially has an impact on drug exposure. Replication studies in larger groups of patients are needed to verify the role of CYP3A4*22 for sunitinib clearance.
Contrasting vascular response to sunitinib as measured by DCE-CT, DCE-MRI, and DCE-US in renal cell carcinoma (RCC) patients (pts).
Authors: Hudson John M. , Williams Ross , Milot Laurent M. , Bailey Colleen , Kiss Alex , Atri Mostafa , Stanisz Greg J. , Burns Peter N. , Bjarnason Georg A. 
Published: March 2020

4583 Background: Imaging (DCE-MRI, DCE-CT, DCE-US) provides information about the integrity and hemodynamics of the tumor microvasculature. Methods: 34 treatment (Rx) naive pts with RCC and abdominal tumor suitable for imaging received sunitinib 50 mg on a standard 4/2 schedule. DCE-US, DCE-CT, and DCE-MRI were done at baseline, during the first course and after 2wks off Rx. Imaging parameters included vessel permeability (Ktrans), extracellular volume fraction (ve) and Ktrans/ve=Kep (by DCE-MRI), permeability surface product (PS) by DCE-CT, blood volume (BV), by DCE-CT and DCE-US and blood perfusion (by DCE-US). A morphology parameter (MP) was developed that relates flow kinetics of the microbubble contrast agent to tumor vascular morphology by DCE-US. Results: Several imaging parameters predicted for progression free survival (PFS) in responding pts (N=26). Baseline imaging parameters correlated with PFS: Ktrans by DCE-MR (Spearman r= 0.53, p=0.01, N=24), BV by DCE-CT (r=0.48, p=0.02, N=25) and disorganized vessel morphology (large MP) by DCE-US (r= - 0.45, p=0.02, N=24). Changes from baseline imaging parameters correlated with PFS: BV by DCE-US at 2 wks (r= -0.46, p=0.02, N=24), Kep by DCE-MR at 2 wks (r= -0.45, p=0.03, N=24) and MP at 1wk (r=0.67, p=0.02, N=12). There was a correlation between imaging methods: BV measured by DCE-CT correlated with BV by DCE-US (r=0.46, p=0.03, N=23) and Kep by DCE-MR (r=0.59, p=0.003, N=22); Permeability measured by DCE-MR (Ktrans) and DCE-CT (PS) correlated at 2wks (r=0.56, p=0.01, N=21). A combination of baseline US and MR parameters identified responders and non-responders with a sensitivity of 83% and specificity of 90%. Conclusions: This is the first study to contrast DCE-US, DCE-CT and DCE-MRI imaging in pts receiving antiangiogenic therapy. Baseline parameters for all three methods can predict for PFS. Changes from baseline in DCE-US and DCE-MRI parameters also predict for PFS. There is a correlation between imaging methods in parameters that measure BV and permeability. A novel DCE-US parameter was developed (MP) that quantifies the degree of tumor vascular disorganization. Baseline values in MP and changes during Rx correlate with PFS. Clinical trial information: OCT1205.
ERG rearrangements and association with clinical outcome in patients (pts) receiving abiraterone acetate (AA): Results from the COU-AA-302 study in chemotherapy (chemo)-naïve metastatic castration-resistant prostate cancer (mCRPC).
Authors: Attard Gerhardt , De Bono Johann Sebastian , Li Weimin , Molina Arturo , Griffin Thomas W. , Kheoh Thian San , Ricci Deborah Sokol , Zelinsky Kathy , Rathkopf Dana E. , Scher Howard I. , Ryan Charles J. 
Published: March 2020

5004 Background: ERG rearrangements result in androgen receptor-modulated up-regulation of ERG and may predict for AA response in mCRPC. Concordance has been shown between ERG status in archival samples and fresh CRPC biopsies (Attard et al., Cancer Res. 2009;69:2912). In this prospectively defined biomarker sub-study, the association between ERG subtypes and clinical outcome in chemo-naïve mCRPC pts receiving AA was evaluated. Methods: COU-AA-302 is a randomized double blind study of AA (1 g) + prednisone (P) (5 mg BID) vs placebo + P in chemo-naïve mCRPC. Fluorescence in situ hybridization (FISH) assays to evaluate ERG subtypes (Attard et al., Oncogene. 2008;27:253) were conducted on 524 archival prostate tissue samples (365 biopsies, 107 RPEs, 44 TURPs, 3 bone marrows, 5 lymph nodes) from 497 pts. Clinical outcome measures included radiographic progression-free survival (rPFS) (central [CEN] and investigator [INV] reviewed), time to PSA progression (TTPP), and PSA ≥ 50% decline. Cox regression was used to evaluate association with time to event endpoints and Cochran-Mantel-Haenszel for PSA response. Results: 337 of 497 pts with tumor samples had evaluable FISH results. An ERG rearrangement was present in 117 of 337 (35%) pts. 112 pts were class Edel, 50 were 2+Edel (interstitial deletion with duplication of fusion sequences) and 18 were ESplit. A trend for an association with greater improved rPFS (CEN) and TTPP in 2+ Edel pts treated with AA + P vs ERG non-rearranged was observed (22 months [m] vs 16 m [HR: 0.59, 95% CI: 0.30-1.16], p = 0.12, and 14 m vs 8 m [HR: 0.68; 95% CI: 0.41-1.15], p = 0.15, respectively). No differences in 2+ Edel vs ERG non-rearranged were observed in the P-alone arm. No association between any ERG sub-class and either rPFS [INV] or PSA ≥ 50% decline in either treatment arm was observed. Conclusions: This represents the largest study to date to molecularly characterize CRPC pts participating in a therapeutic phase 3 trial. These data suggest that chemo-naïve mCRPC pts with a 2+ Edel rearrangement may derive a slightly greater benefit from AA and P than other pts. Clinical trial information: NCT00887198.
Long-term safety and efficacy analysis of abiraterone acetate (AA) plus prednisone (P) in metastatic castration-resistant prostate cancer (mCRPC) without prior chemotherapy (COU-AA-302).
Authors: Rathkopf Dana E. , Smith Matthew R. , De Bono Johann Sebastian , Logothetis Christopher , Shore Neal , De Souza Paul L. , Fizazi Karim , Mulders Peter , Mainwaring Paul N. , Hainsworth John D , Beer Tomasz M. , North Scott A. , Fradet Yves , Griffin Thomas W. , Park Youn Choi , Kheoh Thian San , Small Eric Jay , Scher Howard I. , Molina Arturo , Ryan Charles J. 
Published: March 2020

5009 Background: AA, a CYP17 inhibitor, prolongs the lives of men with progressive pre- or post-chemotherapy treated mCRPC with a favorable safety profile (Rathkopf et al. ASCO-GU 2013. Abstr 5). This post hoc analysis examines the safety and tolerability of long-term treatment (≥ 24 mos) in study COU-AA-302. Methods: 1,088 pts were randomized 1:1 to AA 1000 mg + P 5 mg po BID vs placebo + P. Co-primary endpoints were radiographic progression-free survival (rPFS) and OS. Median times with 95% CI of the end points were estimated using the Kaplan-Meier (KM) method. Post hoc analysis of adverse events (AEs) was performed at pre-specified interim analysis (IA3) (55% OS events). Results: At a median follow-up = 27.1 mos (IA3): rPFS HR (95% CI) = 0.53 (0.45, 0.62), p < 0.0001 and OS was improved over P [0.79 (0.66, 0.96), p = 0.0151]; the latter did not reach the pre-specified efficacy boundary (p = 0.0035). All secondary endpoints favored the AA arm (Rathkopf et al. ASCO-GU 2013. Abstr 5). The incidence rate of selected AEs by duration of exposure is shown below (Table). There was no clinically relevant increase in the incidence rate of AEs with longer exposure using AA + P versus P alone; although pts on treatment for ≥ 24 mos may have had greater tolerability. The percentage of patients who came off study due to an AE was 8% (AA) versus 6% (P). Conclusions: The updated IA3 of COU-AA-302 in pts without prior chemotherapy confirms the delay in progression and prolongation of life with a favorable safety profile including pts treated for ≥ 24 mos with AA + P or P. Clinical trial information: NCT00887198. [Table: see text]
Relationship of baseline PSA and degree of PSA decline to radiographic progression-free survival (rPFS) in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC): Results from COU-AA-302.
Authors: Ryan Charles J. , Londhe Anil , Molina Arturo , Smith Matthew R. , De Bono Johann Sebastian , Mulders Peter , Rathkopf Dana E. , Saad Fred , Logothetis Christopher , Fizazi Karim , Scher Howard I. , Small Eric Jay , Matheny Shannon , Kheoh Thian San , Griffin Thomas W. 
Published: March 2020

5010 Background: Abiraterone acetate (AA), an androgen biosynthesis inhibitor, prolongs overall survival (OS) in mCRPC patients and is approved for use in this population. The relationship of PSA kinetics to rPFS was evaluated in an exploratory analysis of patients from COU-AA-302, a randomized phase III study of AA in chemotherapy-naive mCRPC patients. Methods: 1,088 patients were randomized 1:1 to AA (1 g) + prednisone (P) (5 mg BID) or P alone. rPFS and OS were co-primary endpoints. rPFS was defined as time to first occurrence of bone scan progression by PCWG2 criteria, progression by CT/MRI by modified RECIST 1.0 criteria, or death from any cause; PSA changes were not a factor in determining rPFS. Quartiles of baseline PSA and % PSA decrease from baseline to nadir were analyzed. Stratified Cox regression models were used with factors for treatment, PSA outcomes, and baseline covariates performed at 55% of OS events. Results: 54/546 patients (10%) in AA + P arm achieved undetectable PSA vs 14/542 patients (3%) in the P arm; at median follow-up of 27.1 mos, radiographic progression was observed in 28% (AA + P) vs 50% of patients (P). There was a consistent trend of decreasing hazard of progression with decreasing baseline PSA and increasing % PSA decline (Table). Treatment effect of AA + P vs P with decreasing baseline PSA or % PSA decline remained significant (p=0.001) after adjusting for other factors (PSA, LDH, alk phos, hemoglobin, bone metastasis) in the model. Conclusions: rPFS was positively associated with the magnitude of PSA decline and inversely associated with baseline PSA. These effects remained after correcting for covariates. In all analyses, treatment with AA led to rPFS outcomes superior to P. Clinical trial information: NCT00887198. [Table: see text]
A prognostic model for predicting overall survival (OS) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate (AA) after docetaxel.
Authors: Chi Kim N. , Kheoh Thian San , Ryan Charles J. , Molina Arturo , Bellmunt Joaquim , Vogelzang Nicholas J. , Rathkopf Dana E. , Fizazi Karim , Kantoff Philip W. , Li Jinhui , De Bono Johann Sebastian , Scher Howard I. 
Published: March 2020

5013 Background: COU-AA-301 was a multinational, randomized, controlled, phase III trial comparing AA + prednisone (P) (n = 797) versus placebo + P (n = 398) in mCRPC pts post-docetaxel. Using data from that trial, we developed a prognostic model for predicting OS in pts treated with AA post-chemotherapy, with a focus on readily assessable clinical parameters. Methods: The analyses used data from pts treated with AA in the COU-AA-301 trial for whom relevant baseline data were available (n = 729). Baseline variables were assessed for association with OS through a univariate Cox proportional hazards regression model. High/low values for accepted normal ranges were used for laboratory parameters. The Cox proportional hazards regression was used with a stepwise procedure to identify independent prognostic factors for OS. The model was subject to sensitivity analyses and the C-index was utilized as a measure of model accuracy. Results: The following risk factors were associated with a poor prognosis: ECOG performance status (only pts with scores of ≤ 2 were eligible for this trial) of 2 (HR = 2.19, p < 0.0001), presence of liver metastases (HR = 2.00, p < 0.0001), time from start of initial LHRH agonist therapy to start of AA treatment ≤ 36 months (HR = 1.30, p = 0.0078), low albumin (HR = 1.54, p < 0.0001), high ALP (HR = 1.38, p = 0.0016), and high LDH (HR = 2.31, p < 0.0001). Patients were categorized into 3 risk groups (good prognosis, n = 369; intermediate prognosis, n = 321; poor prognosis, n = 107) based on total number of risk factors and median OS calculated for each group (table). The C-index was 0.74 (95% CI: 0.68, 0.80). Conclusions: This prognostic model uses readily available clinical parameters to conveniently assess risk for mCRPC pts previously treated with docetaxel and initiating treatment with AA + P. If validated, the model will be useful in clinical practice and clinical trials. Clinical trial information: NCT00638690. [Table: see text]