bluuebunny/crossref_metadata_2025_split huggingface dataset:
How to predict sunitinib exposure and toxicity: A pharmacokinetic-pharmacodynamic study.
Authors: Cessot Anatole , Narjoz Celine , Thomas-Schoemann Audrey , Boudou-Rouquette Pascaline , Golmard Jean-Louis , Durand Jean-Philippe , Emile George , Tod Michel , Vidal Michel , Loriot Marie-Anne , Blanchet Benoit , Goldwasser Francois 
Published: March 2020

e15592 Background: Su (su), a tyrosine kinase VEGFR inhibitor, is subject to large inter-individual variability in drug exposure (AUC) and toxicity. We investigated the variability factors influencing AUC as well as the relationship between acute severe toxicity, AUC and genetic polymorphisms in adult cancer patients under su. Methods: The plasma concentrations of su and SU12662 (active metabolite) were assessed on day 7 and 21 of the first cycle. For variability investigation, su, SU 12662 and composite AUC (su+SU12662) were estimated from a population approach, then normalized to 50mg daily dose of su. Genetic polymorphisms for CYP3A4, CYP3A5, CYP1A2, NR1I2, NR1I3, P-gP and BCRP1 were analyzed. Clinical acute toxicity was graded using the NCI 4.0 scale on days 7 and 21. Baseline clinical and biologic characteristics including the lean body mass (LBM), absolute AUC and pharmacogenetic variants were tested univariately for association with toxicities. LBM was simply estimated from gender, height and weight. Candidate variables with p<0.1 were analyzed in a multivariate analysis. Results: Ninety-two pts were evaluable whose 66 for genetic analysis. Sixty-three percent of pts were male, 71% were PS 0-1, 60% had renal carcinoma. A large interindividual variability in normalized composite AUC was observed (CV=40%); LBM and ABCG2polymorphism (421C>A) were identified as major variability factors (p<0.0001 and p=0.014, respectively). Grade³2 hypertension, thrombocytopenia and hand-foot skin reaction were observed in 50, 11 and 10% respectively. Age (OR=1.47 [1.01-2.15], p=0.048) and su AUC (OR=1.16 [1.05-1.28], p=0.005) were independently associated with grade³3 toxicity within the first month, and SU12662 AUC with grade 3 thrombocytopenia (OR=1.27 [1.03-1.57], p=0.028). A formula was built from LBM to define the initial su dose to reach a target composite AUC of 1500ng/mL.h. Conclusions: Monitoring sunitinib and SU12662 exposure may be helpful to prevent severe toxicities. The estimation of LBM, based on gender and anthropometric characteristics, is useful to determine the initial daily dosing of sunitinib.
Efficacy and safety of sequential use of everolimus (EVE) in patients (pts) with metastatic renal cell carcinoma (mRCC) previously treated with bevacizumab (BEV) with or without interferon (INF) therapy: Overall survival (OS) result from the European AVATOR retrospective study.
Authors: Thiery-Vuillemin Antoine , Theodore Christine , Jacobasch Lutz , Schmitz Jorg , Guillot Aline , Papandreou Christos , Emmanouilides Christos E. , Kim Stefano Chong Hun , Ktiouet Meryem , Kelkouli Nadia , Nguyen Thierry 
Published: March 2020

e15607 Background: EVE (Afinitor) has demonstrated activity in the treatment of mRCC after failure of VEGF-targeted tyrosine kinase inhibitors. However, to this date, there is no published data evaluating its activity/safety after failure of first line BEV-based therapy. Methods: Our non-interventional multicenter international study reports retrospective data on EVE in routine use. Eligible patients had mRCC; were given EVE after 1 prior first-line systemic therapy with BEV +/- INF. The data were provided by each center and centralized. Results: Here are the final results: 20 sites included 43 pts between 2011 and 2012, with 42 evaluable patients. Baseline patient characteristics included median age of 69 [38-90] years old; 64.3% male; 97.5% with prior nephrectomy. First-line therapy was BEV + INF in 69% of patients, BEV only for 31%. Prognostic groups at the time of EVE initiation according to Heng (1) and to MSKCC (2) were respectively: (1): good 25%, intermediate 59.4% and poor prognosis 15.6% and (2) good 28.1%, intermediate 56.3% and poor 15.6%. Median duration of treatment with first line therapy was 7.5 months, and it was discontinuated for disease progression in 61.9 % of pts. From initiation of first line therapy 53.3 % of patients were alive at 32 months. Median OS was not reached for the second line; with 52.3% patients who had not progressed 8 months after the start of everolimus. Overall response rate was 9.5 % and disease stabilization rate was 50%. At least one adverse event (AE) occurred in 73.8 % of pts with 13 serious AEs. All grade common AEs were consistent with the toxicity profile of EVE with 31 % of stomatitis, 16.7 % of pneumonitis, 31 % of fatigue. Conclusions: This study provided encouraging results for the activity and safety profile of EVE in this second line mRCC setting after 1 prior first-line therapy with bevacizumab-based regimen. Further studies with larger numbers of pts are planned based on these novel findings.
Predictive value of ribonucleotide reductase regulatory subunit M1 (RRM1) and excision cross-complementing-1 (ERCC1) in advanced urothelial carcinoma (UC) treated with first-line gemcitabine (G) and platinum (P)-based chemotherapy (CT).
Authors: Kim Miso , Ku Ja Hyeon , Kwak Cheol , Lee Eunsik , Kim Hyeon Hoe , Keam Bhumsuk , Kim Tae Min , Lee Se-Hoon , Moon Kyung Chul 
Published: March 2020

e15614 Background: Preclinical and clinical studies suggested that RRM1 and ERCC1 expression are associated with resistance to G and P, respectively. However, data which correlated RRM1 and ERCC1 status with tumor response to G + P in advanced US is lacking. We evaluated the significance of RRM1 and ERCC1 to predict tumor response to G + P and survival in advanced UC. Methods: We retrospectively collected tumor samples and reviewed clinical data of 55 patients (pts) with unresectable or metastatic UC, who were treated with 1st line G + P from Jan. 2006 to Dec. 2011. RRM1 and ERCC1 expression were measured by immunohistochemistry and scored using a semiquantitative H-score based on staining intensity and proportion. Results: The study population was predominantly male (80%) and had a median age of 66 years (range: 28-88). The primary sites of UC were bladder (61%), renal pelvis (27.3%) and ureter (10.9%). The RRM1 and ERCC1 expression were positive in 21.8% (12/55) and 25.4% (14/55), respectively. Thirty (69.8%) among 43 pts with low RRM1 expression achieved clinical responses (complete responses + partial responses), but three (25%) among 12 pts with high RRM1 expression achieved clinical responses after G + P (P=0.008). Twenty-three (56.1%) among 41 pts with low ERCC1 expression achieved clinical responses, but ten (71.4%) among 14 pts with high ERCC1 expression achieved clinical responses after G + P (P=0.361). In multivariate analysis, high RRM1 expression independently predicted for poorer tumor response to G + P (OR=10.04, 95% CI=1.74~57.93, P=0.010). High RRM1 expression were associated with shorter progression free survival (PFS) (P=0.005). Multivariate analysis confirmed that pts with high RRM1 expression had a significantly greater risk of progression than those with low RRM1 expression (OR=3.66, 95% CI=1.60~8.36, P=0.002). ERCC1 status was not statistically significant in terms of PFS. Conclusions: In advanced UC, RRM1 expression was predictive of clinical responses from 1st-line G + P. Large prospective validation trials of the clinical value of RRM1 are warranted.
Retrospective analysis of risk factors for fatigue in clinical trial patients (pts) with metastatic renal cell carcinoma (mRCC).
Authors: Gore Martin Eric , Gruenwald Viktor , Motzer Robert John , Quinn David I. , Rini Brian I. , Lin Xun , Perkins Julia Jane , Simantov Ronit , Choueiri Toni K. 
Published: March 2020

e15624 Background: Fatigue is a common toxicity in pts with mRCC, often associated with therapy, particularly with tyrosine kinase inhibitors (TKI). We performed a pooled retrospective analysis of pts with mRCC treated in clinical studies in order to explore predictors for fatigue. Methods: Data from pts treated in Pfizer mRCC trials (2003-2011) from phase III (NCT00083899, NCT00065468, NCT00678392) and phase II trials (NCT00054886, NCT00077974, NCT00083889, NCT00338884, NCT00137423) were included. Adverse event (CTCAE v3.0) terms of “fatigue” and “asthenia” were used. Hypothyroidism was defined as TSH>ULN or T4<LLN. A multivariate logistic regression analysis was performed to identify significant risk factors for grade (G) 2 (moderate or causing difficulty performing some ADL) or higher fatigue. Results: 2749 pts (71% male) with a median age 60 (33% ≥65) were treated (median 162 days) with axitinib (n=359), sunitinib (n=1059), temsirolimus (TEM) (n=208), interferon-alfa (IFN) (n=560), sorafenib (n=335), or TEM + IFN (n=208). Most pts had baseline ECOG PS of 0 (47%) or 1 (51%), clear cell histology (91%), and nephrectomy (84%). 553 (20%) pts reported fatigue prior to starting study therapy. During study, fatigue was reported in 1794 (65%) pts (21% G1, 26% G2, 17% G3, 1% G4); in 61% pts worst grade was reported within the first 2 months of therapy. Fatigue led to discontinuation in 2%, and dose interruption or adjustment in 8%. Of 1773 pts treated with TKIs, 42% had ≥G2 fatigue. Of pts treated with TEM, IFN or both, 39%, 50% and 50%, respectively, had ≥G2 fatigue. Baseline factors [Odds Ratio] associated (p < 0.05) with ≥G2 fatigue were pretreatment fatigue [1.7] or hypothyroidism [1.6], age ≥65 [1.6], time from diagnosis ≥1 yr [1.4], female gender [1.3], ECOG PS 0 [0.7], and Asian vs Caucasian race [0.5]. Baseline LDH, calcium, and anemia were not significant. Conclusions: Pt attributes and comorbidities at baseline, independent of therapy, are associated with increased risk of clinically significant fatigue in pts treated for mRCC, and can be used to generate a predictive model. Appropriate counseling and control of co-morbid conditions may be important in managing fatigue in pts on TKI therapy.
PSA screening rates in older men in the United States based on nine-year estimated remaining life expectancy.
Authors: Drazer Michael , Prasad Sandip M. , Huo Dezheng , Schonberg Mara A , Szmulewitz Russell Zelig , Dale William , Eggener Scott E. 
Published: March 2020

e16006 Background: PSA screening for prostate cancer (PCa) is controversial, but informed decision making is recommended for men with an estimated 10 years of remaining life expectancy (RLE). The association between screening of men 65+ and estimated 9-year life expectancy is unknown. Our purpose was to determine the association between predicted 9-year life expectancy and PCa screening in 2005 and 2010. Methods: Data were extracted from the 2005 and 2010 National Health Interview Survey. Men 65+ without prostate known PCa were divided into quartiles with a validated index estimating 9-year RLE (<27%, 27-52%, 53-75%, and >75%). The proportions of men screened in 2005 and 2010 were determined. Logistic regression was used to compare screening in 2005 and 2010. Results: Screening rates for men 65+ were 48.3% (95% CI, 45.6-50.9%) in 2005 and 48.5% (95% CI, 45.5-51.6%) in 2010 (p = 0.9). There were no differences in screening between cohorts by age and predicted mortality for 65-74 (all p > 0.05 for <27%, 27-52%, 53-75%, and >76% predicted mortality) and 75+ year olds (all p> 0.05). The most screened group were 65-74 year olds with a <27% chance of 9-year mortality, with 58.3% (95% CI, 53.6–63.1) and 56.1% (95% CI, 50.6-61.5) screened in 2005 and 2010. Conclusions: PSA-based PCa screening did not differ between 2005 and 2010 for men 65+. Over 35% and 33% of older men with limited estimated 9-year RLE were screened in 2005 and 2010 despite minimal clinical benefit. [Table: see text]
The role of FSH in castration-induced adipogenesis: Highlighting differences between orchiectomy, GNRH agonists, and antagonists.
Authors: Pinthus Jehonathan H , Hopmans Sarah , Duivenvoorden Wilhelmina , Kapoor Anil 
Published: March 2020

e16011 Background: Androgen deprivation therapy (ADT) results in weight gain and development of the metabolic syndrome. Inspired by the observation that adiposity accompanies the incremental increase in serum FSH levels in menopause, we hypothesized that GNRH antagonist which lower FSH levels will associate with reduced adiposity as compared to GNRH analogues and orchiectomy. Methods: 3T3-L1 fibroblasts differentiation into adipocytes and intracellular lipid accumulation were examined in the presence of escalating FSH doses (0-1000 IU/L) in charcoal stripped FCS supplemented medium to simulate castration. Cellular lipogenesis was assessed by image analysis (oil red staining) and by immunoblotting for fatty acid synthase (FAS) expression. In vivo, 6-week old C57Bl/6 male mice (n=30) were divided to receive either: orchiectomy + vehicle, sham procedure + vehicle, orchiectomy + GNRH antagonist (degarelix 50 mg/kg in vehicle), sham + degarelix, orchiectomy + GNRH analogue (enantone 2 mg/kg in vehicle), or sham + enantone. Serum testosterone, LH and FSH levels and differences in animal weight, visceral fat mass (VFm) and liver lipogenesis (oil red staining) were determined following sacrifice at 6 weeks. BMI was measured as weight (gr) divided by the distance between the tail root and the lower incisors (cm2). Results: The mean lowest and highest serum FSH levels were recorded in mice treated with Degarelix vs. orchiectomy (0.43 and 0.935 mIU/mL resp,) and the mean lowest and highest serum testosterone levels were in mice treated with orchiectomy+degarelix vs. sham control (0.12 and 13.1 ng/ml resp). Mice treated with degarelix had a significantly lower BMI compared to enantone (p=0.02). VFm (perirenal fat weight) was significantly lower (p=0.035) in mice castrated by degarelix (mean 0.38gr) as compared to enantone(mean 0.47gr)). Addition of degarelix or enanton to orchiectomy increased the differences in VFm and BMI between the two groups (0.12gr vs. 0.47gr and 3.73 vs. 4.29 gr/cm2 resp.) In vitro, FSH increased lipid accumulation and FAS expression in 3T3-L1 cells. Conclusions: FSH level elevation following castration promotes fat accumulation and weight gain in preclinical models.
5-alpha reductase inhibitors and risk of male breast cancer.
Authors: Etminan Mahyar , Brophy James , Hartzema Abraham , Delaney Joseph , Bird Steven 
Published: March 2020

e16013 Background: 5-alpha reductase inhibitors (5ARIs), finasteride and dutasteride, are one of the most popular classes of medications used by older men. The drugs are mainly used for the treatment of benign prostatic hyperplasia (BPH). There have been 50 cases of breast cancer potentially linked to both finasteride and dutasteride reported to the FDA. However, to date, no epidemiologic study has examined this potential link. Methods: We used the LifeLink database (IMS, USA) as the main source of data for this study. The database captures information on approximately 70 million US residents who are enrolled in a private healthcare plan. The database captures information on prescription drugs, hospitalizations, physician visits and demographics. Breast cancer cases were defined as those with a diagnosis (ICD-9-CM 175.X) on two days and either a procedural code (CPT-4) for a mastectomy or a lumpectomy/partial mastectomy with evidence of follow-up treatment (radiation/chemotherapy). The index date was deemed the first diagnostic or procedural code for breast cancer. This definition has been found to have a 93% positive predictive value for incident breast cancer. For each case, twenty controls were selected from the database using risk set sampling and matched on age within 5 years, date of diagnosis within six weeks and follow up time prior to the index date. We used logistic regression to compute adjusted rate ratios. The model was adjusted for the following covariates: age, calendar year, alcoholism, gynecomastia, Klinefelter’s disease, liver damage, obesity, oral estrogen, orchiectomy, and prior radiation. Results: There were 429 male breast cancer cases and matched them to 13,240 controls. 341 (79.5%) met our primary ascertainment, while 88 (20.5%) additional cases met our secondary criteria. We found no increased risk with male breast cancer and use of 1 year (RR=0.70, [95% CI0.34-1.45]) or 3 years of 5-ARIs therapy (RR=0.71, [95% CI:0.25-1.98]). Conclusions: We found no harmful association between sue of 5-ARIs and risk of male breast cancer. Future studies are needed to refute or confirm these findings.
Phase II study of weekly cabazitaxel for "unfit" metastatic castration resistant prostate cancer patients progressing after docetaxel treatment: Preliminary toxicity analysis—SOGUG-CABASEM trial.
Authors: Climent Duran Miguel Angel , Perez-Valderrama Begoña , Domenech Montserrat , Mellado Begoña , Fernandez Calvo Ovidio , Anido Urbano , Polo Susana Hernando , Arranz Arija Jose Angel , Fernandez Parra Eva , Caballero Cristina , Germa-Lluch Jose R. , Castellano Daniel E. ,   Spanish Oncology Genitourinary Group
Published: March 2020

e16014 Background: Docetaxel (D) is standard first-line chemotherapy in patients (pts) with metastatic castration-resistant prostate cancer (CRPC). Cabazitaxel (C), a novel taxane developed to overcome D resistance, showed an overall survival improvement in second line CRPC in a three-weekly dose schedule. Its main toxicity is hematological with a risk of febrile neutropenia, especially in unfit patients. We aimed to evaluate efficacy and safety of weekly C/prednisone in "unfit" metastatic CRPC previously treated with D. Methods: Unfit pts (ECOG 2, dose reduction due to febrile neutropenia during treatment with D or radiation therapy affecting more than 25% of bone marrow reserve) with advanced CRPC progressing after D treatment with ECOG <=2 and adequate bone marrow, liver and kidney functions were included. C 10 mg/m2 was administered on days 1, 8, 15 and 22 of 5-week cycles with daily prednisone 5 mg b.i.d. Radiological and PSA response was evaluated according to the PCCTWG II criteria and toxicity according NCI-CTC AE. Results: To date 28 pts have been enrolled and data are available for 21. Median age was 74 y (range 60-83), 13 (62%) pts had ECOG 2, 16 (76%) had bone metastases. Sixty-one cycles were administered (median: 3; range: 1-6) and 225 weekly administrations (median 10; range 1-24). Mean dose intensity was 94%. Most frequent related adverse events (AEs) of all grades as % of cycles were: asthenia (40%), anemia (34%), leukopenia (11%), thrombocytopenia (13%), diarrhea (10%), rash (8%), nauseas (8%), dysgeusia (8%), xerostomia (8%), anorexia (7%), mucositis (5%) and neuropathy (3%). Grade 3-4 AEs as % of cycles were: thrombocytopenia (8%), asthenia (7%), mucositis (2%), nausea (2%) and vomiting (2%). One patient discontinued the study due to asthenia G3. No grade III/IV diarrhea, neutropenia or febrile neutropenia were observed. Conclusions: Administration of weekly C (10 mg/m2) to unfit pts seems to be safe with no grade ≥3 neutropenia, diarrhea and febrile neutropenia reported. If confirmed in a larger scale, weekly C may represent an attractive option for unfit pts with mCRPC progressing after D treatment. Clinical trial information: NCT01518283.
Activity of cabazitaxel following docetaxel and abiraterone acetate in patients with castration-resistant prostate cancer.
Authors: Sella Avishay , Sella Tal , Peer Avivit , Berger Raanan , Frank Stephen Jay , Gez Eliahu , Sharid David , Hayat Henry , Rosenbaum Eli , Neiman Victoria , Keizman Daniel , Kovel Svetlana 
Published: March 2020

e16023 Background: Cabazitaxel (CAB) and Abiraterone-acetate (AA) have been approved after Docetaxel in castration resistant prostate cancer (CRPC). Both exhibit hormonal effects. AA depletes androgen in microenvironment; taxanes affect the microtubule-dependent trafficking of the androgen receptor. Recently, clinical cross-resistance has been suggested between AA and taxanes. This prompted evaluation of CAB following Docetaxel and AA in CRPC. Methods: Over 13 months until December 2011, 130 CRPC patients received AA after Docetaxel in compassionate programs. Of them, 24 (18.4%) subsequently received CAB. We retrospectively reviewed their data (PCWG2/RECIST and NCI toxicity criteria). Results: Fourteen (58.3%) received CAB/prednisone at 20 mg/m 2 and 10 patients 25 mg/m2 , overall a median of 4 (1-13) cycles. Nineteen (79.1%) received primary G-CSF support. Patient characteristics (median, range in parenthesis): Age 65 (57-85) years, Gleason- 8 (6-10), K.S- 80 (50-90) %. Metastatic sites: liver- 5 (20.8%), visceral- 8 (33.3%), osseous- 22 (91.6%), No. sites involved- 2 (1-4). Lab-work: PSA- 128.1 (0.01-1700) ng/ml, PSA Doubling time- 2.16 (0.64-7.41) months, alkaline phosphatase 129 (35-1200) u/L. Castration sensitive period - 16.2 (2.0-92.1) months. Using Cox univariate analysis, only K.S was near-significant for prediction of survival after initiating CAB, p=0.075, OR=0.315, 95% C.I (0.88-1.125). A PSA response of 30%, 95% C.I (11,8-54,2)% was observed after CAB with non progression occurring in 6 (26%) out of 23 evaluable patients, 95% CI (10.2-48.4)%. At analysis 11 patients are alive. Median survival from initiation of CAB was 8.2 (95% C.I 3.34-13.05) months, from AA 16.1 (95 C.I 11.56-20.64) and from Docetaxel 32.0 (95% C.I 11.56-39.69). Non-progression with Docetaxel (but not AA) was associated with longer survival with CAB, p=0.049, 43.1 v.s 17.4 months. Four (16.6%) patients developed infectious complications, including one death due to septic shock. Conclusions: Limited number of patients with CRPC received CAB following Docetaxel and AA. In this selected population CAB was active. Response to prior Docetaxel was associated with prolonged survival to CAB therapy.
Prognostic value of free testosterone (FT) levels during salvage chemotherapy with carboplatin plus weekly docetaxel in metastatic castration- and docetaxel-resistant prostate cancer (mDRPC).
Authors: Reuter Christoph W. , Morgan Michael A. , Fenner Martin , Grünwald Viktor , Ganser Arnold 
Published: March 2020

e16024 Background: Recent data suggest that carboplatin plus weekly docetaxel (DC) may be effective in mDRPC. Carboplatin, docetaxel and steroids interfere with testosterone biosynthesis and/or metabolism. In this study the impact of DC treatment on testosterone blood levels was analyzed. Methods: Docetaxel failure/resistance was defined as disease progression during docetaxel treatment according to the Prostate Cancer Working Group (PCWG2 2007) criteria. Since February 2005, 74 consecutive DRPC patients (pts.) were treated with at least 2 cycles of carboplatin AUC5 iv for 30 min on day 1 plus docetaxel at a dose of 35 mg/m2 iv for one hour on days 1, 8, (15) every 4 weeks and prednisone 2x5mg/day orally after receiving informed consent until disease progression or occurrence of intolerable adverse effects. Efficacy measures were done following PCWG2 recommendations. FT levels were measured before (n=51) and during DC chemotherapy (n=41). Results: Response of prostate-specific antigen (PSAR; ≥50% PSA) was observed in 36/74 (48.6%) pts. At the current analysis the median follow-up time was 16.6 months and 56/74 pts. had died. Median progression-free survival (PFS) was 6.9 months (CI 95% 5.9, 7.9) and median overall survival (OS) was 18.6 months (CI 95% 12.4, 24.7). Median nadir FT levels were 2.8 pmol/L before and below the RIA detection limit of 0.6 pmol/L during DC treatment (p=0.008). While only 4/51 pts. had FT levels <0.6 pmol/L before DC treatment (all under abiraterone therapy), 28/41 pts. had nadir FT values <0.6 pmol/L during DC chemotherapy (p<0.0001). Median FT levels <0.9 pmol/L during DC treatment were associated with a higher PSA response rate (hazard ratio HR 0.19; CI 0.05, 0.78, p=0.021) and a higher OS (HR 0.34; CI 0.15, 0.81, p=0.015). FT remained statistically prognostic in multivariable analyses. The DC regimen was reasonably well tolerated, with leukopenia/ neutropenia as the most common reversible grade 3/4 toxicity (41.9/37.8%). Conclusions: These data demonstrate for the first time that FT is an important prognostic factor for PSAR and OS in mDRPC pts. during chemotherapy.