bluuebunny/crossref_metadata_2025 huggingface dataset:
Importance of performance status, corrected calcium, and microvascular invasion in predicting overall survival in patients with metastatic renal cell carcinoma at the era of molecular targeted therapy.
Authors: Eto Masatoshi , Kamba Tomomi , Miyake Hideaki , Fujisawa Masato , Kamai Takao , Uemura Hirotsugu , Tsukamoto Taiji , Azuma Haruhito , Matsubara Akio , Nishimura Kazuo , Nakamura Tsuyoshi , Ogawa Osamu , Naito Seiji ,   Japan Immunotherapy SNPs-Study Group for Kidney Cancer
Published: March 2020

e15588

Background: We have recently reported that the single nucleotide polymorphisms (SNPs) in signal transducer and activator 3 (STAT3) gene are significantly associated with better response to interferon (IFN)-α in patients with metastatic renal cell carcinoma (mRCC) in our prospective trail (Eur Urol 2012, Epub ahead). In the present study, we further evaluated which clinical and pathological factors correlated with overall survival (OS) in the trial. Methods: In the multicenter, prospective study, patients with histologically confirmed RCC that was metastatic, measurable disease, age > 20 years, ECOG performance status (PS) 0-1 and adequate organ function received 3 dosages of 5 million U per week of IFN-α treatment. After the failure of IFN-α, molecular targeted drugs were used. We followed the patients for 2 years to define the date of death or loss to follow-up to calculate OS. Association between OS and clinical, pathological factors, such as age, PS, TNM classification, grade, infiltrating type, sarcomatoid component, microvascular invasion, lactate dehydrogenase (LDH), corrected Calcium (Ca), hemoglobin (Hb), C-reactive protein (CRP), platelet (Plt), etc, was analyzed using the Log-rank test. For multivariate analysis, the Stepwise test was used. Results: Two hundreds three eligible pts were enrolled between December 2006 and October 2009. All pts had prior nephrectomy, and 88.7% had ECOG PS 0. Ninety-four percent of patients had clear cell RCC, and 5% had papillary RCC. The response rate of IFN-α was 13.8% (28/203, 9 CR, 19 PR). Median OS was 42.8 months in mRCC patients initially treated with IFN-α. In univariate analysis, PS, TNM classification, grade, infiltrating type, microvascular invasion, corrected Ca, Hb, CRP, and Plt were significantly associated with OS. Among them, PS, microvascular invasion, and corrected Ca were significantly correlated with OS in multivariate analysis. Conclusions: This prospective study demonstrates that PS, corrected Ca, and microvascular invasion are important in predicting OS in mRCC patients initially treated with IFN-α at the era of molecular targeted therapy. Clinical trial information: UMIN000000731.
Proof of concept of correlation between progression-free survival (PFS) and overall survival (OS) in treatment-naive patients with advanced renal-cell carcinoma (mRCC): Final results of a randomized phase II study comparing sorafenib plus interleukin-2 (IL-2) versus sorafenib alone: The ROSORC trial.
Authors: Verzoni Elena , Bracarda Sergio , Ricci Sergio , Sacco Cosimo , Ridolfi Laura , Porta Camillo , Miceli Rosalba , Zilembo Nicoletta , Bajetta Emilio , Procopio Giuseppe ,   Italian Trials in Medical Oncology (ITMO)
Published: March 2020

e15589

Background: The outcome analyses of the randomized phase 2 ROSORC trial, did not show any difference in terms of PFS between mRCC patients undergoing first-line treatment with sorafenib plus IL-2 versus sorafenib monotherapy (7.3 versus 6.9 months in favour of the combination arm; p= 0.109). (Procopio et al BJC 2011). Overall survival analyses are here reported. Methods: In this open-label phase 2 prospective study, 128 treatment-naïve patients with mRCC were randomized to receive either sorafenib 400 mg twice daily plus subcutaneous IL-2 4.5 MIU five times a week for 6 weeks every eight weeks (Arm A), or sorafenib alone (Arm B). The primary endpoint was PFS, while the secondary endpoint was OS. Survival analyses were evaluated by Kaplan-Meier plots and compared by two-sided log-rank test. Results: After a median follow up of 58 months (interquartile range 28-63), the median OS was 38 and 33 months in arm A and B respectively (p= 0.667). The 5-year OS was 26.3 % (95% CI: 15.9-43.5) and 23.1% (95 % CI: 13.2-40.5) in the combination and single agent arm, respectively. Overall we observed 85 deaths and among them, 42 occurred in the Arm B. Overall, 49 (74 %) and 48 (77 %) patients in the Arm A and B, respectively, received at least one targeted therapy (TT) after disease progression, including sunitinib, everolimus, axitinib or temsirolimus. Most common adverse events (AEs) included fatigue, hand-foot syndrome, hypertension and diarrhea and were mild in grade (Grade 1-2). Grade 3-4 AEs were documented in 38 % and 25 % of patients receiving combination and single agent treatment, respectively. Conclusions: While the PFS observed was in keeping with previous literature data regarding sorafenib, either as a single agent or in combination, the OS dramatically improved results reported so far in prospective randomized trials. This outcome suggests lack of correlation between PFS and OS and a synergistic effect of sequential TTs following sorafenib failure. Clinical trial information: NCT00609401.
Antineoplastic effects of specific inhibition of Notch-2 in bladder cancer.
Authors: Hayashi Tetsutaro , Gust Kilian , Jaeger Wolfgang , Awrey Shannon , Li Na , Altamirano-Dimas Manuel , Buttyan Ralph , Li Estelle , Fazli Ladan , Black Peter C.
Published: March 2020

e15590

Background: Notch signaling guides cell fate decisions, establishment of cell lineages, stem cell maintenance and differentiation during early development. Notch is re-activated in many malignancies where it has been shown to regulate tumor growth and progression. We report effects of Notch-2 knockdown and treatment with a specific Notch-2 inhibitor, NRR2Mab, in pre-clinical models of bladder cancer. Methods: UM-UC3, UM-UC13 and UM-UC16 cells, representing invasive bladder cancer cells with high Notch-2 expression, were stably transduced with Notch-2 or non-targeting shRNA in a lentiviral vector. A Notch-2-inactivating monoclonal antibody, NRR2Mab, and an isotype-matched, non-targeting antibody were provided by Genentech, Inc. (San Francisco, CA). Cells were grown under adherent (AH) or anchorage-independent conditions (AI) and the effects of Notch-2 silencing or NRR2Mab inactivation were quantitatively assessed for changes in proliferation, migration and invasive activities using in vitro assays, and for expression of Notch-2 or other common stem cell-related genes using quantitative RT-PCR, Western blotting and immunohistochemistry. In vivo effects were evaluated in an orthotopic bladder cancer xenograft model with bioluminescence imaging. Results: Cells transduced with the Notch-2 shRNA or treated with NRR2Mab demonstrated markedly decreased Notch-2 expression. Both treatments diminished cell proliferation under AI but not AH conditions in UM-UC3 and UM-UC13. When grown in AI conditions, UM-UC3 and UM-UC13 were found to be enriched for expression of stem cell genes. Notch-2 silencing or treatment with NRR2Mab diminished the expression of these genes. Both treatments significantly inhibited cell migration and invasion of these cells. In vivo, stable Notch-2 knockdown significantly inhibited xenograft growth for all 3 cell lines. NRR2Mab treatment also inhibited UM-UC13 xenograft growth and metastasis. Conclusions: Our results provide preclinical evidence that Notch-2 may be a useful target to inhibit growth and progression of bladder cancer. Targeting Notch-2 with a specific inhibitory monoclonal antibody warrants further evaluation in this context.
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.
Association of Gleason 9-10 prostate cancer with worse outcomes compared to Gleason 8 disease.
Authors: Tsao Che-Kai , Gray Kathryn P. , Nakabayashi Mari , Evan Caroline , Galsky Matt D. , Kantoff Philip W. , Oh William K. , Pomerantz Mark
Published: March 2020

e16032

Background: Use of pathological Gleason score for risk stratification of localized prostate cancer is widely accepted. However, data are lacking regarding differences in presentation and outcome among those with Gleason 8-10 disease. Methods: Using the Dana-Farber Cancer Institute Prostate Clinical Research Information Systems database, we identified a cohort of patients with biopsy Gleason 8-10 disease who received definitive radical prostatectomy (RP) or radiation therapy (RT) (external beam or brachytherapy) for curative intent. The study endpoints, time to biochemical recurrence (BCR), time to metastatic disease (MD), and overall survival (OS) were estimated using the Kaplan-Meier method. Cox proportional hazards model was used to investigate the association of the study endpoints and Gleason score groups (8 vs. 9 and 10) adjusted for clinical and pathological factors including age, PSA at diagnosis, type of local therapy, and tumor stage. Results: We identified 848 patients who received either local definitive RT (n=411) or RP (n=437). Median follow-up from diagnosis was 5.3 years. Patient characteristics at diagnosis (race, age, and clinical stage) were similar between the two groups (Gleason 8 vs. Gleason 9-10). Patients with Gleason 9-10 disease were more likely to receive radiotherapy as primary local therapy (58% vs. 46%, p=0.001), and to receive hormonal therapy as a part of their definitive treatment course (64% vs. 48%, p<0.001). Patients with Gleason 9-10 disease had shorter time to BCR, time to MD, and a trend towards worse OS using multivariate analysis adjusted for significant clinical and pathological factors (detailed in the Table below). Conclusions: In our study, we found that patients with localized Gleason 9-10 disease who were treated with definitive therapy with curative intent had worse outcomes compared to patients with Gleason 8 disease. More aggressive, multimodality treatments may be indicated for men diagnosed with the highest Gleason grades. [Table: see text]
Incidence of skeletal-related events (SREs) among prostate cancer patients.
Authors: Ulcickas Yood Marianne , Zyczynski Teresa Maria , Wells Karen , Casso Deborah , Gutierrez Benjamin , Woodcroft Kimberley J. , Cheng Shinta
Published: March 2020

e16035

Background: Skeletal related events (SREs) occur in men with prostate cancer and may result from both bone metastases and exposure to androgen deprivation therapy (ADT). The objective of this study was to quantify the incidence of SREs in patients with prostate cancer treated with ADT or orchiectomy in clinical practice. Methods: Prostate cancer patients served by Henry Ford Health System (HFHS) were identified via the HFHS tumor registry. Eligible patients were newly diagnosed with prostate cancer between 2004 and 2010 and treated with ADT or orchiectomy. Comprehensive population-based data were compiled using tumor registry with linkages to pharmacy, laboratory results, and healthcare encounter databases. SREs included spinal cord compression, surgery to bone, pathologic fracture and radiation to bone. Disease progression and metastases were identified by medical record review. Results: We identified 702 patients with prostate cancer and receipt of ADT or orchiectomy; 57.6% were >70 years of age and 43.7% were African American. 56.3% of patients were initially diagnosed at AJCC stage II, 9.8% at stage III, 22.1% at stage IV, and 11.8% had missing or unknown stage. A total of 93 patients (13.2%) had one or more SREs: radiation to bone (8.5%) and spinal cord compression (3.1%) were the most common SREs. We then limited the cohort to patients initially diagnosed with or progressing to AJCC stage IV prostate cancer (N=207). Among this group, 47.8% were >70 years of age. The mean time from stage IV diagnosis to end of follow-up was 35.6 months. In this subgroup, 16.4% of patients were initially diagnosed at AJCC stage II, 8.2% at stage III, 69.6% at stage IV, and 5.8% had missing or unknown stage. 57 patients (27.5%) had one or more SREs. Conclusions: Some clinical trials have found 36-41% of high-risk metastatic prostate cancer patients developed SREs during 3 years of follow-up. In this population-based cohort of patients with prostate cancer receiving ADT or orchiectomy and treated in real-world clinical practice, we found the incidence of SREs to be lower than what has been reported in clinical trials. Additional analyses exploring the incidence of SREs in patients diagnosed with metastatic castrate resistant prostate cancer will be presented.
Safety profile of recombinant poxviral TRICOM vaccines.
Authors: Kim Joseph W. , Marte Jennifer L. , Singh Nishith K. , Heery Christopher Ryan , Madan Ravi Amrit , Pazdur Mary , McMahon Sheri , Rauckhorst Myrna , Schlom Jeffrey , Kantoff Philip W. , Gulley James L.
Published: March 2020

e16036

Background: Recombinant (rec) poxviruses have been developed as therapeutic cancer vaccines. A multi-institutional, randomized phase II trial of poxviral vaccine, PROSTVAC-V/F, suggested an improvement in median overall survival in men with metastatic castration resistant prostate cancer. A phase III trial in this same population is accruing. Accumulating data suggest a favorable safety profile of the poxviral vaccines (vacs). Methods: We reviewed all vaccine injections (inj) from 297 patients (pts) in 9 clinical trials involving poxviral vaccines. Vacs consisted of rec vaccinia and rec fowlpox encoded with 3 human costimulatory molecules (TRICOM), and a) prostate specific antigen, or b) carcinoembryonic antigen +/-mucin-1. Vacs were administered at doses between 1.2x108 to 2x109 pfu, subcutaneously, in all pts. 21 pts were also vaccinated intra-tumorally. 84 pts received concurrent treatments, such as radiation, celecoxib, ipilimumab, samarium-153, or flutamide in 4 of these trials. All 9 trials involved granulocyte-macrophage colony-stimulating factor (GM-CSF), or rec fowlpox encoding GM-CSF as an immune adjuvant. We report the grade >=2 adverse events (AEs) at least possibly attributed to vaccine. Results: A total of 1,793 poxviral inj were given. 33% (593) of all inj were associated with grade >=2 vaccination emergent AEs. Of those, 25.3 % (454) were local inj site reactions; none serious. There was no contact transmission or inadvertent inoculation. One patient experienced grade 4 myocardial infarction and thrombotic thrombocytopenic purpura (TTP) reported as possibly related to vaccine. Below is the summary of AEs. Conclusions: Recombinant poxviral TRICOM vaccines appear safe and well tolerated at a broad range of doses, routes of administration and in combination with other treatments. Clinical trial information: NCT00081848, NCT00088413, NCT00060528, NCT00060528, NCT00078585, NCT00096551, NCT00113984. [Table: see text]
Determinants of the combined use of external beam radiation therapy and brachytherapy for low-risk localized prostate cancer.
Authors: Quek Ruben G. W. , Master Viraj A. , Ward Kevin C. , Lin Chun Chieh , Virgo Katherine S. , Portier Kenneth M. , Lipscomb Joseph
Published: March 2020

e16039

Background: Prostate cancer treatment patterns have been shown to vary by physician and patient characteristics. For low-risk localized prostate cancer patients, we examined the association between their region of residence and their radiation oncologists’ practice affiliations with medical schools on the likelihood they would receive both external beam radiation therapy (EBRT) and brachytherapy (BT) – a treatment regimen that is at variance with clinical guidelines and has not been shown to improve survival or other patient centered outcomes. Methods: Using the Surveillance, Epidemiology and End Results – Medicare linked database and the American Medical Association Physician Masterfile, we conducted a retrospective cohort study of 4,479 patients aged 66 years or older who were diagnosed between 2004-2007 with low-risk localized prostate cancer, and the 401 radiation oncologists who saw them. Multilevel regression analyses were used to evaluate the influence of patients’ region of residence and radiation oncologists’ practice affiliations with medical schools on the combined use of EBRT and BT on patients within 6 months of diagnosis. Results: Overall, 231 (5.2%) patients received combined EBRT and BT. After adjusting for patient, tumor and radiation oncologist characteristics, patients who saw radiation oncologists with no practice affiliation with medical schools were significantly more likely to receive combined EBRT and BT (odds ratio [OR], 3.14; 95% confidence interval [95% CI], 1.50-6.59, p = 0.003). Regional variations were also observed; the odds of receiving combined therapy for patients residing in California (OR, 0.1; 95% CI, 0.03-0.33, p<0.0001) were significantly less than those in Georgia (OR, 1.0; referent). Conclusions: Low-risk localized prostate cancer patients residing in Georgia were significantly more likely to receive combined EBRT and BT when compared to those in other SEER Regions. Radiation oncologists without practice affiliations with medical schools were significantly more likely to treat patients with combined therapy; such treatment patterns are not consistent with clinical guidelines and unlikely to have significant survival benefit.
Impact of a genomic classifier of metastatic risk on treatment recommendations post-radical prostatectomy: Report from the DECIDE study group.
Authors: Badani Ketan K. , Thompson Darby J. S. , Buerki Christine , Davicioni Elai , Garrison Jill , Ghadessi Mercedeh , Mitra Anirban Pradip , Wood Penelope J. , Hornberger John C.
Published: March 2020

e16044

Background: Only a minority of prostate cancer patients with adverse pathology and biochemical recurrence (BCR) post radical prostatectomy (RP) experience metastasis and die from prostate cancer. Improved risk prediction models using genomic information may enable clinicians to better weigh the risk of metastasis and the morbidity and costs of treatment in a clinically heterogeneous population. We present a clinical utility study that evaluates the influence on urologist treatment recommendations for patients at risk of metastasis using a genomic-based prediction model (Decipher). Methods: A prospective, pre-post design was used to assess urologist treatment recommendations following RP in both the adjuvant (without any evidence of PSA rise) and salvage (BCR) settings. Urologists were presented de-identified pathology reports and genomic classifier (GC) test results for 24 patients from a previously conducted GC validation study in high-risk post RP men. Participants were fellowship trained, high-volume urologic oncologists (n=21) from 18 US institutions. Treatment recommendations for secondary therapy were made based solely on clinical information (pre-GC) and then with genomic biomarker information (post-GC). This study was approved by an independent IRB. Results: Treatment recommendations changed from pre-GC to post- GC in 43% of adjuvant, and in 53% of salvage setting case evaluations. In the adjuvant setting, urologists changed their treatment recommendations from treatment (i.e. radiation and/or hormones) to close observation post-GC in 27% of cases. However, for cases with low GC risk (<3% risk of metastasis), 79% of these men were recommended for observation post-GC. Consistent trends were observed in the salvage setting including 24% patients with low GC risk recommended for observation even after BCR. Conclusions: These results indicate that urologists across a range of practice settings are likely to change many treatment decisions when presented with genomic biomarker information following RP. Implementation of the GC test into routine clinical practice may better direct treatment decision-making post-RP.
Correlation of PSMA ADC exposure with reduction in tumor growth rate determined using serial PSA measurements from a phase I clinical trial.
Authors: Rotshteyn Yakov , Mercier Francois , Bruno Rene , Stambler Nancy , Israel Robert Joseph , Wong Vivien
Published: March 2020

e16047

Background: PSMA ADC is a fully humanized antibody to PSMA conjugated to the potent microtubule disrupting agent monomethyl auristatin E (MMAE). The safety and PK of PSMA ADC as well as changes in PSA levels were evaluated in a phase I dose escalation study in patients with taxane-refractory metastatic castration-resistant prostate cancer (mCRPC) (PSMA ADC 1301). Stein et al. (2010) has previously demonstrated correlation between growth rate derived from serial PSA measurements with survival in patients with mCRPC and suggested that growth rate could serve as a novel endpoint indicative of response to therapy and overall survival. Methods: The PK parameters for PSMA ADC, Total antibody (Ab) and free MMAE obtained from PSMA ADC Study 1301 (N=52) were calculated using non-compartmental analysis. The final data set contains 253 longitudinal PSA observations from 52 subjects dosed with 0.4-2.8 mg/kg PSMA ADC. The Stein model was re-expressed as a 7-parameter population model to describe the longitudinal PSA data which includes: Baseline PSA level (Y0), PSA decrease rate (D), PSA increase rate (G), inter-patient variability for Y0, G and D respectively, and residual variance. Model parameters were estimated using Phoenix/NLME. Exposure-efficacy relationships and correlation between G and covariates were determined. Results: PSMA ADC, Total Ab, and MMAE exposure increased linearly with increasing PSMA ADC dose. Longitudinal PSA data were correctly fitted to the re-expressed Stein model. G continuously decreased with increasing PSMA ADC exposure, suggesting an exposure dependent drug effect. There was no apparent saturation of this effect at the maximum observed exposure, and no influence of age, baseline albumin and ALT/AST levels on G was evident. Conclusions: In a phase I study where PSMA ADC (0.4-2.8 mg/kg) was administered to patients with mCRPC, we observed a correlation of PSMA ADC exposure with the reduction of G, suggesting that PSMA ADC may provide dose-dependent therapeutic benefit to subjects with mCRPC.
A new parameter of bone scintigraphy: Relation between bone scan index and bone metabolic markers in prostate cancer patients with bone metastases.
Authors: Wakabayashi Hiroshi , Nakajima Kenichi , Mizokami Atsushi , Namiki Mikio , Inaki Anri , Taki Junichi , Kinuya Seigo
Published: March 2020

e16072

Background: A computer-aided diagnosis system for bone scan with semiquantitative index of Bone Scan Index (BSI) may be used to quantify the spread of bone metastases. This retrospective study aimed to examine associations between BSI, bone metabolic markers, and prostate specific antigen (PSA) in prostate cancer patients with bone metastases. Methods: A total of 158 scintigraphy of 52 patients (mean examinations/person 3, range 1-8; mean age 71 years, range 46 to 86) were studied. The intervals between bone scan and blood examinations were 0 to 16 days (median 0 day). Subjects were divided into 4 groups according to BSI; Group A: 0 - <2, Group B: 2 - <4, Group C: 4 - <8, and Group D: 8<. The markers of PSA, pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (1-CTP), bone alkaline phosphatase (BAP), and tartate resistant acid phosphatase-5b (TRAP-5b) were examined. As the values of PSA, BAP, and TRAP-5b covered a large range of scales, we also used the logarithms of the variables. BSI, which corresponded amount of metastatic lesions, was automatically calculated by BONENAVI software (FUJIFILM RIPharma, Co. Ltd., Tokyo, Japan; Exini Bone, Exini Diagnostics, Sweden). Results: All scans showed increased uptake at bone metastases. BSI correlated significantly with 1-CTP, BAP, logBAP, TRAP-5b, logTRAP-5b, and logPSA (r=0.39, 0.66, 0.71, 0.69, 0.61 and 0.41, respectively). Statistical F value was 11 in 1-CTP, 31 in BAP, 29 in logBAP, 19 in TRAP-5b, 14 in logTRAP-5b, 3 in PSA, and 9 in logPSA by ANOVA, respectively. Comparison by Dunnett’s test showed significantly higher values in Group D for all bone metabolic markers and logPSA, Group C for BAP, logBAP, TRAP-5b, and logTRAP-5b, and Group B for logTRAP-5b compared with Group A, respectively. However, PSA did not correlate significantly with extent of bone metastases as assessed by BSI. Conclusions: The changes in BSI showed close relationship with all bone metabolic markers but not with PSA. The BSI reflected the activity and extent of bone metastases, and might be used as an imaging biomarker.