bluuebunny/crossref_metadata_2025_split huggingface dataset:
A meta-analysis of individual patient data from randomized trials assessing chemotherapy with and without estramustine in patients with castration-refractory prostate cancer
Authors: Fizazi K. , Hudes G. R. , Berry W. R. , Kelly W. K. , Eymard J. C. , Logothetis C. , Le Maitre A. , Pignon J. P. , Michiels S. 
Published: March 2020

4561 Background: Estramustine phosphate is a mustard-estradiol conjugate, with evidence of both hormonal and non-hormonal effects. In phase II trials, the response rates of microtubule inhibitors are increased when combined with estramustine. Morbidity includes notably thrombosis in about 7% of cases. Whether combining estramustine with chemotherapy increases survival in castration-refractory prostate cancer (CRPC) is still controversial. Methods: Data from all published and unpublished prospective randomized trials assessing chemotherapy + estramustine versus chemotherapy alone in CRPC were sought using electronic database searching, hand searching, and by contacting experts in the field. The primary endpoint was overall survival (OS). The analysis was performed on an intention-to-treat basis. The stratified logrank test was used and an overall hazard ratio (HR) was computed using a fixed effect model. χ2 heterogeneity tests were used to test for statistical heterogeneity. All p-values were two-sided. Multivariate analysis was performed using a Cox model stratified by trial. Results: Individual data were obtained from all 5 randomized trials conducted in the PSA era that had been identified (n = 610). The control arms consisted of docetaxel (1), paclitaxel (1), ixabepilone (1), and vinblastine (2). With a median follow-up of 2.8 years, 510 deaths had occurred. OS was significantly better in the estramustine arm (HR = 0.82 [95% CI: 0.69–0.97]; p = 0.02). Overall, the risk reduction (RR) of death related to estramustine was 18% (± 8). There was no significant interaction (p = 0.66) between the RR of trials using vinblastine (RR = 15% [± 12]) and in those using taxanes or ixabepilone (RR = 21% [± 11]). The estimated 1-year OS rate was 57% and 50% in the estramustine arm and in the control arm, respectively. The 18-months OS rate was 43% and 35%, respectively. There was no interaction between the effect of estramustine and age, performance status, or serum PSA in the Cox model. Conclusions: Combining estramustine with chemotherapy increases OS over chemotherapy alone in patients with castration-refractory prostate cancer. [Table: see text]
The probability of a positive bone scan in patients who were treated with adrogen ablasio therapy for rising PSA after radical prostatectomy
Authors: Dotan Z. A. , Sathyamoorthy K. , Bianco F. J. , Stephenson A. J. , Eastham J. A. , Fearn P. , Schöder H. , Scher H. I. , Scardino P. T. , Kattan M. W. 
Published: March 2020

4574 Background: Physicians often order periodic bone scans to check for metastases in patients treated with androgen ablation therapy (ADT) for rising PSA (biochemical recurrence; BCR) following radical prostatectomy. However, most of these scans are negative. We studied patient characteristics to build a predictive model for a positive scan (+BS) in that setting. Methods: From our prostate cancer database we identified all patients with detectable PSA after radical prostatectomy that were treated by ADT for BCR only. There were 511 BS performed in patients treated with ADT for BCR. Among them, 151 BS were performed for patients with BCR only with out previous evidence of bone metastases (1–8 BS for patient with median of one). We analyzed the following potential predictors for a positive bone scan at the time of each bone scan: preoperative PSA, history of neoadjuvant ADT (NA-ADT), time to BCR, pathologic findings (surgical margin, extracapsular extension, seminal vesicle invasion, lymph node metastases, and Gleason score), PSA before the BS (trigger PSA), PSA doubling time and time from BCR to BS. The results were incorporated into a predictive model. Results: Among the 151 BS, only 35 (23%) were positive for metastases. In multivariate analysis, only trigger PSA (P < 0.001, OR 1.84) and NA-ADT (P = 0.02, OR 1.32) predicted a +BS. Probability of +BS according to PSA of 0–2, 2.1–4, 4.1–10, 10.1–20 and above 20.1 were 4.7%, 15.3%, 29.6%, 46.1% and 63.3% respectively. A nomogram was constructed for predicting the probability of +BS, and was found to have a concordance index of 0.83. Calibration of the nomogram according to bootstrap analysis showed that the nomogram is reasonably accurate. Conclusions: Trigger PSA and a history of neoadjuvant ADT were associated with a +BS. Omitting scans in low-risk patients could reduce substantially the number of scans ordered. No significant financial relationships to disclose.
Biological significance of serum VEGF measurement in renal cell carcinoma
Authors: Patard J. , Rioux-Leclercq N. , Bensalah K. , Fergelot P. 
Published: March 2020

4596 Background: VEGF plays an important role in Renal Cell Carcinoma (RCC) tumor angiogenesis and is a relevant molecular target. Our objective was to correlate serum VEGF measurement to clinical, biological and pathological variables in renal tumors. Methods: 206 patients who were operated for a renal tumor at our institution were prospectively assessed for serum VEGF measurement (enzyme-linked immunosorbent assay, R&D systems). Informed consent was obtained in all cases. Symptoms at presentation, pre-operative biology (haemoglobin, WBC count, platelet count, serum creatinin, calcemia, CRP, ASAT, ALAT, gamma-glutamyltransferase (γGT), Alkaline Phosphatases), TNM stage, Fuhrman grade and final pathology (benign vs malignant histology, histologic subtype) were systematically recorded. Qualitative and quantitative variables were compared by using Chi-square (Fischer exact test) and Student t tests, respectively. Results: There were 128 males (62.1%) and 78 females (37.9%). 185 tumors were malignant at histology (89.8%) including 155 tumors with clear cell histology (83.8%). Median serum VEGF level was 361 ng/ml (41–3090). Mean serum VEGF was not significantly different between benign and malignant tumors as well as between clear cell and non clear cell carcinomas (p: 0.4 and 0.8 respectively). Serum VEGF was strongly associated with symptoms, T Stage (p: 0.0001), N Stage (p: 0.004), Fuhrman grade (p: 0.007) and tumor necrosis (p: 0.004) but not with M Stage (p: 0.3). Serum VEGF was also found to be strongly associated with: haemoglobin, CRP, platelet count (p: 0.0001) and Alkaline phosphatases (p: 0.001). A weaker association was found between serum VEGF and γGT, ASAT (p: 0.05) or ALAT (p: 0.09). Finally serum VEGF was associated with cancer specific survival (p: 0.01). Conclusion: Serum VEGF is strongly associated with most usual clinical, biological and pathological prognostic parameters in RCC. Serum VEGF measurement should be further evaluated for prognostic purpose as well as for treatment monitoring. No significant financial relationships to disclose.
Phase II trial of weekly docetaxel and oral capecitabine in metastatic hormone-refractory prostate cancer
Authors: Marur S. , Heilbrun L. , Kucuk O. , Cher M. L. , Forman J. , Heath E. , Vaishampayan U. 
Published: March 2020

4634 Background: Docetaxel based chemotherapy for hormone-refractory prostate cancer (HRPC) has demonstrated survival benefit. The combination of docetaxel-capecitabine has demonstrated synergistic anti-tumor effect, which is attributable to docetaxel-mediated up-regulation of thymidine phosphorylase (TP). Hence, a phase II trial is being conducted to assess efficacy and tolerability of weekly docetaxel and capecitabine in metastatic HRPC. Methods: Patients with metastatic HRPC, who have not received prior chemotherapy for metastatic disease were eligible to receive docetaxel 36 mg/m2/week IV on days 1,8, and 15 and Capecitabine 1250 mg/m2 /day in two divided doses on days 5–18. Cycles were repeated every 28 days and response was assessed every 2 cycles. The primary end point was response rate. A two stage Simon study design required 15 patients to be accrued in first stage and additional 13 patients in second stage. Results: First stage was completed and response was adequate to proceed to second stage. 21 patients have been registered to this ongoing trial. Baseline characteristics included median age of 71 (range 47–80 years); median performance status of 1; median PSA at study entry of 60.6 ng/ml (range 1.2–3716.9); Of the 21 patients, 16 had bone pain pretherapy, Gleason score ≥ 8 in 14; 8 had measurable disease; 8 had new bone metastases and 14 had PSA progression. 83 cycles have been administered (median 4, range 1–10 cycles). To date 18 patients were assessable for toxicity and response. Grade 3 and 4 neutropenia was noted in 3 patients and Grade 3 hand-foot syndrome in 2 patients. There were no treatment related deaths. A PSA partial response (PR) defined as ≥ 50% decline sustained for ≥ 4 weeks was observed in 14/18 (77%) with ≥90% PSA decline in 7/18 (39%) patients. PR noted in 5/8 measurable disease patients. Stable disease by bone metastases in 15/18. Median time to PSA progression was 5 months (95% CI of 3.5–7.2+ month). Conclusions: The combination of capecitabine and weekly docetaxel demonstrated encouraging activity and acceptable toxicity profile. [Table: see text]
Blood-based biomarkers for detecting aggressive prostate cancer at time of biopsy
Authors: Nam R. K. , Marshall K. W. , Zheng R. , Zhang H. W. , Narod S. A. , Liew C. C. 
Published: March 2020

4637 Background: To date, we have applied our unique methodology (the Sentinel Principle) to identify blood-based gene expressed biomarkers for several diseases including osteoarthritis, bladder cancer and psychiatric disorders. It is well known that new biomarkers for prostate cancer detection are needed, particularly aggressive forms of prostate cancer. Our objective was to identify gene expression signatures and to characterize a set of biomarkers from whole blood to identify patients with aggressive forms of prostate cancer at the time of prostate biopsy. Methods: We conducted a two staged study. The first stage was for gene discovery using microarrays (Affymetrix U133Plus2.0 GeneChips) among 47 patients (all Caucasian) who underwent a prostate biopsy for prostate cancer. We included 16 patients (cases) diagnosed with aggressive forms of prostate cancer defined as having a histologic grade of Gleason Score 7 or more and 31 patients with no evidence of cancer at biopsy (controls). The second stage was a validation study (108 patients) using real-time RT-PCR methods. Logistic regression was used to assess the ability of linear combinations of specific transcripts to distinguish cancers from controls. Results: In the first stage, we identified 1661 probes that were significantly different in blood gene expression profiles between cases and controls (p<0.05). In the second stage, real-time RT-PCR assays validated four genes among 33 cases and 75 controls: three up-regulated genes: A 1.4 fold, p<0.001, B 1.2 fold, p=0.03, C 1.3 fold, p=0.08; and one down-regulated gene D 0.70, p=0.008. Linear combination of these 4 genes discriminated the cases from controls with a sensitivity of 90% and specificity of 53% (AUC: 0.80, 95% C.I.: 0.713∼0.871). The performance of PSA (4 ng/ml cut-off) in the same 108 sample set was 91% sensitivity and 13% specificity (AUC: 0.67, 95% CI: 0.75∼0.98). The performance of combining the four blood biomarkers with PSA yielded an AUC of 0.86 (95% C.I.: 0.77∼0.91) with a sensitivity 90% and specificity 70%. Conclusions: When used with PSA, these four blood-based biomarkers improved the overall accuracy to identify patients with prostate cancer at biopsy. These results would have important implications for new biomarkers discovery for prostate cancer detection. [Table: see text]
Platelet microparticles (PMP): A predictive factor of overall survival in hormone-refractory prostate cancer (HRPC) patients treated by chemotherapy
Authors: Banu A. , Helley D. , Banu E. , Fischer A. M. , Scotte F. , Bouziane A. , Oudard S. 
Published: March 2020

4639 Background: Several studies suggest a causal relationship between platelets activation and cancer metastasis. Activated platelets release PMP, VEGF (vascular endothelial growth factor) and bFGF (basic fibroblast growth factor) which could play a role in patient outcome. Methods: Eligible chemonaive HRPC patients (pts) were required to have: ECOG performance status (PS) ≤2, progressive disease after antiandrogen withdrawal. Before chemotherapy, we quantified PMP in whole blood by flow cytometry using an anti-CD41 monoclonal antibody and plasmatic VEGF and bFGF by ELISA. As primary endpoint, we prospectively evaluated the impact of PMP on overall survival (OS) by Cox regression and log-rank test. Secondary, we studied the correlation between PMP and platelets, and their relationship with OS, incorporating an interaction term in the modelling (PMP and platelets). Results: Between July 2001 and April 2004, thirty-eight HRPC pts were treated by chemotherapy [docetaxel (92%), mitoxantrone (8%)] in our center. Median age was 69 years, with median values of hemoglobin 125 g/L, baseline prostate-specific antigen (PSA) 37.7 ng/mL, PMP 6 867 per μL, VEGF 18.1 pg/mL and bFGF 2.8 pg/mL. Significant correlations were observed between PMP and ECOG PS, hormone-sensitivity duration, Gleason and platelets. Median OS was significantly lower in pts with high PMP values (>6 788 per μL), compared to low PMP pts: 16.7 months (95% CI, 5.1–28.2) vs 25.2 months (95% CI, 20.2–30.3), P = 0.025, log-rank. Univariate analysis by Cox regression showed a significant relationship between OS and PMP level [HR = 0.41 (95% CI, 0.19–0.92), P = 0.04]. PMP kept their significance after adjusting by multivariate analysis for baseline hemoglobin, number of metastatic sites, and PSA doubling-time [HR = 0.37 (95% CI, 0.16–0.87), P = 0.02)]. An interaction term (PMP and platelets) was also predictive on OS (P = 0.01). Conclusions: PMP and their interaction with platelets were a predictive factor of OS in HRPC pts. Our analysis showed that the dynamic interaction between PMP and platelets has a major impact on outcome of HRPC pts. No significant financial relationships to disclose.
Second-line pemetrexed (P) for the treatment of hormone refractory prostate cancer (HRPC): A Hoosier Oncology Group phase II study—Preliminary analysis
Authors: Hahn N. M. , Whalen C. , Sweeney C. J. 
Published: March 2020

4644 Background: We evaluated the efficacy and toxicity of pemetrexed in men with HRPC who had progressed on one prior taxane chemotherapy regimen. Methods: Patients with HRPC received P 500 mg/m2 IV d1 q21d cycle with B12 and folate supplementation until progression or dose-limiting toxicity. The primary outcome measure was PSA response rate (PSAr) defined as a > 50% decline from baseline PSA that was confirmed at least four weeks later. Pts were required to have documented PSA progression prior. If no metastatic disease, a PSA > 20 ng/dL was required. A two-stage Simon phase II design with early stopping rules is being utilized with a PSA response rate of 20% deemed to be clinically relevant. Results: Patient characteristics: To date, 21 of the planned 42 patients have been treated with a median age of 67 years (53–79), median baseline PSA 97.8 (0.7–754.3), and median Karnofsky performance status of 90 (70–100). Treatment Cycles: A total of 83 treatment cycles have been administered with a median of 3 cycles per patient (0–12). Toxicity: 6 of 21 (28.6%) patients experienced a total of 17 grade 3 events. Treatment related grade 3 events included thrombocytopenia (1), anemia (2), mucositis (1), rash (1), and fatigue (1). 3 of 21 (14.3%) patients experienced a total of 8 grade 4 events. Treatment related grade 4 events included neutropenia (2), thrombocytopenia (3), anemia (1), and neutropenic fever (1). Response: Best response observed included 4 PSAr (19.0%, 95% CI 2.2–35.8%), 8 stable disease (SD) (38.1%, 95% CI 17.3–58.8%) and 9 progressive disease (PD) (42.9%, 95% CI 21.7–64.1%). PSAr were maintained at 5, 12+, 5+, and 3+ weeks with sustained SD seen at 15, 12, 15, 21+, 18+, and 12+ weeks. Survival data is immature at this time. Conclusion: This preliminary analysis reveals that pemetrexed has met criteria to move into the second stage of the study and has an acceptable toxicity profile in this patient population. [Table: see text]
The prognostic value of percent positive biopsies in intermediate to high risk prostate cancer treated with brachytherapy and supplemental beam radiotherapy
Authors: Nurani R. D. , Wallner K. E. , Merrick G. S. , Orio P. , Virgin J. , True L. 
Published: March 2020

4645 Background: Percent biopsy core positivity (%BCP) has been correlated with tumor volume, extraprostatic disease and biochemical progression free survival (bPFS) in surgical series. In an external beam series, it can predict time to progression in a subset of patients. Methods: The percentage of biopsy cores involved with cancer was determined from original pathology reports of 566 patients with clinical stage T1c-T2a, Gleason grade 7–10 and/or PSA 10–20 CaP. These patients had previously been treated on a prospective study that randomized between 20 or 44 Gy of supplemental beam radiation therapy followed by Pd-103 brachytherapy. bPFS was defined as having a serum PSA ≤0.5 ng/ml at last follow-up. Patients were censored at last follow-up if their serum PSA was still decreasing. Results: 5 year bPFS was 79% for the entire group of 566 patients and 84% for the sub-group of 333 patients with %BCP quantified. On Cox regression analysis, biological variables analyzed included PSA, PSA < or ≥ 10, Gleason score, Gleason score < or ≥8, %BCP divided into two different grouping schemes (<34, 34 through 50 and ≥50) and < or ≥50. Treatment related variables analyzed included V100, V100 < or ≥90%, D 90, D 90 < or ≥80%, supplemental beam dose of 20 or 40 Gy. On univariate analysis, significant factors were limited to: %BCP < vs. ≥50 (p = 0.004), %BCP <34 Vs. ≥50% (p = 0.006), PSA, PSA < or ≥10, Gleason score, V100 < or ≥90%, D 90. On multivariate analysis, %BCP was the only significant determinant (p = 0.006) irregardless of which stratification scheme was utilized. For %BCP ≥50%, the hazard ratio for biochemical failure was 3.6 (95% confidence interval 1.4 to 8.8). On Kaplan-Meier analysis, 5 year bPFS was 90% and 79% for patients with <50% and ≥50% cores involved respectively (p = 0.002). Conclusions: With implementation of implant techniques that uniformly meet optimal dosimetric criteria in patients felt to be at intermediate to high risk of failure based on Gleason and PSA, the percent of biopsy cores positive with malignancy emerges as the single most important factor in predicting biochemical failure. There is a statistically significant reduction in bPFS in patients with ≥50% of their core needle biopsies involved with malignancy. No significant financial relationships to disclose.
Phase I trial results of PCK3145 in patients (pts) with castrate metastatic prostate cancer (PC)—The US experience
Authors: Slovin S. F. , Daigneault L. , Dulude H. , Panchal C. , Richardson J. , Curley T. , Delacruz A. , Fleisher M. , Morris M. , Scher H. 
Published: March 2020

4650 Background: PCK3145 is a synthetic 15-mer peptide derived from the natural sequence of amino acids of Prostate Secretory Protein (PSCP94), a predominant protein found in seminal fluid. Its expression in PC is down-regulated in pts with metastatic disease and is believed to be a signal transduction inhibitor via multiple pathways in carcinogenesis. Recent data from a phase IIa trial in Great Britain demonstrated safety and suggested reduction in MMP-9 levels, an enzyme involved in angiogenesis, tumor invasion and metastasis. A phase I trial was performed to assess dosing and dosing schedule, pharmacokinetics, safety and impact on MMP-9 levels in pts with castrate metastatic PC who have failed multiple therapies including hormones and chemotherapy. Methods: Two cohorts of 10 pts received either 7.5 mg/m2 twice weekly or 15 mg/m2 weekly, respectively. Pts were treated for 4 weeks followed by a 2 week non-treatment period. Pts could receive addtional two-month cycles if PSAs and scans remained stable. MMP-9 levels, PSA, pharmacokinetics and imaging assessments were done at screening, and at weeks 2, 4 and 6. Results: Ten pts have been enrolled at each dose level. No adverse events were observed, however, declines in MMP-9 levels occurred in most pts by week #3 posttreatment. MMP-9 levels rose when drug was discontinued. Six pts were taken off study due to disease progression whereas 5 pts were discontinued due to rising PSAs. One pt at the 7.5 mg/m2 biweekly dosing schedule received 4 additional cycles with stable PSAs and scans with a PSA doubling time which increased from 4 months pretreatment to 8 months posttreatment. Conclusions: PCK3145 was well-tolerated without toxicity. While early, the weekly dosing schedule appears to result in greater declines in MMP-9 levels and will likely be used in a forthcoming phase II trial in chemotherapy naive pts. [Table: see text]
A phase I study of ABT-751 in combination with docetaxel in patients with metastatic hormone-refractory prostate cancer
Authors: Michels J. E. , Ellard S. , Le L. , Murray N. , Guns E. , Hagey A. , Chi K. N. 
Published: March 2020

4651 Background: ABT-751 (A) is a novel oral sulfonamide anti-microtubule agent with broad-spectrum preclinical activity including paclitaxel-resistant tumors and additive effect with docetaxel (D). Dose-limiting toxicities (DLTs) with ABT-751 include peripheral neuropathy, ileus, and fatigue. The recommended phase II single-agent dose for a 21/28-day schedule is 200 mg/day. Methods: Patients (pts) with hormone-refractory prostate cancer (HRPC), ECOG performance status ≤ 2, and adequate organ function were eligible. D was administered intravenously on day 1 and A was administered orally once daily on days 1–14 of a 21-day cycle for a maximum of 10 cycles. Starting dose was 60 mg/m2 D and 100 mg A; escalated in 4 dose levels (DLs) to 75 mg/m2 D and 200 mg A. Pts received 10 mg oral prednisone daily. Plasma for PK analyses was obtained. Results: 18 pts have been enrolled (3 pts/DL1, 3 pts/DL2, 6 pts/DL3, 6 pts/DL4), 17 pts are currently evaluable: median age 66 years, median PSA 250 μg/L, metastatic sites to bone and/or lymph nodes (17), visceral (2), prior chemotherapy 5 pts. The median number of treatment cycles was 6 (range 2–10). 2 pts experienced DLT (1 febrile neutropenia/DL 3 and 1 diarrhea/grade 4 neutropenia at DL4); these dose levels were expanded to 6 pts with no further DLT. Hematologic toxicities include febrile neutropenia (2 pts), grade 3/4 neutropenia (7 pts). Additional non-hematologic toxicities were grade 1/2 beside 1 episode of grade 3 diarrhea and lethargy each. AUC and Cmax for A were similar to single-agent data. AUC and Cmax for D appeared independent of ABT-751 dosing. PSA decline of ≥50% occurred in 10/16 evaluable pts (63%), ≥30% in 14/16 pts (89%) and <30% in 2/16 pts as best response thus far. Best response per RECIST in 12 pts with measurable disease was partial response in 4 pts (33%) and stable disease in 8 pts (67%). Conclusions: The combination of ABT-751 and docetaxel is well tolerated at the tested doses. PK results suggest no significant PK interaction. Early findings indicate encouraging clinical activity of the combination treatment. Extended accrual to the recommended phase II dose is ongoing to further define activity and toxicity. No significant financial relationships to disclose.