bluuebunny/crossref_metadata_2025_split huggingface dataset:
A multicenter phase II study of cisplatin (C), gemcitabine (G), and bevacizumab (B) as first-line chemotherapy for metastatic urothelial carcinoma (UC): Hoosier Oncology Group GU-0475
Authors: Hahn N. M. , Stadler W. M. , Zon R. T. , Waterhouse D. M. , Picus J. , Nattam S. R. , Johnson C. S. , Perkins S. M. , Waddell M. J. , Sweeney C. J. 
Published: August 2020

5018 Background: Despite CG therapy, most metastatic UC patients die from their disease. Novel approaches are needed. Combining anti-angiogenic therapy with chemotherapy has improved outcomes in other malignancies, offering hope for similar improvements in UC patients. Methods: Metastatic or unresectable chemonaive UC patients (pts) with an ECOG performance status of 0–1 received C 70 mg/m2 iv d1, G 1,000–1,250 mg/m2 iv d1, 8, and B 15 mg/kg iv d1 on a q21d cycle for up to 8 cycles. Gemcitabine was reduced to 1,000 mg/m2 iv d1, 8 for all subsequent pts after 7 thromboembolic events were noted in the first 17 pts. The primary endpoint was progression free survival (PFS). The trial was designed to detect a 33% improvement in PFS from 7.5 months with traditional CG therapy to 11.25 months with CGB. Results: By December 2008, 45 pts were enrolled, with 43 evaluable for toxicity, 36 for response. Demographics include: 33 (77%) male, 10 (23%) female; median age 66 (Range: 41 - 78); 26 (60%) and 17 (40%) ECOG 0/1; 19 (44%) and 24 (56%) lymph node only / visceral metastases. PFS will be evaluated in May 2009 when all pts will have more than 6 month follow-up data. 14 (33%) and 6 (14%) pts experienced grade 3 or 4 hematologic toxicity (4 pts - thrombocytopenia, 2 pts - neutropenic fever). Grade 3 or 4 nonhematologic toxicity was observed in 24 (56%) and 9 (21%) pts (DVT/PE - 9 pts, CNS hemorrhage/proteinuria/hypertension - 1 pt each) Best RECIST response was: complete response 6 pts (17%, 95% CI 6–33%), partial response 18 pts (50%, 95% CI 33–67%); with overall response rate of 67% (95% CI 51–82%). Stable disease lasting at least 12 weeks was observed in 10 pts (28%, 95% CI 14–45%) and progressive disease in 2 pts (5%, 95% CI 1–19%). Conclusions: CGB demonstrates significant clinical activity in the first-line treatment of metastatic UC patients at the expense of considerable toxicity. The durability of disease control will be determined by assessment of PFS. A phase III trial to further define the toxicity risk vs. clinical benefit of bevacizumab addition to platinum-based doublets is planned in this population. [Table: see text]
BC2001: A multicenter phase III randomized trial of standard versus reduced volume radiotherapy for muscle invasive bladder cancer (ISCRTN:68324339)
Authors: Huddart R. A. , James N. D. , Adab F. , Syndikus I. , Jenkins P. , Rawlings C. , Hendron C. , Lewis R. , Rogers S. , Hall E. ,   on behalf of the BC2001 Investigators
Published: August 2020

5022 Background: Radiotherapy (RT) is an alternative to radical cystectomy in the management of muscle invasive bladder cancer. Limitations are probability of attaining and maintaining local tumour control and risk of late bladder toxicity. BC2001 tests whether concomitant chemotherapy (CT) improves loco-regional control and whether RT volume modification reduces late toxicity without detriment to tumour control. Methods: Pts were randomized in a 2x2 factorial design to (i) RT vs RT + concomitant CT (5FU 500mg/m2 d1–5 wks 1 & 4 + mitomycin C 12mg/m2 d1) and/or (ii) standard RT to tumour and whole bladder with 1.5cm margin (sRT) vs reduced volume RT (rvRT) where tumour + 1.5cm margin was treated to 100(±5)% target dose and remaining bladder received 80% target dose. RT dose was 55Gy/20F or 64Gy/32F according to local practice. RT volume comparison results (primary endpoint RTOG toxicity at 1 yr) are reported. Target sample size was 480 pts but the RT randomisation closed early due to slow recruitment. Estimated power is 73% (two-sided α = 0.05) to detect a 20% difference in G3/4 toxicity. Results: 219 pts were recruited (108 sRT; 111 rvRT); 49 received neoadjuvant CT; 31 sRT and 33 rvRT were randomised to concomitant CT. Median age was 74 yrs. Median follow up is 36 mths. There was no difference in loco-regional disease-free survival (LRDFS: HR = 1.06, 95% CI: 0.62–1.84) nor overall survival (HR = 0.99, (0.61 - 1.35)) between randomised RT groups. 2yr LRDFS is 71% in both RT groups. 27 (16) sRT vs 32 (15) rvRT pts have had local (invasive) recurrences (p = 0.09); 32 pts have undergone salvage cystectomy. No difference was seen in CTC G3/4 acute toxicity (26% sRT vs 21% rvRT, p = 0.35), RTOG G3/4 toxicity at 12 mths (8% sRT vs 4% rvRT, p = 0.27) nor Lent Som G3/4 toxicity at 12 mths (45% sRT vs 34% rvRT, p = 0.21). Bladder capacity fell significantly in sRT group (mean reduction at 12 mths: 59mls, 95%CI: 47–118mls, p = 0.02) but not in rvRT group. Conclusions: RT in the modern era can attain local control in most patients with T2-T3 bladder cancer. Acute and late toxicity was less than anticipated in both treatment groups. Modifying standard RT volumes had minimal effect on local control and toxicity in this trial. 2 yr toxicity and quality of life data will be presented. No significant financial relationships to disclose.
Paclitaxel (T) plus ifosfamide (I) followed by high-dose carboplatin (C) and etoposide (E) with autologous stem cell support for patients (pts) with previously treated germ cell tumors (GCT): TI-CE results and prognostic factor analysis in 107 pts
Authors: Feldman D. R. , Sheinfeld J. , Bajorin D. F. , Fischer P. , Turkula S. , Ishill N. , Patil S. , Bains M. , Bosl G. J. , Motzer R. J. 
Published: August 2020

5027 Background: Pts with incomplete response (IR) to first-line chemotherapy or relapsed primary mediastinal non-seminomatous GCT (NSGCT) have <10% 3-year (yr) survival with conventional-dose salvage regimens (Cancer. 67:1305). The doses, schedule, and safety of TI-CE in this population were previously reported (J Clin Oncol. 25: 85). Efficacy and prognostic factor analysis are now presented. Methods: Phase I/II trial of TI-CE conducted in GCT pts with progressive disease following chemotherapy and unfavorable prognostic features (extragonadal primary site, IR to first-line therapy, or relapse/IR to ifosfamide/cisplatin-based conventional-dose salvage). Univariate and multivariate analyses of prognostic factors were performed. Einhorn (N Eng J Med. 357:340) and Beyer (J Clin Oncol. 14: 263) prognostic models were also assessed. Results: Of 107 pts, primary site was testis in 72, mediastinum (all NSGCT) in 21, and other in 14. 81 had 1 prior line of therapy and 26 had ≥2. 79 were platinum-refractory and 7 had late relapses. A complete response was achieved in 54 (50%) and partial response with negative markers in 8 (8%). 5-yr disease-free survival (DFS) was 47% and overall survival 52% with a median follow-up of 61 months (m). No relapses occurred after 2 yrs. 5/21 (24%) primary mediastinal NSGCT and 2/7 late relapses are continuously disease-free. On multivariate analysis, primary mediastinal site (p = 0.0002), ≥2 lines of prior therapy (p = 0.0005), baseline HCG >1000 (p = 0.01), and lung metastases (p = 0.02) significantly predicted adverse DFS. By Beyer model, 79% were intermediate and 21% poor risk (0 good risk). DFS was better for intermediate than poor risk pts (p < 0.002), with 2-year rates of 54% and 23%, respectively. By Einhorn model, 15% pts were good, 38% intermediate, and 47% poor risk; good/intermediate risk pts had superior DFS compared to poor risk pts (p < 0.05) with DFS at 2 yrs of 69% vs. 44%. Conclusions: TI-CE is effective salvage therapy for GCT pts with poor prognostic features. Mediastinal primary site and ≥2 lines of prior therapy were most predictive of adverse DFS. Beyer & Einhorn models can assist in predicting outcome. No significant financial relationships to disclose.
Tumor endothelial interaction, CD44+/CD24- stem cell signature, and prognosis in early-stage breast cancer
Authors: Buess M. , Rajski M. , Vogel B. , Herrmann R. , Rochlitz C. 
Published: August 2020

503 Background: The effects of tumor-endothelial interaction on global gene expression in breast cancer are not yet well characterized. We hypothesized that gene expression signatures induced by tumor-endothelial interaction might be of clinical relevance. Methods: To this aim we set up an ex vivo co-culture model with human benign and a panel of 6 malignant breast epithelial cells in combination with human venous and microvascular endothelial cells and determined associated gene expression changes with cDNA microarrays. Pretreatment gene expression profiles of 295 early stage breast cancers from the Netherlands Cancer Institute with a median follow up of 12.6 years allowed evaluating in vitro effects in vivo. Results: The most prominent response to co-culture was the induction of a set of “M-phase cell cycle” genes in a subset of breast cancer co-cultures, which were absent in co-cultures with normal breast epithelial cells. While in monoculture tumor cells containing the stem cell like CD44+/CD24- signature showed a lower expression of the “M-phase cell cycle” genes than the CD44-/CD24+ cells, in the co-cultures with CD44+/CD24- cells these genes were induced. Interestingly, these tumor cells co- expressed a set of angiogenic factors such as VEGF, PTN, and FGF12 mRNA at significantly higher levels. In vivo, the expression of the gene set derived from the co-culture was remarkably coherent providing a basis for segregation of tumors into two groups. In a univariate analysis, early stage tumors with high expression levels (n= 137) of “M-phase cell cycle” genes had a significantly lower distant metastasis-free survival (p=1.8e-5) (50 % at 10 years) and overall survival rate (p= 5e-9) (52 % at 10 years) than tumors with low expression levels (n= 158) (metastasis-free survival: 73 %; overall survival: 84 % at 10 years). Conclusions: Our results suggest that the interaction of tumor cells expressing the CD44+/CD24- stem cell like signature, implicating a low proliferative potential, with endothelial cells might explain the unexpected and paradoxical association of the CD44+/CD24- signature with highly proliferative tumors with an unfavorable prognosis. Multiple co-expressed angiogenic factors represent potentially interesting additional therapeutic targets. No significant financial relationships to disclose.
Phase II trial of ABT-869 in advanced renal cell cancer (RCC) after sunitinib failure: Efficacy and safety results
Authors: Tannir N. , Wong Y. , Kollmannsberger C. , Ernstoff M. S. , Perry D. J. , Appleman L. J. , Posadas E. , Qian J. , Ricker J. L. , Michaelson D. M. 
Published: August 2020

5036 Background: ABT-869 is a novel, orally active and potent inhibitor of all VEGF and PDGF receptor tyrosine kinases. Results from a phase I study suggested antitumor activity in advanced solid tumors including RCC. The recommended dose for phase II investigation was 0.25 mg/kg (maximum 25 mg) daily. Methods: We conducted an open-label, multicenter phase II trial of oral ABT-869 in advanced RCC. Eligibility criteria included progressive disease (PD) within 100 days of enrollment after at least 2 cycles of sunitinib, prior nephrectomy, and adequate organ function. The primary endpoint was objective response rate (ORR) per RECIST by central imaging. Secondary endpoints were best response, time to progression (TTP), progression free survival (PFS), and overall survival (OS). Safety was assessed by NCI-CTCAE, v3.0. Results: 53 patients (pts, median age, 61 y [range, 40–80]; clear-cell histology [41 pts]; median number of prior therapies, 2 [range, 1–4]) were enrolled from 8/07 to 10/08. All pts were previously treated with sunitinib, and additional prior treatments included cytokine (19%), sorafenib (15%), temsirolimus (4%), and bevacizumab (4%). Preliminary efficacy data are shown in the Table below. Median TTP was 4.9 mos [95% CI: 3.5–6.8] per central imaging. Median OS is not estimable. The most common adverse events (AEs) were diarrhea (78%), fatigue (67%), hypertension (53%), nausea (51%) and vomiting (39%). AEs ≥ grade 3 included hypertension (24%), fatigue (18%), diarrhea (14%) and hand-foot syndrome (14%). 39 pts required dose reductions. Of the 20 pts who have discontinued therapy at the time of this analysis, 16 were due to PD, 3 due to AEs (1 hemoptysis, 1 fatigue, 1 fatigue/hypertension) and 1 withdrew consent. The remaining 33 pts continue protocol treatment, and updated results will be presented. Conclusions: ABT-869 has activity in RCC after sunitinib failure. The dose will be optimized for future studies. [Table: see text] [Table: see text]
ECOG 8802: Phase II trial of doxorubicin (Dox) and gemcitabine (Gem) in metastatic renal cell carcinoma (RCC) with sarcomatoid features
Authors: Haas N. , Manola J. , Pins M. , Liu G. , McDermott D. , Nanus D. , Heath E. , Wilding G. , Dutcher J. 
Published: August 2020

5038 Background: Patients (pts) with RCC containing sarcomatoid features have poor prognoses.Cytokine therapy is ineffective, and experience with mTor inhibitors or multi-targeted tyrosine kinase inhibitors is early. We evaluated Dox/Gem in these pts with locally advanced or metastatic disease to confirm previous activity of this regimen in a single institution trial. Methods: Pts received Dox 50mg/m2 IV push and Gem 1500mg/m2 IV over 30 minutes every 2 weeks (with G-CSF 5 mcg/kg/d days 2 or 3 to 10 or pegfilgrastim 6 mg day 2) until disease progression or unacceptable toxicity. Dose reductions occurred for low granulocytes and or platelets, mucositis, cardiac toxicity, or other grade 3 - 4 toxicities. Dox was discontinued after a cumulative dose of 450 mg/m2 unless pt had normal cardiac function. The study targeted a promising response rate (RR) of 20% vs. 5%, with 90% power and 8% Type I error. A 2-stage design was used; >4 responses were needed for efficacy. Results: From February 2004 to April 2007, 39 pts with RCC of sarcomatoid (47%) or mixed histology (53%) containing sarcomatoid features were accrued by ECOG (n = 35), NCCTG (n = 2), and CALGB (n = 2). 1 pt withdrew before treatment. Pts were mostly male (81%), with cT3/T4 (68%), node negative (61%), M1 (58%) disease at diagnosis and ECOG PS 0–1. Metastases included lung (71%) and lymph nodes (58%). Pts received a median 6.5 cycles (range, 1 - 16). Treatment was moderately tolerable: grade 4 neutropenia (3 pts, 1 with fever), grade 4 dyspnea (1 pt), grade 4 peristomal infection (1 pt). 2 of 38 pts stopped treatment due to toxicity. 1 complete and 5 partial responses (PR) were observed (16%, 90% CI 7.1–28.8%). A 7th patient had an unconfirmed PR and an eighth patient had > 50 percent decrease in tumor burden after an initial progression. 9 patients had stable disease. Two pts are alive without progression (1 with a PFS of 2.5 years), 1 is alive with progression, and 35 patients have died. Median PFS is 3.5 months (95% CI 2.8–5.2 mos). Median OS is 8.8 mos (6.1–11.1 mos). Conclusions: Dox/Gem met efficacy criteria in RCC with sarcomatoid features. A TKI/Gem regimen in ECOG is planned. No significant financial relationships to disclose.
Phase II multicenter study of chemotherapy (chemo)-naive castration-resistant prostate cancer (CRPC) not exposed to ketoconazole (keto), treated with abiraterone acetate (AA) plus prednisone
Authors: Ryan C. , Efstathiou E. , Smith M. , Taplin M. , Bubley G. , Logothetis C. , Kheoh T. , Haqq C. , Molina A. , Small E. J. 
Published: August 2020

5046 Background: AA is a potent inhibitor of the enzyme CYP17, a major contributor to androgen biosynthesis. Keto is also known to inhibit this enzyme but AA is many-fold stronger in its action. 33 pts with progressive metastatic disease, normal organ function, ECOG performance status (PS) 0–1, and no prior chemo were enrolled. Pts with prior keto treatment were excluded. AA (1000 mg qd) plus prednisone (5mg bid) were administered orally in 28 day cycles. Methods: Results: At baseline median age was 71.0 (range 52–85) yrs and median PSA was 24.7 (range 7.1–1110.0) ng/mL;19/26 pts (73%) had an ECOG PS of 0 and 7/26 (27%) had PS of 1; the median number of prior hormonal therapies was 2; all pts were on LHRHa and 73% of pts had received anti-androgen, all of whom had undergone prior anti-androgen withdrawal. Pts were evaluated at each cycle for PSA response according to PSAWG criteria. 27 pts have available data for PSA response. Total maximal PSA declines of ≥30%, ≥50%, ≥90% were observed in 89% (24/27), 85% (23/27) and 41% (11/27) pts, respectively. Week 12 PSA declines displayed a similar and sustained trend: ≥30%, ≥50% and ≥90% PSA decline in 82%, 78%, and 26% of pts. Post-treatment ECOG PS score was 0 in 24 (92%) pts: 19% experienced improvement in PS (PS 1 to 0 in 5 pts) and 19/19 pts maintained a PS of 0; Median time to PSA progression has not been reached. Majority of adverse events were grades 1–2. Incidence of hypokalemia - 12%; HTN - 6%; edema - 15%. One pt experienced a grade 3 drug-related HTN. Conclusions: Abiraterone acetate plus prednisone has significant anti-cancer activity in patients with metastatic CRPC not previously treated with ketoconazole or chemotherapy, as demonstrated by declines in PSA and improvement in performance status, and is well-tolerated. [Table: see text]
The effect of toremifene citrate on BMD in men on ADT: A phase III clinical trial
Authors: Veverka K. A. , Malkowicz B. , Smith M. , Morton R. A. , Steiner M. S. 
Published: August 2020

5055 Background: Androgen deprivation therapy decreases bone mineral density and increases fracture incidence. In a recently completed two-year randomized controlled trial of 1382 men, toremifene increased BMD and decreased vertebral fracture incidence in men receiving ADT for prostate cancer. We now describe the effects of toremifene on BMD in various subject subgroups. Methods: We conducted a randomized double blind placebo controlled trial in 1382 men with histologically confirmed prostate cancer on ADT. Key entry criteria included age ≥ 50 years, continuous ADT for 6 months or longer or intermittent ADT for 12 months or longer. Subjects on intermittent ADT at enrollment had to remain on continuous ADT for the duration of their time on study. Subjects were randomized to receive either 80mg toremifene citrate daily or matching placebo. The primary end point was the incidence of new morphometric vertebral fractures. Secondary endpoints included BMD, clinical fragility fractures, bone turnover markers, lipid profile, hot flashes, and gynecomastia. Results: In the overall study population, toremifene increase BMD of the hip and lumbar spine by 1.6% and 2% after two years compared to placebo. Similar beneficial effects of toremifene were observed in each of the subgroups ( Table ). Conclusions: Toremifene significantly increases bone mineral density of the hip and spine in every subgroup including those men who were older or had prevalent vertebral fractures, longer exposure to ADT, or lower baseline BMD. [Table: see text] [Table: see text]
Survival following early hormone therapy for men with rapid PSA doubling time within 2 years following radical prostatectomy
Authors: Trock B. , Han M. , Humphreys E. B. , Partin A. W. , Eisenberger M. A. , Walsh P. C. 
Published: August 2020

5065 Background: Early hormonal therapy has been used in the salvage setting for men with biochemical recurrence following radical prostatectomy (RP), but no studies to date have been able to evaluate whether such treatment prolongs survival. We examined the impact of salvage hormonal therapy on overall survival (OS) in a cohort with long-term follow-up, and attempted to identify the subgroup most likely to benefit. Methods: Retrospective analysis of a cohort of 488 men undergoing RP at Johns Hopkins Hospital from 1982–2004, who experienced biochemical recurrence and received no salvage therapy (n = 386) or salvage hormonal therapy (n = 102); no one received adjuvant therapy. Survival was defined from biochemical recurrence to death from all causes, and analyzed with proportional hazards models with time-dependent covariates. Results: With median follow-up of 6 years after recurrence and 9 years after RP, there were 143 deaths (29%), including 105 from prostate cancer. After adjusting for PSA doubling time (PSADT), RP Gleason score, and year of surgery, hormonal therapy did not significantly improve OS for all men, compared to no salvage therapy: hazard ratio (HR) = 0.72 (95% confidence interval (CI): 0.45–1.17), p = 0.187. However, when restricted to men with early recurrence, i.e. within 2 years of RP, and with a rapid PSADT<6 months, hormonal therapy was associated with a large, significant improvement in OS: HR = 0.25 (95% CI: 0.08–0.71), p = 0.0095. This subgroup comprised 22% of the cohort. In contrast, there was no benefit of salvage hormonal therapy in men with early recurrence and PSADT>6 months: HR = 1.96 (95% CI: 0.89–4.31), p = 0.093, nor those who recurred more than 2 years after RP, regardless of PSADT. Conclusions: This study suggests that early salvage hormonal therapy may significantly and substantially prolong overall survival in the subgroup of men who experience an early biochemical recurrence with a rapid PSADT. These results are consistent with early recurrences being indicative of metastatic disease, while later recurrences are more likely to represent local recurrence. If validated, these results may provide useful stratification criteria for clinical trials. No significant financial relationships to disclose.
Short-course androgen suppression therapy prior to brachytherapy for favorable-risk prostate cancer and the risk of all-cause mortality in men with or without preexisting cardiovascular disease
Authors: Hayes J. H. , Chen M. , Moran B. J. , Braccioforte M. H. , Dosoretz D. , Salenius S. , Katin M. , Ross R. , D’Amico A. V. 
Published: August 2020

5066 Background: AST is used to reduce prostate size in men with favorable-risk prostate cancer who have pubic arch interference in order to enable them to undergo prostate brachytherapy. While no disease-specific benefit has been demonstrated to AST in this setting, AST use has been associated with both cardiovascular morbidity and mortality. The Objective is to determine the effect of short-course androgen suppression therapy (AST) prior to brachytherapy on all cause mortality (ACM), stratified by the presence or absence of preexisting cardiovascular disease (CVD). Methods: The study cohort included 12,792 men with previously-untreated low or intermediate risk prostate cancer (PSA < 20 ng/mL; Gleason score 7 or below on initial biopsy; clinical category T2c or below) treated between 1992 and 2005 at one of 21 community-based medical centers in Illinois, Florida, New York, or North Carolina. Men were treated with brachytherapy with or without neoadjuvant AST. Multivariate Cox regression analysis was performed to assess whether significant associations between preexisting CVD and ACM existed adjusting for age, year of treatment and known prostate cancer prognostic factors. Results: After a median follow up of 3.76 years (interquartile range, 2.03 to 5.92 years), 1557 deaths had occurred. The use of neoadjuvant AST was significantly associated with an increased risk of ACM in men with pretreatment CVD (adjusted hazard ratio (AHR) 1.62, 95% CI, 1.40 to 1.87, p < 0.001) but not in men without CVD (AHR 1.06, 95% CI, 0.91 to 1.25, p = 0.5). In men with preexisting CVD, AST use was associated with an increased risk of ACM at 5 years compared to men with CVD who did not use AST (17.5% (95%CI, 15.57% to 19.64%) vs. 14.35% (95%CI, 12.80% to 16.06%), p < 0.0001). Conclusions: Preexisting CVD is associated with an increased risk of death in men with favorable-risk prostate cancer treated with short-course AST prior to brachytherapy. No significant financial relationships to disclose.