bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic risk group classification for patients (pts.) with platinum-refractory metastatic urothelial cancer (UC) treated with second-line chemotherapy
Authors: Vaughn D. J. , Hwang W. , Munier S. , George C. 
Published: August 2020

5078 Background: Second-line chemotherapy in pts. with platinum-refractory metastatic UC is associated with low objective response rates and short progression-free and overall survival. Prognostic risk groups in this setting have not been reported. Methods: We studied 151 pts. with platinum-refractory metastatic UC treated with second-line vinflunine (VFL) (Vaughn, GU Cancer Symposium. 2008). Using progression at 6 months as the primary endpoint, baseline patient characteristics were examined in univariate and multivariate analyses. Multivariate logistic regression was used to identify independent predictors of progression at 6 months, and the variable selection result was validated by nonparametric bootstrap. Risk scores were generated from summing the relative importance of the factors identified on multivariate analysis. Patients were classified into risk groups and compared. Results: Of the 151 pts., 80% were male, 54% were aged > 65 years, and 68% had Karnofsky performance status (KPS) > 90%. 115 pts. (76%) progressed or died by 6 months after initiating VFL. The factors associated with an increased odds ratio (OR) for disease progression at 6 months were presence of visceral metastases (OR 8.08; p < 0.001; 2 points), KPS < 90% (OR 6.63; p = 0.002; 2 points), and age < 65 years (OR 3.53; p = 0.008; 1 point). Only 41% of the low-risk group (score 0–1) progressed by 6 months compared to 74% of the intermediate-risk group (score 2) and 91% of the high-risk group (score 3–5). Compared to the low-risk group, the intermediate-risk group had OR for disease progression at 6 months of 4.01 (p = 0.006) and the high-risk group had OR of 15.5 (p < 0.001). Conclusions: We identified risk factors and developed a scoring system that classifies pts. with platinum-refractory UC treated with second-line chemotherapy into risk groups based upon probability of disease progression at 6 months. Similar to the first-line setting, the presence of visceral metastases and decreased KPS predict a worse prognosis. This system should be validated in other independent populations. [Table: see text]
Open versus laparoscopic retroperitoneal lymph node dissection (RPLND) in clinical stage I nonseminomatous germ-cell tumors (NSGCTs): Two contemporary series from a single institution
Authors: Nicolai N. , Biasoni D. , Piedra Aguilera J. , Necchi A. , Piva L. , Stagni S. , Torelli T. , Milani A. , Pizzocaro G. , Salvioni R. 
Published: August 2020

5084 Background: Primary RPLND is our choice for clinical stage I (CSI) NSGCTs. Open RPLND (O-RPLND) has been our standard policy since 1985, while laparoscopic RPLND (L-RPLND) has been introduced since the late-1990s. Methods: Between June 2003-March 2008, 150 consecutive CSI NSGCT patients (pts) have been submitted to O-RPLND (n = 91) or L-RPLND (n = 59). Pts with high risk disease (vascular invasion/embryonal carcinoma > 90% in the primary tumor) were more frequently offered O-RPLND, while pts with low risk disease (none of the 2 above) were usually considered for L-RPLND. We reviewed our data focusing on: complications, operating time (OT), hospital stay (HS), number of removed nodes, occurrence of nodal metastases as well as of metastasis during follow-up and global need of chemotherapy (CT). Results: O-RPLND (91). 59/91 (64.8%) were high-risk patients. Median OT was 140 min (IQR 110–150). Five (5.5%) complications occurred: 4 lymphorrea and 1 hemorrhage. Median HS was 6 days (IQR 5–7). Nodal metastases were found in 24 (26.4%) pts. Median number of removed nodes was 20 (IQR 14–25). L-RPLND (59). 54/59 (91.2%) were low-risk patients. Median OT was 210 min (IQR 180–240). Ten (16.9%) complications occurred: 5 required conversions to open procedure due to intraoperative bleeding (4) or technical impossibility to conclude the procedure (1). Median HS was 4 days (IQR 4–5). Nodal metastases were found in 5 (8.5%) pts: 2 of them received immediate adjuvant CT. Median number of removed nodes was 14 (IQR 11–20). OT and HS were significantly better in O-RPLND and L-RPLND series, respectively (p.0001 at Mann Whitney test). After a median follow-up of 15.1 months (1–52), distant metastases were observed in 10 (0.7%) pts: 7/91 (7.7%) following O-RPLND and 1/59 (1.7%) following L-RPLND. CT was administered to 7 (7.7%) pts following O-RPLND and to 3 (5.1%) pts following L-RPLND. Conclusions: In this large case-series, no excess of recurrences but a higher rate of complications were recorded in L-RPLND pts. O-RPLND had a significant better OT while HS was shorter in L-RPLND series. Both procedures are still being applied: pts are currently offered one of the 2 modalities after counseling. No significant financial relationships to disclose.
Cognitive function in postmenopausal women receiving adjuvant letrozole or tamoxifen in the Breast International Group (BIG) 1–98 trial
Authors: Ribi K. E. , Phillips K. A. , Sun Z. , Stephens A. , Thompson A. , Harvey V. , Thürlimann B. , Cardoso F. , Coates A. S. , Bernhard J. 
Published: August 2020

510 Background: Hormonal therapy for breast cancer (BC) may affect cognition. Methods: Post-menopausal women with hormone receptor positive, early-stage BC were randomized to receive either: A) tamoxifen for 5 years; B) letrozole for 5 years; C) tamoxifen for 2 years followed by letrozole for 3 years; or D) letrozole for 2 years followed by tamoxifen for 3 years, as adjuvant endocrine treatment. During the fifth year of trial treatment, objective cognitive function (speed of psychomotor function, visual attention, working and verbal memory, learning) was evaluated by computerized tests. The difference in the composite score for patients taking letrozole (B+C; N= 65) versus tamoxifen (A+D; N = 55) at the time of testing was the primary comparison. Scores for each domain were standardized according to age-specific norms. Two-way ANOVA controlling for language was used to test the effect of treatment on cognitive function. Self-reported subjective cognitive function, psychological distress, fatigue and quality of life were also assessed. Results: Patient characteristics were balanced between groups. Both groups performed below age norms on most domains. The group taking letrozole had better overall cognitive function than the tamoxifen group (difference in mean composite scores = 0.278, p = 0.038, 95% CI: 0.015–0.540) and outperformed patients on tamoxifen for all domains (n.s.). Comparison of monotherapy arms A versus B supported better cognitive function among letrozole patients. Subjective cognitive function, psychological distress, fatigue, and quality of life did not differ between groups. Conclusions: Although letrozole results in lower circulating estrogen levels than tamoxifen, in this study BC patients taking adjuvant letrozole during the fifth year of treatment had better cognitive functioning than those taking tamoxifen. [Table: see text]
A phase II study of S-1 for the treatment of cytokine-refractory metastatic renal cell carcinoma
Authors: Naito S. , Eto M. , Shinohara N. , Tomita Y. , Fujisawa M. , Namiki M. , Nishikido M. , Usami M. , Tsukamoto T. , Akaza H. 
Published: August 2020

5100 Background: S-1 is a novel oral anticancer agent, contains tegafur (FT), a prodrug of 5-fluorouracil (5-FU), with 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo) at a molar ratio of FT: CDHP: Oxo = 1:0.4:1. The purpose of this study was to evaluate the efficacy and safety of S-1 in cytokine-refractory metastatic renal cell carcinoma (mRCC), and to examine the relation between response and mRNA expression levels of 5-FU-related enzymes. Methods: Eligible patients had a histologically confirmed diagnosis of clear cell or papillary type of RCC, measurable lesions, treatment histories with cytokines, an ECOG performance status of 0 or 1 (2 was allowed in patients with bone metastasis), an age of at least 20 years, prior nephrectomy, and adequate organ functions. Any prior treatment for mRCC was discontinued more than 4 weeks before registration. S-1 was administered orally at a dose of 40 mg/m2 twice daily for 28 days, followed by 14 days of rest. The primary endpoint was the objective response rate (ORR) as confirmed by an independent reviewer. The planned sample size was 44 patients. The threshold response rate was defined as 5%, and the expected rate was set at 17.5%. If the lower limit of the 95% CI exceeded the threshold rate (6 of the 44), S-1 was evaluated to be effective. Formalin fixed paraffin embedded specimens, which had been obtained by radical nephrectomy, were used for mRNA expression assay, performed by RT-PCR method. Results: Between April 2006 and May 2007, 45 patients were enrolled, and 31 assay samples were obtained. ORR was 24.4% (11/45, 95% CI: 12.9 - 39.5%). The median PFS was 9.2 months. The median OS could not be calculated, but the survival rate at 1 year was 87.5%. The most common grade 3–4 adverse events assessed according to the CTCAE v.3.0 included anemia (6.7%), neutropenia (8.9%), anorexia (8.9%), hyperglycemia (6.7%), stomatitis (4.4%), diarrhea (4.4%), and fatigue (4.4%). On mRNA expression analysis, the expression level of 5-FU-related enzyme correlated with ORR and PFS. Conclusions: S-1 is effective and well tolerated in patients with cytokine-refractory mRCC. Measurement of the mRNA level of 5-FU-related enzyme in tumors before treatment may facilitate prediction of the response to S-1. No significant financial relationships to disclose.
A phase II study of two dosing regimens of GSK 1363089 (GSK089), a dual MET/VEGFR2 inhibitor, in patients (pts) with papillary renal carcinoma (PRC)
Authors: Srinivasan R. , Linehan W. M. , Vaishampayan U. , Logan T. , Shankar S. M. , Sherman L. J. , Liu Y. , Choueiri T. K. 
Published: August 2020

5103 Background: GSK089 is a potent, orally available small molecule inhibitor of MET and VEGFR2. Activating mutations and/or amplifications in MET have been described in pts with PRC. Two of 4 PRC pts treated with intermittent dosing of GSK089 on a Phase I study sustained partial responses (PR) for 1 and > 3 years respectively. The aim of the current study is to evaluate the efficacy, safety and tolerability of 2 dosing regimens of GSK089 as a single agent in pts with advanced sporadic PRC (SPRC) or hereditary PRC (HPRC). Methods: Adults with advanced PRC are enrolled in 2 cohorts with different dosing schedules of GSK089: cohort 1) 240 mg/day on days 1–5 of every 14 days (5-on/9-off); cohort 2) 80 mg daily. Pts are stratified based on status of MET-pathway activation (activating MET mutation, MET [7q31] amplification, or trisomy 7). The primary endpoint is RECIST response rate, assessed every 8 weeks. Plasma markers reflecting potential effects of MET inhibition and anti-VEGF therapy are analyzed. Results: As of December 15, 2008, 37 pts were enrolled in the 5-on/9-off cohort (19 with MET activation including 5 HPRC, 18 SPRC without MET activation or unknown MET status), and 16 pts in the daily dosing cohort (2 with HPRC, 14 SPRC with unknown MET status). Enrollment is ongoing in cohort 2. In cohort 1, of the 35 evaluable pts, 4 pts (2 HPRC and 2 SPRC) had confirmed PRs and 27 had stable disease (SD) as best response with 6 ≥12mo, 3 ≥ 9mo and 3 ≥ 6mo. Four of 5 HPRC pts (1 not evaluated) had shrinkage (15–53%) in all measurable tumors. Twenty-three SPRC pts had shrinkage (2–58%) in the sum of measurable tumors. In cohort 2, of the 9 evaluable pts, 2 (both SPRC) had confirmed PRs, and 7 had SD. The most frequent adverse events (AEs) associated with GSK089 were fatigue, hypertension, nausea, vomiting, diarrhea, and increased ALT/AST, primarily grades 1 and 2. Preliminary results from cohort 1 indicated that plasma shed Met (sMET) and VEGF increased and sVEGFR2 decreased after 2 cycles with changes maintained after 4 cycles. Conclusions: GSK089 is well tolerated and demonstrates anti-tumor activity in pts with PRC with both 5-on/9-off and daily dosing. VEGF, sVEGFR2, and sMET are promising pharmacodynamic markers for biological activity of GSK089. [Table: see text]
A phase I study of sorafenib and RAD001 for metastatic clear cell renal cell carcinoma
Authors: Harzstark A. L. , Rosenberg J. E. , Weinberg V. K. , Sun J. , Ryan C. J. , Lin A. M. , Fong L. , Brocks D. R. , Small E. J. 
Published: August 2020

5104 Background: Both RAD001 and sorafenib have activity against advanced clear cell renal cell carcinoma (ccRCC). Inhibition of both mTOR and angiogenesis may improve outcomes; therefore, a phase I trial combining sorafenib and RAD001 was undertaken. Methods: Cohorts of 3 or 6 patients with ccRCC were treated with a 7 day run-in period of sorafenib 400 mg PO BID continuously followed by RAD001 (dose level I: 2.5 mg, dose level II: 5 mg) PO QD and sorafenib 400 mg PO BID continuously. Pharmacokinetic sampling of sorafenib was obtained on day -1, and of both RAD001 and sorafenib on day 15 of combination therapy. Dose-limiting toxicity (DLT) was defined as occurring within the first 28 days of therapy. Results: Fifteen patients with a median age of 65 (range 51–75) have been enrolled. Two patients were not evaluable for response or DLT evaluation. Five pts were treated with sunitinib previously. Zero of 6 pts on dose level 1 experienced a DLT. Two of 9 pts treated at dose level II have experienced protocol-defined DLTs (grade 4 uric acid and grade 3 lipase with grade 2 pancreatitis). Independently-reviewed best objective responses in 13 evaluable pts include 3 confirmed partial responses (10, 17+, and 23+ months), 6 stable disease (2+, 4+, 4.5, 6+, 13, and 23+ months), and 4 progressive disease. Steady state dosing of RAD001 demonstrated a steady state AUC0–24h of RAD001 of 193.3 (± 32.9) ng h/mL at a dosage of 5 mg QD, comparable to the single agent 5 mg QD steady state dosing AUC0–24h of 238 (± 77) ng h/mL, suggesting there is no pharmacokinetic interaction between RAD001 and sorafenib. Linear pharmacokinetics between the 2.5 and 5 mg QD dosages of RAD001 were observed. The AUC0–24h of sorafenib was not significantly changed by concomitant dosing with RAD001 with a steady state AUC0–24h of 134600 (±42072) ng h/mL pre-RAD001 and a post-sorafenib steady state AUC0–24h of 131451 (±53838) ng h/mL. Conclusions: Combination therapy with sorafenib and RAD001 is safe and feasible. No clinically relevant pharmacokinetic interaction was observed. Activity for the combination has been observed and a phase II study is planned at the 5 mg QD dosage of RAD001. No significant financial relationships to disclose.
The effect of zoledronic acid on bone metastasis in patients suffering from renal cell cancer (RCC): A German prospective single-arm clinical trial
Authors: Tunn U. , Stenzl A. , Kindler M. , Strauss A. , Miller K. , Ruebel A. , Albrecht M. , Gruenwald V. 
Published: August 2020

5107 Background: The incidence of RCC increased over the last decades and about 30% of patients will develop bone metastasis. These pts. face considerable skeletal morbidity e.g. bone pain, pathologic fractures, spinal cord compression or tumor induced hypercalcemia (TIH). A prospective trial was initiated in RCC metastatic to bone evaluating the SRE (skeletal related event) rate under therapy with zoledronic acid (ZA). Primary objective was the proportion of pts. with at least one SRE after 12 months. Methods: Patients with RCC must have had ≥1 bone metastasis and ≤2 prior applications of a bisphosphonate. Bone lesions were diagnosed by bone scan and ≥1 lesion was confirmed using X-ray, CT or MRI. Pts. passed a 12 months treatment period receiving 4 mg ZA every 3 weeks. Pts. were followed every 3 weeks for 54 weeks for development of SREs (radiation or surgery to bone, spinal cord compression, pathologic bone fractures) and TIH. A bone scan was done, if AP or LDH were >2xULN or symptoms occurred. Suspected SRE was confirmed by X-ray, CT or MRI. After end of treatment patients entered a survival follow-up. Results: 51 pts. participated in the study. Median age was 63 years and 2/3 were male. Proportions of MSKCC risk groups good/intermediate/poor for pretreated pts. were 8%, 56%, and 18%, respectively. 78% of pts. suffered from ≤6 bone metastases. 18% had already experienced at least one SRE before study entry. 26% obtained prior medications, mainly interferons (20%), interleukins (16%) and chemotherapy (16%). 25 pts. completed the 12 months treatment period. Based on a preliminary analysis 13 pts. (26%) experienced at least one SRE with an absolute number of 23 events. No TIH was observed. Bone lesions response was observed in 3 pts. (2 CR, 1 PR) out of 33 pts. currently available. Final efficacy and safety results of the 12 months treatment phase will be shown at presentation. Conclusions: Pts. with mRCC and bone metastases are at high risk for experiencing an SRE with a reported incidence of up to 74%. This is the first study prospectively evaluating SRE rate in patients with mRCC and bone lesions receiving ZA. A preliminary analysis indicates an SRE-rate of 26% and no TIH was observed. Final results of this trial could further support the use of ZA in mRCC. [Table: see text]
Bortezomib as brief neoadjuvant therapy for localized high-risk prostate cancer (PCa) followed by radical prostatectomy (RP)
Authors: Sonpavde G. , Frolov A. , Macdonell V. , Hayes T. G. , Mims M. P. , Ayala G. E. , Wheeler T. M. , Thompson T. C. , Ittman M. M. , Kadmon D. 
Published: August 2020

5127 Background: Neoadjuvant therapy may provide an important paradigm for the discovery of active agents for the therapy of PCa. Bortezomib is a proteasome inhibitor with preclinical activity in PCa. A rationale can be made to study brief preoperative bortezomib before RP to determine feasibility and biologic activity. Methods: A phase II trial was designed to evaluate bortezomib 1.6mg/m2 as intravenous bolus weekly for 4 weeks followed by RP 24–72 hours after the last dose. Histological evidence of adenocarcinoma of the prostate was required with clinical stage T1c or T2a with Gleason 8–10 disease, or clinical stage T2b-T2c with Gleason grade 7 and PSA of >10 ng/mL, or clinical stage T3. Results: Accrual is complete with 40 patients enrolled, of whom 38 completed neoadjuvant bortezomib followed by RP and are evaluable. The median age was 60.2 years. No pathologic complete responses were noted. Cytopathic effects (cytolysis, nuclear pyknosis) were commonly seen compared to baseline tumor. Upregulation of apoptosis, proliferation and phosphorylated (p)-Akt have been previously reported in a subset of patients by our group (Ayala GE et al, Clin Cancer Res. 2008;14:7511–8). Two of 8 evaluable patients had a >50% decrease in serum PSA with bortezomib treatment; 3 others had PSA declines of 14%, 25%, and 45%, respectively; 1 patient had no change, and 2 displayed PSA increases. Therapy was feasible with generally manageable toxicities, and surgical morbidities did not increase. A comprehensive toxicity analysis will be presented. Feasibility of surgery, extraprostatic extension, positive margin and lymph node positive rates will be compared with matched historical controls and these data will be presented. Conclusions: Bortezomib is feasible as neoadjuvant therapy preceding RP for PCa and demonstrates biologic activity. Given the upregulation of proliferation and pAkt, the further evaluation of bortezomib may be warranted in randomized trials in combination with chemotherapy or Akt inhibitors. [Table: see text]
Comparability of health-related quality of life (HRQOL), treatment decision making, and treatment satisfaction after PSA recurrence among prostate cancer patients who receive hormone therapy (HT) versus observation (OBS): Results from the COMPARE registry
Authors: Luu T. , Sartor O. , Dandade N. , Halabi S. , Bennett C. 
Published: August 2020

5131 Background: HT may lower PSA, but it may also cause hot flashes and sexual dysfunction. OBS is not associated with hot flashes or lower testosterone production, but PSA may rise. Examining patient satisfaction with treatment decision making, treatment choice, and HRQOL may help improve disease management. We compared treatment satisfaction and HRQOL of patients who chose OBS over HT. Methods: The Comprehensive Multicenter Prostate Adenocarcinoma Registry (COMPARE) is an observational registry of men with PSA failure. Data from patient-reported questionnaires were analyzed for patients treated with OBS or HT. Results: 674 patients (82%) chose OBS; 147 (18%) chose HT. The median time between cancer diagnosis and registry enrollment was 6 years. Of men on OBS, 85%, 83%, and 71% were satisfied with treatment decision process, treatment choice, and treatment outcome, respectively. Men on HT had similar rates of satisfaction (82%, 75%, and 71%). Men initially treated with brachytherapy/surgery were less satisfied with OBS. Men initially treated with external beam radiation were less satisfied with HT. Patients reported similar problems with urinary, sexual, and bowel function. Conclusions: Men with PSA failure seem content with treatment choice and decision making and have low rates of urinary/bowel problems. Rates of sexual dysfunction in both groups are similar. Clinical trials may help determine if HT improves long-term outcomes (e.g. overall survival), since short-term patient reported satisfaction is similar between OBS and HT. The reported rate of sexual dysfunction is lower than expected. [Table: see text] [Table: see text]
Development of risk groups in metastatic castration-resistant prostate cancer (mCRPC) to facilitate the identification of active chemotherapy regimens
Authors: Armstrong A. J. , Halabi S. , Tannock I. F. , George D. J. , DeWit R. , Eisenberger M. 
Published: August 2020

5137 Background: Our aim was to develop and validate clinically applicable predictive factors for a >30% PSA decline 3 months following chemotherapy initiation, and to assess the performance of a risk-group based classification in predicting PSA declines and overall survival (OS) in men receiving chemotherapy for mCRPC. Methods: In TAX327, 1006 men with mCRPC were randomized to receive docetaxel (D) in two schedules, or mitoxantrone (M), each with prednisone: 989 provided data on PSA decline at 3 months. Predictive factors for a >30% 3-month decline in PSA levels were identified using multivariate logistic regression in D treated men (n = 656) and validated in M treated men (n = 333). Risk factors were combined to form risk groups to predict PSA declines, OS, tumor, and pain responses. Prostate Cancer Working Group (PCWG2) disease states were evaluated for these outcomes in docetaxel treated men. Results: In multivariate analysis, four independent risk factors predicted for absence of >30% decline in 3-month PSA: significant baseline pain (OR 0.63 p = 0.02), visceral metastases (OR 0.66, p = 0.03), anemia (hemoglobin <13 g/dl, OR 0.72 p = 0.07), and bone scan progression at baseline (OR 0.60 p = 0.009). Predictive accuracy was moderate with a concordance index (c-index) of 0.61. Risk groups (good, intermediate, poor) were developed with median OS of 25.7 (95% CI 23.3–28.6), 18.7 (17.3–19.7), and 12.8 (11.5–14.6) months, respectively (p < 0.0001), and >30% PSA decline in 78, 66, and 58 percent of men (p < 0.001). In the validation M cohort, similar trends for PSA declines and OS were noted across risk groups (OS 22.5, 16.0, 11.8 mo, p < 0.001). PCWG2 subtypes (node only, bone metastatic, and visceral disease), were also highly prognostic and predictive but did not predict OS as well as the TAX327 risk groups (c-index 0.56). Conclusions: Risk groups have been identified and internally validated that predict PSA decline and OS in men with mCRPC. This classification may facilitate evaluation of new regimens of systemic therapy that warrant definitive testing in comparison to docetaxel and prednisone in phase III trials. Prospective validation of these risk groups is needed. [Table: see text]