bluuebunny/crossref_metadata_2025_split huggingface dataset:
Individualized intensification of treatment based on tumor marker decline in metastatic nonseminomatous germ cell testicular cancer (NSGCT): A report from the Swedish Norwegian Testicular Cancer Group, SWENOTECA
Authors: Olofsson S. , Dahl O. , Jerkeman M. , Cohn-Cedermark G. , Klepp O. , Stierner U. , Törnblom M. , Wahlqvist R. , Cavallin-Ståhl E. ,   SWENOTECA
Published: August 2020

5015 Background: From July 1995 to December 2003, 602 adult patients from Sweden and Norway with metastatic testicular NSGCT were included in a population-based multicenter SWENOTECA protocol with strict guidelines for staging, treatment and follow-up. Methods: The basic strategy of this protocol was to individualize treatment according to AFP and β-HCG decline (t1/2). Satisfactory response to treatment was defined as a t½ for AFP ≤ 7 days and/or β-HCG ≤ 3 days. Initial treatment for all patients was 2 courses of standard BEP. Tumor markers were analyzed once a week during treatment. Patients with satisfactory response went on with BEP while patients with unsatisfactory t1/2 received intensified treatment in two steps with addition of ifosfamide (BEP-if/PEI) in step 1. If still unsatisfactory response the treatment was intensified according to step 2 involving high-dose chemotherapy with stem cell rescue. Postchemotherapy surgery was performed according to protocol guidelines. Results: 99,7% (602 of 604) of all patients with metastatic testicular NSGCT in the population were included in the protocol. Median FU was 72 months. 75% of the patients were treated with BEP, median 4 courses, without intensification, 19% according to intensification step 1 and 6% according to intensification step 2. Five year progression free survival (PFS), cancer specific survival (CSS) and overall survival (OS) grouped according to IGCCCG prognostic score are given in the Table below. There was no significant difference in PFS between the good and intermediate risk group. Death due to all causes was 10,1% (n=61) and treatment related deaths were 1,3 % (n=8). Conclusions: Our results, in a population based patient material, with individualized treatment based on tumor marker decline, are highly encouraging in all risk groups, but most notably in the intermediate risk group. [Table: see text] No significant financial relationships to disclose.
Randomized trial of p53 targeted adjuvant therapy for patients (pts) with organ- confined node-negative urothelial bladder cancer (UBC)
Authors: Stadler W. M. , Lerner S. P. , Groshen S. , Stein J. P. , Skinner D. G. , Raghavan D. , Steinberg G. D. , Wood D. , Klotz L. H. , Hall M. C. , Cote R. 
Published: August 2020

5017 Background: Retrospective studies suggest that p53 mutation and associated immunohistochemical (IHC) detectable expression are prognostic for recurrence in pts with organ confined UBC and may be predictive for benefit from MVAC adjuvant chemotherapy. Methods: Pts with pT1–2N0M0 UBC following radical cystectomy and bilateral pelvic lymph node dissection were eligible. IHC for p53 was centrally performed and pts with ≥10% nuclear reactivity were offered randomization to 3 cycles of adjuvant MVAC vs. observation. P53 negative and p53 positive pts who declined randomization were observed. Primary endpoint was recurrence-free survival (RFS) in the randomized population. Secondary endpoints were RFS in p53 negative versus p53 positive pts and overall survival in each of these groups. Using a one-sided log-rank test with α = 0.05 and β = 0.15, 190 p53 positive patients were planned to be randomized to detect an absolute improvement in RFS at 3 years (yrs) from 50% to 70% (corresponding hazards ratio of 0.51). Results: 521 pts were registered, 499 underwent successful p53 assessment (male: 80%, <65 yrs: 57%, Caucasian: 91%, pathologic stage P1/P2: 37%/63%, lymphovascular invasion: 20% yes/28% unknown), 272 (55%) were p53 positive and 114 were randomized (42%). Further accrual was halted based on data safety monitoring board review of futility analysis on the first 100 randomized pts. P53 positive tumors were higher grade (97% vs 93% grade 3/4, p = 0.04) and less likely to express p21 (59% vs 84%, p < 0.001). Overall 5-yr RFS was 80 ± 2% with no difference based on p53 status. P53 positive patients declining were older but otherwise similar to those accepting randomization. Only 67% of pts randomized to MVAC received all 3 cycles with 12 (21%) receiving none. There was no difference in RFS in the randomized population (overall 5 yr RFS 83 ± 4%, hazard ratio = 0.88, p = 0.78). Conclusions: The prognostic and predictive value of p53 IHC were not confirmed in this prospective study, but the lower than expected event rate and failures to receive assigned therapy severely compromised the study's power. The value of p53 mutations is being assessed. No significant financial relationships to disclose.
Circulating tumor cells (CTC) in patients with metastatic castration-resistant prostate cancer (CRPC) receiving abiraterone acetate (AA) after failure of docetaxel-based chemotherapy
Authors: Fleisher M. , Danila D. C. , Leversha M. , Rathkopf D. , Slovin S. , Anand A. , Koscuiszka M. , Haqq C. , Scher H. I. 
Published: August 2020

5049 Background: Selecting targeted therapies and assessing outcome in patients (pts) with CRPC are significant unmet medical needs. A proportion of CRPC remain dependent on androgen receptor (AR) activation. AA inhibits CYP17 to decrease serum androgen to undetectable levels. Methods: AA (1000 mg QD oral) was studied in pts with metastatic CRPC who had progressed on docetaxel based chemotherapy. The primary endpoint was a >50% decline in PSA from baseline. We monitored changes in CTC number with therapy, and performed FISH for AR in CTC as previously described. Results: At MSKCC, 54 pts were screened and 48 treated; 38 pts received prednisone from the start of treatment. The median (IQR) age was 70 yrs (63–79), PSA 99.9 ng/mL (36.4–343), and CTC were 17 (4–49) per 7.5 ml of blood at baseline. Prior systemic therapy included > 3 hormonal therapies in 63%; while 71% received 1, 29% had 2 lines of chemotherapy. Metastatic sites were bone alone in 10 pts (21%), bone and lymph nodes in 21 (44%), 15 (31%) with visceral disease, 2 with soft tissue alone. Baseline CTC count was > 5 in 35 pts, whereas 13 pts had <5; CTC changes with treatment are presented in table below. Pts in Group A were treated on protocol for a median of 8.9 m, compared to 2.8 m in group B (P <0.001). Among pts with baseline CTC > 5, the CTC decline to <5 was associated with a decline in PSA by >50% (p< 0.001). From 28 pts with FISH in CTC, 13 (47%) pts had AR amplification, 8 (29%) pts had copy number gain, and 5 (10%) pts had no evident AR copy number abnormalities; FISH failed in 2 pts. PSA declined > 50% in 5 (38%) pts with AR amplification, 2 (25%) pts with gain, and 4 (80%) pts without AR abnormalities. Conclusions: Changes in CTC with treatment may represent valuable intermediary endpoints for clinical benefit. We are prospectively testing pre and post-therapy CTC, and separately AR FISH profiles and clinical outcomes in COU-AA-301, a phase III trial for CRPC patients who have received docetaxel based chemotherapy. [Table: see text] [Table: see text]
Sensitivity and specificity of a whole-blood RNA transcript-based diagnostic test for the diagnosis of prostate cancer (CaP) compared with prostate-specific antigen (PSA) alone
Authors: Ross R. W. , Bankaitis-Davis D. , Siconolfi L. , Katz L. , Storm K. , Magidson J. , Wassmann K. , Oh W. K. 
Published: August 2020

5052 Background: Screening for CaP with PSA testing is limited by a high number of false postives, particularly in the setting of benign prostatic hypertrophy (BPH). The goal of this study was to develop whole blood RNA transcript-based diagnostic tests that improve the diagnosis of CaP over PSA alone. Methods: From August 2006 to October 2008, three prospective cohorts of men consented to the collection of whole blood in PAXgene Blood RNA tubes for gene expression analysis: men with newly diagnosed, localized, untreated CaP, otherwise healthy men without CaP, and otherwise healthy men with BPH. 168 inflammation and CaP-related genes (Source MDx Precision Profiles) were assayed using optimized Q-PCR technology. Logistic regression methods were used to develop models to optimize prostate cancer diagnosis. Results: 182 men underwent expression analysis (n = 76, 76 and 30 for CaP, normal, and BPH cohorts, respectively). The CaP and normal cohorts were age matched (median age 60 yrs); the BPH cohort median age was 70. Considering only the CaP and normal cohorts, PSA alone (using a cut-off of 4 ng/ml) had a specificity of 94.7%, but sensitivity of only 71.1% for diagnosis of CaP, or 90.8% and 77.6%, respectively, when using age-adjusted PSA criteria. A model consisting of the expression analysis of 6 genes and PSA had a higher specificity (96.1%) and a much improved sensitivity (97.4%) for CaP diagnosis. When the BPH cohort was added, the improvement of the 6-gene model remained (sensitivity and specificity of 97.4% and 92.0% vs 77.6% and 88.1% using the age-adjusted PSA criteria). Further model development using the CaP and BPH cohorts yielded a 5-gene model which, integrated with PSA and age, correctly predicted 96.1% of the CaP pts and 93.3% of BPH pts. Conclusions: These results suggest that specific whole blood RNA transcript levels can assess abnormal gene expression associated with CaP. Such a molecular CaP biomarker would be a powerful tool to reduce unnecessary biopsies in patients without CaP and detect CaP in patients with PSA values below the current cutoff. Validation of these results is ongoing and will be available at the time of the meeting. [Table: see text]
Evaluation of the prostate-specific antigen/solvent interaction analysis (PSA/SIA) assay for prostate cancer (CaP) diagnosis
Authors: Vourganti S. , Stovsky M. , Ponsky L. , Siroky M. , Kipnis V. , Fedotoff O. , Mikheeva L. , Zaslavsky B. , Chait A. , Jones J. S. 
Published: August 2020

5053 Background: We describe the clinical performance of a novel protein structural assay for prostate cancer (CaP) diagnosis. The assay uses Solvent Interaction Analysis (SIA) to accurately detect changes in PSA isoform composition that differentiate benign and malignant disease, independent of total serum PSA (tPSA). Methods: From January 2007 to September 2008, men already undergoing biopsy for accepted clinical criteria at 3 sites [University Hospitals Case Medical Center (Cleveland); Cleveland Clinic (Cleveland); and Veterans Administration Hospital (Boston)] were enrolled in an IRB approved study. Prior to standard transrectal ultrasound (TRUS) guided biopsy, patients received a digital rectal examination with systematic prostate massage followed by collection of voided urine for use in PSA/SIA. The assay determined the relative distribution of the entire heterogeneous PSA isoform population between two coexisting aqueous phases for diagnostic purposes. Results: 222 men were enrolled in the trial. Biopsy results were classified as case (malignant, n = 100) or control (benign, n = 122). Receiver operating characteristic performance results demonstrated AUC of = 0.88 for PSA/SIA and 0.58 for tPSA. At a cut-off value of the composite structural index K = 1.73, PSA/SIA displayed sensitivity = 100%, specificity = 80%, PPV = 83%, and NPV = 100%. For the same patients at tPSA cut-off level of 4 ng/ml, the sensitivity = 82%, specificity = 27%, PPV = 54%, and NPV = 87%. Conclusions: PSA/SIA uniquely exploits the inherent structural heterogeneity in PSA resulting in superior diagnostic performance over conventional biopsy selection criteria. We hypothesize that the high specificity of PSA/SIA is actually underestimated by standard prostate biopsy sampling error. Future trials will assess the utility of the assay in the surveillance of CaP patients after definitive local therapy and other applications in the diagnosis and management of CaP. [Table: see text]
Ixabepilone, mitoxantrone, and prednisone in patients with metastatic castration-resistant prostate cancer refractory to docetaxel-based therapy: A phase II study of the DOD Prostate Cancer Clinical Trials Consortium
Authors: Small E. , Harzstark A. , Weinberg V. K. , Smith D. C. , Mathew P. , Beer T. , Liu G. , Sharib J. , Rosenberg J. 
Published: August 2020

5058 Background: Mitoxantrone (M) plus prednisone (P) and ixabepilone (Ix) each have modest, non cross-resistant activity as second line chemotherapy regimens in docetaxel-refractory patients with CRPC. These agents were therefore combined in a phase I study which demonstrated anti-cancer activity and defined the recommended phase II dose used in this trial. Methods: Patients with metastatic CRPC and progression after 3 or more cycles of docetaxel were enrolled in a phase II multicenter study of the combination of prednisone 5 mg BID, Ix (35 mg/m2) and M (12 mg/m2) administered intravenously on day 1 every 21 days, with pegfilgrastim (6 mg on day 2) support. Results: To date, 43 pts have been enrolled and have received a median of 4 cycles. Of 37 patients currently evaluable for response, 14 (38%; 95% CI: 22–55%) have had a confirmed ≥50% decline in PSA and 19 (51%; 95% CI 34–68%) have had a confirmed ≥30% decline in PSA. Two of 15 patients with evaluable measurable disease (13%) have had a RECIST-defined objective response. All 43 patients are evaluable for toxicity. Grade 3 or 4 neutropenia was seen in 6 pts (17%) and grade 3 or 4 thrombocytopenia was seen in 3 (8%). Nonhematologic grade 3/4 events possibly related to study drug have included grade 3 fatigue (3 pts), grade 3 pneumonia (2 pts), and grade 3 atrial fibrillation, grade 4 myocardial infarction, grade 4 prostatitis, grade 3 nausea/vomiting, grade 3 neuropathy, grade 3 elevated transaminases, grade 3 dizziness, grade 3 dehydration, grade 3 shortness of breath, and grade 4 vasovagal syncope (1 pt each). Grade 2 neuropathy has been seen in 4 patients. Conclusions: The Ix, M, P regimen is active as second-line therapy in CRPC patients with progressive disease after docetaxel therapy and is reasonably well tolerated. Further investigation of this regimen is warranted. This study was supported in part by CTEP/NCI and the DOD Prostate Cancer Clinical Trials Consortium. [Table: see text]
Phase II study of first-line sagopilone combined with prednisone in patients with metastatic castration-resistant prostate cancer (CRPC)
Authors: Beer T. M. , Smith D. C. , Hussain A. , Alonso M. , Wang J. , Giurescu M. , Wang Y. ,   Prostate Cancer Clinical Trials Consortium
Published: August 2020

5059 Background: Epothilones comprise a new class of microtubule stabilizing agents, and sagopilone is a novel, fully synthetic epothilone that has shown significant activity against a broad range of tumor models. Methods: Chemotherapy-naïve metastatic CRPC patients received sagopilone 16 mg/m2 IV over 3 hours every 21 days and prednisone 5 mg PO BID. The primary efficacy evaluation was based on PSA decline (≥50% PSA reduction confirmed at least 28 days apart). The Simon 2-Stage design required 3 responders among the first 13 evaluable patients and 13 responders among the first 46 evaluable patients to declare the agent of interest for further investigation. Results: Between August 2006 and May 2008, 53 patients were enrolled and treated. Sites of metastases were: bones, lymph nodes, and viscera in 72%, 68%, and 25% patients, respectively. Median PSA was 107.5 (6.2–1727) ng/ml. A median of 5 (2–12) cycles were delivered. The median dose delivered per cycle was 13.3 mg/m2. Two patients did not meet all eligibility criteria and were excluded from efficacy analyses; 3 additional patients were excluded from PSA decline and progression-free survival analyses due to missing baseline PSA assessment. Twenty of 48 patients (42%; 80% CI: 32%-52%) had a confirmed PSA decline in excess of 50% and 30 (63%; 95% CI: 47%-76%) had a 30% reduction in PSA within 3 months of enrollment. Of 39 patients with measurable disease by RECIST, 1 had a complete, 9 had a partial confirmed response (26%; 95% CI: 13%-42%). The median PFS was 6.4 months (95% CI: 4.7 to 10.2). All 53 patients are evaluable for safety. Toxicities occurring in ≥ 20% patients included peripheral neuropathy 74% (19% grade 3), fatigue 40% (6% grade 3, 2% grade 4), extremity pain 36% (6% grade 3), arthralgia 23% (no grade 3, 4), and constipation 21% (no grade 3, 4). Conclusions: Sagopilone is active in metastatic chemotherapy-naïve CRPC patients, with probability of PSA decline, measurable disease responses, and PFS approximating the current standard of docetaxel + prednisone. Neuropathy and fatigue are the most common toxicities, while hematologic toxicity is rare. Further evaluation of this agent in prostate cancer is warranted. [Table: see text]
Residual pathologic stage at radical cystectomy and risk stratification of patients with pT2N0 bladder cancer
Authors: Isbarn H. , Sonpavde G. , Shariat S. F. , Palapattu G. S. , Sagalowsky A. I. , Lotan Y. , Schoenberg M. P. , Amiel G. E. , Lerner S. P. , Karakiewicz P. I. 
Published: August 2020

5076 Background: We hypothesized that in patients with pT2N0 transitional cell carcinoma (TCC) of the urinary bladder, residual muscle-invasive disease at radical cystectomy (RC) may confer poorer outcomes than residual non-muscle invasive disease due to larger tumor volume and/or biologically more aggressive disease. Patients with high-risk pT2N0 disease may be candidates for trials of adjuvant therapy. Methods: Patients from the BCRC database with pT2N0 stage (N = 208) at TUR (transurethral resection) whose tumors were organ-confined at RC (≤pT2N0) were analyzed. T1N0 patients (N=33) with pT2 disease at RC were also examined in order to include all pT2 patients. None of the patients had received perioperative chemotherapy. The effect of residual pT-stage at RC on outcomes was evaluated in Kaplan-Meier, as well as in univariable and multivariable Cox-regression models. Covariates consisted of age, gender, grade, lymphovascular invasion, concomitant carcinoma-in-situ (CIS), number of lymph nodes removed, and the year of surgery. Results: Among baseline T2N0 patients, residual pT-stage at RC was pT0 in 24 (11.5%), pTa in 9 (4.3%), pCIS in 22 (10.6%), pT1 in 35 (16.8%), and pT2 in 118 patients (56.7%). The median follow-up was 50.1 months. The 5-year recurrence-free survivals of patients with residual pT0/pTa/pCis, pT1 and pT2 were 100%, 85% and 75%, respectively. The 5-year cancer-specific survival rates for the same patient cohorts were 100%, 93%, and 81%, respectively. In multivariable analyses, the effect of residual stage <pT2 at RC achieved independent predictor status for recurrence (adjusted HR 0.20; p = 0.002), as well as for cancer-specific survival (adjusted HR: 0.24; p = 0.02). Initial T1 patients who were pT2 at RC did not have statistically different outcomes compared to initial T2 followed by pT2 at RC. Conclusions: Patients with pT2N0 TCC of the urinary bladder with residual non-muscle invasive disease at RC have significantly better long-term outcomes compared to residual muscle-invasive disease. With further validation, these data may facilitate the risk-stratification of patients with pT2N0 disease and enable the selection of high-risk patients for trials of adjuvant therapy. No significant financial relationships to disclose.
SPARE: A qualitative study investigating randomization barriers in a Selective Bladder Preservation trial (SBP) (ISCRCTN: 61126465)
Authors: Moynihan C. , Hall E. , Lewis R. , Birtle A. , Mead G. M. , Huddart R. ,   on behalf of the SPARE Trial Management Group
Published: August 2020

5077 Background: Recruitment to randomised trials is challenging, especially when treatment strategies are complex. While studies have demonstrated barriers to recruitment, few have investigated why patients accept or refuse randomisation. The SPARE feasibility study included such an investigation to highlight difficulties that might be dealt with as the study progressed and to inform procedures for a subsequent phase III trial. Methods: Patients had newly diagnosed invasive bladder cancer and were receiving neoadjuvant chemotherapy prior to invitation to a randomised trial (SPARE) that offered the possibility of radical cystectomy or SBP. Patients allocated SBP received cystectomy or radiotherapy dependent on chemotherapy response. 15 acceptors and 10 decliners to randomisation participated in the qualitative substudy. Methods included recorded transcribed interviews and a ‘framework analysis.’ Results: Both groups experienced initial confusion, ‘muddled’ communication, information overload, and lack of time leading to misunderstandings about the trial. Perceived side effects did not necessarily inform decisions. Decision to participate was seldom made unilaterally. Individual specialist input by, and continuity between, professionals and their patients, appeared to make decision making easier. Acceptors were inclined to altruism and trust in the medical profession, often agreeing to participate with minimum understanding regarding randomisation and/or equipoise and a ‘nothing to lose’ attitude as long as withdrawal from the trial was possible. Decliners tended to opt for radiotherapy, perceived as a rational choice in the context of this trial; many abhorred the thought of surgery that was perceived as undermining and a ‘treatment in reserve.’ Conclusions: Health professionals need to consider streamlining procedures and recognise patient preferences in terms of treatments offered and information received. Recognition of the complexity of communicating equipoise and randomisation may increase ‘informed consent’ levels and recruitment rates. A further qualitative substudy investigating doctor/patient consultations in real time with confidential feedback is proposed to optimise recruitment rates. No significant financial relationships to disclose.