bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long-term causes of relative excess mortality after diagnosis of testicular germ cell tumor.
Authors: Kvammen Oivind , Tor Myklebust Åge , Solberg Arne , Møller Bjørn , Klepp Olbjørn Harald , Fosså Sophie , Tandstad Torgrim 
Published: September 2018

4553 Background: Despite today’s excellent cure rates among testicular germ cell tumor (TGCT) patients, reduced long-term relative survival (RS) is an increasing concern. We recently reported a continuing decline in RS among TGCT patients diagnosed in Norway, even beyond 30 years of follow-up. Late effects of treatment is the main culprit. Although several reports describe increased mortality from second cancer (SC), cardiovascular disease (CVD), and other causes (OC) among TGCT survivors, data beyond 20 years of follow-up are scarce. The study aim was to analyze long-term relative risks (RR) and causes of death (CD) among TGCT patients diagnosed in Norway, 1953-2014. Methods: Data sources were the Cancer Registry of Norway and the Norwegian Cause of Death Registry. All men diagnosed with TGCT in Norway during 1953-2014 were included, except spermatocytic seminomas. End of follow-up was December 31st, 2014. Patients were classified by CD, histology, disease extent and age at diagnosis, as well as by decade of diagnosis and follow-up time. Standardized mortality ratios (SMR), compared with the general Norwegian male population, were computed. Results: At end of follow-up, 2359 of 9390 patients were deceased. CD was obtained for 2320 patients; 37.6 % TGCT, 24.5 % SC, 19.1 % CVD and 18.8 % OC. SMR for all SC were significant particularly after 20 years of follow-up (1.8 – 3.1), with similar findings in localized disease at diagnosis. SMR were most consistently elevated beyond 20-30 years for SC of the pancreas, large intestine and bladder. By contrast, SMR for CVD were significant among patients diagnosed 2000-14, both before and after one year of follow-up (2.6). There were no significant SMR for CVD beyond 20 years of follow-up. Several OC SMR were elevated, such as for digestive and genitourinary diseases beyond 20-30 years (2.2 – 5.1). Conclusions: TGCT patients have increased RR of SC and OC death even beyond 20-30 years of follow-up, while the increased RR of CVD death is mostly confined to the first decade. CVD deaths in patients diagnosed 2000-14 are a particular concern. Continuing optimization of TGCT treatment and follow-up schemes is required, including further research on toxicity mechanisms.
Histologic determinants of long-term overall survival in patients (pts) with germ cell tumors (GCT).
Authors: Funt Samuel , Patil Sujata , Feldman Darren R. , Motzer Robert J. , Bajorin Dean F. , Sheinfeld Joel , Tickoo Satish , Reuter Victor E. , Bosl George J. 
Published: September 2018

4555 Background: GCT display totipotential differentiation ranging from pluripotent embryonal carcinoma to extraembryonic (choriocarcinoma, yolk sac) to somatic cell types (teratoma [T]). We hypothesized that long-term survival after platinum-based chemotherapy (PC) is dependent upon histology. Methods: Advanced GCT pts who received PC from 4/1975 to 5/1996 and had a pre-PC primary tumor specimen available were included. Each pre-PC cell type was reviewed and confirmed. Residual tumor size post-PC was recorded when available. Differences in cumulative incidence (CUI) of death due to disease (DOD) between histologic cell types and other baseline characteristics were evaluated using a competing risks approach and the Fine & Gray test. Results: Pre-PC primary tumor specimens (96% testis, 3% mediastinum) were available from 231 pts. Median age was 29 years (y) and median followup 17 y (range 0.3-35 y). 41 pts had pure seminoma; of the remaining 190 with nonseminomatous GCT (NSGCT), 81 had an element of T (n=29 mature T, n=42 immature T, n=10 both). At PC start, 60% of pts were IGCCCG good risk, 26% intermediate, and 13% poor with no difference for NSGCT based on presence vs. absence of T (p=0.53). Of 72 deaths, 50 were DOD, 20 from other causes, and 2 from unknown causes. The 5, 10, and 15 y CUI of death from any cause was 20%, 23%, and 26%, respectively. CUI of DOD at 5, 10 and 15 y was 18%, 20%, 22%, respectively. CUI of DOD at 2, 5, 10 and 15 y by histologic group is provided in the Table. Presence of T was associated with greater CUI of DOD vs. NSGCT without T (p=0.04) and mature T with a greater CUI of DOD vs. immature T (p=0.03). NSGCT pts with T were also more likely to have residual retroperitoneal disease >1cm after PC vs. those without T (50 vs. 4.2%; p=0.01). Conclusions: With long-term followup, the presence of an element of T, particularly mature T, in mixed NSGCT was associated with a higher risk of DOD than tumors without T, which have the same risk of DOD as pure seminoma. These data suggest that the presence of T in the primary tumor may be an important clinical predictor of long-term outcome in men with GCT. [Table: see text]
Pazopanib exposure-response assessment as adjuvant therapy for patients with localized or locally advanced renal cell carcinoma (RCC) following nephrectomy.
Authors: Sternberg Cora N. , Donskov Frede , Haas Naomi B. , Doehn Christian , Russo Paul , Elmeliegy Mohamed , Banerjee Hiya , Aimone Paola , Voi Maurizio , Motzer Robert J. 
Published: September 2018

4564 Background: PROTECT was a Phase 3 randomized placebo-controlled study to evaluate pazopanib efficacy and safety as adjuvant RCC treatment. The starting dose was 800 mg daily, which was reduced to 600 mg in an attempt to improve tolerability. Pazopanib trough concentrations (Ctrough) were collected from 358 patients at the 600-mg starting dose at two timepoints (Week 3/ 5 and Week 16/20). This analysis characterized the relationship between Ctrough and efficacy and safety endpoints. Methods: The relationship between pazopanib Ctrough and disease-free survival (DFS) was explored by Cox regression analysis. DFS of pazopanib Ctrough quartiles was explored using Kaplan-Meier plots. Exposure-safety relationship was explored via summaries of all grade adverse events (AEs), grade 3/4 (G3/4) AEs, and AE-related treatment discontinuation by Ctrough quartiles. Results: The geometric mean (geo-CV%) of Ctrough at 600-mg dose was 31.4 (57%) µg/mL and 25.3 (70%) µg/mL for Week 3/5 and Week 16/20, respectively. At Week 16/20, Ctrough values overlapped among patients receiving 400-, 600-, and 800-mg doses. Cox regression analysis showed pazopanib Ctrough at Week 3/5 as a significant covariate for DFS after adjusting for TNM staging and Fuhrman Nuclear grading (HR: 0.58, 95% CI, 0.42, 0.82; p = 0.002). Longer DFS was observed in higher Week 3/5 Ctrough quartiles (median DFS by quartile—Q1: 41.89 months, Q2-Q4: median DFS not reached). Incidence of all-grade AEs, as well as G3/4 hypertension, increased as Ctrough increased. Treatment discontinuation due to hypertension among pazopanib-treated subjects was low (3.1% vs < 1% in the placebo group). Ctrough was not correlated to G3/4 ALT increase. Incidence of other G3/4 AEs plateaued at higher Ctrough. No relationship was observed between Ctrough and treatment discontinuation due to AEs. Conclusions: Pazopanib Ctrough levels in PROTECT were consistent with levels associated with efficacy in the advanced setting. Higher pazopanib Ctrough correlated with longer DFS. Higher pazopanib exposure did not increase the incidence of G3/4 AEs, with the exception of hypertension, which was adequately controlled and managed. Clinical trial information: NCT01235962.
Long-term response and time to response to pazopanib (PAZ) and sunitinib (SUN) in metastatic renal cell carcinoma (mRCC): COMPARZ subanalysis.
Authors: Tannir Nizar M. , Porta Camillo , Gruenwald Viktor , Choueiri Toni K. , Ahmad Qasim , Carrasco Alfonso Marlene , Dezzani Luca , Han Jackie , Sternberg Cora N. 
Published: September 2018

4572 Background: COMPARZ (NCT00720941) was a phase 3, randomized, controlled, open-label trial that demonstrated comparable efficacy of first-line PAZ and SUN, but favorable safety and quality of life profiles for PAZ in 1110 patients with mRCC (NEJM 2013;369:722). The objectives of this study were to identify patients from COMPARZ who exhibited a long-term response (LTR) to PAZ and SUN, determine time to response, and describe the clinical characteristics of patients who achieved LTR. Methods: Patients in the intention-to-treat population of COMPARZ were analyzed for differences in LTR (≥10 months [mos]) as measured by responder rate with either complete response or partial response (CR/PR) and PFS rate, and time to response. We also compared the clinical characteristics between long-term and shorter-term responders within and between each treatment arm. Results: The overall percentage of long-term responders with CR/PR (PAZ = 14%, SUN = 13%) and PFS (PAZ = 31.4%, SUN = 33.6%) in the PAZ and SUN groups were similar. This similarity was observed regardless of the cut-off for long-term duration of response. However, a shorter time to achieve CR/PR was observed in the overall population with PAZ (11.9 weeks [95% CI, 11.3–12.1] vs 17.4 weeks; [95% CI, 12.7–18.0]). Analysis conducted to identify baseline clinical characteristics that may be related to LTR will be reported. Conclusions: These exploratory subanalyses in long-term responders support the overall efficacy results with PAZ and SUN, which were reported in the COMPARZ trial. However, the results here demonstrate that the time to response was shorter with PAZ versus SUN. Clinical trial information: NCT00720941.
Impact of geographic region on overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC): Results from a pooled clinical trials database.
Authors: Fay Andre Poisl , McKay Rana R. , Lin Xun , Simantov Ronit , Choueiri Toni K. 
Published: September 2018

4583 Background: Health determinants vary according to the geographic region and may impact the outcomes of mRCC patients treated on clinical trials of targeted therapy. We investigate the OS by geographic region of mRCC patients treated in the targeted therapy era. Methods: We conducted a pooled analysis of mRCC patients treated on phase II and III clinical trials. Clinical characteristics and survival data were collected. Statistical analyses were performed using the Kaplan-Meier method and log-rank test in univariate analysis. Results: Overall, 4736 patients were included in the analysis. Patient characteristics differed according to geographic region (table). No statistically significant differences in OS were observed when comparing US/Canada (USC, reference) to other regions: Latin America (LA), Asia/Oceania/Africa (AOA), and Eastern Europe (EE). OS differed among patients enrolled on trials in the USC compared to Western Europe (WE) (20.3 vs.17.4 months, respectively; HR: 1.15; 95%CI 1.03-1.3 p = 0.015). All grade treatment-related adverse events (AE) were reported more frequently in USC. There were no significant differences in grade 3-5 AEs between groups. Conclusions: We highlight that despite differing baseline characteristics, OS was similar among most geographic regions. Factors such as disease biology, access to care, AE reporting, and quality of care that may contribute to potential differences in outcomes among regions need to be further characterized. [Table: see text]
Phase 3 prognostic analysis of the automated bone scan index (aBSI) in men with bone-metastatic castration-resistant prostate cancer (CRPC).
Authors: Armstrong Andrew J. , Edenbrandt Lars , Bondesson Eva , Anand Aseem , Nordle Orjan , Carducci Michael Anthony , Morris Michael J. 
Published: September 2018

5006 Background: Quantitative measures of metastatic bone disease are needed in men with mCRPC. We recently demonstrated the validity/reproducibility of a computational approach to bone scan imaging that employs artificial intelligence called the automated BSI (aBSI), which quantifies the percent of skeletal mass involved by cancer. We aimed to extend the prognostic validation of aBSI in a multinational prospective phase 3 clinical study of men with bone-metastatic CRPC. Methods: Whole-body bone scans were acquired at screening in a placebo-controlled phase 3 trial of men with mCRPC and bone metastases and treated with tasquinimod/placebo (n = 1,245). The prospective aBSI biomarker analysis plan was locked in Sept 2014 prior to treatment unblinding. All scans generated at 241 trial sites in 37 countries were assessed for image quality and analyzed using the EXINI boneBSI v.2 software and were blindly associated with outcomes. Baseline aBSI was evaluated for its independent prognostic association with overall survival (OS), radiographic progression-free survival (rPFS), and symptomatic skeletal related events (SSEs). Results: The aBSI-population (721 pts) was representative of the entire trial population based on patient characteristics at screening and OS outcomes. Median aBSI was 1.07 (SE 0.05). The aBSI-population was divided into quartiles (n = 180-181) with aBSI-levels of 0 - 0.3 (Q1); > 0.3 - 1.1 (Q2); > 1.1 - 4.0 (Q3); and > 4.0 (Q4) and median OS ranging from 35 months (Q1) to 13 mo (Q4) (p < 0.0001). Baseline aBSI was significantly associated with OS (HR 1.2 per doubling of BSI; p < 0.0001) and remained independently associated with OS after adjustment for treatment, PSA, CRP, LDH and albumin. Baseline aBSI was also strongly associated with rPFS (p = 0.0005), time to symptomatic progression (p < 0.0001), and time to SSE (p = 0.001). Conclusions: This analysis represents the first phase 3 evaluation of aBSI as a clinically validated prognostic biomarker for OS, rPFS, and SSEs in men with bone-metastatic CRPC, providing independent prognostic information over commonly measured clinical characteristics. Clinical trial information: NCT01234311.
Circulating tumor cell (CTC) number as a response endpoint in metastatic castration resistant (mCRPC) compared with PSA across five randomized phase 3 trials.
Authors: Heller Glenn , Mccormack Robert Thomas , Kheoh Thian , Smith Matthew Raymond , Dreicer Robert , Saad Fred , De Wit Ronald , Aftab Dana T. , Hirmand Mohammad , MacLean David B. , Fizazi Karim , De Bono Johann S. , Scher Howard I. 
Published: September 2018

5007 Background: Radiographic progression and overall survival (OS) are the traditional clinical benefit measures for mCRPC trials. Reliable indicators of response that occur early are a critical unmet need in practice and clinical research. We explored a week 13 CTC and prostate-specific antigen (PSA) endpoint relative to baseline in 5 prospective randomized phase 3 registration trials that enrolled 5912 pts. OS was the primary endpoint. Methods: CTC number (CellSearch) and PSA values in patients who survived at least 13 weeks were evaluated as response endpoints in COU-AA-301, AFFIRM, ELM-PC-5, ELM-PC-4 and COMET-1. Pts with missing values at week 13 were considered non-responders. The endpoints considered are shown in Table 1. Results: The discriminatory strength of the response endpoints with respect to OS was estimated using the weighted c-index. To summarize discrimination results for each measure, the mean and the standard deviation based on the weighted c-indices from the 5 studies were computed. Conclusions: CTC0 and CTC conversion endpoints had the highest discriminatory power for OS relative to the % decline in CTC or PSA endpoints. The percent of pts eligible and evaluable for the CTC0 endpoint was significantly higher than the conversion endpoint, 75% vs. 51%, respectively. These two absolute measures of CTC can be considered meaningful response indicators in mCRPC clinical trials. [Table: see text] [Table: see text]
Need for re-evaluation of current guidelines based on results from germline genetic testing in prostate cancer.
Authors: Nicolosi Piper L.W. , Michalski Scott T. , Freschi Brandy , O'Leary Erin , Quintana Rita , Wilson Ian , Powers Martin P. , Sartor Oliver 
Published: September 2018

5009 Background: Inherited risk for prostate cancer (PCa) is potentially associated with more aggressive disease. Recent data indicate that DNA repair gene abnormalities may be much more common than previously appreciated, especially BRCA2, ATM, CHEK2, BRCA1, RAD51D, and PALB2. Herein, we investigate the efficacy of a targeted gene panel in men with PCa and evaluate clinical factors in relationship to current guidelines for genetic screening. Methods: DNA sequencing and exon-level copy number analysis were performed in 1158 PCa patients (pts) between 2013 and 2016 at a commercial diagnostic laboratory. The genes requisitioned varied but consistently included 14 genes on a hereditary PCa panel, most of which were DNA repair genes. Evaluation included Gleason scores and eligibility for genetic screening based on any NCCN testing criteria in pts with positive findings (pathogenic, likely pathogenic, and risk allele). Results: Pathogenic findings were identified in 199 of 1158 (17.2%) pts, 13 pts (1.0%) had two variants. Roughly 75% of detected variants were in genes on the hereditary PCa panel, of which 34.4% were BRCA1/2. Positive variants in HOXB13, a gene associated only with PCa risk, were identified in eight (3.8%) pts. DNA mismatch repair variants, alterations with substantial known therapeutic implications, were detected in 1.7% of samples. A total of 12.4% of pts with Gleason scores of ≤6, compared with 15.4% of those with scores of ≥7 had a pathogenic variant. Within this cohort, 126 (63%) patients with positive results were eligible for genetic testing based on currently available NCCN guidelines, whereas 73 (37%) would not have qualified. Conclusions: Current NCCN guidelines and Gleason scores cannot be used to reliably stratify PCa pts for the presence/absence of pathogenic germline variants. Most positive results identified in this study have important management implications for pts and their families. The percentage of pts with germline variants who did not meet current genetic screening criteria underscores the need for revisiting current guidelines which cannot, at this time, reliably be used to predict pathologic findings on genetic testing.
Clinical outcome of metastatic castration-resistant prostate cancer (mCRPC) patients (pts) with a post-treatment circulating tumor cell (CTC) of 0 vs CTC > 0: Post hoc analysis of COU-AA-301.
Authors: Scher Howard I. , Heller Glenn , Yu Margaret K. , Kheoh Thian , Peng Weimin , De Bono Johann S. 
Published: September 2018

5015 Background: Assessment of radiographic response by RECIST in the majority of mCRPC pts is limited by the lack of measurable disease. Changes in CTC counts (CTCs) enumerated using Veridex CellSearch from unfavorable at baseline (BL [≥ 5 cells/7.5 mL]) to favorable (≤ 4) are prognostic for survival, and the test is FDA cleared as an aid in the monitoring of metastatic PC. The CTC cutpoint of ≥ 5 excludes many pts from response assessment. Examining CTCs alone and in combination with other biomarkers as a potential surrogate for clinical benefit was a secondary objective of COU-AA-301, a phase 3 trial of abiraterone acetate + prednisone vs prednisone alone in mCRPC. Methods: Pts from both treatment (tmt) groups with BL CTC > 0 were combined to assess CTC = 0 as a response criterion. Association between CTC response, defined as BL CTC > 0 and post-BL CTC = 0, and clinical outcomes was assessed. CTCs were determined at BL and 4, 8, and 12 wks. Pts with BL CTC > 0 and missing post-tmt CTCs were considered nonresponders. Radiographic response was first assessed at Wk 12. Overall survival (OS) was estimated using the Kaplan-Meier method. Results: Among739 pts with BL CTC > 0, 141 had measurable disease. At Wk 12, 19% (141/739) of pts were CTC responders and 81% (598/739) were CTC nonresponders. Among CTC responders, 74% (104/141) had stable disease or better by RECIST; 26% (37/141) were either not evaluable or had disease progression by RECIST. Median OS was 23.8 and 10.0 mos for CTC responders (n = 141) and nonresponders (n = 598), respectively. Among pts with liver and/or lung metastases, 86% (24/28) of CTC responders at Wk 12 had stable disease or better by RECIST; 14% (4/28) had disease progression by RECIST. Median OS was 19.9 and 7.1 mos for CTC responders (n = 28) and nonresponders (n = 127), respectively. Similar results were observed in Wk 8 CTC responders. Conclusions: For mCRPC pts with BL CTC > 0, CTC response on tmt (CTC = 0) is associated with longer survival and could be considered a response criterion. Additional analysis is required to fully characterize the relationship between CTC = 0 and objective response by RECIST in pts with measurable disease. Clinical trial information: NCT00638690.
Extended versus limited pelvic lymphadenectomy during radical prostatectomy for intermediate- and high-risk prostate cancer: Early outcomes from a randomized controlled phase III study.
Authors: Lestingi Jean Felipe Prodocimo , Guglielmetti Giuliano , Pontes Jr Jose , Mitre Anuar Ibrahim , Sarkis Alvaro , Bastos Diogo Assed , Riechelmann Rachel , Mattedi Romulo Loss , Cordeiro Mauricio , Coelho Rafael , Srougi Miguel , Nahas William Carlos 
Published: September 2018

5018 Background: The role of extended pelvic lymph node dissection (ePLND) in treating prostate cancer (PCa) patients remains controversial, mainly by the lack of RCTs. Methods: Patients with D'Amico intermediate or high risk PCa, absence of bone metastasis and no previous treatment were prospectively computer randomised to undergo extended or limited PLND (1:1) during radical prostatectomy. Limited PLND (lPLND) included the obturator chain bilaterally; ePLND involved bilaterally chains: obturator, external-, internal-, common-iliac and pre-sacral. Surgical specimens and each chain were analyzed separately, according to College of American Pathologists. All patients signed a free and informed consent and local ethics committee approved the study. The primary endpoint was biochemical recurrence-free survival, analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01812902. Results: Since May 2012 until August 2016, 291 patients were randomly assigned, 145 to ePLND and 146 to lPLND. Preoperative data were comparable between groups. Median follow-up was 35.2 months. EPLND increased significantly operative time (54 minutes), estimated blood loss (100 mL), length of hospital stays (1 day) [p≤0.001], transfusion rate [p = 0.05] and postoperative complications according to Clavien scale [p = 0.03]. There was no difference in Pathologic Gleason grade, T stage or positive surgical margin. On ePLND and lPLND groups, 59.3% and 61.7% were staged ≥ pT3a, respectively. EPLND and lPLND yielded median (mean) 17 (19.8) and 3 (4.1) nodes, respectively (p < 0.001). EPLND showed 6.3 times more lymph node metastases (p < 0.001) and only it was able to show positive nodes in intermediate risk. There were no difference in biochemical recurrence (PSA ≥ 0.2 ng/mL) using Kaplan-Meyer method (p = 0.4), Radiotherapy, Androgen Deprivation Therapy, bone metastases or death. Conclusions: Extended lymphadenectomy in intermediate- and high-risk prostate cancer patients is associated with better tumor staging, increased morbidity and no oncological benefits in this initial short follow-up time. Clinical trial information: NCT01812902.