bluuebunny/crossref_metadata_2025_split huggingface dataset:
TAS-118 (S-1 plus leucovorin) versus S-1 in gemcitabine-refractory advanced pancreatic cancer: A randomized, open-label, phase III trial (GRAPE trial).
Authors: Ueno Makoto , Ioka Tatsuya , Ueno Hideki , Park Joon Oh , Chang Heung-Moon , Sasahira Naoki , Kanai Masashi , Chung Ik-Joo , Ikeda Masafumi , Nakamori Shoji , Mizuno Nobumasa , Omuro Yasushi , Yamaguchi Taketo , Hara Hiroki , Sugimori Kazuya , Furuse Junji , Takeuchi Masahiro , Okusaka Takuji , Boku Narikazu , Hyodo Ichinosuke 
Published: September 2018

4099 Background: Addition of oral leucovorin (LV) to S-1 significantly improved progression-free survival (PFS) in a previous randomized phase II trial in Japanese patients (pts) with gemcitabine (GEM)-refractory advanced pancreatic cancer (PC). TAS-118 is an oral drug containing S-1 and LV. This phase III trial conducted in Japan and Korea compared overall survival (OS) between GEM-refractory advanced PC pts treated with TAS-118 and S-1. Methods: GEM-refractory PC pts were randomized in a 1:1 ratio to receive TAS-118 (S-1; 40-60 mg and LV; 25 mg bid for 1w, q2w) or S-1 (S-1; 40-60 mg bid for 4w, q6w). The primary endpoint was OS. The secondary endpoints included PFS, overall response rate, disease control rate, duration of response, and safety. Results: Five hundred and eighty-six pts were eligible for efficacy assessment (TAS-118: n=296 and S-1: n=290). Baseline characteristics were well balanced between the treatment arms. TAS-118 did not result in a statistically significant improvement in OS compared with that achieved with S-1 (median OS, 7.6 months vs. 7.9 months; hazard ratio [HR], 0.98; 95% CI, 0.82 to 1.16; P=0.756). However, it significantly improved PFS compared to that achieved with S-1 (median PFS, 3.9 months vs. 2.8 months; HR, 0.80; 95% CI, 0.67 to 0.95; P=0.009). Pre-planned subgroup analysis of OS showed significant interactions between the treatment effects and pancreatic resection (P=0.025), and between the treatment effects and country (P=0.004). Grade 3/4 drug-related adverse events (≥5% incidences) in TAS-118 and S-1 arms included diarrhea (7.0% vs. 7.3%), anorexia (6.7% vs. 5.0%), stomatitis (6.7% vs. 0.7%), and anemia (3.3% vs. 5.0%). Conclusions: The primary endpoint was not met. Further, the interactions between the treatment effects and pancreatic resection, and between the treatment effects and country, might affect the results. Clinical trial information: 132172. [Table: see text]
A randomized phase II trial comparing different schedules of nab-paclitaxel (nabP) combined with gemcitabine (GEM) as first line treatment for metastatic pancreatic adenocarcinoma (mPDAC).
Authors: Corrie Philippa , Qian Wendi , Basu Bristi , Valle Juan W. , Falk Stephen , Iwuji Chinenyu , Wasan Harpreet Singh , Palmer Daniel H. , Scott-Brown Martin , Wadsley Jonathan , Arif Seema Safia , Bridgewater John A. , Propper David , Gillmore Roopinder , Gopinathan Aarthi , Bax Lisa , Machin Andrea , Neesse Albrecht , Tuveson David A. , Jodrell Duncan Ian 
Published: September 2018

4100 Background: NabP+GEM chemotherapy improves survival compared with GEM monotherapy as treatment for mPDAC. A PDAC mouse model suggested that nabP potentiates GEM activity by reducing cytidine deaminase levels and scheduling may be critical to optimise clinical benefit. Methods: Patients (pts) were randomised to receive standard concomitant (CON) nabP+GEM or sequential (SEQ) administration, with nabP given 24 hours before GEM. After 6 cycles, pts benefiting from treatment could continue the same regimen until disease progression. The primary endpoint was progression-free survival (PFS) by RECIST v1.1; secondary endpoints included safety, objective response rate (ORR), overall survival (OS) and quality of life (QoL). Serial blood and baseline tumour samples were collected for exploratory biomarkers. Results: Between March 2014 and 2016, 146 pts (71 SEQ, 75 CON) were recruited. Median age (range) was 66 (45-82) years; Karnofsky performance status was 70 (in 12% pts), 80 (27%), 90 (38%) or 100 (24%); 47% had pancreatic head primaries; 84% had liver metastases. Median no. cycles received was 4 SEQ, 3 CON; 51 pts (35%) received ≥6 cycles of treatment (42% SEQ, 28% CON). A 24+2hr interval was achieved in > 90% SEQ admin. Grade ≥3 adverse events experienced by ≥10% pts (SEQ, CON) were neutropaenia (54%, 30%; p = 0.003), febrile neutropaenia (12%, 12%), fatigue (22%, 15%), vomiting (7%, 11%) and anaemia (10%, 5%). G-CSF was administered at local investigator's discretion to 35 pts (23 SEQ, 12 CON; p = 0.015). To date, 112 pts have died. 6 month (m) PFS by SEQ and CON arms were 47% and 33%; median PFS were 5.8 and 4.0m; hazard ratio (HR) = 0.66, 95% CI = 0.46-0.95; 12m OS by SEQ and CON arms were 29% and 26%; median OS were 10.1 and 7.9m; HR = 0.88, 95% CI = 0.61-1.29. ORR was 50% SEQ and 33% CON (p = 0.065). Mean baseline QoL Global health status score was 60.6 SEQ and 63.4 CON. The mean change in QoL score from baseline at 24 weeks was -2.1 SEQ and -12.1 CON. Conclusions: Sequential delivery of nabP combined with GEM trended towards improving all clinically relevant efficacy end points: PFS, OS, and ORR. Translational correlates will be reported in due course. Clinical trial information: ISRCTN71070888.
Prospective assessment for pathogenic germline alterations (PGA) in pancreas cancer (PAC).
Authors: Jordan Emmet , Lowery Maeve Aine , Wong Winston , Kemel Yelena , Mukherjee Semanti , Ravichandran Vignesh , Basturk Olca , Yu Kenneth H. , Iacobuzio-Donahue Christine , Lincoln Anne , Varghese Anna M. , Abou-Alfa Ghassan K. , Leach Steven D , Klimstra David S. , Allen Peter J. , Robson Mark E. , Stadler Zsofia Kinga , Vijai Joseph , Offit Kenneth , O'Reilly Eileen Mary 
Published: September 2018

4102 Background: Cancer predisposition syndromes are identified in a subset of PAC. Identifying PGA has implications for therapy as well as for cancer predisposition in blood relatives. Germline testing (GT) in the US is currently performed in a small subset of PAC patients according to NCCN/other guidelines. At MSKCC, we have implemented an ‘opt in’ strategy to perform germline testing in all patients evaluated in PAC clinics at MSKCC. Methods: PAC pts consented prospectively for GT had samples analyzed for pathogenic or likely pathogenic variants using the MSK-IMPACT germline platform (NCT01775072). All pts first had somatic profiling of tumor samples for > 340 genes by MSK-IMPACT. Clinicopathological features, time to progression on platinum (TTPP) and overall survival (OS) were collated. Results: N = 305 PAC pts consented for GT between 9/2015-11/2016.164/305 (54%) were male, 70/305 (23%) were Ashkenazi Jewish. 242 pts (79%) had a family hx of cancer. 67/305 (22%) had a GA identified, 45/67 (67%) were stage III/IV at dx. Median age at PAC dx for all GA carriers was 60 years (y) (range 29-81) compared to 66 y (18-69) without GA. Median age at dx was 54 y (32-68) for BRCA1 and 61 y (37-77) for BRCA2 GA. 3/9 and 3/20 pts with BRCA1/2 GA had a PAC dx < 50 y. 2/63 pts (3%) with no family hx had a GA (CDKN2A, PMS2). N = 5/22 pts (23%) with a 1st degree relative (DR) with PAC had a GA. N = 13/45 pts (29%) had a GA with either a 1st or 2nd DR with PAC. 19/84 pts (23%) with ≥2 1stDR with cancer had a GA detected. For median OS and TTP on platinum therapy, see Table. Pts with BRCA1/2, ATM and those with coexisting GA tended to have a better median OS as well as longer TTP on platinum therapy (Table). Conclusions: GA’s are significantly under identified in PAC using current practices with a high, frequency (22%) observed in this relatively unselected cohort. BRCA mutations are the most frequent GA noted. There are significant implications of these observations for therapy and for blood relatives. [Table: see text]
Defining DDR defectiveness in pancreatic cancer.
Authors: Dreyer Stephan , Paulus-Hock Viola , Lampraki Eirini-Maria , Bailey Peter , Chang David Kuang-Fu , Biankin Andrew 
Published: September 2018

4115 Background: Recent whole genome sequencing analysis of Pancreatic Cancer (PC) revealed that up to 24% of PC may harbor defects in DNA damage response (DDR). There is increasing evidence that DDR defective tumors preferentially respond to DNA damaging agents, representing novel therapeutic strategy for PC using a synthetic lethality approach. The aim of this study is to define and refine DDR defective phenotypes in PC using next-generation preclinical model systems. Methods: From a panel of 40 patient-derived cell lines (PDCL) and 64 patient-derived xenografts (PDX), generated and extensively characterized as part of the International Cancer Genome Initiative (ICGC), we identified DDR defective models using recently described putative biomarkers of DDR defectiveness. Cytotoxic viability assays were performed using a panel of DNA damaging agents and inhibitors of key molecules in DDR pathway, including Cisplatin, PARP inhibitors, ATR inhibitor (AZD6738); and ATM inhibitor (AZD0156). Appropriate subcutaneous PDX models were also generated to test the hypothesis using various therapeutic regimens. Results: DDR defective PDCLs were selected based on a combination of an unstable genome, and/or a high BRCA mutational signature, and/or deleterious mutations in BRCA1/2, PALB2 or ARID1A. DDR defective PDCLs were significantly more sensitive to Cisplatin, PARP and ATR inhibitors. The ATR inhibitor AZD6738, and ATM inhibitor AZD0156 sensitized PDCLs with no putative biomarkers of DDR defectiveness to Cisplatin, demonstrating a ‘fabricated’ synthetic lethality. A BRCA1 mutant PDX model responded exceptionally to Cisplatin and the PARP inhibitor Olaparib monotherapy. Conclusions: This study provides proof of concept data that DDR deficiency represents an attractive segment to target in PC using a variety of DNA damaging agents and novel agents targeting key molecules of the DDR pathway in PC. In addition, the DDR defective segment may be significantly larger than just germline BRCA1/2 mutants, which is current clinical trial recruitment criteria. Robust molecular assays with clinical utility to define DDR defectiveness is urgently needed.
Cancer predisposing germline mutations in patients (pts) with urothelial cancer (UC) of the renal pelvis (R-P), ureter (U) and bladder (B).
Authors: Carlo Maria Isabel , Zhang Liying , Mandelker Diana , Vijai Joseph , Cipolla Catharine Kline , Robson Mark E. , Funt Samuel , Hakimi A. Ari , Iyer Gopa , Rosenberg Jonathan E. , Coleman Jonathan , Solit David B. , Offit Kenneth , Bajorin Dean F. 
Published: September 2018

4510 Background: Urothelial cancers (UC) are suspected to have a substantial hereditary component, but other than highly penetrant genes such as those in mismatch-repair pathway (e.g. MSH2) typically associated with R-P/U primaries, heritable gene mutations have not been systematically studied. We sought to investigate the prevalence of known cancer pre-disposing germline mutations in pts with UC originating from all sites within the urinary tract. Methods: Pts with R-P, U and B primaries, unselected for suspicion of inherited cancer syndrome, were prospectively enrolled from medical oncology and urology clinics to a germline sequencing protocol from June 2016 to January 2017. Germline gene analysis was performed in a CLIA-certified lab using a next generation sequencing (NGS) platform (MSK-IMPACT) that analyzes tumor-normal DNA pairs. The germline gene panel consisted of 76 genes associated with hereditary cancer predisposition. Results: As of January 24, 2017, 101 pts have NGS results available, with median age 63 (31-87), 76% male, 24% female. Primary sites were B (67%), R-P/U (31%), or both (3%). 73% had organ-confined disease and 27% had metastases. 8% had early onset (≤45 yrs at diagnosis), 10% had a family history of UC, 25% had documented non-UC cancers. 25 pathogenic or likely pathogenic (P-LP) mutations were identified in 22 patients. P-LP mutations were present in 29% of pts with R-P/U primaries and 18% of pts with B primaries. 12 DNA damage response gene alterations were found (4 CHEK2, 3 BRCA1, 2 BRCA2, 1 ATM, 1 BRIP1, 1 NBN) and 8 in Lynch syndrome associated genes (5 MSH2, 2 MSH6, 1 MLH1). Other mutations include 2 APC, 1 TP53, and 1 FH. Notably 3 pts had 2 alterations each ( MSH6/ APC, BRCA2/ APC, BRCA1/ CHEK2). 9/22 pts with P-LP mutations did not meet American College of Medical Genetics criteria for genetic screening. Conclusions: 22% of UC pts had a germline mutation in a cancer-associated gene. There was an unexpectedly high frequency of pts with DNA-repair pathway mutations. Active accrual is ongoing to define the full spectrum of alterations. These results have profound implications for genetic counseling and screening and further studies are warranted.
Health-related quality of life as a marker of treatment benefit with nivolumab in platinum-refractory patients with metastatic or unresectable urothelial carcinoma from CheckMate 275.
Authors: Necchi Andrea , Grimm Marc-Oliver , Retz Margitta , Arranz Arija Jose Angel , Bracarda Sergio , Bedke Jens , Baron Ari David , Sharma Padmanee , Galsky Matt D. , Vaena Daniel A. , Kalinka-Warzocha Ewa , Cwikiel Magdalena , Pal Sumanta K. , Morales Rafael , Taylor Fiona , Gooden Kyna McCullough , Plimack Elizabeth R. 
Published: September 2018

4526 Background: CheckMate 275 (NCT02387996), a phase II, single-arm study of nivolumab (3 mg/kg every 2 weeks) treatment in platinum-refractory patients (pts) with metastatic urothelial carcinoma, showed an objective response rate of 19.6% (95% CI, 15.0%–24.9%) with manageable toxicity. The objective of this analysis was to examine the impact of nivolumab on health-related quality of life (HRQoL) in the study. Methods: HRQoL was measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and three-level EQ-5D (EQ-5D-3L) and visual analog scale (VAS). Questionnaires were completed at baseline and every 8 weeks thereafter for the first 48 weeks. The analysis cohort included pts with scores recorded at baseline and ≥1 postbaseline assessments while on treatment. Data were analyzed using mixed models, adjusting for baseline score. Results: Of the 270 patients treated with nivolumab, 168 (62%) had an assessment at baseline and ≥1 postbaseline assessment and were included in HRQoL analyses. Completion rates at baseline were 97% for both questionnaires. Statistically significant ( P< 0.05) improvements in mean scores for the EORTC QLQ-C30 subscales measuring role, emotional, and social functioning; global health status/quality of life; nausea/vomiting; pain; dyspnea; insomnia; appetite loss; constipation; and diarrhea were observed at ≥1 time points. With the exception of cognitive functioning, no significant worsening in subscale scores was observed in the EORTC QLQ-C30. Statistically significant and clinically meaningful improvement (based on a minimally important difference of 7) in EQ-5D VAS was noted between weeks 17 and 41. EQ-5D-3L utility index scores based on the UK tariff remained stable during treatment. Conclusions: Results of CheckMate 275 indicate that pts with metastatic or unresectable urothelial carcinoma whose disease progressed or recurred after treatment with a platinum agent exhibited stable, or in some cases statistically significantly improved, HRQoL while being treated with nivolumab, as measured by EORTC QLQ-C30 and EQ-5D-3L. Clinical trial information: NCT02387996.
Survival outcomes in elderly patients with muscle invasive bladder cancer: An analysis of the National Cancer Database.
Authors: Fischer-Valuck Benjamin Walker , Rao Yuan , Rudra Soumon , Hui Caressa , Baumann Brian , Gay Hiram Alberto , Michalski Jeff M. 
Published: September 2018

4538 Background: Many elderly patients are precluded from radical cystectomy (RC) due to existing comorbidities or morbidities associated with RC. Chemoradiation therapy (CRT) is an alternative treatment in this population, but remains widely under-utilized with many receiving chemotherapy (CT) or radiation therapy (RT) alone. This population-based analysis sought to determine if CMT has similar overall survival (OS) to RC, and if CRT is associated with improved OS compared to monotherapy in these patients. Methods: We queried the National Cancer Database (NCDB) for all newly diagnosed MIBC (cT2-T4a N0 M0) cases in patients aged 80 years or older from 2004 to 2013. All included patients underwent TURBT followed by RC, RT alone, CT alone, CRT, or no further treatment. Only patients with radiation doses ( > = 50Gy) were included as receiving RT. Kaplan-Meier, log-rank, and multivariate Cox proportional hazards regression was performed with OS as the primary outcome. Results: 10,055 patients aged > = 80 years were identified. 1,588 underwent RC, 839 received RT, 1,013 received CT, 1,035 had CRT, and 5580 had no further treatment. Mean age was 85.1 years (range, 80-90). 82.1% of patients had Stage II disease. Mean follow-up was 27.6 months (range, 0-137.8). Mean survival of the entire cohort was 28.0 months (95% CI, 27.2-28.8). Mean survival was 43.8 months (95% CI, 41.2-46.3) for patients with RC and 40.8 months (95% CI, 38.2-43.3) for CRT (P = 0.85). Mean survival was 29.1 months (95% CI, 26.8-31.4) and 30.7 months (95% CI, 28.2-33.2) for RT alone vs. CT alone, respectively (P < 0.0001 for both RC and CRT comparisons). 5-year OS for CT alone, RT alone, CRT, and RC was 15.7%, 15.1%, 24.0% and 29.6%, respectively. Multivariate analysis adjusting for age, year of diagnosis, gender, race, treatment location, treatment facility, insurance status, Charlson/Deyo Score, grade, and stage demonstrated an OS benefit in favor of CRT (HR 0.70; 95% CI, 0.63-0.77; P < 0.0001) and RC (HR 0.69; 95% CI, 0.63-0.76; P < 0.0001). Conclusions: For elderly patients with MIBC, both RC and CRT were associated with improved OS compared to CT or RT alone. CRT has similar OS compared to RC, and could be considered standard treatment in this population.
Thromboembolic events after high-intensity training during cisplatin-based chemotherapy for testicular cancer.
Authors: Thorsen Lene , Fossa Sophie D. , Haugnes Hege Sagstuen , Tandstad Torgrim , Brydoy Marianne , Wisloff Torbjorn , Edvardsen Elisabeth , Gjerset Gunhild Maria , Larsen Karl-Otto , Sandset Per Morten , Henriksson Carola , Negaard Helene FS 
Published: September 2018

4551 Background: Physical activity (PA) is believed to reduce acute side-effects as deconditioning, fatigue and nausea during chemotherapy and enhance post-treatment physical and psychosocial recovery. The national multicenter randomized TAST-trial (clinicaltrial.gov: NCT02577172) aimed to determine the effect of high-intensity training (HIT) during chemotherapy for testicular cancer (TC) on acute and post-treatment physical- and psychosocial outcomes. Methods: Patients aged 18 – 60 years with newly diagnosed metastatic TC, planned for 3 or 4 cisplatin-based chemotherapy cycles in combination with etoposide (EP) or etoposide plus bleomycin (BEP), were randomized to HIT during 9 or 12 weeks of chemotherapy or to one lifestyle counseling session (LCS) during first cycle. The HIT included two supervised endurance interval sessions per week, of which 10-15 minutes per session at 85 – 95 % of peak heart rate. The intensity, duration and number of the intervals were predetermined, but adjusted in accordance to the patients’ daily condition. Thromboembolic (TE) complications were registered consecutively. Results: Among the first 9 patients randomized to HIT, 33% (3 patients aged 22, 30 and 44 years) developed severe TE complications; 2 cases of pulmonary embolism (respectively at day 9 and 7 of BEP cycle 2) and 1 myocardial infarction (at day 7 of BEP cycle 3). Common for these patients were non-seminoma TC, clinical stage IIA, good prognosis group and no known risk factors for TE events. TE complications were not observed among the 10 patients randomized to the LCS. Conclusions: Since TC patients within good prognosis group are expected to have about 5 % risk of TE complications during or shortly after cisplatin-based chemotherapy, we cannot exclude that the HIT may have contributed to the unexpected high number of TE events. Until possible mechanisms explaining our observations have been explored, we discourage high-intensity endurance training during cisplatin-based chemotherapy for TC. These observations led to closure of the TAST-trial after inclusion of 19 of 94 planned patients. Clinical trial information: NCT02577172.
Individualization of high dose carboplatin based on therapeutic drug monitoring (TDM) for the treatment of testicular germ cell tumors (TICE protocol): Results of a multicenter phase II study.
Authors: Thomas Fabienne , Moeung Sotheara , Broutin Sophie , Guitton Jerome , Boisdron-Celle Michele , Ciccolini Joseph , Massard Christophe , Flechon Aude , Delva Remy , Gravis Gwenaelle , Lotz Jean-Pierre , Bay Jacques-Olivier , Gross-Goupil Marine , Paci Angelo , Poinsignon Vianney , Fizazi Karim , Lafont Thierry , Lochon Isabelle , Chevreau Christine , Chatelut Etienne 
Published: September 2018

4554 Background: We conducted a national phase II multicenter trial that aimed at evaluating the efficacy and tolerance of Paclitaxel plus Ifosfamide followed by high-dose carboplatin plus etoposide treatment (TICE) in previously treated germ cell tumors. The particularity of our study (in comparison with the standard protocol [Motzer RJ, et al. J Clin Oncol 2000 Mar; 18(6): 1173-1180.]) is that the carboplatin dose was individualized for each patient according to therapeutic drug monitoring (TDM) in order to reach the target AUC of 24 mg.min/ml over 3 days. Methods: In total, 89 patients were evaluable for pharmacokinetic study. Blood samples were taken on day 1 to determine the carboplatin clearance using a Bayesian approach (NONMEM 7.2) and to adjust the dose on day 3 to reach the target AUC of 24 mg.min/ml over 3 days. On days 2 and 3, samples were taken for retrospective assessment of the actual AUC and the intra- and inter-cycle clearance variability. Secondly, a population pharmacokinetic analysis was also performed on 59 patients using NONMEM to develop a covariate equation for carboplatin clearance prediction adapted for future patients treated with the TICE protocol. The performance of this new equation was then prospectively evaluated on the other 30 patients along with different methods of carboplatin clearance prediction. Results: TDM allowed us to control the carboplatin exposure with a mean actual AUC of 24.5 mg.min/ml (22.2 and 28.0 for 5th and 95thpercentile respectively) per cycle. We observed a modest but significant decrease of carboplatin clearance over cycles (median value of change of -11.8% from cycle 1 to cycle 3, maximum value of -36%). The new covariate equation allows unbiased and more accurate prediction of carboplatin clearance in the prospective validation cohort compared to other equations. Conclusions: Carboplatin TDM allowed the target AUC to be accurately reached and thereby avoid over- or under-exposure. We propose a new equation to predict carboplatin clearance more adapted to these particular patients (young males) that could be used as an alternative if the TDM cannot be organized. Clinical trial information: 2008-005068-14.