bluuebunny/crossref_metadata_2025_split huggingface dataset:
Economic burden of select adverse events (AEs) in patients (Pts) with advanced urothelial cancer (aUC) treated with first-line (1L) systemic therapy.
Authors: Grivas Petros , Laliberté François , Doleh Yunes , O'Connor Cristi , Duh Mei Sheng , Shenolikar Rahul 
Published: March 2019

363 Background: Limited information on costs related to incident AEs in pts with aUC in the real-world setting is available. Methods: Pts with aUC treated with 1L systemic therapy (94% chemotherapy, 6% immune checkpoint inhibitor) between 1/2012-9/2017 (first therapy administration defined the index date) were identified using IQVIA Real-World Data Adjudicated Claims – US database. Pts with continuous enrollment for ≥6 months pre- and ≥3 months post-index and ≥1 UC diagnosis code were included. Proportions of pts with febrile neutropenia (FN), dehydration, acute kidney injury (AKI), sepsis, colitis, hepatitis, adrenal insufficiency, and pneumonitis (select AEs), and per-pt-per month (PPPM) healthcare costs were assessed. Incident AEs during 1L therapy were identified using outpatient/inpatient claims and a subgroup of severe AEs (identified using only inpatient claims) was analyzed separately. Incremental costs of AEs were calculated as cost differences (CDs) between pts with and without AEs using multivariate linear regression to adjust for baseline differences. Results: Pts with (n = 666) and without (n = 569) select AEs had similar median age of 62 years; pts with select AE had more women (34.4% vs. 29.0%) and chemotherapy-treated pts than pts without select AEs (96.1% vs. 91.0%) (both p < 0.05). Baseline characteristics were similar in pts with (n = 290) and without (n = 1,290) severe AEs. FN (28.0%; severe 6.3%), dehydration (26.5%; severe 8.3%), AKI (11.3%; severe 8.8%), and sepsis (8.8%; severe 8.0%) occurred most frequently during 1L therapy (median duration: 15 weeks). Adjusted PPPM CDs between pts with and without AEs were $1,716 overall and $6,130 for severe AEs, with the greatest CDs observed for pneumonitis ($14,400; severe $20,242), sepsis ($8,581; severe $9,490) and AKI ($7,977; severe $8,843) (all p < 0.05). Inpatient costs had the largest impact on CDs. Conclusions: Costs of AEs, especially severe, during 1L treatment of aUC can cause substantial burden to healthcare system. Biomarker-based therapy selection, education/awareness early recognition and management of AEs may reduce hospitalizations and healthcare costs, and may impact care quality.
Bladder-preserving therapy using a real-time tumor-tracking radiotherapy system for muscle-invasive bladder cancer.
Authors: Miyata Haruka , Osawa Takahiro , Frumido Jun , Kikuchi Hiroshi , Matsumoto Ryuji , Abe Takashige , Maruyama Satoru , Nishioka Kentaro , Shimizu Shinichi , Hashimoto Takayuki , Shirato Hiroki , Shinohara Nobuo 
Published: March 2019

364 Background: Bladder-preserving therapy with a real-time tumor-tracking radiotherapy system (RTRT system) has been used for muscle-invasive bladder cancer (MIBC) since 1998 in our institution. We evaluate long term outcomes of this therapy. Methods: From 1998 to 2016, 38 patients with a T2-T4N0M0 bladder cancer who were clinically inoperable or refused surgery were enrolled. Transurethral tumor resection (TUR) and 40 Gy irradiation to the whole bladder was followed by TUR of the tumor bed (1st Evaluation) and endoscopic implantation of fiducial markers in the bladder wall around the primary tumor. Then, a boost of 25 Gy was made to the primary tumor using RTRT system. Protocol TUR of the tumor bed was performed 6 months later (2nd Evaluation). Patients with adequate renal function (CCR>45ml/min) received concurrent chemoradiotherapy with nedaplatin (cisplatin analog made in Japan, 70mg/m2 intravenously, day1, day22, day50). Results: Median follow-up for surviving patients was 6 yr. 5- and 10-yr OS were 55%, 40%, and 5- and 10-yr PFS were 55% and 39%, respectively. The CR rate at 1st evaluation was 66%, in those patients 5- and 10-yr OS rates were 70% and 61%. Among the patients with non-CR at 1st evaluation, CR rate at 2nd evaluation was 31%. Local recurrence occurred in 13 patients. One of them was performed cystectomy and 9 were performed TUR and/or bladder injection therapy. 11 patients experienced distant recurrence, 2 of those was performed chemotherapy. In univariate analysis, male (OS; HR: 0.33, 95% CI: 0.12-0.92, PFS; HR:0.25, 95% CI: 0.09-0.69) and PS0-1 (OS; HR: 0.26, 95% CI: 0.09-0.79, PFS; HR: 0.29, 95% CI: 0.10-0.85) were significantly associated with good OS and PFS (shown in Table). In multivariate analysis, the both of these covariates were also significantly associated with good OS and PFS (male; OS; HR: 0.31, 95% CI: 0.11-0.88, PFS; HR: 0.21, 95% CI: 0.07-0.62, PS0-1; OS; HR: 0.25, 95% CI: 0.08-0.76, PFS; HR: 0.24, 95%CI: 0.09-0.75). Conclusions: Bladder-preserving therapy is a considerable option in patients medically unfit for or not desiring cystectomy.
Interim analysis of ibrutinib plus paclitaxel for patients with metastatic urothelial carcinoma previously treated with platinum-based chemotherapy.
Authors: Castellano Daniel E. , Morales-Barrera Rafael , Duran Ignacio , Keam Bhumsuk , Chung Ik Joo , Arkenau Tobias , Vaishampayan Ulka N. , Tuthill Mark , Gajate Pablo , Shin Sang Joon , Dang S. Paul , Ju Chia-Hsin , Lin Jennifer , Cole George , James Danelle Frances , Reig Torras Oscar 
Published: March 2019

365 Background: In patients (pts) with advanced urothelial carcinoma (aUC) who progressed after platinum-based chemotherapy (CT), median overall survival (OS) is ~6 mo with CT and 8-10 mo with novel immune checkpoint inhibitors (ICIs). Ibrutinib (ibr), a first-in-class, once-daily, inhibitor of Bruton’s tyrosine kinase (BTK) with immunomodulatory properties, plus paclitaxel (pac) may be an effective treatment (tx) for pts with UC. Methods: One cohort in this phase 1b/2 study assessed ibr + pac in pts who had 1-2 prior tx (≥1 platinum-based and/or ICIs) with aUC. Recommended phase 2 dose per Phase 1b was ibr 840 mg/d + weekly pac 80 mg/m2 in 21-d cycles; starting ibr dose: 560 mg/d. Preliminary BTK/other kinase assessment in baseline tumor biopsies was done by NanoString gene expression assay. Results: Based on interim analysis of the first 29 pts treated (ibr 840/560 mg/d, n = 25/4), median time on study/ tx was 7.2/2.3 mo (max tx: 11.5 mo). Median age was 67 y; 52% had 2 prior regimens (prior PDL-1 inhibitors, 100%). Unconfirmed ORR was 41% (complete/partial response: 10%/31%) and disease control rate was 62%. ORR was 71% for subset of 7 pts with only lymph node metastases, and 36% for 14 pts with 1 prior tx and 47% for 15 with 2 prior tx. Median duration of response was 4.2 mo (90% CI: 1.9, 7.1). Median PFS was 3.6 mo (90% CI: 1.6, 5.4) and median OS was 14.7 mo (90% CI: 7.7, 15.9). Follow-up for durability/survival is ongoing with 6 pts alive without progression, with 4 still on ibr tx. 76% of pts had grade ≥3 adverse events (AEs); 4 discontinued ibr + pac due to AEs and 1 had major hemorrhage. Pac exposure was not impacted by ibr; pac geometric mean Cmax (2066 ng/mL) and AUC0-∞ (3813 ng.h/mL) were consistent with historical data. Preliminary tumor biopsy data showed a non-significant trend of higher BTK/ITK/BMX expression in responders; analyses are ongoing for ibr-targeted kinases. Conclusions: These results indicate that ibr + pac shows promising results for ORR and OS in pts with aUC previously treated with platinum-based CT and ICIs. There were no unexpected safety signals; ibr + pac seemed tolerable. Follow up of these and additional pts will support the efficacy and safety of ibr + pac in this study. Clinical trial information: NCT02599324.
Comparing costs of radical cystectomy versus trimodal therapy for patients diagnosed with localized muscle-invasive bladder cancer.
Authors: Ray-Zack Mohamed Danny , Shan Yong , Kerr Preston , Kosarek Christopher David , Hudgins Hogan K , Jazzar Usama , Tyler Douglas S. , Freedland Stephen J. , Swanson Todd A. , Baillargeon Jacques G. , Hu Jim C. , Kaul Sapna , Kamat Ashish M. , Gore John L. , Mehta Hemalkumar B , Williams Stephen Bentley 
Published: March 2019

372 Background: Studies on the cost of muscle-invasive bladder cancer treatments lack granularity and are limited to 180 days. This study aimed to compare the one-year costs of trimodal therapy versus radical cystectomy, accounting for survival and intensity effects on total costs. Methods: Using Surveillance, Epidemiology, and End Results (SEER)-Medicare linked data, we included a total of 2,963 patients aged ≥66 years diagnosed with clinical stage T2-4a bladder cancer between 2002 and 2011. We compared total Medicare costs within one year of diagnosis among patients following radical cystectomy or trimodal therapy using inverse probability of treatment weighted (IPTW) propensity score models, which included a two-part estimator to account for intrinsic selection bias. Results: Median total costs were significantly higher for trimodal therapy than radical cystectomy in 90 days ($83,754 vs. $68,692; median difference $11,805, 95% CI $7,745 to $15,864), 180 days ($187,162 vs. $109,078; median difference $62,370, 95% CI $55,581 to $69,160), and 365 days ($289,142 vs. $148,757; median difference $109,027, 95% CI $98,692 to $119,363), respectively. Outpatient, radiology, pharmacy and pathology/laboratory costs contributed largely to the significantly higher costs associated with trimodal therapy. On IPTW-adjusted analyses, patients undergoing trimodal therapy had $142,337 (95% CI $117,423-$175,300) higher costs compared with radical cystectomy one year after treatment (Table). Conclusions: Compared to radical cystectomy, trimodal therapy was associated with higher costs among patients with muscle-invasive bladder cancer. Extrapolating cost figures to the total US population resulted in excess spending of $853 million for trimodal therapy compared with radical cystectomy for patients diagnosed in 2018. [Table: see text]
Prognostic significance of history of nonmuscle invasive bladder cancer in patients with muscle invasive bladder cancer treated with neoadjuvant chemotherapy followed by surgery.
Authors: Lee Yongjune , Kim Young Seok , Hong Bumsik , Cho Yong Mee , Lee Jae-Lyun 
Published: March 2019

375 Background: Efficacy of cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) for T2-4aN1M0 muscle-invasive bladder cancer (MIBC) was proved by randomize controlled trials. Recent retrospective studies suggested that MIBC patients who had a history of non-muscle invasive bladder cancer (NMIBC) had lower pathologic complete response and worse overall survival rate to NAC and RC. This study aimed to compare clinical outcomes between MIBC that progressed from NMIBC (secondary MIBC) and primary MIBC. Methods: A retrospective analysis of patients with urothelial carcinoma (cT2-4aN0-1M0) who received neoadjuvant chemotherapy from January 2011 and December 2017 in Asan Medical Center was conducted. Clinicopathologic outcomes were compared between 187 patients with primary MIBC and 38 patients with secondary MIBC. Results: Baseline characteristics are well balanced between the groups. Downstaging rate ( < ypT2 and no N upstaging) are 46.7% for secondary MIBC group, 55.6% for primary MIBC group (p = 0.390), and positive pathologic metastatic nodes (ypN1+) are observed in 23.3% for secondary MIBC group, 18.3% for primary MIBC group (p = 0.523). There were no differences in overall survival (OS) (3 year OS 69.3% for secondary MIBC, 70.3% for primary MIBC, p = 0.420), disease-free survival (DFS) (3 year DFS 57.7% vs 56.6%, p = 0.880) between the groups. History of NMIBC is not independent prognostic factor for OS on multivariable analysis. Conclusions: Patients with secondary MIBC treated with NAC showed no differences in NAC response, pathologic downstaging rate, OS, DFS compared to patients with primary MIBC. Prospective or larger cohort study are required in the future. Genomic analysis is ongoing to identify genetic differences between two groups.
Comparing clinical outcomes between patients with urothelial carcinoma who treated neoadjuvant chemotherapy by gemcitabine-cisplatin and dose-dense MVAC.
Authors: Lee Yongjune , Kim Young Seok , Hong Bumsik , Cho Yong Mee , Lee Jae-Lyun 
Published: March 2019

376 Background: Prospective randomized trials demonstrated efficacy of MVAC (Methotrexate, Vinblastine, Doxorubicin, Cisplatin) neoadjuvant chemotherapy (NAC) in muscle invasive bladder cancer (MIBC). In metastatic setting urothelial cell carcinoma (UCC), clinical trials showed no difference in oncologic outcomes between Gemcitabine-Cisplatin (GC) and MVAC, and another prospective trial proved dose-dense (dd) MVAC had significantly better overall survival (OS) and response rate then MVAC. Comparative data between GC and ddMVAC are limited in neoadjuvant setting. Methods: A retrospective analysis of patients with urothelial carcinoma (cT2-4aN0-1M0) who received NAC from January 2011 and December 2017 in Asan Medical Center was conducted. Patients who received GC were compared to patients received ddMVAC in terms of outcomes including downstaging ( < ypT2 and no N upstaging), pathologic complete response (pCR, ypT0N0), disease-free survival (DFS), and overall survival (OS) and tolerability. Results: In a total of 277 patients, 176 patients received NAC with GC and 41 patients with dose-dense MVAC. The median chemotherapy cycle is 4 (IQR 3-4) cycles for GC group, 4 (IQR 3-5.5) cycles for dose-dense MVAC group. With an exception of age; GC group is associated with younger age (p = 0.002), other baseline characteristics are well balanced between groups. Downstaging rate are 50.8% in GC group, 58.1% in dose-dense MVAC group (p = 0.47). The rates of achieving ypT0 (28.7% vs 22.6%, p = 0.68), ypN0 (78.3% vs 81.5%, p = 0.39). There were no differences in overall survival (OS) at 3 year (72.2% vs 73.2%, p = 0.58), disease-free survival (DFS) at 3 years (54.9% vs 63.3%, p = 0.21) according to chemotherapy regimens. ddMVAC with prophylactic G-CSF are associated with higher incidence of febrile neutropenia (p = 0.004) than GC. NAC regimen is not independent prognostic factor for OS on multivariable analysis. Conclusions: GC regimen had no significant difference in oncologic outcomes compare to ddMVAC as NAC in UCC.
Mature results from EV-101: A phase I study of enfortumab vedotin in patients with metastatic urothelial cancer (mUC).
Authors: Rosenberg Jonathan E. , Sridhar Srikala S. , Zhang Jingsong , Smith David C. , Ruether Joseph D. , Flaig Thomas W. , Baranda Joaquina Celebre , Lang Joshua Michael , Plimack Elizabeth R. , Sangha Randeep S. , Heath Elisabeth I. , Merchan Jaime R. , Quinn David I. , Srinivas Sandy , Milowsky Matthew I. , Wu Chunzhang , Gartner Elaina M , Melhem-Bertrandt Amal , Petrylak Daniel Peter 
Published: March 2019

377 Background: Enfortumab vedotin (EV) is an antibodydrug conjugate that delivers MMAE, a microtubule disrupting agent, to tumors expressing Nectin-4, a protein found on most urothelial cancers. Preliminary results of the EV-101 study (NCT02091999) suggest EV is active and tolerable. Methods: Patients with mUC treated with ≥1 prior chemotherapy, or those ineligible for cisplatin, received EV 1.25 mg/kg on Day 1, 8, and 15 every 28 day cycle. The primary objective was tolerability; antitumor activity (ORR per RECIST v1.1), assessed every 8 wk, was a secondary objective. Results: As of14 Sept 2018,112 pts with mUC received EV with a median follow up of 13.4 mo. Bladder was the primary tumor site in 86 pts (77%) and 33 (29.5%) had liver metastases (LM). Nearly all pts received prior platinum chemotherapy; 89 (79.5%) received prior anti-PD(L)1. EV was well tolerated; fatigue (53%), alopecia (46%), and decreased appetite (42%) were the most commonly reported treatment-related AEs (TRAEs). Anemia (8%), hyponatremia (7%), UTI (7%), and hyperglycemia (6%) were the grade ≥3 AEs reported in ≥5% of pts regardless of attribution; 4 fatal TRAEs were reported (respiratory failure, urinary tract obstruction, diabetic ketoacidosis, multi-organ failure). Confirmed ORR was 42% (CR, n = 5; PR, n = 42). Among responders, median duration of response was 7.7 mo (95% CI 5.6, 9.6) and 23.4% of responses were ongoing with a median follow up of 11.3 mo. Estimated median PFS and OS were 5.4 mo (95% CI 5.1, 6.3) and 12.5 mo (95% CI 9.3, 16.1), respectively; OS at 1 yr was 51.8%. Similar results were seen in pts with prior anti-PD(L)1 and with LM (Table). Conclusions: Single-agent EV was generally well tolerated and provided encouraging response and survival data in a population with an unmet medical need including pts with LM, which is associated with poor prognosis. Phase 2 and 3 monotherapy studies as well as evaluation of combination therapies are ongoing. Clinical trial information: NCT02091999. [Table: see text]
Impact of sarcopenia on kidney function during neoadjuvant chemotherapy and post cystectomy complications in patients treated for localized muscle-invasive bladder cancer.
Authors: Regnier Pierre , De Luca Valeria , Brunelle Serge , Sfumato Patrick , Walz Jochen , Rybikowski Stanislas , Maubon Thomas , Branger Nicolas , Fakhfakh Sami , Durand Matthieu , Gravis Gwenaelle , Pignot Geraldine 
Published: March 2019

387 Background: Sarcopenia is suspected to influence the complication rates in patients undergoing radical cystectomy. The aim of our study was to assess variations in sarcopenia in patients scheduled for neoadjuvant cisplatin-based chemotherapy (NAC) and radical cystectomy for muscle invasive bladder cancer (MIBC) and to explore the impact of sarcopenia on complications linked to NAC and surgery. Methods: Between January 2012 and December2017, 82 consecutive patients who underwent NAC and RC for cT2-T4 N0 M0 MIBC were retrospectively selected. Using CT scan before and after NAC, Lumbar Skeletal Muscle Index (SMI) was assessed by two observers blinded to patient’s status. We defined severe sarcopenia as SMI < 50 cm2/m2 for men and SMI < 35 cm2/m2 for women. We evaluated pre- and post-NAC cisplatin-based chemotherapy renal function and post-operative complication rates after cystectomy using the Clavien-Dindo classification. We explored risk factors of complications by logistic regression models. Results: According to the SMI cut offs, 47 patients (57.3%) were classified as sarcopenic and 35 patients (42.7%) non-sarcopenic. Patients’ characteristics between sarcopenic and non-sarcopenic patients were not significantly different except for BMI (p < 0.001). Among patients non-sarcopenic before NAC, 9 (19.1%) became sarcopenic after NAC. In multivariate analysis, sarcopenia was an independent significant predictor of renal impairment after NAC (OR 3.01; 95% CI 1.13–8.05; p = 0.02). There was a trend towards a higher rate of stage 3B kidney failure (GFR < 45 mL/min/1.73m2) after NAC in sarcopenic patients (OR 2.79; 95% CI 0.70–11.1) but the difference was not statistically significant (p = 0.14). Moreover, sarcopenia and ASA score were independent significant predictors of postoperative early complications ≤90 days (p = 0.01 and p = 0.02 respectively). Conclusions: We observed significant changes in sarcopenic status during NAC. Sarcopenia, estimated by the lumbar SMI measurement, was an independent predictor associated with the risk of renal impairment during NAC and early postoperative complications after RC.
NKTR-214 + nivolumab in first-line advanced/metastatic urothelial carcinoma (mUC): Updated results from PIVOT-02.
Authors: Siefker-Radtke Arlene O. , Fishman Mayer N. , Balar Arjun Vasant , Grignani Giovanni , Diab Adi , Gao Jianjun , Tagliaferri Mary Ann , Hannah Alison L. , Karski Erin E. , Zalevsky Jonathan , Hoch Ute , Rizwan Ahsan NAQI , Bilen Mehmet Asim 
Published: March 2019

388 Background: Single-agent checkpoint inhibitors have changed the mUC treatment landscape; however, unmet need remains in first-line (1L) cisplatin ineligible mUC, particularly for PD-L1 negative (–) patients (pts). NKTR-214 is a CD122-biased agonist designed to provide sustained signaling through the IL-2 βγ receptor. PIVOT-02 is an ongoing study of NKTR-214 + nivolumab (nivo) in pts with advanced cancers, including mUC. Methods: Pts with mUC who were 1L cisplatin ineligible or refused standard of care (SOC) received NKTR-214 IV 0.006 mg/kg + nivo IV 360 mg q3w. Responses were assessed every 8 wks. Matched blood and tumor biopsies were evaluated for biomarkers including PD-L1 expression (assessed by Dako 28-8 PharmaDx IHC; PD-L1+ defined as ≥ 1% tumor cell staining). Results: As of 11 Oct. 2018, 34 pts received ≥ 1 dose of treatment (cisplatin ineligible [n=22]; refused SOC [n=12]). Median age was 70. Of 34 pts, 23 were efficacy evaluable (defined per protocol as having ≥ 1 post-treatment scan), 7 were pending a first scan, 1 pt was excluded for non-eligibility (no target lesion), and 3 discontinued prior to first scan. Thresholds for efficacy were exceeded in all 1L mUC cohorts under a pre-specified Fleming ORR analysis. In the efficacy evaluable population, overall ORR was 48% (11/23; 95% CI 27–69%) with a 17% CR rate (4/23) and 70% (16/23) DCR. The ORR was 50% in PD-L1– pts (5/10; 95% CI 19–81%) and 56% in PD-L1+ pts (5/9; 95% CI 21–86%). PD-L1 status was unknown in 4 efficacy-evaluable pts. The most common treatment-related AEs (TRAE, >30%) were fatigue (59%), pyrexia (38%), chills (32%), and flu-like symptoms (32%). Grade ≥ 3 TRAEs occurred in 18% of pts and 8.8% discontinued due to TRAEs. No G4/G5 TRAEs occurred. 22 pts had available baseline PD-L1 results (PD-L1+ [n=11]; PD-L1– [n=11]). 10 of the 11 PD-L1– baseline samples had matched wk 3 biopsies. Of these, 6/10 (60%) converted to PD-L1+ at wk 3. Updated results will be presented. Conclusions: NKTR-214 + nivo showed encouraging clinical activity, including CRs, and an acceptable preliminary safety profile in pts with mUC. Efficacy appears independent of PD-L1 status with a similar ORR in PD-L1– and + tumors. These data support further evaluation of the combination. Clinical trial information: NCT02983045.