bluuebunny/crossref_metadata_2025 huggingface dataset:
Antitumor efficacy of M3814 as a radiation sensitizer in neuroendocrine tumor (NET) preclinical models.
Authors: Chauhan Aman , Rychahou Piotr , Izumi Tadahide , Arnold Susanne M. , Anthony Lowell Brian , Evers Mark , Kunos Charles
Published: May 2019

e15699

Background: Recent FDA approval of peptide receptor radiotherapy paved the way for radiation-based treatment for gastroenteropancreatic neuroendocrine tumors (GEPNETs). M-3814, a DNA-dependent Protein Kinase Inhibitor (DNA-PKi), is known to potentiate the effects of radiation therapy in various solid tumor in vivo models. Currently there is no data evaluating anti-tumor efficacy of DNA-PK inhibitors in preclinical NET models. M-3814 inhibits DNA damage repair mechanism; antitumor efficacy of M-3814 in NETs is unknown. Methods: The efficacy of M-3814 in combination with radiation therapy (XRT) was evaluated in QGP-1 (pancreatic NET cell line) mouse model. Mice were injected with QGP-1 cells (5 mice) in 100 µL of PBS into the flank of mice with a 27-gauge needle. When tumor volumes reached average ~200 mm3, tumors were excised, separated into equal size tumor pieces and implanted subcutaneously into athymic nude mice. Next, mice were randomized into 4 groups for treatment with either placebo (n = 5), M-3814 (n = 5) alone (100 mg/Kg body weight (BW), XRT (n = 5) alone or in combination with M-3814 (n = 5). Treatment started when palpable tumors were established (200 mm3). Mice received M-3814 by gavage 30 minute prior to radiation therapy and irradiated with 4 daily doses of XRT at 2Gy per dose. Results: XRT and XRT+M-3814 treatment significantly decreased tumor size compared to control group. Combination treatment resulted in marked anti-tumor activity compared to both control group and XRT group. Tumors treated with XRT+M-3814 were also visibly less vascular. (Images will be provided in the poster). M-3814 alone had no effect on tumor growth as expected. Similar mouse weight changes were observed in both XRT and XRT+M-3814 treatment groups. Conclusions: M-3814 is a potent radiation sensitizer in preclinical neuroendocrine models. Strong antitumor activity was observed in QGP-1 xenograft model with marked reduction of tumor growth. Our enthusiasm for current project is driven not only by its inherent scientific importance, but also by its translational potential and the possibility to provide a more effective and less toxic radiation based treatment regimen for neuroendocrine tumors. [Table: see text]
Epidemiology, national trends and clinical associations of pancreatic adenocarcinoma in chronic pancreatitis patients: A nationwide inpatient sample (NIS) study.
Authors: Elkafrawy Ahmed , Asif Samia , Othman Hasan F. , Shrestha Anuj
Published: May 2019

e15737

Background: Chronic pancreatitis (CP) is a known risk factor for pancreatic adenocarcinoma (PA). The aim of this study was to evaluate epidemiology, national trends and clinical associations of PA in hospitalized US patients with CP using the NIS database. Methods: ICD-9 CM codes were used to identify patients with CP and PA between 2002-2014. Age, gender, race, mortality, length of stay (LOS) and commonly associated comorbidities were correlated. Statistical analysis was done using SPSS 25. Results: We identified 1,677,517 patients with CP between 2002-2014. Patients with concurrent PA comprised 1.3 % (21,832) of total patients with CP. During the study period, the prevalence of PA in CP patients remained nearly steady (1.2% in 2002 and 1.3% in 2014). Median LOS was 8 days and decreased from 10 days in 2002 to 6 days in 2014. Overall mortality was 3.5% during hospitalization with the trend of mortality not showing a significant change in the study period (4.2% in 2002 and 4.1% in 2014). Median cost of total hospitalization for CP with PA was 52,116 USD, almost three-folds higher than for CP alone (18,797 USD) and increased from 42,241 USD in 2002 to 55,525 USD in 2014. For patients with CP and PA, 87.5% were above 50-years-old; 55.6% were males; Caucasians and African-Americans represented 72.2% and 12.6% of patients respectively. Interestingly, factors less associated with PA in CP included alcohol (OR 0.27, 95% CI 0.26-0.29, P < .0001), Diabetes Mellitus (DM) (OR 0.78, 95% CI 0.74-0.82, P < 0.0001), Chronic hepatitis C (OR 0.56, 95%CI 0.48-0.66, P < 0.0001) and pancreatic cysts and pseudocyst (OR 0.76, 95%, CI 0.69-0.83, P < 0.0001). Tobacco use, metabolic syndrome, Chronic hepatitis B and H. Pylori infection were not statistically associated with PA. Conclusions: In hospitalized patients with CP, 1.3% had PA. During the study duration, trends of prevalence and mortality did not show significant change, median LOS decreased and hospitalization cost of charge increased. Risk factors for PA like alcohol, DM, chronic hepatitis C, and pancreatic cysts were less associated with PA in patients with CP. Future studies are needed for early detection of PA in patients with CP.
Adjuvant nab-paclitaxel plus gemcitabine versus gemcitabine in resected pancreatic ductal adenocarcinoma: A Chinese single institution.
Authors: Yin Zhuzeng , Liu Rong
Published: May 2019

e15740

Background: Adjuvant chemotherapy with gemcitabine (GEM) is standard care for resected pancreatic ductal adenocarcinoma (PDAC). Nab-paclitaxel plus gemcitabine (AG) vs gemcitabine (GEM) have shown better survival and tumor response with in advanced or metastatic PDAC. We aimed to determine the efficacy and safety of AG compared with GEM for resected PDAC. Methods: We retrospectively reviewed resectable PDAC patients (pts) who received AG or GEM as adjuvant chemotherapy from January 2013 to December 2016 at the Chinese PLA General Hospital, Bei Jing, China. Pts received nab-paclitaxel (125mg/m2) followed by GEM (1,000 mg/m2) on days 1, 8 every 3 weeks or GEM (1,000 mg/m2) alone on days 1, 8 every 3 weeks for 6 cycles unless disease progression or there was unacceptable level of adverse events. Disease free survival (DFS), overall survival (OS) and toxicity were analyzed. Results: Among 70 pts received AG or GEM as adjuvant chemotherapy, 10 pts were excluded due to the serious complication or R2 resection. The analysis was based on 30 pts in each group undergone complete macroscopic (R0 or R1) resection. Median DFS was 15.8 months (95% CI 13.1-18.5) in AG group (6 pts not arrived) compared with 12.2 months in GEM group (95% CI 9.6-14.8, P= 0.039, 3 pts not arrived). Median OS was 28.3 months (95% CI 21.9-34.6) in AG group (11 pts not arrived) as compared with 20.6 months in GEM group (95% CI 11.2-29.9, P= 0.028, 7 pts not arrived). The 2 years survival rate was 63.3% versus 43.3% in AG group versus GEM group. The most common adverse events of grade 3 or higher were leukopenia (32.3% in AG group vs. 20.7% in GEM group, P= 0.387), neutropenia (45.2% vs.31%, P= 0.298), G-CSF use (41.9% vs. 24.1%, P= 0.177), sensory peripheral neuropathy (51.6% vs. 24.1%, P= 0.036) and fatigue (3.2% vs. 3.4%, P= 0.737). Conclusions: Our results provide the first evidence that the adjuvant combination of nab-paclitaxel plus gemcitabine significantly improved DFS and OS of resected PDAC. Future RCTs with multi-center participation, particularly focused on adjuvant AG, can further provide information to confirm and strengthen these data.
Proton pump inhibitor (PPI) exposure and risk of pancreatic cancer (PC): Meta-analysis.
Authors: Al Khushaym Nasser Mubarak , Almutairi Abdulaali , Fallatah Saad , Althagafi Abdulhamid , Oh Mok , McBride Ali , Babiker Hani M. , Abraham Ivo
Published: May 2019

e15755

Background: PPIs are widely used in the treatment of various acid related disorders. Observational studies have raised concern about an association of PPI use and PC but findings have been inconsistent. This meta-analysis aimed to estimate from published studies the pooled PC risk among subjects exposed and not exposed to PPIs. Methods: We searched PubMed, EMBASE, Scopus, Cochrane Library and clinicaltrials.gov to identify relevant studies on the association of PPI exposure and PC risk. Three reviewers independently screened search results for eligibility and extracted data from retained studies. Our primary analysis quantified PC risk among subjects exposed vs not exposed to PPI, expressed as the pooled (adjusted) odds ratio (OR/aOR) and 95% confidence interval (95%CI) as estimated in a random effect model. We performed similar secondary analyses in selected subgroups. Results: Of the 2683 reports yielded by the search 1 randomized trial, 2 cohort, and 9 case-control studies with 1,093,766 subjects (123,214 cases; 970,552 controls) were retained. Our main analysis (exposed vs non exposed) revealed a significant overall association between PPI exposure and PC risk (OR 1.77, 95%CI 1.14-2.74). Secondary analyses showed higher risk estimates from high quality (NOS > 7) studies (OR 2.04, 95%CI 1.03-4.02), observational studies (aOR, 1.70 95%CI 1.08-2.68), and studies with PPI use and PC risk as main outcome (aOR 2.01, 95%CI 1.06-3.83). Subgroup analyses by comorbidities showed an association with diabetes (aOR 1.98, 95%CI 1.02-3.82) but not pancreatitis (aOR 1.77, 95%CI 0.93-3.35). PC risk was not associated with duration of PPI use longer 1 (aOR 1.36 95%CI 0.81-2.28 and > 3 yrs (aOR 1.21 95%CI 0.73-2.02). In addition to the overall PPI class effect in the primary analysis, rabeprazole was singularly associated with PC risk (aOR 5.40 95%CI 1.98-14.70). Conclusions: Pooled risk estimates suggest that the class of PPIs is associated with a general 1.77 fold increase in PC risk, independent of duration of PPI exposure. Diabetic patients are at a significant incremental risk over the base risk.
Adjuvant therapy with gemcitabine and stereotactic body radiation therapy versus gemcitabine alone for resected stage II pancreatic cancer: A prospective, randomized, open label, single-center trial.
Authors: Ma Tao , Bai Xueli , Wei Qichun , Gao Shunliang , Huang Bingfeng , Chen Wei , Wang Ji , Liang Tingbo
Published: May 2019

e15765

Background: Although adjuvant chemotherapy with gemcitabine has for years been the standard of care for resected pancreatic cancer, the role of adjuvant radiation is still debatable. We aimed to investigate the efficacy of gemcitabine combined with stereotactic body radiation therapy (SBRT) as adjuvant therapy for resected stage II pancreatic cancer. Methods: This single center randomized controlled trial was designed to enroll 512 patients with stage II pancreatic cancer that underwent curative-intended radical resection from a large-volume tertiary pancreatic center in China. Patients were randomly assigned to gemcitabine-alone adjuvant chemotherapy or adjuvant SBRT (25 Gray in 5 fractions) followed by gemcitabine chemotherapy. The primary endpoint was recurrence-free survival (RFS). Secondary endpoints included locoregional recurrence-free survival (LRFS), overall survival (OS), and incidence of adverse events. Interim analysis was planned at the time of 2.5-years’ enrollment. Results: 40 patients were randomly assigned to treatment between Sep 1, 2015, and Mar 31, 2018 (21 to the gemcitabine group and 19 to the gemcitabine plus SBRT group). Of these, one was excluded because of ineligibility and one did not receive any treatment. The median RFS was 12.4 (9.3-15.6) months in the gemcitabine group and 14.7 (9.2-20.1) months in the gemcitabine plus SBRT group ( P= 0.753), with median LRFS of 18.2 (14.6-21.7) months in the gemcitabine group and 13.1 (9.1-16.8) months in the gemcitabine plus SBRT group ( P= 0.333). The median OS was 21.7 (19.5-24.0) months in the gemcitabine group and 16.9 (12.8-20.9) in the gemcitabine plus SBRT group ( P= 0.066). Grade 3 or 4 neutropenia, thrombocytopenia, nausea or vomiting, and liver dysfunction were all comparable between the two groups. Evaluation of data from the first 40 enrolled patients indicated that the addition of adjuvant SBRT was not associated with either better local disease control or recurrence free survival. And because of failure to achieve the accrual target, the trial was terminated prematurely. Conclusions: Adjuvant SBRT neither provided a survival benefit nor improved local disease control in resected stage II pancreatic cancer. Clinical trial information: NCT02461836.
Transducer array layout optimization for the treatment of pancreatic cancer using Tumor Treating Fields (TTFields) in the phase 3 PANOVA-3 trial.
Authors: Naveh Ariel , Hershkovich Hadas Sara , Kirson Eilon David , Weinberg Uri , Bomzon Zeev
Published: May 2019

e15766

Background: TTFields is an antimitotic cancer treatment that utilizes low intensity (1-3 V/cm) alternating electric fields in the intermediate frequency (100-300 kHz), which are delivered in two orthogonal directions using 2 pairs of transducer arrays. Based on favorable results in a Phase 2 study in locally-advanced pancreatic cancer (LAPC), an ongoing Phase 3 PANOVA-3 trial [NCT03377491] is investigating the efficacy of adding TTFields to nab-paclitaxel and gemcitabine in LAPC. Preclinical studies show that the effect of TTFields is intensity-dependent with a therapeutic threshold of 1 V/cm. The field distribution within the body is known to changes with array placement. The current study was designed to develop clinical practice guidelines for optimizing the layout of arrays applied to patients participating in the TTFields arm of the PANOVA-3 study. Methods: Three realistic computerized models of a male, a female and an obese male were used to simulate delivery of TTFields to the abdomen. For each model, 6-8 different layouts utilizing combinations of arrays with either 13 or 20 disks per-array were tested. The arrays were placed over the upper 6 standard abdominopelvic regions, and field intensity distributions within these regions were evaluated. Results: In all simulations, the large arrays generated higher field intensities than the smaller arrays. However, models with lower BMI were almost covered entirely using large arrays, increasing the potential of skin toxicity from TTFields. However, these Low BMI models were able to receive TTFields at an anti-mitotic intensity with smaller arrays. The clinical guidelines were formulated based on the following principles: the target tumor region should be directly between the arrays, (b) the extent of disease as well as the anatomy of the patient determines the size of arrays determined using waist circumference measurements. Conclusions: A matrix for selecting between 8 individual array layouts was generated based on these principles. The clinical practice guidelines allow the optimization of TTFields delivery to individual patients treated in the PANOVA-3 Study.
Pancreatic cancer survival trends overall, by stage, and histologic sub-type: An analysis of Surveillance, Epidemiology and End Results (SEER) population-based data (2000-2015).
Authors: Karimi Parisa , Gordon-Dseagu Vanessa L , Chernyavskiy Pavel , Goggins Michael , Rosenberg Philip S. , Stolzenberg-Solomon Rachael
Published: May 2019

e15772

Background: Pancreatic cancer (PC) is the third leading cause of cancer mortality in the United States, with an overall relative 5-year survival rate of 8.2%. We conducted a comprehensive evaluation of survival trends after PC diagnosis overall and by stage and histologic sub-type. Methods: We conducted a retrospective, population-based study of 91,234 PC cases using nationally representative data from the SEER program to evaluate 5-year survival trends by histologic sub-type from 2000 to 2015. Our model incorporated sub-type-specific random intercepts to effectively stabilize survival estimates by borrowing information across all sub-types. The estimation was performed in a fully Bayesian setting in R. Results: Adenocarcinoma, not otherwise specified (NOS) and ductal adenocarcinomas comprised 81% of PC. Cancer stage and histologic sub-type were both important factors in explaining variability in 5-year survival. We observed a consistent ordering of cancer stages within each histologic sub-type from highest to lowest survival for local, regional, and metastatic disease, respectively. Adenocarcinoma not otherwise specified, ductal adenocarcinoma, ductal specified as mucinous, and poorly specified type had the lowest 5-year survival with fitted ranges of 25-35% for localized, 5-19% for regional and < 4% for metastatic disease. Ductal arising from intraductal papillary mucinous neoplasm, ductal specified as cystic, acinar cell, other adenocarcinoma, and non-carcinomas had intermediate 5-year survival of 54-75%; while endocrine non-secretory or neuroendocrine, endocrine secretory, carcinoid, and solid pseudopapillary cancers had the best survival (87-98%). On average, across histologic sub-types, PC survival improved by 0.5% (90% credible interval 0.01%, 1.0%) per year, or 5.1% (0.1%, 10.0%) per decade. Some improvement in fitted survival occurred across all stages and histologic sub-types. Conclusions: Overall survival for patients with PC has improved by around 5% per decade from 2000 to 2015, with significant heterogeneity by histologic sub-type.
Defining the heterogeneity landscape of pancreatic cancer copy number alterations.
Authors: Baslan Timour , Wu Jie , Cheung Yee Him , Bermeo Jonathan , Dimitrova Nevenka
Published: May 2019

e15776

Background: Pancreatic cancer (PDAC) is projected to become the second leading cause of cancer related mortality by 2030. Bulk whole genome sequencing studies of PDAC have characterized the landscape of clonal mutations and highlighted the prominence of copy number alterations (CNAs) in PDAC genomes. However, little is known with regards to the extent of sub-clonal heterogeneity of somatic CNAs and it is hypothesized that this heterogeneity is a contributing factor to the limited effectiveness of existing therapies. Methods: We retrieved absolute copy number information using bulk sparse whole genome sequencing of multi-region sampled PDAC samples as well as matching primary-metastasis tumor samples from over 100 patients. In addition, we analyzed copy number variations in a subset of these samples (n = 15) at single-cell resolution (~1000 cells in total). Results: We describe a detailed picture of sub-clonal CNAs genetic heterogeneity. Our results illustrate, among other findings, (1) extensive sub-clonal diversity of CNAs giving rise to many genetically unique sub-clonal cancer populations, (2) somatic mosaicism of chromosomal amplicons in single-cancer cells, (3) variation in the dosage of cancer genes, including the KRAS oncogene, in different tumor sub-clones and (4) somatic alterations, such as amplification of 8q11 containing the metastasis promoting gene IKBKB, associated with primary PDAC progression to liver metastasis. Conclusions: Our results offer an in-depth view of the sub-clonal heterogeneity of somatic CNAs in pancreatic cancer and illustrate ways in which such heterogeneity could lead to therapeutic resistance.
Profile of somatic mutations in young adults with pancreatic cancer.
Authors: Rodrigues Livia Munhoz , Maistro Simone , Katayama Maria Lucia Hirata , Roela Rosimeire Aparecida , Koike Folgueira Maria A. A.
Published: May 2019

e15790

Background: Most pancreatic carcinomas (PC) occur in older people, however a few cases are detected in young adults. In this age group, the carcinogenic process is less well understood. Our goal was to identify and to characterize cancer driver genes in early age onset PC. Methods: Somatic variants of individuals affected by PC aged ≤45 years were searched in the COSMIC and CBioPortal databases. The variants were annotated using Oncotator, excluding the silent and intronic variants. Implication in cancer causality was evaluated in the Cancer Gene Census (CGC) and the Candidate Cancer Gene Database (CCGD). The most frequently mutated genes were identified and investigated to determine if they configured FrequentLy mutAted GeneS (FLAGs). Results: Whole genome (4) or exome (29) sequencing was available from 33 individuals (14 females and 19 males). A median of 31 (7-102) alterations per tumor, mainly represented by C > T substitutions (median 16, 2-71), was detected. A median of 3 (0-11) truncated alterations, 4 (1-13) genes cataloged as CGC and 8 (1-22) genes cataloged as CCGD rank A or B was identified per tumor. The most frequently affected genes were those characteristic of tumor promotion in pancreatic cancer carcinogenesis, such as KRAS (79%), TP53 (64%), SMAD4 (18%), followed by RYR1 (15%) and TTN (12%) genes, the latter two classified as FLAGs and, finally, HERC2, GREB1 and DMBT1 (9%). Seventeen samples presented variants in both TP53 and KRAS (17/33), 9 and 4 presented only KRAS or TP53 variants, respectively. Three samples with mutations in neither of these genes presented mutations in genes such as BCLAF1, DCC, BRAF, CDH11 and CDKN2A, both CGCs. Three out of 9 samples carrying KRAS but not TP53 mutations presented variants in DNA homologous repair (HHR) genes. Among all the altered genes, the main biological processes were cell adhesion (139 genes involved) and anatomical structure formation involved in morphogenesis (127), while the most enriched pathways were Wnt (45) and Cadherin (30). Conclusions: TP53 and KRAS are the somatic mutations most frequently detected in PC. 10% of the samples showed no change in these genes, but showed changes in other CGCs. HERC2, GREB1 and DMBT1 are potential cancer drivers in young adult PCs.
DNA repair deficiency association with prognosis in pancreatic cancer: A single-institution experience.
Authors: Bajwa Suhaib , Odeny Thomas A , Saeed Anwaar , Kasi Anup
Published: May 2019

e15798

Background: Understanding survival outcomes of various pathogenic mutations helps guide treatment decision making for patients. Classic pancreatic cancer mutations such as KRAS and TP53 have well documented survival outcomes while other mutations leading to DNA repair deficiency do not have well understood survival outcomes. Methods: We retrospectively evaluated survival outcomes of 70 pancreatic cancer patients who had their cancers genetically profiled by NGS methods. Patients with DNA repair deficiency harbored mutations in genes such as BRCA1 (1 Pts), BRCA2 (8 Pts), ATM (5 Pts), NBN (1 Pt), and BRIP1 (1 Pt). We compared baseline characteristics, tumor stage and clinical outcomes between patients with DNA repair deficiency versus DNA repair proficient cancer patients. Comparative survival analysis between the two groups was performed using Kaplan-Meir methods. Results: Baseline characteristics for all patients are recorded in (Table). Median OS is 24 months for DNA repair proficient group and 20 months for DNA repair deficient group. A comparison of Kaplan-Meir survival curves between the two groups yielded a p-value of 0.72. This is most likely due to sample size and different chemotherapy regimens which make it hard to retrospectively compare patient groups. Conclusions: Patients with mutated DNA repair genes did not have significantly worse survival. We are designing a clinical trial utilizing a PARP inhibitor, for these patients in order to better control for all factors in order to better ascertain any survival differences between the two groups. PARP inhibitor will create multiple single strand breaks which cancer cells deficient in DNA repair genes cannot repair and thus trigger cancer cell death[Table: see text]
Programmed death-ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1) expression in bladder cancer (BC): Differences in recurrent, progressive, and metastatic disease.
Authors: Hegele Axel , Wahl Franziska , Rexin Peter , Nimphius W , Hofmann Rainer , Haenze Joerg
Published: May 2019

e16001

Background: The significance of PD-L1/PD-1 expression in BC is still unclear. In the present study we evaluated the PD-L1/PD-1 expression in tumor tissue (TT) and immune cells (IC) in the primary BC tumor as well as in case of BC recurrence and/or metastasis to detect possible changes in PD-L1/PD-1 expression using immunohistochemstry. Methods: PD-L1/PD-1 expression was determined in histological specimens of 20 pat. with a recurrent non-muscle invasive BC (NMIBC – Cohort 1) as well as in 20 pat. with muscle-invasive BC (MIBC- Cohort 2) treated by radical cystectomy and appearance of metastases during follow up using commercial available assays (E1L3N, Cell Signaling/ Zytomed). Staining intensity was performed using the Cologne Score. PD-L1/PD-1 status was compared between primary tumor and metastatic/recurrent/progressive BC tissue and correlated with clinical data. Results: Cohort 1: In NMIBC (18m,2f) a recurrent tumor occurred after 25 mo (1-114). In the recurrent TT PD-L1 expression was higher compared to primary BC in 15%. In case of progression higher PD-L1 expression was detectable in 42.9%. IC showed higher PD-L1 expression in 50% of recurrent NMIBC and in 42% in case of progression. PD-1 expression on IC rose in 70% in recurrent and 71% in progressive NMIBC without correlation to time interval of appearance. Cohort 2: After curative cystectomy (17m,3f) metastases occurred after a median time of 20.5 mo (0-58). Comparing PD-L1 expression in cystectomy specimens and metastases we found differences in 52.9% (4x down/5x up). Expression of PD-L1 in primary BC tissue correlated significantly with the time to metastasis (p < 0.05). Conclusions: In case of metastasis after cystectomy as well as in recurrent/progressive NMIBC we found distinct variations in PD-L1/PD-1 expression in TT and IC. In MIBC primary PD-L1 status correlates with the time to metastasis. Whether PD-L1/PD-1 status can be helpful for clinical decisions (i.e. adjuvant therapy, instillation therapy) or as prognosticator have to be subject of further study.
Cost-effectiveness of pembrolizumab as second-line therapy for the treatment of locally advanced or metastatic urothelial carcinoma in the United States.
Authors: Zhong Yichen , Lai Yizhen , Li Haojie , Batteson Rachael , Meng Yang , Frenkl Tara L. , Godwin James Luke , Sonpavde Guru
Published: May 2019

e16010

Background: Pembrolizumab is approved by the US Food and Drug Administration for the treatment of locally advanced or metastatic urothelial carcinoma (mUC) following platinum-based chemotherapy, based on results from KEYNOTE-045. In this randomized phase 3 trial, pembrolizumab significantly prolonged overall survival (OS) vs. chemotherapy in mUC patients (cut-off: Oct 26, 2017). The current analysis evaluates the cost-effectiveness of pembrolizumab vs. standard-of-care chemotherapy (docetaxel or paclitaxel) as second-line (2L) treatment for mUC, from a US payer perspective. Methods: We developed a partitioned-survival model to measure the costs and effectiveness over a 20-year time horizon to capture long-term costs and benefits from the treatments. Clinical efficacy, time on treatment, safety and utility data were derived from KEYNOTE-045. OS and progression-free survival were extrapolated beyond the trial period using piecewise models, i.e., Kaplan-Meier data followed by parametric function. Costs (in 2018 $US) for drug acquisition/administration, disease monitoring, adverse events management and terminal care were included. Costs and outcomes were discounted at 3% per year. Deterministic and probabilistic sensitivity analyses were conducted to assess the robustness of the results. Results: Pembrolizumab resulted in a mean gain of 1.33 life years (LYs) and 1.14 quality-adjusted life-years (QALYs) at an incremental cost of $103,861 vs. chemotherapy. The incremental cost-effectiveness ratios were $91,103/QALY and $78,254/LY. Key drivers of cost-effectiveness were extrapolation methods for OS data, time horizon and utility values. Pembrolizumab had a 72% or 100% probability of being cost-effective vs. chemotherapy at a $100,000 or $150,000 willingness-to-pay threshold, respectively. Conclusions: Pembrolizumab appears to be cost-effective vs. docetaxel or paclitaxel monotherapy as 2L mUC therapy when accounting for durable survival seen in a subset of patients receiving pembrolizumab. The model was established based on robust estimates, with key clinical endpoints directly drawn or derived from patient level data in KEYNOTE-045.
Sequencing chemotherapy and immune checkpoint inhibitors (ICI) in metastatic urothelial carcinoma (UC): Meet-Uro1 study.
Authors: Bandini Marco , Farè Elena , Raggi Daniele , De Giorgi Ugo , Banna Giuseppe Luigi , Basso Umberto , Losanno Tania , Bersanelli Melissa , Buti Sebastiano , Santini Daniele , Mucciarini Claudia , Tucci Marcello , Tambaro Rosa , Farnesi Azzurra , Ficorella Corrado , Caffo Orazio , Naglieri Emanuele , Pederzoli Filippo , Pignata Sandro , Necchi Andrea ,   Italian Network for Research in Urologic Oncology (Meet-Uro)
Published: May 2019

e16013

Background: Several ICI are now approved in different therapeutic settings of metastatic UC. The identification of the optimal therapeutic sequence that includes standard chemotherapy (CT) use is a key objective of further research, mainly in the first-line (1L) setting. In this study, we analyzed the pathways of treatment post-ICI and focused on the effects of CT post-ICI in both 1L and salvage-line (≥2L) therapy of metastatic UC. Methods: Data from 15 Italian centers were collected. Patients (pts) should have received ICI in any line of treatment for metastatic UC and have experienced a disease progression (PD) according to RECIST 1.1. Cox regression analyses were performed within the subgroups, and adjusted Kaplan-Meier curves analyzed the progression-free survival (PFS) and overall survival (OS) post-ICI PD, according to the treatment line. Results: 278 pts (79 in 1L; 199 ≥2L) were analyzed. In total, after ICI, pts were treated with CT (N = 69), ICI beyond PD (N = 20) or no treatment (N = 189). Features associated with no therapy post-ICI were rapid PD on ICI (p < 0.001) and number of metastatic sites (p = 0.002). The objective response (OR) to CT post-ICI was 23.1% in 1L, and 18.5% in ≥2L. Median PFS was 5 months (m) in 1L and 3m ≥2L, median OS on CT was 13m in 1L and 9m ≥2L. Post-ICI CT was not significantly associated with improved OS in 1L on multivariable analyses (MVA): HR: 0.43 (95%CI: 0.15-1.23), but it was significant in MVA in ≥2L pts (HR: 0.22, 95%CI: 0.10-0.48). The type of previous ICI (combination-ICI vs single-agent ICI, p = 0.789), as well as the OR to previous ICI (p = 0.871) had no effect on OS with sequential CT on MVA. In the total population adjusted by line, median OS post-CT was 17m (range 15-NA), and with ICI beyond PD was 8m (6-NA) (p < 0.001). Conclusions: This large multicentric appraisal indicated that CT post-salvage ICI is endowed with similar activity and efficacy compared to ICI-naïve pts. Conversely, CT administered post-ICI in 1L determined less responses and was not significant on MVA. These effects are likely determined by the inability to rescue pts with rapidly aggressive disease. Shifting to salvage CT at the time of PD on ICI remains the preferable option in all suitable pts.
Impact of timing of adjuvant chemotherapy following radical cystectomy for bladder cancer on patient survival.
Authors: Grunewald Camilla Marisa , Henn Alina , Galsky Matt D. , Plimack Elizabeth R. , Harshman Lauren Christine , Yu Evan Y. , Crabb Simon J. , Pal Sumanta K. , Alva Ajjai Shivaram , Powles Thomas , De Giorgi Ugo , Agarwal Neeraj , Bamias Aristotelis , Ladoire Sylvain , Necchi Andrea , Vaishampayan Ulka N. , Sternberg Cora N. , Bellmunt Joaquim , Baniel Jack , Niegisch Guenter
Published: May 2019

e16017

Background: Trials of adjuvant chemotherapy following radical cystectomy generally require chemotherapy to start approximately 90 days postoperatively. However, it is unclear, whether the interval between surgery and start of adjuvant therapy (S-AC-interval) impacts the oncological outcome. Methods: Using the Retrospective International Study of Invasive/Advanced Cancer of the Urothelium (RISC) data base, we identified patients who underwent radical cystectomy for muscle invasive bladder cancer and subsequent adjuvant chemotherapy. Uni- and multi-variate analysis of patient characteristics, surgical factors and tumor characteristics regarding their impact on S-AC-interval was performed. Uni- and multivariate analysis of progression-free and overall survival (starting from day 1 of adjuvant chemotherapy) was analysed in relation to SAC interval (both continuous and dichotomous with a cut-off at 90 days), patient characteristics, surgical factors and tumor characteristics by Kaplan-Meier and COX regression analysis. Results: Two hundred thirty-eight eligible patients were identified (83% male, median age: 64 years, 76% T3/T4, 66% pN+, 15% R+, 75% urothelial carcinoma, 71% cisplatin-based adjuvant chemotherapy). Median S-AC-interval was 57 days (range 10-321 days, ≤ 90 days: 87%, 91-120 days: 6%, > 120 days: 7%). S-AC-interval did not have association with any patient/tumor characteristics or surgery related factors (type of surgery, diversion). S-AC-interval did not impact patients´ outcomes when adjuvant chemotherapy was initiated 90 days after surgery. Median PFS and OS in patients with an S-AC-interval of 90 days was 37 and 73 months, respectively, as compared to 24 and 48 months in patients with an S-AC-interval > 90 days. Only differences in PFS reached statistical significance (37 (95% CI 26-48) months vs. 24 (95% CI 12-36) months p = .042; Log Rank test). When analyzed by different multivariate models, the impact of S-AC-interval on PFS and OS was negated by tumor related factors (pathological T-stage and N-stage). Conclusions: An S-AC-interval of below 90 days is likely to be optimal in bladder cancer patients requiring adjuvant therapy. However, regarding prognosis, tumor related pathological factors seem to be more important than the S-AC-interval.
Endogenous DNA damage levels in peripheral blood mononuclear cells in patients with muscle-infiltrating urothelial bladder carcinoma.
Authors: Palacka Patrik , Sestakova Zuzana , Holickova Andrea , Kalavska Katarina , Rejlekova Katarina , Kollárik Boris , Chovanec Michal , Obertova Jana , Sycova-Mila Zuzana , De Angelis Valentina , Slopovsky Jan , Svetlovska Daniela , Mego Michal , Chovanec Miroslav
Published: May 2019

e16020

Background: Cisplatin-based combination chemotherapy is used as a standard neoadjuvant treatment of patients with muscle-infiltrating urothelial bladder carcinoma (MIUBC). DNA damage represents one of the most important factors contributing to its toxicity. The objective of this prospective study is to evaluate the prognostic value of the endogenous DNA damage level in peripheral blood mononuclear cells (PBMCs) from MIUBC patients before treatment with neoadjuvant chemotherapy. Methods: PBMCs isolated from 25 consecutive MIUBC patients (16 men, 64%) were included into this study. Karnofsky index < 80% was present in 1 patient (4%). DNA damage levels in PBMCs were evaluated by the Comet assay and scored as percentage of DNA in tail by the Metafer-MetaCyte analyzing software. Cut-off of 5.25 was used to dichotomize DNA damage level as “high” or “low” based on the previous study. Results: At the median follow-up 12.1 months, 13 patients progressed (52%) and 8 patients (32%) died. The median and IQR (interquartile range) of endogenous DNA damage level was 7.52 (4.07-27.9). Patients with low DNA damage levels had non-significantly better progression free survival (HR = 0.33, 95% CI: 0.09-1.29) and overall survival (HR = 0.64, 95% CI: 0.11-3.87) compared to patients with high DNA damage levels. Conclusions: These data suggest that endogenous DNA damage levels in PBMCs from MIUBC patients may serve as a prognostic marker early identifying patients with poor outcome. This study is supported by VEGA 2/0053/19 and APVV-17-0384.
First-line PD(L)1 inhibitors for platinum-ineligible advanced urothelial carcinoma (aUC).
Authors: Agarwal Archana , Pond Gregory Russell , Gupta Ruby , Ornstein Moshe Chaim , Barata Pedro C. , Garcia Jorge A. , Drakaki Alexandra , Lee Jae-Lyun , Kanesvaran Ravindran , Bilen Mehmet Asim , Lorenzo Felipe R. , Grivas Petros , Hussain Syed A. , Curran Catherine , Sonpavde Guru
Published: May 2019

e16024

Background: FDA modified the label for 1st-line pembrolizumab or atezolizumab to PD-L1 high cisplatin-ineligible or platinum-ineligible aUC patients (pts) regardless of PD-L1 expression. However, the outcomes when using PD-(L)1 inhibitors for platinum-ineligible pts are unclear. We hypothesized that treatment response and outcomes are comparable to data reported in trials in the 1st line setting of aUC, and conducted a retrospective study to test this hypothesis using data outside the clinical trial setting. Methods: We collected data from 8 institutions for aUC pts with locally advanced unresectable or metastatic UC. The following criteria were used to define pts platinum-ineligible while comorbidities, age and physician discretion were also allowed: Cr Cl < 30 ml/min, ECOG PS 3, Cr Cl 30-59 ml/min and ECOG PS 2. Demographic & clinical variables and outcomes (overall response rate [ORR], overall survival [OS]) were collected. A Cox regression analysis was used to explore associations of baseline variables with response and outcomes. Results: Data were available for 79 pts. Pts received atezolizumab [n = 41], pembrolizumab [n = 28], nivolumab [n = 7] or durvalumab [n = 3]. Median age was 74 years (45-93). Reasons for platinum-ineligibility were: Cr Cl < 30 ml/min (n = 26), ECOG PS 3 (n = 8), ECOG-PS 2 and Cr Cl < 30-59ml/min (n = 14), elderly/co-morbidities (n = 17), and ‘unavailable’ (n = 14). Median OS was 45 weeks (CI 32-80) and ORR was 27.9%: Complete response in 4 pts [5.1%], partial response in 18 pts [22.8%], stable disease in 19 pts [24.1%], progressive disease in 34 pts [43 %]; data for 4 pts [5.1%] was unavailable for best response. Toxicity of any grade and Grade ≥3 was seen in 41.8% and 31.7% of pts, respectively. Hemoglobin (HR = 0.78, 95% CI 0.68 - 0.90, P = 0.001) and liver metastasis (HR = 1.13, 95% CI 0.51 - 2.53, P = 0.036) correlated with OS. Conclusions: The efficacy and toxicities of 1st-line PD-(L)1 inhibitors for platinum-ineligible pts outside clinical trials appear comparable to those reported in trials for unselected cisplatin-ineligible pts. Further validation is required including data based on PD-L1 status and other biomarkers. Platinum-ineligible pts with aUC warrant evaluation of novel safe and effective agents.
Correlation between FGFR mutation and PD-L1 expression of urinary bladder cancers: A real-world based biomarker study.
Authors: Maraz Aniko , Takacs Peter , Lawson Joe , Santiago-Walker Ademi , Pajor Laszlo , Sukosd Farkas , Revesz Janos
Published: May 2019

e16030

Background: Programmed cell death (PD)-1 / PD-ligand 1 (PD-L1) inhibitors have made a breakthrough mainly in the treatment of PD-L1 positive advanced urothelial bladder cancer (UBC). The effect of Fibroblast Growth Factor Receptor 3 (FGFR3) mutation on the treatment outcomes of PD-L1 treatment still remains unclear. Our goal was to assess the frequency of FGFR mutations in different tumor stages, in relation with PD-L1 status. Methods: Enrolled patients were diagnosed with UBC and underwent radical cystectomy between 2006-2016 at the University of Szeged, Hungary. FGFR3 mutation analysis by targeted next-generation sequencing and PD-L1 (28-8 DAKOR and SP142 VentanaR) tests were carried out from the most infiltrative area of tumors, in T0 cases from the earlier resection samples. The treatment and survival data were collected from the National Health Insurance Fund (NHIF), Hungary. Independence between covariates was tested using chi-square tests, survival analysis was performed using Kaplan-Meier models and Cox proportional hazards regression. Results: 215 of all 310 UBC samples (T0:19 (8.8%); superficial 43(20%); muscle invasive 41(19%); extraorgan 112 (52%)) could be tested for both PD-L1 and FGFR successfully. Pairwise dependency between tumor stage, FGFR3 mutation status and PD-L1 expression were all found to be significant (p < 0.01). In cases of less advanced diseases FGFR mutation was more often detected. We have found that FGFR mutated samples are less likely to be PD-L1 positive than wild type ones. The effect of all covariates on survival was found to be in accordance with the effect of tumor stage. Conclusions: FGFR alteration frequency varied with stage of disease, with higher positivity rates in early stages, but that lower PD-L1 expression was observed in FGFR mutant patients across disease stages.
Adjuvant carboplatin for clinical stage I testicular seminoma in New Zealand centers: Retrospective analysis of efficacy and long-term adverse effects.
Authors: Chandran Elias Aris , Chindewere Aaron Farai , North Richard T. , Jameson Michael B.
Published: May 2019

e16041

Background: Adjuvant carboplatin reduces relapse risk in clinical stage I (CS1) testicular seminoma, though there is a paucity of long-term safety data. While some studies report that two cycles is more effective than one, there is no randomised trial evidence or consensus on the optimal number of cycles. European guidelines recommend a risk-based approach to consider adjuvant carboplatin in those with either rete testis involvement (RTI) or tumour size > 4cm, and surveillance for other patients. We report long-term outcomes of 2 cycles of adjuvant carboplatin dosed at area under the curve (AUC) of 7 as standard management of CS1 seminoma since 2000. Methods: We performed a retrospective analysis on treatment and outcomes of patients with CS1 seminoma who received adjuvant carboplatin from 2000 to 2016 at the Waikato, Lakes and Bay of Plenty District Health Boards. We also collected information on mortality, causes of death and subsequent malignant neoplasms (SMN). Results: Of 160 patients, median age 39 (range 20-73) years, 154 received 2 cycles of carboplatin: 148 dosed at AUC7 and six at AUC6; another six patients had one cycle of carboplatin AUC7, curtailed due to toxicity in 3 patients. Two relapses occurred: one at 10 months (in hindsight stage 2a at diagnosis) and one at 22 months (died of pulmonary embolism 2 months after achieving complete response with BEP chemotherapy). Neither RTI (present in 21.3%) nor tumour size > 4cm (in 43.1%) were predictive of relapse. No patients died of seminoma. At median follow up of 109 (range 17-209) months, relapse-free survival was 98.7%, overall survival was 97.5% and disease-specific survival was 100%. A SMN occurred in 11 patients (6.9%) at median 96 months and caused 4 deaths (melanoma, myeloma, small cell lung cancer and glioblastoma); 4 patients (2.6%) had a contralateral testicular germ cell tumour (at median 69 months). One patient had persistent grade 1 thrombocytopenia at 46 months. Conclusions: This data adds to the body of evidence that two cycles of carboplatin AUC7 is safe, effective adjuvant treatment for CS1 seminoma. It did not have significant long-term adverse effects in our population.
Prognostic value of serum tumor marker (STM) rate of decline during high-dose chemotherapy (HDCT) and peripheral-blood stem-cell transplant (PBSCT) for relapsed germ-cell tumors (rGCT).
Authors: Adra Nabil , Althouse Sandra K. , Liu Hao , Abonour Rafat , Abu Zaid Mohammad Issam , Cary Clint , Masterson Timothy A. , Foster Richard , Albany Costantine , Hanna Nasser H. , Einhorn Lawrence H.
Published: May 2019

e16044

Background: Rate of STM decline is prognostic in patients (pts) with metastatic GCT receiving first-line chemotherapy. We investigated the prognostic value of STM decline in pts with rGCT treated with HDCT and PBSCT. Methods: 444 consecutive pts with rGCT were treated with HDCT and PBSCT at Indiana University between 2004-2018. All pts were planned for 2 consecutive HDCT courses. Pts with elevated STM (AFP > 25 and/or hCG > 4.9) were included in this analysis. Slope and half-life (T1/2) were calculated for weekly AFP and hCG values during HDCT starting with peak value during days 1-7 to avoid interference from lysis. T1/2 AFP≤7 days and hCG≤3 days were categorized as satisfactory (SAT); normalization within 7 days was also considered SAT regardless of T1/2. Pts with elevated AFP and hCG must have adequate decline in both to be SAT. Progression-free (PFS) and overall survival (OS) were compared for SAT vs unsatisfactory (UNSAT) using log-rank test and analyzed using Kaplan-Meier methods. Results: 2-yr PFS for pts with elevated STM at initiation of HDCT (N = 335) was inferior to pts with normal STM (N = 109) [49% vs. 89%; p < 0.001]. Among the 335 pts with elevated STM, 300 had non-seminoma and 35 had seminoma. Median age was 31 (range, 17-58). Primary site: testis (285), mediastinum (25), and retroperitoneum/other (25). Metastatic sites included retroperitoneum (267), lung (226), liver (81), brain (76), and bone (21). At initiation of HDCT, 73 pts had elevated AFP only, 215 had elevated hCG only, and 47 had elevated both AFP and hCG. Median AFP 9 (1-21,347) and hCG 115 (1-178,140). 307 pts (92%) completed 2 planned cycles of HDCT. Overall, 45/335 pts had SAT decline (13 for AFP; 29 for hCG; 3 for both). Pts with SAT STM decline had superior outcomes compared to UNSAT: 2-yr PFS 71% vs 46% (p = 0.004) and 2-yr OS 77% vs 52% (p = 0.004). When evaluating each STM separately, SAT decline in hCG had superior outcomes vs UNSAT: 2-yr PFS 76% vs 47% (p = 0.002). There was statistically non-significant difference in outcomes for AFP: 2-yr PFS 50% vs 43% (p = 0.55). Conclusions: SAT rate of STM decline predicts superior outcomes in pts with rGCT undergoing HDCT and PBSCT. Although UNSAT STM decline does not preclude long-term remissions, these pts are at higher risk of relapse and death.
A single center experience of the impact of treatment-related toxicity in the clinical outcomes of elderly patients with metastatic germ cell tumors.
Authors: Sharma Anand , Palmer David , Brown Hannah , Merrick Sophie , Gogbashian Andrew , Vasdev Nikhil , Pullar Ben , Hall Marcia
Published: May 2019

e16048

Background: Germ cell tumours (GCT) are predominantly a disease of the young, with < 10% of cases being diagnosed at ≥45 years. Platinum based chemotherapy is the gold standard in treating these patients. Data regarding outcomes and treatment toxicities in elderly patients is lacking. We studied the efficacy, toxicities and survival rates in a cohort of men diagnosed with GCT aged ≥45 years receiving chemotherapy in a metastatic setting. Methods: Data was collected retrospectively from 48 patient’s ≥45 years with GCT’s identified at Mount Vernon Cancer Centre, London. The histology, stage and international germ cell consensus (IGCC) risk classification was identified in all patients. Data was collected regarding chemotherapy regimens, number of cycles completed, toxicities and complications that led to treatment modifications or early cessation. Treatment toxicities were evaluated using the common terminology criteria for adverse events (ctCAE) grading. We then assessed progression free survival, relapse rates and overall survival (OS). Results: We identified 48 patients diagnosed with GCTs aged ≥45 years. The median age at diagnosis was 52 (range 45-70) and 75% of patients were aged ≥50. Classic seminoma and nonseminomatous GCTs were seen in 65% and 35% of patients, respectively. 75% of patients were ≥stage II at diagnosis. In total 29 patients received BEP, 4 EP, 7 Carboplatin AUC10, 2 Carboplatin AUC7 and 5 received POMBACE. 73 % (35/48) of patients experienced one or more complication/s from chemotherapy (15/48 ctCAE grade ≥3), of which the most common were neuropathies (27%), thromboembolism (10%) and tinnitus (10%). In 8 cases omissions or dose reductions had to be made and treatment delays occurred in 3 cases. Only 2 patients did not complete all intended cycles. Over 70% (35/48) of patients had an OS of > 5 years. One patient died during chemotherapy due to gastro-intestinal bleed. Conclusions: Survival rates in patients with GCTs aged ≥45 treated with chemotherapy are good with the majority achieving a > 5 year OS. Although age is not a prognostic factor, these patients are more prone to toxicities and have underlying comorbidities. This data will be of value to oncologists weighing up the risks versus benefits of treatment in this older cohort of patients in combination with similar studies.