bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical benefit in oncology trials: Is this a patient-centered or tumor-centered endpoint?
Authors: Ohorodnyk P. , Eisenhauer E. A. , Booth C. M. 
Published: August 2020

6564 Background: Clinical benefit (CB) was first successfully used as an endpoint in 1997 in the pivotal study of gemcitabine in advanced pancreas cancer. In the trial by Burris et al (J Clin Oncol. 1997) CB was a composite measure of pain, performance status, and weight. Here we describe how CB has been used in oncology trials since that time. Methods: We performed an electronic search ( www.jco.org ) for reports of all clinical trials (phase I, II, III) published in the Journal of Clinical Oncology 1997–2008 citing ‘clinical benefit.‘ Eligible trials were those reporting clinical benefit as an endpoint. Details related to study methodology, sponsorship, and endpoints were abstracted. Use of CB was classified as patient-centered if it referred to improvement in the clinical parameters used by Burris et al or in other disease-related symptoms. CB was classified as tumor-centered if it related to objective tumor criteria for partial/complete response and/or stable disease. Descriptive statistics were used to summarize findings and the chi-square test used to compare proportions. Results: 71 trials reporting CB as an endpoint were identified: 37 in breast, 8 in pancreas, and 26 in other cancers. The definition of CB was patient-centered in 21 trials (30%) and tumor-centered in 50 trials (70%). Only 20% (14/71) of trials (including all 8 pancreas studies) used the original Burris definition. In the second half of the study period there was an increase in the number of trials using CB as an endpoint (17 to 54 trials) and in the proportion of trials with a tumor-centered definition (10/17, 59% to 41/54, 76%, p = 0.09). Study variables associated with the use of a tumor-centered definition include: disease site (breast 35/37, 95%; all others 16/34, 47%, p < 0.001) and intervention (hormone or targeted agent 38/40, 95%; chemotherapy 13/31, 42%, p < 0.001). There was no association with sponsorship (industry 41/56, 73%; non-industry 10/15, 67%, p = 0.86) or phase of trial (phase I/II 36/48, 75%; phase III 15/23, 65%, p = 0.56). Conclusions: Despite its initial definition, clinical benefit is often used to describe objective tumor findings. Clinical trials should use endpoints in a consistent manner to enable clear communication between investigators, clinicians, and patients about the benefit of novel therapies. No significant financial relationships to disclose.
Adjuvant hormone strategies in postmenopausal women with breast cancer: An economic evaluation based on the EBCTCG meta-analyses
Authors: Younis T. , Rayson D. , Skedgel C. 
Published: August 2020

6574 Background: Meta-analyses conducted by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) demonstrated significant improvements in breast cancer (BC) outcomes associated with tamoxifen (TAM) and/or aromatase inhibitor (AI) therapy. We conducted an economic evaluation, based on these meta-analyses, to examine the cost-effectiveness (CE) of adjuvant TAM, sequential TAM-AI and upfront AI in post menopausal (PM) women with BC. Methods: A generic model was developed to calculate cumulative costs and quality adjusted life year gains (QALYG) over 25-year horizon in hypothetical cohorts of PM women with BC undergoing 5-year treatment with TAM alone, upfront AI, or sequential TAM-AI. We examined different cohorts with varying 10-year baseline recurrence risk (RR) without adjuvant hormonal treatments to reflect the natural spectrum of breast cancer disease encountered (low = 25%; average = 38%; high = 50%; very high = 75%). The efficacy outcomes were derived from the EBCTCG meta-analyses, with 10-year duration of benefit assumed for all strategies. Costs and utilities were derived from the literature, and local resources. The analysis took a direct payer perspective and reports costs in 2008 Cdn$. Costs and benefits were discounted at 3%. CE was based on the $50,000/QALY gained threshold. Adverse events were not included in the primary analysis. Sensitivity analyses were conducted. Results: Adjuvant hormonal treatments with TAM and/or AI are CE strategies in PM women with BC. The costs and QALYG associated with hormonal treatments were dependent on the baseline RR: CE estimates were more favorable in cohorts with higher as opposed to lower RR. The baseline RR also influenced the choice of the optimal economic strategy. Upfront AI was associated with higher costs and more QALY gains compared to TAM-AI. CE however was favorable in patients with average to very high RR and unfavorable in patients with low RR. Conclusions: Adjuvant treatments with TAM and/or AI are associated with favorable CE in PM women with BC. The optimal CE strategies, however, are dependent on the baseline RR without hormonal treatment. A risk-tailored hormonal treatment choice could optimize the overall health system efficiency. [Table: see text]
Cost-effectiveness of predictive markers in breast cancer: An analysis from a Swiss perspective
Authors: Blank P. R. , Schwenkglenks M. , Pestalozzi B. C. , Moch H. , Szucs T. D. 
Published: August 2020

6578 Background: Breast cancer has one of the highest cancer related death rates all over the world. New therapeutic agents like trastuzumab have yielded significant clinical benefits in human epidermal growth factor receptor 2 (HER-2) overexpressing tumors, but have also increased costs substantially. A cost-effectiveness analysis was performed to estimate the economic implications of testing HER-2-status in breast cancer patients. Methods: A Markov state transition model was used to assess the costs and effectiveness of a hypothetical cohort of 10,000 females at the age of 50 years. Probabilities for recurrence and cancer related death have been derived from published trials. The model was run life-long (i.e., for 50 years). Incremental costs were evaluated for diagnostic tests and treatments in both the HER-2 tested and the untested arm. Costs were estimated using data from a third party payer prospective in Switzerland. Results: Predictive testing with immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) accounted for €48 and €312, respectively. The costs for trastuzumab administration for a one year treatment summed up to €38,716 per patient. The life-long Markov model resulted in a total cost difference of €-17,774 in favor of the predictive test strategy. No difference in regard to the effectiveness was evident, yielding in 9 QALYs gained at the end of the modeling cycle for both strategies. The dominance of the testing regimen implied the analysis of the planned cost-effectiveness ratio being superfluous. The model showed robustness for variable variations in the deterministic sensitivity analysis. The probabilistic sensitivity analysis revealed no impact on parameter uncertainties of the model results. The position of the HER-2 testing group was never non dominant. Conclusions: Predictive tests for HER-2-status offer an economically favorable approach to identify patients deriving benefit from trastuzumab treatment. Over a life-long horizon, our model predicts confirms that the usage of HER-2 tests is the dominant strategy. The outcome was robust to changes in the model assumptions. Economically as well as clinically, using HER-2 testing is the preferred strategy in the direction to personalized cancer care. No significant financial relationships to disclose.
An international comparison of barriers in opening oncology clinical trials
Authors: Wang-Gillam A. , Novello S. , Williams K. , Gao F. , Scagliotti G. V. , Govindan R. 
Published: August 2020

6580 Background: Well designed clinical trials are critical to improve the outcomes of patients with cancer. There are significant barriers to accrue patients to clinical trials beginning with processes required to “open” a trial. This study aims to compare the procedures and time required to open thoracic oncology trials at a United States academic center to a similar center in Europe. Methods: A retrospective review was performed of all thoracic oncology therapeutic trials submitted for regulatory review between 2001–2008 at Washington University School of Medicine (WUSM) and the University of Torino, Italy (UT). A process map was drafted by both institutions to establish the order of required events. The timing data for each step was collected and analyzed for comparison. Results: A total of 137 therapeutic thoracic oncology trials were reviewed, 83 from WUSM and 54 from UT. Five major regulatory steps are required to open a trial in WUSM compared to three at UT. The median times to open a trial are 163 days (with inter-quartile range of 91 to 257 days) for WUSM and 122 days for UT (with inter-quartile range of 96 to 159 days) (p = 0.048). The median times for regulatory approval are 75 days (inter-quartile range, 26 to 131 days) for WUSC and 31 days (inter-quartile range, 10 to 67 days) for UT (p<0.0001), attributed to the additional requirement of Scientific Review Committee approval at WUSM prior to consideration by the Institutional Review Board (IRB), while regulatory approval is a single process at UT. However, the median time for contact approval process identified as the limiting step requiring a median of 115.1 (WUSM, inter-quartile range of 78 to 187) or 84 (UT, inter-quartile range of 44 to 124) days (p = 0.011). Conclusions: It takes additional steps and significantly longer time to open a therapeutic thoracic clinical trial at a representative U.S. site (WUSM) compared with a site in Europe (UT). As global trial collaboration increases, uniform strategies must be developed to shorten the administrative process, encouraging the creation of streamlined systems that enable centers to increase the number of agents under investigation. No significant financial relationships to disclose.
Tracking clinical trial accrual strategies and barriers via a Web-based screening tool
Authors: Grubbs S. S. , Gonzalez M. , Krasna M. , Siegel R. , Bryant D. , Tschetter L. , Hayenga L. , Duggan B. , St. Germaine D. , Denicoff A. 
Published: August 2020

6586 Background: The National Cancer Institute Community Cancer Centers Program (NCCCP) has developed a web based tracking tool to monitor screening of patients for clinical trial participation. The system is designed to collect data from multiple research sites throughout the geographically diverse group. The log blindly collects patient demographics, successful trial entry, and reasons for trial enrollment failure. Methods: Seven NCCCP sites utilized the log during the 60 day open accrual period for the Wake Forrest WFU 07–02–03 cancer control trial (chronic lymphocytic leukemia COLD- fX) in Novermber 2008 and December 2008. Results: 327 chronic lymphocytic leukemia patients were screened mostly by chart review. 162 (50%) were eligible for study entry. 45 (14%) entered the trial. 103 (31%) eligible patients declined entry. Of the 103, 72 (70%) did not wish to participate in research, 15 (15%) had travel constraints, 5 (5%) perceived excess toxicity, 9 (9%) gave no reason. 14 (3%) eligible had their physician decline entry. Overall, 28% of eligible patients entered the trial. 165 (50%) were trial ineligible. 82 (50%) for prior therapy, 30 (18%) for co morbid conditions, 10 (6%) missed an entry time requirement, 39 (24%) have incomplete data. Conclusions: The NCCCP trial screening log successfully captures real time clinical trial participation data from a diverse network of clinical trial sites. This data base will allow future analysis of individual clinical trial and site accrual barriers and empower strategies to increase trial participation. No significant financial relationships to disclose.
International comparison of the quality of voluntary adverse event reports for cremophor-containing paclitaxel-associated anaphylaxis submitted to regulatory agencies in the United States, Europe, and Japan
Authors: Calhoun E. , Raisch D. , Luu H. , Carias E. , Irizarry L. , Fisher M. , Sartor O. , Bennett C. 
Published: August 2020

6589 Background: Serious adverse drug events (sADEs) are a significant cause of morbidity and mortality. The FDA's MedWatch program is a voluntary adverse drug reporting program. In Europe and Japan, sADE reports are rarely reimbursed. We evaluated the quality of adverse events reporting in the US, Europe, and Japan for paclitaxel-associated anaphylaxis. Hypersensitivity reactions (presumably due to the diluent cremophor) occur in up to 42% of patients receiving paclitaxel (cremophor- containing paclitaxel was licensed in 1992, a cremophor-free paclitaxel was licensed in 2005). Methods: We reviewed reports of anaphylactic reactions to paclitaxel reported between 1997–2007 contained in the FDA Adverse Event Report System (AERS). Results: Of 171 unique case reports, 34% resulted in death. Cases that resulted in death were mostly incomplete in reporting descriptions of anaphylaxis symptoms and prophylaxis/therapy drug regimens in the US, Europe and Japan. (Table) The median duration between date of event and regulatory notification was 27, 55, and 18 days for the US, Europe, and Japan respectively. Conclusions: Overall, the quality of case reports of serious anaphylaxis reactions to cremophor-containing paclitaxel was poor in the US, Europe, and Japan, despite a substantial number of these reports being associated with death. Surprisingly, among the patients receiving prophylaxis with corticosteroids, anti-histamines, and/or H2-blockers, 36% of patients still died. [Table: see text] No significant financial relationships to disclose.
“Beating the bushes” to identify previously unreported cases of a rare and potentially fatal adverse drug reaction: Comparison of HIV-negative rituximab-associated progressive multifocal leucoencephalopathy (PML) cases obtained by the Research on Adverse Drug Events and Report (RADAR), the FDA, the manufacturer, and a literature review
Authors: Richey E. A. , Carson K. R. , Evens A. M. , Focosi D. , Bennett C. L. 
Published: August 2020

6604 Background: PML is a rare and usually fatal viral reactivation syndrome. As of December 2008, notifications from the FDA and rituximab (R) manufacturers described 26 patients with R-associated PML. Potential risk factors for PML include chemotherapy, corticosteroids, and HIV-infection. The FDA and the manufacturer requested that clinicians report information on all potential cases of R-associated PML. In an independent pharmacovigilance effort, RADAR queried clinicians at academic lymphoma referral centers regarding possible unreported cases of R-associated PML. Methods: RADAR surveyed clinical lymphoma experts at 13 major academic centers and identified 21 previously unreported cases of R-associated PML. Quality of reports is compared to published case reports (n=15) and reports to the FDA and manufacturer of R (n= 20). Duplicate reports were identified based on age, sex, and underlying illness. The search period was from the first FDA approval granted for R in 1997 to December 31, 2008. Results: In this series, the case-fatality rate of R-associated PML was 90%. The estimated incidence is 1 PML case per 4,700 R-treated NHL patients (based on the number of cases in this report, manufacturer estimates of 1,560,000 total global R exposures, and an estimate of six R doses per patient). Conclusions: Clinicians at major academic referral centers assist independent pharmacovigilance efforts in part provided that the requests for information are brief (<20 minutes), patients and providers are assured confidentiality, and safety data is disseminated collaboratively as peer-reviewed abstracts and manuscripts. [Table: see text] No significant financial relationships to disclose.
Heparin use and venous thromboembolism (VTE) among cancer patients receiving chemotherapy with a prior history of VTE
Authors: Cherkowski G. , Dietrich J. , Chen F. , Fryzek J. , Bridges K. 
Published: August 2020

6616 Background: Heparin is an effective treatment option for the prevention of venous thromboembolism (VTE) in cancer patients on chemotherapy. To date, information on the use of both low molecular weight heparin (LMWH) and non-LMWH in cancer patients receiving chemotherapy that have had a prior VTE is lacking. We evaluated heparin treatment patterns as well as the incidence of VTE in a cohort of cancer patients receiving chemotherapy, who have had a VTE prior to their cancer diagnosis. Methods: We conducted a retrospective cohort study using a large claims database representing the U.S. commercially-insured population. The cohort included all patients 18–64 years old from 2000 to 2007 who were diagnosed with cancer, were on chemotherapy, and who had a VTE occurring up to 12 months before cancer (n=331). We defined a diagnosis of cancer as two ICD-9 claims 30 days apart or more. A combination of ICD-9, HCPCS, and CPT codes were used to capture chemotherapy treatment after cancer. A VTE was identified by a single ICD-9 claim of 415.1, 451.2, 451.81, 451.9, 453.1, 453.2, 453.8, or 453.9. VTE claims occurring within 6 months of the index claim were considered part of the same VTE event. A patient was considered to have a VTE after cancer if they had a VTE claim that occurred both after the cancer diagnosis and at least 6 months beyond the most recent pre-cancer index VTE date. Results: Fifty-one percent of cancer patients with a history of VTE were prescribed an anticoagulant (n = 171). Fewer patients took LMWH compared to non-LMWH (6.7% versus 27.8%) while a portion took both (17.2%). A VTE after cancer was experienced by 49.1% of those on any kind of anticoagulant, 45.4% of those taking LMWH, 43.5% of those taking non-LMWH, and 59.6% of those who had taken both types. Fewer VTEs were reported among those taking no anticoagulants (29.4%). Conclusions: Approximately half of all cancer patients receiving chemotherapy were receiving heparin, with a smaller proportion using only LMWH. Even with prophylaxis, VTE recurs in half of cancer patients with a VTE history who receive chemotherapy. Recurrent VTE is a serious risk despite heparin or LMWH prophylaxis. [Table: see text]
Association of serum 25-hydroxy vitamin D and body mass index in cancer
Authors: Gupta D. , Trukova K. , Vashi P. G. , Adams A. , Lambert G. M. , Lammersfeld C. A. 
Published: August 2020

6625 Background: The association between vitamin D and obesity remains unsettled with studies reporting conflicting findings on the relationship between the two. This association assumes even greater importance in cancer because of the alleged role of vitamin D in cancer risk and survival. Currently, the dietary recommendations for Vitamin D do not take into account a person's body mass index (BMI). We investigated the relationship between serum 25-hydroxy-vitamin D [25(OH)D] and BMI in a large sample of cancer patients. Methods: A consecutive case series of 740 cancer patients seen at Cancer Treatment Centers of America from Jan 08 to June 08. Serum 25(OH)D was measured at presentation to the hospital. The cohort was divided in 4 BMI groups (<18.5, 18.5–24.9, 25–29.9, and >30.0 kg/m2). Correlation between 25(OH)D and BMI was evaluated using Spearman correlation coefficient. Mean 25(OH)D was compared across the 4 BMI groups using ANOVA. Linear regression was used to quantify the relationship between BMI and 25(OH)D. Results: Of 740 patients, 303 were males and 437 females. The mean age at presentation was 55.7 years (SD = 10.2). The mean BMI was 27.9 kg/m2 (SD = 6.7). Most common cancers were lung (134, 18.1%), breast (131, 17.7%), colorectal (97, 13.1%), pancreas (86, 11.6%), prostate (45, 6.1%) and ovarian (39, 5.3%). The mean serum 25(OH)D was 21.9 ng/ml (SD = 13.5). Analysis revealed that as BMI groups increased from normal to overweight or obese classifications, there was a significant decrease in 25(OH)D (Table). The Spearman correlation between 25(OH)D and BMI was -0.20 (p = 0.001). Every 1 kg/m2 increase in BMI was significantly associated with a 0.43 ng/ml decline in serum 25(OH)D (p = 0.001). Conclusions: We found that obese cancer patients (BMI >=30 kg/m2) had significantly lower levels of serum 25(OH)D as compared to nonobese patients (BMI <30 kg/m2). BMI should be taken into account when assessing a patient's vitamin D status and more aggressive vitamin D supplementation should be considered in obese cancer patients. [Table: see text] No significant financial relationships to disclose.
Single-agent activity of GCS-100, a first-in-class galectin-3 antagonist, in elderly patients with relapsed chronic lymphocytic leukemia
Authors: Cotter F. , Smith D. A. , Boyd T. E. , Richards D. A. , Alemany C. , Loesch D. , Salogub G. , Tidmarsh G. F. , Gammon G. M. , Gribben J. 
Published: August 2020

7006 Background: GCS-100 is a polysaccharide antagonist of galectin-3, a protein whose overexpression on certain tumor cells is associated with poor prognosis in cancer patients. GCS-100 has been shown to induce apoptosis of patient CLL cells ex vivo. In addition, GCS-100 potentiates the in vitro activity of other agents commonly used to treat CLL, including rituximab. This phase II clinical trial evaluated the potential of GCS-100 as a novel single-agent therapeutic for relapsed CLL. Methods: Patients with Rai Stage II or higher CLL who had relapsed after one or two prior therapies were eligible. Prior therapies included a range of chemotherapy combinations including FCR, cyclophosphamide/vincristine/rituximab, and chlorambucil/prednisone. Patients received GCS-100 i.v. at 160 mg/m2 for 5 days every 21 days until disease progression. Peripheral blood was collected on study days 1, 4, and 8 of each cycle to assess peripheral leukocyte counts and apoptosis. CD38 and Zap70 expression were assessed where possible. Results: 24 pts were enrolled;16 men and 8 women (median age 67 years, range 40–86 years, 15/24 pts were over 65 years). GCS-100 was well-tolerated. There were no cases of drug-related grade 3 or 4 hematological toxicity or other serious AE. Two patients discontinued treatment due to rash, which resolved with cessation of treatment and which has been shown to be responsive to steroids. Six (25%) patients experienced PR, including 4 patients with >50% shrinkage of lymph node lesions. Currently 6 patients remain on study with a median duration of 5 months (range 4.5–9 months). In addition, apoptosis of peripheral leukocytes was confirmed by caspase activation and by DNA fragmentation. Conclusions: GCS-100 has significant single-agent activity in relapsed CLL. Its lack of myelosuppression and potential synergy with other agents makes GCS-100 a strong candidate for further development in CLL, particularly for elderly patients for whom there is a major need for less toxic agents. [Table: see text]