bluuebunny/crossref_metadata_2025 huggingface dataset:
Leadership knowledge and beliefs regarding diversity, equity, and inclusion at SWOG Cancer Research Network.
Authors: Espinoza Gutarra Manuel Ricardo , Figueroa-Moseley Colmar , Gansauer Lucy , Nagaraj Gayathri , McDermott Jessica Dreger , Bangs Rick , Caban-Holt Allison , Robinson Patricia A.
Published: June 2023

e13599

Background: Diversity, Equity, and Inclusion (DEI) is recognized as fundamental in the development of generalizable clinical trials. Both ASCO and the FDA have released statements regarding the importance of representativeness in clinical trials. A paucity of research exists regarding the knowledge and beliefs of the people who lead the development of trials within the NCTN. Methods: An electronic survey on knowledge and beliefs regarding DEI was administered to SWOG leadership from 12.14.2021 to 01.13.2022. Questions were divided into 4 categories including: general beliefs regarding DEI, SWOG’s current status regarding DEI efforts, perception of SWOG’s values and readiness in executing DEI. Twenty questions were asked and answers were recorded using a 5-point Likert scale. Results: A total of 53% (N=47/88) respondents completed the survey (Table 1). The majority of SWOG leadership strongly agree that diversity is an asset (68%) and that they have a role to champion DEI (72%). Less than a quarter of SWOG leadership strongly agree that there are sufficient opportunities for committee members to provide DEI input across the clinical trial life cycle (21%). When evaluating SWOGs current role in DEI efforts, 64% of respondents had a neutral or negative response for each of the 4 questions. When evaluating respondents’ perception of SWOG values regarding DEI, 64% of respondents had a positive or very positive response on average for each of the 6 questions. When evaluating SWOG’s readiness to promote DEI, 57% of respondents had a positive or very positive response for each question. Some of the barriers experienced include technological issues with construction and delivery of the survey to protected email addresses as well as lack of dedicated staff at SWOG to assist. Conclusions: This survey provides insight into SWOG leader’s beliefs and knowledge regarding DEI as well as their perception of SWOG’s current efforts and ability to promote DEI in clinical trials. While respondents tended to value DEI positively personally and through SWOG, their perception of SWOG’s role in promoting DEI was neutral or negative. Perception of SWOGs readiness to promote DEI was positive to a lesser degree. These findings emphasize the importance of capturing baseline beliefs to promote DEI efforts with clinical trial leadership. [Table: see text]
Representativeness of patients with lung cancer in an integrated health care delivery system.
Authors: Yang Mike Z. , Liu Raymond , Von Behren Julie , Lin Katherine , Adams Alyce S. , Kushi Lawrence H. , Quesenberry Charles P. , Velotta Jeffrey B. , Young-Wolff Kelly C. , Gomez Scarlett L. , Shariff-Marco Salma , Sakoda Lori C.
Published: June 2023

e13600

Background: Lung cancer is the leading cause of cancer death in the US, and research is critical to reducing its morbidity and mortality. Minoritized groups (e.g., low income) that face higher lung cancer burden are underrepresented in clinical trials, which are often conducted at NCI-designated cancer centers (NCICCs). Large integrated health systems such as Kaiser Permanente Northern California (KPNC) may be well-positioned to produce research findings that are more representative of patient populations in important clinical and demographic characteristics. In this study, we evaluated the representativeness of lung cancer patients from KPNC compared to those from NCICCs and non-NCICCs in Northern California. Methods: We extracted individual and neighborhood data from the California Cancer Registry, California Neighborhoods Data System, and CalEnviroScreen 4.0 for patients with invasive lung cancer diagnosed from 2015 through 2019 within the KPNC catchment area. We compared these characteristics among patients from KPNC, NCICCs (Stanford, UC Davis, UCSF), and all other non-NCICCs. Results: Of 27,288 patients, 31% are from KPNC, 8% from NCICCs, and 61% from other non-NCICCs (Table). KPNC patients are more similar to other non-NCICC patients and the total lung cancer population than to NCICC patients on most characteristics. KPNC patients are slightly older, more likely to be female, and less likely to be Asian American/Pacific Islander (AAPI), compared to other non-NCICC patients. In contrast, NCICC patients are younger, less likely to be female or non-AAPI minoritized racial and ethnic groups, and present with less stage IV disease and more adenocarcinoma at diagnosis. Both KPNC and NCICC patients are more likely to reside in neighborhoods with the highest socioeconomic status (SES) and lowest pollution burden than other non-NCICC patients. Given large numbers, all differences were statistically significant (p<0.001). Conclusions: These analyses demonstrate that lung cancer patients in KPNC are more broadly representative of the overall lung cancer population than those in NCICCs, and can produce generalizable research findings to improve outcomes for all lung cancer patients. [Table: see text]
FDA analysis of treatment-free survival in frontline advanced immuno-oncology–VEGF TKI renal cell carcinoma trials.
Authors: Chang Elaine , Zhou Jiaxi , Song Chi , Gittleman Haley , Fernandes Laura L. , Weinstock Chana , Atkins Michael B. , Agrawal Sundeep , Sridhara Rajeshwari , Gormley Nicole , Amiri-Kordestani Laleh , Tang Shenghui , Kluetz Paul , Suzman Daniel L. , Pazdur Richard , Rini Brian I. , McDermott David F. , Regan Meredith M.
Published: June 2023

e13602

Background: Treatment-free survival (TFS) with and without (w/o) toxicity are outcome measures that describe health states where patients are experiencing clinically stable disease while off anti-cancer treatment, a clinically meaningful attribute seen with some immune-oncology (IO) regimens. We sought to characterize TFS with and w/o ongoing toxicity in addition to time on protocol therapy (combination and monotherapy) in trials of frontline IO-VEGF tyrosine kinase inhibitor (TKI) combinations in pts with advanced renal cell carcinoma (aRCC). Methods: We pooled randomized trials submitted to FDA evaluating IO-TKI combination in treatment-naïve aRCC with at least 30 months (mos) of median follow-up. OS was partitioned into health states, including TFS, defined as area between Kaplan-Meier curves for 2 time-to-event endpoints originating at randomization: 1) time to all protocol therapy cessation and 2) time to subsequent systemic therapy initiation or death. Health state areas under the curve were estimated by 30-mo restricted mean times. We pooled data by treatment arm. Results: Three trials (KEYNOTE-426, JAVELIN Renal 100, CheckMate 9ER) met criteria for analysis; in total, 1183 pts received IO-TKI vs. 1184 on control arms receiving sunitinib (SUN). IO-TKI and SUN groups spent 9% (2.7 mos [95% confidence interval (CI): 1.8, 3.5]) and 10% (2.9 mos [95% CI: 2.1, 3.8]) of the 30-mo period alive and treatment-free. Mean TFS with grade ≥3 toxicity were 1 and 0.6 mos in the IO-TKI and SUN groups, respectively. Mean TFS w/o grade ≥3 toxicity were 1.7 and 2.3 mos in IO-TKI and SUN groups, respectively. In IO-TKI group, the 30-mo mean time on combination therapy was 13.7 mos (46% of 30-mo period) and 3.9 mos on monotherapy (13% of 30-mo period). Following cessation of one drug in IO-TKI arm, monotherapy duration of TKI was longer than IO: 2.9 and 1 mos, respectively. Conclusions: In this descriptive, exploratory analysis, TFS and TFS w/o toxicity were similar in IO-TKI group compared to SUN group, in contrast to improved TFS in IO-IO vs. SUN seen in published literature. Among pts on IO-TKI, more time was spent on TKI monotherapy than IO monotherapy. These findings may reflect continuation of TKI until progression per protocol design in all trials and discontinuation of IO after 2 years in 2 trials, and may inform individual pt choice of IO-IO vs. IO-TKI. [Table: see text]
A smart clinical cohort selection system for clinical oncology research.
Authors: Basharat Amna , Farooq Muddassar
Published: June 2023

e13613

Background: Cohort selection for specialized clinical trials is a cardinal pillar of the evidence-based medicine; however, it is the most difficult, complex, time consuming, and expensive step. Determining the efficacy of a new treatment (or intervention) requires finding eligible patients meeting the inclusion and exclusion criteria. In specialized scenarios, the complex criteria may even require researchers to do time consuming manual reviews and analyses of electronic health records (EHRs) to shortlist qualified patients. The major contribution of this research is a set of novel semantic models to build a cohort for clinical research by enabling semantic search over electronic health records represented as Knowledge graphs (KGs). Methods: We present the design of a novel cohort retrieval system, satisfying inclusion and exclusion criteria of an oncology clinical research study. Knowledge graphs and semantic models: We construct knowledge graphs (KGs) to interconnect different data sources, stored in a data-lake, and develop semantic models that enable semantic search over the processed data. We designed and constructed an oncology knowledge graph that enables semantics driven cohort selection. In addition, we have built a novel cohort retrieval system, satisfying the inclusion and exclusion criteria of an oncology clinical research study, that utilizes a semantics driven dynamic query engine to generate and execute cohort selection queries on heterogeneous EHR data. Results: We obtained real world oncology data of 21,000 oncology patients and then constructed knowledge graphs for five cancer types -- Colon (C18), Lung (C34), Breast (C50), prostate (C61), and Multiple Myeloma (C90). The cohort building scenarios are designed to represent a mix of criterion types and combinations including both inclusion and exclusion criteria, involving conjunctions, disjunctions and numeric ranges. Our cohort builder is evaluated against ten well known key competency scenarios. A team of experts validated the results of our cohort builder obtained against these competency scenarios by directly querying the graph. Our extensive evaluations demonstrate that the cohort builder searches with 100% accuracy the patients that match the criteria specified in all ten competencies. The average time to build the cohort on all graphs for these competencies is less than 10 seconds compared with that of days when patients are manually searched in EHR systems. Conclusions: Our query engine is not tightly coupled with the architecture of our data-lake; rather its architecture is flexible and can be easily integrated with other enterprise data-lakes or EMR systems. In future, we plan to scale the extent of inclusion and exclusion criteria to provide interoperability with existing clinical trial knowledge. We also aim to empirically evaluate the efficiency of cohort selection queries using a knowledge graph with classical database query approaches.
Design, reporting, and disparities of advanced non–small cell lung cancer phase 3 clinical trials in the era of immunotherapy.
Authors: Ayumi Miyawaki Isabele , Mitre Lucas Pari , Ynoe de Moraes Fabio
Published: June 2023

e13616

Background: Lung cancer remains the main cause of cancer-related mortality globally, with non-small cell (NSCLC) accounting for the majority of cases. The advent of immunotherapy (IO) has expanded treatment options for advanced NSCLC. However, there are no bibliometric studies exploring NSCLC IO-based trials. We aimed to provide a systematic and comprehensive analysis of the design, reporting, population, and disparities of phase 3 trials investigating IO for advanced NSCLC. Methods: MEDLINE search was performed (last decade) for phase 3 trials reporting on patients with advanced (stage IIIA or higher) NSCLC. We assessed relationships between study outcomes, funding transparency, conflict of interest, journal impact factor (IF), region, gender of the first and last authors, population size, and ethnicity. Results: From 2012 to 2022, 2556 articles were screened and 81 were included. Overall survival (OS), followed by progression/disease-free survival (PFS) and overall/objective response (ORR) were the most commonly reported primary endpoints, representing 54%, 44%, and 15% respectively. The majority of the studies ( > 97%) had a funding sources statement and declared COI. Male first and last authorship represented 84% and 74% of studies, respectively. In 62% of trials reporting the patient’s ethnicity, white was the most common (65%). Regarding the source of funding, 74% of trials reported industry-only, 8% academia-only, 11% combined, 4% no funding received and 2.5% were not transparent. 98% of trials were from high-income countries (HIC), being the US (37%) and China (26%) the most reported. The mean number of authors with declared COI was 10.55 [0-25] and the mean total number of authors was 21.3 [5-76]. Publications journals' mean IF was 57.7 [2.1-202.7]. COI declaration was associated with publication in a journal with a higher IF compared to studies with no declared COI (p < 0.05). The journal IF was significantly higher in the US publications compared to China (p < 0.01). Trials assessing OS and PFS as their primary outcome were published with a higher IF in relation to assessing ORR only (p < 0.05). There was a significant association between the first and last authors' gender (p < 0.05), with a higher likelihood of matching genders (OR = 4,5 [1,3-14,4]). There was no association between the proportion of COI among authors, source of funding, and first author’s gender with journal IF. Conclusions: Phase 3 trials exploring IO for advanced NSCLC are majorly done in HIC, report industry funding and COI, and have males as the first and last authors. PFS is the primary outcome of almost 50% of the trials. We identified that among the primary outcomes studied, declaration of COI and author’s geographic affiliation may influence the publication’s IF. Sustained efforts are required to guarantee impartial reporting of clinical trial results and inclusive representation.
The role of micro-CT for intraoperative margin assessment of breast cancer.
Authors: Vasigh Mahtab , Meshkati Yazd Seyed Mostafa , Papazoglou Andreas S. , Liatsos Alexandros , Ranjbar Keivan , Bleicher Richard J. , Williams Austin David , Cruz Pico Christian X. , Pierotti Matthew Lewis , Michaelson James
Published: June 2023

e13620

Background: Breast-conserving surgery (BCS) followed by radiotherapy requires adequate removal of the malignancy with a negative margin. Accurate pathologic margin status is not available intraoperatively and is found to be positive in up to 20% of cases, necessitating re-excision. Specimen mammography (SM), used to find a biopsy marker, may assist with margin status but is only 55% sensitive for Intraoperative margin assessment (IMA). IMA methods are being increasingly investigated. Because micro-computed tomography (micro-CT) produces three-dimensional volumetric images, we aimed to evaluate the diagnostic sensitivity of micro-CT for IMA. Methods: We performed a systematic review according to the PRISMA guidelines by querying Scopus, MEDLINE, EMBASE, PubMed, and Google Scholar through 12/21/22. (https://osf.io/342h8). Studies evaluating the applications of micro-CT scanning in breast cancer were included for systematic review, and those reporting the diagnostic indices of micro-CT for IMA compared to histopathologic results were incorporated in a study-level meta-analysis. A random effects coefficient binary regression model was used when a high level of heterogeneity was observed. Results: Of the 2920 studies, 18 studies were selected. IMA was reported in 7 studies (388 specimens), tumor size in 3 studies, microcalcifications in 12 studies, and sentinel lymph node assessment in 1 study. Half of the studies were performed in the USA; the participant’s ages ranged from 33 to 82 years, and the tumor size was between 0.8 and 55.8mm. Image procurement time ranged from 4 to 30 minutes. A pooled diagnostic sensitivity of 0.67 (95% CI: 0.48 – 0.82) and specificity of 0.75 (95% CI: 0.63 – 0.84) was revealed, and the pooled accuracy was calculated based on the normal-error estimation as 0.76 (95% CI: 0.69 – 0.83) for IMA by micro-CT compared to the histopathological evaluation. Conclusions: Micro-CT can create 3D images of the internal structure and vasculature in less than 30 minutes and detects up to 67% of positive margins intraoperatively, preventing a future reoperation. Although the results of this review are promising, due to the high level of heterogeneity, further investigations should be pursued as to how and who should report the images and whether micro-CT may have a role in IMA. [Table: see text]
Decentralized elements within oncology trials: Labcorp experience.
Authors: Rami Alicia , Alcaide Maria , de las Heras Begona , Vidal Laura , Pascual Joanna , Lumsden Kurt
Published: June 2023

e13630

Background: The concept of digital health using Decentralized elements (DE) has rapidly gained acceptance due to the COVID-19 pandemic, moving clinical trials (CTs) to a more patient-centric model (PCM) with fewer site visits. The primary aims of DE are reducing patient burden, increasing enrolment and retention, maintaining quality of life, and decreasing overall trial cost. Methods: Between 2011 and 2022, Labcorp conducted 491 CTs which incorporated DE: telemedicine, electronic clinical outcome assessments (eCOA), electronic informed consent (eConsent) and mobile clinical services (MCS). All CTs were analyzed by therapeutic area, study phase (1-4) and country. Results: The COVID-19 pandemic increased the implementation of DE. However, digital health uptake between therapeutic area differed. Comparing Oncology with Neurology (higher increase in research), whilst eCOA was implemented most in Oncology, the Neurology MCS increase was over 50% since 2020. Overall, Big Pharma implemented ~1.5% more Decentralized elements, vs the biotech sector. The majority were phase 3, followed by phase 2, with MCS increasing its demand in phase 1. By country, USA, Spain, France, Germany and Canada dominated. The majority were hybrid CTs, with few completely virtual. Conclusions: Labcorp experience demonstrates that overall, the interest to implement DE in CTs continues to grow, promoting the transition to a PCM. Nevertheless, solutions like MCS still need to gain more acceptance in Oncology due to the added complexity and logistics and will require training of all stakeholders, as well as understanding the benefits and potential country-specific limitations. [Table: see text]
Clinical utility of a novel non-invasive technology for monitoring severe neutropenia in anticancer therapy.
Authors: Alva Bianchi Manuel , Iwase Toshiaki , Tolosa Ortega Pablo , Justo Jiménez Pablo , Rodriguez Izquierdo Antonia , Baumann Tycho , Jiménez Ubieto Ana , Sanchez-Bayona Rodrigo , Pottier Elizabeth , Shelton Anthony , Pérez-García José Manuel , Garcia-Mosquera Juan Jose , Martinez-Bueno Alejandro , Hochberg Ephraim P. , Martinez Andrea , Nunez Cesar , McCall David , Ueno Naoto T. , Ciruelos Eva M , Cuglievan Branko
Published: June 2023

e13632

Background: Every year more than 140,000 patients receiving anticancer therapy for malignancies in the US experience febrile neutropenia. Early detection of severe neutropenia could enable preventive strategies to reduce the incidence of febrile episodes. PointCheck is a novel portable optical device that can noninvasively monitor for severe neutropenia at home using microscopy and artificial intelligence. Preliminary clinical results of this device including usability (Lamaj et al., 2022), and sensitivity, and specificity (Pablo-Trinidad et al., 2019) for detection of severe neutropenia have already been reported. Here, we describe an exploratory clinical utility subanalysis. Methods: We conducted an international multicenter study with a primary endpoint of usability including mainly patients with hematological or breast cancer receiving therapy with intermediate/high risk for severe neutropenia, tested at two time points (baseline and nadir tests). Data included demographic information, cancer type, and a differential cell count within 120 minutes of the optical testing. The treating physician also completed an exploratory survey with 11 questions about the device´s potential clinical utility. A mixed-methods approach (descriptive statistics & “Likert” analyses with R 4.2.2) was used to evaluate the results. Results: 79 patients were included in this exploratory subanalysis. The median age was 49.5 (IQR 10.5-78.5) years, and 64 (81%) patients were female. The most common diagnoses were breast cancer (63%) and lymphoma (20%). Preliminary utility results were favorable with attending physicians agreeing that PointCheck could have helped evaluate 85% of the patients. In 82% of the patients, physicians felt that the device could avoid preparation of chemotherapy infusions in the setting of neutropenia. In 73% of the patients, physicians would consider administration of G-CSF or prophylactic antibiotics when sustained grade IV neutropenia was detected. Conclusions: This novel technology is able to non-invasively monitor for severe neutropenia and can add clinical utility as assessed by treating oncologists. Further studies are needed to validate these results.
An ultra-sensitive amplicon-based NGS assay for MRD detection.
Authors: Li Liangjian , Chen Meihong , Xiao Shanshan , Jia Lei , Wu Yalin , Wang Tao
Published: June 2023

e13634

Background: Detection of the minimal residual disease (MRD) has proven a promising noninvasive approach for monitoring the tumor remissions and relapses after surgical resection or other therapies. However, circulating tumor DNA (ctDNA) after surgery in the early-stage cancers can be at very low levels, which makes the MRD detection quite challengeable if the plasma sample only contains a few ctDNA copies. In the clinical practice, an ultra-sensitive and tumor-informed multiplexing variant detection system is required for postsurgical cancer surveillance. Methods: In this study we developed an ultra-sensitive amplicon-based NGS approach, namely UMIamp, to provide a personalized and tumor-informed strategy for MRD detection using plasma sample. Firstly, up to 16 clonal somatic variants can be obtained by whole exome sequencing (WES) of the tumor tissue samples. Then optimized primers were designed to uniformly cover the target DNA regions and those target regions were efficiently enriched by linear amplification. With randomly unique molecular identifiers (UMI) attached to DNA templates and ultra-deep NGS sequencing, the somatic target mutations with very low frequency can be identified using a customized bioinformatic pipeline. To validate the performance of the limit of detection (LOD), the reference standard samples were diluted to the allele frequencies of 0.02%, 0.01%, 0.005% and 0.002%, respectively. Each sample contained 14 single nucleotide variants (SNVs). The sensitivity and specificity were calculated based the mutations called. Results: Single site level sensitivity and specificity were 75% and 100% with the allele frequency of 0.02%, while they were 70.73% and 95.08% with the allele frequency of 0.01%. The results showed UMIamp was very sensitive and was able to detect 2 copies from 60ng cfDNA sample at 0.01% mutation level. Even at the 0.005% and 0.002% allele frequency levels there were less than two copies in 60ng cfDNA, UMIamp still achieved single site sensitivities of 24.18% and 23.07%, respectively. In the MRD clinical practice, sample level sensitivity was important to evaluate the detection capability based on more gene mutations. When combined the 14 variants as a unified indicator to detect the sample level MRD status, the positive rates at the VAFs of 0.02%, 0.01%, 0.005% and 0.002% were all 100%, which demonstrated the LOD of UMIamp approach can reach to as low as 0.002%. Such sensitivity will be adequate for post-surgical early-stage cancer surveillance. Conclusions: We developed an ultra-sensitive amplicon-based NGS approach which can effectively detect MRD status at the allele frequency of 0.002%. The developed approach can be applied in a personalized, tumor-informed MRD detection settings in post-surgical early-stage cancers.
The CLARIFY digital decision support platform: An artificial intelligence tool for exploring multidimensional cancer data.
Authors: Torrente Maria , Menasalvas Ernestina , Sousa Pedro Da Costa , Provencio Mariano
Published: June 2023

e13638

Background: Artificial intelligence has emerged as a mean of improving cancer care with the use of computer science. A digital framework that includes heterogeneous pipelines of real-world data can take advantage of AI, genomics and natural language processing to uncover insights that support decision-making in daily clinical practice. The goal of this study is to present an AI-based solution tool for cancer patients’ and identify clinical factors associated with relapse and survival, and to develop a prognostic model that identifies features associated with poor prognosis and stratifies patients by risk. Methods: This is a hospital-based retrospective registry included in CLARIFY (Cancer Long Survivor Artificial Intelligence Follow-up), a European project supported by the EU Horizon 2020 (grant agreement nº 875160), including 2275 patients diagnosed since 2008 at Medical Oncology Department at Hospital Universitario Puerta de Hierro-Majadahonda with non-small cell lung cancer (NSCLC) and 3000 breast cancer patients. The study was approved by the Ethics Committee at HUPHM (No. PI 148/15) and was carried out in accordance with the Helsinki Declaration. CLARIFY Decision Support Platform (DSP) is an AI-based solution tool which centralizes and analyzes real time anonymized clinical data from heterogeneous sources of data. It shows the clinical user information about individual patients or about the whole population and produces real-time descriptive statistics along with survival analysis (Kaplan Meier estimates and Cox regression model). Integrated data include clinical data from electronic health records from more than 5000 NSCLC patients and breast cancer patients, including more than 1,000,000 clinical notes, more than 900.000 clinical reports, data from wearable devices that produced around 1,000,000 variable values per patient, genomic data and data from quality of life questionnaires. Results: Using the DSP we obtained patients’ profiles, survival probabilities, we stratified over 2000 patients in low and high-risk profile and developed a machine-aided tumour-recurrence prediction model. This computational infrastructure was able to extract knowledge from different data sources allowing clinicians to analyse multiple factors that help stratifying patients by risk, in order to implement a personalized follow up care programme, aiming to make a significant impact in the patients’ quality of life. Conclusions: The reconstruction of the population’s risk profile was achieved and proved useful in clinical practice using AI. This DSP has potential application in clinical settings to improve risk stratification, early detection, and personalized surveillance management of cancer patients and may assist clinicians in their daily clinical practice.
Reveal irAE by analysis of 197,921 claim-based prescriptions.
Authors: Scholl Jeremiah Gordon , Long An Jim , Li Yu-Chuan (Jack)
Published: June 2023

e13639

Background: immune-related adverse effects (irAE) are widely known for immune checkpoint inhibitors (ICI), but medications used to relieve irAE based on patient profile and condition are not offered in guidelines. Publications are available to reveal irAE from hospitals, but the number of cases are normally only a few hundred and insufficient to stratify by more variables. Claim-based data points were also used in a few publications, based on analysis of diagnosis code such as ICD-9 and ICD-10. However, missing or wrong coding of adverse effects are well-known and over-exaggerated for severe adverse events, and are also affected by reimbursement policy. This research used medications from a large national health system to understand irAE and treatments related to them. Methods: 2017-2019 National Health Insurance database (NHIDB) in Taiwan was used. The case group was identified as (2,474) patients who used PD-1 inhibitors (more specifically Nivolumab, Pembrolizumab, and Atezolizumab because only those three were available in the duration). A control group was identified as (6,207) patients given platinum-based chemotherapy (cases using other cancer drugs at the same time were excluded). Odds ratios were calculated to see frequency of irAE and medications in both groups. Results: Top 10 medications are listed. Diphenhydramine and pain killers were the most common AE-relief medications for cancer patients in NHIDB and only anilides (mostly propacetamol) are overlapped. The rest of the drugs with OR > 3, especially steroids (thyroid and corticosteroids), were used mainly for irAE. Conclusions: The research reveals a novel approach to understand how physicians prescribe to treat irAE. The larger number of cases reported compared to previous studies suggests that such a database can be used for future research, including to reveal demographic patterns, and to aid the development of guidelines, teaching aids, and decision support.[Table: see text]
Trends in Medicare utilization and reimbursement for hematology/oncology procedures.
Authors: Conic Julijana Zoran , Reske Thomas
Published: June 2023

e13641

Background: Medicare Part B pays for physician services such as office visits and procedures based on the Medicare Physician Fee Schedule which is re-evaluated annually to maintain budget neutrality. Moreover, national cancer-attributed medical care costs in 2015 were $183 billion and projected to increase 34% to $246 billion by 2030 (Green et al: J Clin Oncol, PMID: 31804856). The aim of this study is to evaluate trends in Medicare reimbursement for procedures in hematology/oncology between 2012-2022. Methods: The data analyzed were extracted from the Physician Fee Schedule Look-Up Tool. CPT Codes were obtained from the Medicare Coverage Database. The following CPT codes were extracted: antineoplastic chemotherapy administration (96405, 96406, 96401, 96409, 96411, 96413, 96415, 96416, 96417, 96420, 96422, 96423, 96425, 96440, 96446, 96450, 96542), antineoplastic hormone therapy administration (96402), non-chemotherapy infusion (96360, 96361, 96365, 96366, 96367, 96368, 96369, 96370, 96371, 96372, 96373, 96374, 96375, 96376 ), bone marrow sampling (38220, 38221, 38222), bone marrow harvest (38230, 38232) and bone marrow transplant (38240, 38241, 38242). Consumer Price Index (CPI) obtained from the U.S. Department of Labor's Bureau of Labor Statistics was used to adjust reimbursement rates for cumulative inflation to 2022 U.S. dollars. The T-test was used to compare the mean prices for each procedure. This research contains publicly available data and as such is exempt from the IRB according to the Institutional Review Board at LSU Health Sciences Center in New Orleans, Louisiana. Results: The procedure with the highest reimbursement rate in 2012 was bone marrow harvest and the procedure with the lowest reimbursement rate in the same year was antineoplastic hormone therapy administration. The procedure with the highest reimbursement rate in 2022 was bone marrow harvest. The procedure with the lowest reimbursement rate in 2022 was antineoplastic hormone therapy. All procedure reimbursement fell significantly (p value of <0.001) over the timer period studied. Conclusions: Between 2012 and 2022 the reimbursement rates for common hematology oncology services fell significantly when adjusted for inflation due to reforms in Medicare part B. [Table: see text]
Temporal trends of atypical drug access at an academic oncology unit: The Verona University Hospital experience.
Authors: Atsina Francesca Mansa , Rossi Alice , Bolcato Ilaria , Fraccaroli Roberta , Alberti Chiara , Scardoni Laura , Patruno Isabella , Zacchi Francesca , Moscarda Viola , Messineo Luisa , Lucin Eleonora , Scaglione Ilaria Mariangela , Dodi Alessandra , Pavarana Michele , Melisi Davide , Leone Roberto , Scroccaro Giovanna , Marini Paola , Milella Michele
Published: June 2023

e13651

Background: In Italy, patient (pt) access to oncological drugs is almost exclusively provided by the NHS, following authorization by the European Medicines Agency (EMA) and negotiation with the Italian Medicines Agency (AIFA) for specific indications. However, regulatory delays (with respect to the availability of scientific evidence) and the need for rapid access to innovative drugs, particularly in the context of orphan and rare diseases, have prompted the utilization of atypical drug access pathways. In addition to enrollment in clinical trials, atypical drug access pathways are expected to be increasingly used in the context of a Precision Oncology practice. Methods: We explored trends in atypical drug access at the Oncology Section of the Verona University and Hospital Trust, by interrogating Oncology and Pharmacy databases and regional registries of rare diseases and reviewing AIFA registries records. Data on atypical drug access were also correlated with the use of NGS-based molecular profiling. Results: Between January 2016 and December 2022, a total of 355 atypical drug access requests for the treatment of cancer pts were recorded, with a peak in 2017 and no discernible temporal trend. Over this period, the two most common atypical access schemes were compassionate (including named patient and early access programs, 61%) and off-label (21%) use. The latter steadily increased over time (from 8% in 2017 to 39% in 2021). Overall, the type of drugs requested through atypical access were almost equally distributed between classical cytotoxic agents (CHT, 36%), immuno-oncology drugs (IO, 29%) and molecularly targeted agents (TT, 35%). Temporal trends in the usage of different classes of drugs are shown. Interestingly, TT requests decreased between 2016 and 2018 and stabilized at approximately 50% of total requests since 2019. Between 2019 and 2021, atypical drug access requests triggered by NGS-based extended molecular profiling significantly increased from 2.8% to 23.1% (p=0.0007). Conclusions: Although atypical drug access did not increase overall during the observation period, a trend towards increased off-label use of TT was identified, especially from 2019 onwards; figures for 2022 are being analyzed and will be presented at the Meeting. Since 2019, NGS-informed requests have significantly increased to constitute almost 1/4 of all atypical drug access requests, clearly identifying a trend towards implementation of Precision Oncology in routine clinical practice and evolving towards the implementation of Molecular Tumor Board case discussions. [Table: see text]
Overall survival information and population correspondence for FDA cancer accelerated approval indications between 2006 and 2021.
Authors: Benedict Agnes , Szabó Gabor , Doherty Bridget , Martin Silas , Marczell Kinga
Published: June 2023

e13653

Background: The US Food and Drug Administration (FDA) Accelerated Approval Program (AAP) was instituted to allow patients earlier access to medications that address large unmet need and are approved based on surrogate endpoints. Recently, approvals have been criticized for not providing overall survival data, and for confirmatory trials conducted in alternative populations. We investigated the availability of overall survival (OS) data for cancer accelerated approval (AA) indications and the correspondence between the population providing OS information and that of the original indication to assess the merit of these critiques. Methods: Approval letters and labels of cancer therapy products approved between January 1, 2006 and June 31, 2021 based on their verification status as of June 10, 2022 were identified from Drugs@FDA. Information was extracted irrespective of the final decision. Information about the exact indications and the trials that were used for AA and were cited for RA (confirmatory trial). OS data was searched for both AA and RA trials irrespective of approval dates, linked by NCT numbers identified in labels and letters. When OS was available only from the trial indicated for the RA, level of correspondence between the source of the OS data and the AA indication were described and then categorized in terms of the population characteristics, treatment lines, disease stage and changes in treatment regimen, to indicate level of correspondence. Results: OS data is available for 83% of closed AAs: 50 among the 57 converted and 12 among 18 withdrawn AAs. Further OS data was identified for seven AAs among the 55 ongoing reviews, creating a set of OS data for 69 out of the 130 total number of AAs identified. Exact or very good population overlap is evident in 50% of cases, defined as the availability of the trial reporting results for a population exact or very close to the original AA population; line change down was defined if the RA trial was conducted in an earlier line (without overlap with the original AA trial); and some additional categories were identified. Conclusions: Overall, OS information was available, and in half of the cases it was reported for a population very close to the original AA indication. Likely for ethical and practical reasons, RA trials are conducted in an indication that differs from the original AA indication and changes in the population was with the consent of the FDA. Policy discussions about AAP are incomplete without assessing its impact on survival and real-world considerations for conducting confirmatory trials. [Table: see text]
Increasing the study of novel anticancer therapies in adolescents: Facilitating adolescent inclusion in adult research.
Authors: Bucci-Rechtweg Christina , Zacharoulis Stergios , Mengou Evgenia , Corriol-Rohou Solange , Gaspar Nathalie , Copland Christopher
Published: June 2023

e13654

Background: Adolescent cancer patients are disproportionately excluded from clinical trials due to trial designs with lower age limits set to the legal age of majority. This has led to a persistent time lag between adult and pediatric approval of new medicines. Publication of new US regulatory guidance encourages inclusion of adolescents in disease- and/or target-appropriate adult trials to facilitate earlier adolescent access to effective therapies. To understand impacts of this and other initiatives fostering adolescent inclusion, a review of recent cancer drug approvals was performed by the ACCELERATE Fostering Age Inclusive Research (FAIR) group. FAIR is an international research collaborative whose aim is to reduce adolescent inequities in access to novel anticancer therapies. Methods: A comprehensive analysis of new oncology drug approvals in Europe (EMA) and the US (FDA) will be conducted. EMA and FDA databases will be interrogated to identify all novel anticancer drug approvals and new use approvals (innovator and generic or biosimilar) between 2018 and 2022. Specific sections of drug labels (Indications and Usage, Dosing and Administration, Use in Specific Populations, Clinical Pharmacology, Clinical studies) will be evaluated. The study team will assess: inclusiveness of the Indication for Use statement; applicability of the approved indication to an adolescent cohort. This analysis will be conducted in sequence: phase 1 analyzes the EMA approvals, phase 2 analyzes the FDA approvals, followed by a comparative analysis across the regions. Phase 1 data are presented using descriptive statistics. Results:. Conclusions: This research evaluating new European drug approvals shows a limited number of anticancer therapies have been adequately studied or approved for adolescent use, even when the approved indication is relevant to adolescents. Recent regulatory guidance to promote the inclusion of adolescents in adult oncology drug trials has not yet led to an increase in adolescent labelling. Increasing awareness of medical oncologists and study sponsors may facilitate cultural mindset change, leading to expansion of eligibility criterion to adolescents and shortening the time lag of adolescent access to novel anticancer therapies. [Table: see text]
Clinical evidence and benefit of special FDA designations in anti-cancer drugs.
Authors: Michaeli Daniel Tobias , Michaeli Julia Caroline , Albers Sebastian , Boch Tobias , Winterhoff Boris , Michaeli Thomas
Published: June 2023

e13655

Background: Over the past decades, US congress enabled the US Food and Drug Administration (FDA) to facilitate and expedite drug development for serious conditions filling unmet medical needs with five special designations: orphan, fast track, accelerated approval, priority review, and breakthrough therapy. It remains unclear whether multiple designations per indication are redundant. This study analyzes cancer drugs with multiple special designations regarding their FDA approval timelines, evidence, benefit, epidemiology and price. Methods: All anti-cancer drugs and their supplemental indication approvals were identified in the Drugs@FDA database from 2000 to 2022. For each indication, clinical trial characteristics, epidemiologic, and price data were collected from FDA labels, the Global Burden of Disease Study, and Medicare & Medicaid Part B and D, respectively. The association between overall survival (OS) and progression-free survival (PFS) hazard ratios (HR) and drug indications’ number of special designations were compared in meta-analyses and meta-regressions. Results: We identified 170 anti-cancer drugs with FDA approval in 455 indications. The median time to first FDA approval was 13.8 years for drugs with zero, 7.3 years with one, 7.1 years with two, 7.8 with three, 5.8 with four, and 5.3 with five special designations (HR per additional designation: 1.27, 95%CI: 1.09-1.48, p=.002). Drug indications with more special designations were more frequently granted to rare diseases with fewer treatment options supported by smaller and shorter open-label phase 1/2 trials. OS HRs were 0.79 for indications with zero, 0.74 with one, 0.73 with two, 0.69 with three, 0.59 with four, and 0.52 with five special designations (p=.024). On average, each additional special designation was associated with lower HRs for OS (ß=-0.03, p=.002) and PFS (ß=-0.07, p<.001). Each additional special designation was associated with a 19.05% (95%CI: 4.56-35.55, p=.013) higher drug price. Conclusions: The FDA’s special designations are non-redundant. Multiple special designations are associated with faster approval times and a greater efficacy for patients with high unmet needs, while multiple special designations are associated with less robust trial evidence and higher drug prices. This study supports the strategy of special FDA designations for unmet clinical needs.
Measuring time toxicity of systemic therapies for advanced esophageal and gastric cancers.
Authors: Agrawal Neha , Thawani Rajat , Chen Emerson Yu-sheng
Published: June 2023

e13660

Background: Immunotherapy checkpoint inhibitors have demonstrated clinical benefit in esophago-gastric cancers. Little is known regarding time spent on treatment and adverse events that patients experienced to receive their care, or time toxicity, with regards to advances in immunotherapy. Methods: Fifteen phase 3 trials of anti-PD1 and anti-PDL1 inhibitors used for esophageal and gastric cancers were selected from clinicaltrials.gov if they were published by February 2021. The published methods and protocol were reviewed to estimate the number of ‘hospital days’ based on required procedures associated with screening and treatment related care and proportion of serious and severe adverse events that served as a surrogate for time toxicity. Once hospital days were estimated for all randomized groups, they were analyzed according to immunotherapy arms, which included chemo-immunotherapy and immunotherapy-only arms, and non-immunotherapy arms, which included chemotherapy only and observation arms. Results: From the 15 trials included, there were 32 randomized groups, as 2 trials had 3 randomized groups. Six trials eventually led to FDA approval. Six were for immune checkpoint inhibitors in first line setting, and 8 were in subsequent line setting, and 1 were in adjuvant or maintenance trials. Only pembrolizumab, nivolumab, and avelumab were represented. The median estimated hospital days was 38 days (range 7-52), or 1.3 months, over one year. There was no difference comparing immunotherapy vs. immunotherapy-free arms (p = 0.5), but there was difference comparing chemotherapy vs. chemotherapy-free arms (p < .05). The median survival in the group of patients who received combination chemo-immunotherapy was 13.9 months, with time toxicity of 1.4 months. The survival and time toxicity of the chemotherapy, immunotherapy and placebo arms were 9.1 and 1.3 months, 10 and 0.9 months, and 7.5 and 0.3 months, respectively. Conclusions: While there is substantial number of days committed to cancer therapies among patients with esophageal or gastric cancer, we noticed a trend of more time toxicity in patients who received chemo-immunotherapy, vs patients who received immunotherapy alone. Given the modest improvement in survival gleaned from these trials, the magnitude of survival benefit should be weighed against the time toxicity incurred in patients.
Inter-regional differences of authorship in secondary analyses of solid malignancies.
Authors: Hamadneh Yazan , Alrawabdeh Jawad , Al Zyoud Muntaser , Odeh Nada Wael , Alzubi Marah , Al Hadidi Samer
Published: June 2023

e13661

Background: With the increasing number of clinical trials and data availability in recent years, the number of secondary analyses had subsequently increased at a global level. However, the results of such analyses must be interpreted carefully. Our study aimed to study the differences of secondary analyses based on the country of residence of the first author. Methods: We searched OVID database for articles subgroup analyses from the year 2000 until Feb 15, 2022. post-hoc, subgroup, secondary, cancer, tumor, breast, colorectal were some of the terms used in the search. Original trials, observational and secondary analyses of cohort studies were excluded. The country of the first author was used for categorizing the articles. Results: 1491 articles were included in final analysis. The first authors of 646 articles were from North America (43.9%), 476 articles from Europe (32.4%), 258 articles from East Asia (17.6%), and 86 articles from the rest of the globe (5.9%). There was a significant increase in the number of secondary analyses from East Asia especially in the last 4 years (<.001). In addition, East Asian secondary analyses were more likely to have had medical writing assistance compared to other regions (<.001). North American contribution to secondary analyses has been decreasing over the years (<.001). European analyses and analyses from the rest of the world didn’t have a significant increase over the years. Although European publication were less likely to be funded, those that were funded had a higher chance of being funded by pharmaceutical companies in comparison to the different regions (<.001). International trials that included US and non-US participants were more likely to be funded by pharmaceutical companies, had medical writing assistance, and had a higher percentage of authors with conflicts of interest than trials that only included US participants or non-US participants (<.001). Conclusions: The results show that there was an increase in secondary analyses especially from the East Asian region and those secondary analyses of international trials are highly funded and supported by pharmaceutical companies. [Table: see text]