bluuebunny/crossref_metadata_2025_split huggingface dataset:
Right-censoring bias in trials shared at the Project Data Sphere platform.
Authors: Barrajon Enrique , López Jiménez Antonio , Barrajon Laura 
Published: June 2021

e13543 Background: Independent of the bias inherent to the design and execution of clinical trials, bias may be the result of patient censoring. A bias index (BI) was developed to detect right-censoring bias and tested in datasets availabe at Project Data Sphere, a data sharing research platform maintained by the CEO Roundtable on Cancer, Inc.,* a nonprofit corporation to improve outcomes for cancer patients by openly sharing deidentified data. Methods: Project Data Sphere platform was searched for clinical comparative trials with available experimental and comparator survival datasets: overall survival (OS) and event-free survival (EFS: disease-free survival, DFS, or progresssion-free survival, PFS). The R language and the integrated development environment Rstudio were used to import and manage the datasets. BI was defined in the events time domain as the adjusted proportion of censor times below the mean event time. Comparison of BI in different datasets were made with the two-sided Wilcoson unpaired test. A weighted regression model was applied to estimate the influence of bias on survival results as measured by the hazard ratio (HR). Results: Out of 184 trials, 19 trials offered both comparator and experimental arms, 3 of them not based on survival analysis and 4 of them with 2 substudies, providing 72 datasets based on OS and/or EFS, for a total of 16532 patients (90.8% of the 18198 patients in published trials). BI over the theshold was found in 24% of EFS datasets (versus 0% in OS datasets, Wilcoxon p = 0.0007), especially in PFS (35% vs 0% in DFS datasets, p = 0.00004). Nearly two thirds of the variance in the HR of EFS datasets was explained by the HR of OS datasets (adj.R2 = 0.638, p = 1.5e-5), approaching to what was found in the corresponding publications (adj.R2 = 0.751, p = 7.81e-5). Though the trials sample is small, introducing the BI of control and experimental datasets in the model decreases the residual standard error (3.831 vs 3.958) and increases the correlation (adj.R2 = 0.99, p < 2.2e-16), resulting in the model: HR(EFR) = 0.985 HR(OS) + 0.36 BI(exper) – 0.42 BI(control). Conclusions: This study is a proof of concept that right-censoring bias may be detected and estimated in clinical trials, especially in PFS datasets, and opens the possibility for correcting biased estimations in survival and increasing the precision in the prediction of OS from preliminary EFS. (*) This abstract is based on research using information obtained from ProjectDataSphere.org, which is maintained by Project Data Sphere LLC. Neither Project Data Sphere nor the owners of any information from the web site have contributed to, approved or are in any way responsible for the contents of this abstract.
Assessment of objective response rate (ORR) by investigator versus blinded independent central review in pivotal trials of drugs approved for solid tumor indications.
Authors: Zettler Marjorie E. , Lee Choo H. , Gajra Ajeet , Feinberg Bruce A. 
Published: June 2021

e13570 Background: Objective response rate (ORR), defined as the proportion of patients with a complete response or partial response to treatment according to Response Evaluation Criteria in Solid Tumors (RECIST), is the most common endpoint used in pivotal trials supporting FDA approval of cancer drugs for solid tumor indications. Blinded independent central review (BICR) is frequently employed in clinical trials to minimize bias in evaluation of response rate, as historically, assessment of response by investigators (INV) has been shown to overestimate treatment effect. In this study, we analyzed the variability in assessment of ORR between INV and BICR in trials supporting recent Food and Drug Administration (FDA) approvals of drugs for solid tumor indications. Methods: The FDA’s novel drug approvals (2015-2019) were reviewed to identify drugs receiving primary approval for solid tumor indications. Drug approval packages accessed via the Drugs@FDA database and primary publications for the pivotal trials accessed via PubMed were reviewed for investigator-assessed and BICR-assessed ORR. For trials reporting both assessments, the difference between INV and BICR ORR was determined across all study arms. Data are presented using descriptive statistics. Results: A total of 36 drugs received primary approval for the treatment of solid tumors between 2015 and 2019. Of the 40 supporting trials, ORR was the primary endpoint for 21 (52.5%), progression-free survival for 13 (32.5%), and overall survival for 2 (5.0%). ORR was evaluated in 35 of the 40 trials (87.5%). Eight (22.9%) of the 35 trials evaluated INV ORR only, 5 (14.3%) evaluated BICR ORR only, and 22 (62.9%) evaluated both INV and BICR ORR. Among the 22 trials (29 arms in total), the mean difference between BICR- and INV-assessed ORR was -4.3% (95% CI: -6.4, -2.3); the range was -13.1 to 5. INV-assessed ORR was greater than BICR-assessed ORR in 22 of 29 arms (75.9%). The mean difference between BICR- and INV-assessed ORR among the 6 arms representing placebo or active control was -6.0 (95% CI: -11.0, -0.9), compared with -3.9 (95% CI: -6.3, -1.5) among the 23 experimental arms. Conclusions: Compared with BICR, INV overestimated ORR in three-quarters of the trial arms, including those representing control and experimental treatments. Despite this variability, for one fifth of the trials supporting approval of drugs to treat solid tumors, INV was the only method used to assess ORR. For consistency, and the ability to make relative cross-trial comparisons of ORR between agents, BICR should be considered for evaluation of tumor response in all registrational trials.
The role of digital clinical measures in improving cancer care and research.
Authors: Goldsack Jennifer , Aguilo Ariel , Coravos Andrea , Economos Chris , Lyden Kate 
Published: June 2021

e13584 Background: From objectively assessing performance status to recording simple vital signs, the adoption of high quality digital clinical measures offers enormous possibilities for transforming cancer care & research. However, the development & deployment of high quality digital measures in oncology lags behind adoption in other therapeutic areas. At the time of submission, the DiMe library of digital endpoints reports 166 unique digital endpoints being used in industry sponsored trials of new medical products, but none are being used in an oncology trial. There are seven digital clinical measures working their way through the FDA qualification program, but none in oncology. During the pandemic, care for patients with cardiac and other chronic conditions transitioned out of the clinic & into the home powered not only by virtual visits, but high quality information from remote monitoring. A study of oncology care facilities worldwide reported 89% finding difficulty in delivering usual care due to the challenges of safely bringing patients into the clinic during COVID. Methods: From March to Sep 2020, cross-industry stakeholders at the Digital Medicine Society (DiMe), Elektra Labs, Genentech, Koneksa, Myokardia, Sage Bionetworks, Scripps Research, and the US Food & Drug Administration came together to synthesize best practices from the digital health field, breaking down silos to create ‘ The Playbook’, the comprehensive and accessible “how-to” guide to support all stakeholders working to advance the safe, effective, ethical, and equitable use of digital clinical measures to improve lives. In October 2020, DiMe -- a 501c3 non-profit dedicated to advancing digital medicine to improve lives -- convenened a pre-competitive collaboration of 44 participants from 29 organizations to drive the adoption of the best practices articulated in The Playbook. Results: The Playbook describes trans-industry consensus for best practices for developing and deploying digital clinical measures across patient care, clinical research, and public health, including for oncology. Conclusions: The clinical, technical, and operational best practices necessary to develop and deploy high quality digital clinical measures into cancer care & research have been established. There is no reason for their successful adoption in oncology to lag behind other therapeutic areas. The Playbook and additional resources to support implementation due for launch on April 30 are critical tools for the field of oncology.
Flow redesign to improve prostate cancer access and care at the public healthcare system in Sao Jose dos Campos, Brazil.
Authors: Pinto Carlos Frederico , Stanzani Danilo , Pontes Elitania , Coelho Stela Maris , Correa Margarete , Benjamin Joana , Silva Messias Borges 
Published: June 2021

e13595 Background: Prostate cancer is the second most common cancer diagnosis in São José dos Campos (SJC) and the sixth cause of cancer mortality. Access to early diagnosis and treatment is one big challenge in the local public healthcare system (Sistema Único de Saude) due limited resources. Between 2018 and 2020 the healthcare public system of SJC redesigned the access flow for diagnosis and prostate cancer care in SJC is a mid-sized city (720,000 hab.) in Sao Paulo state, Brazil. Methods: The local SUS was designed to provide access to all patients with elevated PSA (>4.00µg) to a urologist for further evaluation and subsequent reevaluation if needed. This process created long queues and median time to access the few overburdened specialists available to over a year (410 days median), risking significant disease progression and stage upgrade. The flow redesign was done using lean and queue theory techniques and involved basically a new Fast Track to patients with PSA > 10.0µg with age between 50 and 79, considering the probability of 67% chance of prostate cancer (Catalona, et al. NEJM 1991; 324: 1156-61). Patients were referred from the primary care doctor straight forward to a biopsy and then to a medical oncologist, that would recommend further treatment, including a urologist evaluation. Patients with PSA between 4 and 10 would keep regular access to urology. The aim was to guarantee access to specialist up to 60 days from the first PSA > 4.0µg. Results: From April 2019 to September 2020, 277 patients (PSA > 10.0µg) were submitted to a biopsy through the Fast Track; 150 were positive (54,2%) for prostate cancer; and 72% with Gleason score 7 or higher. The diagnosis of prostate cancer from 2017 to 2020 increased over 300% (from 93 to 283), and access to treatment in less than 60 days increased from 15 to 140 patients in 2020. Patient with PSA > 4.0µg access to urology in less than 60 days also increased dramatically by eliminating several medical appointments and unneeded process steps (Table). Conclusions: The process redesign for patients with elevated PSA was able to provide access to care < 60 days for more than 80% of patients with elevated PSA or positive for prostate cancer by splitting high risk and low risk patients and using alternative flows to reduce urology overloaded agenda. Access to Urology for patients with PSA >4.00 < 10.00µg (not in Fast Track).[Table: see text]
Decrease of oncological patients’ hospital visits during Covid-19 pandemic: The experience of a tertiary Romanian center.
Authors: Crisan Cristina , Cainap Calin Ioan , Deac Andrada Larisa , Havasi Andrei Dan , Balacescu Ovidiu , Balacescu Loredana , Bochis Ovidiu Vasile , Vlad Ioan-Cătălin , Cainap Simona Sorana 
Published: June 2021

e13607 Background: The outbreak of COVID-19 pandemic has changed the provision of medical services worldwide. Oncological patients continued receiving specialty treatments. We assess the impact of the pandemic on the oncological patients' visits to a tertiary cancer center. Methods: We analyzed registrations from the administrative data system of in and outpatients in all departments of the Cluj-Napoca Oncology Institute, during March-October 2020, compared to the same 7-month period of the previous year. Results: The decrease during March-October 2020 was of 40.2% for new referrals overall (with the most significant drop in April, of 80%), of 52.5% for medical oncology inpatients, 39% for pediatric oncology department inpatients, 69% for radiotherapy inpatients, 34.9% for surgical interventions and 31% decrease of issued pathology reports. The decrease was less important for outpatients: only 10% for medical oncology outpatient department, 33% for radiotherapy, and 27% for breast cancer unit outpatients. Imaging investigations were only slightly influenced by the pandemic (reduction of 5% for MRI scans, 19% for mammograms, whereas performed CT scans were even more after the outbreak of COVID-19). Conclusions: Our results show a decrease in the number of patients during the period after the outbreak of the COVID-19 pandemic, more for inpatients and less significant for outpatient departments, probably because of the internal circuits reorganization but also because of healthcare measures taken nationally and locally to limit the spread of the pandemic. Keywords: COVID-19, pandemic, oncology referrals, disruption.
Regorafenib in recurrent glioblastoma patients: A large real-life experience.
Authors: Caccese Mario , Cerretti Giulia , Padovan Marta , Zagonel Vittorina , Lombardi Giuseppe 
Published: June 2021

e14024 Background: Regorafenib (REG), an oral multikinase inhibitor of angiogenic, stromal, and oncogenic receptor tyrosine kinases showed encouraging benefit in recurrent GBM patients enrolled in the randomized, phase 2 REGOMA trial. We investigated the clinical outcome and safety of REG in a real-life population of recurrent glioblastoma patients treated at Veneto Institute of Oncology as off-label use. Methods: The clinical data of patients receiving REG at Veneto Institute of Oncology (Padua, Italy) were entered prospectively into clinical records and were retrospectively analyzed. The primary endpoints of the study were overall survival (OS) and safety. The major inclusion criteria were: histologically confirmed diagnosis of GBM, disease progression as defined by RANO criteria after surgery followed by radiochemotherapy with temozolomide, ECOG PS ≤ 2; PTS with ≥ 2 prior lines of therapy were excluded. According to original schedule, patients received REG 160 mg once daily for the first 3 weeks of each 4-week cycle until disease progression, death, unacceptable toxicity, or consent withdrawal. Kaplan-Meier method was used to estimate the survival curves, RANO criteria for radiological assessment, CTCAE v5.0 for drug related adverse events. Results: From February 2018 to September 2020, 54 consecutive patients were treated with REG and enrolled in this study: median age was 56, ECOG PS 0-1 in 91% of patients, MGMTmet in 53%, second surgery at the time of relapse were performed in 30% of enrolled patient, 41% of patients underwent steroids at baseline. At the time of analysis, median follow-up was 11.1 ms, 30 PTS (56%) had died and 50 PTS (93%) had progressed. Median OS was 10.2 ms (95%CI, 6.4-13.9), 12m-OS was 43%; median PFS was 2.3ms (95%CI, 1.3-3.3) and 6m-PFS was 18%. All patients were evaluable for response: disease control rate (DCR) was 46.3%; stable disease was reported in 38.8% and partial response in 7.4%. Age, MGMT status and corticosteroid use at baseline were not statistically significant on multivariate analysis for OS. Grade 3 drug-related adverse events (AEs) occurred in 10 patients (18%) and the most frequent were hand-foot skin reaction, asthenia and increased lipase and transaminases; 1 PT (2%) reported a grade 4 AE (rash maculo-papular). AEs led to REG dose reductions in 37% of patients and, it was permanently discontinued in 5%. No death was considered to be drug-related. Conclusions: We reported a large, mono-institutional “real world” experience of REG in recurrent glioblastoma patients. Overall, results are close to those reported in REGOMA trial although, we showed a longer OS. Toxicity was moderate and manageable. Encouraging clinical benefits of REG in recurrent GBM population were confirmed.
Combination olaparib and durvalumab for patients with recurrent IDH-mutated gliomas.
Authors: Ramos Ronald , Climans Seth Andrew , Adile Ashley , Ghiassi Pegah , Baker Stephanie , Phillips Madeline J. , Zadeh Gelareh , Chen Eric Xueyu , Mason Warren P. 
Published: June 2021

e14026 Background: Isocitrate dehydrogenase (IDH) mutations are frequently observed in low grade gliomas and secondary glioblastoma. Mutant IDH enzymes aberrantly convert α-ketoglutarate (αKG) to 2-hydroxyglutarate (2HG). Accumulation of 2HG inhibits αKG-dependent dioxygenases, many of which are involved in epigenetic regulation. This can lead to cellular dedifferentiation and tumor formation. IDH-mutated cancer cells exhibit defective homologous recombination repair, providing the rationale for investigating poly (adenosine 5’-diphophate-ribose) polymerase (PARP) inhibitors in these tumors. Blockade of programmed cell death ligand 1 (PD‐L1) re‐sensitizes PARP inhibitor treated cancer cells to T‐cell killing. We report the preliminary results of the glioma arm of a clinical trial of a PARP inhibitor, olaparib plus PD-L1 inhibitor, durvalumab, for IDH-mutated solid cancer. Methods: This is a single arm phase II basket study (NCT03991832). Patients with IDH-mutated solid tumors are divided into three cohorts; A: glioma; B: cholangiocarcinoma; C: all other solid tumors. Major eligibility criteria include IDH mutation by immunohistochemistry or sequencing, progressive disease with maximum two prior systemic therapies, Eastern Cooperative Oncology Group performance status (ECOG) 0 –1 and adequate organ function. Patients were excluded if they had received prior PARP inhibitors or anti-PD-1/PD-L1 antibodies. Patients were treated with olaparib 300 mg orally twice daily continuously and durvalumab 1500 mg IV every 4 weeks. Each cycle was 4 weeks. Tumor response was evaluated by MRI after every 2 cycles of study treatments using response evaluation criteria in solid tumors (RECIST). Results: As of Jan 2021, 9 patients were enrolled in Arm A, 7 men and 2 women. The median age was 42 years. Eight patients had IDH1 mutations and 1 had an IDH2 mutation. There were two patients with 1p/19q codeletion. Two patients had grade 2 tumors, four had grade 3, and three had grade 4 tumors. Median time since tumor diagnosis was 7 years. Objective response was seen in 1 patient with an IDH-mutated glioblastoma who remains on study treatments after 8 cycles. Six patients (67%) had tumor progression after two cycles. Two patients had stable disease as per RECIST but had clinical deterioration and did not continue the combined treatment. Common treatment emergent adverse events were all grade 1: fatigue (8 patients), nausea (6), abdominal pain (3), anemia (3), thrombocytopenia (3), and diarrhea (2). Median progression free survival was 2.5 months (range 1.9–8 months). Updated analysis and correlative studies will be presented at the meeting. Conclusions: Combination treatment with olaparib and durvalumab for patients with IDH-mutated glioma is well tolerated but appears to lack adequate antitumor activity. Clinical trial information: NCT03991832.
Clinical outcomes in patients with malignant brain tumors admitted to the ICU.
Authors: Maus Sarah , Lesser Glenn Jay , Bundy Richa , Hsu Fang-Chi , Miller Peter John 
Published: June 2021

e14034 Background: Primary brain malignancy is distinct from other oncologic diagnoses in its presentation and course. Recent treatment advances have modestly improved survival; yet, prognoses for afflicted patients remain grim, which often leads to non-oncology providers questioning the pertinence of aggressive critical care in this population. By relating patient and disease factors with mortality rates in malignant brain tumor (MBT) patients admitted for critical care, we seek to identify valuable prognostic factors and clarify the expected outcomes following intensive care unit (ICU) admission among these patients. Methods: A single-institution retrospective review was performed of 80 primary MBT patients admitted to neuro- or medical ICUs over a five-year period. The Electronic Health Record (EHR) was queried to identify MBT patients who had been admitted to the ICU. Patients undergoing planned surgical resection or with post-operative complications were excluded, as were patients with brain metastases. A matched control group of 80 solid tumor (ST) patients (excluding brain tumors) was included for comparison. Similar aged matched controls were randomly identified via EHR over the same time period to include non-brain, ST patients admitted to the ICU. Demographic, oncologic, and admission data were related to outcomes, which included complication rates (ICU mortality, six-month mortality) and change in Karnofsky Performance Status (KPS) score. Results: The average age was 55.9 (20-83) and 62.8 (27-89) years in the MBT and ST group, respectively (p = 0.10). ICU mortality was 15% and 21% (p = 0.411) and six-month mortality was 46% and 65% (p = 0.10) in the MBT and control groups, respectively. The most common reasons for ICU admission were seizures (36%) and septic shock (21%) among MBT patients, compared to hypoxic respiratory failure (43%) and septic shock (30%) among ST patients. The MBT group’s KPS score decreased by 23.6 ± 26.82 during their ICU admission, while the control group KPS decreased by 27.0 ± 28.3 (p = 0.87). Average length of ICU stay was 3.82 ± 4.4 days in the MBT group, compared to 2.95 ± 1.83 days in the control ST group (p = 0.29). Average length of hospital stay was 9.07 ± 9.0 days in the MBT group and 8.67 ± 7.76 days in the ST group (p = 0.92). Conclusions: No significant difference was observed in ICU or 6-month mortality when comparing primary MBT and ST patients. Change in KPS score across ICU admissions was similar among the two groups. Our data indicate that despite their guarded prognosis, MBT patients fare no worse than those with other solid tumor types at our institution in the critical care setting. These similarities in mortality and functional scores justify medical ICU admission in patients with primary brain malignancy, and should inform intensivist and oncologist admission patterns.
Single agent activity of ONC201 in non-midline H3 K27M-mutant diffuse gliomas.
Authors: Odia Yazmin , Sumrall Ashley Love , Cloughesy Timothy Francis , Nghiemphu Phioanh Leia Leia , Hall Matthew David , Daghistani Doured , Mehta Minesh P. , Lassman Andrew B. , Arrillaga-Romany Isabel , Gardner Sharon L. , Tarapore Rohinton , Lu Guangrong , Allen Joshua E. , Wen Patrick Y. 
Published: June 2021

e14037 Background: H3 K27M-mutant diffuse midline glioma is an invariably lethal form of brain cancer that disproportionately affects children and young adults and has no effective treatment following front-line radiation. The initial disease definition in the 2016 WHO Classification of Tumors of the Central Nervous System regarded the H3 K27M mutation as pathognomonic, though the definition was updated in 2018 restricting the diagnosis to histologically diffuse gliomas that involve midline CNS structures (cIMPACT-NOW update 2). ONC201 is an investigational anti-cancer small molecule, DRD2 antagonist and ClpP agonist that has induced durable tumor regressions by RANO-HGG criteria in a registration cohort of recurrent diffuse midline glioma, H3 K27M-mutant patients treated with single agent ONC201. Methods: We present 7 patients with H3 K27M-mutant diffuse gliomas were enrolled in ONC201 clinical studies, though excluded from the registration cohort due to involvement of non-midline CNS structures, all within the cerebral hemispheres (3 frontal, 1 temporal, 1 frontotemporal, 1 parietal, and 1 corona radiata). Results: Two of the 7 patients underwent objective responses by RANO-HGG criteria as assessed by investigator, which was associated with clinical benefit that included increased mobility and level of alertness. Conclusions: These results demonstrate that H3 K27M-mutant diffuse gliomas occur outside of midline CNS structures, and suggest that ONC201 has single agent activity in H3 K27M-mutant gliomas irrespective of CNS location.