bluuebunny/crossref_metadata_2025_split huggingface dataset:
Imbalanced censoring as a bias in evaluation of randomized controlled trials: A simulation-based study.
Authors: Rumyantsev Alexey , Tyulyandina Alexandra , Tjulandin Sergei 
Published: June 2023

e13606 Background: Censoring imbalances between experimental and control arms in clinical trials efficacy can compromise efficacy analysis especially if surrogate endpoints are used. We conducted a simulation-based study to assess the impact of imbalanced censoring in clinical trials on the probability of false-positive outcomes. Methods: With BayesCTDesign R package we created a data set of 500,000 simulated trials. The trials had initially negative results, varying sample sizes (100-2000 patients) and median survival times (1.5-9.5 mo.) with no baseline censoring. Trials with no significant baseline differences (p > 0.2) between experimental and control arms were selected. We randomly censored samples of patients from control (0-20% of sample) and experimental (0-40%) arms for analysis. A logistic regression model was created to assess probability of positive results due to censoring (HR<1 and p value after censoring <0.05). Sample sizes and difference in % of censored subjects were predictors as well as interaction term between these variables. Results: A data set consisting of 399,946 trials was included in the analysis. After random censoring, a statistically significant positive transformation was observed in 61797 trials with corresponding HR<1 (0.59-0.91; p < 0.05) in favor of experimental arm. A logistic regression model with above mentioned variables returned a following equation (p <0.05 for all the variables): y = -6.45005797 + 0.27661437*B1 + -0.000070584*B2 + 0.000304167*B3 where B0 is the intercept, B1 – difference in percentage of censored subjects between arms (per %), B2 – sample size (per subject) and B3 – an interaction term (B1*B2). Pseudo R2 coefficient was 0.715. Based on the model we estimated a predicted probability of false-positive results for the trials. Conclusions: Clinicians and researchers should pay special attention to censoring imbalances in the clinical trials as these may have a significant impact on results consistency, validity and lead to false-positive findings. [Table: see text]
Symptomatic adverse events in lung cancer clinical trials included in US drug labels from 2015 to 2021 to inform patient-reported outcomes.
Authors: Horodniceanu Erica , Datla Tejaswi , Murugappan Meena N. , Larkins Erin A. , Singh Harpreet , Bhatnagar Vishal , Kluetz Paul 
Published: June 2023

e13642 Background: FDA recommends assessing expected symptomatic adverse events (symAEs) as a core patient-reported outcome (PRO) in cancer clinical trials (CTs). Several core PRO symptom lists exist that measure the same symptoms across trial contexts; however, many were developed in an era when cytotoxic chemotherapy was the main mechanism of action (MOA). To further research relevant PROs in modern cancer CTs, we identified common symAEs from recently approved lung cancer drugs across MOAs. Methods: We identified lung cancer drug approvals from 2015 through 2021 using an FDA database. The drug US Prescribing Information (PI) was used to extract indication, MOA, CT information, and all-grade symAEs reported in ≥20% of patients in the investigational arm. To improve symAE attribution to the drug, we limited analysis to CTs with a monotherapy investigational arm. We determined the most common symAEs based on the number of CTs reporting a specific symAE in ≥20% of patients. Results: Of 54 approvals identified, 31 lung cancer CTs (30 for NSCLC, 1 for SCLC) with monotherapy investigational arms were included, with AE data from 9,829 patients. Drug MOAs were classified broadly as growth pathway inhibitors (GPI) for 21 CTs (68%), immunotherapy (IO) for 9 CTs (29%), and cytotoxic chemotherapy for 1 CT (3%). Most common symAEs are presented in Table 1 (truncated to symAEs in ≥9 CTs, based on All CTs). In comparing MOAs, symAEs reported at ≥20% incidence in ≥5 GPI CTs but in no IO CTs included: diarrhea (76% of GPI CTs), edema (38%), nail toxicity/paronychia (29%), vomiting (29%), stomatitis (29%), and dry skin (24%). Fifteen other symAEs were reported at ≥20% incidence in ≥3 GPI CTs, but in no IO CTs [data not shown]. Conclusions: While there were several common symAEs across lung cancer CTs, our analysis using AE data in PIs of recently approved drugs showed important variability between CTs and broad GPI and IO groups, demonstrating that consideration of MOA and expected toxicity are important for ensuring relevant high frequency symAEs are included as PROs. Final selection of expected symAEs from a PRO item library is context dependent, requiring consideration of all available clinical data and patient input.[Table: see text]
The impact of SARS-CoV2 Omicron variants epidemic on patients with cancer in China.
Authors: Xiao Ping , Zhong Diansheng , Zhang Linlin 
Published: June 2023

e13652 Background: In December 2022, SARS-CoV2 Omicron variants were widely spread in China, and its impact on cancer patients is unclear. Methods: We retrospectively analyzed 170 cancer patients admitted to Department of Medical Oncology, Tianjin Medical University General Hospital from December 1,2022 to January 31,2023. Results: The proportion of the vaccinated population was 62% (106/170). The prevalence of Omicron variants infection was 82.35% (140/170), 86% (55/64) in unvaccinated patients and 80% (85/106) in vaccinated patients (P＞0.05). Symptoms were 77% fever (108/140), 64% cough (90/140), 35% pharyngalgia (49/140), 25% loss of taste or smell (35/140), 23% fatigue (32/140), 20% aches and pains (28/140), 19% dyspnea (27/140), 9% stuffy or runny nose (13/140) and 8% nausea or diarrhea (11/140). Among them, 48% (67/140) had 1-2 clinical symptoms; 47% (66/140) had 3-5 clinical symptoms and only 4% had more than 5 clinical symptoms. The proportion of hospitalization due to Omicron variants infection was 4%. Duration of symptoms of positive patients was 7 days (1-30)，and it was not related to vaccination status, cancer type and pulmonary disease(chronic obstructive pulmonary disease、emphysema、tuberculosis and bronchiectasis) (p＞0.05). Proportion of patients admitted to hospitalization for anti-tumor therapy at normal time (delayed 0-7 days) after Omicron variants infection was 39%（57/145）, and the hospital stay delayed 8-14 days was 20%（29/145）and 24% (35/145) more than 14 days. And it was not related to vaccination status, cancer type and pulmonary disease(chronic obstructive pulmonary disease、emphysema、tuberculosis and bronchiectasis)(p＞0.05). Conclusions: Patients with cancer had mild symptoms during Omicron variants epidemic, and the impact of Omicron on the rate of hospitalization and anti-cancer delayed treatment were relatively mild.
Recent analysis of frequency of surrogate end points used in oncology clinical trials 2006-2022.
Authors: Chitkara Akshit , Rai Manoj P. , Thawani Rajat , Chen Emerson Yu-sheng 
Published: June 2023

e13658 Background: Surrogate endpoints expedite the clinical trial results at the cost of more uncertainty with clinical efficacy, as they may have a weak correlation with definite endpoints like overall survival (OS). Increased use of surrogate measures such as progression-free survival (PFS) and response rate (RR) are increasingly used by the FDA for drug registration trials in oncology. We conducted this analysis to update our previous analysis (2006-2017) and to study the recent trends in using these surrogate endpoints for approval by FDA. We also study how these surrogate markers are used across various therapy lines. Methods: Our retrospective analysis of US FDA oncology approvals from 2006 to 2022 examined FDA documents from the FDA website, package inserts, and related published trials. Only drug approvals for non-hematologic solid tumors were included. We collected data about the approval type, conversion to regular approval, drug withdrawals (until February 11, 2022), lines of therapy (first-line, second-line, and third or other lines), and endpoints used for FDA approval. All surrogate endpoints were categorized into response rate (RR), generally a proportion, or progression-free survival (PFS), a time-to-event endpoint. Definite endpoints, including patient-reported outcomes (PRO), were all included within the OS category. Results: We identified that OS/PRO endpoints accounted for only 29% (98 of 342) of drug indication approvals. In contrast, 71% of drug approvals (244 of 342) were based on surrogate endpoints; 37% (127 of 342) of drug indications used RR endpoints, followed by 34% (117 of 342) drug indications that used PFS endpoints. These surrogate endpoints (RR, PFS, CR, DFS, EFS, pCR, iDFS, MCR, MFS, ORR, RFS, rPFS combined) showed a trend toward being used in the third- or later-line line setting followed by second-line (91 of 145 drug indications [63%] for first-line vs. 102 of 138 drug indications [74%] for second-line vs. 38 of 43 drug indications [88%] for third- or later-line). Still, they were used in all lines of therapy. Conclusions: FDA commonly accepts surrogate endpoints as criteria for drug approval in oncology since 2006. There has been a trend toward using surrogate endpoints in the third or later lines of drug approvals by the FDA. There is a tradeoff between providing access to cancer therapies and potentially approving therapies that still have unverified clinical benefits.
Trends in FDA approval of solid tumor therapies with analysis of single-agent vs. combination therapies.
Authors: Rai Manoj P. , Chitkara Akshit , Thawani Rajat , Chen Emerson Yu-sheng 
Published: June 2023

e13659 Background: Single agents replacing previous therapies are ideal, but combination therapies with two or more active agents have been proposed to decrease drug resistance, promote mechanistic synergy, and/or have additive cytotoxic effects in cancer treatment. However, approval of combination therapies may increase exposure to new and former drugs, leading to more costs and time commitments to patients. Methods: This retrospective analysis examines all FDA-approved drugs for malignant solid tumors from January 2011 to December 2022. We used the data presented in the package inserts on the US FDA website. At least two reviewers selected all new and clinically meaningful indication changes for data extraction. Drug approvals for topical medications, precancerous conditions, hematologic conditions, primarily pediatric cancers, primary genetic syndrome neoplasms, biosimilars, and minor indication changes were all excluded. The primary endpoint was the proportion of new approvals that replaced former therapies rather than adding to existing therapy to become multi-agent combinations. We also compared single and combination regimes with the differences regarding cancer types, line of therapy, primary endpoints leading to approval, year of approval, type of approval, and type of expedited programs at the FDA. Results: Our analysis identified 247 FDA solid tumor drug indication approvals among 279 drugs from 2011 to 2022, with non-small cell lung cancer (52, 21%), followed by breast cancer (28, 11.3%) and melanoma (22, 8.9%), being the most common. The most common class of drug was small molecular targeted therapies (99, 40%), followed by immunotherapy checkpoint inhibitors (84, 34%). Most approvals were for 1st line (111, 44.9%), followed by 2nd line (106, 42.9%), and adjuvant setting (17, 6.9%). Among 247 approvals, 167 (67.6%) replaced a former therapy to become a new single standard of cancer therapy for that clinical setting, while 80 (32%) added to an existing regimen as a combination. 32 (12.9%) approvals have 3 or more drugs in the new therapy, 49 (19.8%) with 2 drugs in the new therapy. When comparing single-agent vs. combination regimen approvals, there was difference in cancer types, type of regimen, line of therapy, highest endpoints leading to approval, novel therapy, and type of drug approval (p-value < 0.05; test statistic > critical value). However, the year of approval, fast-track, and priority-review status were not statistically significant. Conclusions: Approximately two-thirds (68%) of drug approvals over the past 12 years for non-hematologic solid cancers are replacing or adding a new standard. Still, a significant minority (32%) are adding to existing regimens increasing the complexity of cancer therapies, especially in highly prevalent solid tumors, increasing potential time commitment for patients, costs, and exposure to therapies with notable side effects.
Better together: A team-based approach to improve prior authorization efficiencies and wellness in physicians and advanced care providers.
Authors: Pintova Sofya , Royer Jessica , Sheng Tianxiang , Liu Mark , Noble-Kirk Alana , Smith Cardinale B. , Bhardwaj Aarti Sonia 
Published: June 2023

e13664 Background: The burden of prior authorizations (PAs) required for costly oncologic treatments is high. Upon PA denials, peer-to-peer requests are performed. These requests consume time and effort of physicians and advanced care providers (APPs) contributing to burnout and may have a negative impact on patient care. We aimed to assess the degree to which the PA process contributed to burnout among oncology clinicians prior to implementation of a new streamlined workflow aimed at improving clinician wellness. Methods: A baseline wellness survey was sent to all hematology-oncology faculty and APPs at the largest clinical site of our academic cancer center. Burn out, our primary outcome, was measured using the work-related Copenhagen Burnout Inventory. We included selected questions from the American Medical Association (AMA) surveys regarding physician perceived impact of PAs on clinical workload and care delivery. We asked physicians and APPs to rate the impact of PAs on burnout on a scale of 0-100. Analysis was conducted using descriptive statistics. This study was sponsored by our Office of Well-Being and Resilience. Results: The wellness survey was completed by 35 physicians and 21 APPs with a response rate of 53% in both. The median Copenhagen burnout score for physicians was 46.43 (35.71-60.71) with higher burn out scores among those identifying as females, in practice less than 15 years and with more than 60% time in direct patient care. The median burn out score for APPs was 64.28 (50-83.03). Similar to physicians, APPs with less clinical experience had higher burn out scores. When asked about the impact of PAs on burnout on a scale of 0-100, physicians at the main site reported a median of 13.5, while APPs reported a median of 53.5. Conclusions: Physicians and APPs report noteworthy baseline rates of burnout and dedicate a significant portion of the week to completing PAs. Importantly, APPs perceived the PAs to have a high impact on their burn out compared to physicians. We will use these data to determine the efficacy of a new process that utilizes a single EMR platform for finance and cancer registry teams to abstract and document all of the required elements to streamline the PA process for intravenous/injection cancer treatments with the goal to reduce the number of PAs and improve wellness. [Table: see text]
Combination of regorafenib with BRAF-/MEK-inhibitors for the treatment of patients with refractory melanoma brain metastases.
Authors: Dirven Iris , Vander Mijnsbrugge An-Sofie , Vounckx Manon , Tijtgat Jens , Wilgenhof Sofie , Neyns Bart 
Published: June 2023

e14003 Background: there are no active treatment options available for patients (pts) diagnosed with melanoma brain metastases (MBM) that progress despite treatment with immune checkpoint inhibitors (ICI), and BRAF-/MEK-inhibitors (BRAF/MEKi) in pts with BRAF V600mutant melanoma. Regorafenib (REGO), an oral multi-target kinase inhibitor, including potent inhibition of RAF-dimers, has single-agent activity in pretreated melanoma (AS Vander Mijnsbrugge et al. SMR 2022). Here we report our single-institution experience with REGO in combination with BRAF/MEKi in pts with refractory MBM. Methods: pts were identified prospectively, medical records were reviewed retrospectively. Results: 13 pts with stage IV-M1d melanoma were included (6F, med age 54y [range 33-72], WHO PS: 0/1/2/3 resp. n = 1/4/6/2 pts, BRAF V600mut: n = 9, NRAS Q61mut: n = 4). Pts previously progressed on ICI (anti-PD-1 and -CTLA-4; 13 pts); BRAF-/MEK-inhibitor (all BRAF V600mut pts); chemotherapy (3 pts), T-VEC (2 pts), REGO mono (2 pts), and REGO+ICI (2 pts). At baseline, 11 pts had active MBM (8 pts on corticosteroids); 10 pts had extracranial evaluable disease. Pts were treated with REGO (40-80 mg QD) combined with BRAF/MEKi in 9 BRAF V600mut pts (dabrafenib/trametinib: n = 4; encorafenib/binimetinib: n = 5) or, in 4 NRAS Q61mut pts, with trametinib or binimetinib (+ low-dose BRAF-inhibitor if needed to mitigate skin toxicity). Treatment was stopped in 8 pts because of PD and is ongoing in 5 pts (3-49 wks after initiating therapy). There were no grade 4-5 TRAE. Grade 3 TRAE included: arterial hypertension (n = 4), hepatotoxicity (n = 2), diverticular bleeding (n = 1), and duodenal perforation, treated conservatively (n = 1). None of the 2 pts without active MBM at baseline progressed within the CNS. In 11 response evaluable pts (incl. 10 with evaluable extracranial metastases), best objective intracranial response (according to RANO-BM) was PR in 4 pts (36%; 3 BRAF V600mut pts), and SD in 4 pts (36%; 3 BRAF V600mut pts). Intracranial responses corresponded with extracranial responses in all but 3 pts (1 NRAS Q61mut pt with a PR intra-, had SD extracranially; 1 BRAF V600mut pt and 1 NRAS Q61mut pt with SD intra-, had PD extracranially); considering a potential clinical benefit of therapy beyond first PD, both pts continued treatment and remained clinically stable at the latest FU (resp. 15 and 49 wks after initiating therapy). Median time on REGO+BRAF/MEKi in BRAF V600mut pts was 15.9 wks (range 3-46), and on REGO+MEKi in NRAS Q61mut pts: 7.6 wks (range 3-49). Median PFS and OS: 12.9 and 26.4 wks (resp. 15.3 and 26.4 wks in BRAF V600mut pts; 8.6 and 10.1 wks in NRAS Q61mut pts). Conclusions: in heavily pretreated patients with MBM combination of REGO with BRAF-/MEK-inhibitors demonstrated promising anti-tumor activity. Further investigation of safety and clinical activity in a prospective trial is warranted.
Baseline characteristics, hospital outcomes, and palliative care utilization in leptomeningeal disease: A nationwide analysis.
Authors: Turk Ekrem , Obeidat Khaldun , Litvin Rafaella , Vakil Jay , Deenadayalan Vaishali , Olafimihan Ayobami Gbenga , Ibrahim Muhammad Bilal , Boduroglu Eda Sevim , Shaka Hafeez , Batra Kunnal 
Published: June 2023

e14004 Background: Leptomeningeal metastasis (LM) is a rare but devastating manifestation of cancer metastasis. Most solid tumors are known to cause LM, but the most common etiology is breast cancer and lung cancer. The incidence of LM has been increasing due to increased survival rates secondary to the improved systemic cancer treatment. Here we aim to explore the baseline characteristics, epidemiologic differences, palliative care utilization. and hospital outcomes of LM. Methods: Nationwide Inpatient Sample (NIS) database 2016-2019 was queried to determine adult hospitalized patients with LM and relevant cancers by using ICD-10 codes. We studied the racial and socioeconomic differences, palliative care utilization, length of stay (LOS), total hospital charges (THC), and all-cause mortality in cancer patients with and without LM. Multivariate logistic regression analysis was conducted to adjust for confounders. Results: There were 15,325 admissions with LM, 20% had lung cancer (LC) and 20.4% had breast cancer (BC). The prevalence of LM was 1.9% and 0.5%, respectively, in LC and BC patients. LM patients were younger (LC 63 vs 69; BC 56 vs 64 p<0.001), more likely to be non-White, and more likely to have private insurance (37% vs. 19%, p<0.001). LM admissions had significantly increased LOS and higher THC compared to other cohorts. BC or LC with LM was associated with significantly increased Palliative care consult rate ( LC 31% vs 16%; BC 29% vs 10% p<0.001) compared to BC and LC without LM. Palliative care use was more common in the African American race. The all-cause mortality rate in hospitalizations with LM was increased compared to cancer without LM (LC 11% vs 8.6% p=0.008 aOR 1.41; BC 12.8% vs 4.5% p<0.001 aOR 3.39). The white race (OR 0.6, p<0.001) and Medicare (OR 0.58 p<0.001) were associated with lower odds of mortality, while the Hispanic race (OR 1.43, p=0.042) and Medicaid (OR 1.39, p=0.041) were associated with higher odds of mortality among LM hospitalizations. Conclusions: While actionable mutations and targeted therapies are developing rapidly, therapeutic options for LM remain limited, with a median survival of 4-5 months. Palliative care remains essential for a better quality of life; hence further studies should be conducted to improve the utilization of palliative care and investigate racial and economic disparities in the utilization of such.
Survival in patients with brain metastasis secondary to breast cancer from Saudi Arabia.
Authors: Abusanad Atlal M. , Iskanderani Omar , Al-hajeili Marwan R. , Ujaimi Reem , Alwassia Rolina 
Published: June 2023

e14018 Background: Breast cancer (BC) is the most common malignancy in women from Saudi Arabia. Nearly one-third of the patients present with metastatic disease. Data on the incidence, pattern and outcome of brain metastasis (BM) in breast cancer patients is yet to be reported to inform the practice and help in assessing the current standard of care. Methods: A retrospective cohort study between the years 2015 and 2020 that included BC patients with BM was conducted. Demographic data, tumor clinico-pathological features, treatment modalities and outcomes were obtained. Survival, factors influencing survival time and the risk of death were examined. A p-value of less than 0.05 was considered statistically significant. Results: 111 patients with BM due to BC were included in the analysis. All are female with a mean age 50.28 ± 11.61 years. IDC histology (93%), grade III (71%), tumor > T2 (64%) and N-positive (60%) BC accounted for the majority. Human epidermal growth factor receptor2 (HER2)-positive/Hormone receptors (HR)-negative was 21%, HER2-positive/HR-positive was 16%, HR-positive/HER2-negative was 31%, TNBC was 22.5% and unknown subtype in 10%. 60% had metastatic disease on presentation with 41% had both skeletal and visceral metastases. Brain lesions > three were reported in nearly half of the cohort. Whole brain radiotherapy (WBRT), surgical resection and SRS were reported in 84%, 16% and 22%, respectively. The mean survival time was 3.31 years with a maximum of 4.23 years and a minimum of 2.39 years. Patients with HR-positive and HER2-positive BC had a significant longer survival (p=0.039, 0.033 respectively). Neither tumor size nor nodal status in BC patients with BM influenced survival time. The presence of visceral metastasesincreased the likelihood of death in BC patients with BM up to 6 folds (p=0.031). The relationship between risk of death, treatment modalities, and response of BM is shown. Conclusions: Although BM secondary to BC represents a therapeutic challenge with an expected unfavorable impact on survival, mortality was associated with the presence of extra-cranial metastases, particularly visceral metastases in this cohort. Longer survival was seen with specific subtypes (HR-positive and HER2-positive), suggesting advancement in systemic treatments against them. [Table: see text]