bluuebunny/crossref_metadata_2025 huggingface dataset:
Transforming the site feasibility assessment process for oncology clinical trials.
Authors: Kurbegov Dax , Hurley Patricia A. , Waterhouse David Michael , Nowakowski Grzegorz S. , Kim Edward S.
Published: May 2020

e14092

Background: Current methods to assess trial sites for clinical trial participation are onerous, with unnecessary redundancies and no-value steps that impact research site resources and clinical trial participation. This project sought stakeholder feedback on recommendations to transform industry sponsor and contract research organization (CRO) processes for evaluating sites for trials. Methods: An ASCO task force developed recommendations to improve the feasibility assessment process and standardize and centralize questions and forms. A survey was conducted with sites, industry trial sponsors, and CROs to obtain feedback and assess buy-in for the recommendations. Results: Respondents were from 28 oncology research sites (19 academic, 9 community-based), 8 sponsors, and 4 CROs. All stakeholders agreed that the current process is burdensome (93% sites, 90% sponsors, 100% CROs), standardization will improve the process (86% sites, 87% sponsors, 75% CROs). All agreed a centralized portal will reduce burdens (93% sites, 100% sponsors, 75% CROs) and expedite trial start-up (89% sites, 100% sponsors, 75% CROs). Site certification was a viable option for sites (86%) and CROs (75%), but less so for sponsors (57%). Most respondents preferred a two-tier model: 1) a short site questionnaire followed by a pre-study visit for new interactions, and 2) only a pre-study site visit or a teleconference if there is an existing relationship. The greatest benefits were time savings, expedited start-up, reduction in personnel resources, and cost savings. The greatest barriers to adoption were buy-in and alignment from sponsors/CROs and insufficient information about site or protocol. Top predictors of a site’s success on a trial were physician engagement, available patients, and site experience. Conclusions: Site feasibility assessments are important for all stakeholders to establish trial suitability. However, current methods impose tremendous burdens on site resources (reported by authors elsewhere). While this sample is limited, the proposed process and standardization changes show promise to reduce burdens and costs for all stakeholders and expedite patient enrollment onto clinical trials.
A simulation study of loss to follow up: The impact on time to event and prevention.
Authors: Levy Donna Elise , Wu Bingyan , Quinn Daniel , Jentzsch Sophie , Lusk Christine , Bentley Jane Kristina
Published: May 2020

e14097

Background: Patient attrition during study follow up is a concern in all clinical trials, although its impact on study results has rarely been assessed. In oncology, in particular, where studies are lengthier and may be extended into longitudinal studies, there is an increased likelihood of loss to follow up (LTFU) (Gill et al., 2018). This creates a heightened need to understand how it affects the trial’s validity. The loss of data from patients who have been LTFU can reduce a study’s precision and power. This imprecision not only impacts the results of the current study but can also affect future research as well as future patient treatment options. Studies have found that participant characteristics differ in individuals LTFU as compared to those who remain in follow up (Childs et al., 2011; Geng et al., 2008; Hochheimer et al., 2016). This further emphasizes how attrition can skew study results and their interpretation and supports the need to minimize patient attrition during follow up in order to reduce bias and generate robust study estimates. Methods: This study assessed the impact of LTFU rates on the study estimates through simulations using SAS software. While all endpoints can be affected by LTFU, this study assessed time-to-event endpoints. Exponential distribution was assumed with varying rates of LTFU. In addition, the work covered suggestions for reducing LTFU. Results: Even for low rates of LTFU, biases are introduced in time-to event endpoints. Conclusions: Researchers should make every effort to minimize the extent of LTFU in the design and of and conduct of their trials.
Optimizing cancer care using digital technologies requires coordinated multi-stakeholder effort.
Authors: Ramalingam Sendhilnathan , Holmgren A Jay , Goldsack Jennifer , Conner-Simons Adam , Robinson Edmondo
Published: May 2020

e14108

Background: Oncology has unique characteristics that predict early benefit from digital technologies including a culture of patient involvement in trials, genetic testing, and longitudinal assessments including objective measures. However, implementation of digital tools is slow for many reasons including lack of incentives/interoperability, and high-profile cases highlighting inadequate data governance. We report results from the Digital Medicine Society’s study of the stakeholders involved in using digital technologies to optimize health, with a focus on oncology. Methods: We performed 16 interviews with diverse Key Opinion Leaders (KOLs) including physicians, executives, senior government officials, patients, payers, tech innovators, and investors. KOLs received a pre-interview list of topics. We used the Delphi method, an evidence-based approach to compile expert opinions, to iteratively refine recommendations. Results: We identified priorities for 5 stakeholder groups to facilitate digital tool implementation (Table); all groups must also act now to develop a framework for data governance. We describe 4 categories of early success in oncologic digital tools: regimen/drug choice, drug approval efficiency, digital user training, and patient generated health data. Conclusions: Data and technology have great potential to improve cancer care. Multi-stakeholder involvement and a framework for US health data governance are needed. [Table: see text]
Social media and gynecologic cancers: The impact of Twitter #GYNCSM.
Authors: Lizaso Christina , Sparacio Dorinda , Westin Shannon Neville , Boulay Richard Mark , Temkin Sarah Madhu
Published: May 2020

e14113

Background: Patients (pts) with gynecologic malignancies look for support and information outside traditional clinical settings. We report the results of a needs assessment of the GYN Cancer Social Media (#gyncsm) Twitter community. Methods: An online needs assessment was publicized on Twitter using the #gyncsm hashtag in 2019 for 23 days. Percentages were calculated to provide observational data. Results: Of 33 respondents, 26 (79%) were pts, 7 (21%) healthcare providers, 2 (6%) cancer researchers, and 1 (3%) caregiver. 15 (60%) pts reported having ovarian cancer; 6 (24%) endometrial/uterine cancer; 2 (8%) sarcoma; 2 (8%) breast cancer; and 1 (4%) vulvar cancer. Participating providers were gynecologic oncologists 3 (21%); pharmacists 2 (14%); medical and radiation oncologist, researcher, social worker therapist and genetic counselor 1 (7%) each. 41% (13) reported tweeting and retweeting #gyncsm tweets; 22% (11) read the blog posts or transcripts of a twitter chat; 28% (9) followed or participated in a twitter chat. Chat topics with importance are shown in the Table. Pts reported that #gyncsm twitter chat helped them advocate for themselves (9, 60%); learn about genetic testing (7, 46%); and investigate clinical trials (4, 26%). Conclusions: Social media has a role in healthcare, especially in pt education and empowerment. Side effects, toxicity, and communication were topics of interest. Inclusion of cervical cancer pts and rare malignancies should be a priority. [Table: see text]
Use of artificial intelligence to improve access to initial leukemia diagnosis in low- and middle-income countries.
Authors: Cerrato Tania Raquel
Published: May 2020

e14117

Background: Disparities in access to cancer diagnostic methods affect especially low and middle-income countries (LMIC). Honduras, a country with limited resources of laboratory, and trained personnel to diagnose leukemia have an estimated incidence of leukemia of 5.8 per 100,000 person-years and the mortality is 4.8 per 100,000 person-years. This country has a single immunophenotyping center and similar to many other LMICs, the preliminary diagnosis of leukemia is performed by a morphological study of blood. Machine learning (ML) is a form of artificial intelligence (AI) that has the potential to improve medical attention in several medical fields. The purpose of this study is to evaluate the impact of ML use, as a method to reduce the time interval and the access to a diagnosis of leukemia in Honduras, where the current average time to perform an initial diagnosis of leukemia is from 2 weeks to 3 months. Methods: A quantitative correlational study was designed. With the help of local informatic developers, an automated image processing algorithm was designed, which was fed with a total of 1009, digital images of bone marrow aspirates and peripheral blood of patients with proven leukemia through immunophenotyping. The images were captured using a microscope Carl Zeiss lens with a 100x objective, the process included the segmentation of leukemia cells for its analysis. Bivariate outcomes were assessed using the Pearson chi-squared test. Results: From 2016 to 2018, a total of 341 samples of patients with any symptom of leukemia were included. After anonymization of patient identification, the samples were analyzed using our algorithm by comparing the cells with its database. Posteriorly, an expert hematologist performed an analysis of the sample. A total of 20 samples (5.8%), were diagnosed with a preliminary diagnosis of leukemia. Of the 20 samples, a total of 10(50%) were acute myeloid leukemia, 6 samples (30%) lymphoblastic leukemia and the remaining 4 samples (20%) were compatible with chronic myeloid leukemia. The average time to make an initial diagnosis of leukemia was 75% and 24% in 24 and 48 hours respectively. Local hematologists managed to make treatment decisions earlier with benefit to the patients. In 19 of the samples (95%), there was correspondence between the morphology diagnosis obtained by our algorithm and the immunophenotyping diagnosis. Conclusions: This preliminary study demonstrates that the use of artificial intelligence constitutes an important element to improve access and shortening of the time required to obtain a diagnosis of leukemia in LMCIs, and represents a method to reduce disparities in access to diagnosis of hematological cancers.
The use of patient health information outside the circle of care: Consent preferences of patients from a large academic cancer centre.
Authors: Liu Fei Fei , Tosoni Sarah , Voruganti Indu S , Wong Rebecca , Virtanen Carl , Willison Donald , Heesters Ann
Published: May 2020

e14122

Background: Massive volumes of patient health information (PHI) are required to realize the anticipated benefits of artificial intelligence in future clinical medicine. To maintain public trust in medical research however, consent policies must evolve to reflect contemporary patient preferences. Methods: From January-December 2019, patients attending clinics at a large academic cancer centre were invited to complete a 27-item iPad survey on consent preferences. Survey items focused on: (a) broad vs. specific consent; (b) opt-in vs. opt-out approaches for research contact; (c) comfort sharing with different recipients; (d) perceptions on commercialization; and (e) options to track information use and study results. Demographic questions addressed cancer type, treatment stage, age, gender, ethnicity, education level, and household income. Results: A total of 222 participants were included in the analysis (112 males, 108 females; 2 rather not say); 83% were comfortable sharing PHI with researchers at their own hospital. While 56% of patients preferred broad consent, 38% preferred to be contacted with study details and asked to consent every time (specific consent); 6% prefer not to share at all. Younger patients ( < 49 years) most often chose specific consent (50%); significantly more than those 75+ years (24%; p < .05). Younger patients ( < 49 years) were also significantly more uncomfortable than older patients (50+ years) sharing even within their own hospital (13% uncomfortable vs. 1% uncomfortable; p < .05). A significant majority of patients (63%, p = .0001) preferred to be asked for permission before being entered into a contact pool vs. automatic entry with opportunity to opt-out. The majority of patients were uncomfortable sharing PHI with commercial enterprises (51% uncomfortable, 27% comfortable, 22% neutral). A significant majority expressed the desire to track who is using their PHI (61%, p < .0001), and be notified regarding study results (70%, p < .0001). Conclusions: While most patients were willing to share their PHI with researchers at their own hospital, many preferred a transparent and reciprocal consent process. These data also suggest a generational shift, wherein younger patients preferred more informed consent options. Modernizing consent policies to reflect increased patient interest in the exercise of their autonomy is crucial in fostering sustained public engagement in medical research.
Reimbursement recommendations for cancer drugs supported by phase II evidence in Canada.
Authors: Li Regina , Mai Helen , Chiasson Kaitlyn , Trudeau Maureen E. , Chan Kelvin K. , Cheung Matthew C.
Published: May 2020

e14133

Background: Historically, pharmaceutical companies submitted phase III evidence for consideration of public reimbursement; however, phase II data is being more commonly used as primary evidence. Whether submissions with phase II data lead to similar rates of positive reimbursement recommendations as phase III data has not been comprehensively investigated. We compared frequency of reimbursement recommendations between phase II and phase III submissions for oncologic drugs and assessed for factors associated with a positive or conditional recommendation. Methods: We identified all submissions with phase II data from the CADTH pCODR’s expert review committee (pERC) recommendations from July 2011 to July 2019. We identified fourteen binary variables relating to clinical benefit, patient-based values, economic impact, and adoption feasibility. We used Fisher’s exact test to characterize associations between all variables and the final recommendation. We conducted multivariable analysis with logistic regression for three variables: feasibility of phase III study, hematologic indication, and unmet need. Results: We identified 139 submissions with a pERC final recommendation. Twenty-seven (19%) submissions were supported by phase II evidence, with 63% having a positive recommendation in comparison to 82% among submissions with phase III evidence. Clinical benefit (p < 0.001), gap in current treatment standards (p = 0.047), and patient alignment (p = 0.015) were associated with a positive recommendation, whereas the future feasibility of conducting a phase III study was associated with a negative recommendation (p = 0.040). No significant association was found between the recommendation and factors related to cost effectiveness or adoption feasibility. In multivariable analysis, only feasibility of a phase III study was significantly associated with a negative recommendation (p = 0.024, OR = 0.132). Conclusions: Oncologic submissions with phase II data were less likely to be recommended for public reimbursement than phase III studies. Positive or conditional recommendation was more likely if they demonstrated clinical benefit and aligned with patient values. pERC was less likely to recommend a submission with phase II if a phase III trial was either possible or already initiated.
Saudi Cancer Patient Experience: Benchmarking a single center report to the United Kingdom National Experience.
Authors: Jradi Hoda , Alharbi Alanood Abdulaziz , Alrashed Maali Omar , Alshoaibi Mishael Ali , Alkaiyat Mohammad , Jazieh Abdul Rahman
Published: May 2020

e14138

Background: Diagnosis and treatment of cancer are regarded as stressful experiences impacting the patients and their families. This study aims at comparing the Saudi cancer patient experience with the United Kingdom cancer patient experience throughout their continuum of care. Methods: Results from the United Kingdom (UK) National Cancer Patient Experience Survey (NCPES 2017) were compared to the reported results from the experience of 100 cancer patients for the same year at the National Guard Health affairs Health system in Riyadh, Saudi Arabia. Similar concepts relating to the experience were investigated and compared. Results: Compared to the UK survey, the Saudi survey had mainly higher score regarding receiving an overall positive cancer care. Scores related to provision of clear answers to all important questions, judging the hospital staff as always working well together, and family members being given the opportunity to communicate with the doctor were significantly higher among Saudis. The UK patient scored significantly higher on receiving information about diagnostic tests, treatment side effects, and discharge instructions, and being informed about support groups and on-going cancer research. Conclusions: The overall experience of the Saudi cancer patients compared favorably to the UK cancer patients; however, in the domain of information provision as an essential part of the cancer experience is still lacking in the Saudi cancer care approach. Quality improvement should focus on the findings of this study for better health outcomes. [Table: see text]
Substantial ninety-nine percent reduction of turnaround time for QTc diagnostics using smartphone-based tele-cardiology.
Authors: Fink Lena-Sophie , Schinkoethe Timo , Wuerstlein Rachel , Harbeck Nadia
Published: May 2020

e14155

Background: Numerous anti-cancer drugs may lead to long QT syndrome as a cardiotoxic side effect, which could lead to sudden cardiac death. But the outcome of a long QT syndrome is not necessarily fatal. When diagnosed and managed in time, prolongation of the QT interval is reversible. Regular QT interval assessment is, therefore, necessary to ensure the optimal care for these patients. Evaluation of the QT interval requires timely support of the attending oncologist by a cardiologist. The idea for the presented solution was to replace the conventional interaction between oncologists and cardiologists by a smartphone APP solution supporting single-lead ECG records directly at the cancer center and sent from APP to APP to a cardiologist for immediate diagnostic (named as ‘QTc Tracker’). Methods: 54 cancer centers in Germany were equipped with the ‘QTc Tracker’ and a connected single-lead ECG device. Before implementation, all participants were asked in a structured interview about their routine ECG workflow, turnaround time, and satisfaction. After implementation, the centers were contacted again for a comparative evaluation of the turnaround time and satisfaction. Results: The mean total turnaround time of the routine QT/QTc evaluation was 140 h (± 333 h, range 0.3 - 1993 h). 25 cancer centers had direct access to a cardiologist. In these centers, the mean turnaround time was 1.2 h (± 1.3 h, range 0.33-6.5 h), whereas 9 centers with a cardiologist but no direct access needed a mean of 78 h (± 74 h, range 24-192 h). Centers without a cardiologist needed a mean of 354 h (± 490 h, range 24-1993 h) to receive their ECG report. Using the QTc Tracker APP, the mean turnaround time for all centers went down to 47 minutes. Conclusions: A reduction of the mean ECG turnaround time from 140 h down to 47 minutes equals a reduction of 99 %. This also enables centers without a cardiologist on site to provide the QT/QTc report within a single patient visit. Having the ECG result on the same day reduces uncertainties for the patients, and increases treatment continuity and patient safety. In particular as a regular side-effect monitoring, this application promises more convenience for patients and their physicians. The tool is currently integrated in several phase III-IV clinical trials in Germany.
The next generation of cerebrospinal fluid (CSF)-based molecular diagnostics: Improving sensitivity and actionability in breast and lung cancer patients with CNS involvement.
Authors: Singh Veena M. , Fisher Deanna M , Berz David , Schultz Robbie , Mayer Julie A , Boorgula Smitha , Nguyen Minhdan , Troung Judy , Dobrawa Lucia , Gill Jaya , Carrillo Jose Arganda , Kesari Santosh
Published: May 2020

e14502

Background: Liquid biopsy has emerged as a minimally invasive and cost-effective strategy to assess cancer biomarkers without the risk of complications associated with surgical biopsies. Once a tumor has metastasized to the brain, circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) can be found in the cerebrospinal fluid (CSF). We analyzed CSF samples from patients(pts) with primary lung or breast cancer with either brain (BM) or leptomeningeal metastases (LM). Here we report the analytical and clinical validation of Target Selector CSF assays. Validation testing included pre-analytical and analytical steps. Methods: CSF was collected prospectively from pts with a prior solid tumor diagnosis and suspected BM or LM. CTCs were captured utilizing a primary ten antibody cocktail followed by biotinylated secondary antibodies that bind selectively to CTCs followed by staining with cytokeratin (CK), CD45, streptavidin and DAPI. CTCs were captured in a microfluidic channel,classified as either CK+ or CK-. Cell-free total nucleic acids (cfTNA) was extracted from CSF supernatant and underwent both Target Selector™ single gene and next-generation sequencing (NGS) lung and breast multi-gene testing to assess for molecular alterations. For NGS, data analysis was performed using Torrent Suite with annotation and curation by Ion Reporter and Oncomine Knowledgebase Reporter software. Results: The Target Selector CTC platform assays performed on clinical samples (n = 89) resulted in clinical accuracy = 85.4%, clinical precision (intra-assay, inter-assay, inter-operator, and inter-instrument) = 100% for each measure, clinical sensitivity = 80.0%, clinical specificity = 96.6%, positive predictive value (PPV) = 98%, negative predictive value (NPV) = 70.0%, and analytical specificity = 96.0% (acceptance criteria was 95%) at a limit of detection of 2 CTCs. For molecular analyses, Target Selector™ platform assays resulted in clinical accuracy = 87.4%, clinical sensitivity = 85.2%, clinical specificity = 88.3%, PPV = 76.7%, and NPV = 93.0%. Conclusions: Target Selector is a viable, sensitive, reproducible platform for CTC detection and molecular analysis of CSF samples from patients with breast or lung cancer with CNS metastases especially as the sensitivity of CSF cytology is low and MRI findings can be equivocal. Identifying CTCs and molecular alterations can help characterize both tumor genomic evolution as well as guide treatment following cancer metastasis to the CNS.
Institutional outcomes of whole brain radiotherapy for metastatic melanoma brain metastases.
Authors: Jiang Cecilia , Switchenko Jeffrey M. , Lawson David H. , Yushak Melinda Lynne , Khan Mohammad Khurram
Published: May 2020

e14504

Background: The management of melanoma with multiple brain metastases (MBM) is complex given improvements in targeted agents, immunotherapy, and radiotherapy. Whole brain radiation therapy (WBRT) is a radiotherapy technique with limited outcomes data. We report our institutional outcomes for MBM patients receiving WBRT and assess whether certain clinical factors impact prognosis. Methods: A retrospective review of a single institution database was performed. Patients diagnosed with MBM from 2000-2018 treated with WBRT, with or without systemic treatments, were included. Post-WBRT brain MRI scans were assessed at timed intervals for radiographic response. Clinical and treatment variables associated with overall survival (OS), progression free survival (PFS), intracranial failure-free survival (IFFS), and local failure-free survival (LFFS) were assessed. Data was collected on radiation-induced side effects, including radionecrosis, hemorrhage, and memory deficits. Results: Of 1347 patients treated with WBRT from 2000-2018, 63 patients had melanoma. 69% of patients had ≥5 brain metastases at the time of WBRT, 68% had extracranial disease, and 71% received steroids during their overall treatment course. Most had received previous therapies and had WBRT as a last resort. Median WBRT dose was 30 Gray over 10 fractions. Median follow-up was 4.0 months. Six-month OS, PFS, IFFS, and LFFS were 52.7%, 20.4%, 52.3%, and 43%. Median OS, PFS, IFFS, and LFFS were 7.0 months, 2.2 months, 6.1 months, and 4.9 months. Performance status correlated with OS on univariate and multivariate analysis. BRAFi was the only systemic therapy to significantly impact OS on univariate analysis (HR 0.24, 95% CI 0.07-0.79, p = 0.019), although this was not seen on multivariate analysis. There was a 19% rate of memory deficits. Among the 46 patients with post-WBRT brain scans, 17% had radionecrosis and 28% had intralesional hemorrhage. Not all radiographically noted radiotoxicities were clinically significant, although hemorrhage decreased IFFS on both univariate and multivariate analysis. Conclusions: Outcomes for MBM patients receiving WBRT indicate that WBRT remains a worthy option to control intracranial disease. Treatment-related effects such as hemorrhage, necrosis, or cognitive changes are considerations. Median PFS and IFFS suggest that systemic disease control continues to be the greater issue. The role of WBRT should be re-evaluated in the modern era, which features advanced imaging detection ability, newer systemic agents, and improved steroid avoidance strategies.
Anti-PD-1 for patients with leptomeningeal metastasis from advanced solid tumors: Efficacy, safety, and biomarkers of response.
Authors: Naidoo Jarushka , Schreck Karisa C. , Hu Chen , Douville Christopher Blair , Santa-Maria Cesar Augusto , Connolly Roisin M , Holdhoff Matthias , Lipson Evan J. , Parkinson Rose , Riemer Joanne , Barnes Amanda , Venkatesan Arun , Bettegowda Chetan , Grossman Stuart A. , Brahmer Julie R.
Published: May 2020

e14506

Background: Leptomeningeal metastasis (LMM) from solid tumors are rare and often refractory to standard therapies. Pembrolizumab (anti-PD-1) has efficacy in patients (pts) with brain metastases from ICI-responsive tumors, however pts with LMM are often excluded from ICI trials. We hypothesized that: 1. Pembrolizumab will lead to CNS response in LMM, and 2. Genomic/immunologic analyses on CSF could identify CNS biomarkers of response. Methods: We conducted an investigator-initiated open-label phase 2 trial of Pembrolizumab in pts with LMM from any solid tumor (NCT03091478). Eligible pts had: LMM on MRI ( > 3mm lesion) or CSF cytology, ECOG PS ≤1, and were PD-naïve. Prior RT to LMM was allowed > 3 months before study start or to non-target areas. Pembrolizumab was administered IV 200mg q3W until disease progression/unacceptable toxicity. The primary endpoint was CNS response after 12 weeks, defined as radiologic (RECIST 1.1)/cytologic/clinical response to therapy. Serial CSF samples were assessed by chromosomal copy number changes using a PCR-based approach (RealSeqS) to detect tumor-derived DNA (CSF-tDNA), and 16-color flow cytometry. Results: Thirteen of a planned 18 pts were treated 04/2017-12/2019, the study was closed early for low accrual. Median age was 58 years (22-79), 53% were female. Pts had breast carcinoma (38%, n = 5), NSCLC (23%, n = 3), high-grade glioma (23%, n = 3), HNSCC (8%, n = 1) and cutaneous squamous cell carcinoma (8%, n = 1). Median no. of prior therapies was 4 (0-8), 76% of pts had prior RT to LMM. CNS response was seen in 38% of pts (5/13: 2 = complete response (NSCLC; Squamous skin); 3 = stable disease (NSCLC, Glioma, HER2+BC) by RECIST 1.1. Treatment-related adverse events were seen in 31% (4/13) of pts, 15% (2/13) G3+ (fatigue = 1, infection = 1). CSF cytology was negative at ICI start in 6 cases, but positive by CSF-tDNA in 5/6 cases. In addition, CSF-tDNA levels can correlate with disease status. CSF flow cytometry demonstrated increase in CD45R0+ activated memory T-cells, and a shift from immature to antibody-secreting B-cells in both pts with CRs in LMM. Conclusions: Pembrolizumab was well-tolerated and demonstrated anti-tumor activity in pts with LMM in ICI-responsive tumors. Correlative analyses identified CSF-tDNA can potentially be used from diagnosis to longitudinally monitor LMM; and that T and B cell populations may be enriched in the CSF of pts whose LMM regressed. These findings support inclusion of pts with LMM in ICI studies and interrogation of CSF biomarkers. Clinical trial information: NCT03091478.
Leptomeningeal metastasis from non-small cell lung cancer- outcomes from a tertiary care center.
Authors: Vallathol Dilip Harindran , Patil Vijay Maruti , Noronha Vanita , Joshi Amit , Menon Nandini Sharrel , Prabhash Kumar
Published: May 2020

e14508

Background: Leptomeningeal metastasis from Non-Small Cell Lung Cancer is often an underdiagnosed entity. Despite advances in treatment, the outcomes of Leptomeningeal Metastasis continues to be dismal. The data on outcomes of leptomeningeal metastasis from a tertiary care centre is limited. Methods: Data collected from the 4 prospective randomised controlled trials conducted on Non Small cell Lung cancer patients at our centre in the last decade was used in the analysis. These included 1. Patients who had EGFR sensitizing mutations enrolled in the Pemetrexed versus Gefitinib maintenance trial and Gefitinib versus Gefitinib plus chemotherapy trial. 2. Patients who were diagnosed as Squamous Cell Carcinoma of lung enrolled in the Low Dose Gemcitabine versus Standard-Dose Gemcitabine trial. 3. Patients with adenocarcinoma who were enrolled in the Pemetrexed versus Erlotinib maintenance trial. We separated the patients who developed Leptomeningeal Metastasis from these trials and studied its incidence, presenting features and outcomes. Statistical analysis was done using cox regression analysis and kaplan meier plots. Results: Out of 1148 patients, 36 patients (0.031%; 95%CI 0.022-0.043) developed leptomeningeal metastasis. In these patients, the median time to development of LM was 14.92 months (IQR 7.7-21.84). The median overall survival after development of LM was 61 days (95%CI 38.95-83.05). None of the tested factors- Age (Hazard ratio-0.886; 95% CI 0.424-1.851, P-value = 0.747), ECOG PS (Hazard ratio-0.719; 95%CI 0.299-1.729) or driver mutation status ( Hazard ratio-2.080, 95%CI 0.739-5.855) had an impact on OS. The median OS in driver mutated patients was 66 days (95% CI 14.74-117.26) versus 51 days (95% CI 14.5-87.5) (P-value = 0.201). Conclusions: In our study, there was no single factor which impacted survival in patients who developed Leptomeningeal Metastasis. The median survival was in the range of 2 months. This reiterates the overall poor prognosis of development of Leptomeningeal Metastasis in Non small Cell Lung Cancer even with the development of newer therapeutic modalities. Keywords- Leptomeningeal metastasis, Non small cell lung cancer, Incidence, Survival.
Does extent of resection of glioblastoma multiforme affect survival?
Authors: Nabil Emad Eldin , Elyamany Ashraf
Published: May 2020

e14514

Background: Glioblastoma Multiforme (GBM) is the most common primary intracranial tumor. The effect on survival of extent of tumor resection for GBM tumors remains controversial. Our study aims to detect the role of extent of tumor resection in improvement of survival in patients with GBM. Methods: A prospective study for 84 patients with GBM, was conducted between March 2013 and September 2016 in Sohag University Hospital and Sohag Cancer Center. For all of them surgery was done. Either biopsy (stereotactic or open), debulking or gross total resection (complete). All patients received radical radiotherapy concurrent with Temozolomide chemotherapy followed by six to eight cycles of Temozolomide. All patients were followed by clinical examination and brain imaging. Results: 59% of our patients were males and 41% were females. About 78% of the patients had either Eastern Cooperative Oncology Group (ECOG) Performance Status 1 or 2. Median age was 51years with a range (25-70 years). In 38 patients (45.8%) debulking was done, while complete resection was done in 20 patients (24.1%). only biopsy was done in 30% of patients. We found a statistically significant effect for the extent of resection on overall survival (OS)(22 vs 19.5 months) and progression free survival (PFS)(18.25 vs17.42 months) for patients with complete resection vs patients with debulking only. In addition younger age patients had a statistically significant longer survival. Conclusions: Gross total resection (complete resection) of intracranial GBM was associated with longer survival. Gross total resection should be performed whenever possible.
Survival characteristics of patients with first progression of glioblastoma at Cleveland Clinic Foundation.
Authors: Rauf Yasmeen , Yao Jimmy , Barnett Addison , Chen Yanwen , Hobbs Brian , Stevens Glen , Peereboom David M. , Ahluwalia Manmeet Singh
Published: May 2020

e14526

Background: Glioblastoma (GBM) is the most common primary central nervous system malignancy, with a median overall survival of 14 to 17 months. First progression refers to progressive disease after initial radiation with or without chemotherapy. The median overall survival of patients with the first progression of GBM is nine months. Currently, there is no standard treatment for progressive GBM. Common treatment options include clinical trials, surgical resection, re-irradiation, stereotactic radiosurgery, cytotoxic chemotherapies, bevacizumab, and tumor treating fields. Methods: This retrospective study reviewed 244 patients with the first progression of GBM who were treated at CCF between Jan 2012 to Jan 2020. Statistical analyses included patients who had biopsy-proven GBM, a known MGMT methylation status, a KPS of more than 70 and presented with the first progression on MRI brain. Four cohorts of patients were evaluated: Group 1 received cytotoxic chemotherapy, Group 2 received bevacizumab alone, Group 3 received surgical or radiation therapy alone, Group 4 received experimental treatments. Results: The median overall survival (OS) and progression-free survival (PFS) was 12.4 months (95% CI: 10.9 to 14.3) and 4.3 months (95% CI: 3.9 to 5.4), respectively. The cohorts demonstrate statistical significant differentiation for PFS (p = 0.021) but not OS (p = 0.19). Second progression was noted at a median interval of 5.6 months in Group 4, 4.3 months in Group 2, 3.8 months Group 3 and 3.2 months in Group 1. Conclusions: Patients with the first progression of GBM had a better progression-free survival on experimental clinical trials than those in other cohorts.
Updated safety/feasibility study of concurrent tumor treating fields (TTFields) and radiation therapy for newly diagnosed glioblastoma.
Authors: Grossman Rachel , Bokstein Felix , Blumenthal Deborah T. , Limon Dror , Ben Harush Carmit , Ram Zvi
Published: May 2020

e14535

Background: Tumor Treating Fields (TTFields), a non-invasive, loco-regional, anti-mitotic treatment comprises low-intensity alternating electric fields. In the phase III EF-14 study in newly diagnosed glioblastoma (ndGBM), TTFields in combination with temozolomide (TMZ) significantly improved survival compared to TMZ alone. In preclinical studies TTFields had a radiosensitizing effect and increased the efficacy of radiation therapy (RT). This pilot study [NCT03780569] evaluated the feasibility and safety of TTFields administered concurrently with RT and TMZ in ndGBM patients. Methods: Patients with histologically confirmed ndGBM were treated with TTFields/RT/TMZ followed by adjuvant TMZ/TTFields. TTFields (200 kHz) were delivered for ≥18 hours/day with transducer arrays removed during RT delivery. RT was administered to the tumor bed in 30 fractions (total dose 60 Gy) in combination with daily TMZ (75 mg/m2). In the adjuvant phase, patients received monthly TMZ (150–200 mg/m2 for 5 days) plus TTFields. The primary outcome was safety of the combined therapies; secondary outcomes included progression-free survival (PFS) and overall survival (OS). Adverse events (AEs) were graded per CTCAE v4.0. Results: Ten patients were enrolled at a single center between April and December 2017. Median age was 60.2 years, median Karnofsky Performance Score was 90.0, and eight (80%) patients were male. Five (50%) patients had undergone tumor resection while the remainder had biopsy only. Eight patients experienced ≥1 RT treatment delay; delays were unrelated to TTFields treatment. All patients experienced ≥1 AE. Three patients suffered from serious AEs (urinary tract infection, confusional state, and decubitus ulcer) that were considered unrelated to TTFields. The most common AE was skin toxicity, reported in eight (80%) patients; all were of low severity (CTCAE grade 1–2) and were reported as related to TTFields treatment. Median PFS from enrollment was 8.9 months; median OS was not reached at the time of study closure. Conclusions: Eighty percent of patients experienced grade 1–2 TTFields-related skin toxicity. No other TTFields-related toxicities were observed and there was no increase in RT- or TMZ-related toxicities as a result of combining TTFields with these therapies. Based on the safety and preliminary efficacy results of this pilot study, a phase 2 randomized trial (N = 60; NCT03869242) and the Phase 3 TRIDENT trial have been initiated to further investigate the efficacy of concomitant RT/TMZ/TTFields in ndGBM. Clinical trial information: NCT03780569.
NF1 may serve as a novel genetic biomarker of response to treatment and prognosis in glioblastoma (GBM).
Authors: Huang Bin , Yang Ju , Wang Kongcheng , Chen Weitao , Ni Hongbin , Yan Jing
Published: May 2020

e14539

Background: The intrinsic capacity of glioblastoma (GBM) tumor cells to infiltrate normal brain predictably results in high rates of early recurrence. Little has changed over the last decade in the treatment available for GBM with survival remaining poor and a novel genetic biomarker is necessary found to predict response to treatment and prognosis in GBM. Methods: Biomarker discovery was performed by a genome-wide screen using DNA extracted from tissue and blood samples of GBM patients. The biomarker was then evaluated for its predictability in OS of GBM patients compared with the Chinese Glioma Genome Atlas (CGGA) and revealed the relationship with tumor-associated macrophages (TAMs). Results: Median OS for NF1-deleted/mutated GBM patients (n = 11) treated with surgery and Chemoradiotherapy was 9.1 mon vs 17.2 mon for NF1 wildtype ones(n = 47), HR (95% CI) 1.83 (0.8753,3.817), p = 0.1. In addition, NF1-deleted/mutated GBMs showed reduced tumor purity and more infiltration of tumor-associated macrophages through pathological stainings. Conclusions: These data suggest that NF1-deleted/mutated GBM patients have a poor prognosis and NF1 may play a role in organizing the tumor microenvironment. NF1 in GBM will be further evaluated in a planned randomized ph 2b study in newly diagnosed GBM patients.
Safety and efficacy of bevacizumab biosimilar in glioma.
Authors: Singh Gunjesh Kumar , D'souza Hollis , Srinivas Sujay , Vallathol Dilip Harindran , Boppana Mounika , Rajpurohit Annu , Mahajan Abhishek , Janu Amit , Chatterjee Abhishek , Krishnatry Rahul , Gupta Tejpal , Jalali Rakesh , Patil Vijay Maruti
Published: May 2020

e14541

Background: Anti-VEGF antibody Bevacizumab (Avastin: Roche Pharma AG) is the recommended drug for recurrent glioma. Multiple low-cost bio-similars of this drug are now available however their clinical efficacy has never been compared against the original molecule. The aim of the current analysis is to compare the overall survival (OS) between recurrent glioma patients with bio-similar and innovator molecule. Methods: Adult recurrent glioma patients treated with bevacizumab from 1st July 2015 to 30th July 2019 were identified from the Neuro-Medical Oncology database. These patients were either offered Avastin or Bevacizumab biosimilar (BevaciRel: Reliance Life sciences or Bryta: Zydus Oncosciences) depending upon the financial affordability. The primary endpoint of the study was OS. It was defined as the time in months from the start of bevacizumab to death. Progression-free survival (PFS) was defined as the time in months from the start of bevacizumab to progression or death. The time to event variables was estimated using Kaplan Meier method. The median with its 95% confidence interval (CI) was calculated using Brookmeyer and Crowley method. The estimates were compared between the original and bio-similar bevacizumab cohort using the log-rank test. The hazard ratio was calculated using COX regression analysis. Results: There were 82 patients, out of which 57 received innovator and 25 received bio-similar bevacizumab. At median follow up of 26 months, 76 patients had an event for progression. The median PFS was 3.66 (95% CI 2.08 to 5.25) and 3.3 months (95% CI 2.38 to 4.21) in innovator and bio-similar arm respectively (Log-rank test P-value = 0.072). The hazard ratio for progression was 0.61 (95% CI 0.35 to 1.05; P-value = 0.075). At the time of data cutoff, there were 69 deaths. The median OS was 5.53 (95% CI, 5.07 to 5.99) vs 7.33 months (95% CI, 5.63 to 9.03) in innovator and bio-similar arm respectively (Log-rank test P-value = 0.51). The hazard ratio for death was 1.21 (95% CI, 0.67 to 2.17; p-value = 0.51). Conclusions: In the brain tumor patients, both innovator and bio-similar bevacizumab seem to have similar clinical efficacy.
Post-operative disposition and readmission rates in repeat resections for glioblastoma.
Authors: Guzner Alex , Bushara Omar , Hou Alexander , Scholtens Denise M. , Burdett Kirsten Bell , Tate Matthew , Kumthekar Priya
Published: May 2020

e14543

Background: Glioblastoma Multiforme is an aggressive primary brain tumor that will inevitably recur despite initial resection and maximal medical treatment, and re-resection is often pursued. Surgical resection has been shown to impact survival both in the upfront and recurrent settings, but it is unknown if subsequent resections impart worsened neurologic outcomes. The goal of this study was to evaluate patient’s post-operative disposition, hospital length of stay, and readmission within 30 days of discharge as a function of number of resections. Methods: This project was a retrospective chart review. Demographic information was collected regarding patients’ age, sex, IDH-1 mutation, and MGMT methylation status, and each patient’s discharge summary and hospital encounters were reviewed to determine length of hospital stay, location of disposition (home, acute rehabilitation facility, or skilled nursing facility), and readmission within 30 days of initial release. Univariate associations between each clinical predictor and outcome of interest were evaluated. Results: 162 patients with Glioblastoma as indicated on initial surgical pathology report met the inclusion criteria. 108 patients underwent two resections, 48 underwent three resections, and 6 underwent four resections. No statistically significant associations were observed between resection number and age, sex, MGMT methylation status, IDH-1 mutational status, disposition category, hospital length of stay, or readmission within 30 days. Disposition category after first resection was significantly associated with disposition category after second resection (p = 0.041) and readmission within 30 days after second resection was significantly associated with readmission within 30 days after third resection (p = 0.003). Hospital length of stay after second or third resections was not significantly different than a patient’s length of stay after first resection. Conclusions: These data demonstrate for the first time that subsequent resections are not associated with worse patient outcomes and that patient disposition after initial resection is an important predictor of disposition with subsequent resections.
Tolerability of radiation with concurrent temozolomide and effect on survival in chemo-refractory CNS lymphoma.
Authors: Laucis Anna Mary Brown , Selwa Katherine , Sun Yilun , Kim Michelle Miran , Cuneo Kyle Clifford , Lawrence Theodore Steven , Wahl Daniel Richard , Umemura Yoshie , Junck Larry
Published: May 2020

e14554

Background: There is no consensus for the treatment of central nervous system lymphoma (CNSL) refractory to first line high dose methotrexate-based chemotherapy. Whole brain radiation (WBRT) has often been used but may lead to unacceptable neurocognitive dysfunction. We examined our institutional experience with treating CNSL with radiotherapy (RT) and concurrent temozolomide (TMZ) including the resultant acute and long term toxicities. Methods: This single institution IRB approved retrospective study examined treatment, toxicity, and outcome variables in adults with primary or secondary CNS lymphoma. Inclusion criteria were brain-directed RT and development of the treatment plan at our institution. Three main RT field designs were used, including low and high dose WBRT and low dose WBRT with a focal boost to residual disease (WBRT+boost). We assessed relationships between treatment approach (RT field design and concurrent TMZ use) and clinical outcomes and toxicities using multivariable logistic regression models and Kaplan-Meier methods. Toxicity was recorded using the Common Terminology Criteria for Adverse Events version 5. Results: A total of 93 patients with median age of 57 years (range 24 – 86) treated from 2004 – 2019 were included, and 26 patients received concurrent TMZ. The RT field design of low dose WBRT (median dose: 23.4Gy) plus focal boost (median dose: 21.6Gy) was associated with favorable overall survival (OS) and progression free survival (PFS) without any significant difference in Grade 3+ toxicity compared to low dose WBRT (p = 0.20) or WBRT without boost (p = 0.80). Concurrent TMZ with RT was associated with significantly improved OS (HR 0.46, p = 0.025) and CNS PFS (HR 0.49, p = 0.019). Four of nine (44%) Grade 3+ non-hematologic toxicities occurred in patients receiving concurrent TMZ (p = 0.40). The most common non-hematologic toxicities included fatigue and nausea. Long term neurocognitive dysfunction was similar whether or not patients received concurrent TMZ (21% in TMZ group vs 23% in non-TMZ group; OR 0.87, 95% CI 0.25 – 2.68, p = 0.82) and irrespective of RT field design (WBRT+boost vs low dose WBRT p = 0.25, WBRT+boost vs WBRT without boost p = 0.19). Conclusions: Our findings suggest that concurrent TMZ use with brain RT for chemo-refractory CNSL is a promising strategy, with improved survival and no major additional toxicity. Further research that includes rigorous neurocognitive assessments is needed in prospective clinical trials to guide treatment approaches using concurrent TMZ with brain RT in CNSL patients.