tbuckley/cabot-search huggingface dataset:
Effect of activity monitoring on quality of life in patients with gastrointestinal cancer undergoing chemoradiation.
Authors: Kristine N Kim, Nishant Shah, Amardeep S. Grewal, Elissa Klinger, Edgar Ben-Josef, John P Plastaras, James M. Metz, Andrzej Wojcieszynski
Journal: Journal of Clinical Oncology (2021)

e18671 Background: Patients undergoing concurrent radiation therapy and systemic therapy often experience significant toxicities, which can adversely affect their quality of life. We sought to determine if activity monitoring and early outpatient intervention could lead to improved quality of life (QoL) in patients with gastrointestinal malignancies undergoing chemoradiotherapy. Methods: In this prospective randomized trial, patients with gastrointestinal malignancies undergoing concurrent chemoradiotherapy were randomized to activity monitoring versus standard of care (observation). Each group was provided a commercially available fitness tracker but only the intervention group was actively monitored. If a patient in the intervention arm had a 20% decrease in step count or 20% increase in heart rate from their baseline, a triage visit was triggered to further evaluate and manage symptoms. In the observation group, step count and heart rate were recorded but no triage visit was triggered. All patients had weekly on treatment visits and access to standard communication methods for symptom management during and after-hour business hours. The primary endpoint was the rate of completed triage visits. QoL was a secondary endpoint and was collected from both arms at radiation simulation (baseline) and weekly during treatment using the EORTC QLQ-C30 (v.3). The mixed model for repeated measures was used for longitudinal analysis of global health status (GHS) and overall QoL scores (range 1-7) to determine the impact of intervention and time on QoL. Results: A total of 40 patients were evaluable in this study: 22 in the intervention group and 18 in the observation group. The primary endpoint was met with an increased rate of triage visits in the active monitoring group compared to the observation group (86.4% vs 39.9%, OR 9.95, 95% CI 2.12 -46.56, p = 0.015). EORTC QLQ-C30 questionnaires were completed by 97.5% of patients. The baseline QoL scores were similar in both arms (mean GHS 5.06 vs 5.50, p = 0.28 and mean QoL 4.98 vs 5.73, p = 0.09 in observation vs intervention group, respectively). There was a trend towards improved mean GHS, and QoL scores in the intervention group at all timepoints, although it did not reach statistical significance. Overall, GHS and QoL scores deteriorated from week 1 to week 6 during treatment in both groups (mean QoL 5.06 to 4.46, p = 0.16 in observation; mean QoL 5.55 to 5.03, p = 0.16 in intervention group). Conclusions: This study supports the feasibility of using activity monitor to actively track step count and heart rate to successfully trigger triage visits for patients at high risk for toxicity. Early outpatient intervention with the use of activity monitoring may improve quality of life in patients undergoing chemoradiotherapy.
Unaltered IL-2 encapsulated in acoustically active lipid microspheres for systemic but targeted microdose delivery to tumor microenvironment.
Authors: Clayton Larsen, Llew Keltner, William L Redmond, Rhodemann Li
Journal: Journal of Clinical Oncology (2021)

e14535 Background: In order to take local advantage of exogenous interleukin-2 (IL-2) on effector T-cells within the tumor microenvironment while simultaneously avoiding systemic T reg immunosuppressive effects, microdoses of recombinant human IL-2 (rhIL-2) were encapsulated in gas-filled lipid microspheres (eIL-2), then activated with ultrasound. This novel therapeutic agent (eIL-2) was selectively delivered to the tumor via sonoporation and its anti-tumor effects were determined alone and in combination with PD-1 blockade. Methods: In an MC38 colon cancer model, jugular button catheters (Instech) were surgically implanted in a total of 56 animals (8 animals per arm) prior to tumor inoculation to facilitate repeatable IV injection of both anti-PD-1 (RMP1-14; BioXCell) and microspheres. Imagent perflexane lipid microspheres were incubated with rhIL-2 and the high concentration infranatant was separated, discarded, and replaced with sterile saline to resuspend microspheres to formulate eIL-2 on-site. Tumor-bearing mice were dosed on Days 1, 4, 8, and 12. Ultrasound (US) settings used were 2.2 MHz frequency, and 0.339 mechanical index (MI) during insonation. Once every 10 seconds a microbubble destruct pulse of 1.304 MI lasting 1,100 milliseconds was applied. Total insonation time was 5 minutes using a commercial ultrasound scanner (Mindray TE7) operating within diagnostically safe exposure limits. Study groups included Group 1: no treatment; Group 2: aPD-1, 3 mg/kg; Group 3: aPD-1, 3 mg/kg, Imagent + US; Group 4: Free rhIL-2, 10,000 IU (0.61μg)/animal; Group 5: eIL-2, approximately 0.2 μg encapsulated/animal; Group 6: Free rhIL-2, 10,000 IU (0.61μg)/animal, aPD-1, 3 mg/kg; Group 7: eIL-2, approximately 0.1 μg encapsulated/animal, aPD-1, 3 mg/kg. Results: The anti-PD-1 dose of 3 mg/kg demonstrated an expected tumor growth inhibition over control of -38.2% on Day 6, -35.6% on Day 8 and -30.3% on Day 12. Adding eIL-2 + ultrasound external stimuli approximately doubled the tumor inhibition effect of RMP1-14 to -68.1% on Day 6, -69.2% on Day 8 and -62.0% on Day 12. We also analyzed cytokine levels in the peripheral blood (Day 12) using a multiplex ELISA and observed elevated levels of pro-inflammatory cytokines including IFN-g, IL-12, and IL-1a, which likely serve to enhance anti-tumor immunity. IL-15 was also increased following treatment, which supports effector T cell survival. Conclusions: Using a novel form of recombinant human interleukin-2 encapsulated within a gas-filled lipid microsphere, we demonstrated that ultrasound-activated local delivery via sonoporation plus systemic PD-1 blockade led to improved tumor control and increased expression of pro-inflammatory cytokines. This novel approach enhances the efficacy of checkpoint blockade for the treatment of solid tumors. Further experiments are underway to interrogate mechanisms of action.
HGG-37. UPFRONT TARGETED THERAPY FOR THE TREATMENT OF BRAFV600E-MUTANT PEDIATRIC HIGH-GRADE GLIOMA – A MULTI-INSTITUTIONAL EXPERIENCE
Authors: Tom Rosenberg, Kee Kiat Yeo, Mrinal Joshirao, George Michaiel, Hung Tran, Sonika Dahiya, Kara Kachurak, Gregory Friedman, Michael Huang, Karen Wright, Dolly Aguilera, Tobey MacDonald, Susan Chi, Matthias Karajannis
Journal: Neuro-Oncology (2021)

Abstract Introduction Sustained responses to molecular targeted therapy with BRAF with or without MEK inhibitors have been reported in patients with recurrent BRAFV600E-mutant pediatric high-grade gliomas (pHGG). The role of upfront targeted therapy in this population, however, has not yet been established. Methods We performed a retrospective, multi-institutional record review of patients with BRAFV600E-mutant pHGGs, treated with off-label BRAF and/or MEK inhibitors as part of their initial adjuvant therapy. Results Seventeen patients were identified (median age at diagnosis, 8.8 years, range 1.8–20.2). Histologic diagnoses included HGG/glioblastoma (n=10), anaplastic ganglioglioma (n=3), high-grade neuroepithelial tumor (n=2), diffuse midline glioma (n=1) and anaplastic astroblastoma (n=1). Ten patients underwent biopsy (n=8) or subtotal resection (n=2), while near-total or complete resection was accomplished in seven. Concomitant genetic alterations including CDKN2A/B loss, H3K27M and TERT promotor mutations were found in eight tumors. Thirteen patients received focal radiation therapy (RT) and one received craniospinal irradiation prior to targeted therapy. Adjuvant targeted therapy was initiated shortly after diagnosis or completion of RT. Five patients received BRAF-inhibitor monotherapy (dabrafenib or vemurafenib). Twelve patients received combination therapy with the addition of a MEK inhibitor (trametinib). For patients with measurable disease, best responses per COG criteria were CR (n=3), PR (n=7), SD (n=3) and PD (n=1). With median follow-up of 29 months (range 8–78), two-year PFS and OS for the cohort were 74.7% and 81.1%, respectively. Ten (59%) patients remain free of disease recurrence or progression. Grade 3 or higher toxicities were reported in four patients (neutropenia, skin toxicity/photosensitivity, fatigue and weight loss), leading to therapy discontinuation in two. Conclusions Upfront targeted therapy for patients with BRAFV600E mutant pHGG appears tolerable and effective, with a durable disease control rate that is superior to historical data. This promising paradigm is currently being evaluated prospectively in the COG ACNS1723 clinical trial.
Early detection of lung cancer with an incidental lung nodule program (ILNP).
Authors: Matthew Smeltzer, Wei Liao, Meghan Meadows-Taylor, Nicholas Faris, Carrie Fehnel, Jordan Goss, Sara C. Williams, Olawale Akinbobola, Alicia Pacheco, Amanda Epperson, Joy Luttrell, Denise McCoy, Keith Tokin, Rob Optican, Jeffrey Wright, Edward Todd Robbins, Shailesh R. Satpute, Parker Harris, Meredith Ray, Raymond U. Osarogiagbon
Journal: Journal of Clinical Oncology (2021)

8553 Background: Lung cancer early detection improves survival, but risk-based low-dose CT screening (LDCT) only identifies a minority of patients. We implemented an ILNP in a community healthcare system, and evaluated its risks and benefits. Methods: Patients with lung lesions on routinely-performed radiologic studies were flagged by radiologists and triaged using evidence-based guidelines. We tracked demographics, clinical characteristics, procedures, complications, and health outcomes. We analyzed ILNP subjects’ eligibility for LDCT by National Lung Screening Trial (NLST), Center for Medicaid Services (CMS), NEderlands Leuvens Screening ONderzoek (NELSON), National Comprehensive Cancer Network (NCCN) Risk Groups 1 and 2 (screening recommended), NCCN Risk Group 3 (screening not currently recommended), and US Preventive Services Task Force (USPSTF) criteria from 2013 and 2020. Statistical analysis used the chi-square test and Kaplan Meier method. Results: From 2015-2020, 13,710 patients were evaluated in the ILNP program: median age, 64 years; 42% male; 65% White, 29% Black; 667 (4.9%) were diagnosed with lung cancer. Lung cancers diagnosed from ILNP were 39% adenocarcinoma / 20% Squamous Cell with clinical stage distribution 49% I, 8% II, 17% III, and 16% IV. 832 (6.1%) had invasive diagnostic testing- CT-guided biopsy (50%), bronchoscopy (30%), and/or EBUS (26%); 11% of the 832 had &gt;1 invasive diagnostic test. The most common complications from invasive testing were pneumothorax and chest tube placement. Only 11%-20% of all ILNP patients would have been eligible for LDCT. In ILNP patients diagnosed with lung cancer, only 33% were eligible for screening by NLST criteria; the proportion increased substantially when USPSTF 2020 or NCCN Group 2 criteria were applied (Table). Compared to NLST, NCCN Group 2 criteria increased screening eligibility among cancer patients by 22% (from 33% to 55%), while only increasing screening eligibility by 6% (from 8% to 14%) in non-cancer patients. Aggregate 1-year and 3-year survival rates for lung cancer patient diagnosed through ILNP were 76% (95% CI: 73, 80) and 64% (95% CI: 59, 69). Conclusions: The ILNP identified early-stage lung cancer more frequently than most LDCT programs, with promising survival rates. The majority of subjects with lung cancer were not eligible for LDCT, we still need to optimize risk-based screening criteria. Even with new, expanded criteria for LDCT, structured ILNP is necessary to expand early detection of lung cancer.[Table: see text]
Impact on survival of surgical therapeutic strategy in the initial management of advanced ovarian cancer: A study from the Cote d’Or gynaecological cancer registry from 1998 to 2015.
Authors: Alix Amet, Hélène Costaz, Jean-David Fumet, Laurent Arnould, Laure Favier, Françoise Beltjens, Leila Bengrine, Tienhan Sandrine Dabakuyo, Charles Coutant
Journal: Journal of Clinical Oncology (2021)

e17537 Background: The management of ovarian cancer is based on a combination of surgery and chemotherapy. The aim of surgery is to achieve zero residual tumour at the end of the procedure. In advanced stage ovarian cancer, two therapeutic approaches are possible: primary debulking surgery, or primary chemotherapy followed by interval debulking surgery. The primary objective of this study was to describe overall survival (OS) in FIGO stage III and IV ovarian cancers according to the therapeutic sequence (i.e. primary surgery or interval surgery). Methods: We performed a retrospective, observational study using data from the gynecological cancer registry of the Cote d’Or, for patients diagnosed with FIGO stage III or IV ovarian cancer between 1998 and 2015. We recorded FIGO stage, histological type, treatment and completeness of cytoreduction. Results: In total, 460 patients were included. OS at 5 years was 47% in patients with primary surgery, versus 38% in patients with interval surgery (p = 0.06). Five-year OS was 45% in patients with complete cytoreduction, versus 30% in those with incomplete cytoreduction (p &lt; 0.001). The rate of complete cytoreduction was 43% in patients with primary surgery, versus 55% in those with interval surgery. Conclusions: OS appears to be slightly better in patients receiving primary surgery, and when cytoreduction is complete. Every effort should be made during surgery to achieve complete cytoreduction, by an experienced team. Primary surgery should be preferred in these patients.
Documentation of goals of care (GOC) by medical oncologists is associated with improved oncology patient end-of-life (EOL) care outcomes.
Authors: Han Xiao, Michael Riley, Richard Donopria, Steven Martin, Judith Eve Nelson, Andrew S. Epstein
Journal: Journal of Clinical Oncology (2021)

1507 Background: Documenting GOC is integral to patient care and quality performance but has been underutilized by oncologists due to many barriers. As oncologists play a key role in initiating GOC discussions, we implemented a clinical initiative to improve their GOC documentation and evaluated the impact of such documentation on patient care during the EOL (last 30 days of life). Methods: We launched the initiative among 270 medical oncologists in an academic cancer center in 4/2020. A newly formulated GOC note to ease documentation was embedded in oncology outpatient and inpatient notes. Oncologists completed components in the GOC note that applied to their communication about GOC with the patient: 1) cancer natural history, 2) patient goals, and 3) EOL discussion: patient resuscitation preferences and, when pertinent, receptivity to hospice referral. GOC notes were pulled to a centralized location in the electronic health record (EHR) that displays documents relevant to patients’ values, goals and preferences. A dashboard allowed continual monitoring of documentation performance. We evaluated the association between GOC notes and outcomes of patient care at EOL. We further analyzed the impact of EOL discussion on EOL care. Results: The GOC note completion rate steadily rose after implementation. GOC notes were present in EHR for 46% of 10,006 patients who were either seen in outpatient clinic or discharged from hospital during the 1 st week of January 2021. Among 1790 patients who died between 7/1/20 and 12/31/20 and had either at least an outpatient visit or hospitalization during EOL, the median days from first GOC note and first EOL discussion to the patient’s death were 71 days and 24 days, respectively. Linear regression analysis demonstrated that patients who had GOC note 60 days before death spent less time as inpatient during EOL (0.4 day less/patient, from 8.1 to 7.7, P = 0.01). When EOL discussion was documented 30 days before death, patients also spent less time in the hospital (1.2 days less/patient, from 9.7 to 8.5, P &lt; 0.001) and in the ICU (0.3 days less/patient, from 1.7 to 1.4 ICU days, P = 0.04), and were 4% less likely to receive chemotherapy (from 38% to 34%, P = 0.004) at EOL. During the same period, among 1,009 patients with hospital admission in the last 30 days of life, those with a prior documented EOL discussion had shorter inpatient stay (7.7 vs 13.1 days, P &lt; 0.001) and were more likely to be discharged to hospice (34% vs 22%, P = 0.003). Conclusions: During the COVID-19 pandemic, we successfully implemented GOC documentation by medical oncologists that is easily visible by the full care team. Documentation of GOC including EOL discussion was associated with fewer days in the hospital and ICU, increased hospice referral, and lower likelihood of receiving chemotherapy during patients’ last 30 days of life.
Long-term real-world outcomes of first-line (1L) pembrolizumab (pembro) monotherapy in PD-L1 ≥50% metastatic NSCLC.
Authors: Vamsidhar Velcheti, Xiaohan Hu, Bilal Piperdi, Lingfeng Yang, Thomas A. Burke
Journal: Journal of Clinical Oncology (2021)

e21184 Background: Pembro monotherapy was approved in the US in October 2016 as 1L therapy for patients with metastatic NSCLC and PD-L1 tumor proportion score (TPS) ≥50% based on findings from KEYNOTE-024. With 5-year follow-up in KEYNOTE-024, median overall survival (OS) was 26.3 months (95% CI, 18.3–40.4) in the pembro arm. With 4-year follow-up in KEYNOTE-042, median OS was 20.0 months (15.9–24.2) in the pembro PD-L1 ≥50% subgroup. Our aim was to describe long-term, real-world outcomes with 1L pembro monotherapy for patients treated at US oncology practices with disease characteristics similar to those in the KEYNOTE trials. Methods: Patients initiating 1L pembro monotherapy from December 1, 2016, through November 30, 2017, were selected from the US nationwide Flatiron Health de-identified, electronic health record-derived database if they had stage IV or recurrent metastatic NSCLC with PD-L1 TPS ≥50%, ECOG performance status 0–1, and no known EGFR/ALK/ROS1 aberration (confirmed negative EGFR/ALK for nonsquamous tumors). Enhanced manual chart review was used to determine real-world progression (rwP), tumor response (rwTR), and reasons for pembro discontinuation. OS and real-world progression-free survival (rwPFS) were estimated using the Kaplan-Meier method. Data cutoff was August 31, 2020. Results: Median study follow-up was 38.4 months (range, 33.1–44.9). Of 228 eligible patients, median age was 71 years (range, 46–82); 123 (54%) were women; 156 (68%), 12 (5%), and 60 (26%) had nonsquamous, not otherwise specified, and squamous NSCLC, respectively; and 209 (92%) were current/former smokers. History of brain metastasis was recorded for 17 (7%). Pembro was discontinued by 151 patients (66%), most commonly because of disease progression (70; 46%) and secondarily for toxic effect of therapy (35; 23%); 87 patients (38%) received ≥1 additional lines of therapy. OS, rwPFS, and rwTR results are shown below. Conclusions: In this real-world study with 3-year follow-up, patients with PD-L1 TPS ≥50% metastatic NSCLC without known EGFR/ALK aberrations and good performance status treated with 1L pembro monotherapy experienced median OS of 23 months, similar to the OS observed in phase III pivotal clinical trials, supporting the long-term OS benefits of 1L pembro monotherapy in this patient population.[Table: see text]
Genomic profiles of BRAF inhibitor resistance mechanisms in metastatic colorectal cancer.
Authors: Ting Xu, Xicheng Wang, Qi Changsong, Zhenghang Wang, Jian Li, Lin Shen, Jia Wang, Xuan Lin, Lu Zhang, Jing Lin, Xi Li
Journal: Journal of Clinical Oncology (2021)

e15527 Background: BRAF mutations are present in 5-10% of metastatic colorectal cancers (mCRCs). Patients with mCRC whose tumors harbor BRAF V600 mutation generally respond poorly to standard chemotherapy. Treatment with BRAF inhibitors has been shown to improve outcomes, whereas the resistance develops through undefined mechanisms. Therefore, it is imperative to accurately comprehend the genomic profiling of resistance mechanisms to BRAF inhibitors in mCRC for exploring its clinical treatment strategies. Methods: We analyzed next-generation sequencing results in 520 cancer-associated genes for 22 patients who had BRAF V600E mutant mCRC in order to characterize genomic predictors of treatment outcome and track the acquired resistance (AR) mechanisms during the vemurafenib/dabrafenib/encorafenib treatment in combination with cetuximab +/- trametinib. The median age of the patients was 61 years old, 54.5% were male, 54.5% had right-sided mCRC, and 81.8% received one or more prior chemotherapy lines. Tissue and/or plasma samples were collected at baseline (prior to anti-BRAF treatment) and upon disease progression (PD). Objective tumor responses were radiologically assessed every 6 weeks according to RECIST v1. 1. Results: By Feb 2021, treatment had been discontinued in 15 (63.2%) of the patients due to disease progression, while the other 7 cases were still under treatment. The median PFS (mPFS) for all patients was 4.5 months. The overall response rate was 32%, and the disease control rate was 86%. In addition to BRAF V600E, the most common concomitant mutations were identified in TP53 (20/22), RNF43 (8/22), LRP18 (7/22), APC (7/22) and PIK3CA (5/22). Patients with baseline alterations in RNF43 (n = 8; p = 0.0466), or RECQL4 (n = 4; p = 0.0406) had significantly longer PFS than their respective wild type counterparts. In contrast, baseline alterations in PPP2R2A (n = 3; p = 0.0131), RUNX1T1 (n = 3; p = 0.0147), and receptor tyrosine kinase (RTK) signaling pathway genes (n = 6; p = 0.0057) were each significantly associated with shorter PFS. Among the 15 patients whose disease progressed, 9 were identified with newly developed AR mutations in PD tumor or plasma samples. MET amplification was the most common AR mechanism (n = 4) followed by BRAF amplification, KRAS, NRAS mutations (n = 3 each), and MAP2K1, PIK3R1 mutations (n = 1 each). Q61 substitution was the most dominant form for both KRAS and NRAS AR mutations (83%, 5/6). In terms of signaling pathway, MAPK (67%, 6/9) and RTK (44%, 4/9) pathway alterations were most frequently observed. Conclusions: Our study illustrated the landscape of genetic alterations in patients with BRAF V600E mutant mCRC upon BRAF inhibitor treatment, which could be critical to predict responses to BRAF inhibitors and guide personalized clinical decision-making after disease progression.