Neurocognitive Function Tests Research Articles

Reduced-Dose Whole Brain Radiation Therapy Combined With Stereotactic Irradiation For Solitary Or Oligo Brain Metastases Aiming At Minimizing Deterioration Of Neurocognitive Function Without Compromising Intracranial Tumor Control: Preliminary Results

To minimize cognitive decline without increasing the intracranial tumor recurrence rate by optimizing whole brain dose fractionation pattern when WBRT is combined with stereotactic irradiation (STI) in patients with no more than 4 brain metastases. JROSG 13-1 was a single-arm multi-institutional phase II study of RD-WBRT. At multiple institutions in Japan, eligible patients; no more than 4 brain metastases and Karnofsky Performance Status ≥ 60; received RD-WBRT of 25Gy in 10 fractions and STI. Contrast-enhanced MRI was taken at baseline and 4, 6, 9, and 12 months and every 6 months thereafter. Neurocognitive function tests including Hopkins Verbal Learning Test-Revised, Controlled Oral Word Association and Trail Making Tests, and health-related quality of life questionnaires were performed at baseline and 4, 8, and 12 months and every 6 months thereafter. The primary endpoint was the free from incidence of new intracranial metastases at 6 months and that analyzed by Kaplan-Meier method. The free from incidence of new intracranial metastases at 6 months in the WBRT+SRS group of JROSG99-1 was 81% (95%CI: 67.4-93.6%), so this study allowed a 10% difference, up to 71%. Twenty analyzable patients were required to ensure 80% statistical power with α = 0.05. If the survival rate at six months is calculated as 60%, the minimum required number of cases was 33, but the final required number of cases was set to 40, assuming some cases of dropout. Secondary endpoints were the neurocognitive function, the intracranial local control rate, the adverse events and overall survival. Regarding neurocognitive function, early cognitive failure was defined as reliable change index decline on one or more tests at 4 months. We enrolled 40 patients with no more than 4 brain metastases at multiple institution in Japan from April 2013 to October 2018. Since the observation period ended in November 2019, the data has not yet been fixed. This presentation is preliminary results up to 6 months. The mean age was 68.3 years, 60% of primary cancers were non-small cell lung cancer, and 20 patients had solitary brain metastasis. The primary endpoint, the free-from incidence of new intracranial metastases at 6 months, was 73.8% (95%CI: 60.4-90.2%). The frequency of early cognitive failure was 65.7% (95%CI: 50.6-80.8%). RD-WBRT may not compromise free-from intracranial tumor control. However, the effect of minimizing early cognitive deterioration at 4 months was modest. The analysis of the status of neurocognitive function at 8 months or later is now underway.

Cut-Off Scores of an Olfactory Function Test for Mild Cognitive Impairment and Dementia.

ObjectiveWe aimed to find the optimal cut-off scores for screening of odor detection threshold, odor discrimination, and odor identification tests for detection of mild cognitive impairment (MCI) and dementia in Korean elderly. MethodsA total of 195 elderly people were divided into three groups: the normal cognition (NC), MCI, and dementia groups. All participants underwent neurocognitive and olfactory function tests. We used k-means cluster analysis and receiver operating characteristic (ROC) analysis to identify the most appropriate cut-off value. ResultsTo distinguish the MCI from NC groups, odor identification [area under the curve (AUC)=0.670, p<0.007] with a cut-off point of 7 showed greater validity for screening (sensitivity/specificity=0.462/0.837) than did other olfactory function tests. To distinguish the MCI and dementia from NC as well, odor identification (AUC=0.817, p=0.002) with a cut-off point of 7 showed the highest validity for screening (0.785/0.654). To distinguish MCI from AD, an odor detection threshold (AUC=0.722, p=0.001) with a cut-off point of 2 showed the highest validity for screening (0.785/0.654). Conclusion Olfactory function tests may be a useful screening tool for cognitive decline before clinical symptoms of dementia have completely developed. This tool can be used as a supplementary tool to enhance the sensitivity of traditional cognitive tests to screen for dementia.

Abstract LB-330: Phase I study of procaspase activating compound-1 (PAC-1) for treatment of advanced malignancies

Abstract Background: PAC-1 is a small molecule that directly activates procaspase-3 and induces apoptosis of cancer cells. This first-in-human, phase I, multicenter study for treatment of solid tumors or lymphoma evaluated safety, pharmacokinetics (PK), and preliminary clinical activity of single agent PAC-1 (NCT02355535). Methods: A modified- Fibonacci dose-escalation 3+3 design was used in both components. The primary objective was to assess maximum tolerated dose (MTD). PAC-1 was dosed from 75 to 750 mg daily orally (7 dose levels (DL)) on days 1-21 on 28 days cycle. Dose limiting toxicity (DLT) was assessed during first two cycles of therapy. For all dose cohorts, PK of PAC-1 was assessed following doses administered on days 1 and 21 of the first cycle. Disease response evaluation was done every two cycles. Neurologic and neurocognitive function (NNCF) tests were performed throughout the study due to concerns for potential neurotoxicity. Results: Forty-eight patients were enrolled with thirty-three completing two cycles of therapy and evaluable for DLT and response. DL 1-5 no DLTs were observed. DL 6 was expanded to 6 patients due to one episode of intracranial bleed that occurred during cycle 4 of treatment, assessed initially as possibly related to study drug, but later attributed to new brain metastasis and unrelated to PAC-1. Grade 1 and 2 neurological adverse events such as ataxia and hallucinations were noted in DL 7 and that DL was established as MTD and expanded to 9 patients to assure safety. This cohort was later expanded by additional 3 patients with diagnosis of gastrointestinal or pancreatic neuroendocrine tumors (NET), because of partial response was seen in one patient in first 9 patients at this DL. Review of NNCF testing showed a consistent pattern of stable neurologic and cognitive evaluations. Twenty patients had progressive disease, eleven stable disease (SD), and two patients had partial response (PR) (both with diagnosis of NET). The longest progression free survival was seen in patient with leiomyosarcoma (12 months). Three patients with NET had SD for 4, 6, and 8 months, two had PR with disease control for 4, and 6 months. The PK data demonstrated satisfactory systemic delivery of PAC-1 following oral administration and acceptable absorption and elimination profiles. The dose proportionality was shown for PAC-1 systemic exposure. The PAC-1 half-life was established at 31.1 hours. Conclusions: Single agent PAC-1 is well tolerated and 750 mg was determined to be safe and recommended for phase 2 studies. Intriguing activity of PAC-1 was seen in all patients with NET refractory to standard therapies that warrants further investigation in phase 2 clinical setting. Citation Format: Oana C. Danciu, Matthias Holdhoff, Richard A. Peterson, Paul J. Hergenrother, Theodore M. Tarasow, Arkadiusz Z. Dudek. Phase I study of procaspase activating compound-1 (PAC-1) for treatment of advanced malignancies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-330.

Chronic Use of Synthetic Cannabinoids Is Associated With Impairment in Working Memory and Mental Flexibility.

BackgroundWe have recently shown that chronic use of Synthetic Cannabinoids (SCs) has been associated with mood disorders and impairments in executive functions. There is also evidence indicating that chronic SC users have higher rates of comorbidity with depression and psychotic symptoms. Here, we investigate performance on executive function and emotional processing tasks in regular SC users and a measure of schizotypal traits.MethodThirty chronic SC users, 32 recreational cannabis users, and 32 non-using control participants, without history of mental disorder, or current substance abuse diagnosis (mean age 26 ± 4.27 years; 85 males, 9 females), were tested in addiction treatment centers in Israel. Computerized neurocognitive function tests; the N-back task, Go/No-Go task, Wisconsin Sorting Card-like Task (WSCT), and emotional face recognition task and questionnaires of depression, anxiety and schizotypal traits and symptoms were used.ResultsSC users have performed worse than recreational cannabis users and non-cannabis users on the N-back working-memory task (lower accuracy) and the WSCT cognitive flexibility task. SC users showed greater schizotypal traits and symptoms compared with recreational cannabis users and non-user control participants. A positive association was found in cannabinoid-user groups between schizotypal traits and symptoms and cognitive and emotional processing measures. Finally, SC users have scored higher on depression and state-trait anxiety measures than recreational cannabis users or healthy control participants.ConclusionsRepeated use of SCs is associated with impairment in executive functions and emotional processing. These alterations are associated with depression and schizotypal traits and symptoms. This adds to existing evidence on the long-term consequences of SC drugs and their risks for mental health.

Association between Shift Work and Neurocognitive Function among Firefighters in South Korea: A Prospective Before-After Study.

Background: Recent research indicates that shift work is associated with neurocognitive function. However, studies that examine the association between shift work and neurocognitive function in firefighters have not yet been performed. We examined the effect of shift work on neurocognitive function in firefighters by measuring and comparing neurocognitive function before and after night shift. Methods: 352 firefighters from eight fire stations in South Korea were included in this study. We performed neurocognitive function test using central nervous system vital signs (CNSVS) during daytime work and on the next day after night work. We performed paired t-tests to assess differences between neurocognitive function before and after night work. We also compared neurocognitive function in insomnia and depression. We used a general linear model to analyze the associations between shiftwork schedule and the changes in neurocognitive function. Results: The neurocognitive function significantly decreased in six domains (composite memory, verbal memory, visual memory, complex attention, psychomotor speed, and motor speed) as did the neurocognitive index on the next day after night work compared with during day work. These decreased domains were the same following night work regardless of the type of shift work. Conclusion: Night work in firefighters may cause neurocognitive decline.

Whole-brain irradiation with hippocampal sparing and dose escalation on metastases: neurocognitive testing and biological imaging (HIPPORAD) \u2013 a phase II prospective randomized multicenter trial (NOA-14, ARO 2015\u20133, DKTK-ROG)

BackgroundWhole brain radiation therapy (WBRT) is the standard therapy for multiple brain metastases. However, WBRT has a poor local tumor control and is associated with a decline in neurocognitive function (NCF). Aim of this trial is to assess the efficacy and safety of a new treatment method, the WBRT with hippocampus avoidance (HA) combined with the simultaneous integrated boost (SIB) on metastases/resection cavities (HA-WBRT+SIB).MethodsThis is a prospective, randomized, two-arm phase II multicenter trial comparing the impact of HA on NCF after HA-WBRT+SIB versus WBRT+SIB in patients with multiple brain metastases. The study design is double-blinded. One hundred thirty two patients are to be randomized with a 1:1 allocation ratio. Patients between 18 and 80 years old are recruited, with at least 4 brain metastases of solid tumors and at least one, but not exceeding 10 metastases ≥5 mm. Patients must be in good physical condition and have no metastases/resection cavities in or within 7 mm of the hippocampus. Patients with dementia, meningeal disease, cerebral lymphomas, germ cell tumors, or small cell carcinomas are excluded. Previous irradiation and resection of metastases, as well as the number and size of metastases to be boosted have to comply with certain restrictions. Patients are randomized between the two treatment arms: HA-WBRT+SIB and WBRT+SIB. WBRT is to be performed with 30 Gy in 12 daily fractions and the SIB with 51 Gy/42 Gy in 12 daily fractions on 95% of volume for metastases/resection cavities. In the experimental arm, the dose to the hippocampi is restricted to 9 Gy in 98% of the volume and 17Gy in 2% of the volume. NCF testing is scheduled before WBRT, after 3 (primary endpoint), 9, 18 months and yearly thereafter. Clinical and imaging follow-ups are performed 6 and 12 weeks after WBRT, after 3, 9, 18 months and yearly thereafter.DiscussionThis is a protocol of a randomized phase II trial designed to test a new strategy of WBRT for preventing cognitive decline and increasing tumor control in patients with multiple brain metastases.Trial registrationThe HIPPORAD trial is registered with the German Clinical Trials Registry (DRKS00004598, registered 2 June 2016).

Neurophysiological and Cognitive Correlates of Error Processing Deficits in Internet Gaming Disorder

The ability to detect and correct errors is a critical aspect of human cognition. Neuronal dysfunction in error processing has been reported in addictive disorders. The aim of this study was to investigate neural systems underlying error processing using event-related potentials (ERPs) and current source localization as well as neurocognitive executive function tests in patients with Internet gaming disorder (IGD). A total of 68 individuals (34 patients with IGD and 34 healthy controls [HCs]) were included, and two ERP components, error-related negativity (ERN) and error positivity (Pe), were extracted during a GoNogo task. Patients with IGD exhibited significantly reduced ERN and Pe amplitudes compared with HCs. Standardized low-resolution brain electromagnetic tomography (sLORETA) in between-group comparisons revealed that patients with IGD had decreased source activations of the Pe component in the anterior cingulate cortex (ACC) under the Nogo condition. These ERP changes were associated with deficits in decision-making and response inhibition in IGD patients. The results suggest that IGD may be associated with functional abnormalities in the ACC and alterations in neural activity related to both the early unconscious and the later conscious stages of error processing, as well as deficits in area of decision-making.

Study protocol: watchful observation of patients with limited small cell lung cancer instead of the PCI\u2014prospective, multi-center one-arm study

BackgroundProphylactic cranial irradiation (PCI) is a current standard of care after confirmed response to radical chemoradiotherapy for limited disease small cell lung cancer (LD-SCLC). This standard is mostly based on results of old randomized studies when brain imaging with magnetic resonance (MRI) was not available. Survival benefit of PCI in extended disease SCLC was recently challenged by the results of randomized phase III study from Japan.MethodsEighty patients with LD-SCLC after response to chest chemoradiotherapy will be enrolled. Patients will be followed up by brain MRI every 3 to 6 months up to 3 years. Neurocognitive function tests will be performed at baseline and after 12 and 24 months. Patients who develop brain metastases will be irradiated with stereotactic (SRT) or whole brain RT (WBRT). The primary endpoint is overall survival. The secondary endpoints are: response rate to radiotherapy of early detected brain metastases, analysis of efficacy of SRT and WBRT; assessment and analysis of neurocognitive functions and QoL in the studied cohorts: QLQ-C30 questionnaire and the California Verbal Learning Test, Color connection test, Benton visual retention test, and verbal fluency test will be carried out.DiscussionThe results of this trial may contribute to changing of LD-SCLC clinical management by deescalating the treatment. There is a lack of prospective, recent studies in LD-SCLC patients with omission of PCI and modern radiation therapy technologies for developed brain metastases. The comprehensive neurocognitive function testing will help to assess the impact of modern radiotherapy (SRT) compared with WBRT and no-PCI in SCLC patients. A subgroup of long-term survivors, who will not develop brain metastases, will not be exposed to unnecessary brain irradiation with its deleterious consequences. The limitation of our study is a lack of parallel randomized control arm. This is a potential source of bias; however, randomized study will be difficult to complete for two major reasons: (1) limited population of LD-SCLC eligible for the study and (2) opinions of our patients, who after information and discussion about benefits and potential harms of PCI, often choose to omit PCI in our practice.Trial registrationClinicalTrials.gov Identifier: NCT04168281, 19 Nov. 2019.

Impact of Early Prophylactic Cranial Irradiation With Hippocampal Avoidance on Neurocognitive Function in Patients With Limited Disease Small Cell Lung Cancer. A Multicenter Phase 2 Trial (SAKK 15/12)

Our purpose was to evaluate neurocognitive function (NCF) and clinical outcomes after early hippocampal avoidance (HA) prophylactic cranial irradiation (PCI) in limited disease (LD) small cell lung cancer (SCLC). In a phase 2 trial, patients with LD SCLC received HA-PCI concomitant with the second cycle of chemotherapy and thoracic radiation therapy. All patients underwent objective NCF testing at baseline, 6 weeks, and 6 and 12 months after HA-PCI. NCF tests included Hopkins Verbal Learning Test Revised, Controlled Oral Word Association, and Trail Making Tests A and B. The primary endpoint was NCF decline at 6 months after HA-PCI. We assumed ≤30% of patients with no NCF decline to be unpromising. Secondary endpoints included brain metastases-free survival (BMFS), overall survival (OS), and safety of the concomitant treatment. Among the 44 patients enrolled in the trial, 38 had evaluable NCF assessment at 6 months after HA-PCI. The proportion of evaluable patients showing no NCF decline at 6 and 12 months was 34.2% (90% confidence interval [CI], 21.6-48.8) and 48.5% (95% CI, 30.8-66.5), respectively. Median follow-up was 13.2 months (95% CI, 12.6-14.1). At 12 months, BMFS was 84.2% and OS was 87.7% (95% CI, 73.0-94.7). Four patients died of SCLC, 1 of respiratory failure, 1 of hemorrhage, and 1 for unknown reason. The most frequently reported grade ≥3 acute adverse events were anemia (21.4%), febrile neutropenia (19.1%), and fatigue (14.3%). The proportion of patients showing no NCF decline 6 and 12 months after early HA-PCI does not appear to be better than, but rather similar to, that observed in patients receiving sequential PCI without HA. Early HA-PCI in LD SCLC is feasible, with observation of promising BMFS and OS in this selected population.

Early Stage Markers of Late Delayed Neurocognitive Decline Using Diffusion Kurtosis Imaging of Temporal Lobe in Nasopharyngeal Carcinoma Patients.

Purpose: To determine whether the early assessment of temporal lobe microstructural changes using diffusion kurtosis imaging (DKI) can predict late delayed neurocognitive decline after radiotherapy in nasopharyngeal carcinoma (NPC) patients.Methods and Materials: Fifty-four NPC patients undergoing intensity-modulated radiotherapy (IMRT) participated in a prospective DKI magnetic resonance (MR) imaging study. MR imaging was acquired prior to IMRT (-0), 1 month (-1), and 3 (-3) months after IMRT. Kurtosis (Kmean, Kax, Krad) and Diffusivity (Dmean, Dax, Drad) variables in the temporal lobe gray and white matter were computed. Neurocognitive function tests (MoCA) were administered pre-radiotherapy and at 2 years post-IMRT follow-up. All the patients were divided into neurocognitive function decline (NFD group) and neurocognitive function non-decline groups (NFND group) according to whether the MoCA score declined ≥3 2 years after IMRT. All the DKI metrics were compared between the two groups, and the best imaging marker was chosen for predicting a late delayed neurocognitive decline.Results: Kurtosis (Kmean-1, Kmean-3, Kax-1, Kax-3, Krad-1, and Krad-3) and Diffusivity (Dmean-1 and Dmean-3) of white matter were significantly different between the two groups (p<0.05). Axial Kurtosis (Kax-1, Kax-3) of gray matter was significantly different between the two groups (p<0.05). By receiver operating characteristic (ROC) curves, Kmean-1 of white matter performed best in predicting of MoCA scores delayed decline (p<0.05). The radiation dose was also significantly different between NFD and NFND group (p=0.031).Conclusions: Temporal lobe white matter is more vulnerable to microstructural changes and injury following IMRT in NPC. Metrics derived from DKI should be considered as imaging markers for predicting a late delayed neurocognitive decline. Both temporal lobe white and gray matter show microstructural changes detectable by DKI. The Kmean early after radiotherapy has the best prediction performance.

Physician Medical Assessment in a Multidisciplinary Concussion Clinic.

Concussive brain injury (CBI) is encountered by clinicians in sports medicine, pediatrics, neurosurgery, neurology, physiatry, and primary care. There is no gold standard diagnostic test for CBI, nor is there consensus on what neuromusculoskeletal physical examination tests should be performed on patients who have sustained CBI. This article presents an approach to the history and physical examination of the patient who has sustained a CBI that is based on a review of the literature evidence and the authors' extensive experience with this patient population. Suggested components include an elemental neurological examination that emphasizes the oculomotor/ophthalmologic and vestibular systems, as well as appropriate musculoskeletal assessment of the craniocervical and upper shoulder girdle complex. The use of supplementary tests for CBI, including assessment of exercise tolerance using the Buffalo Concussion Treadmill Test and tests of neurocognitive function, can aid in the differential diagnosis of CBI. The proposed protocol is envisioned for initial and follow-up assessments in the clinic after CBI, as well as for those with more protracted signs or symptoms. If symptoms persist beyond 2 weeks in adults or 4 weeks in adolescents, then referral to a multidisciplinary center that focuses on CBI is recommended.

P1.16-40 Real-World Neurocognitive Function in Lung Cancer: Initial Results of the PRO-Long Study

Changes in neuro-cognitive function (NCF) as a result of treatment and disease have been repeatedly reported in cancer patients. However, contradictions exist on the prevalence and extent of impairment. Evidence in the lung cancer population is very limited. We here report the initial results of NCF in non-small cell lung (NSCLC) cancer patients receiving radiotherapy and/or systemic therapy in the PRO-Long study. PRO-Long is a monocentric, prospective, longitudinal study, investigating the effect of first-line chemotherapy, radiotherapy and/or immunotherapy on patient-reported health-related quality of life (HRQoL), toxicity, functional exercise capacity (6-minute walking test – 6MWT) and NCF in locally-advanced and metastatic NSCLC patients. HRQoL and toxicity data are collected with patient-reported outcome measurements (PROMs). NCF data is collected with the Reys-Osterrieth Complex Figure Test (ROCF), Hopkins Verbal Learning Test-Revidsed (HVLT-R) free recall, delayed recall and recognition; Trail Making Test (TMT) A and B, Controlled Oral Word Association Test (COWA), Wechsler Adult Intelligence Scale (WAIS) digit span and the Stroop Color and Word Test (SCWT). Demographic data are collected at baseline; outcome data (survival, local and loco-regional control and metastatic relapse) during follow-up. NCF data is collected pre-treatment, and 2-3 months, 6 and 12 months after the end of treatment in patients receiving chemo- and/or radiotherapy or after start of immunotherapy. The mixed model approach was applied to determine statistical significance (p < 0.05). Meaningful clinical important difference (MCID) in NCF is defined as a decline greater than one standard deviation from baseline. Between January 2016 and December 2018, 50 patients (mean age: 63) were recruited. The majority was male (60%), had locally-advanced disease (54%) and received chemotherapy with (50%) or without (24%) radiotherapy. NCF data is available of 49, 28, 16 and 10 patients at baseline, 2-3 months, 6 months and 1 year respectively. So far no significant decline was found in any NCF test. At 2-3 and 6 months after treatment, 42% and 34% of patients had a MCID decline in one or more tests. NCF decline was mostly detected in the HVLT-R free recall test, respectively 15 and 23% at 2-3 and 6 months. The initial data suggest that systemic treatment, all or not combined with radiotherapy may result in a clinically meaningful NCF decline in locally-advanced and metastatic NSCLC patients. Particularly, immediate recall seems to be affected. Updated results will be presented.

Significant Preservation of Neurocognitive Function (NCF) and Patient-Reported Symptoms with Hippocampal Avoidance (HA) during Whole-Brain Radiotherapy (WBRT) for Brain Metastases: Final Results of Nrg Oncology CC001

NRG Oncology CC001, a phase III trial of WBRT plus memantine (WBRT+M) with or without HA, sought to evaluate the neuro-protective effects of avoiding the hippocampus using intensity-modulated radiotherapy. Patients (pts) with brain metastasis were stratified by RPA class and prior radiosurgery/surgery and randomized to WBRT+M or HA-WBRT+M (30Gy in 10 fractions). Standardized NCF tests were performed at baseline, 2, 4, 6, and 12 months (mos). The primary endpoint was NCF failure, defined as decline using the reliable change index on Hopkins Verbal Learning Test-Revised, Trail Making Test, or Controlled Oral Word Association. Patient-reported symptoms were assessed using the MD Anderson Symptom Inventory Brain Tumor module. Cumulative incidence estimated time to NCF failure (death without NCF failure was competing risk); between-arms differences tested using Gray’s test. Deterioration at each collection time point was tested using a chi-square test. Patient-reported symptoms were assessed using the MD Anderson Symptom Inventory Brain Tumor module and analyzed using mixed effects models and t-tests. From 7/2016 to 3/2018, 518 pts were randomized. Median age was 61.5 years. Median follow-up for alive patients was 7.9 mos. HA-WBRT+M was associated with lower risk of NCF failure (adjusted HR=0.74, 95% confidence interval (CI): 0.58-0.95, p=0.02). The difference was first seen at 4 months (62.7% HA-WBRT+M vs. 54.5% WBRT+M) and was attributable to improvements in executive function at 4 mos (p=0.01) and encoding (p=0.049) and consolidation (p=0.02) at 6 mos. Age≤61 predicted lower risk of NCF failure (HR=0.60, 95%CI: 0.46-0.79, p=0.0002); non-significant test for interaction indicated independent effects of HA and age on NCF. Patient-reported fatigue (p=0.036), difficulty speaking (p=0.049) and problems remembering things (p=0.013) at 6 mos favored the HA-WBRT+M arm. Imputation models accounting for missing data confirmed NCF results and also favored the HA-WBRT+M arm for patient-reported cognition (p=0.011) and symptom interference (p=0.008) at 6 mos. Toxicity, overall survival, and intracranial progression were not significantly different between the treatment arms. Hippocampal avoidance during WBRT better preserves neurocognitive function and patient-reported symptoms, while achieving similar intracranial control and survival, and should be considered standard of care for patients eligible to receive WBRT and anticipated to live 4 months or longer. Data analyses for longer-term (12-mo) follow-up are planned for June 2019 and will be presented for the first time at the meeting. Supported by grants UG1CA189867 (NCORP), U10CA180868 (NRG Oncology Operations), DCP from the National Cancer Institute.

Characterizing psychiatric symptoms and neurocognitive functioning among substance-naïve early adolescents: Associations with sleep problems.

Evidence consistently links psychiatric symptoms, reduced neurocognitive functioning (NCF) and sleep problems to the initiation of a wide range of risk behaviours. Less is known, however, about the associations between sleep problems with psychiatric symptoms and NCF among early adolescents yet to engage in substance use. The present study examined baseline data from an ongoing prospective study of 529 youth aged 10-12 years who completed a battery of instruments measuring symptom counts for four psychiatric disorders, performance on six tests of NCF and five types of sleep behaviour on week days. We used latent class analysis to classify the 473 substance-naïve youth into subtypes characterized by probabilistic patterns of psychiatric symptoms and poorer NCF. Four subtypes emerged: normative (24% of the sample); nonspecific mental health symptoms (27%); lower neurocognitive function (24%) and comorbid psychiatric symptoms and lower neurocognitive function (25%). In a multivariable latent regression model, three or more sleep arousals per night, sleep phase of two or more hours and sleep latency of 20 minutes or more were significantly associated with the two classes having higher symptom counts. Lack of family support was significantly associated with the two classes having lower neurocognitive function and comorbid psychiatric symptoms. The youth subtypes in this study provide an important baseline characterization to subsequently understand how these neuropsychiatric relationships may change when substance use and other risk behaviours develop during adolescence. Implications for preventing and treating sleep problems associated with psychiatric comorbidity and neurocognitive dysfunctions are discussed.

Impact of Resolution of Hyponatremia on Neurocognitive and Motor Performance in Geriatric Patients

This observational study investigated the impact of hyponatremia resolution on the results of a comprehensive geriatric assessment (CGA) in 150 patients with age ≥70 years and serum sodium <130 mEq/L. The test battery including Barthel index of Activities of Daily Living (ADL) and various tests of neurocognitive function, motor performance and mood stability was applied on admission and at discharge. Changes of individual test results (Δ) were analyzed and normonatremic patients matched for age, gender, and ADL served as reference group. Most CGA test results improved. The improvement was more pronounced in the hyponatremia group with respect to ADL (ΔADL: 14.3 ± 17.1 vs. 9.8 ± 14.7; p = 0.002) and MMSE (ΔMMSE: 1.8 ± 3.0 vs. 0.7 ± 1.9; p = 0.002). Effect sizes were small (i.e., >0.2) in the overall analysis for ΔADL and ΔMMSE and moderate (i.e., >0.5) for ΔMMSE in the euvolemic subgroup. Beneficial effects on ΔADL and ΔMMSE were only observed in the subgroup of patients in which [Na+] was raised by >5 mEq/L and multivariable linear regression analysis confirmed [Na+] increase to be an independent predictor of MMSE improvement. Resolution of hyponatremia has a beneficial impact on the geriatric patients’ overall functional status, in particular in euvolemic cases.

NRG Oncology CC001 Neurocognitive Final Analysis: A Phase III Trial of Hippocampal Avoidance (HA) in Addition to Whole-Brain Radiotherapy (WBRT) Plus Memantine to Preserve Neurocognitive Function (NCF) in Patients With Brain Metastases (BM)

Abstract INTRODUCTION NRG CC001, a phase III trial of whole-brain brain radiotherapy (WBRT) plus memantine (WBRT + M) with or without hippocampal avoidance (HA), sought to evaluate the neuroprotective effects of lowering hippocampal radiation dose. METHODS Patients with brain metastases (BM) were stratified by RPA class and prior radiosurgery/surgery and randomized to WBRT + M or HA-WBRT + M (30 Gy/10 fractions). Neurocognitive function (NCF) testing was performed at baseline, 2, 4, 6, and 12 mo. The primary endpoint was NCF failure, defined as reliable change index determined decline on Hopkins Verbal Learning Test-Revised, Trail Making Test, or Controlled Oral Word Association. Cumulative incidence estimated NCF failure (death without NCF failure was competing risk); between-arms differences tested using Gray's test. Deterioration at each time point was tested using a chi-square test. Patient-reported symptoms were assessed using the MD Anderson Symptom Inventory with Brain Tumor module (MDASI-BT) and analyzed using mixed effects models and t-tests. RESULTS From 7/2015 to 3/2018, 518 patients were randomized. Median follow-up was 7.9 mo. HA-WBRT + M was associated with lower NCF failure risk (adjusted hazard ratio (HR) = 0.74, P = .02) due to lower risk of deterioration in executive function at 4 mo (P = .01), and encoding (P = .049) and consolidation (P = .02) at 6 mo. Age = 61 predicted lower NCF failure risk (HR = 0.60, P = .0002); nonsignificant interaction test indicated independent effects of HA and age. On the patient-reported MDASI-BT, mixed effects models for Symptom Severity (P = .03) showed a time-by-treatment interaction favoring HA-WBRT. Changes in the MDASI-BT Cognitive Factor at 6 mo (P = .034) favored the HA-WBRT + M arm. The MDASI-BT items of problems remembering things (P = .013), difficulty speaking (P = .049), and fatigue (P = .036) at 6 mo also favored the HA-WBRT + M arm. Treatment arms did not differ in toxicity, overall survival, or intracranial progression. CONCLUSION HA during WBRT for BM better preserves NCF and patient-reported symptoms, while achieving similar intracranial control and survival.

RADI-11. NRG ONCOLOGY CC001: A PHASE III TRIAL OF HIPPOCAMPAL AVOIDANCE IN ADDITION TO WHOLE-BRAIN RADIOTHERAPY (WBRT) PLUS MEMANTINE TO PRESERVE NEUROCOGNITIVE FUNCTION IN PATIENTS WITH BRAIN METASTASES (BM)

BACKGROUND: NRG CC001, a phase III trial of WBRT+memantine (WBRT+M) with or without Hippocampal Avoidance (HA), sought to assess the neuro-protective effects of lowering the radiation dose received by the hippocampus. METHODS: Patients (pts) with brain metastases were stratified by RPA class and prior radiosurgery/surgery and randomized to either WBRT+M or HA-WBRT+M (30Gy/10 fractions). Standardized neurocognitive function (NCF) tests were performed at baseline, 2, 4, 6, and 12 months (mos.). The primary endpoint was NCF failure, defined as decline using the reliable change index on Hopkins Verbal Learning Test-Revised, Trail Making Test, or Controlled Oral Word Association. Cumulative incidence estimated NCF failure (death without NCF failure was competing risk); between-arms differences tested using Gray’s test. Deterioration at each collection time point was tested using a chi-square test. Patient-reported symptoms were assessed using the MD Anderson Symptom Inventory with Brain Tumor module and analyzed using mixed effects models and t-tests. RESULTS: From 7/2016 to 3/2018, 518 patients were randomized. Median follow-up was 7.9 mos. HA-WBRT+M was associated with lower NCF failure risk (adjusted HR=0.74, p=0.02) due to lower risk of deterioration in executive function at 4 mos. (p=0.01); and encoding (p=0.049) and consolidation (p=0.02) at 6 mos. Age≤61 predicted for lower NCF failure risk (HR=0.60, p=0.0002); non-significant test for interaction indicated independent effects of HA and age. Patient-reported fatigue (p=0.036); difficulty speaking (p=0.049); and problems remembering things (p=0.013) at 6 mos. favored the HA-WBRT+M arm. Imputation models accounting for missing data also favored the HA-WBRT+M arm for patient-reported cognition (p=0.011) and symptom interference (p=0.008) at 6 mos. Treatment arms did not significantly differ in toxicity; intracranial progression or overall survival. CONCLUSIONS: While achieving similar intracranial control and survival; Hippocampal Avoidance during WBRT+M for brain metastases better preserves NCF and patient-reported symptoms. Supported by UG1CA189867 (NCORP) and DCP from the NCI.

Abstract CT027: Phase I study of procaspase activating compound -1 (PAC-1) in the treatment of advanced malignancies and in combination with temozolomide in refractory high-grade astrocytomas

Abstract Background: PAC-1 is a small molecule that directly activates procaspase-3 and induces apoptosis of cancer cells. PAC-1 crosses the blood-brain-barrier. This first-in-human, phase I, multicenter study consists of 2 components. Component 1 evaluated safety, pharmacokinetics (PK), and preliminary clinical activity of single agent PAC-1 in patients with solid tumors or lymphoma. Component 2 combines PAC-1 with temozolomide in patients with refractory high-grade astrocytomas. Methods: Patients with metastatic solid tumors or lymphomas were enrolled in component 1 and patients with refractory high-grade astrocytomas were enrolled in component 2. A modified- Fibonacci dose-escalation 3+3 design was used in both components. The primary objective was to assess maximum tolerated dose (MTD). In component 1, PAC-1 was dosed from 75 to 750 mg daily orally (7 dose levels (DL)) on days 1-21 on 28 days cycle. For all dose cohorts, PAC-1 PK was assessed following doses administered on days 1 and 21 of the first cycle. In component 2, PAC-1 is dosed from 375 to 750 mg daily (up to 4 DL) plus temozolomide orally 150 mg/m2 daily for 5 days. PAC-1 PK was assessed following doses administered on days 7 and 12 and temozolomide PK is performed on Day 12 of the first cycle. Disease assessment was done every 2 cycles. Neurologic and neurocognitive function (NNCF) tests were performed throughout the study due to concern for neurotoxicity. Results: Forty-four patients were enrolled in part 1 and 12 in component 2. In part 1, at DL 1-5 no dose-limiting toxicities (DLTs) were observed. DL 6 was expanded to 6 patients due to one episode of intracranial bleed that occurred during cycle 4 of treatment, assessed initially as possibly related to study drug, but later attributed to new brain metastasis and unrelated to PAC-1. Grade 1 and 2 neurological adverse events such as ataxia and hallucinations were noted in DL 7 and this DL was expanded to 9 patients to assure safety. All other serious adverse events were determined to be unrelated or unlikely related to the study drug. Eleven patients (25%) did not complete 2 cycles of treatment due to rapid progression or withdrawal. Eight patients (18%) had stable disease for at least 2 cycles. One patient (2%) had partial response. In component 2 treating refractory high-grade astrocytomas, 7 patients were accrued to DL 1, and 5 patients to DL 2. No DLT was observed. Nine patients were evaluable for response. Five patients (42 %) had disease progression. Two patients (16%) had stable disease for at least 2 cycles, and two (16%) had partial response. Review of NNCF testing showed a consistent pattern of stable neurologic and cognitive evaluations. The PK data demonstrated satisfactory systemic delivery of PAC-1 following oral administration and acceptable absorption and elimination profiles. Conclusions: Single agent PAC-1 is well tolerated and 750 mg was determined to be the MTD. The combination of PAC-1 plus temozolomide continues to enroll patients in this study. Citation Format: Oana C. Danciu, M. Kelly Nicholas, Matthias Holdhoff, Richard A. Peterson, Neeta Venepalli, Rozina Chowdhery, Paul J. Hergenrother, Theodore M. Tarasow, Arkadiusz Z. Dudek. Phase I study of procaspase activating compound -1 (PAC-1) in the treatment of advanced malignancies and in combination with temozolomide in refractory high-grade astrocytomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT027.

NRG Oncology CC001: A phase III trial of hippocampal avoidance (HA) in addition to whole-brain radiotherapy (WBRT) plus memantine to preserve neurocognitive function (NCF) in patients with brain metastases (BM).

2009 Background: NRG CC001, a phase III trial of WBRT plus memantine (WBRT+M) with or without HA, sought to evaluate the neuro-protective effects of lowering the hippocampal radiation dose. Methods: Patients (pts) with BM were stratified by RPA class and prior radiosurgery/surgery and randomized to WBRT+M or HA-WBRT+M (30Gy/10 fractions). Standardized NCF tests were performed at baseline, 2, 4, 6, and 12 months (mos). The primary endpoint was NCF failure, defined as decline using the reliable change index on Hopkins Verbal Learning Test-Revised, Trail Making Test, or Controlled Oral Word Association. Cumulative incidence estimated NCF failure (death without NCF failure was competing risk); between-arms differences tested using Gray’s test. Deterioration at each collection time point was tested using a chi-square test. Patient-reported symptoms were assessed using the MD Anderson Symptom Inventory Brain Tumor module and analyzed using mixed effects models and t-tests. Results: From 7/2016 to 3/2018, 518 pts were randomized. Median follow-up was 7.9 mos. HA-WBRT+M was associated with lower NCF failure risk (adjusted hazard ratio (HR) = 0.74, p = 0.02) due to lower risk of deterioration in executive function at 4 mos (p = 0.01) and encoding (p = 0.049) and consolidation (p = 0.02) at 6 mos. Age≤61 predicted lower NCF failure risk (HR = 0.60, p = 0.0002); non-significant test for interaction indicated independent effects of HA and age. Patient-reported fatigue (p = 0.036), difficulty speaking (p = 0.049) and problems remembering things (p = 0.013) at 6 mos favored the HA-WBRT+M arm. Imputation models accounting for missing data also favored the HA-WBRT+M arm for patient-reported cognition (p = 0.011) and symptom interference (p = 0.008) at 6 mos. Treatment arms did not differ in toxicity, overall survival, or intracranial progression. Conclusions: HA during WBRT+M for BM better preserves NCF and patient-reported symptoms, while achieving similar intracranial control and survival. Supported by grants UG1CA189867 (NCORP), U10CA180868 (NRG Oncology Operations), DCP from the National Cancer Institute. Clinical trial information: NCT02360215.

The Impact of Brain Metastases and Associated Neurocognitive Aspects on Health Utility Scores in EGFR Mutated and ALK Rearranged NSCLC: A Real World Evidence Analysis.

In lung cancer, brain metastases (BM) and their treatment are associated with high economic burden and inferior health-related quality of life. In the era of targeted therapy, real world evidence through health utility scores (HUS) is critical for economic analyses. In a prospective observational cohort study (2014-2016), outpatients with stage IV lung cancer completed demographic and EQ-5D-3L surveys (to derive HUS). Health states and clinicopathologic variables were obtained from chart abstraction. Patients were categorized by the presence or absence of BM; regression analyses identified factors that were associated with HUS. A subset of patients prospectively completed neurocognitive function (NCF) tests and/or the FACT-brain (FACT-Br) questionnaire, which were then correlated with HUS (Spearman coefficients; regression analyses). Of 519 patients with 1,686 EQ-5D-3L-derived HUS, 94 (18%) completed NCF tests and 107 (21%) completed FACT-Br; 301 (58%) never developed BM, 24 (5%) developed first BM during study period, and 194 (37%) had BM at study entry. The sample was enriched (46%) for EGFR mutations (EGFRm) and ALK-rearrangements (ALKr). There were no HUS differences by BM status overall and in subsets by demographics. In multivariable analyses, superior HUS was associated with having EGFRm/ALKr (p < .0001), no prior radiation for extracranial disease (p < .001), and both intracranial (p = .002) and extracranial disease control (p < .01). HUS correlated with multiple elements of the FACT-Br and tests of NCF. Having BM in lung cancer is not associated with inferior HUS in a population enriched for EGFRm and ALKr. Patients exhibiting disease control and those with oncogene-addicted tumors have superior HUS. In the setting of EGFR mutations or ALK rearrangement non-small cell lung cancer (NSCLC), a diagnosis of brain metastases no longer consigns the patient to an inferior health state suggesting that new economic analyses in NSCLC are needed in the era of targeted therapies. Additionally, the EQ-5D questionnaire is associated with measures of health-related quality of life and neurocognitive scores suggesting this tool should be further explored in prospective clinical studies.